Cycloaddition reactions of β-trifluoroacetylvinyl ethers

Article abstract of DOI:10.1016/S0040-4020(03)00344-2

β-Trifluoroacetyl vinyl ethers ROCH = CHCOCF₃ react smoothly as dienophiles with α,β-unsaturated carbonyl compounds to give the unexpected 2-alkoxyl-5-trifluoroacetyl-3,4-dihydro-2H pyrans. These products are formed by elimination and addition of the alcohol to the products of the normal hetero Diels-Alder reaction (2-alkoxyl-3-trifluoroacetyl-2,3-dihydro-2H pyrans). In contrast, 1,3-dipolar cycloaddition of ROCH = CHCOCF₃ with ArCH = N(O)Me proceeds via a Z-endo transition state to give regio- and stereospecific 4-trifluoroacetyl substituted isoxazolidines and their derivatives.

Full text of DOI:10.1016/S0040-4020(03)00344-2

Tetrahedron 59 (2003) 2899–2905
Cycloaddition reactions of b-trifluoroacetylvinyl ethers
a
a
b
Shizheng Zhu,a Guifang Jin, Weimin Peng and Qichen Huang
,
*
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
bDepartment of Chemistry, Peking University, Beijing 100871, People’s Republic of China
Received 6 November 2002; revised 3 February 2003; accepted 27 February 2003
Abstract—b-Trifluoroacetyl vinyl ethers ROCHvCHCOCF3 react smoothly as dienophiles with a,b-unsaturated carbonyl compounds to
give the unexpected 2-alkoxyl-5-trifluoroacetyl-3,4-dihydro-2H pyrans. These products are formed by elimination and addition of the
alcohol to the products of the normal hetero Diels–Alder reaction (2-alkoxyl-3-trifluoroacetyl-2,3-dihydro-2H pyrans). In contrast, 1,3-
dipolar cycloaddition of ROCHvCHCOCF3 with ArCHvN(O)Me proceeds via a Z-endo transition state to give regio- and stereospecific
4-trifluoroacetyl substituted isoxazolidines and their derivatives. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
b-Trifluoroacetyl vinyl ethers ROCHvCHCOCF3 1 are
potential fluorinated 1,3-dicarbonyl compounds and were
first prepared in 1967. Since then, their preparation and
chemical transformations have been extensively investi-
gated.1 However, their cycloaddition reactions have not
been extensively studied. During our investigations on
pull–push olefins,2 we found that 1 reacted readily as a
dipolarophile with pyridinium or isoquinolinium N-ylides to
give the corresponding 1-trifluoroacetyl substituted
indolizines and their derivatives (Scheme 1).
Scheme 2.
construction of fluorine containing five and six membered
heterocycles, we recently investigated the cycloaddition
reactions of compound 1 such as the hetero Diels–Alder and
the 1,3-dipolar cycloaddition reactions. Herein we report
our results.
Recently, Hojo et al.3 reported reactions of b-(trifluoro-
acetyl)vinyl ether or b,b-bis(trifluoroacetyl)vinyl ether with
electron-rich alkenes such as vinyl ether, or ethyl vinyl
sulfide. Several 6-trifluoromethylated 3,4-dihydro-2H
pyrans were prepared (Scheme 2).
2. Results and discussion
However, the Diels–Alder reaction of compound 1 using as
the dienophiles with the heterodienes has not been studied
until now.
The [2þ4] cycloadditions of 1 with a little excess a,b-
unsaturated aldehydes R1CHvC(R2)CHO 2 (R1,R2¼H,
CH3) were carried out in a sealed glass tube at 1408C
without solvent. A small amount of 2,4-di-tert-butyl-4-
In order to develop the application of compound 1 in the
Scheme 1.
Keywords: b-trifluoroacetyl vinyl ethers; hetero Diels–Alder reaction; 1,3-dipolar cycloaddition; nitrones; trifluoroacetylated isoxazolidines.
*
Corresponding author. Fax: þ86-21-64166128; e-mail: zhusz@pub.soc.ac.cn
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00344-2

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S. Zhu et al. / Tetrahedron 59 (2003) 2899–2905
Scheme 3.
methylphenol (1 mol%) was added to avoid polymerization
of 2. After stirring for 8 h, TLC analysis showed that the
reaction was finished. Separation and purification of the
reaction products were accomplished by fractional distilla-
tion and column chromatography. The pure products were
obtained as yellow oils.
the products as 2-alkoxyl-5-trifluoroacetyl-3,4-dihydron
pyrans (Scheme 3).
For the formation of the products 3, there are two possible
reaction pathways (Scheme 4).
In order to verify the above proposed possibilities, we
carried out the reaction of BuiOCHvCHCOCF3 (1b) with
CH3CHvCHCHO (2b) in CD3OD solvent. After similar
It was surprising that according to the NMR and IR spectra,
the product was not the expected 2-alkoxyl-3-trifluoro-
acetyl-3,4-dihydro-2H pyran. For example, the H NMR
1
treatment,
2-methoxyl-d3-3-deuterium-4-methyl-5-
spectrum of the product 3a has only one alkene proton,
which is a single peak at 7.71 ppm. The chemical shift of the
CF3 group in the 19F NMR spectrum of 3a is 268.5 ppm
indicating that the CF3CO group is bonded to an unsaturated
carbon atom. In the 13C NMR spectrum of 3a, the chemical
shift of double bond carbon atoms are 159.5 ppm (q,
4JC–F¼5.3 Hz) and 111.87 ppm(s), which are very close to
the spectrum of 5-trifluoroacetyl-3,4-dihydron-2H pyran
trifluoroacetyl 3,4-dihydro-2H-pyran 3f as well as the
normal product (2-isobutoxyl-4-methyl-5-trifluoroacetyl
3,4-dihydro-2H-pyran 3d) were obtained. The ratio of
3d/3f is about 3:2 (Scheme 5).
From this result it is clear that the products 3 should come
from an elimination-addition process of the normal Diels–
Alder cycloaddition product. It was noticed that the reaction
of 1a with crotonaldehyde 2b gave a mixture of cis- and
trans-adducts of 2-ethyl-4-methyl-5-trifluoroacetyl-3,4-
dihydro-2H pyran 3b in a ratio of 55:45, according to the
1H NMR spectrum. It was not possible to separate the cis-
and trans-mixtures by preparative TLC. However, when 1
4
[(162.2 ppm (q), JC–F¼5.3 Hz), 111.2 ppm (s)].4 The IR
spectrum of 3a shows strong absorptions at 1613 cm21 and
1683 cm21, which indicate that there is a conjugated
carbonyl group. The other products (3b–e) have similar
NMR and IR spectra. According to these data, we assigned
Scheme 4.
Scheme 5.

S. Zhu et al. / Tetrahedron 59 (2003) 2899–2905
2901
Scheme 6.
Scheme 7.
was treated with 2c, only one product was obtained. Similar
results were also obtained when 1b was reacted with 2b and
2c. The product 3d is a cis/trans isomer mixture, while 3e is
not (Scheme 3). Methyl vinyl ketone 2d reacted similarly
with 1a to give 2-ethoxyl-2-methyl-5-trifluoroacetyl-
dihydro-2H-pyran 3g as the sole product (Scheme 6).
derivatives by the [2þ3] cycloaddition of trifluoremethyl-
ated alkenes with nitrones. However, in many cases these
reactions gave the mixtures of regio- and stereoisomeric
cycloaddition products. An example is shown in Scheme 7.6
The 1,3-dipolar cycloaddition of C-arylnitrones ArCH-
vN(O)Me 4 (Ar¼Ph, 4-CH3C6H4, 4-ClC6H4) with
EtOCHvCHCOCF3 were carried out in toluene at 408C
which is a lower reaction temperature compared to other
similar reactions.7 For example, reaction of ethyl-3-
trifloromethyl cinnamate or 1-trifluormethyl styrene with
4a was reported in refluxing toluene (1408C). The observed
difference in the reactivity between 1 and the above
mentioned dipolarophiles can be attributed to the presence
of the powerful electron-withdrawing CF3CO group. After
stirring for 4 days, TLC analysis showed that the reaction
had finished and only one product was formed. It was found
that the 4-trifluoroacetyl isoxazolidines 5 were easy to
Utilization of 1 and 3 as synthetic intermediates for the
preparation of various CF3 containing compounds with
potential biological activity is now under investigation.
Next, we tried to investigate the 1,3-dipolar cycloaddition of
1 with nitrones. Amongst the 1,3-dipolar reagents, nitrones
have been widely applied in the preparation of
isoxazolidines.
In the past decades, several research groups5 reported the
preparation of trifluoromethylated isoxazolidines and their
Scheme 8.
Scheme 9.

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S. Zhu et al. / Tetrahedron 59 (2003) 2899–2905
between a p-orbital of the nitrogen atom and the p-orbital of
the CvO group.10 Hence, we believe that the [2þ3] dipolar
cycloaddition of 1 with nitrones 4 proceeds via a Z-endo
transition, which minimizes the steric interaction to give
exclusively the 3,4-trans, 4,5-trans product 5 (Scheme 10).
It was noteworthy that when cyclic 3-trifluoroacetyl 2,3-
dihydro-2H furan 8 was reacted with nitrones, a similar
regio- and stereospecific cycloaddition product bicyclo-
isoxazolidine 9 was obtained, accompanied by a small
amount of 4-trifluoroacetyl-5-(N-methylamino)-2,3-di-
hydro-2H furan 10 as by-product. Compound 10 could
arise from the nucleophlic reaction of 8 with MeNHOH,
which could come from the decomposition of 4
(Scheme 11).
The bicycle isoxazodilidine 9 is stable and did not hydrate
during the chromatographic process. In the 19F NMR
Figure 1. The structure of compound 6a.
Scheme 10.
Scheme 11.
hydrate or eliminate to give compounds 6 and 7 during the
purification process by column chromatography on a silica
gel (Scheme 8).
spectra of 9, the chemical shift of the CF3CO group is
271.5 ppm which is more downfield compared with the
products 6 (284.5 ppm) in which the CF3CO group was
hydrated and 7 (274.5 ppm) in which the CF3CO group was
conjugated with a carbon–carbon double bond.
Eguchi and Depons7 reported that 2-trifluoromethyl styrene
reacted with N-methyl C-phenylnitrone to give two stereo-
isomeric cycloaddition products, while 1-ethoxycarbonyl-
3,3,3-trifluoro-propene gave two regioisomers (Scheme 9).
Under similar reaction conditions when 4c was reacted with
8, the only isolated product was 10 and no corresponding
[2þ3] cycloaddition product 9c formed. We repeated this
reaction three times in different solvents (CH3C6H5, C6H6,
CCl4) and different temperatures (40–808C) but all failed to
give 9c. It is difficult to explain why 4c was all decomposed
to HN(Me)OH under these reaction conditions.
However, in our case the [2þ3] cycloaddition gave only one
product (presumed to be 5) according to the TLC analysis of
the reaction mixture. The 1H NMR spectra of 6 have a value
of the coupling constant (8 Hz) between 3-H and 4-H
indicates their trans relationship which was similar to
examples in the literatures.5a,7b The structure of compound 6
was also confirmed by X-ray diffraction analysis of 6a
(Fig. 1).
Table 1. The reaction of the nitrones 4 with the pull–push alkenes 1 or 8
Entry
Reactant
(1 or 8)
Products and yield (%)a
4
6 and 7
Or 9 and 10
It is known that aldonitrones generally exist in the more
stable Z configuration.8 Bjorgo9 also reported that the
N-methyl C-phenylnitrone 4a exists as a mixture of Z and E
isomers at 1478C. Under our reaction conditions (408C),
however, nitrones 4 should react with 1 in their Z form.
Since an electron-withdrawn group (CF3CO) is present in
dipolarophile 1, the endo transition state should be more
favorable, because of the secondary orbital interaction
1
2
3
4
5
6
7
1
1
1
1
8
8
8
4a
4b
4c
4d
4a
4b
4c
6a (38)
6b (40)
6c (43)
6d (18)
9a (36)
9b (28)
7a (16)
7b (17)
7c (13)
7d (6)
10 (5)
10 (15)
10 (30)
a
Isolated yield based on 1 or 8.

S. Zhu et al. / Tetrahedron 59 (2003) 2899–2905
2903
A summary of all the reaction results of the nitrones with the
pull–push alkenes (1 or 8) are listed in Table 1.
CDCl3) 1.22 (3H, t, J¼7.1 Hz, CH3), 1.85, 2.01 (2H, m,
3-H), 2.36 (2H, dd, J¼8.0, 5.4 Hz, 4-H), 3.66 (2H, dq,
J¼12.0, 7.2 Hz, CH3CH2O), 3.89 (1H, dq, J¼12.0, 7.2 Hz,
CH3CH2O), 5.23 (1H, dd, J¼4, 2.6 Hz, 2-H), 7.71 (1H, s,
6-H); dF (282 MHz, CDCl3) 269.0 (3F, s, CF3); dC
(75.3 MHz, CDCl3) 14.5 (CH3CH2O), 14.8 (3-C), 25.4
(4-C), 64.9 (CH3CH2O), 99.1 (2-C), 111.9 (5-C), 116.7 (q,
In summary, some new cycloaddition reaction of b-tri-
fluoroacetyvinyl ethers with alkene and vinyl nitrones have
been developed.
4
JC–F¼282 Hz, CF3), 159.5 (q, JC–F¼5.7 Hz, 6-C),178.8
2
(q, JC–F¼34.2 Hz, CvO); IR (KBr) nmax¼1683, 1613,
3. Experimental
3.1. General
1190, 1143 cm21; MS (m/z, %): 224 (Mþ, 7.16), 205
(Mþ2F, 8.70), 179 (Mþ2OEt, 57.78), 178 (Mþ2EtOH,
35.29), 127 (Mþ2COCF3, 7.67), 72 (C3H4Oþ2 , 63.16), 69
(CFþ3 , 25.75), 44 (COþ2 , 100.00).
Solvents were purified and dried before use. Melting points
were determined on a Mel-Temp apparatus and are
uncorrected. 1H NMR and 19F NMR spectra were recorded
on Varian-360 or Bruker AM-300 instruments with Me4Si
and CFCl3 (with upfield negative) as internal and external
standards respectively; NMR spectra were recorded in
chloroform-d unless otherwise stated. IR spectra were
obtained with a Perkin–Elmer 983G, spectrophotometer
using KBr disks of the compound. Low and high-resolution
mass spectra were obtained on HP 5989a and Finnigan
MAT instruments, respectively. Elemental analyses were
performed by this institute. The X-ray structure analysis was
performed with a Rigaku/AFC 7R Diffractometer
3.1.3. 2-Ethoxyl-3-methyl-5-trifluoroacetyl-3,4-dihydro-
2H pyran 3c. Yield 35%. Yellow oil; dH (300 MHz, CDCl3)
1.00 (3H, d, J¼7.0 Hz, 3-CH3), 1.08 (3H, t, J¼7.2 Hz,
CH3CH2O), 1.23 (3H, d, J¼7.0 Hz, 3-CH3), 1.70–2.49 (3H,
m, 3-H and 4-H), 3.65 (1H, dq, J¼12.0, 7.2 Hz CH3CH2O),
3.83 (1H, dq, J¼12.0, 7.2 Hz, CH3CH2O), 4.78 (1H, d,
J¼5.6 Hz, 2-H), 5.03 (1H, d, 2-H), 7.63 (1H, s, 6-H); dF
(282 MHz, CDCl3) 269.3 (3F, s, CF3); IR (KBr)
nmax¼1683, 1613, 1141, 1100 cm21; MS (m/z, %): 239
(MþH, 3.13), 238 (Mþ, 3.75), 220 (MþH–F, 23.11), 192
(Mþ2OEt, 44.84), 123 (Mþ2EtOH–CF3, 30.77), 97
(CF3COþ, 21.73), 69 (CF3þ, 27.89), 58 (C3H6Oþ2 , 100.00);
HRMS (EI): Mþ, found 238.0838. C10H13F3O3 requires
238.08361.
4-(Ethoxy)-1,1,1-trifluoromethyl-3-en-2-one 1,11a aryl-N-
methyl nitrones 4,11b and 4-trifluoroacetyl-2,3-dihydron-
2H furan 82b were prepared according to the literature
methods.
3.1.4. 2-(3-Methylbutoxyl)-4-methyl-5-trifluoroacetyl-
3,4-dihydro-2H pyran 3d. Yield 39%. Yellow oil,
[Found: C: 54.16; H: 6.36 C12H17F3O3 requires C, 54.14;
H, 6.39%]; dH (300 MHz, CDCl3) 0.91 (3H, d, J¼7.0 Hz,
(CH3)2CH), 0.93 (3H, d, J¼7.0 Hz, (CH3)2CH), 1.15 (3H, d,
J¼7.0 Hz, 4-CH3 cis), 1.24 (3H, d, J¼7.0 Hz, 4-CH3 trans),
1.86–1.95 (2H, m, 3-H), 1.92 (1H, m, (CH3)2CH), 2.75 (m,
4-H, cis), 2.89 (m, 4-H, trans), 3.36 (1H, dd, J¼9.2, 6.9 Hz,
CH2O), 3.71 (1H, dd, J¼9.2, 6.8 Hz, CH2O), 5.14 (1H, d,
J¼5.8 Hz, 2-H, cis), 5.24 (1H, d, J¼7.2 Hz, 2-H trans), 7.68
(1H, s, 6-H); dF (282 MHz, CDCl3) 269.8 (3F, s, CF3); IR
(KBr) nmax¼1686, 1607, 1191, 1141 cm21; MS (m/z, %):
266 (Mþ, 2.43), 197 (Mþ2CF3, 1.86), 193 (Mþ2iBuO,
25.73), 192 (Mþ2iBuOH, 36.49), 123 (Mþ2iBuOH–CF3,
21.43), 95 (Mþ2iBuOH–CF3CO, 8.43), 57 (C4Hþ9 ,
100.00).
3.1.1. General reaction procedure for the Diels–Alder
reaction of 1 with a,b-unsaturated carbonyl compounds.
A mixture of 1a (1.96 g, 10 mmol), 2b (1.05 g, 15 mmol)
and 2,6-di-tert-butyl-4-methylphenol (0.44 g) in a sealed
glass tube was heated at 1408C and stirred for 8 h. The crude
product was distilled out under vacuum, then purified by
column chromatography using ethyl acetate and pentane
(1:60) as eluent to give 2-ethoxyl-4-methyl-5-trifluoro-
acetyl-3,4-dihydro-2H pyran 3b (0.9 g, 40%) which is a
trans and cis mixture (3:4); yellow oil, [Found: C, 50.28; H,
5.30 C10H13F3O3 requires C, 50.42; H, 5.50%]; dH
(300 MHz, CDCl3) 1.16 (3H, d, J¼7.2 Hz, 4-CH3), 1.22
(3H, t, J¼7.2 Hz, CH3CH2O), 1.28 (3H, d, J¼7.2 Hz,
4-CH3), 1.88 (2H, m, 3-H), 1.95 (2H, m, 3-H), 2.76 (1H, m,
4-H), 2.90 (1H, m, 4-H), 3.66 (1H, dq, J¼12.0, 7.2 Hz,
CH3CH2O), 3.90 (1H, dq, J¼12.0, 7.2 Hz CH3CH2O), 5.17
(1H, t, J¼5.7 Hz, 2-H), 5.27 (1H, t, J¼3.0 Hz, 2-H), 7.69
(1H, s, 6-H); dF (282 MHz, CDCl3) 268.3 (3F, s, CF3); dC
(75.3 MHz, CDCl3) 15.0 (CH3CH2O), 19.5, 20.1 (4-CH3),
22.2, 23.5 (3-C), 32.7, 33.8 (4-C), 65.1, 65.2 (CH3CH2O),
99.3, 99.5 (2-C), 116.1, 116.7 (5-C), 116.8 (q,
3.1.5. 2-(3-Methylbutoxyl)-3-methyl-5-trifluoroacetyl-
3,4-dihydro-2H pyran 3e. Yield 36%. Yellow oil; dH
(300 MHz, CDCl3) 0.89 (6H, d, J¼6.4 Hz, 2-CH3), 1.09
(3H, d, J¼6.6 Hz, 3-CH3), 1.89 (1H, m, (CH3)2CH), 1.91–
2.07 (1H, m, 3-H), 2.10 (1H, m, 4-H), 2.40 (1H, m, 4-H),
3.34 (1H, d, J¼6.9 Hz, CH2O), 3.68 (1H, d, J¼6.6 Hz,
CH2O), 5.04 (1H, s, 2-H), 7.68 (1H, s, 6-H); dF (282 MHz,
CDCl3) 269.3 (3F, s, CF3); dC (75.3 MHz, CDCl3) 15.7 (3-
CH3), 19.1 ((CH3)2CH), 22.0 ((CH3)2CH), 28.5 (3-C), 30.3
(4-C), 76.1 (CH2O), 101.9 (2-C), 112.4 (5-C), 113.9 (q,
1
1JC–F¼282 Hz, CF3), 158.9, 159.8 (q, JC–F¼5.5 Hz,
2
6-C), 178.8 (q, JC–F¼32 Hz, CvO); IR (KBr)
nmax¼1683, 1611, 1191, 1142 cm21; MS (m/z, %): 238
(Mþ, 8.36), 220 (MþH2F, 36.10), 205 (MþH2F–CH3,
99.84), 192 (Mþ2EtOH, 29.63), 123 (Mþ2EtOH–CF3,
72.92), 97 (CF3COþ, 19.85), 69 (CF3þ, 24.10), 57 (C3H5Oþ,
100.00).
4
1JC–F¼280 Hz, CF3), 159.0 (q, JC–F¼5.7 Hz, 6-C), 179.2
(q, 2JC–F¼32 Hz, CvO); IR (KBr) nmax¼1683, 1614, 1101,
1064 cm21; MS (m/z, %): 266 (Mþ, 2.43), 197 (Mþ2CF3,
1.86), 193 (Mþ2iBuO, 25.73), 192 (Mþ2iBuOH, 36.49),
123 (Mþ2iBuO–CF3, 21.43), 96 (Mþ2iBuOH– COCF3,
4.95), 57 (C4Hþ9 , 100.00); HRMS (EI): Mþ, found
266.11298. C12H17F3O3 requires 266.11162.
3.1.2. 2-Ethoxyl-5-trifluoroacetyl-3,4-dihydro-2H pyran
3a. Yield 46%. Yellow oil, [Found: C, 48.17; H, 4.88
C9H11F3O3 requires C, 48.22; H, 4.95%]; dH (300 MHz,

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S. Zhu et al. / Tetrahedron 59 (2003) 2899–2905
3.1.6. 2-Ethoxyl-2-methyl-5-trifluoroacetyl-3,4-dihydro-
2H pyran 3g. Yield 30%. Yellow oil; dH (300 MHz, CDCl3)
1.35 (3H, t, J¼7.1 Hz, CH3CH2O), 2.14 (3H, s, 2-CH3),
2.21–2.58 (4H, m, 3-H and 4-H), 4.20 (2H, q, J¼7.1 Hz,
CH3CH2O), 7.52 (1H, s, 6-H); dF (282 MHz, CDCl3) 270.3
reflections were monitored after every 100 reflections, but
no significant decay was found. The structure was solved by
a direct method. All non-hydrogen atoms were positioned
and anisotropic thermal parameters refine from 4639
reflections by a full-matrix least-squares technique to
R¼0.055 (for 3930 observed reflections with F.4s (F))
and R¼0.087 (for all). The calculations were performed on a
PC computer with SHELXS 97 programs. Atomic scattering
factors were taken from the International Tables for X-ray
Crystallography (1974, vol. IV). Crystallographic data
(excluding structure factors) for the structure in this paper
have been deposited with the Cambridge Crystallographic
Data Center as supplementary publication numbers CCDC
202097.
(3F, s, CF3); IR (KBr) nmax¼1680, 1605, 1195, 1140 cm21
;
MS (m/z, %): 239 (Mþþ1, 100.00), 193 (Mþ2OEt, 39.01),
123 (Mþ2EtOH–CF3, 4.75), 69 (CFþ3 , 4.47), 43 (C2H3Oþ,
24.99); HRMS (EI): Mþ, found 238.08228. C10H13F3O4
requires 238.08168.
3.1.7. 2-Methoxyl-d3-3-deuterium-4-methyl-3,4-di-
hydro-2H pyran 3f. Yield 16%. Yellow oil; dH
(300 MHz, CDCl3) 1.15 (3H, d, J¼5.7 Hz, 4-CH3, cis),
1.22 (3H, d, J¼7.2 Hz, 4-CH3, trans), 1.85–1.97 (1H, m,
3-H), 2.76 (1H, q, J¼4.8 Hz, 4-H, cis), 2.91 (1H, q,
J¼6.0 Hz, 4-H, trans), 5.08 (1H, d, J¼5.4 Hz, 2-H, cis),
5.14 (1H, d, J¼5.7 Hz, 2-H, trans), 7.69 (1H, s, 6-H); dF
(282 MHz, CDCl3) 269.1 (s, CF3); IR (KBr) n¼1680, 1615,
1183, 1141 cm21; MS (m/z, %): 209 (Mþ2F, 83.73), 194
(Mþ2CD3O, 22.29), 159 (Mþ2CF3, 1.81), 131
(Mþ2COCF3, 1.82), 97 (COCF3, 24.10), 69 (CF3,
100.00); HRMS (EI): Mþ2F, found 209.09273.
C9H7D4F2O3 requires 209.09440.
3.3.1. 2-(N-Methyl)-3-phenyl-4-(trifluoroacetyl) isoxa-
zole 7a. Yellow oil; dH (300 MHz, CDCl3) 2.63 (3H, s,
NCH3), 4.53 (1H, s, 3-H), 6.93 (5H, s, C6H5), 7.43 (1H, s,
5-H); dF (282 MHz, CDCl3) 274.0 (3F, s, CF3); IR (KBr)
nmax¼3066, 1672, 1595, 1195–1120 cm21; MS (m/z, %):
257 (Mþ, 33.08), 188 (Mþ2CF3, 8.10), 180 (Mþ2Ph,
100.00), 160 (Mþ2COCF3, 42.68), 77 (C6Hþ5 , 25.19);
HRMS (EI): Mþ, found 257.06255. C12H10F3O2N requires
257.06636.
3.2. General procedure for the reaction of the nitrone
with 1
3.3.2. 2-(N-Methyl)-3-(4-methoxylphenyl)-4-(1,1-di-
hydroxyl-2,2,2-trifluoroethyl)-5-ethoxyl-isoxazolidine
6b. White solid; mp 97–988C, [Found: C, 51.43; H, 5.67; N,
3.91 C15H20F3O5N requires C, 51.28; H, 5.74; N, 3.99%];
dH (300 MHz, CDCl3) 1.19 (3H, t, J¼7.0 Hz, CH3CH2O),
2.42 (3H, s, N–CH3), 3.04 (1H, d, J¼8.0 Hz, 3-H), 3.26
(2H, s, 2OH), 3.47 (1H, m, 4-H), 3.74 (2H, q, J¼7.0 Hz,
CH3CH2O), 3.76 (3H, s, OCH3), 5.24 (1H, d, J¼1.5 Hz,
5-H), 6.85 (2H, AB, J¼8.0 Hz, ArH), 7.34 (2H, AB,
J¼8.0 Hz, ArH); dF (282 MHz, CDCl3) 284.8 (3F, s, CF3);
IR (KBr) nmax¼3342, 2938, 1612, 1349–1300, 1200–
1000 cm21; MS (m/z, %): 333 (Mþ2H2O, 16.27), 287
(Mþ2H2O–OEt, 6.33), 164 (CH3OC6H4CvN(Me)Oþ,
100.00), 77 (C6Hþ5 , 9.91).
4-(Ethoxy)-1,1,1-trifluoromethyl-3-en-2-one 1 (0.5 g,
3 mmol) was added into a 25 mL flask containing a solution
of phenyl-N-methyl nitrone 4a (0.41 g, 3 mmol) and toluene
(10 mL). This reaction mixture was stirred at 408C for 4
days, TLC analysis showed that the reaction finished. After
removal of solvent, the residue obtained was separated and
purified by column chromatography using ethyl acetate and
pentane (1:10) as elute to give the two pure products 6a
(0.35 g, solid) and 7a (0.15 g, oil).
3.2.1. 2-(N-Methyl)-3-phenyl-4-(1,1-dihydroxyl-2,2,2-tri-
fluoroethyl)-5-ethoxyl-isoxazolidine 6a. White solid mp
95–978C, [Found: C, 52.39; H, 5.67; N, 4.23 C14H18F3O4N
requires C, 52.34; H, 5.65; N, 4.36%]; dH (300 MHz,
CDCl3) 1.16 (3H, t, J¼7.1 Hz, CH3CH2O), 2.40 (3H, s,
NCH3), 3.06 (1H, d, J¼8.0 Hz, 3-H), 3.11 (2H, s, 2OH),
3.46 (1H, dd, J¼8.0, 2.1 Hz, 4-H), 3.75 (2H, q, J¼7.2 Hz,
CH3CH2O), 5.24 (1H, d, J¼2.1 Hz, 5-H), 7.0 (5H, m,
C6H5); dF (282 MHz, CDCl3) 285.0 (s, CF3); IR (KBr)
nmax¼3286, 2974, 1605, 1200–1000 cm21; MS (m/z, %):
321 (Mþ, 1.57), 303 (Mþ2H2O, 8.33), 257 (Mþ2EtOH–
H2O, 11.54), 160 (Mþ2EtOH–H2O–CF3CO, 7.41), 135
(C6H5CHvNþ(Me)O, 60.13), 134 (C6H5CþvN(Me)O,
100.00), 77 (C6Hþ5 , 10.55).
3.3.3. 2-(N-Methyl)-3-(methoxylphenyl)-4-(trifluoro-
acetyl)-isoxazole 7b. Yellow oil; dH (300 MHz, CDCl3)
2.43 (3H, s, NCH3), 3.70 (3H, s, OCH3), 4.60 (1H, s, 3-H),
6.93 (2H, AB, J¼8.0 Hz, ArH), 7.34 (2H, AB, J¼8.0 Hz,
ArH), 7.46 (1H, s, 5-H); dF (282 MHz, CDCl3) 274.5 (3F, s,
CF3); IR (KBr) nmax¼2481, 1680, 1598, 1190–1120 cm21
;
MS (m/z, %): 287 (Mþ, 17.51), 190 (Mþ2CF3CO, 12.03),
180 (Mþ2Ar, 39.42), 135 (Mþ2Ar–NOMe, 100.00);
HRMS (EI): Mþ, found 287.07463. C13H12F3O3N requires
287.07693.
3.3.4. 2-(N-Methyl)-3-phenyl-4-(1,1-dihydroxyl-2,2,2-tri-
fluoroethyl)-5-ethoxyl-isoxazolidine 6c. White solid mp
97–1008C, [Found: C, 53.59; H, 6.02; N, 3.89
C15H20F3O4N requires C, 53.73; H, 6.01; N, 4.18%]; dH
(300 MHz, (CD)2CO) 1.19 (3H, t, J¼8.0 Hz, CH3CH2O),
2.28 (3H, s, Ar-CH3), 2.43 (3H, s, N–CH3), 3.06 (1H, d,
J¼7.0 Hz, 3-H), 3.38 (2H, s, 2OH), 3.44 (1H, m, 4-H), 3.76
(2H, q, J¼8.0 Hz, CH3CH2O), 5.25 (1H, d, J¼1.0 Hz, 5-H),
7.10 (2H, AB, J¼8.0 Hz, ArH),7.31 (2H, AB, J¼8.0 Hz,
ArH); dF (282 MHz, (CD)2CO) 284.5 (s, CF3); IR (KBr)
nmax¼3256, 2976, 1519, 1200–1136, 1075–974,
809 cm21; MS (m/z, %): 335 (Mþ, 2.91), 317 (Mþ2H2O,
3.3. Crystal structure data of compound 6a
C14H18NO4F3 MW¼321.3, monoclinic, space group Cc,
˚
a¼20.754(3), b¼10.690(1), c¼14.243(2) A, b¼90.93(1)8,
3
˚
V¼3159.5(7) A , Z¼8 (two molecules in asymmetric unit),
Dc¼1.351 g/cm3. F(000)¼1344.0, l (Mo Ka)¼0.71369,
crystal size¼0.1£0.4£0.3 mm3. Intensity data were
collected at 208C with a Sciemens P4 diffractometer, and
employing v/2u scanning technique, in the range of
21#h#26, 213#k#1, 218#l#18. Three standard

S. Zhu et al. / Tetrahedron 59 (2003) 2899–2905
2905
10.99),
226
(Mþ2C7Hþ7 –H2O,
4.86),
148
(EI): Mþ2OCH3–CH3, found 285.06339. C13H10F3O3N:
285.05993.
(ArCvN(Me)Oþ, 100.00), 91 (C7Hþ7 , 37.60), 77 (C6Hþ5 ,
4.79).
3.3.10. 2-Methylamino-3-trifluoroacetyl-4,5-dihydro-
furan 10. [Found: C, 43.00; H, 4.09; N, 7.02 C7H8F3O2N
requires C, 43.08; H, 4.10; N, 7.18%]; dH (300 MHz,
CDCl3) 3.03 (3H, d, J¼5.0 Hz, NHCH3), 3.12 (2H, t,
J¼8.0 Hz, CH2CH2O), 4.60 (2H, t, J¼8.0 Hz, CH2CH2O),
9.35 (1H, s, NH); dF (282 MHz, CDCl3) 274.8 (3F, s, CF3);
IR (KBr) nmax¼3200, 2970, 1672, 1599 cm21; MS (m/z, %):
195 (Mþ, 75.78), 126 (Mþ2CF3, 100.00), 97 (CF3COþ,
13.48), 69 (CF3, 54.84).
3.3.5. 2-(N-Methyl)-3-benzyl-4-(trifluoroacetyl)-isoxa-
zole 7c. Yellow oil; dH (300 MHz, CDCl3) 2.05 (3H, s,
CH3C6H4), 2.46 (3H, s, NCH3), 4.63 (1H, s, 3-H), 6.90 (4H,
m, ArH), 7.43 (1H, s, 5-H); dF (282 MHz, CDCl3) 274.0
(3F, s, CF3); IR (KBr) nmax¼1672, 1594, 1190–1120 cm21
;
MS (m/z, %): 272 (Mþþ1, 57.53), 271 (Mþ, 50.79), 180
(Mþ2C7H7, 100.00), 174 (Mþ2COCF3, 16.23), 91 (C7Hþ7 ,
16.73); HRMS (EI): Mþ, found 271.08101. C13H12F3O2N
requires 271.08201.
3.3.6. 2-(N-Methyl)-3-(4-chlorophenyl)-4-(1,1-di-
hydroxyl-2,2,2-trifluoroethyl)-5-ethoxyl-isoxazolidine
6d. White solid mp 97–998C; dH (300 MHz, CDCl3) 1.23
(3H, t, J¼8.0 Hz, CH3CH2O), 1.60 (2H, broad, 2OH), 2.60
(3H, s, N–CH3), 3.58 (1H, dd, J¼8.0 Hz, 4-H), 3.80 (1H, d,
J¼7.0 Hz, 3-H), 3.85 (2H, q, J¼8.0 Hz, CH3CH2O), 5.23
(1H, d, J¼1.5 Hz, 5-H), 7.35 (4H, AB, ArH); dF (282 MHz,
CDCl3) 278.8 (3F, s, CF3); IR (KBr) nmax¼3250, 1590,
1490, 1200–1090, 1050 cm21; MS (m/z, %): 339/337
(Mþ2H2O, 12.40/33.80), 293/291 (Mþ2H2O–EtOH,
4.04/10.21), 226/264 (Mþ2EtOH–N(Me)O, 7.67/22.66),
248/246 (Mþ2EtOH–N(Me)O–H2O, 2.26/6.55), 168
(Mþ2H2O–C7H8ClNO, 100.00); HRMS (EI): Mþ, found
337.07074. C14H17F3O4NCl requires 337.07194.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NNSFC) (No. 20032010, 20072049)
and the Innovation Foundation of Chinese Academy of
Sciences for financial support.
References
1. (a) Germs, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine
Chem. 1994, 69, 195. (b) Zhu, S. Z.; Qin, C. Y.; Wang, Y. L.;
Chu, Q. L. J. Fluorine Chem. 1999, 99, 183. (c) Song, L. P.;
Chu, Q. L.; Zhu, S. Z. J. Fluorine Chem. 2001, 107, 107–112.
(d) Gambaryan, N. P.; Simonyan, L. A.; Petrovskii, P. V. Izv
Akad Nauk SSSR Ser Khim 1967, 918. (e) Hojo, M.; Masuda,
R.; Kokuryo, Y.; Shioda, H.; Matsuo, S. Chem. Lett. 1976,
499. (f) Gerus, I. I.; Gorbunova, M. G.; Vdovenko, S. I.;
Yagupolskii, Y. L.; Kukhar, V. P. Zh. Org. Khim. 1990, 26,
1877. (g) Vdovenko, S. I.; Gerus, I. I.; Gorbunova, M. G.
J. Chem. Soc. Perkin Trans. 2 1993, 559. (h) Gorbunova,
M. G.; Gerus, I. I.; Kukhar, V. P. J. Fluorine Chem. 1993, 65,
25.
3.3.7. 2-(N-Methyl)-3-(4-chlorophenyl)-4-(trifluoro-
acetyl)-isoxazole 7d. Yellow oil; dH (300 MHz, CDCl3)
3.00 (3H, s, NCH3), 5.05 (1H, s, 3-H), 7.35 (4H, m, ArH),
7.83 (1H, s, 5-H); dF (282 MHz, CDCl3) 274.5 (3F, s, CF3);
IR (KBr) nmax¼3069, 1675, 1598, 1190–1110 cm21; MS
(m/z, %): 293/291 (Mþ, 5.42/16.20), 224/222 (Mþ2CF3,
3.45/12.32), 196/194 (Mþ2COCF3, 15.68/48.42), 180
(Mþ2C6H4Cl, 100.00); HRMS (EI): Mþ, found
291.06457. C12H9F3O2ClN requires 291.06836.
2. (a) Zhu, S. Z.; Qin, C. Y.; Xu, G. L. Tetrahedron Lett. 1998,
39, 5265. (b) Zhu, S. Z.; Xu, G. L.; Qin, C. Y.; Chu, Q. L.; Xu,
¨
Y. Monatshefte fur Chem. 1999, 130, 671.
3.3.8. Tetrahydrofurano-[4,5-d]-2-methyl-3-phenyl-8-
trifluoroacetyl-isoxazolidine 9a. White solid mp 110–
1128C, [Found: C, 55.74; H, 7.67; N, 4.44 C14H14F3O3N
requires C, 55.82; H, 4.68; N, 4.65 %]; dH (300 MHz,
CDCl3) 1.93 (1H, m, 4-H), 2.25 (1H, m, 4-H), 2.65 (3H, s,
N–CH3), 4.20 (1H, m, 5-H), 4.23 (1H, s, 3-H), 4.43 (1H,
dd, 5-H), 5.93 (1H, s, 7-H), 7.40 (5H, m, C6H5); dF
(282 MHz, CDCl3) 272.0 (3F, s, CF3); IR (KBr)
nmax¼1741, 1582–1491, 1230–1125, 1018 cm21; MS
(m/z, %): 301 (Mþ, 13.77), 256 (Mþ2N(Me)O, 1.51), 135
(C6H5CHvN(Me)Oþ, 57.47), 134 (C6H5Cþ–N(Me)Oþ,
100.00), 77 (C6Hþ5 , 0.75).
3. (a) Hojo, M.; Masuda, R.; Okada, E. Synthesis 1989, 215.
(b) Hojo, M.; Masuda, R.; Okada, E. Synthesis 1990, 347.
4. Zhu, S. Z.; Xu, G. L.; Qin, C. Y.; Chu, Q. L.; Xu, Y.
¨
Monatshefte fur Chem. 1999, 130, 671.
5. (a) Tsuge, H.; Okano, T.; Eguchi, S. J. Chem. Soc. Perkin
Trans. 1 1995, 2761. (b) Bravo, P.; Bruche, L.; Mele, A.;
Zecchi, G. J. Chem. Res. (s) 1991, 81. (c) Begue, J. P.; Bonnet-
Depons, D.; Legceux, T. J. Chem. Soc. Perkin Trans. 1 1991,
2888.
6. Tanaka, K.; Mori, T.; Mitsukashi, K. Bull. Chem. Soc. Jpn
1993, 66, 263.
7. (a) Eguchi, T.; Aoyama, T.; Kakinuma, K. Tetrahedron Lett.
1992, 33, 5545. (b) Bonnet-Depons, D.; Begue, J. P.; Legueux,
T.; Ourevitch, M. Tetrahedron 1996, 52, 59.
8. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New
York, 1984.
3.3.9. Tetrahydrofurano-[4,5-d]-2-methyl-3-(4-meth-
oxylphenyl)-8-trifluoroacetyl-isoxazolidine 9b. Oil. dH
(300 MHz, CDCl3) 1.93 (1H, m, 4-H), 2.15 (1H, m, 4-H),
2.63 (3H, s, N–CH3), 3.80 (3H, s, OCH3), 4.20 (2H, s,
CH2O), 4.33 (1H, s, 3-H), 5.90 (1H, s, 7-H), 7.34 (5H, m,
C6H5); dF (282 MHz, CDCl3) 271.5 (3F, s, CF3); IR (KBr)
nmax¼1740, 1580, 1250–1167, 1091 cm21; MS (m/z, %):
312 (MþH, 5.92), 311 (Mþ, 9.31), 266 (MþH–OCH3–CH3,
3.26), 165 (CH3OC6H4CHvN(Me)O, 100.00), 164 (CH3-
OC6H4CvN(Me)Oþ, 99.89), 97 (CF3COþ, 9.26); HRMS
9. Bjorgo, J.; Boyd, D. R.; Neill, D. C. J. Chem. Soc. Chem.
Commun. 1974, 478.
10. Joucla, M.; Hamelin, J. J. Chem. Res. (S) 1978, 276.
11. (a) Gorbunova, M. G.; Gerus, I. I.; Kukhar, V. P. J. Fluorine
Chem. 1993, 65, 25. (b) Shindo, H.; Umezawa, B. Chem.
Pharm. Bull. 1962, 10, 492.