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Valentine Nenajdenko Editor
Fluorine in Heterocyclic Chemistry Volume 1
5-Membered Heterocycles and Macrocycles
Volume 1: ISBN 978-3-319-04345-6 ISBN 978-3-319-04346-3 (eBook)Volume 2: ISBN 978-3-319-04434-7 ISBN 978-3-319-04435-4 (eBook)Set ISBN 978-3-319-06036-1 DOI 10.1007/978-3-319-04346-3DOI 10.1007/978-3-319-04435-4 Springer Cham Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014942653
© Springer International Publishing Switzerland 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.
Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
Editor Valentine Nenajdenko Department of Chemistry Moscow State University Moscow, Russia
157V. Nenajdenko (ed.), Fluorine in Heterocyclic Chemistry Volume 1: 5-Membered Heterocycles and Macrocycles, DOI 10.1007/978-3-319-04346-3_4,© Springer International Publishing Switzerland 2014
Abstract The chapter is devoted to the synthesis and application of indolizines bearing fl uorine atoms, perfl uorinated alkyl (aryl) groups, and COCF 3 fragments.
Keywords Indolizine • Fluorine • Trifl uoromethyl group • Synthesis • Fluorinated heterocycles
Fluorinated Indolizines
Eugene V. Babaev
E. V. Babaev (*) Department of Chemistry , Moscow State University , Leninskie Gory , Moscow 119992 , Russian Federation
Moscow Institute of Physics and Technology , Institutskii per. 9 , 141700 Dolgoprudny, Moscow Region , Russia e-mail: [email protected]
Contents
1 Introduction ........................................................................................................................ 1582 Synthesis of Indolizines with Substituent in Pyrrole Fragment ......................................... 158
2.1 Indolizines with Substituent at Position 3 ................................................................. 1582.2 Indolizines with Substituent at Position 1 ................................................................. 1652.3 Indolizines with Substituent at Position 2 ................................................................. 168
3 Synthesis of Indolizines with Substituent in Pyridine Ring............................................... 1723.1 Indolizines with Substituent at Position 6 and 8 ....................................................... 1723.2 Indolizines with Substituent at Position 7 ................................................................. 1763.3 Indolizines with Substituent at Position 5 ................................................................. 177
4 Conclusion ......................................................................................................................... 177References ................................................................................................................................ 178
158
1 Introduction
Fluorinated heterocycles have received increasing attention due to their important biological properties. Considerable efforts have been paid to the exploitation of new synthetic routes to these fl uorinated compounds. Indolizine is an important funda-mental ring system in view of its similarity to indole. This heterocycle occurs com-monly as a fully reduced form in natural products. Owing to the increasing importance of fl uorine containing heterocycles in biology, pharmacology, and industrial application, synthesis of fl uorine-containing indolizines became of con-siderable interest. In spite of existence of numerous reviews on the chemistry of indolizines [ 1 ] no attention have been paid to its fl uorinated derivatives. In fact, this area is relatively young (the fi rst research paper on this topic appeared 30 years ago). In spite of many efforts, up to now no indolizines with perfl uorinated groups appeared on the market.
The review is organized in the following way. First, indolizines with substituents at pyrrole fragment are covered. This includes indolizines substituted at positions 3 and 1 (since these positions are most easily substituted), and then 2-substituted derivatives. Then, indolizines substituted at pyridine ring are covered: structures with 6(8)-perfl uorinated groups are reviewed, and fi nally, 7- and 5-derivatives are discussed. Major attention is paid to indolizines; benzo-derivatives are also included.
2 Synthesis of Indolizines with Substituent in Pyrrole Fragment
2.1 Indolizines with Substituent at Position 3
Although the position 3 in the indolizine ring is the most reactive toward electro-philic attack, no direct fl uorination of indolizines have been reported. Instead, in the recent work [ 2 ] 1,3-dipolar cycloaddition was studied to difl uoro-substituted pyri-dinium ylides.
N+
CF F
X
N
F
XY
YN
X
Y
Y
N
XY
Y
F
CF2Br2/Pb/Bu4NBr
CH2Cl2/ultrasound
X = CN, CO2Et, COPh
Y = CO2Me, CN
MnO2
:CF2
1
E.V. Babaev
159
Pyridine Dipolarophile Yield (%)
4-COPh CO 2 Me 18 ( 1a ) 4-COPh CN 31 ( 1b ) 4-CO 2 Et CO 2 Me 23 ( 1c ) 4-CO 2 Et CN 28 ( 1d ) 4-CN CO 2 Me 48 ( 1e ) 4-CN CN 43 ( 1f ) 3-CN CO 2 Me 16 ( 1g:1h ) (1:1)
Difl uoromethylides were prepared from 4-cyano, 4-benzoyl- and 4-ethoxycarbonyl- substituted pyridines under difl uorocarbene generation condi-tions (ultrasound, CF 2 Br 2 /Pb/Bu 4 NBr) and trapped with dimethyl maleate or fuma-ronitrile. 3-Fluoroindolizines were isolated as fi nal products of the reaction which involves dehydrofl uorination of the primary cycloadducts followed by dehydroge-nation by active MnO 2 .
These ylides where shown to dissociate to carbene and pyridine with low activation barrier. The equilibrium constant of the reaction increases with increasing electron- withdrawing ability of substituents in the pyridine ring. There was no reaction with unsubstituted pyridine or picolinic acid nitrile. In the reaction of nicotinic acid nitrile with the fumaronitrile a mixture of the regioisomeric products was formed:
N
FNC
CN
CN
N+
NC
F
F
N
F
CN
CN
CN
+ 1g
1h
C
The reaction of N-CH 2 CF 3 pyridinium salt with dimethyl acetylenedicarboxylate or perfl uorobut-2-yne in the presence of base (Et 3 N or K 2 CO 3 ) [ 3 ] has provided fi rst formation of indolizines 2 with CF 3 -group in position 3.
N
CF3
X
XN+
CF3
X X
N Et3Nor K2CO3
TfOCH2CF3
90%
X = CO2Me (11%); CF3 (12%)
2TfO-
Fluorinated Indolizines
160
Similarly, the reaction of ylide formed from N-CH 2 COCF 3 pyridinium salt and dimethyl acetylenedicarboxylate or perfl uorobut-2-yne gave rise to 3-COCF 3 - indolizines 3 [ 4 ].
N
X
X
OCF3
N+
CH
O CF3
X X
X = CO2Me (70%)
X = CF3 (20%)
3
The same methodology was applied to N-CH 2 COF 3 γ,γ’-bipyridinium salt lead-ing to intermediate indolizine 4 or fi nal aminosugar 5 with 3-COCF 3 group [ 5 ].
N
O CF3
CO2ArR
N+
O CF3
R
Br
O
OArNH2-Sugar
O
NH-Sugar
R
N
OCF3
ON
Sugar
Et3N/DMF/2h
4 (42%)
DMF/12h7%
DMF/12h20%
5R= γ-Py
It should be mentioned that isoquinoline 2-oxide reacted with perfl uorobut-2-yne similarly forming (among other products) 1,2,3-tris(trifl uoromethyl)- and 1,2-bis(trifl uoromethy1)-3-trifl uoroacethylpyrrolo[2,1-a]isoquinoline [ 6 ].
N
CF3
CF3
OCF3
N+
O
CF3 CF3
N
CF3
CF3
CF3+
traces
Finally, 3-COC 6 F 5 indolizine 6 was obtained together with more saturated prod-uct 7 by cycloaddition of the corresponding ylide and methyl acrylate [ 7 ].
E.V. Babaev
161
N
O
CO2Me CO2Me
N+
O C6F5 C6F5C6F5Br
O
OMe
N
O
Et3N
6 (11%)
+
7 (35%)
Meanwhile, it is much easier to prepare indolizines with perfl uoroacyl substitu-ent at position 3 by perfl uoroacylation reaction. The reaction yields are strongly depended on the basicity of the parent indolizine: thus 2-phenylindolizine under-went trifl uoroacetylation to form 8 in 36 %; the rest (60 % after regeneration) was indolizinium cation formed by protonation of starting material [ 8 ].
NPh N
Ph
COCF3
N+ Ph+(CF3CO)2O
CF3CO2-
8
Nitroindolizines having 6- and 8-nitro group in the same reaction led to trifl uo-roacetyl derivatives 9 – 12 in quantitative yield [ 9 ]. It was shown that their basicity is decreased.
NR
R'
X
YN
R
COCF3
R'
X
Y
(CF3CO)2O
9-12
Indolizine Yield (%)
9 3-COCF 3 -6-NO 2 -2-Ph-7-Me 97 10 3-COCF 3 -6-NO 2 -2-Me 96 11 3-COCF 3 -8-NO 2 -2-Me 100 12 3-COCF 3 -8-NO 2 -2-Ph 100
5-Bromoindolizine underwent trifl uoroacetylation selectively at position 3 lead-ing to compound 13 ; the yield was 83 % [ 10 ]. 2-Carbomethoxyindolizine is trans-formed to 3-COCF 3 derivative 14 in 85 % yield [ 11 ].
N
Br
N
Br COCF3
(CF3CO)2O
13
Fluorinated Indolizines
162
N
O
OMeN
O
OMe
COCF3
(CF3CO)2O
14
There is only one example of trifl uoroacylation in the series of benzoindolizines. 3-Perfl uoroacyl derivatives 15 and 16 were obtained in high yield [ 12 ] using trifl uo-roacetic and perfl uorosuccinic anhydride as acylating agents.
NAr'
Ar
OMe
MeO
NAr'
Ar
OMe
MeO
COCF3
N
Ar'Ar
MeO
MeOO
FF F
F
OOH
OO
O
FFF
F
(CF3CO)2O
16 (95%)15 (73%)
Ar=3,4-(MeO)2C6H3
Ar'=4-ClC6H4
Pyrrolo[1,2-a]pyrazinum (7-azaindolizinium) cations may underwent ring open-ing and transformation of the pyrazinium fragment under the action of MeNH 2 . The rearrangement is known as Kost-Sagitullin (enamine) rearrangement.
N+
N
RMeNH2
N
N
R
MeNH
NH
N
R
MeNH
HN
NHR
On the other hand, 7-azaindolizinium cations with COCF 3 group may be involved in haloformic recyclization leading to oxo-derivatives of pyrrolo[1,2-a]pyrazines.
Here the NHMe-amino group was originated from the reagent.
N
N
O
R
O
N+
N
R
F3COC
MeNH2
NN
MeN
R
HO CF3
MeN
N
R
F3COC
NH
- MeNH2
- CHF3
E.V. Babaev
163
At lower temperature the product 17 of enamine rearrangement to pyridine ring predominated, whereas at higher temperature (and in water solution) the ring trans-formation occurred with haloformic reaction to form 18 [ 13 ].
MeN
N
R
COCF3
HN
N
N
R
F3COC
MeNH
N
F3COC
NHMe
R
N
N
O R
O
N+
N
R
F3COC
MeNH217a-c
18a,b
№ R
17:18
30 °C 170 °C
a Et 10:39 45:6 b n-Pr 15:50 44:10 c PhCH 2 60:0 70:0
Electrophilic nature of 3-COCF 3 group is displayed by the reaction of indolizine 14 with hydrazine forming pyridazinone derivative 19 in the yield 79 % [ 11 ].
N
O
OMeCOCF3
N
O
NN
CF3
N2H4
14 19
3-Trifuoroacetyl indolizines underwent removal of 3-COCF 3 group in good yield by the reaction with cold alkali [ 9 , 4 , 12 ].
NPh
NPh
COCF3
N
X
X
COCF3
N
X
X
NAr'
Ar
OMe
MeO
NAr'
Ar
OMe
MeO
COCF3
X=CF3
OHOHOH
8 163
58% 95%83%
Fluorinated Indolizines
164
It should be mentioned that similar pyrroles, indoles and azulenes bearing COCF 3 group all reacted with alkali with haloformic removal of CHCF 3 ; the “strange” behavior of 3-COCF 3 indolizines was explained by their higher basicity and possi-bility of substitution of trifl uoroacetate ion by ipso-protonation [ 14 ].
NPh
NPh
COCF3
NPh
HOO
CF3
NPh
O OCF3
H
OH−
- CF3CO2-
+
Particularly, this statement was confi rmed by reaction of trifl uoroacetyl deriva-tives of 6- and 8-nitroindolizines with alkali. Being less basic these compounds underwent haloformic reaction to form nitroindolizine-2-carboxilic acids. The reac-tion, however, did not stop at this point and fi nalized with transformation of pyridine ring (of indolizines) to benzene ring of indoles [ 9 ].
N
COCF3
Me
O2N
PhN
Me
O2N
Ph
CO2HNH
O2NCOOH
Me
Ph
NR
COCF3
NO2
NR
NO2
COOH
NH
R
NO2
COOH
OH-OH-
OH-OH-
9 20 21
11,12 22 23,24
Indolizine Indole (acid) Yield of indole (acid), %
9 21 ( 20) 98 (67) 11 23 (22) 72 (42) 12 24 80
It should be mentioned that conversion of indolizines to indole 2-carboxylic acids proceeded in higher yields and in milder conditions (0 °C) than for indolizines without COCF 3 group. The overall mechanism is of the ANRORC type:
E.V. Babaev
165
N
R
NO2
HOOC
HN
R
O2N
HOOC
N
R
NO2-
HOOC
HON
R
HOOCHO
NO2
NR
COOH
~H
OHO2NH
H
OH-
- OH-
2.2 Indolizines with Substituent at Position 1
Position 1 of the indolizine ring is the second one (after position 3) that can be attacked by electrophiles. However, there are no examples of direct fl uorination of indolizine ring at position 1. Among the benzoindolizines there is such an example [ 15 ] where the desired F-containing scaffold 25 was obtained by use of Selectfl uor.
N
OO
Oi-Pr
OMe
MeO O-i-Pr
N
OO
Oi-Pr
OMe
MeOO-i-Pr
FN+
N+F
Cl 2BF4-
53%25
Another example of direct incorporation of perfl uorinated substituent at the posi-tion 1 is the insertion of CF 3 S group using CF 3 SCl as electrophile [ 16 ]. Reaction proceeded at positions 1 and 3 even in the case of deactivated 3-COMe indolizine quantitatively. In the case of 3-benzylindolizine substitution at C-1 is accompanied by insertion of electrophile in the benzyl fragment as well.
NR
R'
NR
SCF3
SCF3
N
SCF3
CF3S
27a-c26a-d27d
CF3SClCF3SCl
26a R=R’=H 27a 26b R=H, R’=Me 27b 26c R=Me, R’=Ac 27c 26d R=Me, R’=PhCH 2 27d
Fluorinated Indolizines
166
As it was shown recently [ 17 ], perfl uorophenyl group can be inserted at position 1 and 3 under the cross-coupling conditions. This regioselective reaction took place with pyridine, potassium phosphate, copper (I) iodide, 1,10-phenanthroline and iodine in 1,4-dioxane at 120–130 °C during 74 h.
N
CN
N
CN
FF
F
FF
F
FF
F
FF
F
F
F
F
CuI/I2
78%
Investigation of the direction of trifl uoroacetylation of 2-methylindolizine has shown minor amounts of the 1-substituted isomer formed in addition to the “usual” product of substitution in the 3 position [ 18 ].
N N
F3COC
N COCF3+
(CF3CO)2O
28 (93%) 29 (3.5%)
Na2CO3
Furthermore, 1-COCF 3 isomer is formed when 3-COCF 3 indolizine was heated in CH 3 COOH (together with 1- and 3-acetylindolizines) [ 14 ]. The reaction mecha-nism seemed to be intramolecular.
N
F3COC
N COCF3 N COMe N
MeOC
+
29 (7%)28
AcOH +
30 (13%) 26c (11%)
N
R
Rf
PO(OR')2N+
CH
R
Rf PO(OR')2
31
E.V. Babaev
167
Compound Rf R’ R Yield (%)
31a CF 3 Et CN 74 31b CF 3 Pr CN 70 31c C 2 F 5 Et CN 73 31d C 2 F 5 Pr CN 49 31e CF 3 Et CO 2 Et 47 31f CF 3 Pr CO 2 Et 51 31g C 2 F 5 Et CO 2 Et 51 1 h CF 3 Et COPh 77 31i C 2 F 5 Et COPh 65 31j C 3 F 7 Et COPh 70
In addition to direct insertion of perfl uorinated group at position 1, there are plenty of methods how to introduce such a group via cycloaddition reaction. Thus, conve-nient method to perfl uoroalkylated indolizinyl-phosphonates 31 was reported [ 19 ]. The reaction proceeded regioselectively via the 1,3-cycloaddition of pyridinium N-ylide and perfl uoroalkynyl phosphonate in 49–77 % yields. Similar reaction was proposed to obtain pyrrolo[1,2-a]isoquinolinyl phosphonates in 48–78 % yields [ 20 ].
R
PO(OR')2
Rf
N
CH
R
N+
Rf PO(OR')2
In the reaction of 2-bromo-3,3,3-trifl uoropropene with pyridinium ylides cyclo-addition occurred readily leading to 1-CF 3 derivatives of indolizines [ 21 ]. Similar reaction took place in the cases of pyridazinium and isoquinolinium ylides.
N
R'CF3
R
N+
R
R'
Br
FFF
N
CF3
R
N+
R
Br
FFF
CF3
R
NN
R'
RN+
NR'
Br
FF
F
base
32
base base
Fluorinated Indolizines
168
R R’ Yield (%) R R’ Yield (%)
COPh H 40 COPh Me 49 COMe H 24 COMe Me 27 CO 2 Et H 35
The reaction of 3-COCF 3 pyridinium ylide with 1,1,1-trifl uoropropyne pro-ceeded similarly giving 1-CF 3 indolizine in low yield [ 4 ]. Similarly behaved other pyridinium ylides with benzoyl and ester groups [ 22 ].
N
CF3
OR
N+
CH
O R
CF3 R = CF3 33 (4%)
Ph 34 (14%)EtO 35 (22%)
Pyridinium ylides reacted with 4-ethoxy-1,1,1-trifl uorobut-3-en-2-one to give the corresponding 1-trifl uoroacetyl-substituted indolizines [ 23 ]. Isoquinolinium ylides behaved similarly.
N
R
COCF3N+
CHR
OMe
CF3 O
N+
CHR
N
R
COCF3
OMe
CF3 O
36
70-75%
R Yield (%)
COPh 76 % CN 74 % CO 2 Et R=CO 2 Et/Me
2.3 Indolizines with Substituent at Position 2
2-Fluoroindolizines are easily available via cycloaddition of fl uorinated vinyl tosyl-ates and pyridinium ylides [ 24 ]. Using β-substituted pyridinium ylides both isomers (6 and 8) were formed with clear predominance of 8-isomers. One product with 3-CO 2 Et group was recently patented as the intermediate [ 25 ]. The reaction also proceeded with isoquinolinium and benzimidazolium ylides.
N
FR
R'
R"
N+
R
R'
R" F
F
OTos
N
F R
R'
R"
Et3N/K2CO3
DMF/70 �C
+
37
E.V. Babaev
169
R R’ R” Yield (%) R R’ R” Yield (%)
COPh H H 34 CO 2 Et H COPh 8 (1:1.5) COPh CH 3 H 23 CN H H 59 COPh H CH 3 37 (1:2) CN CH 3 H 33 COPh H Br 27 (1:1.5) CN H CH 3 67 (1:10) CO 2 Et H Br 40 (1:6) CN H Br 58 (1:1.7)
N
R
F
N+
R R
NN
R'
FR
N+N
R'
F
FOTos
base base10-68% 12-61%
Further modifi cation of the strategy was proposed; 1-chloro-2,2,2- trifl uoroethane (bp 6 °C) or 1,1,1,2-tetrafl uoroethane (bp –27 °C) gave the corresponding 2- fl uoroindolizines 38 via 1,3-dipolar cycloaddition at 80–100 °C in DMSO at atmospheric pressure in normal glassware [ 26 ]. The reaction started with the elimi-nation of HF from CF 3 CH 2 X and can be applied to isoquinolinium ylides.
NF
R
R'
N+
R
R'F
FXF
Et3N / K2CO3
38
X R, R’ Yield of 38 X R, R’ Yield of 38
Cl COPh, H 45 F COPh, H 37 Cl COPh, Me 67 F CO 2 Et, H 47 Cl CO 2 Et, H 82 F CO 2 Et, Me 28 Cl CO 2 Et, Me 76
In the presence of base, 2,2-dihydropolyfl uoroalkanoates of the type R F CF 2 CH 2 CO 2 Et reacted with N-(cyanomethyl)pyridinium ylides to give the corre-sponding indolizine derivatives carrying both a fl uoroalkyl and a cyano group [ 27 ].
N
R
CN
CO2Et
N+
R
CN
K2CO3
Cl(CF2)nCH2CO2Et(CF2)mX
39
R n m X Yield R n m X Yield
H 2 1 H 76 Me 2 1 H 90 H 4 3 Cl 70 Me 4 3 Cl 83 H 6 5 Cl 61 Me 6 5 Cl 88 H 8 7 Cl 52
Fluorinated Indolizines
170
Ethyl 2,2-dihydropoly(per)fl uoroalkanoates reacted with N-phenacylpyridinium ylides in DMF to give poly(per)fl uoroalkyl-substituted indolizines 40 and 41 [ 28 ]. Origin of the products 41 is explained by the adduct aromatization.
N
RCO2Et
COPh
N+
R
COPh
K2CO3 N
R
CO2Et
COPh
F
F
Cl(CF2)nCH2CO2Et(CF2)mX
40 (0-82%)
(CF2)kX
41 (0-63%)
+
R=H,Me,CN
N-Benzylpyridinium ylides (generated in situ from the N-benzylpyridinium bro-mide and alkali) reacted with ethyl 3-fl uoro-3-fl uoroalkyl acrylates to give one or two fl uoroalkylated indolizine derivatives through 1,3-dipolar cycloaddition fol-lowed by an oxidative aromatization or 1,3-H-shift aromatization process [ 29 ].
NCF2CF2CF2Cl
RCO2Et
X
N+
R X
NCHFCF2CF2Cl
RCO2Et
X
Cl(CF2)3CF=CHCO2Et
42 43
+
NaOH
Pyridinium salt Products and yield (%)
R=H, X=H 42a (18) 43a (14) R=H, X=OMe 42b (31) 43b (18) R=H, X=NO 2 42c (31) 43c (29) R=CO 2 Et, X=H 42d (35) 43d (8) R=Me, X=NO 42e (5) – R=CO 2 Et, X=NO 2 42f (33) –
In the presence of K 2 CO 3 and Et 3 N, pyridinium N-ylides, generated in situ from their halides, reacted with gaseous fl uoroalkenes CF 2 =CFX (X=Cl, Br) in DMF under atmospheric pressure in normal glassware at 70 °C to give the corresponding 1,2-fl uorinated indolizines. Similar results were obtained with tetrafl uoroethene in an autoclave [ 30 ].
E.V. Babaev
171
N+
R
R'
NF
R
FR'
F
F
X
F
K2CO3
Et3N 44
Alkene/X Ylide, R,R’ Yield
Cl COPh, H 66 Cl COPh, Me 64 Cl CO 2 Et, H 37 Br COPh, H 57 Br COPh, Me 77 Br CO 2 Et, H 75 F COPh, Me 32
The reaction proceeded also with quinolinium, isoquinolinium and benzimidazo-lium ylides. In the reaction of ylide obtained from β-picoline the mixture of 6- and 8-isomers was formed.
N+
CORF
F
X
FK2CO3
Et3N
K2CO3
Et3NK2CO3
Et3N
CORN
FF
N+
COPh
COPh
NF
F
NN+
COR
Ph
N
COR
Ph
N
F
F
F
F
X
F
F
F
X
F
N+
Me
COPh
NF
F
MeCOPh
F
F
X
F
NF
FMe
COPh
K2CO3
Et3N
+
X=Cl 60%, X=F 37%
1:1
Similar reaction took place for hexafl uoropropene to form 1-CF 3 indolizines. The result was similar to the early one by Banks with NCH 2 CO 2 Bu t [ 31 ], [ 32 ], NCH 2 COCF 3 [ 4 ] and NCH 2 COR [ 22 ] pyridinium salts.
Fluorinated Indolizines
172
N+
R
R'
NF
R
CF3R'
F
F
CF3
F
K2CO3
Et3N 45
R, R’ Yield of 45 (%) R Yield of 46 (%)
COPh, H 62 CO 2 Bu t 37 COPh, Me 71 COCF 3 10 CO 2 Et, H 57 COPh 12 CO 2 Et, Me 53 CO 2 Et 13
N+
R
NF
R
CF3F
F
CF3
F
46
NaH
3 Synthesis of Indolizines with Substituent in Pyridine Ring
3.1 Indolizines with Substituent at Position 6 and 8
It is diffi cult to obtain pure isomers containing fl uoro (or perfl uorinated group) at 6- or 8-position. Since the substituents cannot be inserted directly into the pyridine fragment of indolizine ring, they should already exist in the precursors of the cor-responding indolizines. However, this caused loss of regioselectivity (if β-substituted pyridinium salts were used) or necessity to use poorly available β-substituted α-picolines.
N+
R
RfN
R
Rf
N
R
Rf
N
Rf
N
Rf
For example, reaction between 3-fl uorosubstituted pyridinium N-bis-(methoxy- carbonyl)methylide and methyl propiolate [ 33 ] proceeded in the yield 53 % giving predominant formation of 8-isomer ( 47a:47b = 65:35). CNDO2 calculations showed that the site selectivity can be rationalized by dipole-dipole interactions.
E.V. Babaev
173
N+
F
O
O
OMe
MeO
NF
N
F
CO2Me
CO2Me CO2Me
CO2Me
CO2Me+
47a 47b
Pd(0)53%
Another example was the copper(I)-catalyzed cycloaddition of ethyl isoprope-nyldiazoacetate to 3-F-pyridine [ 34 ]; reaction took place in the yield 60 % with clear predominance of 8-isomer ( 48a:48b = 3:1). The process represents the fi rst successful example of metal-catalyzed cyclization of a π-defi cient heterocyclic sys-tem with alkenyldiazo compounds.
NF
NF
N
F CO2Et CO2Et
N+N
O
OEt
CuBr
+
48a 48b
NCuBr
O
OEt
CuBr-
O
OEt
N CO2Et
N+
N+
N
O
OEt
CuBr
More one example is connected with generation of unsubstituted ylides [ 35 ]. As facile precursors for non stabilized pyridinium methylides N-(trimethylsilylmethyl)pyridinium trifl ates were synthesized. Cesium fl uoride induced desilylation of the precursors liberated the nonstabilized pyridinium methylides which were trapped as the cycloadducts to dimethyl acetylenedicarboxylate. Trapping of 3-CF 3 -pyridinium ylide gave the mixture of isomers ( 50a:50b = 1:5) in 53 % overall yield.
N+
F3Si
CF3
N
N
CF3
N+
CH2
CF3
CF3
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CsF
50a
50b
Fluorinated Indolizines
174
In the patent literature there were two examples of preparation of indolizyl-1- acetic acid according to Chichibabin methodology: the fi rst one – 6- fl uoroindilinzine 51 [ 36 ] and the second one – 6-CF 3 -derivative [ 37 ].
NF
CO2Et
NF
CO2Et
NCF3
CO2Et
NCF3
CO2Et
NaHCO3
BrCH2COMe
26%
51
BrCH2COMe
5236%
Successful cycloisomerization of acyclic alkynyl imines to pyrroles caused an attempt to the cycloisomerization of the cyclic alkynyl imines; thus 2-alkynyl pyri-dine with CF 3 -group gave a product of cyclization, indolizine 53 [ 38 ].
NCF3
NCF3
CuCl/Et3N
73%53
2-(Pyridin-2-yl-methylene)malonates and arynes reacted to produce pyrido[1,2- a]indoles which in some cases ( 54 , 55 ) correspond to 6-fl uoroderivatives of benzo-indolizines [ 39 ].
NF
CO2Et CO2EtEtO2CEtO2C
NF
NF
N
NF
N PhSiMe3
SiMe3
OSO2CF3
OSO2CF3
39%
54
22%
55
A base-promoted conversion of ortho-trifl uoromethyl benzyl derivatives of NH-heterocycles into a respective fl uorinated isoquinolines (38–57 % isolated yields) was reported [ 40 ]. The reaction is general for the benzylated derivatives of the electron-rich NH heterocycles, particularly indoles. The outcome of the reaction
E.V. Babaev
175
could be explained by an intermediate formation of a highly reactive quinone methylide species.
N
F
R
R'N
F
F
R
R'
NFF
F
R
R'
LDA
N
FF
F
R"
LDAN
F
R"
- HF - HF
R R’ R” Yield, % R R’ R” Yield, %
H H – 38 – – H 44 Me H – 39 – – Cl 52 Me Me – 48 – – OMe 43
In several cases the reported structures of 8-fl uoro indolizine were in fact mix-tures; however, no analysis of traces of the 6-fl uoro isomer was performed. Thus, to the product of reaction of 3-fl uoropyridine, CH-acid and active quinone compound the structure of 8-F-indolizine was assigned [ 41 , 42 , 43 ]. Similarly, cycloaddition to β-CF 3 -pyridinium ylide is claimed to result in 8-CF 3 -derivative of indolizine [ 25 ].
NF
O
X
O
O
O
Cl
Cl
N N
O
O
F COX
N
+ +
N+
R
CF3
OiPr
N
CF3
CO2Me
OiPr
R
N R=C6H4CO2Me
baseMnO2
19%
A novel and effi cient preparation of 4-polyfl uoroaryl substituted pyrrolo[1,2-a]quinolines via a palladium-catalyzed reaction of 1-[2-(2,2-dibromo-ethenyl)phenyl]-1H-pyrrole with polyfl uorinated arenes was described [ 44 ]. The reaction is also applicable to obtain indoloquinolines with the same substitution pattern.
Fluorinated Indolizines
176
N
F
F
X
F
FN
BrBr
FF
F
F
X
Pd(OAc)2
Ru-Phos
X Yield, % X Yield, %
F 90 Me 68 MeO 80 CF 3 82
3.2 Indolizines with Substituent at Position 7
7-F or 7-CF 3 indolizines can be found only in the patent literature, namely com-pounds 56a [ 45 ], 56b [ 25 ], 56c , 56d [ 46 ] and 56e [ 37 ].
N
F
Op-FC6H4
N
CF3
N
CF3
CO2EtN
CF3
CN
N
CF3
CO2Et
56a 56b
56c 56d
56e
A water-accelerated palladium-catalyzed reaction of gem-dibromoolefi ns with a boronic acid via a tandem Suzuki-Miyaura coupling and direct arylation was reported [ 47 ]. One of the products, 57 , corresponded to 7-CF 3 derivative of benzoindolizine.
N
CF3
Ph
N
BrBr
CF3
Pd(OAc)2
S-Phos
B(OH)2
85%
+
57
E.V. Babaev
177
3.3 Indolizines with Substituent at Position 5
The only reaction which allowed introducing fl uorine atom at position 5 of indoli-zine ring was the Ugi-type reaction [ 48 ]. The resulting 5-fl uoroinolizine 58 was sensitive to nucleophiles giving rise to mini-library of 5-subsituted derivatives.
N
F
CN
N
F
CN
NH
NC
CHON
Nu
CN
NH
Nu
58
Indolizine (Nu) Yield, % Indolizine (Nu) Yield, %
F ( 58 ) 65 O(CH 2 ) 3 NMe 2 17 SCH 2 CO 2 Me 98 1-Morpholinyl 61 SCH 2 CO 2 H 95 NH(CH 2 ) 2 NMe 2 48 SMe 49
Finally, a palladium- and copper-catalyzed tandem N-H/C-H bond functionaliza-tion reaction of ortho-(2-chlorovinyl)bromobenzenes with indoles and pyrroles has been developed [ 49 ].
N
CF3
Cl
CF3
Br
N
N
CF3N
Cl
CF3
Br
RR'
RR"
R
R'
R
R"
+
+
50-73%
51-77%
A variety of CF 3 -containing indolo- and pyrrolo[2,1-a]isoquinolines were pre-pared in moderate to good yields via the cyclization of 1-bromo-2-(2-chloro-3,3,3-trifl uoroprop- 1-enyl)benzenes with indoles and pyrroles.
4 Conclusion
Fluorinated indolizines remained relatively rare class of compounds. In contrast to indolizines substituted at pyrrole fragment the structures having a perfl uoro- substituent in the pyridine ring are less available. This is caused by the fact that 3
Fluorinated Indolizines
178
and 1 substituted indolizines are easily available by direct insertion of fl uorine containing group. It should be mentioned that 1-, 2- and 3-substituted indolizines could be easily obtained by 1,3-dipolar cycloaddition reactions, whereas there is lack of general methods to the structures substituted in pyridine ring.
Acknowledgments This work was funded by RFBR (grant 12-03-00644-a).
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