An unexpected highly diastereoselective double Baylis-Hillman reaction of per- (or poly)fluorophenyl aromatic aldimines with methyl vinyl ketone

Article abstract of DOI:10.1016/j.tet.2005.01.130

Aza-Baylis-Hillman reaction of per- (or poly)fluorophenyl aromatic aldimines 1 with methyl vinyl ketone (MVK) was studied. It was found that both the used Lewis base and solvent can significantly affect the reaction. Using triphenylphosphine as a Lewis ba

Full text of DOI:10.1016/j.tet.2005.01.130

Tetrahedron 61 (2005) 3841–3851
An unexpected highly diastereoselective double Baylis–Hillman
reaction of per- (or poly)fluorophenyl aromatic aldimines with
methyl vinyl ketone
a,
b
Xinyuan Liu,a Jinwei Zhao,a Guifang Jin,a Gang Zhao,a, Shizheng Zhu and Shaowu Wang
*
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin lu,
Shanghai 200032, People’s Republic of China
bCollege of Chemistry and Materials Science, Anhui Normal University, Wuhu, 241000, People’s Republic of China
Received 4 November 2004; revised 27 January 2005; accepted 28 January 2005
Abstract—Aza-Baylis–Hillman reaction of per- (or poly)fluorophenyl aromatic aldimines 1 with methyl vinyl ketone (MVK) was studied. It
was found that both the used Lewis base and solvent can significantly affect the reaction. Using triphenylphosphine as a Lewis base, the
reaction of 1 with MVK proceeded smoothly to give the normal Baylis–Hillman adduct 2 along with the double Baylis–Hillman adduct 3 as
by-product in THF. When 1,4-diazabicyclo[2.2.2]octane was used as a Lewis base in DMF, the aza-Baylis–Hillman reaction of 1 with MVK
gave the double aza-Baylis–Hillman adduct 3 exclusively in moderate to good yields with excellent diastereoselectivities. The double
Baylis–Hillman adduct 3 was conveniently converted to fluorine-containing 4-alkylidene-2-cyclohexen-1-ones under mild reaction
conditions in good yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
yields. While using methyl vinyl ketone (MVK) as the
active olefin, no such double aza-Baylis–Hillman reaction
product could be formed at all (Scheme 2).4 As part of our
ongoing projects in fluorooganic chemistry,5 we examined
the Baylis–Hillman reaction of per- (or poly)fluorophenyl
aromatic aldimines with MVK in the presence of different
Lewis bases, and found that the double Baylis–Hillman
reaction product could be exclusively formed with high
diastereoselectivity in the presence of 1,4-diazabicyclo-
[2.2.2]octane (DABCO).
Mild and selective carbon–carbon bond formations rep-
resent one of the major challenges in organic synthesis. In
the same perspective, atom-economic reactions become
more and more a need and a requirement.1 One of the
carbon–carbon bond forming reaction which fulfills the
above criteria is the Baylis–Hillman reaction.2,3 In this
transformation, Michael acceptors are coupled with
aldehydes to form highly functionalized a-methylene-b-
hydroxycarbonyl compounds (Scheme 1).
Scheme 1.
Scheme 2.
Previously, Shi and co-workers reported that, in the reaction
of sulfonated imines with phenyl vinyl ketone catalyzed by
DABCO, the highly diastereselective double aza-Baylis–
Hillman reaction products were formed in moderate to good
It is well known that the biological properties of medicinal
compounds can often be influenced by fluorine substi-
tution.6 The physical properties of several electronic and
optical devices also depend immensely on the structure of
fluoroorganic molecules.7 Fluorine substitution provides
organic chemists with an opportunity to study an extreme
case of electronic effect in reactions.6,7 Herein we report an
unexpected highly diastereoselective double Baylis–
Keywords: Per- (or poly)fluorophenyl aromatic aldimines; Lewis base;
Baylis–Hillman reactions; Methyl vinyl ketone.
*
Corresponding authors. Tel.: C86 21 64166128; fax: C86 21 64166128;
e-mail: zhusz@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.130

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X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
Hillman reaction of per- (or poly)fluorophenyl aromatic
aldimines with methyl vinyl ketone (MVK).
adduct 2a or 3a, but only 1a by itself decomposed in the
presence of stronger Lewis base such as tri-n-butyl-
phosphine (PBu3) to provide a mixture of compounds
(Table 1, entry 8). On the other hand, using DMAP, Et3N or
Me2S, no reaction occurred under the same reaction
conditions due to their low catalytic activity as a Lewis
base to initiate the aza-Baylis–Hillman reaction (Table 1,
entries 9–11). Thus, PPh3 is the best Lewis base for this
version of normal aza-Baylis–Hillman reaction in THF,
while DABCO is the best Lewis base for this version of
double aza-Baylis–Hillman reaction in DMF. Moreover, on
the basis of the 1H, 19F and 13C NMR spectroscopic data and
X-ray diffraction analysis, we were pleased to find that, in
this aza-Baylis–Hillman reaction, the double aza-Baylis–
Hillman reaction product 3a was formed diastereo-
selectively in the anti-configuration (Fig. 1).
2. Results and discussion
The promoters and solvents for the aza-Baylis–Hillman
reaction of N-pentafluorophenyl-pentafluorophenyl
aldimine (1a) with methyl vinyl ketone were systematically
examined first, and the results were summarized in Table 1.
We found that every parameter, such as solvent and catalyst
influenced the reaction of N-pentafluorophenyl-pentafluoro-
phenyl aldimine (0.5 mmol) with MVK (1 mmol)
drastically (Scheme 3; Table 1). Using 20 mol % of
triphenylphosphine as a Lewis base in THF, the reaction
proceeded very well to give the normal aza-Baylis–Hillman
adduct 2a as a major product in good yield (Table 1, entry
1). In DMF and CH2Cl2, the corresponding normal aza-
Baylis–Hillman adduct 2a was obtained in 63% and 48%
yield along with the double aza-Baylis–Hillman adduct 3a
in 27 and 31% yield, respectively (Table 1, entries 2 and 3).
In CH3CN, the aza-Baylis–Hillman reaction of N-penta-
fluorophenyl-pentafluorophenyl aldimine with MVK was
sluggish because of the poor solubility of 1a in the reaction
media (Table 1, entry 4). For the influence of Lewis bases, a
variety of Lewis base catalysts (20 mol %) were also
screened. The use of tertiary amines such as 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) as a Lewis base gave the
corresponding normal aza-Baylis–Hillman adduct in low
yield along with many unidentified products (Table 1, entry
5). While using DABCO (20 mol %) as a Lewis base in
DMF, we delightfully found that the double aza-Baylis–
Hillman adduct 3a was formed exclusively in good yield
(Table 1, entry 7). In contrast to other Lewis base, no
reaction of 1a with MVK occurred to give the corresponding
In Tables 2 and 3, the results of the aza-Baylis–Hillman
reaction of per- (or poly)fluorophenyl aromatic aldimines
with methyl vinyl ketone in the presence of Lewis bases
PPh3 and DABCO were summarized, respectively.
The other per- (or poly)fluorophenyl aromatic aldimines
(1b–1k) (0.5 mmol) could react with MVK (1 mmol)
smoothly in the presence of Lewis base PPh3 under the
optimized reaction conditions to give the corresponding
normal aza-Baylis–Hillman adducts 2b–2k and the double
Baylis–Hillman adducts 3b–3h in excellent to moderate
yields; while the product ratio was dependent on electronic
features of aryl substituents of the corresponding imines
(Table 2). The aza-Baylis–Hillman adducts 2 and double
Baylis–Hillman adducts 3 were formed in good yields in the
reaction of MVK with imines with an electron-withdrawing
group on the benzene ring (Table 2, entries 4–9), whereas an
electron-donating substituent lowered the yields (entries
Table 1. Results of aza-Baylis–Hillman reactions of N-pentafluorophenyl-pentafluorophenyl aldimine with MVKa
Entry
Lewis base
Solvent
Time (h)
Yield of 2ab (%)
Yield of 3ab (%)
1
PPh3
PPh3
PPh3
PPh3
DBU
DABCO
DABCO
PBu3
DMAP
Et3N
Me2S
THF
12
12
12
12
6
12
12
24
12
12
12
80
63
48
Trace
30
12
18
27
31
Trace
0
72
2
DMF
CH2Cl2
CH3CN
THF
3c
4
5c
6
THF
7
DMF
THF
THF
THF
THF
Trace
0
87
0
8d
9
e
e
e
e
e
e
10
11
a All reactions carried out at room temperature; the molar ratio of 1a to MVK was 1:2.
b Isolated yields.
c Determined by 19 F NMR.
d An unidentified mixture of products was obtained.
e No reaction occurred.
Scheme 3.

X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3843
10–11). To our surprise, the aza-Baylis–Hillman reaction of
N-(4-chloro-2,3,5,6-tetrafluoro) phenyl-4-nitrophenyl aldi-
mine 1d with MVK, under the similar reaction conditions,
gave the normal Baylis–Hillman adduct 2d exclusively
(Table 2, entry 4). And decreasing the reaction temperature
to 0 8C yielded 80% of the normal Baylis–Hillman adduct
2d and no corresponding double aza-Baylis–Hillman adduct
3d was isolated (entry 5). 4-Methylphenyl, 4-methoxy-
phenyl or 4-propenyl-phenyl aldimines 1i–1k could also
react with MVK to give the normal aza-Baylis–Hillman
adducts 2i–2k in moderate yields along with some
unidentified products, respectively, but only if the reaction
temperature was kept at 60 8C due to their low reactivity.
None of the corresponding double aza-Baylis–Hillman
adducts was formed, possibly due to the decomposition or
side reaction at high reaction temperature (entries 10–12).
The above results indicated that the substituents on ArF and
Figure 1. X-ray crystal structure of 3a.
a
Table 2. Aza-Baylis–Hillman reactions of per- (or poly)fluorophenyl aromatic aldimines with MVK in THF in the presence of PPh3
Entry
Ar
ArF
Time (h)
Temperature (8C)
Yield of 2b(%)
Yield of 3b(%)
1
2
3
4
5
6
7
8
C6F5
C6H5
C6H5
C6F5
C6F5
12
96
72
24
24
24
72
72
58
48
72
72
rt
2a, 80
2b, 20
2c, 51
2d, 90
2d, 80
2e, 51
2f, 35
2g, 61
2h, 53
2i, 45
2j, 34
2k, 30
3a, 18
3b, 25
3c, 17
0
40
40
40
0
40
40
40
40
60
60
60
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
p-NO2C6H4
p-NO2C6H4
o-NO2C6H4
p-BrC6H4
o-BrC6H4
o-ClC6H4
p-MeC6H4
p-MeOC6H4
0
3e, 35
3f, 37
3g, 27
3h, 25
9
c
10
11
12
—
c
—
c
—
a The molar ratio of imine with MVK was 1:2.
b Isolated yields.
c An unidentified mixture of products was obtained.
Table 3. Results of aza-Baylis–Hillman reactions of per- (or poly)fluorophenyl aromatic aldimines with MVK in DMF in the presence of DABCOa
Entry
Ar
ArF
Time (h)
Temperature (8C)
Yield of 3b (%)c
1d
2
3
4
5
6
7
8
C6F5
C6H5
C6H5
p-NO2C6H4
o-NO2C6H4
p-BrC6H4
o-BrC6H4
o-ClC6H4
C6F5
C6F5
12
25
60
60
K78w0
K78w0
25
25
25
3a, 87
3b, 35
3c, 47
3d, 30
3e, 69
3f, 65
3g, 61
3h, 61
240
240
24
48
60
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
4-ClC6F4
48
60
a The molar ratio of imine to MVK was 1:5.
b All the products 3 were anti-configuration.
c Isolated yields.
d The molar ratio of imine with MVK was 1:2.

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X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
Scheme 4.
Ar affected the reactions, and electron-withdrawing sub-
stituents on the groups (Ar) would favor this version of the
aza-Baylis–Hillman reaction.
It should be emphasized here that for other Michael
acceptors such as methyl acrylate and acrylonitrile reacted
with 1, no such double aza-Baylis–Hillman reaction product
could be observed at all. For example, the aza-Baylis–
Hillman reaction of N-pentafluorophenyl-pentafluorophenyl
aldimine 1a with methyl acrylate in DMF in the presence of
DABCO (20 mol %) was completed within 24 h to provide
98% yield of the product 4. Under the same reaction
conditions, it reacted with acrylonitrile within 68 h
providing 2-(pentafluorophenyl-pentafluorophenylamino
-methyl)-acrylonitrile 5 in 72% yield (Scheme 4).
On the other hand, if using DABCO as a Lewis base in
DMF, in all cases the corresponding double aza-Baylis–
Hillman adducts were obtained exclusively as the sole
product with the anti-configuration (Table 3). In order to
obtain 3 in higher yields, 5 equiv of MVK was employed in
all cases (Table 3). For substrates having an electron-
withdrawing group on the benzene ring, the reaction
proceeded very well to give 3 in good yields within shorter
reaction time (Table 3, entries 5–8). Rising of the reaction
temperature and prolonged reaction time were effective with
less-reactive substrates like 1b,1c (Table 3, entries 2–3).
Specifically, when N-(4-chloro-2,3,5,6-tetrafluoro)phenyl-
4-nitrophenyl aldimine 1d bearing a strong electron-with-
drawing nitro group on the benzene ring was used as the
substrate, it was found that 1d decomposed rapidly, and the
corresponding double aza-Baylis–Hillman adduct 3d
could only be obtained in 30% yield along with many
unidentified products, when the reaction temperature was
kept at K78w0 8C (Table 3, entry 4).
This result stimulated us to seek out other versions of aza-
Baylis–Hillman reactions using other fluorinated imines.
Therefore, several fluorine-containing imines have been
prepared and used as the substrates (Scheme 5). The
reaction of [1-(4-bromophenyl)-meth-(E)-ylidene]-(2,3,4,5-
tetrafluoro-6-nitrophenyl)-amine 6 which had an electron-
withdrawing group (o-NO2) on ArF with MVK proceeded
smoothly under the same conditions as those described
above, the corresponding normal aza-Baylis–Hillman
adduct 7 was formed exclusively in 92% yield within
12 h. However, under the same reaction conditions,
Scheme 5.

X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3845
Scheme 6.
Table 4. Synthesis of fluorine-containing 4-alkylidene-2-cyclohexen-1-ones 11 and 12
Entry
Ar
ArF
Time (h)
Yielda/%
Ratio (11/12)
1
2
3
C6F5
o-BrC6H4
o-ClC6H4
C6F5
4-ClC6F4
4-ClC6F4
4
4
4
90
79
97
1:2b
37:42c
48:49c
a Isolated yield.
b Determined by 19F NMR.
c Determined by isolated weight.
N-benzyliden-2, 4-difluor-anilin 8 did not react with MVK
and even at higher temperature no reaction occurred to give
the corresponding product due to its low reactivity. These
results indicated that the electron-withdrawing nature of the
N-substituent was necessary for a successful aza-Baylis–
Hillman reaction. When N-phenyl-pentafluorophenyl
aldimine 9 was subjected to similar reaction conditions,
many unidentified products were formed, and none of the
corresponding aza-Baylis–Hillman adduct was obtained.
We also prepared trans-crotonaldehyde-4-chloro-2,3,5,6-
tetrafluoro-phenylimine 10 which was very labile and must
be used immediately for the reaction. In the aza-Baylis–
Hillman reaction of 10 with MVK in the presence of PPh3
under the same conditions, the corresponding normal aza-
Baylis–Hillman adduct was formed in very low yield.
of fluorine-containing 4-alkylidene-2-cyclohexen-1-one
derivatives.
The double Baylis–Hillman reaction mechanism of electron
deficient N-sulfonylimine and aldehyde had been proposed
in Scheme 7.4,14 The first mechanism is the Michael
addition of enolate derived from DABCO and MVK to
the Baylis–Hillman adduct, and the second is the aldol
condensation reaction of enolate derived from DABCO and
MVK (a MVK dimer type enloate) with the substrate.
To confirm the reaction mechanism of the formation of the
In 1998, Amri and co-workers reported a convenient
synthesis of 4-alkylidene-2-cyclohexen-1-ones via the
tandem three-step: SN20 substitution–deacetylation–cycliza-
tion reactions (Scheme 6).8 We intended to convert the
double Baylis–Hillman adducts 3 to fluorine-containing
4-alkylidene-2-cyclohexen-1-ones, which represented the
main structural feature of some natural and synthetic
products9–11 characterized by important biological
activities12 and considered as useful flavouring materials
and perfumes.13 However, under the reported reaction
conditions, we found that the double aza-Baylis–Hillman
adducts were transformed to the corresponding two isomers
11 and 12 in good yields at room temperature (Table 4). The
structure of 12h was determined by X-ray diffraction
(Fig. 2). Specifically, when 3a was used as a substrate, the
aza-Baylis–Hillman adduct was transformed to the corre-
sponding two isomers 11a and 12a in a ratio of 1:2
according to the 19F NMR spectra which could not be
separated by flash column chromatography. This transform-
ation could provide a convenient method for the preparation
Figure 2. X-ray crystal structure of 12h.

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X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
Scheme 7.
Scheme 8.
double aza-Baylis–Hillman product 3, we conducted the
reaction of MVK with the normal aza-Baylis–Hillman
adduct 2a under the same conditions (Scheme 8). To our
surprise, only trace 3a was obtained and the main product
was the dimmer of MVK. We also confirmed that the MVK
dimmer did not react with N-pentafluorophenyl-pentafluoro-
phenyl aldimine 1a in the presence of DABCO (Scheme 8).
This was simply due to the fact that the MVK dimmer type
enolate (show in mechanism 2 of Scheme 7) could not be
formed from the MVK dimmer with DABCO. These results
suggested that the double aza-Baylis–Hillman products 3
were not derived from the first mechanism as shown in
Scheme 7, and this unexpected highly diastereoselective
double aza-Baylis–Hillman reaction could only proceed via
the second mechanism. Namely, a MVK dimmer type
enolate was formed during the reaction which was further
reacted with per- (or poly)fluorophenyl aromatic aldimines
to give exclusively the double aza-Baylis–Hillman adduct
(show in mechanism 2 of Scheme 7).
aldimines 1 with MVK, the Lewis base and solvent could
significantly affect the reaction. Using triphenylphosphine
as a Lewis base, the reaction of 1 with MVK proceeded
smoothly to give the normal Baylis–Hillman adduct 2 along
with the double Baylis–Hillman adduct 3 as by-product in
THF. On the other hand, in the aza-Baylis–Hillman reaction
of 1 with MVK using DABCO as a Lewis base, double aza-
Baylis–Hillman adducts 3 were formed exclusively in the
anti-configuration, which was confirmed to be derived from
the Baylis–Hillman reaction of the enolate of the MVK
dimmer induced by DABCO and MVK with per- (or
poly)fluorophenyl aromatic aldimines. The double Baylis–
Hillman adducts 3 were conveniently converted to fluorine-
containing 4-alkylidene-2-cyclohexen-1-ones under mild
reaction conditions in good yields. Further studies on
applications of these aza-Baylis–Hillman reactions are
underway.
4. Experimental
3. Conclusion
Unless otherwise stated, all reactions were carried out under
an argon atmosphere. All per- (or poly)fluorophenyl
aromatic aldimines15 were prepared according to the
In conclusion, we have found that in the aza-Baylis–
Hillman reaction of per- (or poly)fluorophenyl aromatic
1
literature. H, 13C and 19F NMR spectra were recorded in

X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3847
CDCl3 on Bruker AM-300 instruments with Me4Si and
CFCl3 (with upfield negative) as the internal and external
standards, respectively. IR spectra were obtained with a
Nicolet AV-360 spectrophotometer. Lower resolution mass
spectrum or high-resolution mass spectra (HRMS) were
obtained on a Finnigan GC-MS 4021 or a Finnigan MAT-
8430 instrument using the electron impact ionization
technique (70 ev), respectively. Elemental analyses were
performed by this Institute. X-ray crystal structure analysis
was performed on a Bruker P4 instrument. Melting points
were measured in Temp-Melt apparatus and were
uncorrected.
(1H, d, JZ9.6 Hz, NH), 5.81 (1H, d, JZ9.3 Hz, CH), 6.05
(1H, s), 6.28 (1H, s), 7.28–7.37 (5H, m, Ar); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.8 (2F, d, 3JFFZ20.6 Hz),
3
K156.7 (2F, d, JFFZ19.7 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 26.6, 60.1, 99.9, 125.7, 126.8, 127.1, 128.0,
128.7, 138.0 (m, 1JCFZ241.3 Hz), 140.1, 144.6 (m, 1JCF
Z
244.2 Hz), 148.2, 198.8; MS (EI) m/e 357 (MC, 6.06), 43
(MCK314, 100). Anal. Calcd for C17H12NOF4Cl: C, 57.08;
H, 3.36; N, 3.92. Found: C, 57.21; H, 3.56; N, 3.66.
4.1.4. 3-[(4-Chloro-2,3,5,6-tetrafluorophenylamino)-(4-
nitrophenyl)-methyl]-but-3-en-2-one (2d). Yellow solid
(181 mg, 90%); mp 97–99 8C; IR (film) y 1681 cmK1
1
4.1. Typical reaction procedure for the triphenyl-
phosphine-catalyzed Baylis–Hillman reaction of methyl
vinyl ketone with per- (or poly)fluorophenyl aromatic
aldimines
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 2.37 (3H, s,
Me), 4.90 (1H, d, JZ9.3 Hz, NH), 5.75 (1H, d, JZ9.9 Hz,
CH), 6.13 (1H, s), 6.35 (1H, s), 7.56 (2H, d, JZ9.0 Hz, Ar),
8.22 (2H, d, JZ8.7 Hz, Ar); 19F NMR (CDCl3, TMS,
282 MHz) d K142.8 (2F, d, 3JFFZ13.0 Hz), K156.9 (2F, d,
3JFFZ16.9 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d
26.5, 60.6, 101.2, 123.9, 125.1, 127.4, 128.8, 138.3 (m,
1JCFZ232.5 Hz), 144.6 (m, 1JCFZ247.0 Hz), 147.1, 147.4,
147.6, 198.77; MS (EI) m/e 402 (MC, 2.89), 43 (MCK359,
100). Anal. Calcd for C17H11N2O3F4Cl: C, 50.70; H, 2.75;
N, 6.96. Found: C, 50.62; H, 2.87; N, 6.85.
To a solution of N-pentafluorophenyl-pentafluorophenyl
aldimine (181 mg, 0.5 mmol) and triphenylphosphine
(26 mg, 0.1 mmol) in THF (1.0 mL) at room temperature
was added methyl vinyl ketone (70 mg, 1 mmol). The
reaction was monitored by TLC; when the imine dis-
appeared, the solvent was removed under reduced pressure,
and the residue was purified by flash chromatography [SiO2,
EtOAc–petroleum ether (1:20)] to yield 2a (172 mg, 80%)
as a colorless liquid and 3a (45 mg, 18%) as a colorless
solid.
4.1.5. 3-[(4-Chloro-2,3,5,6-tetrafluorophenylamino)-(2-
nitrophenyl)-methyl]-but-3-en-2-one (2e). Yellow solid
(103 mg, 51%); mp 109–111 8C; IR (film) y 1683 cmK1
1
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 2.37 (3H, s,
4.1.1. 3-(Pentafluorophenyl-pentafluorophenylamino-
methyl)-but-3-en-2-one (2a). Colorless liquid; IR (film) y
Me), 4.46 (1H, d, JZ8.1 Hz, NH), 5.90 (1H, s), 6.24 (1H, s),
6.43 (1H, d, JZ8.1 Hz, CH), 7.49 (1H, m, Ar), 7.66 (1H, m,
Ar), 7.76 (1H, m, Ar), 7.98 (1H, m, Ar); 19F NMR (CDCl3,
1
1678 cmK1 (C]O); H NMR (CDCl3, TMS, 300 MHz) d
3
2.39 (3H, s, Me), 4.29 (1H, d, JZ11.4 Hz, NH), 6.03 (1H, d,
JZ10.8 Hz, CH), 6.24 (1H, s), 6.41 (1H, s); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.0 (2F, d, 3JFFZ18.9 Hz),
TMS, 282 MHz) d -143.2 (2F, d, JFFZ18.8 Hz), -157.9
3
(2F, d, JFFZ16.6 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 26.0, 55.6, 100.4, 125.4, 125.6, 127.4,
3
3
1
K154.2 (1F, t, JFFZ21.4 Hz), K157.7 (2F, d, JFFZ
128.4, 129.2,133.3, 135.3, 137.9 (m, JCFZ241.1 Hz),
3
1
24.5 Hz), K161.3 (2F, m), K163.2 (2F, t, JFFZ22.0 Hz),
144.4 (m, JCFZ249.0 Hz), 147.7, 148.1, 198.0; MS (EI)
K167.5 (1F, t, JFFZ17.2 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 26.1, 50.9, 114.2, 121.3, 126.8, 135.3 (m,
m/e 402 (MC, 0.98), 43 (MCK359, 100). Anal. Calcd for
C17H11N2O3F4Cl: C, 50.70; H, 2.75; N, 6.96. Found: C,
50.73; H, 3,04; N, 6.79.
3
1JCFZ288.2 Hz), 136.3, 137.8 (m, 1JCFZ239.1 Hz), 139.1,
1
1
141.7 (m, JCFZ211.6 Hz), 144.9 (m, JCFZ245.9 Hz),
145.8, 197.6; MS (EI) m/e 431 (MC, 7.05), 43 (MCK388,
100). Anal. Calcd for C17H7NOF10: C, 47.35; H, 1.64; N,
3.25. Found: C, 47.71; H, 1.79; N, 3.26.
4.1.6. 3-[(4-Bromophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-but-3-en-2-one (2f). Colorless
1
liquid (76 mg, 35%); IR (film) y 1680 cmK1 (C]O); H
NMR (CDCl3, TMS, 300 MHz) d 2.35 (3H, s, Me), 4.75
(1H, d, JZ9.0 Hz, NH), 5.70 (1H, d, JZ9.0 Hz, CH), 6.05
(1H, s), 6.27 (1H, s), 7.20 (2H, d, JZ8.1 Hz, Ar), 7.47 (2H,
d, JZ8.1 Hz, Ar); 19F NMR (CDCl3, TMS, 282 MHz) d
4.1.2. 3-(Pentafluorophenylamino-phenyl-methyl)-but-3-
en-2-one (2b). Colorless liquid (34 mg, 20%); IR (film) y
-1
1
1681 cm (C]O); H NMR (CDCl3, TMS, 300 MHz) d
2.35 (3H, s, Me), 4.56 (1H, d, JZ9.3 Hz, NH), 5.70 (1H, d,
JZ9.6 Hz, CH), 6.04 (1H, s), 6.26 (1H, s), 7.27–7.36 (5H,
m, Ar); 19F NMR (CDCl3, TMS, 282 MHz) d K158.20 (2F,
d, 3JFFZ25.4 Hz), K164.2 (2F, t, 3JFFZ22.8 Hz), K170.6
3
3
K143.2 (2F, d, JFFZ21.4 Hz), K157.3 (2F, d, JFFZ
22.8 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d 26.5,
60.0, 101.7, 121.8, 125.4, 127.4, 128.4, 131.9, 139.2, 138.0
1
1
(m, JCFZ236.2 Hz), 139.2, 144.5 (m, JCFZ262.15 Hz),
147.8, 198.7; MS (EI) m/e 435 (MC, 2.90), 43 (MCK392,
100). HRMS (MALDI) m/e calcd for C17H12N2O3F4Br
(MCH)C 435.9727, found 435.9746.
(1F, m); 13C NMR (CDCl3, TMS, 75.44 MHz) d 19.7, 60.6,
1
116.7, 122.6, 126.7, 126.8, 127.9, 128.8, 133.9 (m, JCF
Z
241.9 Hz), 138.3 (m, 1JCFZ232.2 Hz), 140.2, 148.3, 198.8;
MS (EI) m/e 341 (MC, 12.11), 159 (MCK182, 61.39), 43
(MCK298, 100). Anal. Calcd for C17H12NOF5: C, 59.83;
H, 3.54; N, 4.10. Found: C, 60.10; H, 3.48; N, 3.91.
4.1.7. 3-[(2-Bromophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-but-3-en-2-one (2g). Colorless
-1
1
liquid(133 mg, 61%); IR (film) y 1680 cm (C]O); H
NMR (CDCl3, TMS, 300 MHz) d 2.36 (3H, s, Me), 4.76
(1H, d, JZ9.3 Hz, NH), 5.72 (1H, d, JZ9.0 Hz, CH), 6.07
(1H, s), 6.30 (1H, s), 7.20–7.50 (4H, m, Ar); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.2 (2F, d, 3JFFZ21.4 Hz),
4.1.3. 3-[(4-Chloro-2,3,5,6-tetrafluorophenylamino)-
phenyl-methyl]-but-3-en-2-one
(2c).
Colorless
1
liquid(91 mg, 51%); IR (film) y 1680 cmK1 (C]O); H
NMR (CDCl3, TMS, 300 MHz) d 2.36 (3H, s, Me), 4.75

3848
X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3
3
K157.3 (2F, d, JFFZ22.8 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 26.6, 60.2, 102.7, 122.9, 125.3, 126.4, 127.6,
26.2 Hz), K156.5 (2F, d, JFFZ24.8 Hz); 13C NMR
(CDCl3, TMS, 75.44 MHz) d 26.6, 59.8, 100.0, 125.6,
1
1
129.7, 130.3, 131.0, 138.0 (m, JCFZ243.5 Hz), 142.4,
126.6, 127.4, 128.0, 128.6, 132.3, 136.1, 137.9 (m, JCF
Z
144.9 (m, 1JCFZ292.9 Hz), 147.6, 198.6; MS (EI) m/e 435
(MC, 3.69), 43 (MCK392, 100). Anal. Calcd for C17H11-
NOF4ClBr: C, 46.76; H, 2.54; N, 3.21. Found: C, 47.18; H,
2.81; N, 2.97.
239.9 Hz), 138.8, 144.5 (m, 1JCFZ246.3 Hz), 147.6, 199.1;
MS (EI) m/e 383 (MC, 10.13), 185 (MCK198, 100), 43
(MCK340, 93.02); HRMS m/e calcd for C19H14NOF4Cl
383.0700, found. 383.06837.
4.1.8. 3-[(2-Chlorophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-but-3-en-2-one (2h). Colorless
4.2. Typical reaction procedure for the DABCO-
catalyzed Baylis–Hillman reaction of methyl vinyl
ketone with per- (or poly)fluorophenyl aromatic
aldimines.
1
liquid (104 mg, 53%); IR (film) y 1681 cmK1 (C]O); H
NMR (CDCl3, TMS, 300 MHz) d 2.39 (3H, s, Me), 4.62
(1H, d, JZ9.0 Hz, NH), 6.01 (1H, s), 6.23 (1H, d, JZ
8.7 Hz, CH), 6.32 (1H, s), 7.21–7.45 (4H, m, Ar); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.5 (2F, d, 3JFFZ14.9 Hz),
To a solution of N-pentafluorophenyl-pentafluorophenyl
aldimine (181 mg, 0.5 mmol) and DABCO (12 mg,
0.1 mmol) in DMF (1.0 mL) at room temperature was
added methyl vinyl ketone(175 mg, 2.5 mmol) under an
argon atmosphere and the reaction mixture was stirred for
12 h at room temperature. The reaction mixture was washed
with water (3!10 mL) and extracted with dichloromethane
(2!10 mL). The organic layer was dried over anhydrous
Na2SO4, the solvent was removed under reduced pressure,
the residue was purified on silica gel using ethyl acetate
(hexane (V/V: 1:20) as an elute to give a white solid product
3a, which was further recrystallized from dichloromethane-
hexane (V/V: 1:1) to give the pure product 3a (218 mg,
87%) as a colorless crystal.
3
K158.1 (2F, d, JFFZ12.7 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 26.6, 56.7, 100.6, 125.6, 127.2, 127.9, 128.2,
1
129.2, 130.2, 133.6, 137.5, 137.9 (m, JCFZ239.9 Hz),
144.5 (m, 1JCFZ246.3 Hz), 147.4, 198.5; MS (EI) m/e 391
(MC, 13.14), 43 (MCK348, 100). Anal. Calcd for C17H11-
NOF4Cl2: C, 52.06; H, 2.83; N, 3.57. Found: C, 52.25; H,
2.88; N, 3.50.
4.1.9. 3-[(4-Chloro-2,3,5,6-tetrafluorophenylamino)-p-
tolyl-methyl]-but-3-en-2-one (2i). Colorless liquid
1
(84 mg, 45%); IR (film) y 1680 cmK1 (C]O); H NMR
(CDCl3, TMS, 300 MHz) d 2.34 (3H, s, Me), 3.35 (3H, s,
Me), 4.71 (1H, d, JZ8.7 Hz, NH), 5.78 (1H, d, JZ9.3 Hz,
CH), 6.04 (1H, s), 6.25 (1H, s), 7.16 (2H, d, JZ7.8 Hz, Ar),
7.24 (2H, d, JZ7.8 Hz, Ar); 19F NMR (CDCl3, TMS,
282 MHz) d K143.7 (2F, d, 3JFFZ16.9 Hz), K157.7 (2F, d,
3JFFZ18.3 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d
21.1, 26.7, 59.8, 99.9, 125.6, 126.4, 126.7, 129.5, 137.1,
4.2.1. (4,5-trans)-3-Methylene-5-(pentafluorophenyl-
pentafluorophenylamino-methyl)-heptane-2,6-dione
(3a). Colorless solid; mp 102–104 8C; IR (film) y 1713 cmK1
(C]O); 1670 cmK1 (C]O); 1H NMR (CDCl3, TMS,
300 MHz) d 2.40 (3H, s, Me), 2.31 (1H, dd, JZ13.8,
5.7 Hz), 2.34 (3H, s, Me), 2.50 (1H, dd, JZ13.8, 9.0 Hz),
3.36 (1H, ddd, JZ9.3, 9.0, 5.7 Hz), 4.56 (1H, d, JZ
11.7 Hz, NH), 5.27 (1H, dd, JZ11.7, 9.3 Hz, CH), 5.82 (1H,
s), 6.08 (1H, s); 19F NMR (CDCl3, TMS, 282 MHz) d
1
1
137.8, 137.9 (m, JCFZ225.4 Hz), 144.6 (m, JCF
Z
248.0 Hz), 148.4, 198.8; MS (EI) m/e 371 (MC, 7.14),
173 (MCK 198, 54.03), 43 (MCK328, 100). Anal. Calcd
for C18H14NOF4Cl: C, 58.16; H, 3.80; N, 3.78. Found: C,
58.43; H, 3.87; N, 3.55.
3
3
K143.9 (2F, d, JFFZ17.2 Hz), K152.8 (1F, t, JFFZ
20.3 Hz), K157.7 (2F, d, 3JFFZ20.6 Hz), K160.4 (2F, m),
3
3
4.1.10. 3-[(4-Chloro-2,3,5,6-tetrafluorophenylamino)-(4-
methoxy-phenyl)-methyl]-but-3-en-2-one (2j). Colorless
K163.1 (2F, t, JFFZ17.8 Hz), K167.3 (1F, t, JFFZ
18.1 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d 25.5,
liquid (68 mg, 35%); IR (film) y 1680 cmK1 (C]O); H
30.7, 31.8, 53.2, 54.8, 114.2, 121.3, 128.5, 135.3 (m, 1JCF
Z
1
1
NMR (CDCl3, TMS, 300 MHz) d 2.35 (3H, s, Me), 3.80
(3H, s, Me), 4.67 (1H, d, JZ8.7 Hz, NH), 5.78 (1H, d, JZ
8.7 Hz, CH), 6.03 (1H, s), 6.25 (1H, s), 6.88 (2H, d, JZ
6.6 Hz, Ar), 7.27 (2H, d, JZ6.6 Hz, Ar); 19F NMR (CDCl3,
TMS, 282 MHz) d K143.6 (2F, d, 3JFFZ26.2 Hz), K157.6
288.2 Hz), 136.3, 137.8 (m, JCFZ239.1 Hz), 139.1, 141.7
1
1
(m, JCFZ211.6 Hz), 144.6, 144.9 (m, JCFZ245.9 Hz),
198.8, 209.0; MS (EI) m/e 501 (MC, 0.53), 362 (MCK139,
55.76), 43 (MCK458, 100). Anal. Calcd for
C21H13NO2F10: C, 50.31; H, 2.61; N, 2.79. Found: C,
50.32; H, 2.62; N, 2.66.
3
(2F, d, JFFZ23.4 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 26.7, 55.3, 59.5, 100.0, 114.2, 125.6, 126.1,
128.2, 132.2, 137.8 (m, 1JCFZ235.4 Hz), 144.5 (m, 1JCF
Z
4.2.2. (4,5-trans)-3-Methylene-5-(pentafluorophenyl-
amino-phenyl-methyl)-heptane-2,6-dione (3b). Colorless
solid (72 mg, 35%); mp 86–87 8C; IR (film) y 1717 cmK1
(C]O); 1662 cmK1 (C]O); 1H NMR (CDCl3, TMS,
300 MHz) d 1.92 (3H, s, Me), 2.37 (3H, s, Me), 2.56 (1H,
dd, JZ13.2, 6.3 Hz), 2.68 (1H, dd, JZ13.2, 8.4 Hz), 3.24
(1H, ddd, JZ8.4, 6.3, 5.7 Hz), 4.79 (1H, dd, JZ10.5,
5.7 Hz, CH), 5.32 (1H, d, JZ10.5 Hz, NH), 5.91 (1H, s),
6.13 (1H, s), 7.13–7.32 (5H, m, Ar); 19F NMR (CDCl3,
TMS, 282 MHz) d K158.0 (2F, d, 3JFFZ23.1 Hz), K164.4
(2F, t, 3JFFZ17.5 Hz), K170.60 (1F, m); 13C NMR (CDCl3,
254.8 Hz), 148.4, 159.3, 198.8; MS (EI) m/e 387 (MC,
3.47), 318 (MCK69, 100), 43 (MCK344, 57.65). Anal.
Calcd for C18H14NO2F4Cl: C, 55.76; H, 3.64; N, 3.61.
Found: C, 56.09; H, 3.83; N, 3.42.
4.1.11. 3-(4-Chloro-2,3,5,6-tetrafluorophenylamino)-3-
methylene-6-(trans)-phenyl-hex-5-en-2-one (2k). Color-
less liquid (58 mg, 30%); IR (film) y 1678 cmK1 (C]O); 1H
NMR (CDCl3, TMS, 300 MHz) d 2.39 (3H, s, Me), 4.78
(1H, d, JZ9.9 Hz, NH), 5.23 (1H, dd, JZ9.9, 7.2 Hz, CH),
6.06 (1H, s), 6.20 (1H, s), 6.34 (1H, dd, JZ7.2, 6.9 Hz, CH),
6.59 (1H, d, JZ6.9 Hz, CH), 7.23–7.39 (5H, m, Ar); 19F
TMS, 75.44 MHz) d 25.8, 31.7, 32.0, 56.1, 60.4, 116.7,
Z
1
122.2, 126.2, 127.9, 128.7, 128.9, 133.9 (m, JCF
3
1
NMR (CDCl3, TMS, 282 MHz) d K143.3 (2F, d, JFFZ
241.9 Hz), 138.3 (m, JCFZ232.2 Hz), 140.4, 145.2,

X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3849
199.4, 212.8; MS (EI) m/e 411 (MC, 1.05), 272 (MCK139,
100), 43 (MCK368, 32.97). Anal. Calcd for C21H18NO2F5:
C, 61.31; H, 4.41; N, 3.40. Found: C, 61.42; H, 4.31; N,
3.18.
2,6-dione (3f). Colorless solid (165 mg, 65%); mp 112–
120 8C; IR (film) y 1707 cmK1 (C]O); 1677 cmK1
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 1.95 (3H, s,
1
Me), 2.42 (3H, s, Me), 2.63 (1H, dd, JZ13.2, 8.1 Hz), 2.76
(1H, dd, JZ13.2, 6.6 Hz), 3.31 (1H, ddd, JZ8.1, 6.6,
4.2 Hz), 4.95 (1H, dd, JZ9.3, 4.2 Hz, CH), 5.94 (1H, d, JZ
9.3 Hz, NH), 5.95 (1H, s), 6.20 (1H, s), 7.36 (2H, d, JZ
8.7 Hz, Ar), 8.17 (2H, d, JZ8.7 Hz, Ar); 19F NMR (CDCl3,
TMS, 282 MHz) d K142.9 (2F, d, 3JFFZ21.7 Hz), K157.6
4.2.3. (4,5-trans)-3-[(4-Chloro-2,3,5,6-tetrafluorophenyl-
amino)-phenyl-methyl]-5-methylene-heptane-2,6-dione
(3c). Colorless liquid (101 mg, 47%); IR (film) y
1707 cmK1 (C]O); 1678 cmK1 (C]O); 1H NMR
(CDCl3, TMS, 300 MHz) d 1.90 (3H, s, Me), 2.37 (3H, s,
Me), 2.59 (1H, dd, JZ13.2, 6.9 Hz), 2.71 (1H, dd, JZ13.2,
8.1 Hz), 3.26 (1H, ddd, JZ8.1, 6.9, 5.1 Hz), 4.87 (1H, dd,
JZ11.1, 5.1 Hz, CH), 5.66 (1H, d, JZ11.1 Hz, NH), 5.91
(1H, s), 6.14 (1H, s), 7.10 - 7.32 (5H, m, Ar); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.8 (2F, d, 3JFFZ25.4 Hz),
3
(2F, d, JFFZ22.0 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 22.7, 29.7, 32.2, 55.1, 59.4, 100.1, 121.8,
1
125.5, 127.9, 129.1, 132.0, 138.1 (m, JCFZ237.1 Hz),
139.7, 144.5 (m, 1JCFZ254.1 Hz), 144.9, 199.4, 212.8; MS
(EI) m/e 505 (MC, 2.21), 366 (MCK139, 69.72), 43 (MCK
462, 100); HRMS (MALDI) m/e calcd for C21H18NO2F4-
ClBr (MCH)C 506.0146, found 506.0124.
3
K157.3 (2F, d, JFFZ25.9 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 25.9, 32.0, 32.1, 60.0, 65.9, 100.0, 125.5,
1
126.1, 127.9, 128.7, 129.0, 137.9 (m, JCFZ241.1 Hz),
4.2.7. (4,5-trans)-3-[(2-Bromophenyl)-(4-chloro-2,3,5,6-
tetrafluorophenylamino)-methyl]-5-methylene-heptane-
2,6-dione (3g). Colorless solid (155 mg, 61%); mp 124–
126 8C; IR (film) y 1705 cmK1 (C]O); 1673 cmK1
142.9, 144.5 (m, 1JCFZ248.0 Hz), 145.2, 199.4, 213.0; MS
(EI) m/e 427 (MC, 4.26), 288 (MCK139, 100), 43 (MCK
384, 55.18); HRMS (MALDI) m/e calcd for C21H18NO2F4-
ClNa (MCNa)C 450.0860, found 450.0898.
1
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 1.94 (3H, s,
Me), 2.45 (3H, s, Me), 2.67 (1H, dd, JZ13.2, 9.3 Hz), 2.90
(1H, dd, JZ13.2, 5.1 Hz), 3.40 (1H, ddd, JZ9.3, 5.1,
3.6 Hz), 5.30 (1H, dd, JZ10.2, 3.6 Hz, CH), 6.02 (1H, s),
6.24 (1H, s), 6.26 (1H, d, JZ10.2 Hz, NH), 7.09–7.28 (3H,
m, Ar), 7.53–7.56 (1H, m, Ar); 19F NMR (CDCl3, TMS,
282 MHz) d K143.5 (2F, d, 3JFFZ26.2 Hz), K158.2 (2F, d,
3JFFZ22.0 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d
25.6, 31.5, 32.2, 51.8, 58.0, 100.1, 122.6, 125.6, 127.5,
4.2.4. (4,5-trans)-3-[(4-Chloro-2,3,5,6-tetrafluorophenyl-
amino)-(4-nitrophenyl)-methyl]-5-methylene-heptane-
2,6-dione (3d). Yellow solid (71 mg, 30%); mp 150–
152 8C; IR (film) y 1709 cmK1 (C]O); 1678 cm -1 (C]O);
1H NMR (CDCl3, TMS, 300 MHz) d 1.94 (3H, s, Me), 2.39
(3H, s, Me), 2.57 (1H, dd, JZ13.2, 7.2 Hz), 2.70 (1H, dd,
JZ13.2, 7.8 Hz), 3.24 (1H, ddd, JZ7.8, 7.2, 4.5 Hz), 4.82
(1H, dd, JZ9.6, 4.5 Hz, CH), 5.74 (1H, d, JZ9.6 Hz, NH),
5.92 (1H, s), 6.16 (1H, s), 7.04 (2H, d, JZ8.7 Hz, Ar), 7.42
(2H, d, JZ8.4 Hz, Ar); 19F NMR (CDCl3, TMS, 282 MHz)
1
127.9, 128.7, 129.2, 133.5, 138.1 (m, JCFZ239.5 Hz),
139.3, 144.5 (m, 1JCFZ262.2 Hz), 145.0, 198.9, 213.2; MS
(EI) m/e 505 (MC, 2.21), 366 (MCK139, 69.72), 43 (MCK
462, 100). Anal. Calcd for C21H17NO2F4ClBr: C, 49.78; H,
3.38; N, 2.76. Found: C, 49.76; H, 3.34; N, 2.55.
3
3
d K143.4 (2F, d, JFFZ26.2 Hz), K157.3 (2F, d, JFFZ
18.3 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d 25.9,
31.8, 32.1, 55.5, 59.5, 100.2, 124.2, 125.5, 127.3, 127.4,
1
1
129.6, 137.9 (m, JCFZ241.1 Hz), 144.4 (m, JCF
Z
4.2.8. (4,5-trans)-3-[(2-Chlorophenyl)-(4-chloro-2,3,5,6-
tetrafluorophenylamino)-methyl]-5-methylene-heptane-
2,6-dione (3h). Colorless solid (141 mg, 61%); mp 88–
90 8C; IR (film) y 1706 cmK1 (C]O); 1674 cmK1 (C]O);
1H NMR (CDCl3, TMS, 300 MHz) d 1.94 (3H, s, Me), 2.42
(3H, s, Me), 2.63 (1H, dd, JZ13.2, 9.3 Hz), 2.87 (1H, dd,
JZ13.2, 5.1 Hz), 3.36 (1H, ddd, JZ9.3, 5.1, 3.6 Hz), 5.33
(1H, dd, JZ9.9, 3.6 Hz, CH), 5.98 (1H, s), 6.18 (1H, d, JZ
9.9 Hz, NH), 6.21 (1H, s), 7.14–7.36 (4H, m, Ar); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.6 (2F, d, 3JFFZ18.9 Hz),
249.0 Hz), 144.7, 148.2, 199.5, 212.4; MS (EI) m/e 472
(MC, 4.26), 333 (MCK139, 88.90), 43 (MCK429, 100);
HRMS m/e calcd for C21H17N2O4F4Cl 472.0813, found
472.0815.
4.2.5. (4,5-trans)-3-[(4-Chloro-2,3,5,6-tetrafluorophenyl-
amino)-(2-nitrophenyl)-methyl]-5-methylene-heptane-
2,6-dione (3e). Yellow solid (163 mg, 69%); mp 144–
146 8C; IR (film) y 1704 cmK1 (C]O); 1678 cmK1
K158.2 (2F, d, JFFZ18.1 Hz); 13C NMR (CDCl3, TMS,
1
3
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 2.08 (3H, s,
Me), 2.51 (3H, s, Me), 2.61 (1H, dd, JZ13.2, 10.5 Hz), 2.97
(1H, dd, JZ13.2, 3.6 Hz), 3.44 (1H, ddd, JZ10.5, 3.6,
3.0 Hz), 5.50 (1H, dd, JZ10.2, 3.0 Hz, CH), 5.94 (1H, s),
6.25 (1H, s), 6.58 (1H, d, JZ10.2 Hz, NH), 7.38–7.59 (3H,
m, Ar), 7.96–7.99 (1H, m, Ar); 19F NMR (CDCl3, TMS,
282 MHz) d K143.1 (2F, d, 3JFFZ23.1 Hz), K158.7 (2F, d,
3JFFZ22.3 Hz); 13C NMR (CDCl3, TMS, 75.44 MHz) d
25.8, 31.7, 32.0, 52.3, 53.8, 100.2, 125.5, 125.4, 128.5,
75.44 MHz) d 25.6, 31.5, 32.1, 51.9, 55.6, 99.6, 125.7,
125.3, 125.4, 128.8, 128.9, 130.2, 132.4, 137.8, 138.0 (m,
1JCFZ224.9 Hz), 144.5 (m, 1JCFZ244.4 Hz), 145.0, 199.0,
213.2; MS (EI) m/e 461 (MC, 1.51), 322 (MCK139, 100),
43 (MCK458, 56.81). Anal. Calcd for C21H17NO2F4Cl2: C,
54.56; H, 3.71; N, 3.03. Found: C, 54.86; H, 3.53; N, 2.95.
4.2.9. 2-(Pentafluorophenyl-pentafluorophenylamino-
methyl)-acrylic acid methyl ester (4). Colorless liquid
1
128.6, 129.0, 133.7, 136.7, 137.9 (m, JCFZ241.1 Hz),
144.4 (m, 1JCFZ249.0 Hz), 144.6, 148.2, 199.3, 213.8; MS
(EI) m/e 333 (MCK139, 20.47), 43 (MCK429, 100). Anal.
Calcd for C21H17N2O4F4Cl: C, 53.35; H, 3.62; N, 5.92.
Found: C, 52.93; H, 3.57; N, 5.70.
(219 mg, 98%); IR (film) y 3408, 1728, 1525, 1504 cmK1
;
1H NMR (CDCl3, TMS, 300 MHz) d 3.78 (3H, s, Me), 4.44
(1H, d, JZ11.1 Hz, NH), 6.00 (1H, s), 6.04 (1H, d, JZ
11.7 Hz, CH), 6.54 (1H, s); 19F NMR (CDCl3, TMS,
282 MHz) d K143.0 (2F, d, 3JFFZ21.4 Hz), K153.8 (1F, t,
3
4.2.6. (4,5-trans)-3-[(4-Bromophenyl)-(4-chloro-2,3,5,6-
tetrafluorophenylamino)-methyl]-5-methylene-heptane-
3JFFZ22.0 Hz), K157.7 (2F, d, JFFZ21.7 Hz), K161.2
3
(2F, m), K163.2 (2F, t, JFFZ20.9 Hz), K167.5 (1F, t,

3850
X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3JFFZ21.7 Hz); MS (EI) m/e 447 (MC, 91), 387 (60), 362
(100), 265 (50). Anal. Calcd for C17H7N2O2F10: C, 45.66;
H, 1.58; N, 3.13. Found: C, 45.85; H, 1.68; N, 3.11.
m/e calcd for C21H11NOF10 Na (MCNa)C 506.0579, found
506.0600.
4.3.2. 3-Methyl-6-methylene-4-(pentafluorophenyl-
pentafluorophenylamino-methyl)-cyclohex-2-enone
(11a). Yellow liquid (16 mg, 30%); IR (film) y 1668 cmK1
4.2.10. 2-(Pentafluorophenyl-pentafluorophenylamino-
methyl)-acrylonitrile (5). Colorless liquid (149 mg,
1
72%); IR (film) y 3396, 1510, 1505 cmK1 1H NMR
;
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 2.14 (3H, s,
Me), 2.35–2.42 (1H, m), 2.86–2.93 (1H, m), 2.99–3.11 (1H,
m), 4.48 (1H, d, JZ9.6 Hz, NH), 5.13–5.21 (1H, m, CH),
5.35 (1H, s), 5.56 (1H, s), 5.95 (1H, s); 19F NMR (CDCl3,
TMS, 282 MHz) d K142.9 (2F, d, 3JFFZ13.8 Hz), K153.5
(CDCl3, TMS, 300 MHz) d 4.40 (1H, d, JZ10.8 Hz, NH),
5.78 (1H, d, JZ11.4 Hz, CH), 6.15 (1H, s), 6.25 (1H, s); 19F
3
NMR (CDCl3, TMS, 282 MHz) d K142.8 (2F, d, JFFZ
3
12.7 Hz), K150.7 (1F, t, JFFZ20.9 Hz), K156.7 (2F, d,
3
3
3
3JFFZ22.8 Hz), K159.3 (2F, m), K162.2 (2F, t, JFFZ
(1F, t, JFFZ20.0 Hz), K158.0 (2F, d, JFFZ24.8 Hz),
3
3
K161.0 (2F, m), K163.8 (2F, t, JFFZ15.6 Hz), K168.7
23.1 Hz), K165.2 (1F, t, JFFZ22.6 Hz); MS (EI) m/e 414
3
(1F, t, JFFZ17.2 Hz); 13C NMR (CDCl3, TMS,
75.44 MHz) d 19.7, 34.6, 50.8, 52.0, 114.2, 118.3, 121.5,
(MC, 81), 362 (80), 232 (100), 182 (31). Anal. Calcd for
C16H4N2F10: C, 46.40; H, 0.97; N, 6.76. Found: C, 46.75; H,
1.35; N, 7.00.
126.1, 135.3 (m, 1JCFZ288.2 Hz), 136.3, 137.8 (m, 1JCF
Z
1
239.1 Hz), 138.8, 139.1, 141.7 (m, JCFZ211.6 Hz), 144.9
(m, 1JCFZ245.9 Hz), 154.4, 197.7; MS (EI) m/e 483 (MC,
3.75), 362 (MCK121, 61.10), 122 (MCK361, 100), 107
(MCK376, 53.12); HRMS (MALDI) m/e calcd for C21-
H11NOF10Na (MCNa)C 506.0579, found 506.0600.
4.2.11. 2-[(4-Bromophenyl)-(2,3,4,5-tetrafluoro-6-nitro-
phenylamino)-methyl]-but-3-en-2-one (7). Yellow liquid
1
(206 mg, 92%); IR (film) y 1681 cmK1 (C]O); H NMR
(CDCl3, TMS, 300 MHz) d 2.35 (3H, s, Me), 5.82 (1H, d,
JZ8.1 Hz, CH), 5.97 (1H, s), 6.27 (1H, s), 6.84 (1H, d, JZ
8.1 Hz, NH), 7.20 (2H, d, JZ8.1 Hz, Ar), 7.48 (2H, d, JZ
8.7 Hz, Ar); 19F NMR (CDCl3, TMS, 282 MHz) d K144.2
(1F, m), K146.6 (1F, m); K153.2 (1F, m), K168.8 (1F, m);
13C NMR (CDCl3, TMS, 75.44 MHz) d 26.4, 59.6, 122.1,
127.2, 128.6, 130.4, 132.1, 134.7, 136.5, 138.8, 141.6,
143.2, 145.1, 148.2, 198.1; MS (EI) m/e 446 (MC, 0.06), 43
(MCK403, 100); HRMS (MALDI) m/e calcd for C17H12-
N2O3F4Br (MCH)C 446.9967, found 446.9973.
4.3.3. 4-[(2-Bromophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-3-methyl-6-methylene-cyclohex-
2-enone (11g). Colorless liquid (23 mg, 37%); IR (film) y
1
1664 cmK1 (C]O); H NMR (CDCl3, TMS, 300 MHz) d
2.10 (3H, s, Me), 2.94–2.97 (2H, m), 3.12–3.19 (1H, m),
5.13–5.18 (1H, m, CH), 5.33 (1H, d, JZ10.8 Hz, NH), 5.45
(1H, s), 5.50 (1H, s), 5.91 (1H, s), 7.08–7.14 (1H, m, Ar),
7.27–7.35 (1H, m, Ar), 7.50–7.63 (2H, m, Ar); 19F NMR
(CDCl3, TMS, 282 MHz) d K143.6 (2F, d, 3JFFZ26.5 Hz),
3
K156.5 (2F, d, JFFZ21.7 Hz); 13C NMR (CDCl3, TMS,
4.3. Typical experimental procedure for the synthesis of
fluorine-containing 4-alkylidene-2-cyclohexen-1-ones 11
and 12
75.44 MHz) d 19.6, 36.3, 51.4, 60.4, 100.9, 117.4, 123.2,
1
125.8, 127.5, 127.7, 129.0, 133.1, 133.2, 138.6 (m, JCF
Z
252.0 Hz), 141.1, 142.7, 144.4 (m, 1JCFZ237.9 Hz), 154.2,
200.0; MS (EI) m/e 487 (MC, 0.84), 366 (MCK121, 32.48),
210 (MCK277, 27.63), 122 (MCK365, 100), 107 (MCK
380, 44.84); HRMS (MALDI) m/e calcd for C21H15NOF4-
ClBrNa (MCNa)C 509.9859, found 509.9879.
To absolute ethanol solution of anhydrous potassium
carbonate was mixed with 3-methylene-5-(pentafluoro-
phenyl-pentafluorophenylamino-methyl)-heptane-2,6-dione
3a. The mixture was stirred at room temperature for a given
time (TLC, see Table 4). After removed of ethanol in vacuo,
the residue was shaken with water to dissolve the salts. The
resulting mixture was extracted three times with 10 mL of
ether. The organic phase was dried on MgSO4, concentrated
and the crude products 11a and 12a were purified by flash
chromatogryphy (EtOAc/Hexane, 1:40).
4.3.4. 6-[(2-Bromophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-3-methyl-4-methylene-cyclohex-
2-enone (12g). Colorless solid (26 mg, 42%); mp 127 8C; IR
(film) y 1652 cmK1 (C]O); 1H NMR (CDCl3, TMS,
300 MHz) d 2.05 (3H, s, Me), 2.61–2.69 (1H, m), 2.82–2.89
(1H, m), 3.15–3.22 (1H, m), 5.42 (2H, s), 5.62 (1H, brs,
NH), 5.70–5.75 (1H, m), 5.96 (1H, s), 7.08–7.54 (4H, m,
Ar); 19F NMR (CDCl3, TMS, 282 MHz) d K143.7 (2F, d,
4.3.1. 3-Methyl-4-methylene-6-(pentafluorophenyl-
pentafluorophenylamino-methyl)-cyclohex-2-enone
(12a). Yellow liquid (32 mg, 60%); IR (film) y 1668 cmK1
3
3JFFZ16.9 Hz), K157.2 (2F, d, JFFZ19.5 Hz); 13C NMR
(CDCl3, TMS, 75.44 MHz) d 19.7, 32.6, 49.8, 58.2, 100.0,
117.2, 124.0, 125.8, 127.7, 128.4, 128.8, 129.2, 133.4, 138.6
1
(C]O); H NMR (CDCl3, TMS, 300 MHz) d 2.10 (3H, s,
1
1
(m, JCFZ252.0 Hz), 138.9, 140.9, 144.4 (m, JCF
Z
Me), 2.93–3.11 (3H, m), 4.35 (1H, d, JZ10.8 Hz, NH),
5.13–5.21 (1H, m, CH), 5.45 (1H, s), 5.52 (1H, s), 5.84 (1H,
s); 19F NMR (CDCl3, TMS, 282 MHz) d K143.7 (2F, d,
237.9 Hz), 154.6, 198.6; MS (EI) m/e 487 (MC, 1.68),
366 (MCK121, 34.82), 210 (MCK277, 34.17), 122
(MCK365, 100), 107 (MCK380, 37.99); HRMS
(MALDI) m/e calcd for C21H15NOF4ClBrNa (MCNa)C
509.9859, found 509.9883.
3
3JFFZ18.6 Hz), K154.2 (1F, t, JFFZ20.9 Hz), K157.5
3
(2F, d, JFFZ22.5 Hz), K161.6 (2F, m), K163.4 (2F, t,
3
3JFFZ21.4 Hz), K167.7 (1F, t, JFFZ20.3 Hz); 13C NMR
(CDCl3, TMS, 75.44 MHz) d 19.7, 34.1, 50.9, 51.8, 114.2,
1
118.3, 121.3, 126.8, 135.3 (m, JCFZ288.2 Hz), 136.3,
4.3.5. 4-[(2-Chlorophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-3-methyl-6-methylene-cyclohex-
2-enone (11h). Colorless liquid (21 mg, 48%); IR (film) y
137.8 (m, 1JCFZ239.1 Hz), 139.0, 139.2, 141.7 (m, 1JCF
211.6 Hz), 144.9 (m, JCFZ245.9 Hz), 154.8, 197.1; MS
(EI) m/e 483 (MC, 0.53), 362 (MCK121, 61.10), 122
(MCK361, 100), 107 (MCK376, 53.12); HRMS (MALDI)
Z
1
1
1664 cmK1 (C]O); H NMR (CDCl3, TMS, 300 MHz) d
2.03 (3H, s, Me), 2.76–2.84 (2H, m), 3.00–3.07 (1H, m),

X. Liu et al. / Tetrahedron 61 (2005) 3841–3851
3851
˚
5.07–5.12 (1H, m), 5.18 (1H, brs, NH), 5.34 (1H, s), 5.43
(1H, s), 5.84 (1H, s), 7.10–7.27 (3H, m, Ar), 7.45–7.48 (1H,
m, Ar); 19F NMR (CDCl3, TMS, 282 MHz) d K143.4 (2F,
radiation (lZ0.71073 A). The structure was solved by
direct methods and explained using Fourier techniques. The
nonhydrogen atoms were refined anisotropically, hydrogen
atoms were included but not refined. The final cycle of full
matrix least-squares refinement was based on F2, respect-
ively. All calculations were performed using SHELXS-97
and SHELXL-97 programs. X-ray data for compounds 3a
and 12h are listed in Table 5.
3
3
d, JFFZ22.8 Hz), K156.3 (2F, d, JFFZ19.5 Hz); 13C
NMR (CDCl3, TMS, 75.44 MHz) d 14.1, 35.9, 51.4, 58.2,
100.0, 117.6, 125.7, 127.0, 127.4, 128.4, 128.8, 129.9,
1
132.9, 138.2, 138.4 (m, JCFZ228.1 Hz), 140.9, 144.5 (m,
1JCFZ253.7 Hz), 154.3, 200.0; MS (EI) m/e 443 (MC,
0.65), 322 (MCK121, 39.24), 210 (MCK233, 28.66), 122
(MCK321, 100), 107 (MCK336, 49.97); HRMS (MALDI)
m/e calcd for C21H15NOF4Cl2 Na (MCNa)C 466.0365,
found 466.0383.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (NNSFC) (No. 20372077 and D20032010) and the
Excellent Young Scholars Foundation of Anhui Province
for financial support.
4.3.6. 6-[(2-Chlorophenyl)-(4-chloro-2,3,5,6-tetrafluoro-
phenylamino)-methyl]-3-methyl-4-methylene-cyclohex-
2-enone (12h). Colorless solid (22 mg, 49%); mp 122 8C;
1
IR (film) y 1648 cmK1 (C]O); H NMR (CDCl3, TMS,
300 MHz) d 1.96 (3H, s, Me), 2.51–2.60 (1H, m), 2.75–2.82
(1H, m), 3.08–3.15 (1H, m), 5.33 (2H, s), 5.61–5.67 (1H,
m), 5.85 (1H, s), 5.71 (1H, brs, NH), 7.06–7.30 (4H, m, Ar);
19F NMR (CDCl3, TMS, 282 MHz) d K143.5 (2F, d, 3JFFZ
References and notes
3
23.4 Hz), K157.1 (2F, d, JFFZ22.8 Hz); 13C NMR
1. Trost, B. M. Science 1991, 254, 1471–1477.
(CDCl3, TMS, 75.44 MHz) d 14.1, 32.9, 49.9, 56.9, 100.0,
117.2, 125.6, 127.2, 128.3, 128.8, 128.9, 130.0, 133.7,
2. (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996,
52, 8001–8062. (b) Drewes, S. E.; Roos, G. P. Tetrahedron
1988, 44, 4653–4670. (c) Ciganek, E. Org. React. 1997, 51,
201–350.
137.2, 138.3 (m, 1JCFZ242.4 Hz), 140.9, 144.4 (m, 1JCF
Z
246.05 Hz), 154.7, 198.4; MS (EI) m/e 443 (MC, 1.36), 322
(MCK121, 42.69), 210 (MCK233, 27.45), 122 (MCK
321, 100), 107 (MCK336, 43.94); HRMS (MALDI) m/e
calcd for C21H15NOF4Cl2Na (MCNa)C 466.0365, found
466.0403.
3. (a) Mortia, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn.
1968, 41, 2815–2816.Baylis, A. B.; Hillman, M. E. D. German
Patent 2,155,113, 1972; Chem. Abstr. 1972, 77 34174q.
4. Shi, M.; Li, Y.-M. J. Org. Chem. 2003, 68, 4784–4790.
5. (a) Zhu, S.-Z.; Liu, X.-Y.; Wang, S.-W. Tetrahedron 2003, 59,
9669–9676. (b) Liu, X.-Y.; Zhu, S.-Z.; Wang, S.-W. Synthesis
2004, 5, 683–691. (c) Zhu, S.-F.; Liao, Y.-X.; Zhu, S.-Z. Org.
Lett. 2004, 3, 377–380. (d) Wang, Y.-L.; Zhu, S.-Z. Org. Lett.
2003, 5, 745–748.
4.4. X-ray crystal structure data of compounds (3a) and
(12h)
Intensity data were collected at 293(2) K on Bruker P4
diffractometer with graphite monochromator and Mo Ka
6. For several recent reviews see: Biomedical Frontiers of
Fluorine Chemistry ACS Symposium Series, 636; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; American Chemical
Society: Washington DC, 1996.
Table 5. X-ray data collection and processing parameters for compounds
3a and 12h
7. (a) For several recent reviews see: (a) Asymmetric fluoro-
oganic chemistry; Ramachandran, P. V., Ed.; ACS Symposium
Series, 746; American Chemical Society: Washington, DC,
2000. (b) For a review on the effect of fluorine on OH, NH,
and CH acidities, see: Schlosser, M. Angew. Chem., Int. Ed.
1998, 37, 1496–1513.
Compound
3a CCDC 260807
12h CCDC 260807
Formula
C21H13F10NO2
0.27!0.22!0.16
P2 (1)/C
Monoclinic
9.748(2)
25.814(5)
9.028(2)
90.00
111.00(3)
90.00
2120.9(7)
4
1.570
0.16
293(2)
3–55
6033
1008
4872
0.0343
1535
C21H15Cl2F4NO
0.51!0.44!0.41
P2 (1)/n
Monoclinic
19.201(1)
8.1936(5)
26.4171(17)
90.00
110.6980(10)
90.00
3887.8(4)
8
1.518
0.384
293(2)
4–54
22164
1808
8430
0.0756
8430
Size (mm)
Space group
Crystal system
˚
a (A)
˚
b (A)
8. Chamakh, A.; Amri, H. Tetrahedron Lett. 1998, 39, 375–378.
9. Nemoto, H.; Hushimoto, M.; Kurobe, H.; Fukumoto, K.;
Kametani, T. J. Chem. Soc., Perkin Trans. 1985, 927–934.
10. Ihara, M.; Toyota, M.; Fukomoto, K.; Kametani, T.
Tetrahedron Lett. 1984, 25, 3235–3238.
˚
c (A)
a (8)
b (8)
g (8)
3
˚
V (A )
Z-value
Dcalc (g cmK3
11. (a) Hanno, W.; Liborius, B. Angew. Chem., Int. Ed. Engl.
1991, 103, 1729. (b) Hanno, W.; Liborius, B. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 1685–1687.
)
m (mmK1
T (K)
2q range (8)
)
12. Atsumasa, K.; Masami, S.; Sachiko, O.; Xiangloug, Z.;
Marcus, A. T.; Hirota, F. Cancer Res. 1993, 53, 3462–3464.
13. Nobuhiko, I.; Kimio, K.; Takeaki, E. Japan Patent. Appl.
91/322, 279, 02 Oct. 1991.
Total reflections
F(000)
Independent reflections
Rint
IO2s (I)
Parameters
Goodness of fit
Final R indices (IO2s (I))
R indices (all data)
14. Shi, M.; Li, C.-Q.; Jing, J. K. Chem. Commun. 2001, 833–834.
15. Li, A. W.; Xu, B.; Zhu, S. Z. J. Fluorine Chem. 1994, 68,
145–148.
360
0.904
0.2000; 0.0530
0.1479; 0.1062
533
0.875
0.0476; 0.1122
0.0889; 0.1264