Stereoselective Rearrangement of (Trifluoromethyl)prolinols to Enantioenriched 3-Substituted 2-(Trifluoromethyl)piperidines

Article abstract of DOI:10.1021/acs.orglett.5b01084

3-Substituted 2-(trifluoromethyl)piperidines B were synthesized by ring expansion of (trifluoromethyl)prolinols A, which were obtained from l-proline via an aziridinium intermediate C. The ring opening of the (trifluoromethyl)aziridinium intermediate by different nucleophiles is regio- and diastereoselective.

Full text of DOI:10.1021/acs.orglett.5b01084

Letter
pubs.acs.org/OrgLett
Stereoselective Rearrangement of (Trifluoromethyl)prolinols to
Enantioenriched 3‑Substituted 2‑(Trifluoromethyl)piperidines
Sarah Rioton,† Aurelie Orliac,† Zeina Antoun,‡ Roselyne Bidault,‡ Domingo Gomez Pardo,*,†
́
and Janine Cossy*,†
†Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), UMR 8231 ESPCI ParisTech/CNRS/PSL
Research University, 10 rue Vauquelin, 75231-Paris Cedex 05, France
‡Laboratoire GlaxoSmithKline 100 Route de Versailles, 78160 Marly le-Roi, France
S
* Supporting Information
ABSTRACT: 3-Substituted 2-(trifluoromethyl)piperidines B were
synthesized by ring expansion of (trifluoromethyl)prolinols A, which
were obtained from L-proline via an aziridinium intermediate C. The
ring opening of the (trifluoromethyl)aziridinium intermediate by
different nucleophiles is regio- and diastereoselective.
he incorporation of a fluorine atom in compounds can
have a profound impact on the physical and chemical
properties of the compounds as it can imply the modification of
their biological activity.1 As substituted piperidines are present
in a great variety of natural products and bioactive compounds,2
the search for new methods to prepare CF3-containing
piperidines is of interest.
Scheme 1. Synthesis of Substituted Piperidines by Ring
Expansion of Pyrrolidines
T
The ring expansion of pyrrolidines to piperidines by attack of
a nucleophile on an aziridinium intermediate is well-
established.3 Depending on the nucleophile, the reaction can
be under thermodynamic or kinetic control (Scheme 1). When
the nucleophile is a good leaving group such as a halide or a
trifluoroacetate, a thermodynamic equilibrium is taking place
and the formation of the piperidine is favored (Scheme 1, eq 1).4
When the nucleophile is a poor leaving group such as azide,
cyanide, or alkoxide, the reaction is under kinetic conditions,
and a mixture of pyrrolidine and piperidine is observed.3f,5
However, the ratio of pyrrolidine/piperidine can be modified by
appropriate substitution of the pyrrolidine ring. Thus, when a
bulky nitrogen protecting group, a bulky substituent at C4, and/
or a quaternary center is present at C2 on the pyrrolidine, the
formation of the piperidine is favored.5c,6 In addition, Charette
et al. have shown that the ring expansion of unsaturated
pyrrolidines such as IV can produce unsaturated piperidines
VII.7 The ring expansion of the unsaturated pyrrolidine has
taken place under kinetic conditions, and the regioselective
attack of the nucleophile is governed by the presence of the
double bond (attack at the allylic position) (Scheme 1, eq 2).
Based on the regio- and stereoselective ring-opening of
monocyclic (trifluoromethyl)aziridinium ions,8 we have envis-
aged the access to 3-substituted 2-(trifluoromethyl)piperidine B
by a regioselective ring expansion of pyrrolidine A due to the
presence of a CF3 group at the C1′ position. This ring-opening
should be under kinetic control (Scheme 1, eq 3).
N-trityl group is necessary to avoid the epimerization of the
stereogenic center during the transformation of proline 1 to 4
and 5,9 the esterification of L-proline (SOCl2, MeOH, rt, 24 h)
and N-tritylation (TrCl, Et3N, CHCl3, rt, 18 h) allowed access
to ester 1 with a yield of 75%. This ester was then reduced by
LiAlH4 (2 equiv) to furnish quantitatively prolinol 2, which was
oxidized to the corresponding prolinal 3 (71%) by using a Swern
oxidation.4e,9 The transformation of 3 to 4 and 5 was realized in
a three-step sequence. After treatment of 3 with TMS-CF3 in the
presence of CsF (THF, rt, 24 h), the N-trityl group was replaced
by a N-benzyl group in order to achieve the ring expansion of
Prolinols A such as 4 and 5 were prepared from L-proline
following a six-step sequence. The synthesis of 4 and 5 started
with the preparation of N-tritylprolinal 3. As the presence of an
Received: April 14, 2015
© XXXX American Chemical Society
A
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the prolinol.5c,4e After deprotection of the (trifluoromethyl)-
prolinol (HCl 3 M, MeOH, rt, 1.5 h) and reprotection using
benzyl bromide (Et3N, refluxing CH2Cl2, 3.5 h), compounds 4
and 5 were formed, separated by flash chromatography on silica
gel, and isolated in 23% and 30% yield, respectively (Scheme 2).
medium, the desired 3-substituted 2-(trifluoromethyl)-
piperidines were produced in good yields and with excellent
diastereoselectivities (superior to 97/3, measured by NMR and/
or GC/MS), whatever the nucleophiles used.7
When secondary amines were utilized as the nucleophiles,
prolinols 4 and 5 were transformed to the corresponding 3-
amino-2-(trifluoromethyl)piperidines 10a−d and 11a−d in
good to excellent yields and diastereoselectivities (dr >97:3).
The enantiomeric excesses of 10d and 11d were measured by
SFC and chiral HPLC and proved to be excellent (ee >95%).11
In addition, when aniline was used, 10e and 11e were formed,
respectively, from 4 and 5 in 96% and 79% yields and with an
enantiomeric excess superior to 95%11 (Table 1).
Scheme 2. Synthesis of (Trifluoromethyl)prolinols 4 and 5
Table 1. Ring Expansion of (Trifluoromethyl)prolinols 4 and
5 with Amines
The spectral data of 4 and 5, as well as their αD values, matched
with those reported in the literature.10 The enantiomeric excess
was determined by SFC and chiral HPLC and proved to be
superior to 95% for both of them, showing the preservation of
the stereogenic center issued from the L-proline throughout the
synthesis.11
As the ring expansion of prolinols to 3-fluoropiperidines was
achieved with DAST (Et2NSF3),6 trifluoromethylated com-
pounds 4 and 5 were treated with this reagent (1.4 equiv) in
THF (1 h, 0 °C then 1 h at rt) to produce piperidines 6 and 7,
respectively, in good yields (89−81%). Compounds 4 and 5
were also transformed to 3-iodopiperidines 8 and 9, respectively,
by using PPh3 and I2 in the presence of imidazole.12 Under these
conditions, 8 was isolated in 69% yield and 9 in 86% yield. In
each case, an excellent diastereoselectivity was obtained and
proved to be superior to 95/5 (measured by NMR) (Scheme 3).
As aziridinium ions can be opened by nucleophiles such as
amines, alkoxides, alcohols, and sulfur derivatives as well as
carbanions, aziridinium intermediates C were formed from 4
and 5 at −15 °C in CH2Cl2 using triflic anhydride (Tf2O) in the
presence of N,N,N′,N′-tetramethylnaphthalene-1,8-diamine D,
a proton sponge. After addition of a nucleophile in the reaction
Scheme 3. Synthesis of 3-Fluoro- and 3-Iodo-2-
(trifluoromethyl)piperidine by Ring Expansion of 4 and 5
It is worth mentioning that the relative configurations of cis-
and trans-piperidines were established by measuring the
coupling constant between H2 and H3 and between H3 and
H4. For the cis-piperidines, the value of the coupling constant
between H2−H3 is comprise in between 3 and 5 Hz (4.3 Hz on
average), and the value of the coupling constant between H3−
H4 is comprise in between 7 and 12 Hz. These values confirmed
that, in the cis-piperidines, H3 and H4 are in an axial−axial
position and, as a consequence, H3 and H2 are axial−equatorial
in the cis-piperidines. For the trans-piperidines, the value of the
coupling constant in between H2 and H3 is in between 1 and 3
Hz (2.3 Hz on average). Furthermore, no coupling constant
B
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Letter
with a value of 7−12 Hz was measured for H3−H4, suggesting
that H2−H3 are in an equatorial−equatorial position (see the
Table 2. Ring Expansion of (Trifluoromethyl)prolinols 4 and
5 with Oxygenated Nucleophiles
1
Supporting Information, H NMR of 12f and 13f as a clear
example). As a result, in trans-piperidines, the CF3-group at C2
and the substituent at C3 are axial which can be explained by a
possible anomeric effect between the nitrogen of the heterocycle
and the CF3 group (Figure 1).13
Figure 1. Conformations of cis- and trans-piperidines.
Water (6 equiv) was the first oxygenated nucleophile tested,
and 4 and 5 were transformed to the corresponding 3-
hydroxypiperidines 12a and 13a, respectively, in 79% and 82%
yields. When alcohols were used as the nucleophiles, the
corresponding 3-alkoxy-2-(trifluoromethyl)piperidines 12b−d
and 13b−d were, respectively, obtained from 4 and 5 in 50−
88% yield (Table 2, entries 2−4). It is worth mentioning that
when 2.5 equiv of alcohol were utilized, the conversion of 4 and
5 was not complete, but by using 5 to 6 equiv of alcohol, a
complete conversion of 4 and 5 was observed and piperidines
12b−d were isolated in good yields (55−65%) as well as
piperidines 13b−d (50−88%).
Due to the low nucleophilicity of phenol, the conversion of 4
and 5 was incomplete even after 72 h (Table 2, entry 5).
However, by using sodium phenoxide (2.5 equiv), the
conversion of 4 and 5 was total, and 12e and 13e were,
respectively, isolated in good yields after 3 h. In addition, the
enantiomeric excesses were measured and revealed to be
superior to 95%.11
When 4 and 5 were treated with n-Bu4NOAc, the ring
expansion took place, and the corresponding 3-acetoxypiper-
idines 12f (86%) and 13f (78%) were isolated (Table 2, entry
7).
The reactivity of sulfur derivatives such as ethanethiol was
examined and 3-(ethylthio)-2-(trifluoromethyl)piperidines 14
and 15 were formed in 73% and 50% yield, respectively, from
prolinols 4 and 5 (Scheme 4). The enantiomeric excess of 14
was also determined by SFC and proved to be excellent (ee
>95%).11
a
Tf2O (1.1 equiv), proton sponge D (1.25 equiv), 5 min at −15 °C
The formation of a carbon−carbon bond was also possible by
the attack of the aziridinium intermediate C by a carbanion.
then n-Bu4NOAc (2.5 equiv) at −15 °C for 1−1.5 h. (See the
Supporting Information.)
Scheme 4. Ring Expansion of (Trifluoromethyl)prolinols 4
and 5 with Ethanethiol
Thus, when 4 and 5 were treated with TBACN, the resulting
piperidines 16 and 18 were formed in 81% and 78% yield,
respectively, and the enantiomeric excesses measured for 16 and
18 were excellent (ee >95%).11 When 4 and 5 were treated with
n-BuCu(CN)Li,14 the corresponding 3-butyl 2-(trifluoro-
methyl)piperidines were also obtained in good yields, as 17
was isolated in 79% yield and 19 in 59% yield (Schemes 5 and
6).
In conclusion, we have developed a straightforward pathway
for the synthesis of a great variety of 3-substituted
2‑(trifluoromethyl)piperidines by ring expansion of the easily
accessible (trifluoromethyl)prolinols. This method is regio- and
diastereoselective. It is worth mentioning that all enantiomers of
3-substituted 2-(trifluoromethyl)piperidines are accessible
C
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910. (b) Le Bourdonnec, B.; Goodman, A. J.; Michaut, M.; Ye, H.;
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Scheme 5. Ring Expansion of (Trifluoromethyl)prolinol 4
with Carbanion
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ASSOCIATED CONTENT
* Supporting Information
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■
S
Experimental procedures, characterization data for all com-
pounds, and copies of 1H and 13C NMR spectra for all
compounds as well as experimental chromatograms of
enantiomeric excess for the products concerned. The Support-
ing Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01084.
(7) Charette, A. B.; Scott, B. D. J. Org. Lett. 2011, 13, 3830−3833.
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Kimpe, N.; Van Nguyen, T.; Thi, T. A. D.; Nguyen, V. D.; Verniest, G.;
D’Hooghe, M.; Kenis, S. Org. Biomol. Chem. 2011, 9, 7217−7223.
(d) Stankovic, S.; D’hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: domingo.gomez-pardo@espci.fr.
*E-mail: janine.cossy@espci.fr.
(9) Bejjani, J.; Chemla, F.; Audouin, M. J. Org. Chem. 2003, 68, 9747−
9752.
(10) Xiu-Hua, X.; Qiu, X. L.; Qing, F. L. Tetrahedron 2008, 64, 7353−
7361.
(11) See the Supporting Information for SFC and chiral HPLC
Notes
The authors declare no competing financial interest.
conditions used.
ACKNOWLEDGMENTS
(12) Mino, T.; Saito, A.; Tanaka, Y.; Hasegawa, S.; Sata, Y.; Sakamoto,
M.; Fujita, T. J. Org. Chem. 2005, 70, 1937−1940.
■
GlaxoSmithkline is acknowledged for a grant to S. R. and for
financial support. Diverchim is acknowledged for its help for the
determination of the enantiomeric excess.
́ ́
(13) (a) Spanedda, M. V.; Crousse, B.; Begue, J. P.; Bonnet-Delpon,
D. Tetrahedron Lett. 2004, 45, 5023−5025. (b) Erxleben, N. D.;
Kedziora, G. S. Theor. Chem. Acc. 2014, 133, No. 1491.
(14) Marino, J. P.; Jaen
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, J. C. J. Am. Chem. Soc. 1982, 104, 3165−3172.
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