Highly regio- and stereoselective diels-alder cycloaddition of difluoro(methylene)cyclopropanes

Article abstract of DOI:10.1002/ejoc.200700992

The Diels-Alder reactions of difluoro(methylene)cyclopropanes (F ₂MCPs) with cyclic dienes are described. These cycloaddition reactions exhibited complete regioselectivity and high endo-stereoselectivity. The obtained cycloadducts underwent a retro-Diels-Alder reaction to give the original dienophiles and dienes when heated, reflecting the reversible Diels-Alder reactivity of F₂MCPs. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700992

FULL PAPER
DOI: 10.1002/ejoc.200700992
Highly Regio- and Stereoselective Diels–Alder Cycloaddition of
Difluoro(methylene)cyclopropanes
Xiao-Chun Hang,[a] Qing-Yun Chen,[a] and Ji-Chang Xiao*[a]
Keywords: Difluoro(methylene)cyclopropanes / Diels–Alder reaction / Regioselectivity / Diastereoselectivity / Cyclorever-
sion
The Diels–Alder reactions of difluoro(methylene)cyclopro-
panes (F2MCPs) with cyclic dienes are described. These cy-
cloaddition reactions exhibited complete regioselectivity and
high endo-stereoselectivity. The obtained cycloadducts
underwent a retro-Diels–Alder reaction to give the original
dienophiles and dienes when heated, reflecting the revers-
ible Diels–Alder reactivity of F2MCPs.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Methylenecyclopropane derivatives (MCPs) have served
as useful synthetic intermediates in organic chemistry over
the last decade.[1] The attractive feature of these compounds
is their surprising stability, accompanied by a high level of
angular strain. This confers on them remarkable chemical
reactivity, allowing them to undergo such processes as cy-
cloadditions and ring-opening reactions.[2] The introduction
of fluorine onto the ring of such methylenecyclopropanes
would have profound effects on their chemical reactivities
and physicochemical properties, due to the strongly elec-
tron-withdrawing effect of fluorine. However, the synthesis
of these fluorinated analogues,[3] such as difluoro(methyl-
ene)cyclopropanes (F2MCPs), is very difficult. Recently,
we found that F2MCPs could be readily prepared from
the direct difluorocyclopropanation of allenes, using
FSO2CF2CO2SiMe3 as the difluorocarbene precursor
(Scheme 1). It was shown that these F2MCPs could un-
dergo a variety of reactions both at the double bond and on
the difluorocyclopropane ring, demonstrating very different
reactivity from the nonfluorinated analogues (MCPs).[4]
These interesting results prompted us to investigate further
the chemical reactivity of F2MCPs.
Scheme 1. Synthesis of difluoro(methylene)cyclopropanes (for R1,
R2 see Table 2).
case of F2MCPs, Dolbier has found that their Diels–Alder
reactivity was dramatically increased by the geminal
allylic fluorines, preferentially affording CF2-endo prod-
ucts.[1a–1c,3a] The carbon–carbon double bond present in
F2MCPs 1 might exhibit a much stronger electrophilic char-
acter than that of Dolbier’s F2MCPs, because F2MCPs 1
contain an electron-withdrawing sulfonyl group as well as
the two geminal allylic fluorines, leading to lower LUMO
energies. As a consequence, they would be expected to be
good dienophiles in the Diels–Alder reaction.
Results and Discussion
Diels–Alder Reaction of F2MCPs with Cyclic Dienes
To examine this dienophilic nature, we investigated the
Diels–Alder reaction of F2MCPs 1 and the retro-Diels–Al-
der reaction of the corresponding cycloadducts. Unusually
high regio- and Tos-endo stereoselectivity was observed in
the Diels–Alder reaction of 1 with cyclic dienes, which is
contrary to Dolbier’s results. At elevated temperature, 1
could be regenerated from the cycloreversion reaction of the
Diels–Alder adducts. Herein, we describe these preliminary
results, which could provide a good understanding of the
stability and reactivity of F2MCPs.
The Diels–Alder reaction is among the most fundamen-
tal and useful synthetic processes for the construction of
numerous complex molecular architectures. A fascinating
aspect of the Diels–Alder reaction is its regio- and stereose-
lectivity.[5] For example, highly endo-selective Diels–Alder
cycloaddition reactions have been employed as the key step
for the total synthesis of many natural products.[6] In the
[a] Key Laboratory of Organofluorine Chemistry, Shanghai Insti-
tute of Organic Chemistry, Chinese Academy of Sciences,
354 Fengling Road 200032, China
It is well known that the yield and stereochemistry of the
Diels–Alder reaction are strictly dependent on the reaction
conditions.[7] Therefore, significant efforts were made to
Fax: +86-21-64166128
E-mail: jchxiao@mail.sioc.ac.cn
Eur. J. Org. Chem. 2008, 1101–1106
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X.-C. Hang, Q.-Y. Chen, J.-C. Xiao
FULL PAPER
screen the reaction conditions for optimized yield and
stereoselectivity. F2MCPs 1 were prepared according to our
previous report with a slight modification.[4] Furan was first
used as the diene. It was found that solvent and temperature
have a significant effect. Good results were obtained when
the reaction was performed in ether at 50 °C with a large
excess of furan (Table 1, entry 9). This cycloaddition
showed a strong preference for the endo product.
Table 1. Optimization of conditions for Diels–Alder reaction of
F2MCPs with furan.[a]
Entry Solvent
Temp.
[°C]
Time
[h]
%
endo/exo[b]
(tosyl)
Yield[a]
1
2
3
4
5
6
7
8
9
10
none
none
chloroform
chloroform
acetone
methanol
benzene
petroleum ether
diethyl ether
[BMIm][PF6]
50
120
120
50
50
50
50
50
50
50
24
10
10
24
24
24
30
30
24
20
0
–
75:25
67:33
90:10
91:9
91:9
–
92:8
88:12
93:7
Figure 1. Crystal structure of cycloadduct 2a.
84
60
59
48
47
0
49
90
99
Table 2. Diels–Alder reaction of F2MCPs with symmetrical dienes.
[a] Isolated yield based on F2MCP. [b] Determined by 19F NMR
and HPLC.
It was reported that endo selectivity could be greatly im-
proved when the Diels–Alder reaction was performed in
ionic liquid, although the mechanism behind the ionic li-
quid’s impact on the reaction is not well understood.[8] As
an extension of our interest in ionic liquid chemistry,[9] we
investigated the Diels–Alder reaction of F2MCPs in ionic
liquid. It was found that a further improvement of yield
and endo selectivity was obtained when the reaction was
carried out in a commonly used ionic liquid (butylmethyl-
imidazolium hexafluorophosphate, [BMIm][PF6]), giving a
93:7 (endo/exo) mixture of diastereomers in almost quanti-
tative yield (Table 1, entry 10). The ionic liquid could be
Entry R1
1
R2
X
Product
%
endo/exo
Yield[a] (tosyl)[b]
–(CH2)5–
O
O
CH2
CH2
2b
2c
2d
2e
2f
96
75
99
96
47
90:10
75:25
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
2
3
4
5
CH3CH2 CH3CH2
CH3
CH3
–(CH2)5–
CH3CH2 CH3CH2 CH2
[a] Isolated yield based on F2MCP. [b] Determined by 19F NMR
and HPLC.
Prompted by the good reactivity of F2MCPs with furan,
recovered and reused after extraction with diethyl ether. we then extended our study to the Diels–Alder reaction of
The mixture of endo/exo isomers could not be separated by F2MCPs with cyclopentadiene. Much to our surprise, these
normal column chromatography because of their very sim- reactions proceeded with unusually high endo diastereo-
ilar polarities. Fortunately, the pure major endo isomer 2a selectivity, giving almost pure cycloadducts with endo-con-
was easily obtained after recrystallization. The structure of figuration (Table 2, entries 3–5).
2a was confirmed by single-crystal X-ray analysis. As
Reaction of an unsymmetrical dienophile with an un-
shown in Figure 1, the tosyl group is below the six-mem- symmetrical diene can give rise to two regioisomeric ad-
bered ring and on the opposite side than the CF2 group. ducts. In order to explore the regioselectivity of F2MCPs in
The oxygen bridge and the CF2 group are on the same side Diels–Alder reaction, we extended our investigation to the
of the molecule.
reaction of F2MCPs with unsymmetrical dienes like 2-sub-
With the optimized reaction conditions in hand, we then stituted furans. Much to our delight, all of these Diels–
examined this [4+2] cycloaddition with other F2MCPs in Alder reactions of F2MCPs with 2-substituted furans were
[BMIm][PF6]. It can be seen that the introduction of bulky completely regio- and endo-stereoselective, giving the corre-
cyclohexyl or ethyl groups into the cyclopropane ring re- sponding cycloadducts as
sulted in slightly lower yield and stereoselectivity (Table 2, (Table 3). The regio- and endo-diastereoselectivity of the cy-
entries 1–2). cloadducts was established through single-crystal X-ray
a
single diastereoisomer
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Eur. J. Org. Chem. 2008, 1101–1106

Diels–Alder Cycloaddition of Difluoro(methylene)cyclopropanes
structure determination of 2j (Figure 2). As shown in Fig- cloreversion may not occur. Therefore the retro-Diels–Alder
ure 2, the substituent on the bridge carbon and the tosyl reaction could demonstrate the relative stability of the cy-
group are present on the same side of the molecule.
cloadducts, which further reveals the corresponding reactiv-
ity of the dienophiles and dienes. In order to gain more
insight into the properties of these highly strained difluo-
ro(methylene)cyclopropanes, the thermal stability of these
Diels–Alder cycloadducts was thus investigated.
Table 3. Diels–Alder reaction of F2MCPs with unsymmetrical
dienes.
Although the above adducts 2a–n were all stable at room
temperature for long periods of time, compound 2a under-
went a retrodiene decomposition when it was heated in
[BMIm][PF6] at 100 °C for 14 h, giving the parent com-
pound 1a in 34% yield (Table 4, entry 1). Changing the sol-
vent to benzene or tert-butyl alcohol resulted in a higher
cycloreversion (Table 4, entries 2–3). The corresponding di-
enophile 1a could be obtained almost quantitatively when
2g was subjected to the same reaction conditions as above
(Table 4, entry 5). Nevertheless, the cycloadduct 2d re-
mained intact under those reaction conditions (Table 4, en-
try 6), which indicated that the cyclopentadiene moiety in
2d was difficult to cleave under thermal cycloreversion reac-
tion conditions. This is in agreement with the previous ob-
servation that furan adducts are more reactive than cyclo-
pentadienes toward the retro-Diels–Alder reaction.[11]
Entry R1
R2
G
Product
% Yield[a]
1
2
3
4
5
6
7
8
CH3
CH3
–(CH2)5–
CH3
CH3
2g
2h
2i
2j
2k
2l
83
81
48
72
75
48
44
63
CH3CH2 CH3CH2 CH3
CH3
CH3
–(CH2)5–
CH2OH
CH2OH
CH3CH2 CH3CH2 CH2OH
CH3
CH3
–(CH2)5–
CH2OCH3
CH2OCH3
2m
2n
[a] All yields refer to analytically pure compounds.
Table 4. Selected examples of the retro-Diels–Alder reaction.
Entry R1
R2
X
G
Solvent
Time Product
[h]
%
Yield[a]
1
2
3
4
5
6
CH3 CH3
CH3 CH3
CH3 CH3
–(CH2)5–
CH3 CH3
CH3 CH3 CH2
O
O
O
O
O
H
H
H
H
[BMIm][PF6] 14
1a
1a
1a
1b
1a
–
34
55
57
79
99
–
C6H6
8
8
8
8
8
tBuOH
tBuOH
CH3 tBuOH
tBuOH
H
[a] Isolated yields.
Figure 2. Crystal structure of cycloadduct 2j.
Conclusions
Compared with the symmetrical dienes described above
(Table 2), the yields were lower for these 2-substituted fu-
rans (Table 3), which indicated that this Diels–Alder reac-
tion is very sensitive to the steric influence of the substitu-
ents attached to the reactants.
In summary, we have successfully developed a fully regio-
and endo-selective Diels–Alder reaction of F2MCPs. This
complete regio- and endo-selectivity might result from a
combination of multiple factors including the olefin struc-
ture, solvent effects, steric interactions, electrostatic forces,
hydrogen bonds, etc. The corresponding cycloadducts un-
dergo an efficient retro-Diels–Alder reaction under mild
Retro-Diels–Alder Reaction of the Cycloadducts
It is well known that the Diels–Alder reaction has been conditions to release the F2MCPs. These features provide
frequently used as a method for protection of a double new understanding of the relative stability and reactivity of
bond because the alkene moiety can be regenerated through F2MCPs with high ring strain. We are currently exploiting
a thermal retro-Diels–Alder reaction.[10] However, if the cy- structural effects on this peculiar reactivity and other chem-
cloadducts are too labile, the Diels–Alder adducts may be- ical conversions of F2MCPs, which will be reported in due
come difficult to handle; and if they are too stable, the cy- course.
Eur. J. Org. Chem. 2008, 1101–1106
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1103

X.-C. Hang, Q.-Y. Chen, J.-C. Xiao
FULL PAPER
(300 MHz, CDCl3): δ = 1.26 (s, 3 H), 1.49 (s, 3 H), 2.49 (s, 3 H),
4.18 (d, J = 4 Hz 1 H), 4.45 (d, J = 4 Hz, 1 H), 4.84 (s, 1 H), 6.54
(d, J = 6 Hz, 1 H), 6.72 (d, J = 6 Hz, 1 H), 7.42 (d, J = 7.1 Hz, 2
H), 7.77 (d, J = 7.1 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3):
δ = –141.0 (d, J = 150 Hz, 1 F), –149.3 (d, J = 150 Hz 1 F) ppm.
Experimental Section
1
General: Melting points were uncorrected. H NMR spectra were
recorded with a Bruker AM 300 (300 MHz) spectrometer with
TMS as an internal standard (negative for upfield). 19F NMR spec-
tra were recorded with a Bruker AM 300 (282 MHz) with CFCl3
as an external standard (negative for upfield). 13C NMR spectra
were recorded with a Bruker AM 300 (75 MHz) spectrometer with
CDCl3 as an internal standard (negative for upfield).The solvent
for NMR measurement was CDCl3, which was purchased from
Cambridge Isotope Laboratories, Aldrich or Acros. MS and
HRMS were recorded with a Hewlett–Packard HP-5989A spec-
trometer and a Finnigan MAT-8483 mass spectrometer. Elemental
analyses were obtained with a Perkin–Elmer 2400 Series II Elemen-
tal Analyzer. Infrared spectra were measured with a Perkin–Elmer
983 spectrometer. TLC analysis was performed on silica gel plates,
column chromatography over silica gel (mesh 300–400), both ob-
tained from Qingdao Ocean Chemicals. All solvents were purified
by standard methods. FSO2CF2COOSiMe3 (TFDA),[12] sulfonyl
allenes,[13] and [BMIm][PF6][14] were prepared as described in the
literature. All commercially available reagents and chemicals were
purchased from Aldrich, Acros or Alfa Aesar.
IR (film): ν = 3018, 2976, 2954, 2936, 1944, 1832, 1597, 1495, 1475,
˜
1438, 1324, 1315, 1308, 1292, 1189, 1183, 1156, 1143, 1087 cm–1.
MS (ESI): m/z = 358.0 [M + NH4+]. C17H18F2O3S (340.09): calcd.
C 59.99, H 5.33, F 11.16; found C 60.00, H 5.28, F 11.04.
2b: Yield 58 mg (96%), solid, m.p. 162–164 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.20–1.50 (m, 3 H), 1.52–1.83 (m, 6 H),
2.36 (d, J = 13 Hz, 1 H), 2.48 (s, 3 H), 4.16 (d, J = 5.5 Hz, 1 H),
4.42 (d, J = 5.5 Hz 1 H), 5.00 (s, 1 H), 6.50 (d, J = 5.5 Hz, 1 H),
6.67 (d, J = 5.5 Hz, 1 H), 7.40–7.43 (d, J = 8.0 Hz, 2 H), 7.77 (d,
J = 8.0 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ = –142.0
(d, J = 150 Hz, 1 F), –149.8 (dd, J = 150, J = 6.1 Hz 1 F) ppm. IR
(film): ν = 3012, 2944, 2926, 2856, 1598, 1496, 1465, 1454, 1442,
˜
1324, 1309, 1295, 1193, 1163, 1143, 1113, 1107, 1087, 1043 cm–1.
MS (ESI): m/z = 398.2 [M + NH4+]. C20H22F2O3S (380.12): calcd.
C 63.14, H 5.83, F 9.99; found C 63.22, H 5.86, F 9.77.
2c: Yield 46 mg (75%), solid, m.p. 108–110 °C. 1H NMR
(300 MHz, CDCl3): δ = 0.92–1.04 (m, 6 H), 1.30–1.50 (m, 1 H),
1.78–2.10 (m, 3 H), 2.48 (s, 3 H), 4.19 (d, J = 4.1 Hz, 1 H), 4.54
(d, J = 4.1 Hz, 1 H), 4.90 (s, 1 H), 6.53 (d, J = 5.3 Hz, 1 H), 6.68
(d, J = 5.5 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.77 (d, J = 8.2 Hz,
2 H) ppm. 19F NMR (282 MHz, CDCl3): δ = –141.7 (d, J =
Typical Procedure for the Addition of Difluorocarbene to Allenes 1a–
c: The allene 1-methyl-4-(3-methylbuta-1,2-dienylsulfonyl)benzene
(2 g, 9.2 mmol), NaF (38 mg, 10 mol-%) and xylene (20 mL) were
placed under N2 in a three-necked flask fitted with a magnetic stir-
ring bar and a pressure-equalizing dropping funnel. After the mix-
ture was heated to 120 °C (oil bath), TFDA (5.75 g, 2.5 equiv.) di-
luted in xylene (5 mL) was added dropwise over a period of about
1 h. The mixture was then stirred for an additional 1 h to ensure
that the substrate was consumed. After cooling the mixture to
room temperature, the solvent was removed under reduced pres-
sure. The residual product was purified by chromatography on a
silica gel column (petroleum ether/ethyl acetate, 10:1) to yield 1a,
154 Hz, 1 F), –148.8 (d, J = 158 Hz, 1 F) ppm. IR (film): ν = 3094,
˜
3035, 2980, 2945, 2884, 1942, 1595, 1471, 1449, 1328, 1320, 1293,
1263, 1186, 1164, 1145, 1116, 1090, 1046, 1027 cm–1. MS (ESI):
m/z = 386.4 [M + NH4+]. C19H22F2O3S (368.1): calcd. C 61.94, H
6.02, F 10.31; found C 61.75, H 6.06, F 10.36.
2d: Yield 63 mg (99%), solid, m.p. 182–184 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.24 (s, 3 H), 1.32 (d, J = 13.8 Hz 1 H),
1.45 (s, 3 H), 2.39 (s, 3 H), 2.85 (s, 2 H), 3.95 (s, 2 H), 6.17 (d, J =
6.3 Hz, 1 H), 6.43 (d, J = 6.3 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 2 H),
7.77 (d, J = 7.2 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ =
–139.5 (d, J = 147 Hz 1 F), –150.4 (d, J = 148 Hz, 1 F) ppm. IR
1
2.1 g (85% based on allene), solid. H NMR (300 MHz, CDCl3): δ
= 1.45 (t, J = 1.5 Hz, 6 H), 2.46 (s, 3 H), 7.00 (s, 1 H), 7.37 (d, J
= 8.1 Hz, 2 H), 7.80 (d, J = 8.1 Hz, 2 H) ppm. 19F NMR
(282 MHz, CDCl3): δ = –138.7 (s, 2 F) ppm.
(film): ν = 3069, 3022, 3003, 2956, 2929, 1598, 1482, 1432, 1322,
˜
1288, 1276, 1187, 1168, 1146, 1089, 1060 cm–1. MS (ESI): m/z =
356.3 [M + NH4+]. C18H20F2O2S (338.12): calcd. C 63.88, H 5.96,
F 11.23; found C 63.77, H 5.85, F 11.50.
1b: The TFDA was added dropwise to the reaction without being
1
diluted. Yield 64%, solid. H NMR (300 MHz, CDCl3): δ = 1.34–
1.44 (m, 3 H), 1.68–1.90 (m, 5 H), 1.96–2.08 (m, 2 H), 2.46 (s, 3
H), 6.95 (s, 1 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.76 (d, J = 8.4 Hz, 2
H) ppm. 19F NMR (282 MHz, CDCl3): δ = –140.4 (s, 2 F) ppm.
2e: Yield 62 mg (96%), solid, m.p. 169–171 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.18–1.75 (m, 12 H), 2.38 (d, J = 12.7 Hz,
1 H), 2.41 (s, 3 H), 2.93 (s, 1 H), 3.96 (s, 1 H), 6.10 (m, 1 H), 6.31
(m, 1 H), 7.31–7.33 (d, J = 8.1 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 2
H) ppm. 19F NMR (282 MHz, CDCl3): δ = –140.1 (dd, J = 150, J
= 4.2 Hz, 1 F), –150.1 (dd, J = 154, J = 6.5 Hz, 1 F) ppm. IR
1c: The reaction temperature was 110 °C. Yield 50%, solid, m.p.
1
82–84 °C. H NMR (300 MHz, CDCl3): δ = 1.09 (t, J = 7.6 Hz 3
H), 1.66–1.83 (m, 5 H), 1.60–2.09 (m, 2 H), 2.46 (s, 3 H), 7.03 (s,
1 H), 7.35–7.38 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 8.0 Hz, 2 H)
ppm. 19F NMR (282 MHz, CDCl3): δ = –138.7 (s, 2 F) ppm. IR
(film): ν = 3068, 3008, 2926, 2853, 1654, 1467, 1453, 1321, 1274,
˜
1257, 1184, 1158, 1143, 1128, 1094, 1053 cm–1. MS (ESI): m/z =
396.4 [M + NH4+]. C21H24F2O2S (378.2): calcd. C 66.64, H 6.39,
F 10.04; found C 66.28, H 6.60, F 10.08.
(film): ν = 3065, 2979, 2946, 1922, 1805, 1596, 1458, 1339, 1320,
˜
1182, 1154 cm–1. MS (ESI): m/z = 301.2 [M + H+]. C15H18F2O2S
(300.10): calcd. C 59.98, H 6.04, F 12.65; found C 59.86, H 6.08,
F 12.80.
2f: Yield 41 mg (47%), solid, m.p. 151–153 °C. 1H NMR
(300 MHz, CDCl3): δ = 0.92–1.04 (m, 6 H), 1.30–1.55 (m, 3 H),
1.88–1.95 (m, 1 H), 2.00–2.04 (br., 2 H), 2.47 (s, 3 H), 2.57 (s, 1
H), 2.97 (d, J = 2.7 Hz 1 H), 4.07 (d, J = 2.4 Hz 1 H), 6.13 (m, 1
H), 6.38–6.39 (m, 1 H), 7.37 (d, J = 7.8 Hz, 2 H), 7.77 (d, J =
7.8 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ = –141.5 (d, J
General Procedure for Diels–Alder Reaction of Compounds 1 with
Furan and Other Dienes:
A sample containing 1a (50 mg,
0.184 mmol), furan (0.05 mL, Ͼ3 equiv.) and [BMIm][PF6]
(0.5 mL) was stirred in a 5-mL sealed tube at 50 °C for 20 h. The
homogeneous phase was extracted several times with diethyl ether
(5 mL), until TLC showed that no additional compound could be
extracted from the IL system. The diethyl ether was removed and
the residue was purified by chromatography (petroleum ether/ethyl
acetate, 8:1). The pure endo product was obtained by recrystalli-
= 147 Hz 1 F), –149.8 (d, J = 147 Hz, 1 F) ppm. IR (film): ν =
˜
3072, 3057, 2907, 2936, 2877, 1940, 1838, 1598, 1460, 1438, 1332,
1318, 1302, 1290, 1182, 1159, 1144, 1126, 1087, 1054 cm–1. MS
(ESI): m/z = 384.4 [M + NH4+]. C20H24F2O3S (366.15): calcd. C
65.55, H 6.60, F 10.37; found C 65.44, H 6.64, F 10.44.
1
zation to yield 2a, 62 mg (99%), solid, m.p. 190–191 °C. H NMR
1104
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Diels–Alder Cycloaddition of Difluoro(methylene)cyclopropanes
2g: Yield 83%, solid, m.p. 134–136 °C. 1H NMR (300 MHz, 2l: Yield 48%, solid, m.p. 147–149 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.19 (s, 3 H), 1.28 (s, 3 H), 1.37 (s, 1 H), 2.45 (s, 3 H), CDCl3): δ = 0.78–0.85 (t, J = 7.1 Hz, 3 H), 0.97–1.04 (t, J = 7.1 Hz,
3.87 (d, J = 1.2 Hz 1 H), 4.75 (s, 1 H), 6.48 (d, J = 5.9 Hz 1 H), 3 H), 1.28–1.46 (m, 2 H), 1.82–2.07 (m, 3 H), 2.46 (s, 3 H), 3.93–
6.66 (dd, J = 5.6, J = 1.2 Hz 1 H), 7.38 (d, J = 8.3 Hz, 2 H), 7.78
(d, J = 8.2 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ = –141.0 1 H), 6.70–6.75 (dd, J = 5.7 Hz, 1 H), 7.33–7.36 (d, J = 7.9 Hz, 2
(d, J = 148 Hz 1 F), –150.2 (d, J = 148 Hz, 1 F) ppm. 13C NMR H), 7.73–7.76 (d, J = 7.5 Hz, 2 H) ppm. 19F NMR (282 MHz,
(75 MHz, CDCl3): δ = 18.2, 18.3 (d, JFC = 5.7 Hz), 18.5, 18.9, 19.0 CDCl3): δ = –143.8–142.2 (d, J = 150 Hz 1 F), –149.2–148.7 (dd,
4.10 (m, 2 H), 4.52 (s, 1 H), 4.92 (s, 1 H), 6.65–6.69 (d, J = 5.8 Hz,
(d, JFC = 7.3 Hz), 21.7, 36.0 (m, 1 C), 45.3 (m, 1 C), 72.3, 80.1 (d,
JFC = 8.9 Hz), 89.7, 114.6 (m, 1 C), 128.3, 130.0, 135.8, 138.0
J = 150, J = 5.4 Hz, 1 F) ppm. IR (film): ν = 3515, 2977, 2881,
˜
1596, 1454, 1319, 1307, 1294, 1183, 1145, 1077, 1053, 1002 cm–1.
(138.02, 138.06, 2 C), 145.1 ppm. IR (film): ν = 3026, 2970, 1597, MS (ESI): m/z = 416.2 [M + NH4+]. C20H24F2O4S (398.5): calcd.
˜
1471, 1435, 1391, 1319, 1303, 1293, 1262, 1207, 1143, 1111, 1187,
1007 cm–1. MS (ESI): m/z = 377.2 [M + Na+]. C18H20F2O3S: calcd.
C 61.00, H 5.91; found C 60.51, H 5.91. HRMS (ESI) calcd. for
C18H20F2O3S H+: 355.1174; found 355.1180.
C 60.28, H 6.09, F 9.54; found C 60.22, H 6.39, F 9.72.
1
2m: Yield 44%, solid. H NMR (300 MHz, CDCl3): δ = 1.27 (s, 3
H), 1.30 (s, 3 H), 2.47 (s, 3 H), 3.28 (s, 3 H), 3.40 (d, J = 11.4 Hz,
1 H), 3.53 (d, J = 11.4 Hz, 1 H), 4.55 (s, 1 H), 4.84 (s, 1 H), 6.51
(d, J = 5.8 Hz, 1 H), 6.71 (d, J = 6.0 Hz, 1 H), 7.36 (d, J = 8.4 Hz,
2 H), 7.76 (d, J = 8.2 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3):
δ = –141.5 (d, J = 153 Hz 1 F), –150.0 (d, J = 151, J = 6 Hz 1
2h: Yield 81%, solid, m.p. 140–142 °C 1H NMR (300 MHz,
CDCl3): δ = 1.17 (s, 3 H), 1.19–1.47 (m, 4 H), 1.61–1.94 (m, 6 H),
2.45 (s, 3 H), 3.85 (s, 1 H), 4.81 (s, 1 H), 6.44 (d, J = 5.6 Hz, 1 H),
6.60 (d, J = 5.5 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 2 H), 7.71 (d, J =
7.9 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ = –142.2 (d, J
= 151 Hz, 1 F), –150.0 (dd, J = 152, J = 6.1 Hz 1 F) ppm. IR
F) ppm. IR (film): ν = 2937, 1597, 1469, 1435, 1317, 1305, 1203,
˜
1182, 1145, 1116 cm–1. MS (ESI): m/z = 385.0 [M + H+].
C19H22F2O4S (384.12): calcd. C 59.36, H 5.77; found C 59.38, H
5.76.
(film): ν = 2929, 2856, 1596, 1492, 1442, 1320, 1303, 1191, 1163,
˜
1144, 1118, 1085, 1072, 1003 cm–1. MS (ESI): m/z = 412.0 [M +
NH4+]. C21H24F2O3S (394.14): calcd. C 63.94, H 6.13; found C
64.21, H 6.39.
2n: Yield 63%, solid, m.p. 126–128 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.08–1.39 (br., 4 H), 1.45–1.79 (br., 6 H), 2.40 (s, 3
H), 3.21 (s, 3 H), 3.27 (d, J = 11.5 Hz, 1 H), 3.45 (d, J = 11.5 Hz,
1 H), 4.46 (s, 1 H), 4.83 (s, 1 H), 6.40–6.42 (d, J = 6.1 Hz, 1 H),
6.59 (d, J = 6.0 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 2 H), 7.68 (d, J =
8.4 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ = –142.9 (d, J
= 152 Hz, 1 F), –149.9 (dd, J = 150, J = 6 Hz, 1 F) ppm. IR (film):
2i: Yield 48%, solid, m.p. 104–106 °C. 1H NMR (300 MHz,
CDCl3): δ = 0.78 (t, J = 7.5 Hz, 3 H), 0.93 (t, J = 7.5 Hz, 3 H),
1.17–1.34 (m, 2 H), 1.38 (s, 3 H), 1.76–2.01 (m, 2 H), 2.40 (s, 3 H),
3.81 (s, 1 H), 4.75 (s, 1 H), 6.51 (d, J = 5.7 Hz, 1 H), 6.57 (d, J =
5.7 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 2
H) ppm. 19F NMR (282 MHz, CDCl3): δ = –142.7 (d, J = 152 Hz,
1 F), –149.1 (d, J = 155 Hz, 1 F) ppm. 13C NMR (75 MHz,
ν = 2930, 2855, 1597, 1471, 1447, 1310, 1307, 1291, 1185, 1160,
˜
1146, 1118, 1085, 1066 cm–1. MS (ESI): m/z = 425.2 [M + H+].
C22H26F2O4S (424.15): calcd. C 62.25, H 6.17; found C 62.06, H
6.36.
CDCl3): δ = 9.3–9.3 (d, JFC = 2.4 Hz), 10.5, 18.8, 19.9 (d, JFC
=
3.8 Hz), 21.7, 21.9–22.0 (d, JFC = 6.6 Hz), 37.3 (m), 46.8 (m), 71.9,
80.0 (d, JFC = 9.8 Hz), 89.6, 115 (t, JFC = 285.5 Hz), 127.9, 129.8,
General Procedure of Retro-Diels–Alder Reaction of Compound 2:
A sample containing 2a (50 mg, 0.147 mmol) and tert-butyl alcohol
(0.1 mL) was stirred in a 5-mL sealed tube at 100 °C for 8 h. The
heating was then stopped and the product was purified by flash
chromatography (petroleum ether/ethyl acetate, 10:1) to yield 1a
(29 mg, 57%).
136.4, 138.6, 138.9, 144.8 ppm. IR (film): ν = 3026, 2970, 1597,
˜
1471, 1435, 1391, 1319, 1303, 1293, 1262, 1207, 1143, 1111, 1187,
1007 cm–1. MS (ESI): m/z = 405.0[M + Na+]. Anal. HRMS (ESI)
calcd. for C20H25F2O3S H+: 383.1487; found 383.1490.
2j: Yield 72%, solid, m.p. 157–158 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.28 (s, 3 H), 1.83 (dd, J = 8.4, J = 5.4 Hz, 1 H), 2.45
(s, 3 H), 3.67 (dd, J = 12.7, J = 8.2 Hz, 1 H), 3.78 (dd, J = 12.7, J
= 5.4 Hz, 1 H), 3.49 (s, 1 H), 4.84 (s, 1 H), 6.57 (d, J = 5.7 Hz, 1
H), 6.73 (dd, J = 5.7, J = 1.6 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 2 H),
7.76 (d, J = 8.1 Hz, 2 H) ppm. 19F NMR (282 MHz, CDCl3): δ =
–141.0 (d, J = 152 Hz 1 F), –149.7 (dd, J = 150 Hz, 1 F) ppm. IR
Acknowledgments
We thank the Chinese Academy of Sciences (Hundreds of Talents
Program) and the National Natural Science Foundation for finan-
cial support.
(film): ν = 3480, 3091, 2995, 2972, 2933, 2916, 1596, 1487, 1465,
˜
1434, 1319, 1307, 1291, 1203, 1189, 1145, 1099, 1089, 1077, 1062,
1054, 1002 cm–1. MS (ESI): m/z = 388.2 [M + NH4+]. C18H20F2O4S
(370.10): calcd. C 58.37, H 5.44; found C 58.36, H 5.23.
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2k: Yield 75%, solid, m.p. 145–147 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.10–1.48 (m, 2 H), 1.57–1.88 (m, 8 H), 2.47 (s, 3 H),
3.62–3.70 (dd, J = 12.8, J = 8.3 Hz, 1 H), 3.72–3.82 (dd, J = 12.8,
J = 5.3 Hz, 1 H), 3.47 (s, 1 H), 4.91 (s, 1 H), 6.52–6.57 (d, J =
5.8 Hz, 1 H), 6.66–6.70 (dd, J = 5.7, J = 1.5 Hz, 1 H), 7.35–7.39
(d, J = 8.3 Hz, 2 H), 7.74–7.79 (d, J = 8.4 Hz, 2 H) ppm. 19F NMR
(282 MHz, CDCl3): δ = –143.2–142.7 (d, J = 152 Hz 1 F), –150.3–
149.7 (dd, J = 151, J = 5.8 Hz 1 F) ppm. IR (film): ν = 3545, 3486,
˜
3086, 2977, 2926, 2856, 1923, 1598, 1470, 1457, 1444, 1399, 1312,
1306, 1293, 1192, 1161, 1141, 1086, 1052, 1014 cm–1. MS (ESI):
m/z = 428.2 [M + NH4+]. C21H24F2O4S (410.14): calcd. C 61.45,
H 5.89; found C 61.51, H 5.89.
Eur. J. Org. Chem. 2008, 1101–1106
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1105

X.-C. Hang, Q.-Y. Chen, J.-C. Xiao
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Received: October 19, 2007
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1106
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