Study on the selectivity in the electrophilic monofluorination of 2,3-allenoates with Selectfluor: An efficient synthesis of 4-fluoro-2(5H)-furanones and 3-fluoro-4-oxo-2(E)-alkenoates

Article abstract of DOI:10.1039/b917793k

Different from the reaction of 2,3-allenoic acids with Selectfluor, 4-fluoro-2(5H)-furanones and (E)-3-fluoro-4-oxo-2-alkenoates were highly selectively generated from 2,4-disubstituted 2,3-allenoates with Selectfluor under different conditions in moderate yields. The reaction of 2, 4, 4-trisubstituted 2,3-allenoates afforded the corresponding 4-fluoro-2(5H)-furanones highly selectively with up to 95% yield under different conditions. The scope of the substrates has been carefully explored. Due to the more readily availability of 2,3-allenoates as compared to 2,3-allenoic acids, new 4-fluoro-2(5H)furanones were prepared. Based on the isolation and characterization of the minor fluorohydroxylation product E-5m, a mechanism has been proposed. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b917793k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Study on the selectivity in the electrophilic monofluorination of 2,3-allenoates
with SelectfluorTM: an efficient synthesis of 4-fluoro-2(5H)-furanones and
3-fluoro-4-oxo-2(E)-alkenoates†
Bo Lu¨, Chunling Fu and Shengming Ma*
Received 28th August 2009, Accepted 7th October 2009
First published as an Advance Article on the web 19th November 2009
DOI: 10.1039/b917793k
Different from the reaction of 2,3-allenoic acids with SelectfluorTM, 4-fluoro-2(5H)-furanones and
(E)-3-fluoro-4-oxo-2-alkenoates were highly selectively generated from 2,4-disubstituted 2,3-allenoates
with SelectfluorTM under different conditions in moderate yields. The reaction of 2,4,4-trisubstituted
2,3-allenoates afforded the corresponding 4-fluoro-2(5H)-furanones highly selectively with up to 95%
yield under different conditions. The scope of the substrates has been carefully explored. Due to the
more readily availability of 2,3-allenoates as compared to 2,3-allenoic acids, new 4-fluoro-2(5H)-
furanones were prepared. Based on the isolation and characterization of the minor fluorohydroxylation
product E-5m, a mechanism has been proposed.
methyl-5-phenyl-2(5H)-furanone 4a was formed together with an
Introduction
1
unknown product. However, from H NMR and 13C NMR, IR,
Many fluorinated organic compounds have been identified as
MS and HRMS analysis, we identified this new product as ethyl
biologically active molecules,1 probably due to the fact that the
fluorine most closely resembles hydrogen in size among the atoms
but is much more electronegative than oxygen.2 Monofluorination
has been usually conducted using the common but very dangerous
and environmentally unfriendly fluorine gas. Considering this
problem, chemists have developed a series of highly efficient
and easily controlled electrophilic fluorination reagents such as
DAST,3 CF3OF,4 XeF2,5 N-fluoropyridinium triflate,6 NFSI,7
3-fluoro-2-methyl-4-oxo-4-phenyl-2(E)-butenoate 3a.13,14
With the addition of Li2CO3,13 the selectivity for the formation
of 3a was improved; however, the yield was still very low, indicating
the difference of the reaction of 2,3-allenoates with PhSeCl
and SelectfluorTM (Table 1, entry 2). Increasing the amount of
SelectfluorTM could also improve the yield (Table 1, entry 3). Other
bases such as Na2CO3, K2CO3, and Cs2CO3 are also unsuitable in
this reaction (Table 1, entries 4–6). The carbonyl functionality
formed in compound 3a should have something to do with the
trace amount of water in the commercially available MeCN or air,
thus, the reaction was carried out under N2 in anhydrous MeCN,
which had been refluxed in the presence of calcium hydride for
10 h and distilled immediately before use, to afford E-3a in 26%
yield with a selectivity of 3a/4a as high as 98/2 (Table 1, entry 7).
Encouraged by these results, a series of experiments were carried
out by adding a fixed amount of water (Table 1, entries 8–9). The
best results were given when 0.5 equiv of water was used to afford
E-3a in 60% yield with the 3a/4a ratio being 97/3 (Table 1, entry 8,
Conditions A). In addition, it is interesting to observe that further
increasing the amount of water led to almost exclusive formation
of 4a (Table 1, entries 10–13). When running the reaction with 1.7
equiv of SelectfluorTM in MeCN–H2O = 2/1 at 80 ◦C, lactone 4a
was formed as the only product in 56% yield (Table 1, entry 14,
Conditions B).
SelectfluorTM 8,9 etc. Among these reagents, SelectfluorTM has been
,
proven to be a highly efficient fluorination reagent, and thus, has
been widely used in organic synthesis.
In 2008, we reported that 4-fluoro-2(5H)-furanones could be
synthesized conveniently by the cyclization of 2,3-allenoic acid
in the presence of SelectfluorTM
cyclization reaction using 4,5-allenoic acid and SelectfluorTM has
also been reported by Zhao, Zhu, and their co-workers.9 Since
the acids are usually prepared from the hydrolysis of esters,10 it
is desirable to prepare lactones directly from 2,3-allenoates.11a,b In
this paper, we wish to report our recent study on the reaction of
2,3-allenoates with SelectfluorTM, which affords 4- fluoro-2(5H)-
furanones and 3-fluoro-4-oxo-2(E)-alkenoates under different
reaction conditions, respectively.12
8a
.
Recently, this type of fluoro-
Results and discussion
The configuration of the carbon–carbon double bond in
E-3a was determined by 1H–19F HOESY analysis (heteronuclear
Overhauser effect spectroscopy, see Fig. 1 and ESI†).
The scope of selective fluorination of 2,3-allenoates to form
(E)-3-fluoro-4-oxo-2-butenoates 3 was then explored under Con-
ditions A. Some typical results are summarized in Table 2. The
R1 group could be substituted phenyl group; R2 could be alkyl or
benzyl group.
The initial experiment was carried out by using ethyl 2-methyl-
4-phenyl-2,3-butadienoate 1a and 1.2 equiv of SelectfluorTM
2
in MeCN at 80 ◦C (Table 1, entry 1). Interestingly, 4-fluoro-3-
Laboratory of Molecular Recognition and Synthesis, Department of Chem-
istry, Zhejiang University, Hangzhou, 310027, Zhejiang, P. R. China.
E-mail: masm@mail.sioc.ac.cn; Fax: (+86) 21-62609305
† Electronic supplementary information (ESI) available: The synthesis of
new 2,3-allenoates 1j, 1l, and 1q and 1H, and 13C spectra for all compounds.
See DOI: 10.1039/b917793k
However, the reaction could not be extended to 4-alkyl-
substituted 2,3-allenoate 1k (Scheme 1). The reaction of ethyl
274 | Org. Biomol. Chem., 2010, 8, 274–281
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Table 1 Fluorination reaction of 1a under different conditions
NMR Yield (%)b
Entry
2a
Solvent
Additive (equiv)
Time/h
E-3a
4a
Ratio (3a/4a)b
1a (%)c
1
2
3
4
5
6
7
1.2
1.2
2.0
2.0
2.0
2.0
3.0
3.0
3.0
1.5
1.5
1.5
1.5
1.7
MeCN
MeCN
MeCN
MeCN
—
19.5
11.5
14
19.3
19.3
19
9
10.5
10
19
12.5
32
9
10
Trace
26
60
26
—
—
—
—
35
4.5
13
3
—
Trace
—
1.6
1.3
54
50
57
44
56
35/65
74/26
71/29
75/25
87/13d
—
7
8
Li2CO3 (2.0)
Li2CO3 (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
—
—
3.5
28
33
—
—
—
3
2
4
—
—
MeCN
MeCN
MeCNe
98/2d
97/3
8
9
MeCNe
H2O (0.5)
H2O (1.0)
MeCNe
95/5
10
11
12
13
14
MeCN–H2O = 5/1
MeCN–H2O = 3/1
MeCN–H2O = 2/1
MeCN–H2O = 1/1
MeCN/H2O = 2/1
12
1/99 d
1/99d
1/99d
1/99d
1/99d
11.5
11.5
10.5
14.7
—
a Equivalents of 2. b Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-trimethylbenzene as the internal standard. c 1a recovered
after the reaction. d Determined by 19F NMR analysis. e The reaction was carried out under N2; MeCN was refluxed in the presence of calcium hydride
for 10 h and distilled immediately before use.
Table 2 Synthesis of (E)-3-fluoro-4-oxo-2-butenoates 3 from the reaction of 2,4-disubstituted 2,3-allenoates with SelectfluorTM under Conditions Aa
Entry
1
R1
R2
Time/h
Product
Yield (%)b
3/4c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
p-FC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
p-MeC6H4
p-MeC6H4
Me
Et
n-Pr
Bn
Me
Me
Me
n-Pr
Me
Et
10.5
10
11
11.5
10
10.5
12
10.5
10
9.5
E-3a
E-3b
E-3c
E-3d
E-3e
E-3f
E-3g
E-3h
E-3i
E-3j
55
56
53
45
45
46
55
46
43
39
97/3
98/2
98/2
98/2
99/1
98/2
98/2
98/2
98/2
98/2
1g
1h
1i
10
1j
a Conditions A: A solution of 1 (0.2–0.3 mmol), 2 (3 equiv), and water (0.5 equiv) was stirred in 2–3 mL of anhydrous MeCN under N2 at 80 ◦C. b Isolated
yield. c The ratio of 3/4 was determined by 19F NMR spectra of crude products.
of SelectfluorTM were required to form the corresponding lactones
(Table 3, entries 2 and 3). The reaction of fully substituted 1m
afforded 4m under Conditions B in 86% yield together with the
fluorohydroxylation product, i.e., ethyl 3-fluoro-4-hydroxyl-4,4-
diphenyl-2-propyl-2(E)-butenoate (5m) in 7% yield, indicating the
existence of a 5m-type intermediate for this type of transformation
Fig. 1 1H–19F HOESY analysis of E-3a and E-5m.
(Scheme 2). Treatment of 1m with SelectfluorTM under Conditions
A still led to the formation of lactone 4m in 93% isolated
yield together with E-5m in 5% isolated yield (Scheme 2). The
4-(2-chlorophenyl)-2-methyl-2,3-butadienoate (1l) afforded ke-
tone E-3l together with lactone 4l in a ratio of 87/13 (3l/4l)
(Scheme 1).
The fluorolactonization of 2,3-allenoates was also demonstrated
under Conditions B (Table 3): When R2 is ethyl or propyl, 2.5 equiv
configuration of the carbon–carbon double bond in E-5m was
1
determined by H-19F HOESY analysis (see Fig. 1 and ESI†).
Further screening led us to observe that 4m could be afforded
when 1m was treated with just 1.2 equiv of SelectfluorTM in MeCN
at 80 ◦C (Conditions C) in 90% isolated yield with a selectivity
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Table 3 Synthesis of 4-fluoro-2(5H)-furanones 4 from the reaction of 2,3-allenoates with 2
1
Entry
R1
R3
R2
Conditionsa
t/h
Yield (%)b
4/3b
4/5b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
p-FC6H4
p-BrC6H4
p-MeC6H4
Ph
Ph
Ph
H
H
H
H
H
H
Me
Ph
Et
Et
Et
Me (1a)
Et (1b)
B
14.7
23.5
23.5
26
21.5
21
5.3
5.5
5.5
5
51 (4a)
50 (4b)
47 (4c)
60 (4e)
42 (4g)
64 (4i)
80 (4n)
93 (4o)
95 (4p)
91 (4q)
76 (4r)
30 (4s)
42 (4s)
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
—
—
—
—
—
—
—
—
—
—
—
99/1
99/1
98/2
99/1
98/2
98/2
98/2
Bc
Bc
B
n-Pr (1c)
Me (1e)
Me (1g)
Me (1i)
Me (1n)
Me (1o)
Me (1p)
n-Pr (1q)
H (1r)
B
B
C
C
C
C
C
C
Cd
9
10
11
12
13
Ph
Ph
5
11
10.8
-(CH2)5-
-(CH2)5-
Me (1s)
Me (1s)
—
—
a Conditions B: A solution of 1 (0.2–0.4 mmol) and 2 (1.7 equiv) was stirred in 2–4 mL of MeCN–H2O (2/1 (v/v)) at 80 ◦C; Conditions C: A solution of
1 (0.2 mmol) and 2 (1.2 equiv) was stirred in 2 mL of MeCN at 80 ◦C. b The ratios of 4/3 and 4/5 were determined by the 19F NMR analysis of the crude
products. c A quantity of 2.5 equiv of 2 was used. d MeNO2 was used instead of MeCN.
Scheme 1
Scheme 2
of 4m/5m being 98/2 as determined by 19F NMR analysis of the
crude reaction mixture (Scheme 2).
However, complicated products were observed when 2,4-
disubstituted 2,3-allenoate 1k was treated with SelectfluorTM under
either Conditions B or Conditions C (Scheme 3). For 4,4-dialkyl
substituted allenoate 1t, either in MeCN or in MeNO2, the
corresponding lactone could not be afforded (Scheme 3).
A plausible mechanism was proposed for this reaction (Scheme
4): The relatively electron-rich carbon–carbon double bond of 2,3-
allenoate firstly interacts with F+ in SelectfluorTM to form cyclic
intermediate 6, which explains the E-stereoselectivity observed
A series of 4,4-disubstituted 4-aryl 2,3-allenoates were then
treated with SelectfluorTM under Conditions C. The corresponding
4-fluoro-2(5H)-furanones could also be afforded in excellent yields
(Table 3, entries 7–11, Conditions C). MeNO2 is more effective
than MeCN leading the lactonization reaction of 2,4,4-trialkyl
substituted ethyl 3-cyclohexylidene-2-methylacrylate (1s) to afford
4s in relatively higher yields (Table 3, entries 12 and 13).
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and characterization of the minor fluorohydroxylation product
E-5m. Due to the readily availability of 2,3-allenoates and the
formation of different types of monofluorinated products with
functionalities for further elaboration under different conditions,
this method shows more potential than that of 2,3-allenoic acids.
Further studies in this area are being conducted in our laboratory.
Experimental section
1. Preparation of 3-fluoro-4-oxo-2(E)-butenoates (3a–j)
Scheme 3
(1) Preparation of ethyl 3-fluoro-2-methyl-4-oxo-4-phenyl-
2(E)-butenoate (3a). Typical procedure (Conditions A). Ethyl
2-methyl-4-phenyl-2,3-butadienoate (1a) (39.9 mg, 0.20 mmol)
and 1 mL of H2O–MeCN (premixed, 0.9 mL mL-1) were added
into a flame-dried Schlenk vessel, which was pre-evacuated and
backfilled with nitrogen three times. SelectfluorTM (95%, 223.2 mg,
0.60 mmol) and another 1 mL of H2O–MeCN (premixed,
0.9 mL mL-1) were added seque◦ntially under nitrogen. The
resulting mixture was heated at 80 C with a preheated oil bath.
After 10.5 h, the reaction was complete as monitored by TLC. The
reaction mixture was then quenched with 10 mL of H2O, extracted
with ether (40 mL + 2 ¥ 10 mL), washed with 10 mL of brine,
and dried over anhydrous Na2SO4. Filtration, evaporation, and
purification by chromatography (petroleum ether–ethyl acetate =
1
80 : 1) on silica gel afforded 3a (25.8 mg, 55%): liquid; H NMR
(300 MHz, CDCl3) d 7.96–7.89 (m, 2H), 7.66–7.58 (m, 1H), 7.53–
7.45 (m, 2H), 3.99 (q, J = 7.2 Hz, 2H), 2.05 (d, J = 4.2 Hz, 3H),
0.98 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 187.2 (d,
J = 28.1 Hz), 166.1 (d, J = 17.4 Hz), 158.9 (d, J = 276.2), 134.6,
134.1, 129.2, 128.8, 114.9 (d, J = 16.9 Hz), 61.4, 13.4, 10.7 (d, J =
5.4 Hz); 19F NMR (282 MHz, CDCl3) d -100.5; IR (neat) n/cm-1
3064, 2984, 2936, 1725, 1682, 1598, 1583, 1451, 1369, 1302, 1202,
1176, 1113, 1082, 1019; MS (70 eV, EI) m/z (%): 236 (M+, 7.13),
105 (100); HRMS calcd for C13H13O3F (M+): 236.0849. Found:
236.0842.
Scheme 4
here. Hydroxylation at the 5-position would lead to the formation
of fluorohydroxylation product 5, which was confirmed by the
isolation and characterization of E-5m (Scheme 2). If R3 = H,
subsequent oxidation by SelectfluorTM15 would form ketone 3 (Path
I, Scheme 4). Corresponding dealkylation of intermediate 6 may
lead to lactonization to form 4 (Path II, Scheme 4).
This reaction may easily be carried out with 5 mmol of ethyl
4-phenyl-2,3-butadienoate 1a to afford 3a and 4a, respectively
(Scheme 5).
The following compounds were prepared according to this
typical procedure.
(2) Ethyl 2-ethyl-3-fluoro-4-oxo-4-phenyl-2(E)-butenoate (3b).
The reaction of 1b (64.1 mg, 0.30 mmol) and SelectfluorTM
(95%, 336.2 mg, 0.90 mmol) in 3 mL of H2O–MeCN (premixed,
0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3b (41.5 mg, 56%)
1
as a liquid; H NMR (300 MHz, CDCl3) d 7.95–7.88 (m, 2H),
7.66–7.58 (m, 1H), 7.54–7.46 (m, 2H), 4.01 (q, J = 7.1 Hz, 2H),
2.53 (qd, J = 7.6 Hz and 3.6 Hz, 2H), 1.91 (t, J = 7.6 Hz, 3H),
1.01 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 187.1 (d,
J = 28.8 Hz), 165.9 (d, J = 16.5 Hz), 158.0 (d, J = 276.8 Hz),
134.7, 134.1, 129.2 (d, J = 2.0 Hz), 128.8, 121.5 (d, J = 15.4 Hz),
61.4, 19.2 (d, J = 4.4 Hz), 13.4, 12.8 (d, J = 2.0 Hz); 19F NMR
(282 MHz, CDCl3) d -104.5; IR (neat) n/cm-1 2981, 2940, 1727,
1683, 1598, 1582, 1450, 1369, 1309, 1276, 1256, 1201, 1176, 1122,
1024; MS (70 eV, EI) m/z (%): 250 (M+, 6.31), 105 (100); HRMS
calcd for C14H15O3F (M+): 250.1005. Found: 250.1007.
Scheme 5
Conclusions
In conclusion, we have developed an efficient way to synthesize 3-
fluoro-4-oxo-2(E)-alkenoates and 4-fluoro-2(5H)-furanones from
the same starting materials 4-aryl-2-alkyl or benzyl-2,3-allenoates
and SelectfluorTM in acetonitrile. The reaction of fully substi-
tuted 2,3-allenoates with SelectfluorTM afforded 4-fluoro-2(5H)-
furanones highly selectively in excellent yields under Conditions A,
B, and C. A mechanism has been proposed based on the isolation
(3) Ethyl
3-fluoro-4-oxo-4-phenyl-2-propyl-2(E)-butenoate
(3c). The reaction of 1c (70.2 mg, 0.31 mmol) and SelectfluorTM
(95%, 339.3 mg, 0.91 mmol) in 3 mL of H2O–MeCN (premixed,
0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3c (42.8 mg, 53%)
1
as a liquid; H NMR (300 MHz, CDCl3) d 7.96–7.89 (m, 2H),
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7.65–7.58 (m, 1H), 7.54–7.46 (m, 2H), 4.00 (q, J = 7.2 Hz, 2H),
2.53–2.45 (m, 2H), 1.68–1.54 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H),
1.00 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 187.1 (d,
J = 29.0 Hz), 166.0 (d, J = 16.6 Hz), 158.4 (d, J = 275.2 Hz),
134.7, 134.1, 129.2 (d, J = 1.4 Hz), 128.8, 120.1 (d, J = 16.0 Hz),
61.4, 27.5 (d, J = 3.4 Hz), 21.4 (d, J = 1.9 Hz), 13.8, 13.4; 19F
NMR (282 MHz, CDCl3) d -103.9; IR (neat) n/cm-1 3065, 2966,
2936, 2875, 1728, 1682, 1598, 1582, 1451, 1369, 1305, 1275, 1229,
1200, 1177, 1124, 1033, 1002; MS (70 eV, EI) m/z (%): 264 (M+,
10.02), 105 (100); HRMS calcd for C15H17O3F (M+): 264.1162.
Found: 264.1166.
(M+(35Cl), 8.83), 139 (100); HRMS calcd for C13H12O335ClF (M+):
270.0459. Found: 270.0453.
(7) Ethyl 4-(4¢-bromophenyl)-3-fluoro-2-methyl-4-oxo-2(E)-
butenoate (3g). The reaction of 1g (83.8 mg, 0.30 mmol) and
SelectfluorTM (95%, 335.5 mg, 0.90 mmol) in 3 mL of H2O–MeCN
(premixed, 0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3g
1
(51.5 mg, 55%) as a liquid; H NMR (300 MHz, CDCl3) d 7.78
(d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 4.03 (q, J = 7.2 Hz,
2H), 2.04 (d, J = 4.2 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 186.1 (d, J = 28.7 Hz), 166.0 (d, J = 15.9 Hz),
158.3 (d, J = 276.6 Hz), 133.4, 132.2, 130.6 (d, J = 1.0 Hz), 129.5,
115.5 (d, J = 16.0 Hz), 61.5, 13.5, 10.8 (d, J = 5.2 Hz); 19F NMR
(282 MHz, CDCl3) d -101.8; IR (neat) n/cm-1 3091, 2984, 2936,
2872, 1728, 1682, 1586, 1484, 1446, 1399, 1369, 1304, 1202,1173,
1112, 1069, 1012; MS (70 eV, EI) m/z (%): 316 (M+(81Br), 17.93),
314 (M+(79Br), 17.55), 185 (99.06), 183 (100); HRMS calcd for
C13H12O379BrF (M+): 313.9954. Found: 313.9952.
(4) Ethyl
2-benzyl-3-fluoro-4-oxo-4-phenyl-2(E)-butenoate
(3d). The reaction of 1d (83.9 mg, 0.30 mmol) and SelectfluorTM
(95%, 336.1 mg, 0.90 mmol) in 3 mL of H2O–MeCN (premixed,
0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3d (42.1 mg, 45%)
1
as a liquid; H NMR (300 MHz, CDCl3) d 7.97–7.88 (m, 2H),
7.66–7.57 (m, 1H), 7.53–7.44 (m, 2H), 7.36–7.21 (m, 5H), 3.93 (q,
J = 7.2 Hz, 2H), 3.85 (d, J = 3.6 Hz, 2H), 0.90 (t, J = 7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 186.9 (d, J = 28.4 Hz), 165.3
(d, J = 17.0 Hz), 159.2 (d, J = 278.6 Hz), 137.6 (d, J = 2.6 Hz),
134.5, 134.2, 129.2, 128.9, 128.7, 128.6, 126.7, 118.3 (d, J =
14.4 Hz), 61.5, 31.1 (d, J = 4.0 Hz), 13.2; 19F NMR (282 MHz,
CDCl3) d -100.3; IR (neat) n/cm-1 3084, 3064, 3030, 2983, 2937,
1724, 1682, 1598, 1582, 1495, 1451, 1370, 1310, 1276, 1203,
1182, 1103, 1037, 1022; MS (70 eV, EI) m/z (%): 312 (M+, 4.06),
266 (100); HRMS calcd for C19H17O3F (M+): 312.1162. Found:
312.1168.
(8) Ethyl
4-(4¢-bromophenyl)-3-fluoro-4-oxo-2-propyl-2(E)-
butenoate (3h). The reaction of 1h (91.1 mg, 0.29 mmol) and
SelectfluorTM (95%, 330.6 mg, 0.89 mmol) in 3 mL of H2O–MeCN
(premixed, 0.9 mL mL-1) at 80 ◦C under nitrogen afforded
3h (46.7 mg, 46%) (flash chromatography, eluent: petroleum
1
ether–ethyl acetate = 100 : 1) as a liquid; H NMR (300 MHz,
CDCl3) d 7.81–7.73 (m, 2H), 7.67–7.60 (m, 2H), 4.05 (q, J =
7.2 Hz, 2H), 2.54–2.42 (m, 2H), 1.67–1.55 (m, 2H), 1.06 (t, J =
7.2 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 186.0 (d, J = 30.0 Hz), 165.9 (d, J = 15.4 Hz), 157.8 (d, J =
275.0 Hz), 133.5, 132.2, 130.6 (d, J = 2.0 Hz), 129.4, 120.8 (d, J =
16.0 Hz), 61.5, 27.6 (d, J = 3.5 Hz), 21.3 (d, J = 2.2 Hz), 13.8,
13.5; 19F NMR (282 MHz, CDCl3) d 105.3; IR (neat) n/cm-1
2965, 2935, 2874, 1728, 1687, 1586, 1484, 1464, 1399, 1369, 1311,
1272, 1228, 1199, 1173, 1124, 1070, 1011; MS (70 eV, EI) m/z
(%): 344 (M+(81Br), 20.01), 342 (M+(79Br), 20.23), 185 (98.06), 183
(100); HRMS calcd for C15H16O379BrF (M+): 342.0267. Found:
342.0263.
(5) Ethyl
3-fluoro-4-(4¢-fluorophenyl)-2-methyl-4-oxo-2(E)-
butenoate (3e). The reaction of 1e (65.8 mg, 0.30 mmol) and
SelectfluorTM (95%, 335.6 mg, 0.90 mmol) in 3 mL of H2O–MeCN
(premixed, 0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3e
(34.1 mg, 45%) as a liquid; 1H NMR (300 MHz, CDCl3) d
8.00–7.92 (m, 2H), 7.22–7.12 (m, 2H), 4.04 (q, J = 7.2 Hz,
2H), 2.05 (d, J = 4.5 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) d 185.6 (d, J = 28.8 Hz), 166.3 (d, J =
256.1 Hz), 166.0 (d, J = 16.8 Hz), 158.6 (d, J = 276.5 Hz), 132.0
(dd, J = 9.8 Hz and 1.4 Hz), 131.1 (d, J = 3.2 Hz), 116.2 (d, J =
22.1 Hz), 115.2 (d, J = 16.0 Hz), 61.5, 13.5, 10.8 (d, J = 5.8 Hz);
19F NMR (282 MHz, CDCl3) d -101.2, -102.7; IR (neat) n/cm-1
3078, 2985, 2937, 1727, 1683, 1600, 1507, 1446, 1413, 1370, 1306,
1240, 1202, 1155, 1114, 1082, 1018; MS (70 eV, EI) m/z (%):
254 (M+, 6.93), 123 (100); HRMS calcd for C13H12O3F2 (M+):
254.0755. Found: 254.0761.
(9) Ethyl 3-fluoro-2-methyl-4-(4¢-methylphenyl)-4-oxo-2(E)-
butenoate (3i). The reaction of 1i (64.6 mg, 0.30 mmol) and
SelectfluorTM (95%, 335.9 mg, 0.90 mmol) in 3 mL of H2O–MeCN
(premixed, 0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3i
(32.4 mg, 43%) as a liquid; 1H NMR (300 MHz, CDCl3) d
7.85–7.79 (m, 2H), 7.31–7.26 (m, 2H), 3.99 (q, J = 7.2 Hz, 2H),
2.42 (s, 3H), 2.04 (d, J = 4.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 186.8 (d, J = 28.2 Hz), 166.1 (d,
J = 17.6 Hz), 159.3 (d, J = 277.2 Hz), 145.3, 132.2, 129.5, 129.4
(d, J = 1.2 Hz), 114.4 (d, J = 15.4 Hz), 61.4, 21.8, 13.4, 10.7
(d, J = 5.5 Hz); 19F NMR (282 MHz, CDCl3) d 99.9; IR (neat)
n/cm-1 3033, 2984, 2934, 2872, 1727, 1681, 1606, 1574, 1446,
1410, 1369, 1299, 1202, 1177, 1113, 1081, 1019; MS (70 eV, EI)
m/z (%): 250 (M+, 8.05), 119 (100); HRMS calcd for C14H15O3F
(M+): 250.1005. Found: 250.1003.
(6) Ethyl
4-(4¢-chlorophenyl)-3-fluoro-2-methyl-4-oxo-2(E)-
butenoate (3f). The reaction of 1f (71.4 mg, 0.30 mmol) and
SelectfluorTM (95%, 335.4 mg, 0.90 mmol) in 3 mL of H2O–MeCN
(premixed, 0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3f
(37.2 mg, 46%) as a liquid; 1H NMR (300 MHz, CDCl3) d
7.90–7.83 (m, 2H), 7.50–7.44 (m, 2H), 4.03 (q, J = 7.2 Hz, 2H),
2.04 (d, J = 4.2 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 185.9 (d, J = 29.0 Hz), 166.0 (d, J = 16.6 Hz),
158.4 (d, J = 276.3 Hz), 140.7, 133.0, 130.6 (d, J = 1.5 Hz),
(10) Ethyl
2-ethyl-3-fluoro-4-(4¢-methylphenyl)-4-oxo-2(E)-
butenoate (3j). The reaction of 1j (69.3 mg, 0.30 mmol) and
SelectfluorTM (95%, 336.0 mg, 0.90 mmol) in 3 mL of H2O–MeCN
(premixed, 0.9 mL mL-1) at 80 ◦C under nitrogen afforded 3j
(30.7 mg, 39%) as a liquid; 1H NMR (300 MHz, CDCl3) d
7.84–7.78 (m, 2H), 7.31–7.25 (m, 2H), 4.01 (q, J = 7.2 Hz,
2H), 2.52 (qd, J = 7.4 Hz and 3.6 Hz, 2H), 2.42 (s, 3H), 1.18
129.2, 115.4 (d, J = 16.1 Hz), 61.5, 13.5, 10.8 (d, J = 4.7 Hz); 19
F
NMR (282 MHz, CDCl3) d -101.7; IR (neat) n/cm-1 2984, 2937,
1728, 1682, 1589, 1572, 1488, 1445, 1402, 1369, 1304, 1203, 1173,
1113, 1015; MS (70 eV, EI) m/z (%): 272 (M+(37Cl), 2.93), 270
278 | Org. Biomol. Chem., 2010, 8, 274–281
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(t, J = 7.4 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 186.7 (d, J = 29.0 Hz), 165.9 (d, J = 16.6 Hz), 158.3 (d,
J = 276.2 Hz), 145.2, 132.2, 129.5, 129.4 (d, J = 1.0 Hz), 121.0
(d, J = 16.0 Hz), 61.3, 21.8, 19.1 (d, J = 4.5 Hz), 13.4, 12.8 (d,
J = 2.0 Hz); 19F NMR (282 MHz, CDCl3) d -103.9; IR (neat)
n/cm-1 3033, 2981, 2939, 2879, 1727, 1681, 1606, 1574, 1462,
1369, 1317, 1277, 1256, 1177, 1120, 1061, 1025; MS (70 eV, EI)
m/z (%): 264 (M+, 6.53), 119 (100); HRMS calcd for C15H17O3F
(M+): 264.1162. Found: 264.1166.
(d, J = 248.1 Hz), 128.7 (d, J = 7.7 Hz), 128.1 (t, J = 3.0 Hz),
116.2 (d, J = 21.7 Hz), 105.0 (d, J = 6.4 Hz), 77.1 (d, J = 23.1 Hz),
6.0 (d, J = 2.3 Hz); 19F NMR (282 MHz, CDCl3) d -110.3, -110.9;
IR (KBr) n/cm-1 2933, 1781, 1724, 1608, 1513, 1392, 1347, 1298,
1234, 1115, 1080, 1012; MS (70 eV, EI) m/z (%): 211 (M+ + 1,
11.85), 210 (M+, 90.78), 123 (100); Anal. Calcd. for C11H8F2O2 :
C, 62.86; H, 3.84. Found: C, 62.65; H, 3.81%.
(5) 5-(4¢-Bromophenyl)-4-fluoro-3-methyl-2(5H)-furanone
(4g). The reaction of 1g (113.0 mg, 0.40 mmol) and SelectfluorTM
(95%, 254.8 mg, 0.68 mmol) in a mixture of 2.7 mL of MeCN and
1.3 mL of H2O at 80 ◦C afforded 4g (45.3 mg, 42%) as a white solid:
2. Preparation of 4-fluoro-2(5H)-furanone (4a–i)
◦
1
(1) Preparation of 4-fluoro-3-methyl-5-phenyl-2(5H)-furanone
(4a). Typical procedure (Conditions B). A mixture of ethyl 2-
methyl-4-phenyl-2,3-butadienoate (1a) (40.7 mg, 0.20 mmol) and
SelectfluorTM (95%, 126.6 mg, 0.34 mmol) was stirred in a mixture
of 1.4 mL of MeCN and 0.65 mL of water at 80 ◦C with a preheated
oil bath. After 14.7 h, the reaction was complete as monitored by
TLC. The reaction mixture was then quenched with 10 mL of
H2O, extracted with ether (40 mL + 2 ¥ 10 mL), washed with
10 mL of brine, and dried over anhydrous Na2SO4. Filtration,
evaporation, and purification by chromatography (petroleum
ether–ethyl acetate = 30 : 1) on silica gel afforded 4a8a (19.9 mg,
mp: 62.4–64.2 C (hexane). H NMR (300 MHz, CDCl3) d 7.55
(dt, J = 8.7 Hz and 2.1 Hz, 2H), 7.24–7.17 (m, 2H), 5.75–5.70 (m,
1H), 1.87 (t, JH–H = 2.0 Hz, JH–F = 2.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 173.9 (d, J = 295.2 Hz), 171.3 (d, J = 21.6 Hz), 132.3,
131.3 (d, J = 1.9 Hz), 128.2, 124.1, 105.0 (d, J = 7.2 Hz), 77.0 (d,
J = 22.4 Hz), 6.1 (d, J = 1.8 Hz); 19F NMR (282 MHz, CDCl3)
d -110.3; IR (KBr) n/cm-1 3067, 2965, 2930, 2863, 1778, 1716,
1590, 1489, 1411, 1390, 1345, 1300, 1198, 1114, 1069, 1009; MS
(70 eV, EI) m/z (%): 272 (M+(81Br), 27.78), 270 (M+(79Br), 28.42),
191 (M+ - Br, 100); Anal. Calcd. for C11H8BrFO2: C, 48.74; H,
2.97. Found: C, 48.91; H, 2.88%.
1
51%): liquid; H NMR (300 MHz, CDCl3) d 7.45–7.38 (m, 3H),
(6) 4-Fluoro-3-methyl-5-(4¢-methylphenyl)-2(5H)-furanone
(4i). The reaction of 1i (86.8 mg, 0.40 mmol) and SelectfluorTM
(95%, 254.8 mg, 0.68 mmol) in a mixture of 2.7 mL of MeCN and
7.36–7.30 (m, 2H), 5.79–5.75 (m, 1H), 1.88 (t, J = 1.8 Hz, 3H);
19F NMR (282 MHz, CDCl3) d -110.0.
The following compounds were prepared according to this
typical procedure.
◦
1.3 mL of H2O at 80 C afforded 4i (52.6 mg, 64%) as a liquid;
1H NMR (300 MHz, CDCl3) d 7.25–7.18 (m, 4H), 5.75–5.70 (m,
1H), 2.36 (s, 3H), 1.87 (t, JH–H = 2.1 Hz, JH–F = 2.1 Hz, 3H); 13
C
(2) 3-Ethyl-4-fluoro-5-phenyl-2(5H)-furanone (4b). The re-
action of 1b (42.6 mg, 0.20 mmol) and SelectfluorTM (95%,
186.9 mg, 0.50 mmol) in a mixture of 1.3 mL of MeCN and
NMR (75 MHz, CDCl3) d 174.3 (d, J = 294.8 Hz), 171.7 (d, J =
22.1 Hz), 139.9, 129.7, 129.1 (d, J = 2.8 Hz), 126.6, 104.7 (d, J =
6.3 Hz), 77.7 (d, J = 23.5 Hz), 21.2, 6.0 (d, J = 2.8 Hz); 19F NMR
(282 MHz, CDCl3) d -110.0; IR (neat) n/cm-1 2929, 1778, 1723,
1516, 1448, 1420, 1391, 1346, 1301, 1198, 1112, 1081, 1037, 1007;
MS (70 eV, EI) m/z (%): 207 (M+ + 1, 13.76), 206 (M+, 100);
HRMS calcd for C12H11O2F (M+): 206.0743. Found: 206.0744.
◦
0.7 mL of H2O at 80 C afforded 4b (20.3 mg, 50%) as a liquid;
1H NMR (300 MHz, CDCl3) d 7.45–7.39 (m, 3H), 7.36–7.27 (m,
2H), 5.77–5.73 (m, 1H), 2.35 (qt, JH-H1 = 7.6 Hz, JH-H2 = 1.2 Hz,
JH–F = 1.2 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 174.0 (d, J = 295.8 Hz), 171.2 (d, J = 22.0 Hz), 132.3
(d, J = 2.0 Hz), 129.9, 129.1, 126.6, 110.1 (d, J = 6.1 Hz), 77.5 (d,
J = 22.5 Hz), 15.2 (d, J = 3.2 Hz), 11.7 (d, J = 2.0 Hz); 19F NMR
(282 MHz, CDCl3) d 110.5; IR (neat) n/cm-1 3069, 3033, 2978,
2940, 2877, 1778, 1715, 1497, 1456, 1362, 1313, 1265, 1091, 1062,
1035, 1005; MS (70 eV, EI) m/z (%): 207 (M+ + 1, 13.77), 206
(M+, 100); HRMS calcd for C12H11O2F (M+): 206.0743. Found:
206.0741.
3. Preparation of 4-fluoro-2(5H)-furanone (4m–s)
(1) 4-Fluoro-5,5-diphenyl-3-propyl-2(5H)-furanone (4m). Ty-
pical procedure (Conditions C). A mixture of ethyl 4,4-diphenyl-
2-propyl-2,3-butadienoate (1m) (60.9 mg, 0.20 mmol) and
SelectfluorTM (85.3 mg, 0.24 mmol) was stirred in 2 mL of MeCN
at 80 ◦C with an oil bath. After 5.5 h, the reaction was complete
as monitored by TLC. The reaction mixture was quenched with
10 mL of H2O, extracted with ether (40 mL + 2 ¥ 10 mL),
washed with 10 mL of brine, and dried over Na2SO4. Filtration,
evaporation, and purification by chromatography (petroleum
ether–ethyl acetate = 30 : 1) on silica gel afforded 4-fluoro-5,5-
diphenyl-3-propyl-2(5H)-furanone (4m)8a (52.8 mg, 90%): liquid;
1H NMR (300 MHz, CDCl3) d 7.41–7.35 (m, 10H), 2.31 (td, J =
7.5 Hz and 1.2 Hz, 2H), 1.72–1.58 (m, 2H), 0.95 (t, J = 7.4 Hz,
3H); 19F NMR (282 MHz, CDCl3) d -106.2.
(3) 4-Fluoro-5-phenyl-3-propyl-2(5H)-furanone (4c). The re-
action of 1c (46.5 mg, 0.20 mmol) and SelectfluorTM (95%,
187.3 mg, 0.50 mm◦ol) in a mixture of 1.3 mL of MeCN and
0.7 mL of H2O at 80 C afforded 4c2 (20.8 mg, 47%) as a liquid; 1H
NMR (300 MHz, CDCl3) d 7.45–7.40 (m, 3H), 7.35–7.30 (m, 2H),
5.78–5.74 (m, 1H), 2.34–2.26 (m, 2H), 1.70–1.57 (m, 2H), 0.96 (t,
J = 7.5 Hz, 3H); 19F NMR (282 MHz, CDCl3) d -110.0.
(4) 4-Fluoro-5-(4¢-fluorophenyl)-3-methyl-2(5H)-furanone
(4e). The reaction of 1e (85.4 mg, 0.39 mmol) and SelectfluorTM
(95%, 246.8 mg, 0.66 mmol) in a mixture of 2.7 mL of MeCN
and 1.3 mL of H2O at 80 ◦C afforded 4e (48.6 mg, 60%) as a
white solid: mp: 52.5–53.5 ◦C (hexane). 1H NMR (300 MHz,
CDCl3) d 7.36–7.28 (m, 2H), 7.15–7.07 (m, 2H), 5.78–5.72 (m,
1H), 1.88 (t, JH–H = 2.0 Hz, JH–F = 2.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 174.0 (d, J = 294.7 Hz), 171.3 (d, J = 21.4 Hz), 163.5
The formation of 4m and E-5m under Conditions A:
The reaction of 1m (0.6162 g, 2.01 mmol) and SelectfluorTM
(95%, 2.2435 g, 6.02 mmol) in 20 mL of H2O–MeCN (premixed,
0.9 mL mL-1) at 80 ◦C under nitrogen afforded 4m (0.5558 g, 93%)
and E-5m (0.0375 g, 5%) (petroleum ether–ethyl acetate = 30 : 1
to 5 : 1) as a liquid.
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4m: 1H NMR (300 MHz, CDCl3) d 7.43–7.30 (m, 10H), 2.35–
2.27 (m, 2H), 1.73-1.57 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).
5H), 5.53 (d, J = 1.5 Hz, 1H), 2.36–2.09 (m, 2H), 0.96 (t, J =
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) 182.7 (d, J = 304.8 Hz),
169.0 (d, J = 23.4 Hz), 136.1 (d, J = 2.8 Hz), 128.8, 124.8, 124.7,
96.2 (d, J = 7.3 Hz), 86.6 (d, J = 18.6 Hz), 30.1 (d, J = 1.4 Hz),
7.6; 19F NMR (282 MHz, CDCl3) d -99.8; IR (neat) n/cm-1 3124,
3064, 2979, 2941, 2883, 1771, 1674, 1601, 1496, 1450, 1357, 1328,
1288, 1222, 1174, 1098; MS (70 eV, EI) m/z (%): 207 (M+ + 1,
2.72), 206 (M+, 20.54), 177 (100); HRMS calcd for C12H11O2F
(M+): 206.0743. Found: 206.0746.
1
E-5m: liquid; H NMR (300 MHz, CDCl3) d 7.45–7.30 (m,
10H), 4.25 (q, J = 7.1 Hz, 2H), 2.92 (d, J = 2.1 Hz, 1H), 1.98–1.89
(m, 2H), 1.34–1.15 (m, 5H), 0.65 (t, J = 7.4 Hz, 3H); 13C NMR
(75 MHz, CDCl3) 167.6 (d, J = 5.0 Hz), 159.5 (d, J = 261.8 Hz),
142.7, 128.3, 127.5, 117.8 (d, J = 13.3 Hz), 80.7 (d, J = 30.4 Hz),
61.1, 28.6 (d, J = 3.2 Hz), 21.8 (d, J = 2.6 Hz), 14.2, 13.7; 19F
NMR (282 MHz, CDCl3) d -96.5; IR (neat) n/cm-1 3479, 3061,
3028, 2962, 2932, 2873, 1713, 1600, 1493, 1464, 1449, 1368, 1295,
1232, 1181, 1110, 1031; MS (ESI) m/z: 397 (M+ + Na + MeOH),
365 (M+ + Na), 360 (M+ + NH4), 325 (M+ - OH); HRMS calcd
for C21H23FO3Na (M++Na): 365.1523. Found: 365.1536.
The formation of 4m under Conditions B:
(7) 4-Fluoro-3-methyl-1-oxaspiro[4.5]3-decen-2-one
(4s).
The reaction of (1s) (39.7 mg, 0.20 mmol) and S◦electfluorTM
(95%, 90.9 mg, 0.24 mmol) in 2 mL of MeCN at 80 C afforded
1
4s8a (11.2 mg, 30%) as a liquid; H NMR (300 MHz, CDCl3) d
1.82–1.60 (m, 12H), 1.36–1.20 (m, 1H); 19F NMR (282 MHz,
CDCl3) d -112.8.
The reaction of 1m (61.8 mg, 0.20 mmol) and SelectfluorTM
(95%, 126.3 mg, 0.34 mmol) in a mixture of 1.3 mL of MeCN and
0.65 mL of H2O at 80 ◦C afforded 4m (51.6 mg, 86%) and E-5m
(4.9 mg, 7%) (petroleum ether–ethyl acetate = 20 : 1 to 5 : 1) as a
liquid.
The reaction of (1s) (37.8 mg, 0.19 mmol) and SelectfluorTM
(95%, 88.5 mg, 0.24 mmol) in 2 mL of MeNO2 at 80 ◦C afforded
4s8a (14.9 mg, 42%) as a liquid.1H NMR (300 MHz, CDCl3) d
1.85–1.58 (m, 12H), 1.35–1.18 (m, 1H); 19F NMR (282 MHz,
CDCl3) d -112.8.
4m: 1H NMR (300 MHz, CDCl3) d 7.42–7.33 (m, 10H), 2.36–
2.27 (m, 2H), 1.73–1.58 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
E-5m: 1H NMR (300 MHz, CDCl3) d 7.45–7.30 (m, 10H), 4.25
(q, J = 7.1 Hz, 2H), 2.91 (d, J = 2.1 Hz, 1H), 1.98–1.88 (m, 2H),
1.35–1.14 (m, 5H), 0.65 (t, J = 7.4 Hz, 3H).
4. Large scale reactions
(1) Ethyl
3-fluoro-2-methyl-4-oxo-4-phenyl-2(E)-butenoate
The following compounds were prepared according to the
Conditions C.
(3a). Following Conditions A, a mixture of ethyl 2-methyl-4-
phenyl-2,3-butadienoate (1a) (1.0130 g, 5.0 mmol), SelectfluorTM
(95%, 5.5996 g, 15.0 mmol), and 50 mL of H2O–MeCN (premixed,
0.9 mL mL-1) were added into a flame-dried Schlenk vessel which
was pre-evacuated and backfilled with nitrogen three times. The
resulting mixture was then heated at 80 ◦C with an oil bath.
After 11 h, the reaction was complete as monitored by TLC. The
reaction mixture was quenched with 50 mL of H2O, extracted
with ether (100 mL + 2 ¥ 25 mL), washed with 50 mL of brine,
and dried over Na2SO4. Filtration, evaporation, and purification
by chromatography (petroleum ether–ethyl acetate = 80 : 1 to 20 :
1) on silica gel afforded 3a (0.5162 g, 44%) and 4a (0.0323 g, 3%),
respectively.
(2) 4-Fluoro-3,5-dimethyl-5-phenyl-2(5H)-furanone
(4n).
The reaction of 1n (43.4 mg, 0.20 mmol) and SelectfluorTM
(85.3 mg, 0.24 mmol) in 2 mL of MeCN at 80 ◦C afforded
1
4n8a (33.0 mg, 80%) as a liquid; H NMR (300 MHz, CDCl3) d
7.50–7.31 (m, 5H), 1.90 (s, 3H), 1.81 (d, J = 1.8 Hz, 3H); 19F
NMR (282 MHz, CDCl3) d -111.2.
(3) 4-Fluoro-3-methyl-5,5-diphenyl-2(5H)-furanone
(4o).
The reaction of 1o (55.8 mg, 0.20 mmol) and SelectfluorTM
(85.3 mg, 0.24 mmol) in 2 mL of MeCN at 80 ◦C afforded
1
4o8a (49.9 mg, 93%) as a liquid; H NMR (300 MHz, CDCl3)
d 7.41–7.28 (m, 10H), 1.90 (d, J = 2.1 Hz, 3H); 19F NMR
(282 MHz, CDCl3) d -106.1.
(2) 4-Fluoro-3-methyl-5-phenyl-2(5H)-furanone
(4a).
Following Conditions B, a mixture of ethyl 2-methyl-4-phenyl-
2,3-butadienoate (1a) (1.0101 g, 5.0 mmol) and SelectfluorTM
(95%, 3.1655 g, 8.5 mmol) were stirred in a mixture of 33.5 mL
of MeCN and 16.5 mL of water at 80 ◦C in an oil bath. After
15 h, the reaction was complete as monitored by TLC. The
reaction mixture was quenched with 50 mL of H2O, extracted
with ether (100 mL + 2 ¥ 25 mL), washed with 50 mL of brine,
and dried over Na2SO4. Filtration, evaporation, and purification
by chromatography (petroleum ether–ethyl acetate = 30 : 1) on
silica gel afforded 4a (0.5532 g, 58%).
(4) 5-Ethyl-4-fluoro-3-methyl-5-phenyl-2(5H)-furanone (4p).
The reaction of 1p (45.5 mg, 0.20 mmol) and SelectfluorTM
◦
(85.1 mg, 0.24 mmol) in 2 mL of MeCN at 80 C afforded 4p8a
(41.5 mg, 95%) as a liquid; 1H NMR (300 MHz, CDCl3) d 7.48–
7.32 (m, 5H), 2.33–2.20 (m, 1H), 2.19–2.06 (m, 1H), 1.80 (d, J =
2.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d -110.3.
(5) 5-Ethyl-4-fluoro-5-phenyl-3-propyl-2(5H)-furanone (4q).
The reaction of 1q (52.4 mg, 0.20 mmol) and SelectfluorTM
(85.4 mg, 0.24 mmol) in 2 mL of MeCN at 80 ◦C afforded
1
4q8a (45.7 mg, 91%) as a liquid; H NMR (300 MHz, CDCl3) d
Acknowledgements
7.50–7.26 (m, 5H), 2.36–2.05 (m, 4H), 1.63–1.50 (m, 2H), 0.93 (t,
J = 7.4 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H); 19F NMR (282 MHz,
CDCl3) d -110.5.
Financial support from the National Basic Research Program of
China (NO. 2009CB825300) and National Natural Sciences Foun-
dation of China (20972135) is greatly appreciated. Shengming Ma
is a Qiu Shi Adjunct Professor at Zhejiang University. We thank
Mr Jing Li for reproducing the results presented in Table 2, entries
4 and 9 and Table 3 entries 5, 14, and 15.
(6) 5-Ethyl-4-fluoro-5-phenyl-2(5H)-furanone (4r). The reac-
tion of 1r (43.2 mg, 0.20 mmol) and SelectfluorTM (84.8 mg,
0.24 mmol) in 2 mL of MeCN at 80 ◦C afforded 4r (31.4 mg,
1
76%) as a liquid; H NMR (300 MHz, CDCl3) d 7.50–7.32 (m,
280 | Org. Biomol. Chem., 2010, 8, 274–281
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reactions, see: P. T. Nyffeler, S. G. Duro´n, M. D. Burkart, S. P. Vincent
and C.-H. Wong, Angew. Chem., Int. Ed., 2005, 44, 192; (e) J.-A. Ma
and D. Cahard, Chem. Rev., 2004, 104, 6119; J.-A. Ma and D. Cahard,
Chem. Rev., 2008, 108, PR1; (f) R. P. Singh and J. M. Shreeve, Acc.
Chem. Res., 2004, 37, 31; (g) K. L. Kirk, Org. Process Res. Dev., 2008,
12, 305; (h) G. S. Lal, G. P. Pez and R. G. Syvret, Chem. Rev., 1996, 96,
1737; (i) M. Shimizu and T. Hiyama, Angew. Chem., Int. Ed., 2005, 44,
214.
References
1 (a) For reviews on the bioactivities of fluorinated compounds, see:
B. E. Smart, J. Fluorine Chem., 2001, 109, 3; (b) P. Kirsch, Modern
Fluoroorganic Chemistry, 1st edn, Wiley-VCH, Weinhein, 2004; (c) W.
K. Hagmann, J. Med. Chem., 2008, 51, 4359.
2 N. Shibata, T. Ishimaru, S. Nakamura and T. Toru, J. Fluorine Chem.,
2007, 128, 469.
3 W. J. Middleton, J. Org. Chem., 1975, 40, 574.
4 D. H. R. Barton, L. S. Godinho, R. H. Hesse and M. M. Pechet, Chem.
Commun., 1968, 804.
5 M. A. Tius, Tetrahedron, 1995, 51, 6605.
6 (a) T. Umemoto, K. Kawada and K. Tomita, Tetrahedron Lett., 1986,
27, 4465; (b) T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K.
Kawada and K. Tomita, J. Am. Chem. Soc., 1990, 112, 8563.
7 (a) T. D. Beeson and D. W. C. MacMillan, J. Am. Chem. Soc., 2005,
127, 8826; (b) M. Marigo, D. Fielenbach, A. Braunton, A. Kjœrsgaard
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 3703; (c) Y.
Hamashima, K. Yagi, H. Takano, L. Tama´s and M. Sodeoka, J. Am.
Chem. Soc., 2002, 124, 14530; (d) Y. Hamashima, H. Takano, D. Hotta
and M. Sodeoka, Org. Lett., 2003, 5, 3225.
9 H. Cui, Z. Chai, G. Zhao and S. Zhu, Chin. J. Chem., 2009, 27, 189.
10 (a) S. Ma and S. Wu, J. Org. Chem., 1999, 64, 9314; (b) H. D. Venkruijsse,
L. Brandsma, Synthesis of Acetylenes, Allenes and Cumulenes. A
Laboratory Manual, Elsevier, Amsterdam, The Netherlands, 1981, p.
33.
11 (a) G. Chen, C. Fu and S. Ma, Tetrahedron, 2006, 62, 4444; (b) C. Fu
and S. Ma, Eur. J. Org. Chem., 2005, 3942.
12 For a review on ionic addition of allenes, see: S. Ma, Chapter 10
in Modern Allene Chemistry, Wiley-VCH, Weinheim, 2004. For an
account on electrophilic addition and cyclization reactions of allenes,
see:; S. Ma, Acc, Chem. Res., 2009, 42, 1679.
13 G. Chen, C. Fu and S. Ma, J. Org. Chem., 2006, 71, 9877.
14 Y. Wang and D. J. Burton, Org. Lett., 2006, 8, 1109.
8 (a) C. Zhou, Z. Ma, Z. Gu, C. Fu and S. Ma, J. Org. Chem., 2008, 73,
772; (b) C. Zhou, J. Li, B. Lu¨, C. Fu and S. Ma, Org. Lett., 2008, 10,
581; (c) R. G. Syvret, K. M. Butt, T. P. Nguyen, V. L. Bulleck and R.
D. Rieth, J. Org. Chem., 2002, 67, 4487; (d) For reviews on fluorination
15 (a) J. Anaya, M. C. Grande, M. Grande, A.-I. Patino and P. Torres,
Synlett, 1999, 1429; (b) G. R. Krow, D. Gandla, W. Guo, R. A.
Centafont, G. Lin, C. DeBrosse, P. E. Sonnet, C. W. Ross, III, H.
G. Ramjit and K. C. Cannon, J. Org. Chem., 2008, 73, 2122.
This journal is
The Royal Society of Chemistry 2010
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