Difluorocarbene chemistry: Synthesis of gem-difluorocyclopropenyl ketones and gem-difluorinated dihydrofurans

Article abstract of DOI:10.1055/s-2006-926266

The cycloaddition reactions of difluorocarbene, generated by the decomposition of FSO₂CF₂CO₂SiMe₃, with α,β-acetylenic ketones give gem-difluorocyclopropenyl ketones in good yields. Treatment of these gem-difluo

Full text of DOI:10.1055/s-2006-926266

478
LETTER
Difluorocarbene Chemistry: Synthesis of gem-Difluorocyclopropenyl Ketones
and gem-Difluorinated Dihydrofurans
S
ynthesis of gem
h
-Difluorocy
a
clopropeny
n
l
K
etones an
-
d
gem-D
L
ifluorinated
D
i
i
hydrof
u
n
rans g Cheng, Qing-Yun Chen*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, 200032 Shanghai, P. R. of China
E-mail: chenqy@mail.sioc.ac.cn
Received 3 November 2005
F
F
Abstract: The cycloaddition reactions of difluorocarbene, generat-
ed by the decomposition of FSO2CF2CO2SiMe3, with a,b-acetylen-
ic ketones give gem-difluorocyclopropenyl ketones in good yields.
Treatment of these gem-difluorocyclopropenyl ketones with aque-
ous potassium carbonate results in the formation of gem-difluorinat-
ed dihydrofurans.
O
TFDA (3 equiv)
R1
R2
R1
R2
NaF (10%)
DG
120 °C
1
2
O
Scheme 1 Cycloaddition of difluorocarbene to 1
Table 1 Cycloaddition of Difluorocarbene to 1a
Key words: difluorocarbene, gem-difluorocyclopropenes, gem-di-
fluorocyclopropenyl ketones, gem-difluorinated dihydrofurans
Entry Substrate 1
Product 2 Yieldb (%)
The cycloaddition of difluorocarbene to carbon–carbon
double or triple bonds is one of the most important meth-
ods for the synthesis of organofluorine compounds.1 As
the smallest cyclic organofluorine, gem-difluorocyclopro-
pene derivatives command much attention on account of
their theoretical interest and synthetic application.2
1
2
3
4
5
6
7
8
9
1a (R1 = Ph, R2 = Ph)
2a
2b
2c
2d
2e
2f
89
85
80
71
65
95
90
88
55
50
88
1b (R1 = Ph, R2 = 4-t-BuC6H4)
1c (R1 = Ph, R2 = 4-MeC6H4)
1d (R1 = Ph, R2 = 4-BrC6H4)
1e (R1 = Ph, R2 = 4-CF3C6H4)
1f (R1 = 4-MeOC6H4, R2 = Ph)
1g (R1 = 4-MeC6H4, R2 = Ph)
1h (R1 = 4-BrC6H4, R2 = Ph)
1i (R1 = 3-CF3C6H4, R2 = Ph)
1j (R1 = n-C5H11, R2 = Ph)
1k (R1 = Ph, R2 = n-C4H9)
During the course of our studies on difluorocarbene chem-
istry, we conducted cyclopropanation reactions using our
difluorocarbene precursor, i.e., trimethylsilyl fluorosulfo-
nyldifluoroacetate (TFDA), with 1-iodoalkynes3 and a,b-
unsaturated aldehydes or ketones.3 It was found that intro-
duction of an iodine atom into the alkyne of the former
leads to the formation of stable 3,3-difluoro-1-iodocyclo-
propene, whereas carbonyl groups in the latter should be
protected as 1,3-dioxolanes, otherwise the reaction did not 10
occur. Furthermore, deprotection of these fluorinated
compounds with oxalic acid either gave the corresponding
gem-difluorocyclopropyl ketones or 2-aryl-3-fluoro-
furans. In connection with the above, we were interested
in the cycloaddition reaction of difluorocarbene with a,b-
acetylenic ketones; herein, we present the results.
2g
2h
2i
2j
11
2k
a Reagents: 1/NaF/TFDA, 1:0.1:3, 120 °C, 3 h.
b Isolated yield based on conversion of 1.
As shown in Table 1 the yields of gem-difluorocyclopro-
penyl ketones 2 varied from modest to good. When R1 or
R2 was a phenyl with electron-donating groups such as
OMe or Me, the yields of 2 were higher than those sub-
strates with electron-withdrawing groups such as Br, CF3
(Table 1, entries 2, 3 vs 4, 5 and entries 6, 7 vs 8, 9). When
R1 was an alkyl group, the yield of 2 was lower than when
R1 was an aryl group (Table 1, entry 10 vs 11).
Unlike a,b-unsaturated aldehydes and ketones, a,b-acety-
lenic ketone 1a, without protection, reacted smoothly with
TFDA (3 equiv) in diglyme (DG) in the presence of 10
mol% anhydrous NaF at 120 °C for about three hours to
give the corresponding adduct 3,3-gem-difluorocyclopro-
penyl ketone (2a), in 83% conversion and 89% yield
(Scheme 1). The use of more TFDA (5 equiv) did not in-
crease the conversion or yield significantly. Similarly,
other a,b-acetylenic ketones4 reacted under the same
conditions5 (Table 1).
The structures of all gem-difluorocyclopropenyl ketones 2
were confirmed by H and 19F NMR spectroscopy, MS,
1
and elemental analysis or HRMS. The structure of 2a was
further determined by single-crystal X-ray analysis
(Figure 1), which suggests that the molecule is almost pla-
nar. Notably the length of C1–C2 is 1.33 Å, similar to that
of a normal carbon–carbon double bond (1.34 Å).6
SYNLETT 2006, No. 3, pp 0478–0480
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5.
0
2.
2
0
0
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Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926266; Art ID: W08105ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of gem-Difluorocyclopropenyl Ketones and gem-Difluorinated Dihydrofurans
Table 2 Synthesis of Difluorinated Dihydrofuransa
479
Entry Substrate 2
Product 3 Yieldb (%)
1
2
2a (R1 = Ph, R2 = Ph)
3a
3b
3c
3d
3e
3f
75
88
80
97
89
88
92
90
75
70
75
2b (R1 = Ph, R2 = 4-t-BuC6H4)
2c (R1 = Ph, R2 = 4-MeC6H4)
2d (R1 = Ph, R2 = 4-BrC6H4)
2e (R1 = Ph, R2 = 4-CF3C6H4)
2f (R1 = 4-MeOC6H4, R2 = Ph)
2g (R1 = 4-MeC6H4, R2 = Ph)
2h (R1 = 4-BrC6H4, R2 = Ph)
2i (R1 = 3-CF3C6H4, R2 = Ph)
2j (R1 = n-C5H11, R2 = Ph)
2k (R1 = Ph, R2 = n-C4H9)
3
4
5
6
Figure 1 X-ray structure of 2a
7
3g
3h
3i
To compare gem-difluorocyclopropenyl ketones 2 with
gem-difluorocyclopropenes,3 we studied the ring-opening
reactions of compounds 2. Using 2a as an example, it was
found that acids such as HCl or BF3·OEt2 as catalyst in
various solvents always resulted in a complex reaction. To
our surprise, when treating 2a with aqueous 10% K2CO3
in MeOH, a new product was obtained in high yield and
was characterized as 3,3-difluoro-2-methoxy-2,5-diphen-
yl-2,3-dihydro-furan 3a (Figure 2).8 The X-ray analysis of
3a shows that the torsion angle of C(1)–C(2)–C(3)–C(4)
and C(1)–O(1)–C(4)–C(3) are –6.3° and 5.64°, indicating
that the fluorinated dihydrofuran ring is almost coplanar.
To our knowledge, this is the first X-ray structure of
difluorinated dihydrofuran.
8
9
10
11
3j
3k
a Excess aq K2CO3 was used.
b Isolated yield after silica gel column chromatography.
withdrawing groups, the reactions proceeded smoothly to
furnish 3 in good yields (Table 2, entries 2–9), but alkyl
substituents resulted in a slightly lower yield of 3.
The formation of 3 may be rationalized as follows: addi-
tion of methanol to cyclopropene gives A. The carbon
bearing methoxy group in A is then subjected to intra-
molecular attack by the enolate ion generated by collapse
of the cyclopropane B (Scheme 3).
F
F
F
F
H
R2
OMe
R1
R1
R2
O
3
O
2
MeOH
K2CO3
F
F
F
F
R1
R1
R2
R2
MeO
Figure 2 X-ray structure for 3a
O
Me
O
O
B
A
In a similar fashion, other gem-difluorocyclopropenyl
Scheme 3 A possible mechanism for the formation of 3.
ketones
2
were converted to gem-difluorinated
dihydrofurans7 (Scheme 2, Table 2).
The data in Table 2 demonstrate that when R1 and R2 were
aryl groups having either electron-donating or electron-
In conclusion, we have accomplished the synthesis of
gem-difluorocyclopropenyl ketones by the cycloaddition
of difluorocarbene to a,b-acetylenic ketones. These
ketones can be converted into gem-difluorinated dihydro-
furans easily in high yields under basic conditions.
F
F
F
F
H
R2
aq K2CO3 (10%)
OMe
R1
R1
R2
O
MeOH
r.t.
Acknowledgment
O
2
3
We thank the Natural Science Foundation of China (Nos.
20272026, 20032010, 20532040) for support of this work.
Scheme 2 Synthesis of gem-difluorinated dihydrofurans
Synlett 2006, No. 3, 478–480 © Thieme Stuttgart · New York

480
Z.-L. Cheng, Q.-Y. Chen
LETTER
14.83. Found: C, 75.06; H, 3.82; F, 14.86. X-ray
References and Notes
crystallographic data for 2a: crystal system, monoclinic;
space group, P2 (1)/n; unit cell dimensions: a = 8.4778 Å,
b = 9.0567 Å, c = 17.022 Å, a = 90°, b = 103.462°, g = 90°,
Z = 4, F(000) = 528, R1 = 0.0623, wR2 = 0.1635 (all data),
CCDC No. 287907.
(1) (a) Chemistry of Organic Fluorine Compounds II; Hudlicky,
M.; Pavlath, A. E., Eds.; American Chemical Society:
Washington D.C., 1995. (b) Brahams, D. L. S.; Dailey, W.
P. Chem. Rev. 1996, 96, 1585. (c) Gerstenberger, M. R. C.;
Haas, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 647.
(d) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(2) Dolbier, W. R. Jr.; Battiste, M. A. Chem. Rev. 2003, 103,
1071.
(3) (a) Xu, W.; Chen, Q.-Y. J. Org. Chem. 2002, 67, 9421.
(b) Xu, W.; Chen, Q.-Y. Org. Biomol. Chem. 2003, 1, 1151.
(c) Cheng, Z. L.; Chen, Q.-Y. J. Fluorine Chem. 2005, 126,
39.
(4) Prepared according to the literature: (a) Klein, J.; Gurfinkel,
E. Tetrahedron 1970, 26, 2127. (b) Yoshikazu, K.; Steven,
L. J. Org. Chem. 1982, 2493. (c) Corey, E. J.; Fuchs, P. L.
Tetrahedron Lett. 1972, 3769. (d) Sashida, H. Synthesis
1998, 745. (e) Yamaguchi, M.; Shibato, K.; Fujiwara, S.;
Hirao, I. Synthesis 1986, 421.
(5) gem-Difluorocyclopropenyl Ketone 2a: a,b-Acetylenic
ketone 1a (0.73 g, 3.55 mmol), NaF (19 mg, 10 mol%), and
DG (2 mL) were added under a N2 atmosphere to a Schlenk
tube charged with a magnetic stirring bar and a pressure-
equalized dropping funnel. After the mixture was heated to
about 120 °C (oil bath), TFDA (2.71 g, 3 equiv) was added
dropwise. The mixture was stirred at this temperature for
about 3 h. Then the mixture was cooled to r.t. and purified by
flash column chromatography on silica gel; yield: 0.67 g
(89%) [recovered 1a: 0.12 g (conversion 83%)]; solid; mp,
80–85 °C. IR (film): 1759, 1681, 1650, 1597,1577, 1494,
1450, 1313, 1299, 1226 cm–1. 1H NMR (CDCl3, 300 MHz):
d = 8.15–8.18 (m, 2 H), 8.01–8.05 (m, 2 H), 7.52–7.72 (m, 6
H). 19F NMR (CDCl3, 282 MHz): d = –103.74 (s, 2 F). MS:
m/z (%) = 256 (M+, 11.37), 228 (6.99), 151 (6.11), 105 (100),
77 (40.21). Anal. Calcd for C16H10OF2: C, 75.00; H, 3.93; F,
(6) (a) Abdo, B. T.; Alberts, I. L.; Attfield, C. J.; Banks, R. E.;
Blake, A. J. J. Am. Chem. Soc. 1996, 118, 209. (b) Brisdon,
A. K.; Crossley, I. R.; Flower, K. R.; Pritchard, R. G.;
Warren, J. E. Angew. Chem. Int. Ed. 2003, 42, 2398.
(7) Difluorinated Dihydrofuran 3c: To a solution of 2c (50
mg, 0.18 mmol) in MeOH (5 mL) was added 10% aq K2CO3
(0.1 mL). The mixture was stirred at r.t. and the progress of
the reaction was monitored by 19F NMR spectroscopy. When
the reaction had reached completion, H2O (10 mL) was
added and the reaction was extracted with EtOAc (3 × 10
mL). The combined organic layer was dried over MgSO4.
After the solvent was removed under reduced pressure, the
residue was purified by flash column chromatography on
silica gel; yield: 45 mg (80%); white solid. IR (film): 3117,
2935, 1650, 1616, 1579, 1515, 1494, 1452, 1343, 1285,
1271, 1149, 1071, 1047, 968, 731 cm–1. 1H NMR (CDCl3,
300 MHz): d = 2.40 (s, 3 H), 3.39 (s, 3 H), 5.69 (s, 1 H),
7.23–7.50 (m, 7 H), 7.75–7.80 (m, 2 H). 19F NMR (CDCl3,
282 MHz): d = –82.27 (d, J = 247 Hz, 1 F), –111.31 (d, J =
248 Hz, 1 F). MS: m/z (%) = 302 (M+, 10.13), 283 (12.21),
282 (10.24), 271 (24.50), 243 (14.40), 177 (9.80), 152 (100),
151 (65.65), 119 (59.20), 105 (93.95), 84 (99.36). Anal.
Calcd for C18H16O2F2: C, 71.51; H, 5.33. Found: C, 71.52; H,
5.64.
(8) X-ray crystallographic data for 3a: C17H14F2O2, M 288.28;
monoclinic; space group, P2 (1)/n; unit cell dimensions:
a = 13.6673 Å, b = 7.1944 Å, c = 14.8156 Å, a = 90°, b =
92.034°, g = 90°, Z = 4, Dcalcd = 1.315 g/cm3, F(000) = 600,
R1 = 0.0812, wR2 = 0.1246, CCDC No. 287908.
Synlett 2006, No. 3, 478–480 © Thieme Stuttgart · New York