A one-step approach to 1-(fluoroalkyl)indolizine derivatives

Article abstract of DOI:10.1055/s-1999-3675

A facile one-step method is presented for the synthesis of 1- (fluoroalkyl)-substituted indolizine derivatives in moderate to good yields by reactions of pyridinium, 4-methylpyridinium, isoquinolinium, and pyridazinium ylides with 2-bromo-3,3,3-trifluorop

Full text of DOI:10.1055/s-1999-3675

SHORT PAPER
51
A One-Step Approach to 1-(Fluoroalkyl)indolizine Derivatives
Xue-chun Zhang, Wei-yuan Huang*
Laboratory of Organoßuorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
Fax: +86(21)64166128; E-mail: wyhuang@pub.sioc.ac.cn
Received 20 April 1998; revised 2 June 1998
Abstract: A facile one-step method is presented for the synthesis of
1-(fluoroalkyl)-substituted indolizine derivatives in moderate to
good yields by reactions of pyridinium, 4-methylpyridinium, iso-
quinolinium, and pyridazinium ylides with 2-bromo-3,3,3-trifluo-
ropropene and 1-iodo-2-(polyfluoroalkyl)ethenes, respectively, in
the presence of base.
Key words: 1-(fluoroalkyl)indolizines, heteroaromatic N-ylides,
1,3-dipolar addition
In recent years, fluorinated heterocycles have received in-
creasing attention due to their potential biological proper-
2a X = CH, R = COPh, R1 = R2 = H
ties and considerable efforts have been paid to the
2b X = CH, R = COMe, R1 = R2 = H
exploitation of new synthetic routes to these fluorinated
compounds. Compared with fluorination and halogen ex-
change reactions,1,2 the application of fluorine-containing
building blocks in organic synthesis is becoming an im-
portant strategy for the construction of fluorinated hetero-
cycles because of its higher selectivity and milder
conditions.3 We have previously reported the synthesis of
2-(fluoroalkyl)-substituted indolizine derivatives from the
reactions of pyridinium N-ylides with 2,2-dihydropoly-
fluoroalkanoates.4 In this paper, we will describe a conve-
nient approach to 1-(fluoroalkyl)indolizines.
2-Bromo-3,3,3-trifluoropropene5 and 1-iodo-2-(polyfluo-
roalkyl)ethenes6 are both easily obtained fluorine-con-
taining synthons and can be used directly for the synthesis
of fluorinated compounds.7 1,3-Dipolar cycloaddition of
these building blocks with pyridinium, 4-methylpyridini-
um, isoquinolinium and pyridazinium ylides provides a
convenient one-step route to the construction of fluorinat-
ed indolizine derivatives.
2c X = CH, R = CO2Et, R1 = R2 = H
2d X = CH, R = COPh, R1 = H, R2 = Me
2e X = CH, R = COMe, R1 = H, R2 = Me
2f X = N, R = COPh, R1 = R2 = H
2g X = CH, R = COPh, R1,R2 = Ð(CH)4Ð
2h X = CH, R = CO2Et, R1,R2 = Ð(CH)4Ð
Scheme 1
When Rf = Cl(CF2)2, the expected adduct was formed as
the sole product. When Rf = Cl(CF2)4 and Cl(CF2)6, the
defluorinated cycloadducts 4 were obtained as the major
products accompanied by a trace of the expected ones 3
(Scheme 2).
In the presence of base, the reaction of pyridinium ylides
with 2-bromo-3,3,3-trifluoropropene (1a) in dimethylfor-
mamide gave 1-(trifluoromethyl)-substituted indolizine
derivatives. The reactions of isoquinolinium 2gÐ2h and
pyridazinium 2f ylides with 2-bromo-3,3,3-trifluoropro-
pene also gave the corresponding products. The resulting
heterocycles were pyrrolo[2,1-a]isoquinoline 3ag, 3ah
and pyrrolo[1,2-b]pyridazine derivatives 3af, respectively
(Scheme 1).
In a similar way, when 1-iodo-2-(polyfluoroalkyl)ethenes
were employed to react with isoquinolinium N-ylides, the
pyrrolo[2,1-a]isoquinolines with a fluoroalkyl group at
the 1-position were formed.
1b
2i
Rf = Cl(CF2)2; 1c Rf = Cl(CF2)4; 1d Rf = Cl(CF2)6
X = CH, R = CN, R1, R2 = Ð(CH)4Ð
Scheme 2
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52
X-c. Zhang, W-y. Huang
SHORT PAPER
Table The Isolated Yields of Compounds 3 and 4
1
Rf
2
X
R
R1
R2
3/Yield (%)
4/Yield (%)
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1d
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Cl(CF2)2
Cl(CF2)2
Cl(CF2)4
Cl(CF2)6
Cl(CF2)6
2a
2b
2c
2d
2e
2f
2g
2h
2g
2h
2g
2g
2i
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
COPh
COMe
CO2Et
COPh
COMe
COPh
COPh
CO2Et
COPh
CO2Et
COPh
COPh
CN
H
H
H
H
H
H
H
H
H
Me
Me
H
3aa/40
3ab/24
3ac/35
3ad/49
3ae/27
3af/36
3ag/35
3ah/33
3bg/55
3bh/36
trace
–(CH)4–
–(CH)4–
–(CH)4–
–(CH)4–
–(CH)4–
–(CH)4–
–(CH)4–
4cg/81
4dg/70
4di/60
trace
trace
Scheme 3
From the coupling constant (3JFF = 145 Hz), we can de-
duce that the two alkenyl fluorine atoms of defluorinated
compounds are trans-located.
Column chromatography was performed using silica gel H, particle
size 10Ð40 µ.
3-Benzoyl-1-(trifluoromethyl)indolizine (3aa); Typical
Procedure for the Preparation of Compounds 3 and 4
The process of defluorination may be depicted as shown
in Scheme 3.
A
solution of 2-bromo-3,3,3-trifluoropropene (1a) (0.18 g,
1.0 mmol), pyridinium salt 2a (0.33 g, 1.2 mmol), Et3N (0.20 g,
2.0 mmol) and K2CO3 (0.1 g, 1.5 mmol) in DMF (5 mL) was stirred
The detailed results are shown in the Table.
In conclusion, we have not only provided a one-step ap- at r.t. for 2 h and then heated to 80¡C for 4 h. After the reaction was
completed, the mixture was poured into 1 M HCl solution to make
the final solution pH 6. The resulting solution was extracted with
CH2Cl2 (3 × 20 mL). The organic phase was combined and washed
with sat. brine, dried (anhyd Na2SO4). After removal of solvent, the
proach to 1-(fluoroalkyl)-substituted indolizine deriva-
tives, but also enlarged the scope of utilizing 2-bromo-
3,3,3-trifluoropropene and 1-iodo-2-(polyfluoroalkyl)-
ethene as building blocks in organic synthesis.
residue obtained was purified by column chromatography (petro-
leum ether/EtOAc 6:1) to give the product 3aa (0.12 g, 40%).
All reagents were of chemically pure or analytical reagent. IR spec-
3aa: mp 88Ð89¡C.
IR (KBr): ν = 1610 (C=O), 1100Ð1240 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 9.98 (d, 1H, 3JHH = 8 Hz, C5-H), 7.81Ð7.08
(m, 9H, Ar-H).
19F NMR (CDCl3): δ = 55.5 (s).
MS: m/z (%) = 289 (M+, 100.0), 220 (10.6), 212 (59.3), 184 (27.4),
tra were recorded on a Bio-Rad FTS-20E or FTS 185 spectropho-
1
tometer, using KBr pellets. H 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. In 19F
NMR spectra, chemical shifts (in ppm) were positive for upfield
shifts and the values are reported as δCFCl3 (δCFCl3 = δTFA +
76.8). MS were taken on a Finnigan GC-MS 4021 spectrometer.
105 (15.2), 77 (27.3).
Synthesis 1999, No. 1, 51Ð54 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A One-Step Approach to 1-(Fluoroalkyl)indolizines
53
3ab: mp 119Ð121¡C.
3bg: mp 107Ð110¡C.
IR (KBr): ν = 1630 (C=O), 1090Ð1220 cmÐ1 (CÐF).
IR (KBr): ν = 3147, 1622 (C=O), 1537, 1115Ð1267 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 9.87 (m, 1H, C5-H), 7.75Ð7.00 (m, 4H, Ar-
H), 2.58 (s, 3H, COCH3).
1H NMR (CDCl3): δ = 9.62 (d, 1H, 3JHH = 7 Hz, C10-H), 8.52 (d,
1H, 3JHH = 6 Hz, C5-H), 7.82Ð7.18 (m, 10H, Ar-H).
19F NMR (CDCl3): δ = 55.5 (s).
19F NMR (CDCl3): δ = 67.1 (m, 2F), 97.5 (m, 2F).
MS: m/z (%) = 227 (M+, 7.7), 212 (M+ Ð CH3, 11.4), 184 (7.9), 44
MS: m/z (%) = 405 (M+, 22.5), 320 (10.6), 216 (11.6), 105 (9.4), 77
(100.0).
(10.5).
3ac: mp 54Ð56¡C.
3bh: mp110Ð112¡C.
IR (KBr): ν = 1700 (C=O), 1090 cmÐ1 (CÐF).
IR (KBr): ν = 1705 (C=O), 1085Ð1230 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 9.48 (d, 1H, 3JHH = 9 Hz, C5-H), 7.70Ð6.94
(m, 4H, Ar-H), 4.39 (q, 2H, -OCH2-), 1.37 (t, 3H, -CH3).
1H NMR (CDCl3): δ = 9.38 (m, 1H, C10-H), 8.40 (m, 1H, C5-H),
7.73Ð7.13 (m, 5H, Ar-H), 4.41 (q, 2H, -OCH2-), 1.44 (t, 3H, -CH3).
19F NMR (CDCl3): δ = 55.5 (s).
19F NMR (CDCl3): δ = 67.8 (m, 2F), 98.1 (m, 2F).
MS: m/z (%) = 257 (M+, 93.5), 229 (100.0), 212 (88.4).
MS: m/z (%) = 373 (M+, 43.4), 319 (43.4), 288 (100.0), 260 (79.8).
3ad: mp 136Ð138¡C.
4cg: mp 118Ð120¡C.
IR (KBr): ν = 1610 (C=O), 1090Ð1230 cmÐ1 (CÐF).
IR (KBr): ν = 3136, 1691, 1621 (C=O), 1104Ð1297 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 9.87 (d, 1H, 3JHH = 7 Hz, C5-H), 7.79 (s, 1H,
C8-H), 7.77 (s, 1H, C2-H), 7.59Ð7.48 (m, 5H, Ar-H), 6.91 (d, 1H,
3JHH = 7 Hz, C6-H), 2.48 (s, 3H, Ar-CH3).
19F NMR (CDCl3): δ = 55.5 (s).
1H NMR (CDCl3): δ = 9.62 (d, 1H, 3JHH = 7.6 Hz, C-10H), 8.22 (s,
1H, C2-H), 7.88Ð7.25 (m, 10H, Ar-H).
19F NMR (CDCl3): δ = 71.0 (s, 2F), 114.7 (m, 2F), 124.2 (d, 1F, 3JFF
= 146 Hz), 164.0 (d, 1F, 3JFF = 146 Hz).
MS: m/z (%) = 303 (M+, 100.0), 234 (8.8), 226 (52.1), 198 (29.4),
MS: m/z (%) = 467 (M+, 96.06), 382 (31.41), 332 (57.39), 302
105 (9.0), 77 (17.9).
(71.42), 105 (100.0), 77 (46.08).
3ae: mp 161Ð163¡C.
4dg: mp 88Ð90¡C.
IR (KBr): ν = 1630 (C=O), 1090Ð1230 cmÐ1 (CÐF).
IR (KBr): ν = 3144, 1699, 1627 (C=O), 1137Ð1299 cmÐ1 (CÐF).
3
1H NMR (CDCl3): δ = 9.76 (d, 1H, 3JHH = 7 Hz, C5-H), 7.65 (s, 1H,
C8-H), 7.48 (s, 1H, C2-H), 6.84 (d, 1H, 3JHH = 7 Hz, C6-H), 2.54 (s,
3H, -Ar-CH3), 2.46 (s, 3H, -COCH3).
19F NMR (CDCl3): δ = 55.5 (s).
1H NMR (CDCl3): δ = 9.62 (d, 1H, JHH = 7.5 Hz, C10-H), 8.21Ð
7.25 (m, 11H, Ar-H).
19F NMR (CDCl3): δ = 68.0 (s, 2F), 116.5Ð123.0 (m, 6F), 124.5 (d,
1F, 3JFF = 145 Hz), 161.0 (d, 1F, 3JFF = 145 Hz).
MS: m/z (%) = 241 (M+, 79.9), 226 (100.0), 198 (59.3).
MS: m/z (%) = 567 (M+, 43.12), 382 (32.44), 332 (28.50), 105
(100.0), 77 (44.24).
3af: mp 83Ð85¡C.
4di: mp 74Ð76¡C.
IR (KBr): ν = 2219 (-CN), 1500, 1138Ð1205 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 8.41 (d, 1H, JHH = 7.7 Hz, C10-H), 7.79Ð
7.17 (m, 6H, Ar-H).
IR (KBr): ν = 1650 (C=O), 1090Ð1260 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 8.54 (d, 1H, 3JHH = 8 Hz, C8-H), 8.23Ð7.11
(m, 8H, Ar-H).
19F NMR (CDCl3): δ = 54.8 (s).
MS: m/z (%) = 290 (M+, 100.0), 262 (50.6), 213 (71.4), 105 (38.2),
3
19F NMR (CDCl3): δ = 68.5 (s, 2F), 115.5Ð122.0 (m, 6F), 126.0 (d,
1F, 3JFF = 144 Hz), 161.0 (d, 1F, 3JFF = 144 Hz).
77 (28.2).
MS: m/z (%) = 488 (M+, 47.57), 453 (20.34), 303 (85.66), 283
3ag: mp 128Ð130¡C.
(61.36), 253 (77.60), 223 (100.0), 205 (60.63).
IR (KBr): ν = 1625 (C=O), 1185Ð1275 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 9.67 (d, 1H, 3JHH = 8 Hz, C10-H), 8.52 (m,
1H, C5-H), 7.85Ð7.29 (m, 10H, Ar-H).
Acknowledgement
We are grateful to the National Natural Science Foundation of
China for partial Þnancial support, Grant Approval Number
29632003.
19F NMR (CDCl3): δ = 55.5 (s).
MS: m/z (%) = 339 (M+, 100.0), 262 (61.1), 234 (37.4), 105 (39.1),
77 (41.2).
References
3ah: mp 106Ð108¡C.
IR (KBr): ν = 1700 (C=O), 1090Ð1230 cmÐ1 (CÐF).
1H NMR (CDCl3): δ = 9.36 (d, 1H, 3JHH = 8 Hz, C10-H), 8.45 (d,
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MS: m/z (%) = 307 (M+, 100.0), 279 (80.0), 262 (58.2), 235 (83.3).
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X-c. Zhang, W-y. Huang
SHORT PAPER
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Synthesis 1999, No. 1, 51Ð54 ISSN 0039-7881 © Thieme Stuttgart · New York