Preparation of 1-trifluoroacetyl indolizines and their derivatives via the cycloaddition of pyridinium N-ylides with 4-4-ethoxy1-1,1,1-trifluorobut-3-en-one

Article abstract of DOI:10.1016/S0022-1139(99)00145-1

Under basic reaction conditions pyridinium or isoquinolinium N-ylides (C₅H₅N⁺ CH₂YBr^- or C₉H₇N⁺CH₂YBr^-, Y : CO₂R, CN, PhCO) reacted readily with 4-ethoxyl-1,1,1-trifluorobut-3-en-2-one to give the corresponding 1-trifluoroacetyl substituted indolizines or pyrrolo-[1,2-a]isoquinolines. The molecular structure of 1-trifluoromethyl-3-methoxyl-pyrrolo-[1,2-a]isoquinoline is presented.

Full text of DOI:10.1016/S0022-1139(99)00145-1

Journal of Fluorine Chemistry 99 (1999) 183±187
Preparation of 1-tri¯uoroacetyl indolizines and their derivatives
via the cycloaddition of pyridinium N-ylides with
4-4-ethoxy1-1,1,1-tri¯uorobut-3-en-one
Shi-zheng Zhu*, Chao-yue Qin, Yan-Li Wang, Qian-li Chu
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 26 May 1999; accepted 6 July 1999
Abstract
Under basic reaction conditions pyridinium or isoquinolinium N-ylides (C5H5N+ CH2YBr or C9H7N+CH2YBr , Y : CO2R, CN, PhCO)
reacted readily with 4-ethoxyl-1,1,1-tri¯uorobut-3-en-2-one to give the corresponding 1-tri¯uoroacetyl substituted indolizines or pyrrolo-
[1,2-a]isoquinolines. The molecular structure of 1-tri¯uoromethyl-3-methoxyl-pyrrolo-[1,2-a]isoquinoline is presented. # 1999 Elsevier
Science S.A. All rights reserved.
Keywords: 1,3-dipolar cycloaddition; Pyridinium N-ylides; Isoquinolinium N-ylides; 1-tri¯uoroacetyl indolizine; 1-tri¯uoromethyl-3-methoxyl-pyrrolo-[1,2-
a]isoquinoline.
1. Introduction
2. Results and discussion
Owing to the increasing importance of ¯uorine-contain-
ing heterocycles in the ®elds of biology and pharmacology,
the development of new and more ef®cient methods for the
synthesis of these compounds are of considerable interests
[1±5]. The reaction of pyridine-derive ylids with a,b-unsa-
turated ketones and esters to form indolizines is known in the
literature [6±9]. However, high yielding regiospeci®c meth-
ods for the synthesis of ¯uorinated functionality substituted
heteroaromatic compounds are still limited [10,11]. 1,3-
dipolar cycloaddition is one of the most important methods
for constructing ®ve-membered heterocycles. Many exam-
ples are available on inter- or intramolecular cycloadditions
involving 1,3-dipoles such as nitroxides, nitrilimines,
azides, nitrones, and nitrone ylides with various dipolaro-
philes [12,13]. However, the ¯uorinated alkenes or alkynes
as dipolarophiles are studied rarely [14]. During the studies
on ¯uorine-containing push±pull ethylenes [15,16], we
found that 4-ethoxyl-1,1,1-tri¯uorobut-3-en-2-one reacted
readily as a dipolarphile with the pyridinium or isoquino-
linium N-ylides to give to corresponding 1-tri¯uoroacetyl
substituted indolizines and their derivatives.
In the presence of potassium carbonate and triethylamine, a
mixtureofpyridiniumN-ylides,whichwerepreparedfromthe
reaction of pyridine with corresponding bromides (such as
bromo acetonitrile, methyl bromoacetate etc.) and 4-ethoxyl-
1,1,1-tri¯uorobut-3-en-2-one in DMF was heated for 24 h at
708C to complete the cycloaddition reaction. After general
work-up, the crude product was chromatographed to give ®ne
crystals. All the products were stable solids and had high
melting point (See Table 1). The products were characterized
spectroscopically and- by elemental analyses to be indolizine
derivatives. The yields of the 1-tri¯uoroacetylindolizine deri-
vatives 3 (a±c) are around 70% (Scheme 1)
A possible mechanism for the indolizine ring formulation
is shown in Scheme 2. The 1H-NMR spectra of 3 show that
the chemical shift of 5-H is at the lowest ®eld (9.0±9.3 ppm),
and is a doublet (JHH=6 Hz). All the indolizines have
stronger molecule ion peak. In the IR spectrum of 3a, the
1
two carbonyl group absorptions are 1690 cm (COCF3)
1
and 1620 cm (COPh), respectively. The initial-formed
®ve membered intermediate [A] underwent further elimina-
tion of EtOH in the basic reaction conditions followed by
dehydrogenation by air ®nally to give the 1,3-substituted
indolizine derivatives 3. The driving force for dehydrogena-
tion should be aromatization.
*Corresponding author.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 4 5 - 1

184
S.-z. Zhu et al. / Journal of Fluorine Chemistry 99 (1999) 183±187
Table 1
Table 2
Ê
Reaction results of 1 with pyridinium or isoquinolinium N-ylides
Selected bond lengths (A) and bond angles (8) of compound 7c
Ê
Bond lengths (A)
Entry
Reagents
Products
M.p.(8C)
Yield (%)
Bond angles (8)
1
2
3
2a
2b
2c
3a
3b
128±130
148±150
130±132;
226±118
160±164
198±202
158±160
144±146
76
74
O(2)±C(15)
O(3)±C(16)
N(1)±C(10)
C(1)±C(2)
1.199(4)
1.449(4)
1.391(4)
1.425(4)
1.408(4)
1.372(5)
1.383(5)
1.197(4)
1.385(3)
1.393(3)
1.449(4)
1.422(4)
1.333(4)
1.362(4)
C(2)±N(1)±C(12)
N(1)±C(2)±C(3)
N(1)±C(12)±C(15)
C(15)±C(12)±C(18)
O(1)±C(13)±C(14)
C(2)±N(1)±C(10)
C(10)±N(1)±C(12)
C(2)±C(1)±C(18)
N(1)±C(2)±C(1)
C(1)±C(2)±C(3)
C(2)±N(3)±C(8)
C(1)±N(10)±C(9)
N(1)±C(12)±C(18)
O(2)±C(15)±C(12)
110.1(2)
118.1(2)
124.3(2)
127.9(3)
114.5(3)
123.1(2)
126.8(2)
107.5(2)
105.8(2)
136.1(3)
118.2(3)
119.3(3)
107.8(2)
126.4(3)
3c + 3c
41 + 39
4
5
6
7
4a
6a
6b
6c
5
52
73
70
75
C(1)±C(18)
C(4)±C(5)
7a
7b
7c
C(12)±C(15)
O(1)±C(13)
N(1)±C(2)
N(1)±C(12)
C(1)±C(13)
C(3)±C(8)
Inwasnotedthatinthereactionof2cwith1,twoproducts3c
and 3c' were obtained in nearly 1 : 1 ratio and could be
separated by column chromatography. The product 3c should
be formed by ester exchange (see Schemes 3 and 4.)
Quinolinium N-ylides were also tried to react with 1,
however, only N-[(phenylcarbonyl)- methyl]quinolinium
ylide gave the expected cycloaddition product, and the yield
is only 52%.
It is dif®cult to explain why under the same reaction
conditions other N-quinolinium ylides such as N-(cyano-
methyl) or N-[(ethoxylcarbonyl)methyl] derivatives did not
react with 1 to give the corresponding cycloaddition product
(See Schemes 5 and 6).
C(9)±C(10)
C(12)±C(18)
out by its 1H-NMR spectrum and X-ray diffraction analysis.
The molecular structure of 7c is shown in Fig. 1. The full
molecule is nearly planar (the angle between isoquinoline
plane and the pyrrole plane is only 1.48) and contains also
the two carbonyl groups of COOMe and COCF3. All the
C±C bond lengths and all the C±N bond lengths of this
molecule are nearly same, which indicated that this mole-
cule is a conjugated ꢀ-system Table 2.
Some corresponding cycloaddition reactions involving
the isoquinolinium N-ylides with 1 have also been studied
and all give the expected 1-tri¯uoroacetyl indolizine deri-
vatives 7(a±c). This reaction was regiospeci®c and gave
only one product, the other possible regioisomer 7 was ruled
The 1,3-dipolar cycloaddition reaction results of the N-
ylides with 1 are summarized in Table 1.
In summary, a new and high yielding method for pre-
paration of 3-tri¯uoroacetyl indolizines and their derivatives
has been discovered. Further synthetic utility of the ¯uori-
Scheme 1.
Scheme 2.

S.-z. Zhu et al. / Journal of Fluorine Chemistry 99 (1999) 183±187
185
Scheme 3.
Scheme 4.
Scheme 5.
Scheme 6.
nated push±pull alkene in the preparation of the ¯uorinated
heterocycles is under study, and the results will be published
in the forthcoming paper.
uncorrected. IR spectra were recorded on an Bio±Rad FTS-
20E or FTS185 spectrophotometer, using Kbr pellets.
1H-NMR spectra were measured on a Bruker AM 300
(300 MHz) spectrometer, using TMS as internal standard.
19F-NMR spectra were recorded on a Varian EM-360L
spectrometer (56.4 MHz) using TFA as external standard,
3. Experimental
All reagents and solvents were puri®ed before use. Melt-
ing points were taken on a Melt±Temp apparatus and are
and the values (in ppm) reported as ꢁCFCl ꢀꢁCFCl ˆ ꢁTFA‡
3
3
76:8†. X-ray diffraction structure analysis was performed

186
S.-z. Zhu et al. / Journal of Fluorine Chemistry 99 (1999) 183±187
Fig. 1. The molecular structure of 7c.
with a Rigaku AFC 7R diffractometer. Mass spectra were
recorded on a Finnegan GC-MS 4021 spectrometer.
1.93), 115(M+-COCF3-COCF3-PhCO, 4.47), 105(PhCO,
26.51). Elemental analysis for C16H10F3NO2 Calcd: C:
64.35%, H: 3.15%, N: 4.41%. Found: C: 64.38%, H:
3.27%, N: 4.25%.
3.1. Typical procedure
3b
Methyl bromoacetate (3.06, 10 mmol) was added into
a 50 ml ¯ask containing pyridine (1.58 g, 10 mmol) and
CH3CO2Et (20 ml). This reaction mixture was stirred
at room temperature for 8 h. The reaction mixture was
®ltered to give a white solid, which was washed with
ethyl acetate (10 ml) and dried for 1 h under reduced
pressure to give the crude 2c (5.50 g, 97%). A mixture
of 2c (1.1 mmol), 4-ethoxyl-1,1,1-tri¯uorobut-3-en-2-one
(1 mmol), triethylamine (1.5 mmol) and potassium carbo-
nate (1.5 mmol) in 5 ml DMF were stirred at 608C for
24 h to complete the conversion. This reaction mixture
was cooled to room temperature and acidi®ed with
1 M aqueous HCl, then the solution was extracted with
dichloromethane (3 Â 30 cm3), and the organic layers
were combined and washed with saturated brine and
dried over anhydrous sodium sulfate. After removal the
solvent, the residue obtained was puri®ed by column chro-
matography using light petroleum ether and ethyl acetate
(5 : 1) as eluant to give 3c. Other products are prepared
similarly.
1H NMR(CDCl3) ꢁ(ppm): 8.46(m, 2H, C5-H, C8-H),
7.75(s, 1H, C2-H), 7.53(t, 1H, C7-H, JH-H=6 Hz), 7.27(t,
1H, C6-H, JH-H=6 Hz). 19F NMR(CDCl3) ꢁ(ppm): 71.2 (s,
CF3). IR (ꢂmax, (KBr)/cm 1): 3042, 3097(w, Ar-H),
2217(m, CN), 1690(s, COCF3), 1495(s, C±C), 1143,
1205, 1288(s, C-F). MS (m/e, %) 238(M+, 57.61),
169(M+-CF3, 100.00), 141(M+-COCF3, 18.57). HRMS
for C11H5F3N2O Calcd: 238.0354 Found: 238.0360.
3c
1H NMR (CDCl3) ꢁ(ppm): 9.65 (d, 1H, C5-H, JH-H=6 Hz),
8.60(d, 1H, C8-H, JH-H=6 Hz), 8.00(s, 1H, C2-H), 7.55(t, 1H,
C7-H, JH-H= Hz), 7.17(t, 1H, C6-H, JH-H=6 Hz), 4.45(q,
CH2), 1.45(t, CH3). 19F NMR (CDCl3) ꢁ(ppm): 71.6(s, CF3).
IR (ꢂmax, (KBr)/cm 1): 3133(w, Ar-H), 2871(w, C-H),
1700(s, COCF3), 1670(s, CO2Et), 1105-1373(s, C-F). MS
(m/e, %): 285(M+, 39.56), 240(M+-OEt, 11.58), 216(m+-
CF3, 73.38), 188(M+-COCF3, 100.00), 143(M+-COCF3-
OEt, 14.27), 115(M+-COCF3-CO2Et, 26.29). Element ana-
lysis for C13H10F3NO3 Calcd: C: 54.74%, H: 3.51%, N:
4.91%. Found: C: 54.74%, H: 3.58%, N: 4.84%.
3c0
3a
1H NMR (CDCl3) ꢁ(ppm): 9.97 (d, 1H, C5-H, JH-H
6 Hz), 8.63(d, 1H, C8-H, JH-H=6 Hz), 7.50±7.83(m, 8H,
=
1H NMR (CDCl3) ꢁ(ppm): 9.47 (d, 1H, C5-H,
JH-H=6 Hz), 8.45(d, 1H, C8-H, JH-H=6 Hz), 7.87(s, 1H,
C2-H), 7.40(t, 1H, C7-H, JH-H=6 Hz), 7.03(t, 1H, C6-H,
JH-H=6 Hz), 3.90(s, CH3). 19F NMR (CDCl3) ꢁ(ppm):
71.3(s, CF3). IR (ꢂmax, (KBr)/cm 1): 3043, 2872(w,
C-H), 1700(s, COCF3), 1667(s, CO2Me), 1105±1373(s,
Ar-H), 19F NMR (CDCl3) ꢁ(ppm): 71.6 (s, CF3). IR(ꢂmax
,
(KBr)/cm 1): 3140, 3190(w, Ar-H), 1690(s, COCF3),
1620(s, COHh), 1150±1340(s, C±F). MS (m/e, %):
317(M+, 51.58), 248(M+-CF3, 100.00), 220(M+-COCF3,

S.-z. Zhu et al. / Journal of Fluorine Chemistry 99 (1999) 183±187
187
C-F). MS (m/e, %): 271(M+, 31.97), 240(M+-OCH3, 15.16),
212(M+-CO2CH3, 4.18), 200(M+-COCF3, 100.00),
174(M+-COCF3, 6.65). HRMS for C11H5F3N2O Calcd:
271.0456. Found: 271.0452.
C6-H, JH-H=6 Hz), 19F NMR (CDCl3) ꢁ(ppm): 69.6(s, CF3).
IR (ꢂmax, (KBr)/cm 1): 3058, 3121(w, C-H), 1680(s,
COCF3), 1625(s, COPh), 1137, 1363(s, C-F). MS (m/e,
%): 288(M+, 37.25), 219(M+-CF3, 100,00), 191(M+-
COCF3, 23.32), 164(M+-COCF3-CN+1, 18.93). HRMS
for C11H5F3N3O Calcd: 288.0510. Found: 288.0518.
7c
1H NMR (CDCl3) ꢁ(ppm): 9.75(m, 1H, C5-H), 9.45(d,
1H, C6-H, JH-H=7 Hz), 8.07(m, 1H), 7.75(m, 1H), 7.37(d,
1H, JH-H=6 Hz), 19F NMR (CDCl3) ꢁ(ppm): 69.3(s, CF3). IR
(ꢂmax, (KBr)/cm 1): 2934, 2987(w, C-H), 1706(s, COCF3),
1671(s, CO2Et), 1224, 1213, 1139, 1094(s, C-F). MS (m/e,
%): 335(M+, 81.74), 290(M+-OEt, 9.50), 266(M+-CF3,
100.00), 238(M+-COCF3, 96.55), 165(M+-COCF3-CO2Et,
15.43), Elemental analysis for C13H10F3NO3 Calcd: C:
60.89%, H: 3.58%, N: 4.18%. Found: C60.70%, H:
3.51%, N: 4.12%.
5a
1H NMR (CDCl3) ꢁ(ppm): 8.65(m, 1H, C10-H), 7.70±
8.40(m, 11H, Ar-H). 19F NMR (CDCl3) ꢁ(ppm): 71.7(s,
CF3). IR (ꢂmax, (KBr)/cm 1): 3055, 2962(w, C-H), 1686(s,
COCF3), 1635(s, COPh), 1131, 1162, 1204, 1291(s, C-F).
MS (m/e, %): 367(M+, 14.72), 366(M+-1, 55.37), 298(M+-
CF3, 100.00), 270(M+-COCF3, 8.90), 105(COPh+, 42.32).
77(Ph+, 39.36). Element analysis for C13H10F3NO3 Calcd:
C: 68.66%, H: 3.27%, N: 3.81%. Found: C: 68.28%, H:
3.12%, N: 3.71%.
7a
1H NMR (CDCl3) ꢁ(ppm): 9.95(m, 1H, C5-H), 7.37±
7.97(m, 11H, Ar-H). 19F NMR (CDCl3) ꢁ(ppm): 69.3(s,
CF3). IR (ꢂmax, (KBr)/cm 1): 3058, 3121(w, C-H), 1680(s,
COCF3), 1625(s, COPh), 1137, 1363(s, C-F). MS (m/e, %):
367(M+, 41.31), 298(M+-CF3, 100,00), 270(M+-COCF3,
2.97), 165(M+-COCF3-COPh, 7.81), 105(COPh+, 23.65).
77(Ph+, 20.26). Element analysis for C13H10F3NO3 calcd:
C: 68.66%, H: 3.27%, N: 3.81%. Found: C: 68.39%, H:
3.10%, N: 3.73%.
Acknowledgements
The authors thank the National Natural Science Founda-
tion of China (NNSFC No. 29872051 and 29672041) for
®nancial support.
3.2. Crystal structure analysis
References
C13H10F3NO3: M = 335.28, triclinic, space group
Ê
BP1(No. 2), a = 9.154(3)A, b = 12.202(4)A c = 7.288(2)A,
Ê
Ê
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ꢃ = 93.27(3)8, ꢄ = 105.46(2)8, ꢅ = 76.96(3)8, V=764.4
3
3
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Ê
(4)A8 , Z = 2, Dc = 1.457 g/cm . Absorption coef®cient =
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1.24 cm
,
F(000) = 344.
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0.71069 A). Crystal dimensions, 0.20 mm  0.20 mm Â
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7b
1H NMR (CDCl3) ꢁ(ppm): 9.60(m, 1H, C5-H), 8.10(d,
C6-H, JH-H=6 Hz), 7.63±7.83(m, 4H, Ar-H), 7.35(d, 1H,
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È
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