Synthesis of monofluorinated indolizines and their derivatives by the 1,3-dipolar reaction of N-ylides with fluorinated vinyl tosylates

Article abstract of DOI:10.1016/j.tet.2004.04.012

Monofluorinated indolizines 4, benzo[d]indolizines 7 and 4H-pyrrolo[1,2-a]benzimidazoles 8 were synthesized in moderate yields by 1,3-dipolar reaction between fluorinated vinyl tosylates 2a and N-ylides of pyridinium, isoquinolinium and benzimidazolinium, generated in situ from their halides salts. When the same N-ylides were allowed to react with 2,3,3-trifluoro-1-propenyl tosylate 2b, the unexpected product formylated indolizines and their derivatives 9 were obtained. The reaction mechanism is also proposed.

Full text of DOI:10.1016/j.tet.2004.04.012

Tetrahedron 60 (2004) 5487–5493
Synthesis of monofluorinated indolizines and their derivatives by
the 1,3-dipolar reaction of N-ylides with fluorinated vinyl tosylates
a
b
,
Xiang Fang,a,b Yong-Ming Wu,a Juan Deng and Shao-Wu Wang
,
*
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
bDepartment of Chemistry, Anhui Normal University, 1 Renming Road, Wuhu Anhui 241000, China
Received 15 July 2003; revised 24 February 2004; accepted 1 April 2004
Abstract—Monofluorinated indolizines 4, benzo[d]indolizines 7 and 4H-pyrrolo[1,2-a]benzimidazoles 8 were synthesized in moderate
yields by 1,3-dipolar reaction between fluorinated vinyl tosylates 2a and N-ylides of pyridinium, isoquinolinium and benzimidazolinium,
generated in situ from their halides salts. When the same N-ylides were allowed to react with 2,3,3-trifluoro-1-propenyl tosylate 2b, the
unexpected product formylated indolizines and their derivatives 9 were obtained. The reaction mechanism is also proposed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
under atmospheric pressure ylides fluorinated heterocycles.7
Zhu reported the reactions of 4-ethoxyl-1,1,1-trifluorobut-3-
ene-2-one with N-ylides to synthesize trifluoroacetyl
substituted heterocycles.8 In the present paper, we wish to
report a new approach towards monofluorinated indolizines
and 4H-pyrrolo[1,2-a]benzimidazoles via the reaction of
ylides of N-containing heterocycles with fluorinated alkenyl
tosylates.
Indolizine derivatives possess valuable biological activities
and have been studied for their psychotropic anti-inflam-
matory, analgesic, antimicrobial, antiexudative and hypo-
glycemia activities.1 Meanwhile, fluorinated heterocyclic
compounds have received increasing attention due to their
potential biological and industrial applications.2 In the past
few decades, considerable efforts have been paid to the
exploitation of new and convenient synthetic routes to these
compounds.3 Comparing with direct fluorination and halo-
exchange reactions, the application of fluorine-containing
building blocks in organic synthesis has become a more and
more important strategy for the construction of fluorinated
heterocycles due to its higher selectivity and milder
conditions. 1,3-Dipolar cycloaddition is one of the most
important methods for constructing five-membered hetero-
cycles.4 Recently, it has also been used for the synthesis of
fluorinated heterocyclic compounds. In 1980s, Banks
reported a series of papers on the 1,3-dipolar cycloaddition
reactions of pyridinium ylides with various perfluoro-
alkenes, perfluoroazaolefins and trifluoroacetonitrile to
synthesize monofluoro- or tirfluoromethyl-substituted
heterocycles, such as pyrazolo[1,2-a]pyridines and
indolizines.5 Huang reported the reactions of various
nitrogen-containing heterocycles ylides with 2,2-dihydro-
perfluoroalkanoates to form perfluoroalkylated hetero-
2. Results and discussion
The starting material—fluorinated alkenyl tosylates were
prepared from the corresponding fluorinated alcohol9
(Scheme 1).
Scheme 1. Preparation of fluorinated alkenyl tosylates.
2.1. Preparation of fluorinated indolizines and 4H-
pyrrolo[1,2-a]benzimidazoles
cycles.6 Chen recently presented
a reaction of
N-containing heterocycles with gaseous fluoroalkenes
The fluorinated indolizines was prepared in moderate yield
by heating a mixture of 2,2-difluorovinyl tosylate 2a,
pyridinium halides 3, K2CO3 and Et3N in DMF at 70 8C for
24 h (Scheme 2 and Table 1).
Keywords: 1,3-Dipolar reaction; N-Ylides; Fluorinated vinyl tosylate;
Monofluorinated indolizines and derivatives; Synthesis.
*
Corresponding authors. Tel.: þ86-21-64163300; fax: þ86-21-64166128;
When R3–H, a mixture of 6- and 8-substituted indolizine
e-mail address: ymwu@mail.sioc.ac.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.012

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X. Fang et al. / Tetrahedron 60 (2004) 5487–5493
Scheme 2. Synthesis of fluorinated indolizines.
Table 1. Synthesis of fluorinated indolizines 4
(Fig. 1) it was a doublet, coupled with proton at C-6.
According to Table 1, we find that for the same R1 substrate,
the ratio of 4 and 40 was related to the steric hindrance of R3
group. More 40 (8-substituted indolizine) were formed when
R3 was a sterically hindered substitutes (Me, Br, PhCO) than
a smaller group (CN) (entry 3 vs 4; entry 5 vs 6 and entry 9
vs 10, Table 1). If R2 was an electron-withdrawing group
(e.g., acetyl), then only less than 5% yield of the desired
products could be obtained (from 19F NMR spectra).
Entry
Pyridinium halides 3
Product
Yield (%)a of 4
R1
R2
R3
1
2
3
4
5
6
7
COPh
COPh
COPh
COPh
CO2Et
CO2Et
CN
H
CH3
H
H
H
H
H
CH3
Br
Br
COPh
H
4a
4b
34
23
37
27
40
8
59
33
67
58
60
4c:4c0 (1:2)b
4d:4d0 (1:1.5)
4e:4e0 (1:6)
4f:4f0 (1:1.5)
4g
H
H
Under the same conditions when isoquinolinium halides 5,
benzimidazolinium halides 6 were treated with 2a, respect-
ively, fluorinated benzo[d]indolizines 7 and 4H-pyrrolo[1,2-
a]-benzimidazoles 8 were obtained in moderate yields
(Scheme 3, Table 2).
8
9
10
11
CN
CN
CN
COPh
CH3
H
H
H
CH3
Br
4h
4i:4i0(1:10)b
4j:4j0 (1:1.7)
4k
H
CN
a
Isolated yields.
The mixture cannot be separated by flash chromatography.
b
As reported by Banks,5a the reaction mechanism is proposed
in Scheme 4. The 1,3-dipolar cycloaddition between
pyridinium, isoquinolinium or benzimidazolinium N-ylides,
generated in situ from the corresponding halides in the
presence of a base, with the 2,2-difluorovinyl tosylate 2a,
gave the intermediate which aromatized by eliminating a
HF and TsOH to yield the fluorinated indolizine or 4H-
pyrrolo[1,2-a]benzimidazole, respectively, (Scheme 4).
It is essential to choose a suitable base for these reactions.
The base should not only be able to deprotonate the
pyridinium, isoquinolinium or benzimidazolinium halides
to form the corresponding N-ylides, but also to effectively
eliminate HF and TsOH to produce the indolizines or 4H-
pyrrolo[1,2-a]benzimidazoles after the 1,3-dipolar cyclo-
addition. A mixture of organic and inorganic bases, K2CO3
and Et3N, was found to give the best results. To compare the
Figure 1. Structure of 6-benzoyl- and 8-benzoylindolizine derivatives 4f
and 4f0.
derivatives 4 and 40 were obtained in various ratio (entries
3–6,10, Table 1). The structures of products 4 and 40 were
determined on the basis of 1H NMR spectroscopy. The
proton at C-5 of product 4f was a singlet while in product 4f0
Scheme 3. Synthesis of fluorinated benzo[d]indolizines 7 and 4H-pyrrolo[1,2-a]benzimidazoles 8.

X. Fang et al. / Tetrahedron 60 (2004) 5487–5493
5489
Table 2. Synthesis of fluorinated benzo[d]indolizines 7 and 4H-
pyrrolo[1,2-a]benzimidazoles 8
2.2. Preparation of formyl indolizines and derivatives
When 2,3,3-trifluoro-1-propenyl tosylate 2b was allowed to
react with pyridinium 3 and isoquinolinium 5 N-ylides
under similar conditions, the product obtained unexpect-
edly, showed no 19F NMR signal. Meanwhile, its 1H NMR
spectroscopy showed a single peak at low field (ca. d
10.2 ppm), which could be assigned to the proton of
aldehyde or acid. The molecular structure was determined
by a single-crystal X-ray diffraction study (Fig. 2). The
selected bond lengths and bond angles of 9d are listed in
Table 3.13
Entry
R1
Product
Yield (%)a of 7,8
1
2
3
4
5
6
COPh
CO2Et
CN
COPh
CO2Et
CN
7a
7b
7c
8a
8b
8c
59
10
68
31
61
12
a
Isolated yields.
Scheme 4.
Scheme 5.
Other N-ylides gave similar results when they were treated
with 2b. The detailed results are listed in Scheme 6 and
Table 3. When meta-substituted pyridinium salt 3b, 3e
reacted with 2b, only 8-substituted indolizines 9 could be
isolated (Table 4, entries 1–3).
From these results, it was found that the N-ylide did not
directly attack 2,3,3-trifluoro-1-propenyl tosylate 2b. From
Figure 2. The X-ray crystal structure of 9d.
Table 3. The selected bond lengths and bond angles of 9d
˚
Bond lengths (A)
Bond angles (8)
solvent effect, the same reaction was also carried out in
THF, 1,4-dioxane, acetonitrile. However, they all gave
lower yield than DMF did.
O(1)–C(14)
O(2)–C(13)
N(1)–C(1)
1.225(3)
1.206(3)
1.385(3)
1.387(3)
1.397(3)
1.437(3)
1.495(3)
1.419(3)
1.439(3)
1.382(3)
1.373(3)
1.362(3)
C(1)–N(1)–C(9)
122.8(2)
127.0(2)
110.17(19)
119.5(3)
126.6(12)
113.9(12)
121.7(2)
120.5(13)
106.0(2)
117.9(2)
123.5(2)
123.7(3)
C(1)–N(1)–C(12)
C(9)–N(1)–C(12)
C(2)–C(1)–N(1)
C(2)–C(1)–H(1)
N(1)–C(1)–H(1)
C(1)–C(2)–C(3)
C(1)–C(2)–H(2)
N(1)–C(9)–C(10)
N(1)–C(9)–C(8)
O(1)–C(14)–C(12)
O(2)–C(13)–C(10)
N(1)–C(9)
N(1)–C(12)
C(12)–C(14)
C(14)–C(15)
C(9)–C(10)
C(10)–C(13)
C(10)–C(11)
C(11)–C(12)
C(1)–C(2)
It was noticed that the cycloaddition product 3k (entry 11,
Table 1) showed no 19F NMR signal. It was characterized by
1H NMR spectroscopy, MS and micro analysis. The reaction
mechanism is depicted in Scheme 5. A second molecule of
pyridinium salt in enol form (3k0) is attacked by N-ylide
followed by cyclization, and aromatization to give the
product 4k.

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X. Fang et al. / Tetrahedron 60 (2004) 5487–5493
Scheme 6. The reaction of N-ylides with 2b.
Table 4. Synthesis of formyl indolizines 9
Entry
Halides
Product
Yield (%)a
of 9
1
9a
9b
57
50
Scheme 7.
2
3. Experimental
3.1. General
3
4
9c
9d
9e
63
65
58
Melting points and boiling points are uncorrected. IR
spectra were obtained with a Perkin–Elmer 983G spec-
trometer on KBr disks. NMR spectra were recorded either
on a Varian-360L or a Bruker AM-300 spectrometer with
CDCl3 as solvent. Chemical shifts were reported in parts per
million relative to TMS as an internal standard (dTMS¼0)
[dCFCl3¼0] for 19F NMR (upfield shift being designated as
negative) spectra. Coupling constants are given in Hertz
(Hz). Low- and high-resolution mass spectra were recorded
on a Hewlett–Packard HP-5989A and a Finnigan MAT
spectrometer, respectively. Elemental analyses were
performed at SIOC. Single-crystal X-ray diffraction was
performed by SMART APEX CCD diffractometer and the
analysis software was Shelx97. Pyridinium, isoquinolinium,
benzimidazolinium halides were prepared by the reported
method.11
1
for H NMR spectra and CFCl3 as an internal standard
5
a
Isolated yields.
the view point of molecular polarity (Scheme 7), N-ylide
should attack at C2 of the tosylate 2b and as a result the
2-substituted product should be formed. However, only
1-substituted product was obtained. Funabiki10 reported that
2,3,3-trifluoro-1-propenyl tosylate 2b underwent cleavage
of the enol oxygen–sulfur bond with fluoride ion, followed
by the loss of an allylic fluorine atom to generate a,b-
difluoroacrylaldehyde 2b0 (Scheme 7).
3.2. General procedure for the preparation of
fluorinated indolizines and 4H-pyrrolo[1,2-a]benz-
imidazoles
To a solution of N-ylide halide (3, 5 or 6) (1.5 mmol) in N,N-
dimethylformamide (DMF, 10 mL) were added K2CO3
(1.5 mmol), Et3N (1.5 mmol) and 2,2-difluorovinyl tosylate
2a (1.0 mmol). After stirring at 70 8C for 24 h, 1 N HCl was
added to neutralize the reaction mixture and the aqueous
layer was extracted with diethyl ether (3£30 mL). The
combined extracts were washed with brine (2£20 mL) and
dried over Na2SO4. After removal of the solvent at reduced
pressure the residue was purified by flash column chroma-
tography on silica gel using ethyl acetate and petroleum
(1:20) as eluent.
In our experiment, a trace of fluoride ion can indeed
accelerate the reaction. When a catalytic amount of
tetrabutylamonium fluoride (10% mol) was added to the
reaction system, the reaction temperature could be reduced
to room temperature. In this way, the mechanism may be
depicted as shown in Scheme 7.
In conclusion, we have developed a new method for the
synthesis of monofluorinated indolizine 4, benzo[d]indoli-
zines 7, 4H-pyrrolo[1,2-a]benzimidazoles 8 and formyl
indolizines derivatives 9. Further studies on the application
of fluorinated vinyl tosylates in organic synthesis are in
progress.
3.2.1. 2-Fluoro-3-benzoylindolizine 4a. Yield 34%; yellow
1
solid; mp 95–97 8C, (95–97 8C12); H NMR (300 MHz,

X. Fang et al. / Tetrahedron 60 (2004) 5487–5493
5491
CDCl3) d 9.81 (1H, d, J¼6.9 Hz), 7.78–7.73 (2H, m), 7.59–
7.45 (4H, m), 7.24 (1H, d, J¼8.4 Hz), 6.96 (1H, t,
J¼6.9 Hz), 6.20 (1H, s); 19F NMR (282 MHz, CCl4) d
2134.60 (1F, s); MS (m/z) 239 (Mþ, 100), 220 (4), 211(54).
Anal. Calcd for C15H10FNO: C, 75.30; H, 4.21; N, 5.85; F,
7.94. Found: C, 75.19; H, 4.04; N, 5.70; F, 7.91.
3.2.7. 2-Fluoro-3-cyanoindolizine 4g. Yield 59%; white
needles; mp 95–96 8C; 1H NMR (300 MHz, CDCl3) d 8.16
(1H, d, J¼6.9 Hz), 7.43 (1H, d, J¼8.7 Hz), 7.11 (1H, t,
J¼8.1 Hz), 6.89 (1H, t, J¼6.9 Hz), 6.19 (1H, s); 19F NMR
(282 MHz, CCl4) d 2143.15 (1F, s); MS (m/z) 160 (Mþ,
100), 133 (20); IR (cm-1, neat) 2208, 1447. Anal. Calcd for
C9H5FN2: C, 67.50; H, 3.15; N, 17.49. Found: C, 67.19; H,
3.13; N, 17.49.
3.2.2. 2-Fluoro-3-benzoyl-7-methylindolizine 4b. Yield
1
23%; yellow solid; mp 102–104 8C, (102–104 8C12); H
NMR (300 MHz, CDCl3) d 9.71 (1H, d, J¼7.2 Hz), 7.76–
7.71 (2H, m), 7.54–7.46 (3H, m), 7.24 (1H, s), 6.80 (1H, d,
J¼7.2 Hz), 6.07 (1H, s), 2.42 (3H, s); 19F NMR (282 MHz,
CCl4) d 2134.22 (1F, s); MS (m/z) 253 (Mþ, 13), 77 (100).
Anal. Calcd for C16H12FNO: C, 75.88; H, 4.78; N, 5.53; F,
7.50. Found: C, 75.83; H, 4.68; N, 5.27; F, 7.45.
3.2.8. 2-Fluoro-3-cyano-7-methylindolizine 4h. Yield
33%; white needles; mp 114–115 8C; 1H NMR
(300 MHz, CDCl3) d 8.04 (1H, d, J¼6.9 Hz), 7.19 (1H, s),
6.72 (1H, d, J¼6.9 Hz), 6.04 (1H, s), 2.38 (3H, s); 19F NMR
(282 MHz, CCl4) d 2143.09 (1F, s); MS (m/z) 174 (Mþ,
100), 155 (4); IR (cm21, KBr) 2198, 1455. Anal. Calcd for
C10H7FN2: C, 68.96; H, 4.05; N, 16.08. Found: C, 68.93; H,
4.02; N, 16.28.
3.2.3. 2-Fluoro-3-benzoyl-6-methylindolizine 4c and 2-
fluoro-3-benzoyl-8-methylindolizine 4c0. Yield 37%;
1
yellow solid; mp 79–80 8C; H NMR (300 MHz, CDCl3)
3.2.9. 2-Fluoro-3-cyano-6-methylindolizine 4i and 2-
fluoro-3-cyano-8-methylindolizine 4i0. Yield 67%; pale
red needles; mp 126–127 8C; 1H NMR (300 MHz, CDCl3)
d 8.04 (1H, d, J¼6.9 Hz), 6.91 (1H, d, J¼6.9 Hz), 6.82 (1H,
t, J¼6.9 Hz), 6.16 (1H, s), 2.42 (3H, s); 19F NMR
(282 MHz, CCl4) d 2143.67 (1F, s); MS (m/z) 174 (Mþ,
100), 155 (5); IR (cm-1, KBr) 2207, 1473. Anal. Calcd for
C10H7FN2: C, 68.96; H, 4.05; N, 16.08. Found: C, 68.79; H,
3.91; N, 16.22.
d 9.68–9.63 (1H, d), 7.76–7.70 (2H, m), 7.57–7.29 (3H,
m), 7.06–6.84 (2H, m), 6.17–6.12 (1H, d), 2.45–2.37 (3H,
d); 19F NMR (282 MHz, CCl4) d 2135.27 (1F, s), 2135.04
(1F, s); MS (m/z) 253 (Mþ, 100), 234 (3); IR (cm21, KBr)
1597, 1470. Anal. Calcd for C16H12FNO: C, 75.88; H, 4.78;
N, 5.53; F, 7.50. Found: C, 75.67; H, 4.81; N, 5.48; F, 7.48.
3.2.4. 2-Fluoro-3-benzoyl-6-bromoindolizine 4d. Yield
1
27%; yellow solid; mp 120–121 8C; H NMR (300 MHz,
CDCl3) d 9.99 (1H, s), 7.79–7.72 (5H, m), 7.41–7.28 (2H,
m), 6.25 (1H, s); 19F NMR (282 MHz, CCl4) d 2134.04 (1F,
s); 2-fluoro-3-benzoyl-8-bromoindolizine 4d0. 1H NMR
(300 MHz, CDCl3) d 9.75 (1H, d, J¼7.2 Hz), 7.61–7.45
(6H, m), 6.84 (1H, t, J¼6.9 Hz), 6.43 (1H, s); 19F NMR
(282 MHz, CCl4) d 2133.42 (1F, s); MS (m/z) 319 (Mþ1,
21), 317 (22), 77 (100); IR (cm21, KBr) 1601, 1460. Anal.
Calcd for C15H9BrFNO: C, 56.63; H, 2.85; N, 4.40; F, 5.97.
Found: C, 56.71; H, 2.94; N, 4.16; F, 5.88.
3.2.10. 2-Fluoro-3-cyano-6-bromoindolizine 4j. Yield
1
58%; yellow solid; mp 179–180 8C; H NMR (300 MHz,
CDCl3) d 8.30 (1H, s), 7.35 (1H, s), 7.18 (1H, d, J¼9.3 Hz),
6.23 (1H, s); 19F NMR (282 MHz, CCl4) d 2142.01 (1F, s);
2-fluoro-3-cyano-8-bromoindolizine
4j0.
1H
NMR
(300 MHz, CDCl3) d 8.15 (1H, d, J¼7.5 Hz), 7.33 (1H, s),
6.79 (1H, t, J¼7.5 Hz), 6.39 (1H, s); 19F NMR (282 MHz,
CCl4) d 2141.42 (1F, s); MS (m/z) 240 (Mþ1, 97), 238
(100); IR (cm21, KBr) 2210, 1463. Anal. Calcd for
C9H4BrFN2: C, 45.22; H, 1.69; N, 11.72. Found: C,
45.24; H, 1.59; N, 11.63.
3.2.5. 2-Fluoro-3-ethoxycarbonyl-6-bromoindolizine 4e.
Yield 40%; reddish solid; mp 41–42 8C; 1H NMR
(300 MHz, CDCl3) d 9.57 (1H, s), 7.83 (1H, d, J¼7.8 Hz),
7.38 (1H, d, J¼7.8 Hz), 6.22 (1H, s), 4.42 (2H, q,
J¼7.2 Hz), 1.43 (3H, t, J¼7.2 Hz); 19F NMR (282 MHz,
CCl4) d 2138.39 (1F, s); 2-fluoro-3-ethoxycarbonyl-8-
3.2.11. 2-Benzyl-3-benzoyl-6-cyanoindolizine 4k. Yield
60%; bright yellow solid; mp 211–212 8C; 1H NMR
(300 MHz, CDCl3) d 10.12 (1H, S), 7.62 (1H, d,
J¼9.0 Hz), 7.44 (2H, d, J¼8.1 Hz), 7.23–7.04 (9H, m),
6.75 (1H, s); MS (m/z) 322 (Mþ, 100), 293 (52); IR
(cm-1, KBr) 2229, 1601. Anal. Calcd for C22H14N2O:
C, 81.97; H, 4.38; N, 8.69. Found: C, 81.78; H, 4.25;
N, 8.52.
0
1
bromoindolizine 4e . H NMR (300 MHz, CDCl3) d 9.37
(1H, d, J¼6.9 Hz), 7.30 (1H, d, J¼7.5 Hz), 6.70 (1H, t,
J¼7.5 Hz), 6.39 (1H, s), 4.42 (2H, q, J¼7.2 Hz), 1.43 (3H, t,
J¼7.2 Hz); 19F NMR (282 MHz, CCl4) d 2137.66 (1F, s);
IR (cm21, KBr) 1689, 1465. HRMS Calcd for C11H9-
BrFNO2: 284.9801, found: 284.9792.
3.2.12. 2-F1uoro-benzoylbenzo[d]indolizines 7a. Yield
59%; yellow needles; mp 139–141 8C, (139–141 8C12);
1H NMR (300 MHz, CDCl3) d 9.40 (1H, d, J¼7.8 Hz),
8.11–8.06 (1H, m), 7.84–7.47 (8H, m), 7.16 (1H, d,
J¼7.5 Hz), 6.75 (1H, s); 19F NMR (282 MHz, CCl4) d
2136.34 (1F, s); MS (m/z) 289 (Mþ, 100), 261 (41). Anal.
Calcd for C19H12FNO: C, 78.88; H, 4.18; N, 4.84; F, 6.57.
Found: C, 78.85; H, 4.21; N, 4.65; F, 6.41.
3.2.6. 2-Fluoro-3-ethoxycarbonyl-6-benzoylindolizine 4f.
Yield 8%; yellow solid; mp 99–100 8C; 1H NMR
(300 MHz, CDCl3) d 9.89 (1H, s), 7.87–7.48 (7H, m),
6.34 (1H, s), 4.38 (2H, q, J¼7.5 Hz), 1.38 (3H, t, J¼7.5 Hz);
19F NMR (282 MHz, CCl4) d 2124.54 (1F, s); 2-fluoro-3-
ethoxycarbonyl-8-benzoylindolizine
4f0.
1H
NMR
(300 MHz, CDCl3) d 9.65 (1H, d, J¼7.5 Hz), 7.70–7.57
(4H, m), 7.46 (2H, d, J¼7.5 Hz), 6.92 (1H, t, J¼7.2 Hz),
6.84 (1H, s), 4.45 (2H, q, J¼6.9 Hz), 1.45 (3H, t, J¼7.5 Hz);
19F NMR (282 MHz, CCl4) d 2122.33 (1F, s); MS (m/z)
311 (Mþ, 100), 283 (18); IR (cm-1, KBr) 1688, 1656, 1469.
HRMS Calcd for C18H14FNO3: 311.0958, found: 311.0953.
3.2.13. 2-F1uoro-ethoxycarbonylbenzo[d]indolizines 7b.
Yield 10%; white solid; mp 115–117 8C, (1115–117 8C12);
1H NMR (300 MHz, CDCl3) d 9.18 (1H, d, J¼7.5 Hz),
8.05–8.01 (1H, m), 7.71–7.67 (1H, m), 7.58–7.53 (2H, m),
7.06 (1H, d, J¼7.2 Hz), 6.75 (1H, s), 4.44 (2H, d,

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X. Fang et al. / Tetrahedron 60 (2004) 5487–5493
J¼7.2 Hz), 1.45 (3H, t, J¼7.2 Hz); 19F NMR (282 MHz,
CCl4) d 2140.49 (1F, s); MS (m/z) 257 (Mþ, 100), 229 (40).
Anal. Calcd for C15H12FNO2: C, 70.03; H, 4.70; N, 5.44; F,
7.38. Found: C, 69.93; H, 4.63; N, 5.43; F, 7.15.
3.3.2. 1-Formyl-3-benzoyl-8-bromoindolizine 9b. Yield
50%; red solid; mp 183–184 8C; 1H NMR (300 MHz,
CDCl3) d 10.20 (1H, s), 10.04 (1H, d, J¼6.9 Hz), 8.04 (1H,
s), 7.84–7.76 (3H, m), 7.63–7.49 (3H, m), 7.00 (1H, d,
J¼7.2 Hz); MS (m/z) 329 (Mþþ1, 93), 328 (Mþ, 97), 327
(Mþ21, 100), 326 (86); IR (cm21, KBr) 1646, 1630. Anal.
Calcd for C16H10BrNO2: C, 58.56; H, 3.07; N, 4.27. Found:
C, 58.65; H, 3.04; N, 4.17.
3.2.14. 2-F1uoro-cyanobenzo[d]indolizines 7c. Yield
68%; yellow needles; mp 135–137 8C, (135–137 8C12);
1H NMR (300 MHz, CDCl3) d 7.99 (1H, d, J¼7.2 Hz), 7.91
(1H, d, J¼7.2 Hz), 7.73–7.54 (3H, m), 7.11 (1H, d,
J¼7.2 Hz), 6.69 (1H, s); 19F NMR (282 MHz, CCl4) d
2144.28 (1F, s).
3.3.3. 1-Formyl-3-ethoxycarbonyl-8-bromoindolizine 9c.
Yield 63%; yellow needles; mp 173–174 8C; 1H NMR
(300 MHz, CDCl3) d 10.99 (1H, s), 9.69 (1H, d, J¼7.5 Hz),
8.21 (1H, s), 7.66 (1H, d, J¼7.2 Hz), 6.89 (1H, t, J¼7.2 Hz),
4.40 (2H, d, J¼7.2 Hz), 1.41 (3H, t, J¼7.2 Hz); MS (m/z)
297 (Mþþ1, 88), 295 (Mþ21, 90), 268 (99), 266 (100); IR
(cm21, KBr) 1701, 1654. Anal. Calcd for C12H10BrNO3: C,
48.67; H, 3.40; N, 4.73. Found: C, 48.60; H, 3.41; N, 4.51.
3.2.15. 1-Benzoyl-2-fluoro-4-benzyl-4H-pyrrolo[1,2-
a]benzimidazole 8a. Yield 31%; yellow solid; mp 148–
149 8C; 1H NMR (300 MHz, CDCl3) d 8.83 (1H, d,
J¼7.8 Hz), 7.86–7.81 (2H, m), 7.57–7.24 (11H, m), 5.46
(1H, s), 5.28 (2H, s); 19F NMR (282 MHz, CCl4) d 2127.91
(1F, s); MS (m/z) 368 (Mþ, 35), 91 (100); IR (cm21, KBr)
1613, 1405. Anal. Calcd for C24H17FN2O: C, 78.25; H,
4.65; N, 7.60; F, 5.16. Found: C, 78.22; H, 4.65; N, 7.35; F,
4.94.
3.3.4. 1-Formyl-3-benzoylbenzo[d]indolizine 9d. Yield
1
65%; reddish solid; mp 145–146 8C; H NMR (300 MHz,
CDCl3) d 10.20 (1H, s), 9.76–9.68 (2H, m), 8.01–7.53 (9H,
m), 7.41 (1H, d, J¼7.2 Hz); MS (m/z) 299 (Mþ, 100), 270
(13); IR (cm21, KBr) 1650, 1618. Anal. Calcd for
C20H13NO2: C, 80.25; H, 4.38; N, 4.68. Found: C, 80.20;
H, 4.43; N, 4.68. Crystal system, space group: monoclinic,
3.2.16. 1-Ethoxycarbonyl-2-fluoro-4-benzyl-4H-pyr-
rolo[1,2-a]benzimidazole 8b. Yield 61%; white feather;
1
mp 90–91 8C; H NMR (300 MHz, CDCl3) d 8.77 (1H, d,
˚
J¼9.3 Hz), 7.36–7.19 (8H, m), 5.42 (1H, s), 5.24 (2H, s),
4.43 (2H, q, J¼7.2 Hz), 1.44 (3H, t, J¼7.2 Hz); 19F NMR
(282 MHz, CCl4) d 2133.54 (1F, s); MS (m/z) 336 (Mþ,
53), 91 (100); IR (cm21, KBr) 1690, 1473. Anal. Calcd for
C20H17FN2O2: C, 71.42; H, 5.09; N, 8.33. Found: C, 71.56;
H, 4.95; N, 8.21.
p2(1)/c. Unit cell dimensions: a¼14.1907(15) A, b¼
˚
˚
3
6.8890(7) A, c¼29.670(3) A, a¼908, b¼96.791(2)8, g¼
˚
908; volume: 2880.2(5) A ; Z, 8; calculated density:
1.381 Mg/m3; absorption coefficient: 0.090 mm3; F(000):
1248; crystal size: 0.366£0.192£0.043 mm; theta range for
data collection: 1.38–28.298; Completeness to theta¼28.32,
92.6%; data/restraints/parameters: 6624/5/520; goodness-
of-fit on F 2: 0.808; final R indices[I.2sigma910]:
3.2.17. 1-Cyano-2-fluoro-4-benzyl-4H-pyrrolo[1,2-
a]benzimidazole 8c. Yield 12%; white solid; mp 133–
134 8C; 1H NMR (300 MHz, CDCl3) d 7.88 (1H, d,
J¼7.5 Hz), 7.43–7.22 (8H, m), 5.34 (1H, s), 5.24 (2H, s);
19F NMR (282 MHz, CCl4) d 2137.27 (1F, s); MS (m/z)
289 (Mþ, 29), 91 (100); IR (cm21, KBr) 2194, 1470. Anal.
Calcd for C18H12FN3: C, 74.73; H, 4.18; N, 14.52. Found:
C, 74.60; H, 4.43; N, 14.36.
R1¼0.0569, wR2¼0.1026;
R
indices(all data): R1¼
0.1471, wR2¼0.1286; extinction coefficient: 0.0020(3);
largest diff. Peak and hole: 0.193 and 20.215 e A23
3.3.5. 1-Formyl-3-ethoxycarbonylbenzo[d]indolizines 9e.
Yield 58%; yellow solid; mp 210–211 8C; 1H NMR
(300 MHz, CDCl3) d 10.21 (1H, s), 9.73 (1H, d,
J¼8.4 Hz), 9.45 (1H, d, J¼7.8 Hz), 8.05 (1H, s), 7.83–
7.67 (3H, m), 7.32 (1H, d, J¼7.5 Hz), 4.45 (2H, q,
J¼7.2 Hz), 1.46 (3H, t, J¼7.2 Hz); MS (m/z) 267 (Mþ,
89), 238 (100); IR (cm21, KBr) 1704, 1670. Anal. Calcd for
C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C, 71.91; H,
5.01; N, 5.23.
3.3. General procedure for the preparation of formyl
indolizines
To a solution of pyridinium 3 or isoquinolinium 5 halide
(1.2 mmol), K2CO3 (1.2 mmol), triethylamine (1.2 mmol)
in N,N-dimethylformamide (DMF, 5 mL) was added a
solution of 2,3,3-trifluoro-1-propenyl tosylate 2b
(1.0 mmol) in DMF (5 mL) at 70 8C. The mixture was
stirred for 24 h and was then quenched with brine, followed
by extraction with diethyl ether, drying over Na2SO4, and
concentration in vacuum. The resulting residue was
chromatographed on a silica-gel column with ethyl acetate
and petroleum (1:10) as eluent.
Acknowledgements
The authors thank partial financial support by the Excellent
Yong Scholars Foundation of Anhui Province.
3.3.1. 1-Formyl-3-ethoxycarbonyl-8-methylindolizine
1
9a. Yield 57%; white feather; mp 117–118 8C; H NMR
References and notes
(300 MHz, CDCl3) d 10.33 (1H, s), 9.55 (1H, d, J¼7.5 Hz),
8.16 (1H, s), 7.22 (1H, d, J¼6.9 Hz), 6.97 (1H, t, J¼6.9 Hz),
4.41 (2H, d, J¼6.9 Hz), 2.80 (3H, s), 1.43 (3H, t, J¼7.2 Hz);
MS (m/z) 231 (Mþ, 89), 202 (100); IR (cm21, KBr) 1688,
1645. Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N,
6.06. Found: C, 67.22; H, 5.47; N, 5.76.
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