Synthesis of trifluoromethyl and trifluoroacetyl substituted dihydropyrrolizines and tetrahydroindolizines

Article abstract of DOI:10.1016/j.tetlet.2020.151633

The trifluoroacetic anhydride promoted cyclization of enaminones derived from proline or pipecolic acid and β-ethoxyvinyl trifluoromethyl ketone was reinvestigated. An operationally simple procedure for the selective synthesis of bicyclic trifluoromethylated pyrroles and bicyclic pyrroles bearing trifluoromethyl and trifluoroacetyl groups on the pyrrole ring was developed. The mechanism of cyclization explaining the formation of bicyclic trifluoromethylpyrroles was discussed and previously described structures of the cyclization products were corrected.

Full text of DOI:10.1016/j.tetlet.2020.151633

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Synthesis of trifluoromethyl and trifluoroacetyl substituted dihydropyrrolizines
and tetrahydroindolizines
Anton A. Klipkov, Alexander E. Sorochinsky, Karen V. Tarasenko, Julia A.
Rusanova, Igor I. Gerus
PII:
S0040-4039(20)30046-0
DOI:
https://doi.org/10.1016/j.tetlet.2020.151633
TETL 151633
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Tetrahedron Letters
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14 January 2020
Please cite this article as: Klipkov, A.A., Sorochinsky, A.E., Tarasenko, K.V., Rusanova, J.A., Gerus, I.I., Synthesis
of trifluoromethyl and trifluoroacetyl substituted dihydropyrrolizines and tetrahydroindolizines, Tetrahedron
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Tetrahedron Letters
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Synthesis of trifluoromethyl and trifluoroacetyl substituteddihydropyrrolizines and
tetrahydroindolizines
Anton A. Klipkova,b, Alexander E. Sorochinskya, Karen V. Tarasenkoa, Julia A. Rusanovac, Igor I. Gerusa,
a Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science,
1 Murmanska str., Kyiv 02094, Ukraine
b Chemistry Department, Faculty of Natural Sciences, National University of Kyiv-Mohyla Academy, 2 Skovorody str., Kyiv 04070, Ukraine
c Department of Chemistry, Taras Shevchenko National University of Kyiv, 64/13 Volodymyrska str., Kyiv 01601, Ukraine
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +38-044-573-2598; fax: +38-044-573-2552; e-mail: igerus@hotmail.com
Article history:
Received
Received in revised form
Accepted
The trifluoroacetic anhydride promoted cyclization of enaminones derived from proline or
pipecolic acid and β-ethoxyvinyl trifluoromethyl ketone was reinvestigated. An operationally
simple procedure for the selective synthesis of bicyclic trifluoromethylated pyrroles and bicyclic
pyrroles bearing trifluoromethyl and trifluoroacetyl groups on the pyrrole ring was developed.
The mechanism of cyclization explaining the formation of bicyclic trifluoromethylpyrroles was
discussed and previously described structures of the cyclization products were corrected.
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Amino acids
Trifluoromethylpyrroles
Trifluoroacetylpyrroles
Cyclization
Introduction
Naturally occurring pyrrolizidine and indolizidine alkaloids have been reported to possess extensive biological activities [1] and
significant attention has been paid to the development of general methods for the syntheses of these azabicyclic systems [2]. The
selective introduction of a trifluoromethyl group to pyrrolizidine and indolizidine alkaloids could provide high lipophilicity, metabolic
stability, and bioavailability making the resulting compounds attractive in bioorganic chemistry [3]. Although several methods for the
synthesis of difluoromethylene bearing pyrrolizidines and indolizidines have been developed [4] only two examples describing the
preparation of trifluoromethylated pyrrolizidine alkaloids have been reported. The catalytic asymmetric Friedel–Crafts alkylation of
pyrrole with β-trifluoromethylated acrylate has been applied to the synthesis of a chiral pyrrole derivative in high yield with 98% ee
(Fig. 1a) [5]. Subsequent hydrolysis to the corresponding carboxylic acid followed by catalytic hydrogenation of the pyrrole moiety,
cyclization and lithium aluminium hydride deoxygenation provided access to trifluorinated heliotridane. Trifluoromethylated
pyrrolizidines have also been synthesised via the reaction of azomethine ylides generated from L-proline and aldehydes with β-
trifluoromethyl acrylamide with excellent diastereoselectivity and moderate regioselectivity (Fig. 1b) [6].
In our previous studies we have developed a new efficient route

2
Tetrahedron
N
N
Pyrrolizidine
Indolizidine
a)
O
O
+
NH
CF3
H
N
F3C
N
O
O
O
O
F3C
O
N
NH
Trifluoroheliotridane
CF3
H
N
+
b)
O
N
F3C
R
O
O
+
+
CO2H
N
H
major
R
N
O
O
H
N
O
CF3
N
R
minor
Figure 1. Synthesis of trifluoromethylated pyrrolizidines.
for the construction of 3-trifluoromethylpyrroles which are difficult to obtain by other methods, employing β-alkoxyvinyl
trifluoromethyl ketones as building blocks [7]. Continuing this work we became interested in developing alternative synthetic
methodologies for accessing trifluoromethylated pyrrolizidine and indolizidine derivatives with defined stereochemistry from bicyclic
trifluoromethylpyrroles after catalytic hydrogenation of the pyrrole moiety [8]. The potential of using bicyclic trifluoromethylpyrroles
in the synthesis of azabicyclic systems has not yet been explored. A key step of this strategy would be effective construction of the
bicyclic trifluoromethylpyrroles. Classical methods to obtain trifluoromethylated pyrrole derivatives include direct trifluoromethylation
of the pyrrole ring, 1,3-dipolar cycloadditions, and cyclizations using trifluoromethylated building blocks such as α,β-unsaturated
trifluoromethylketones and trifluoromethylated 1,3- or 1,4-dicarbonyl compounds [9]. Other methods include one-pot hydroamination
of 2-trifluoromethyl-1,3-enynes with aliphatic primary amines and subsequent halogenating agent-mediated electrophilic
cyclization/oxidation of the hydroamination product [10], gold-catalyzed cyclization of amino trifluoromethylpropargylic alcohols [11],
2H-azirine ring expansion upon treatment with 1-(3,3,3-trifluoro-2,2-dihydroxypropyl)pyridin-1-ium bromide and triethylamine [12],
gold(I)/Brønsted acid co-catalyzed cyclization of N-(2-perfluoroalkyl-3-alkynyl) hydroxylamines [13], and the three-component
reaction between N-aryl-2,2,2-trifluoroacetimidoyl chlorides, dialkyl acetylene dicarboxylate, and isocyanides [14].
In view of the preparation of bicyclic trifluoromethylpyrroles as precursors of trifluoromethylated azabicycles, a method starting from
proline and pipecolic acid appeared to be the most attractive [15]. Mellor and co-workers demonstrated that bicyclic pyrroles 5 and 6
bearing trifluoromethyl and trifluoroacetyl groups on the pyrrole ring can be synthesized from enaminones 1 and 2 via cyclization
promoted by trifluoroacetic anhydride (TFAA) in dichloromethane (Scheme 1). The authors suggested initial trifluoroacetylation of
enaminones 1 and 2 affording enaminodione intermediates 3 and 4, which were not isolated and cyclized to bicyclic pyrroles 5 and 6.
At the same time, the cyclization of thiaproline-derived enaminone 7 under identical conditions led to bicyclic trifluoromethylated
pyrrole 8 in 52% isolated yield, along with bicyclic pyrrole 9 (analogous to
X
O
O
COOH
N
F3C
X
CF3
TFAA
N
CH2Cl2
[15]
F3C
O
COOH
3 X = CH2
1 X = CH2
2
X = CH2CH2
4
X = CH2CH2
CF3
HO
HO2C
X
CF3
O
O
X
N
CF3
N
CF3
5 X = CH2, 70%
6 X = CH2CH2, 24%
CF3
CF3
TFAA
O
S
S
+
S
N
CH2Cl2
[15]
N
CF3
CO2H
N
9, 14%
8, 52%
CF3
F3C
O
TFAA
7
S
N
MeCN
[16]
8,
78%

Scheme 1. Previously reported cyclisations of enaminones 1, 2 and 7.
product 5 isolated from enaminoene 1) in 14% isolated yield [15]. When the solvent was changed from dichloromethane to acetonitrile
the cyclization of thiaproline-derived enaminone 7 with TFAA gave almost exclusively bicyclic trifluoromethylpyrrole 8 in high yield
[16]. Based on the reported data we assumed that the cyclization of enaminones 1 and 2 derived from proline and pipecolic acid could
also be controlled by altering the reaction conditions to afford bicyclic trifluoromethylpyrroles as the main products. In order to test our
hypothesis we re-examined the cyclization of proline and pipecolic acid derivatives 1 and 2, including optimisation of the cyclization
reagent and solvent. Herein, we report the synthesis of bicyclic trifluoromethylpyrroles under mild reaction conditions. The mechanism
of cyclization explaining the formation of bicyclic trifluoromethylpyrroles is also proposed.
Results and Discussion
We began our studies with the synthesis of enaminones 1 and 2 from the corresponding L-amino acids and β-ethoxyvinyl
trifluoromethyl ketone following our previously reported procedure [17] and Mellor’s method [15] (Scheme 2).
X
OEt
X
COOH
N
Procedure A or B
COOH
+
N
H
F3C
O
F3C
O
X = CH2, CH2CH2
(S)-1 X = CH2
Procedure A, 88%
Procedure B, 73%
Procedure A:
1. H2O, NaHCO3
2. H+ [17]
2
(S)- X = CH2CH2
Procedure B:
MeCN, r.t. [15]
Procedure A, 91%
Procedure B, 81%
Scheme 2. Synthesis of enaminones 1 and 2.
The cyclization of proline-derived enaminone 1 utilizing a slight excess (5-10%) of TFAA and acetonitrile as the solvent at room
temperature for 12 h afforded the desired trifluoromethyldihydropyrrolizine 10 along with a small amount of disubstituted
dihydropyrrolizine 11 (~2%) according to 19F NMR analysis of the crude reaction mixture (Scheme 3). Compound 10 was isolated in
70% yield after distillation under reduced pressure.
TFAA, CH2Cl2
87%
CF3
CF3
COOH
N
TFAA
+
N
N
MeCN, rt
O
F3C
O
F3C
10
, 70%
1
11
Scheme 3. TFAA promoted cyclization of enaminone 1.
The structural assignment of trifluoromethyldihydropyrrolizine 10 was based on 1H, 19F and 13C NMR spectroscopy. For example, in the
19F NMR spectrum the CF3 group appeared as a singlet at –56.64 ppm. This chemical shift of the CF3 group was similar to that reported
for the CF3 group in 3-trifluoromethylpyrrole [7]. In the 13C NMR spectrum of 10, the carbon of the pyrrole ring substituted by a CF3
group appeared at 105.2 ppm as a quartet (2JCF = 37.1 Hz) and the signal of the CF3 carbon was observed at 124.6 ppm as a quartet (1JCF
= 266.4 Hz). Finally, the structure of product 10 was proved by NOE experiments (Fig. 2).
nOe
F3C
F3C
H
H
nOe=4%
nOe
nOe=6%
CF3
H
N
N
nOe=27%
O
weak
nOe
11
10
Figure 2. 1H{1H}- and 1H{19F}-NOE of dihydropyrrolizines 10 and 11.
We discovered that simply adding TFAA to the solution of trifluoromethyldihydropyrrolizine 10 in dichloromethane at room
temperature led to trifluoroacetylation of the pyrrole ring at the α-position (Scheme 3). Only a slight excess (5-10%) of TFAA was
1
required for the complete conversion of trifluoromethyldihydropyrrolizine 10. The structure of product 11 was confirmed by H, 19F,
and 13C NMR spectroscopy and NOE experiments (Fig. 2). In the 19F NMR spectrum of 11, the CF3 group on the pyrrole ring appeared
at –58.43 ppm and the CF3CO group gave a signal at –73.14 ppm. In the 13C NMR spectrum the pyrrole ring carbon substituted by a

4
Tetrahedron
CF3 group appeared at 109.7 ppm as a quartet (2JCF = 38.8 Hz), and the signal of the CF3 carbon was observed at 122.8 ppm as a
quartet (1JCF = 265.8 Hz). The molecular structure of 11 was also confirmed by X-ray crystal structure analysis (Fig. 3).
Figure 3. Molecular structure of disubstituted dihydropyrrolizine 11. Ellipsoids are drawn at the 50% probability level.
Unexpectedly, the spectroscopic data (1H and 13C NMR) and melting point for product 11 were in good agreement with the data
reported for the product of cyclisation 5 described by Mellor and co-workers (Scheme 1). Thus Mellor and co-workers incorrectly
assigned the position of the trifluoroacetyl group and disubstituted dihydropyrrolizine 11 might actually be derived from
trifluoroacetylation of the initially formed trifluoromethyldihydropyrrolizine 10.
During this study we made several attempts to utilize the reaction between proline and endione 12 [18] for the synthesis of enamindione
3 as a key cyclization intermediate according to Mellor’s mechanism (Scheme 4). However enamindione 3 was relatively unstable and
spontaneously decomposed to enaminone 1 in the reaction mixture and could not be chromatographically purified. It should be noted
that in the reaction mixtures no signals for the CF3 groups of dihydropyrrolizines 10 and 11 were detected by 19F NMR spectroscopy in
the range of –55 ppm to 60 ppm.
O
O
N
F3C
CF3
+
i-BuO
COOH
N
O
+
COOH
N
H
F3COC
COCF3
COOH
F3C
CF3
O
3
12
1
CF3
or
N
N
F3C
11
10
Scheme 4. Attempted synthesis of enamindione 3.
A possible pathway for the cyclization of 1 involves the initial formation of conjugated azomethine ylide 12 with TFAA as a
cyclodehydrating agent (Scheme 5) [19]. Under the reaction conditions conjugated azomethine ylide 12 loses carbon dioxide and
undergoes 1,5-electrocyclization [20] to give cycloadduct 13 which is a resonance structure of trifluoromethyldihydropyrrolizine 10.
The mechanism of the cyclization was studied by computer simulation: the geometry optimization of the conjugated azomethine ylide
formed after losing CO2 was performed by both semi-empirical AM1 and DFT (ab initio method: B3LYP with basis set 6-311++g2d2p)
methods and the optimized structure was planar with angles and distances between atoms identical to the corresponding values
calculated for product 10 (for more information see the ESI).
COOH
O
C
O
CF3
CF3
N
TFAA
-2 CF3CO2H
N
N
N
-CO2
CF3
O
F3C
13
10
12
1
Scheme 5. Proposed mechanism for the cyclization of 1.
Next an optimization of the cyclization reagent for the transformation of proline derivative 1 to trifluoromethyldihydropyrrolizine 10
was carried out. The aim of this was to avoid the formation by-product 11 (Scheme 3). Our attempts to employ reagents such as TsCl,
CDI, SOCl2, (COCl)2, and triphosgene in acetonitrile or without solvent were unsuccessful and no trace of the target pyrrole 10 was
detected. Performing the cyclization with DCC and TsCl in the presence of Py led to complex reaction mixtures containing

trifluoromethyldihydropyrrolizine 10 in up to 36% yield according to 19F NMR spectroscopy. In contrast, the reaction in acetic
anhydride at 80-100 °C for 12 h afforded exclusively the desired product 10 in 65% yield after purification by vacuum distillation
(Scheme 6). It is interesting to note that the addition of Py or DMAP to the reaction mixture did not accelerate the formation of
trifluoromethyldihydropyrrolizine 10.
CF3
COOH
N
O
(CH3CO)2O
85 °C, 12 h
N
F3C
1
12,
65%
Scheme 6. Acetic anhydride promoted cyclization of enaminone 1.
Encouraged by the selectivity and efficiency of the reaction of 1 in acetic anhydride we decided to examine the cyclization of pipecolic
acid derivative 2 under the same conditions. Unexpectedly the heating of enaminone 2 in acetic anhydride at 85 °C for 12 h provided
tetrahydroindolizine 15 bearing acetate and trifluoroacetyl groups on the pyrrole ring along with the desired
trifluoromethyltetrahydroindolizine 16 in a 25:1 ratio according to 19F NMR analysis of the crude reaction mixture (Scheme 7). In the
19F NMR spectrum the signal of 16 appeared at –56.14 ppm.
OCOCH3
COCF3
CF3
N
O
COOH
(CH3CO)2O
85 °C, 12 h
+
N
N
F3C
15, 73%
16
2
Scheme 7. Acetic anhydride promoted cyclization of enaminone 2.
Product 15 was isolated by evaporation of the reaction mixture and crystallization from hexane in 73% yield. The molecular structure
was unambiguously established by X-ray analysis (Fig. 4).
Figure 4. Molecular structure of disubstituted tetrahydroindolizine 15. Ellipsoids are drawn at the 50% probability level.
A possible pathway for the cyclization of 2 in acetic anhydride begins with the formation of mixed anhydride 17 (Scheme 8).
Intramolecular acylation of the enamine carbon gives the keto form 18a of bicyclic hydroxypyrrole 18b which is then acylated with
acetic anhydride to give product 15. Similar intramolecular transformations of related enaminones have previously been described [21].
O
O
N
O
COOH
(CH3CO)2O
N
O
C
N
O
OCOCH3
-CH3COOH
F3C
F3C
-CH3COOH
F3C
18a
2
17
(CH3CO)2O
OCOCH3
O
OH
O
N
-CH3COOH
N
F3C
15
F3C
18b
Scheme 8. Proposed mechanism for the formation of disubstituted tetrahydroindolizine 15 via the cyclization of 2 in acetic anhydride.
To our delight the treatment of enaminone 2 with a slight excess of TFAA in acetonitrile at –20 oC gave trifluoromethyl-
tetrahydroindolizine 16 as the predominant product as determined by 19F NMR analysis of the crude reaction mixture (Scheme 9).

6
Tetrahedron
Notably, the use of acetonitrile as solvent and low temperature was essential to give the desired product 16 in 28% yield after
chromatography purification. The structure of 16 was assigned by spectroscopic data. In the 13C NMR spectrum of 16, the pyrrole ring
carbon atoms appeared at 106.0 ppm, 109.0 ppm (q, JC-F = 34.7 Hz), 119.0 ppm, and 129.2 ppm. The carbon atom of the CF3 group
2
gave a quartet at 124.8 ppm (1JC-F 266.6 = Hz). The 19F NMR spectrum of 16 showed a characteristic singlet for the CF3 group at –56.13
ppm. These data correspond well to the characteristics described above for trifluoromethyldihydropyrrolizine 10. The mechanism
depicted in Scheme 5 provides a reasonable explanation for the formation of trifluoromethyltetrahydroindolizine 16 via the cyclization
of 2.
As in the case of trifluoromethyldihydropyrrolizine 10, the treatment of trifluoromethyltetrahydroindolizine 16 with TFAA in
dichloromethane led to trifluoroacetylation of the pyrrole ring at the α-position to give disubstituted tetrahydroindolizine 19 in 93%
yield (Scheme 9). The structure of 19 was supported by spectroscopic data. In the 13C NMR spectrum a quartet for the CF3 carbon
appeared at 123.0 ppm with a typical 1JCF value of 267.3 Hz. The CF3 carbon of the CF3CO group was observed as a quartet at 116.8
ppm (1JCF = 290.7 Hz). Additionally, a quartet at 113.3 ppm (2JCF = 37.4 Hz) could be assigned to the pyrrole ring carbon substituted by
a CF3 group. In the 19F NMR spectrum of 19 signals for the CF3 groups were observed as singlets at −58.37 and −72.06 ppm which
were consistent with analogous values for disubstituted dihydropyrrolizine 11 described above. The spectroscopic data (1H and 13C
NMR) and the melting point obtained for product 19 were in good agreement with the literature values reported for product 6 (Scheme
1) indicating that the position of the trifluoroacetyl group in the pyrrole ring was incorrectly indicated by Mellor and co-workers [15].
CF3
CF3
TFAA
N
O
COOH
TFAA
N
MeCN
-20 oC
N
CH2Cl2
COCF3
19, 93%
F3C
16, 28%
2
Scheme 9. TFAA promoted cyclization of enaminone 2 in acetonitrile and the trifluoroacetylation of trifluoromethyltetrahydro-indolizine 16.
Conclusion
In summary, we have developed a convenient method for the synthesis of trifluoromethylated bicyclic pyrroles starting from cyclic
amino acids and β-ethoxyvinyl trifluoromethyl ketone in moderate to good yields. The mechanism of cyclization of intermediates
enaminones explaining the formation of bicyclic trifluoromethylpyrroles and bicyclic pyrroles bearing trifluoromethyl and
trifluoroacetyl groups on the pyrrole ring was proposed and the previously reported structures of the cyclization products were
corrected. Further applications of trifluoromethylated bicyclic pyrroles in the synthesis of trifluoromethylated pyrrolizidine and
indolizidine alkaloids is currently underway in our research laboratory.
Acknowledgments
The authors thank Enamine Ltd. (Kiev) for technical assistance and National Academy of Science of Ukraine [grant № 04-03-18]
for financial support.
Appendix A. Supplementary data
Supplementary data (synthetic procedures and characterization and other materials) to this article can be found online at
https://doi.org/10.1016/j.tetlet.XXX
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Author declaration
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[List funding sources and their role in study design, data analysis, and result interpretation]
The grant N 04-03-18 of National Academy of Science of Ukraine was used for data analysis.
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Tetrahedron
4. Research Ethics
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6. Contact with the Editorial Office
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Igor I. Gerus
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Author’s name (Fist, Last)
Signature
Date
1. __Anton A. Klipkov
2. Alexander E. Sorochinsky
3. Karen V. Tarasenko
4. _Julia A. Rusanova__
_____________
_____________
_____________
_____________
___11.11.2019___
___11.11.2019__
___11.11.2019__
___11.11.2019__

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Tetrahedron
5. __Igor I. Gerus ____
_____________
____11.11.2019__
22.
Graphical Abstract
Synthesis of trifluoromethyl and trifluoroacetyl
substituted dihydropyrrolizines and tetrahydroindolizines
Leave this area blank for abstract info.
Anton A. Klipkov, Alexander E. Sorochinsky, Karen V. Tarasenko, Julia A. Rusanova, Igor I. Gerus
CF3
CF3
(CF3CO)2O
CH2Cl2, rt
X = CH2
X
N
COOH
(CH3CO)2O
85 °C, 12 h
N
N
O
COCF3
CF3
87%
65%
CF3
X = CH2CH2
(CF3CO)2O
CH2Cl2, rt
F3C
N
N
(CF3CO)2O
X = CH2, CH2CH2
MeCN, -20 oC
COCF3
28%
93%
23.
Highlights:




The trifluoroacetic anhydride promoted cyclization of enaminones was reinvestigated
Procedures for synthesis of bicyclic trifluoromethylated pyrroles were developed
Mechanism of bicyclic trifluoromethylpyrroles formation was discussed
Previously described structures of cyclization products were corrected
24.