Reactions of N-benzyl-pyridinium or -isoquinolinium ylides with ethyl 3-fluoro-3-(fluoroalkyl)acrylates to give fluoroalkyl-substituted indolizine and pyrrolo[2,1-a]isoquinoline derivatives

Article abstract of DOI:10.1039/b103586j

In the presence of base, N-benzylpyridinium and N-benzylisoquinolinium ylides generated in situ from the N-benzyl-pyridinium or -isoquinolinium bromides react with ethyl 3-fluoro-3-fluoroalkyl(except bromodifluoromethyl)acrylates to give one or two fluoro

Full text of DOI:10.1039/b103586j

View Article Online / Journal Homepage / Table of Contents for this issue
Reactions of N-benzyl-pyridinium or -isoquinolinium ylides
with ethyl 3-fluoro-3-(fluoroalkyl)acrylates to give fluoroalkyl-
substituted indolizine and pyrrolo[2,1-a]isoquinoline derivatives
1
Weimin Peng and Shizheng Zhu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China. E-mail: zhusz@pub.sioc.ac.cn; Fax: ϩ86(21)64166128
Received (in Cambridge, UK) 23rd April 2001, Accepted 9th October 2001
First published as an Advance Article on the web 19th November 2001
In the presence of base, N-benzylpyridinium and N-benzylisoquinolinium ylides generated in situ
from the N-benzyl-pyridinium or -isoquinolinium bromides react with ethyl 3-fluoro-3-fluoroalkyl(except
bromodifluoromethyl)acrylates to give one or two fluoroalkylated indolizine and pyrrolo[2,1-a]isoquinoline
derivatives through 1,3-dipolar cycloaddition followed by an oxidative aromatization or 1,3-H-shift aromatization
process. While ethyl 3-bromodifluoromethyl-3-fluoroacrylate reacts with 4-nitrobenzylpyridinium ylide, a
trifluoromethylated indolizine derivative was obtained unexpectedly. It is more remarkable that the reaction of ethyl
3
-bromodifluoromethyl-3-fluoroacrylate with N-benzylisoquinolinium ylide produces a fluorocarbonyl-substituted
pyrrolo[2,1-a]isoquinoline derivative, which is fully characterized by spectroscopic methods and X-ray diffraction
analysis, in addition to the 1,3-H-shift aromatization product.
Introduction
Indolizine is an important ring system in view of its similarity
to indole. This heterocycle occurs commonly as a fully reduced
1
form in natural products, such as the alkaloid δ-coniceine,
2
3
pharaoh ant trail pheromone and slatramine, etc. Numerous
works on indolizines concerned with the search for drugs, for
dyestuffs and for spectral sensitizers have been reported
previously. Owing to the increasing importance of fluorine-
containing heterocycles in biology, pharmacology, and indus-
Fig. 1
4
5
6
However, the 1,3-dipolar cycloaddition involving fluorinated
alkenes and pyridinium ylide was relatively undeveloped during
10
the last decade. In particular, previous works on the cyclo-
7
trial application, synthesis of fluorine-containing indolizines
addition reactions of the pyridinium N-ylide A (Fig. 1) with
and pyrrolo[2,1-a]isoquinolines became of considerable interest
to us.
electron-deficient alkenes were mostly concentrated on ylides
1
A
in which X was an electron-withdrawing group such as
Typical molecular constructions of indolizine have been
well reviewed in the literature; among these, the 1,3-dipolar
cycloaddition reaction of pyridinium N-ylide generated in situ
from a pyridinium salt in the presence of base with an
1
1
2
cyano, benzoyl, propanoyl etc. The reaction of ylide A (in
which X was phenyl or substituted phenyl) was reported in
12
only one case.
In continuation of our work on the fluorine-containing
8
electron-deficient alkene was one versatile methodology. For
2
indolizines we recently studied the reactions of ylide A with
example, we have successfully prepared a series of 1-trifluoro-
2
fluorinated acrylate. It was found that ylides A reacted
acetyl-substituted indolizine derivatives through this method
13
smoothly with ethyl 3-fluoro-3-(fluoroalkyl)acrylates to give
9
(
Scheme 1).
one or two fluoroalkylated indolizine derivatives through 1,3-
dipolar cycloaddition followed by an oxidative aromatization
or 1,3-H-shift aromatization process. Herein we report these
results.
Results and discussion
Reactions of N-benzylpyridinium ylide with ethyl 3-fluoro-
3
-(fluoroalkyl)acrylates
10b
First we tried this reaction following the literature method.
Thus, 2,2-dihydropolyfluoroalkanoates were allowed as starting
material to react with N-benzylpyridinium bromide in the pres-
ence of a mixed inorganic and organic base (K CO and TEA)
2
3
in DMF at 75 ЊC. However, it was found that the reaction pro-
gressed very slowly: it took 3 days to finish and gave a compli-
cated mixture which was hard to separate. Alternatively, we
Scheme 1
3
204
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210
DOI: 10.1039/b103586j
This journal is © The Royal Society of Chemistry 2001

View Article Online
Scheme 2
used the ethyl 3-fluoro-3-(fluoroalkyl)acrylate (R = ClC F ) 1a
Table 1 Reaction of ethyl 3-fluoro-3-(fluoroalkyl)acrylates with N-
a
f
3
6
benzyl-pyridinium and -isoquinolinium bromide (2 and 7)
as starting material to react with N-(4-nitrobenzyl)pyridinium
bromide 2c (as an example for illustration) in the presence of a
stronger mixed base (NaOH and TEA), and the reaction was
carried out in toluene at 75 ЊC, and we found that the reaction
then proceeded smoothly.
Products and yield
(%)
Entry
Acrylate
Pyridinium salt
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1c
1c
1a
1b
1c
2a
2b
2c
2d
2e
2f
2c
2c
2c
7
3a (18)
3b (31)
3c (31)
3d (35)
3e (5)
3f (33)
3g (28)
4a (14)
In this reaction, NaOH, as a stronger inorganic base, could
easily deprotonate the N-(4-nitrobenzyl)pyridinium bromide 2c
to form the ylide which was stabilized by the nitrophenyl group.
Using the non-polar solvent toluene instead of DMF could
make the concerted 1,3-dipolar cycloaddition more competi-
4b (18)
4c (29)
4d (8)
14
tive. After general work-up, the two products 3c and 4c were
5 (15)
5 (20)
obtained (Scheme 2).
b
b
6 (25)
c
Compound 3c was the main and normal product which could
10
11
2
8a (42)c
8b (36)
9 (36)
10c
be easily determined. It was formed from oxidative aromatiz-
7
1
7
10 (10)
ation of the intermediate B which was initially produced by
a
[2ϩ3]-dipolar cycloaddition of 1a with N-(4-nitrobenzyl)pyr-
The typical reaction conditions were described in the Experimental
b
idinium ylide followed by dehydrofluorination. The structure of
another product, 4c, was determined by its spectral data and
section using KOH as base and all yields were isolated yields. Using
K CO as base. Final yield including the product transformed from
c
2
3
19
dihydrointermediate.
elemental analysis. Its F NMR spectrum had four peaks from
Ϫ114.4 to Ϫ126.0 ppm, showing an AB system with geminal
2
coupling constant J = 275.1 Hz, which corresponded to the
FF
coupling constant of the two fluorine nuclei on the carbon
vicinal to the asymmetric carbon; another signal at Ϫ189.8 ppm
could be assigned to the single fluorine nucleus at the asym-
metric carbon. In addition to the aromatic ring and ethoxy
obtained in poor yield (5% and 33% respectively, Table 1 entries
5 and 6). For the reaction of the acrylate 1b (R = ClCF ) with
f
2
bromide 2c, only the normal product 3g was formed in 28%
yield (Table 1, entry 7), and in this case, it was also a puzzle that
the initially formed cycloaddition product B did not dehydro-
chlorinate, but only oxidatively aromatize to the product 3g (see
Scheme 2).
1
group protons, the H NMR spectrum of this compound also
had another one-proton signal at δ 7.41, showing an obvious dd
2
3
pattern ( J = 43.6 Hz and J = 21.0 Hz) which was attrib-
HF
HF
uted to the proton at the asymmetric carbon, and the second
J-value corresponds to the coupling constant between the pro-
ton and one of the two fluorine nuclei at the vicinal carbon
atom; the other fluorine nucleus had a very small coupling con-
stant with this proton. In its mass spectrum compound 4c gave
the molecular-ion peak m/z 476 as the base peak. Other analysis
data all confirmed 4c had the structure shown in Scheme 2. It
was formed by dehydrofluorination of the intermediate B, fol-
lowed by 1,3-H-shift aromatization in intermediate C. Similar
treatment of the acrylate 1a with bromide 2a, 2b and 2d gave
two fluoroalkylated indolizine derivatives (see Scheme 2).
We could not explain how, in the reactions of the acrylate 1a
with the bromide 2e or 2f, only the normal products 3e and 3f,
formed from intermediate B by oxidative aromatization, were
In contrast to the foregoing reaction results, when the
acrylate 1c (R = BrCF ) was treated with N-(4-nitrobenzyl)-
f
2
pyridinium bromide 2c using NaOH as inorganic base, only the
1,3-H-shift product 5 was obtained in low yield (15%, Table 1,
entry 8). Interestingly, when K CO was used instead of NaOH,
2
3
this reaction also occurred readily. Two products were isolated;
one was 1,3-H-shift product 5; however, the other product was
not the normal bromodifluoromethyl-substituted indolizine
formed by oxidative aromatization, but a trifluoromethylated
19
indolizine 6, which was fully characterized by F NMR, MS
and microanalysis (C, H, N and F). The formation of the two
compounds might be as depicted in Scheme 3.
It is proposed that in this reaction, when the cycloaddition
intermediate D was formed, elimination of hydrogen bromide
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210
3205

View Article Online
Scheme 3
Scheme 4
to intermediate E should prevail over oxidative aromatization
to the bromodifluoromethyl-substituted product. The inter-
mediate E in one way underwent 1,3-H-shift aromatization
to the indolizine 5; it could also be attacked by fluoride anion
in another reaction route to give intermediate E, then suc-
cessive protonation (to G) and oxidative aromatization gave
the trifluoromethylated product 6. However, the possibility of
SET (single-electron transfer) reaction of the (bromodifluoro-
methyl)indolizine derivatives to produce these two compounds
could not be ruled out.
Reactions of N-benzylisoquinolinium ylide with ethyl 3-fluoro-
3
-(fluoroalkyl)acrylates
The same reaction conditions were also successfully employed
to the reaction of N-benzylisoquinolinium ylide with fluor-
inated acrylates 1a and 1b. Similar treatment of acrylates 1a
and 1b with N-benzylisoquinolinium bromide 7 gave two prod-
ucts which were observed by TLC analysis after the reactions
were complete. However, after general work-up, column chrom-
atography gave only the respective high-polarity products,
which were identified as fluoroalkyl-substituted pyrrolo[2,1-a]-
isoquinolines 8a and 8b, respectively. The low-polarity products
were transformed partly to 8a and 8b on the silica gel column.
When exposed to atmosphere or treatment with chloranil
Fig. 2 Molecular structure of compound 10, with crystallographic
numbering scheme.
15
of compound reported before, the acyl fluoride 10 was a stable
solid to handle. Recrystallization from diethyl ether–hexane
19
(1 : 10) afforded fine crystals for analysis. Its F NMR spec-
trum revealed a very-low-field signal at 38.2 ppm which indi-
cated the presence of a fluoroacyl group. The IR spectrum
(
oxidative reagent) they were also readily transformed to the
respective dehydrogenated compound 8a and 8b. It is reason-
able to suppose that those low-polarity compounds should be
the dihydrointermediate H instead of the 1,3-H-shift product
Ϫ1
showed two strong carbonyl group absorptions, at 1780 cm
(COF) and 1713 cm (COOEt), respectively.
Ϫ1
(
Scheme 4).
This structure was further confirmed by a single-crystal dif-
fraction study (Fig. 2). In molecule 10, the planar pyrrolo[2,1-
a]isoquinoline system is conjugated with the fluorocarbonyl
group: the angle between the two planes is 3Њ, the C(2)–C(16)
bond [1.435(4) Å] is significantly shorter than the standard
However, when the acrylate 1c (R = BrCF ) reacted with the
f
2
N-benzylisoquinolinium bromide 7 under the same conditions,
in addition to the obtained 1,3-H-shift product 9, a 2-fluoro-
carbonyl-substituted product 10 was also unexpectedly formed
under these strongly basic conditions. Similarly to this kind
2
2
16
C(sp )–C(sp ) single bond (1.49 Å), while the C(16)–O(3)
3
206
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210

View Article Online
Scheme 5
bond [1.226 (4) Å] is slightly longer than the standard carbon–
General procedure for preparation of N-benzylpyridinium
17
16
oxygen double bond (1.20 Å). On the other hand, the planes
of the ethoxycarbonyl and phenyl substituents are inclined to
the pyrrolo[1,2-a]isoquinoline plane by 75Њ and 70Њ, respect-
ively, probably due to steric repulsion from the fluorocarb-
onyl group. This and C(1)–C(13) and C(3)–C(17) bond lengths
bromide 2a–f and N-benzylisoquinolinium bromide 7
A solution of the benzyl bromide (50 mmol) in benzene
3
(
30 cm ) was added dropwise over 0.5 h to a stirred mixture of
pyridine (50 mmol) or isoquinoline (50 mmol) in acetone
3
(
30 cm ) at room temperature. After continual stirring at room
[both 1.483(4) Å] indicate the absence of π–π conjugation
temperature for 24 h (in some cases reflux was needed), the
reaction mixture was filtered, and the solid was washed with
diethyl ether and dried by vacuum. N-Benzylpyridinium brom-
ides 2a–f and N-benzylisoquinolinium bromide 7 were obtained
nearly quantitatively.
between these substituents and the pyrrolo[2,1-a]isoquinoline
system.
It was preferred that, notwithstanding the possibility of the
SET pathway described before, in the reaction of 1c with 7,
these two products 9 and 10 were formed through the process
shown in Scheme 5.
General procedure for the reactions of N-benzylpyridinium ylide
and N-benzylisoquinolinium ylide with ethyl 3-fluoro-3-(fluoro-
alkyl)acrylates
Conclusions
The 1,3-dipolar cycloaddition reactions of N-benzylpyrid-
inium ylide and N-benzylisoquinolinium ylide with ethyl
A mixture of an ethyl 3-fluoro-3-(fluoroalkyl)acrylate (1 mmol),
N-benzylpyridinium bromide or N-benzylisoquinolinium
3
2
-fluoro-3-(fluoroalkyl)acrylates were investigated. Thus 3-aryl-
-fluoroalkyl-substituted indolizine and pyrrolo[2,1-a]isoquino-
3
bromide (1.2 mmol), triethylamine (0.28 cm , 2 mmol) and
3
line derivatives were obtained. In particular, in the case of
ethyl 3-bromodifluoromethyl-3-fluoroacrylate, this reaction
unexpectedly afforded a trifluoromethylated indolizine and
a fluorocarbonyl-substituted pyrrolo[2,1-a]isoquinoline deriv-
ative, respectively. These reactions allow the preparation of
products where the substituent at the 3 position of the pro-
duced heterocycle is not limited to an electron-withdrawing
group.
sodium hydroxide (120 mg, 3 mmol) in toluene (20 cm ) was
stirred at 70–80 ЊC for ca. 6 h to complete the conversion of the
fluorine-containing substrates, after which the mixture was
cooled, and acidified with 1 M HCl so that the final sol-
ution had pH 6–7. The organic layer was separated and the
3
water layer was extracted with diethyl ether (3 × 20 cm ); the
combined extracts were washed with brine and dried over
anhydrous sodium sulfate. After removal of the solvent under
vacuum the residue obtained was separated by flash column
chromatography using light petroleum–ethyl acetate mixtures
as eluant to give the products.
Experimental
Instruments
Ethyl 2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-3-phenylindol-
izine-1-carboxylate 3a and ethyl 2-(3-chloro-1,2,2,3,3-penta-
fluoropropyl)-3-phenylindolizine-1-carboxylate 4a. Using the
general procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-hexafluoro-
propyl)-3-fluoroacrylate 1a (303 mg, 1 mmol) and N-benzyl-
pyridinium bromide 2a (300 mg, 1.2 mmol) followed by flash
All melting points were determined on a Melt-Temp apparatus
and are uncorrected. Infrared (IR) spectra were recorded on a
1
Perkin–Elmer 983G spectrophotometer (KBr disc). H NMR
19
and F NMR spectra were recorded on Bruker AM-300
and Varian-360L spectrometers operating at 300 MHz and
5
6.4 MHz in CDCl with TMS and TFA [δ(CFCl ) = δ(TFA)
3
3
column chromatography using hexane–EtOAc (35 : 1; R = 0.3–
f
Ϫ76.8, with high-field negative] as internal and external stan-
dard, respectively. The following abbreviations are used: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doublet of doublets. Coupling constants J are recorded in Hz.
Low- and high-resolution mass spectra were obtained on an
HP 5989a and a Finnigan MAT spectrometer, respectively.
Elemental analyses were performed by this Institute.
0
1
.4) as eluant first afforded compound 4a (64 mg, 0.14 mmol,
4%) as a white solid, mp 125.0–127.0 ЊC (Found: C, 55.58;
H, 3.44; N, 3.21. C H ClF NO requires C, 55.63; H, 3.50;
20
15
5
2
Ϫ1
N, 3.24%); νmax(KBr)/cm 1660, 1500, 1100–1200 and 800;
δ (282.0 MHz; CDCl ; CFCl ) Ϫ68.8 (2 F, s, ClCF ), Ϫ114.3,
F
3
3
2
Ϫ125.4 (2 F, AB system, J 274.3, ClCF CF ), Ϫ191.0 (1 F, m,
2
2
ClCF CF CFH); δ (300 MHz; CDCl ; Me Si) 8.32 [1 H, d,
2
2
H
3
4
J 9.0, C(5)-H], 7.68 [1 H, d, J 7.2, C(8)-H], 6.68–7.63 (8 H,
m, ArH and CFH), 4.45 (2 H, q, J 7.4, OCH CH ), 1.49 (3 H,
General method
2
3
ϩ
Solvents and reagents were obtained using standard pro-
t, J 7.4, OCH CH ); m/z (EI) 431/433 (M , 100.00/35.5%), 403/
2 3
cedures: benzene (Na metal), pyridine (CaH ) and toluene (Na
405 (16.43/5.49), 386/388 (25.82/8.92), 359/361 (33.92/11.67).
2
metal); all other reagents and solvents used as supplied. Flash
column chromatography was performed using silica gel H, par-
ticle size 10–40 µ purchased from QingDao ocean chemical
factory.
Then was furnished compound 3a (35 : 1; R = 0.2–0.3) as a
white solid (81 mg, 0.18 mmol, 18%), mp 102.0–104.5 ЊC
f
(Found: C, 53.55; H, 3.17; N, 3.09. C H ClF NO requires C,
2
0
14
Ϫ1
6
2
53.41; H, 3.14; N, 3.11%); νmax(KBr)/cm 2910, 1700, 1500,
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210
3207

View Article Online
ϩ
1
430, 1100–1270 and 910; δ (56.4 MHz; CDCl ; CFCl ) Ϫ65.7
494/496 (M , 100.00/35.6%), 466/468 (23.04/8.30), 422/424
(47.93/16.73).
F
3
3
(
2 F, s, ClCF ), Ϫ95.2 (2 F, s, ClCF CF CF ), Ϫ125.8 (2 F, s,
2 2 2 2
ClCF CF ); δ (300 MHz; CDCl ; Me Si) 8.38 [1 H, d, J 9.1,
2
2
H
3
4
C(5)-H], 6.60–7.70 (8 H, m, ArH), 4.38 (2 H, q, J 7.2,
OCH CH ), 1.41 (3 H, t, J 7.2, OCH CH ); m/z (EI) 449/451
Diethyl
indolizine-1,7-dicarboxylate 3d and diethyl 2-(3-chloro-1,2,2,3,3-
pentafluoropropyl)-3-phenylindolizine-1,7-dicarboxylate 4d.
2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-3-phenyl-
2
3
2
3
ϩ
(
M , 100.00/35.06%), 421/423 (5.81/1.98), 404/406 (29.09/9.59),
3
77/379 (25.01/8.14), 248 (84.58).
Using the general procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-
hexafluoropropyl)-3-fluoroacrylate 1a (303 mg, 1 mmol) and
N-benzyl-4-(ethoxycarbonyl)pyridinium bromide 2d (388 mg,
1.2 mmol) followed by flash column chromatography using
Ethyl 2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-3-(4-methoxy-
phenyl)indolizine-1-carboxylate 3b and ethyl 2-(3-chloro-1,2,2,3,3-
pentafluoropropyl)-3-(4-methoxyphenyl)indolizine-1-carboxylate
hexane–EtOAc (10 : 1; R = 0.5–0.6) as eluant first afforded
f
4
b. Using the general procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-
hexafluoropropyl)-3-fluoroacrylate 1a (303 mg, 1 mmol) and N-
4-methoxybenzyl)pyridinium bromide 2b (336 mg, 1.2 mmol)
compound 4d (40 mg, 0.08 mmol, 8%) as a light yellow solid,
Ϫ1
mp 118.0–119.0 ЊC; νmax(KBr)/cm 2978, 1711, 1687, 1519,
(
1027–1315 and 764; δF (282.0 MHz; CDCl ; CFCl ) Ϫ68.7
3
3
followed by flash column chromatography using hexane–
(2 F, s, ClCF ), Ϫ114.4, Ϫ125.2 (2 F, AB system, J 274.5,
2
EtOAc (10 : 1; R = 0.4–0.5) as eluant first afforded compound
ClCF CF ), Ϫ191.7 (1 F, m, ClCF CF CFH); δ (300 Hz;
f
2
2
2
2
H
4
b (82 mg, 0.18 mmol, 18%) as a white solid, mp 109.1–112.5 ЊC
CDCl ; Me Si) 9.08 [1 H, s, C(8)-H], 7.13–7.72 (7 H, m, ArH
3 4
(
5
1
Found: C, 54.60; H, 3.58; N, 2.87. C H ClF NO requires C,
and CFH), 4.31–4.58 (4 H, m, 2 × OCH CH ), 1.31–1.58 (6 H,
2 3
ϩ
21
17
Ϫ1
5
3
4.62; H, 3.71; N, 3.03%); νmax(KBr)/cm 2980, 1666, 1610,
569, 1498, 1038–1324; δ (282.0 MHz; CDCl ; CFCl ) Ϫ68.6
m, 2 × OCH CH ); m/z (EI) 503.091 79 (M . C H ClF NO
2 3 23 19 5 4
requires M, 503.092 28), 505 (39.92%), 475/477 (9.78/3.51),
F
3
3
(
2 F, s, ClCF ), Ϫ114.5, Ϫ125.3 (2 F, AB system, J 274.3,
458/460 (17.36/6.24), 431/433 (15.13/4.99). Then furnished
2
ClCF CF ), Ϫ191.3 (1 F, m, ClCF CF CFH); δ (300 MHz;
compound 3d (10 : 1; R = 0.4–0.5) as a light yellow solid
2
2
2
2
H
f
CDCl ; Me Si) 8.29 [1 H, d, J 9.0, C(5)-H], 7.66 [1 H, d, J 7.1,
(182 mg, 0.35 mmol, 35%), mp 70.0–73.0 ЊC (Found: C, 53.12;
3
4
C(8)-H], 6.94–7.48 (7 H, m, ArH and CFH), 4.44 (2 H, q, J 7.3,
OCH CH ), 3.90 (3 H, s, OCH ), 1.43 (3 H, t, J 7.3, OCH CH );
H, 3.50; N, 2.63. C H ClF NO requires C, 52.94; H, 3.48;
23
18
6
4
Ϫ1
N, 2.68%); νmax(KBr)/cm 2924, 1714, 1521, 1184–1316 and
761; δ (56.4 MHz; CDCl ; CFCl ) Ϫ67.0 (2 F, s, ClCF ), Ϫ97.4
2
3
3
2
3
ϩ
m/z (EI) 461/463 (M , 100.00/38.79%), 433/435 (2.37/0.88),
16/418 (12.07/5.44), 389/391 (12.98/4.59), 278 (26.12). Then
F
3
3
2
4
(2 F, s, ClCF CF CF ), Ϫ116.6 (2 F, s, ClCF CF ); δ
2 2 2 2 2 H
was furnished compound 3b (10 : 1; R = 0.3–0.4) as a white
solid (148 mg, 0.31 mmol, 31%), mp 81.0–83.5 ЊC (Found: C,
(300 MHz; CDCl ; Me Si) 9.09 [1H, s, C(8)-H], 7.18–7.68 (7 H,
3 4
f
m, ArH), 4.31–4.58 (4 H, m, 2 × OCH CH ), 1.31–1.58 (6 H, m,
2 3
ϩ
5
3
1
2.70; H, 3.19; N, 2.80. C H ClF NO requires C, 52.67; H,
2 × OCH CH ); m/z (EI) 521/523 (M , 100.00/38.00%), 476/478
2 3
21
16
Ϫ1
6
3
.36; N, 2.92%); νmax(KBr)/cm 2999, 1705, 1610, 1555, 1505,
058–1328 and 867; δ (56.4 MHz; CDCl ; CFCl ) Ϫ65.5 (2 F,
(21.52/7.69), 448/450 (23.54/11.54), 310 (16.64).
F
3
3
s, ClCF ), Ϫ96.4 (2 F, s, ClCF CF CF ), Ϫ115.7 (2 F, s,
Ethyl 2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-7-methyl-3-(4-
nitrophenyl)indolizine-1-carboxylate 3e. Using the general
procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-
3-fluoroacrylate 1a (303 mg, 1 mmol) and 4-methyl-N-(4-
nitrobenzyl)pyridinium bromide 2e (370 mg, 1.2 mmol)
followed by flash column chromatography using hexane–
2
2
2
2
ClCF CF ); δ (300 MHz; CDCl ; Me Si) 8.34 [1 H, d, J 9.0,
2
2
H
3
4
C(5)-H], 7.51 [1 H, d, J 7.3, C(8)-H], 6.58–7.49 (6 H, m,
ArH), 4.41(2 H, q, J 7.3, OCH CH ), 3.91 (3 H, s, OCH ), 1.41
2
3
3
ϩ
(
3 H, t, J 7.3, OCH CH ); m/z (EI) 479/481 (M , 100.00/38.9%),
2 3
4
2
51/453 (4.06/1.42), 434/436 (13.55/5.47), 407/409 (11.87/3.97),
96 (14.48).
EtOAc (10 : 1; R = 0.1–0.2) as eluant afforded compound 3e
f
(
25 mg, 0.05 mmol, 5%) as a yellow solid, mp 166.0–168.0 ЊC
Ethyl
2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-3-(4-nitro-
(Found: C, 49.72; H, 3.10; N, 5.30. C H ClF NO requires C,
21
15
Ϫ1
6
4
phenyl)indolizine-1-carboxylate 3c and ethyl 2-(3-chloro-1,2,2,3,3-
pentafluoropropyl)-3-(4-nitrophenyl)indolizine-1-carboxylate 4c.
Using the general procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-
hexafluoropropyl)-3-fluoroacrylate 1a (303 mg, 1 mmol) and
N-(4-nitrobenzyl)pyridinium bromide 2c (354 mg, 1.2 mmol)
followed by flash column chromatography using hexane–
49.57; H, 2.97; N, 5.51%); νmax(KBr)/cm 1679, 1600, 1515,
1057–1350 and 854; δ (56.4 MHz; CDCl ; CFCl ) Ϫ65.8 (2 F,
F
3
3
s, ClCF ), Ϫ96.1 (2 F, s, ClCF CF CF ), Ϫ115.8 (2 F, s,
2
2
2
2
ClCF CF ); δ (300 MHz; CDCl ; Me Si) 8.40 (2 H, d,
2
2
H
3
4
J 8.9, 2 × o-NO C H H), 8.21 [1 H, s, C(8)-H)], 7.61 (2 H,
2
6
3
d, J 8.9, 2 × m-NO C H H), 7.35 [1 H, d, J 7.1, C(5)-H], 6.61
2
6
3
EtOAc (7 : 1; R = 0.3–0.4) as eluent first afforded compound 4c
[1 H, d, J 7.1, C(6)-H], 4.40 (2 H, q, J 7.3, OCH CH ), 2.41
f
2 3
(
138 mg, 0.29 mmol, 29%) as a yellow solid, mp 172.0–174.0 ЊC
[3 H, s, C(7)-CH ], 1.41 (3 H, t, J 7.3, OCH CH ); m/z (EI)
3 2 3
ϩ
508/510 (M , 100.00/38.9%), 480/482 (23.91/8.06), 463/465
(33.09/11.34), 436/438 (49.06/16.77).
(
5
1
Found: C, 50.53; H, 3.05; N, 5.83. C H ClF N O requires C,
0.38; H, 2.95; N, 5.87%); νmax(KBr)/cm 1680, 1592, 1502,
20
14
5
2
4
Ϫ1
100–1280 and 771; δF (282.0 MHz; CDCl ; CFCl ) Ϫ68.8
3
3
(
2 F, s, ClCF ), Ϫ114.7, Ϫ125.4 (2 F, AB system, J 275.1,
Diethyl 2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-3-(4-nitro-
phenyl)indolizine-1,7-dicarboxylate 3f. Using the general
procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-
3-fluoroacrylate 1a (303 mg, 1 mmol) and 4-ethoxycarbonyl-
N-(4-nitrobenzyl)pyridinium bromide 2f (440 mg, 1.2 mmol)
followed by flash column chromatography using hexane–
2
ClCF CF ), Ϫ189.8 (1 F, m, ClCF CF CFH); δ (300 MHz;
CDCl ; Me Si) 8.36–8.43 [3 H, m, C(5)-H and 2 × o-NO
C H H], 7.64–7.69 [3 H, m, C(8)-H and 2 × m-NO C H H],
7
4
2
2
2
2
H
3
4
2
6
3
2
6
3
.41 (1 H, dd, J 43.6 and 21.0, CFH), 6.78–7.25 (2 H, m, ArH),
.50 (2 H, q, J 7.0, OCH CH ), 1.49 (3 H, t, J 7.0, OCH CH );
2
3
2
3
ϩ
m/z (EI) 476/478 (M , 100.00/35.06%), 448/450 (14.67/5.16),
31/433 (24.37/8.14). Then was furnished compound 3c (7 : 1;
EtOAc (5 : 1; R = 0.4–0.5) as eluant afforded compound 3f
f
4
(187 mg, 0.33 mmol, 33%) as a yellow solid, mp 153.0–155.0 ЊC
R = 0.2–0.3) as a yellow solid (153 mg, 0.31 mmol, 31%),
mp 195.5–197.0 ЊC (Found: C, 48.57; H, 2.67; N, 5.52.
(Found: C, 48.72; H, 3.14; N, 4.83. C H ClF N O requires C,
f
23 17
6
2
6
Ϫ1
48.74; H, 3.02; N, 4.94%); νmax(KBr)/cm 2984, 1716, 1602,
1518 and 1027–1314; δ (56.4 MHz; CDCl ; CFCl ) Ϫ65.8 (2 F,
C H ClF N O requires C, 48.55; H, 2.65; N, 5.66%);
2
0
13
6
2
4
F
3
3
Ϫ1
νmax(KBr)/cm 1670, 1594, 1500, 1100–1257 and 759; δ (56.4
s, ClCF ), Ϫ96.8 (2 F, s, ClCF CF CF ), Ϫ115.8 (2 F, s,
F
2
2
2
2
MHz; CDCl ; CFCl ) Ϫ66.0 (2 F, s, ClCF ), Ϫ96.3 (2 F, s,
ClCF CF ); δ (300 MHz; CDCl ; Me Si) 9.10 [1 H, s, C(8)-H],
2 2 H 3 4
3
3
2
ClCF CF CF ), Ϫ115.8 (2 F, s, ClCF CF ); δ (300 MHz;
8.43 (2 H, d, J 8.7, 2 × o-NO C H H), 7.62 (2 H, d, J 8.7, 2 ×
2
2
2
2
2
H
2 6 3
CDCl ; Me Si) 8.42–8.45 [3 H, m, C(5)-H and 2 × o-NO -
m-NO C H H), 7.46 [1 H, d, J 7.3, C(5)-H], 7.29 [1 H, d, J 7.3,
2 6 3
3
4
2
C H H], 7.62 (2 H, d, J 9.0, 2 × m-NO C H H], 7.46 [1 H,
C(6)-H], 4.40–4.47 (4 H, m, 2 × OCH CH ), 1.41–1.47 (6 H, m,
2 3
ϩ
6
3
2
6
3
d, J 6.8, C(8)-H], 6.80–7.25 (2 H, m, ArH), 4.40 (2 H, q,
J 7.5, OCH CH ), 1.46 (3 H, t, J 7.5, OCH CH ); m/z (EI)
2 × OCH CH ); m/z (EI) 566/568 (M , 100.00/35.85%), 538/540
2 3
(19.32/6.58), 521/523 (35.85/12.86), 494/496 (53.41/18.82).
2
3
2
3
3
208
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210

View Article Online
Ethyl
2-chlorodifluoromethyl-3-(4-nitrophenyl)indolizine-1-
Ethyl 2-chlorodifluoromethyl-3-phenylpyrrolo[2,1-a]isoquinol-
carboxylate 3g. Using the general procedure with ethyl 3-
chlorodifluoromethyl-3-fluoroacrylate 1b (203 mg, 1 mmol)
and N-(4-nitrobenzyl)pyridinium bromide 2c (354 mg, 1.2
mmol) followed by flash column chromatography using
ine-1-carboxylate 8b. Using the general procedure with ethyl
3-chlorodifluoromethyl-3-fluoroacrylate 1b (303 mg, 1 mmol)
and N-benzylisoquinolinium bromide 7 (360 mg, 1.2 mmol),
the obtained residue, after exposure in air for one day fol-
lowed by flash column chromatography using hexane–EtOAc
hexane–EtOAc (5 : 1; R = 0.2–0.3) as eluant afforded com-
f
pound 3g (110 mg, 0.28 mmol, 28%) as a yellow solid, mp
(10 : 1; R = 0.5–0.6) as eluant, afforded compound 8b
(143 mg, 0.36 mmol, 36%) as a white solid, mp 122.0–124.5 ЊC
f
2
14.3–217.5 ЊC (Found: C, 54.69; H, 3.40; N, 6.87.
C H ClF N O requires C, 54.77; H, 3.32; N, 7.10%);
(Found: C, 65.72; H, 4.05; N, 3.41. C H ClF NO requires C,
1
8
17
2
2
Ϫ1
4
22 16
2
2
Ϫ1
νmax(KBr)/cm 1676, 1602, 1515, 1049–1349 and 856; δ (56.4
66.09; H, 4.03; N, 3.50%); νmax(KBr)/cm 2967, 1710, 1527,
1041–1373 and 743; δ (56.4 MHz; CDCl ; CFCl ) Ϫ38.0 (2 F, s,
F
MHz; CDCl ; CFCl ) Ϫ39.0 (s, ClCF ); δ (300 MHz; CDCl ;
3
3
2
H
3
F
3
3
Me Si) 8.28–8.39 [3 H, m, 2 × o-NO C H H and C(5)-H], 7.54–
ClCF ); δ (300 MHz; CDCl ; Me Si) 8.49 [1 H, d, J 8.1, C(5)-
4
2
6
3
2 H 3 4
7
.72 [3 H, m, 2 × m-NO C H H and C(8)-H], 6.70–7.18 (2 H,
H], 7.40–7.58 (9 H, m, ArH), 6.80 [1 H, d, J 8.1, C(6)-H], 4.54
(2 H, q, J 7.2, OCH CH ), 1.48 (3 H, t, J 7.1, OCH CH ); m/z
(EI) 399/401 (M , 95.35/34.26%), 316 (M Ϫ ClCF2 ϩ 1,
2
6
3
m, ArH), 4.40 (2 H, q, J 7.0, OCH CH ), 1.41 (3 H, t, J 7.0,
OCH CH ); m/z (EI) 394/396 (M , 100.00/35.20%), 366/368
2
3
2
3
2
3
ϩ
ϩ
ϩ
2
3
(
(
14.89/5.09), 349/351 (27.70/9.24), 322/324 (40.84/13.67), 360
29.36).
100.00), 354/356 (27.48/10.47), 327/329 (25.10/8.89).
Ethyl 2-difluoromethyl-3-phenylpyrrolo[2,1-a]isoquinoline-1-
carboxylate 9 and ethyl 2-fluorocarbonyl-3-phenylpyrrolo[2,1-
a]isoquinoline-1-carboxylate 10. Using the general procedure
with ethyl 3-bromodifluoromethyl-3-fluoroacrylate 1c (248 mg,
1 mmol) and N-benzylisoquinolinium bromide 7 (360 mg,
1.2 mmol) followed by flash column chromatography using
Ethyl 2-difluoromethyl-3-(4-nitrophenyl)indolizine-1-carboxyl-
ate 5. Using the general procedure with ethyl 3-bromo-
difluoromethyl-3-fluoroacrylate 1c (248 mg, 1 mmol) and
N-(4-nitrobenzyl)pyridinium bromide 2c (354 mg, 1.2 mmol)
followed by flash column chromatography using hexane–
EtOAc (8 : 1; R = 0.2–0.3) as eluant afforded compound
hexane–EtOAc (18 : 1; R = 0.2–0.3) as eluant afforded com-
f
f
5
(54 mg, 0.15 mmol, 15%) as a yellow solid, mp 145.0–
pound 9 (131 mg, 0.36 mmol, 36%) as a white solid, mp 89.0–
Ϫ1
1
47.2 ЊC (Found: C, 60.14; H, 4.07; N, 7.66. C H F N O
93.0 ЊC; νmax(KBr)/cm 2961, 1696, 1606, 1046–1367 and 787;
18
14
Ϫ1
2
2
4
requires C, 60.00; H, 3.91; N, 7.77%); νmax(KBr)/cm 1679,
600, 1514, 1019–1349 and 859; δ (56.4 MHz; CDCl ; CFCl )
δF (56.4 MHz; CDCl ; CFCl ) Ϫ105.2 (d, J 54.6, HCF ); δ
3
3
2
H
1
(300 MHz; CDCl ; Me Si) 9.05 [1 H, d, J 8.1, C(5)-H], 7.48–
3 4
F
3
3
Ϫ107.2 (d, J 55.3, HCF ); δH (300 MHz; CDCl ; Me Si)
7.64 (9 H, m, ArH), 6.98 (1 H, t, J 54.6, HCF ), 6.88 [1 H,
2
3
4
2
8
7
.20–8.57 [3 H, m, 2 × o-NO C H H and C(5)-H], 6.74–
d, J 8.1, C(6)-H], 4.55 (2 H, q, J 7.1, OCH CH ), 1.50 (3 H, t,
2
6
3
2
3
ϩ
.97 (6 H, m, ArH and HCF ), 4.45 (2 H, q, J 7.1, OCH -
J 7.1, OCH CH ); m/z (EI) 365.12291 (M . C H F NO
2
2
ϩ
2 3 22 17 2 2
CH ), 1.46 (3 H, t, J 7.1, OCH CH ); m/z (EI) 360 (M ,
requires M, 365.12273), 337 (19.24%), 320 (46.83), 293 (57.29).
3
2
3
1
00.00%), 332 (31.81), 315 (25.97), 288 (32.85), 269 (11.53), 241
Then using hexane–EtOAc (10 : 1; R = 0.3–0.4) as eluant fur-
f
(
11.05).
nished compound 10 (36 mg, 0.10 mmol, 10%) as a white solid,
mp 127.0–129.5 ЊC (Found: C, 73.20; H, 4.21; N, 3.77; F, 5.07.
C H FNO requires C, 73.12; H, 4.46; N, 3.88; F, 5.26%);
Ethyl 2-trifluoromethyl-3-(4-nitrophenyl)indolizine-1-carbox-
22
16
3
Ϫ1
ylate 6. The same procedure described above for compound
5
νmax(KBr)/cm 2981, 1780, 1713, 1531, 1202 and 747; δF
(56.4 MHz; CDCl ; CFCl ) 38.2 (s, COF); δ (300 MHz;
but using K CO as inorganic base instead of NaOH first
2
3
3
3
H
afforded compound 5 (72 mg, 0.20 mmol, 20%) as a yellow solid
CDCl ; Me Si) 8.01 [1 H, d, J 7.6, C(5)-H], 7.46–7.61 (9 H, m,
3 4
with identical spectroscopic data to those reported above, then
ArH), 6.87 [1 H, d, J 7.6, C(6)-H], 4.57 (2 H, q, J 7.1,
ϩ
furnished compound 6 (8 : 1; R = 0.2–0.3) (95 mg, 0.25 mmol,
OCH CH ), 1.47 (3 H, t, J 7.1, OCH CH ); m/z (EI) 361 (M ,
f
2
3
2
3
2
5%) as a yellow solid, mp 213.0–215.5 ЊC (Found: C, 57.20; H,
100.00%), 333 (11.05).
3
.71; N, 7.62; F, 14.68. C H F N O requires C, 57.15; H, 3.46;
18
13
3
2
4
Ϫ1
N, 7.40; F, 15.07%); νmax(KBr)/cm 1675, 1602, 1515, 1052–
Determination of the X-ray crystal structure†
1
350 and 852; δ (56.4 MHz; CDCl ; CFCl ) Ϫ52.1 (s, CF ); δ
F 3 3 3 H
A colourless crystal of 0.40 × 0.20 × 0.13 mm size was grown
from hexane–diethyl ether. The experiment was carried out on a
Bruker P4 four-circle diffractometer at room temperature, using
graphite-monochromated Mo-Kα radiation (λ = 0.710 73 Å).
Crystal data: C H FNO , M = 361.36, monoclinic, space
(
300 MHz; CDCl ; Me Si) 8.36–8.43 [3 H, m, 2 × o-NO C H H
3
4
2
6
3
and C(5)-H], 7.62–7.65 [3 H, m, 2 × m-NO C H H and C(8)-H],
6
2
6
3
.78–7.20 (2 H, m, ArH), 4.45 (2 H, q, J 7.1, OCH CH ), 1.46
2 3
ϩ
(
(
(
3 H, t, J 7.1, OCH CH ); m/z (EI) 378 (M , 100.00%), 350
27.93), 333 (35.53), 306 (33.37), 287 (13.39), 259 (14.80), 240
8.36), 69 (16.07).
2 3
22
16
3
group C2/c (No. 15), a = 20.375(4), b = 11.151(2), c = 16.522(4)
3
Å, β = 103.55(1)Њ, V = 3649(1) Å (by least-squares refinement
on setting angles of 25 reflections with 5Њ < θ < 12.5Њ), Z = 8,
Ethyl 2-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-3-phenylpyr-
rolo[2,1-a]isoquinoline-1-carboxylate 8a. Using the general
procedure with ethyl 3-(3-chloro-1,1,2,2,3,3-hexafluoropropyl)-
-fluoroacrylate 1a (303 mg, 1 mmol) and N-benzylisoquino-
linium bromide 7 (360 mg, 1.2 mmol) as reactant, the obtained
residue, after exposure in air for one day followed by flash
Ϫ3
Ϫ1
D = 1.315 g cm , µ = 0.09 mm . 5026 Reflections (of which
c
4
199 independent) with 2.06Њ < θ < 27.51Њ were measured in
θ/2θ scan mode and corrected for decay and absorption (by
empirical method; Rint = 0.047). The structure was solved by the
3
direct method and refined by least-squares against F of all
2
18
data, using the program SHELX-97, to R = 0.065 [for 1565
column chromatography using hexane–EtOAc (10 : 1; R = 0.5–
f
observed reflections with I > 2σ(I )] and wR(F2) = 0.150 (for all
data).
0
4
.6) as eluant, afforded compound 8a (210 mg, 0.42 mmol,
2%) as a white solid, mp 143.0–145.5 ЊC (Found: C, 57.85;
H, 3.49; N, 2.53. C H ClF NO requires C, 57.67; H, 3.23;
24
16
6
2
Ϫ1
Acknowledgements
N, 2.80%); νmax(KBr)/cm 2986, 1711, 1526, 1026–1362 and
37; δ (56.4 MHz; CDCl ; CFCl ) Ϫ67.1 (2 F, s, ClCF ), Ϫ98.8
7
F
3
3
2
We thank the National Natural Science Foundation of China
(NNSFC) (No. 20032010 and 20072049) and the Innovation
Foundation of the Chinese Academy of Science for financial
support.
(
2 F, s, ClCF CF CF ), Ϫ117.9 (2 F, s, ClCF CF ); δ
2 2 2 2 2 H
(
300 MHz; CDCl ; Me Si) 8.19 [1 H, d, J 8.0, C(5)-H], 7.22–
3 4
7
.72 (9 H, m, ArH), 6.80 [1 H, d, J 8.0, C(6)-H], 4.60 (2 H, q,
J 7.1, OCH CH ), 1.40 (3 H, t, J 7.1, OCH CH ); m/z (EI)
2
3
2
3
ϩ
4
99/501 (M , 100.00/39.78%), 471/473 (8.59/2.84), 454/456
†
CCDC reference number(s) 163149. See http://www.rsc.org/suppdata/
(
38.81/14.09), 427/429 (32.68/13.39).
p1/b1/b103586j/ for crystallographic files in .cif or other electronic format.
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210
3209

View Article Online
Chemistry, ed. A. R. Katritzky and C. W. Rees, Pergamon Press,
New York, 1984, vol. 8, p. 443.
References
1
The Alkaloids, ed. R. H. F. Manske and H. L. Holmes, Academic
Press, New York, 1952, vol. 2, ch. 5.
9 S. Z. Zhu, C. Y. Qing, Y. L. Wang and Q. L. Chu, J. Fluorine Chem.,
1999, 99, 183.
10 (a) R. E. Banks and S. N. Mohialdin, J. Fluorine Chem., 1991, 51,
373; (b) X. C. Zhang and W. Y. Huang, J. Fluorine Chem., 1998,
92, 13; (c) X. C. Zhang and W. Y. Huang, J. Fluorine Chem., 1998,
87, 57.
11 (a) G. D. Bue and J. Nasielski, Bull. Soc. Chim. Belg., 1997, 106, 97;
(b) A. Padwa, D. J. Austin, L. Precedo and L. Zhi, J. Org. Chem.,
1993, 58, 114; (c) C. A. Henrick, E. Ritchie and W. C. Taylor, Aust. J.
Chem., 1967, 20, 2467; (d ) Y. Kobayashi, I. Kumadaki, Y. Sekine
and T. Kutsuma, Chem. Pharm. Bull., 1973, 21, 1118.
12 R. Huigen, R. Grashey and E. Steingruber, Tetrahedron Lett., 1963,
1441.
13 For preparation method see: B. H. Luo, H. P. Guan, Q. F. Wang and
C. M. Hu, Chin. Chem. Lett., 1997, 8, 583.
14 A. Belen, B. Rafael, R. M. Mohamed, J. Gurnos, J. A. David and
B. H. Michael, Tetrahedron Lett., 1991, 32, 4977.
15 R. Sundaramoorthi, J. J. Robert and P. C. Michael, Tetrahedron
Lett., 1987, 28, 5099.
16 F. H. Allen, O. Kennard, D. G. Wastson, L. Brammer, A. G. Orpen
and R. Taylor, J. Chem. Soc., Perkin Trans. 2, 1987, S1.
17 X. C. Zhang, PhD Thesis, Shanghai Institute of Organic Chemstry,
Academy of Science, China, March, 1998.
2
P. E. Sonnet and J. E. Oliver, J. Heterocycl. Chem., 1975, 12,
2
89.
3
4
W. J. Gensler and M. W. Hu, J. Org. Chem., 1973, 38, 3848.
C. J. Maring, D. A. Degoey, W. J. Flosi, V. L. Giranda, D. J. Kempf,
A. Kennedy, L. L. Klein, A. C. Krueger, K. F. McDaniel, V. S. Stoll,
M. Sun and C. Zhao, WO 2001 029 050, 2001, (Chem. Abstr., 2001,
1
34, 311215r).
5
6
G. D. Cuny, EP 780 443, 1997, (Chem. Abstr., 1997, 127, 110293w).
T. Sato, T. Sakaeda and K. Ichinose, JP 01 260 646, 1989, (Chem.
Abstr., 1990, 113, 68450d).
7
For reviews see: (a) R. Filler and Y. Kobayashi, Biomedical Aspects
of Fluorine Chemistry, Elsevier, New York, 1982; (b) R. E. Banks,
Organofluorine Compounds and Their Applications, Ellis Horwood,
Chichester, 1979; for recent patents see: (c) K. Kato, J. Terauchi,
N. Suzuki and S. Takekawa, WO 2001 025 228, 2001, (Chem. Abstr.,
2
001, 134, 295840h); (d ) S. C. Benson, S. M. Menchen, P. D.
Theisen, K. G. Upadhya and J. D. Hauser, WO 99 16 832, 1999,
Chem. Abstr., 1999, 130, 283357k).
For review see (a) T. Uchida and K. Matsumoto, Synthesis, 1976,
09; (b) F. J. Swinbourne, in Advances in Heterocyclic Chemistry, ed.
A. R. Katritzky and A. J. Boulton, Academic Press, New York,
978, vol. 23, p. 104; (c) W. Flitsch, in Comprehensive Heterocyclic
(
8
2
1
18 G. M. Sheldrick, SHELX-97, University of Gottingen, Germany.
3
210
J. Chem. Soc., Perkin Trans. 1, 2001, 3204–3210