Synthesis of Optically Active α-Trifluoromethylamines by Rearrangement of β-Amino-α-trifluoromethyl Alcohols

Article abstract of DOI:10.1021/acs.orglett.8b02353

The synthesis of various optically active α-trifluoromethylamines has been realized from β-amino-α-trifluoromethyl alcohols via an aziridinium ion intermediate under kinetic conditions.

Full text of DOI:10.1021/acs.orglett.8b02353

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Optically Active α‑Trifluoromethylamines by
Rearrangement of β‑Amino-α-trifluoromethyl Alcohols
Zeina Neouchy, Domingo Gomez Pardo,* and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), ESPCI Paris/CNRS/PSL University, 10
rue Vauquelin, 75231 Cedex 05 Paris, France
S
* Supporting Information
ABSTRACT: The synthesis of various optically active α-
trifluoromethylamines has been realized from β-amino-α-
trifluoromethyl alcohols via an aziridinium ion intermediate
under kinetic conditions.
Scheme 1. Main Strategies for α-Trifluoromethylamine
Synthesis
ompounds containing a trifluoromethyl group have
Creceived extensive attention as the lipophilicity of this
group can increase the bioavailability of the molecules by
increasing their ability to cross membranes. Furthermore, as a
C−F bond is stronger than a C−H bond, an increase of the
metabolic stability of CF3-containing compounds is ob-
served.1 To synthesize α-trifluoromethylamines, two main
strategies have been developed. One strategy consists of the
transformation of trifluoromethylated substrates to α-trifluor-
omethylamines such as reductive amination of trifluoromethyl
ketones,2 addition of organometallic reagents on α,α,α-
trifluoromethylimines,3 generation of radicals from N-acetyl
aminotrifluoromethyl dithiocarbonate, and addition of these
radicals on alkenes,4 as well as the ring opening of
trifluoromethylaziridines or 2-trifluoromethylazetidines by
nucleophiles.5 The second strategy is the introduction of a
CF3 group on the substrates using trifluoromethylating
reagents.6 In this regard, the Ruppert−Prakash reagent has
been added to iminium7−9 as well as to imines.10 In addition,
trifluoromethylphenyl sulfone was used to access α-trifluor-
omethylamines from imines,6b and Umemoto’s reagent was
utilized to synthesize α-trifluoromethyl nitrones, which are
precursors of amines (Scheme 1).11 However, it is worth
mentioning that there are only a few reports on the synthesis
of optically active α-trifluoromethylamines by either diaster-
eo-3a,b,5a,b,f or enantioselective2a,d,3c,d reactions.
In the context of our studies on ring expansion and ring
contraction of heterocycles containing nitrogen12 and on the
rearrangement of β-amino alcohols,13 via aziridinium ion
intermediates,14 we would like to report here that optically
active functionalized α-trifluoromethylamines A can be
obtained from β-amino-α-trifluoromethyl alcohols B with
good diastereo- and enantioselectivity by regioselective ring
opening of an aziridinium ion intermediate C by a variety of
nucleophiles under kinetic conditions (Scheme 2).
At first, β-amino-α-trifluoromethyl alcohols B were
synthesized from commercially available optically active
N,N-dibenzylamino alcohols 1 (Scheme 3). These N,N-
dibenzylamino alcohols 1 were transformed to the corre-
sponding N,N-dibenzylamino aldehydes 2 in good yields by a
Swern oxidation.15 It is worth mentioning that aldehydes 2
were engaged in the next step without any purification to
avoid the epimerization of the stereogenic center. Aldehydes
2 were then treated with the Ruppert−Prakash reagent in the
presence of tetra-n-butylammonium fluoride to produce the
optically active β-amino-α-trifluoromethyl alcohols 3−6 as a
mixture of anti/syn diastereoisomers, which were separated by
Received: July 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of α-Trifluoromethylamines by
Rearrangement of β-Amino-α-trifluoromethyl Alcohols
Scheme 4. Treatment of β-Amino-α-trifluoromethyl
Alcohols 3 with DAST
Scheme 3. Synthesis of β-Amino-α-trifluoromethyl
Alcohols
Table 2. Treatment of the β-Amino-α-trifluoromethyl
Alcohols with DAST
Table 1. Synthesis of β-Amino-α-trifluoromethyl Alcohols
by Trifluoromethylation
a
Isolated yields.
Having compounds anti-3−6 and syn-3−6 in hand,
compounds (+)-anti-3 and (+)-syn-3 were selected as
model substrates. As N,N-diethylaminosulfur trifluoride
(DAST)19 is able to initiate the formation of rearranged
products via the participation of neighboring groups, such as
amines,20 compounds (+)-anti-3 and (+)-syn-3 were treated
with DAST (Scheme 4). When (+)-anti-3 was treated with
1.4 equiv of DAST, compound (−)-anti-7 was isolated with
87% yield with an excellent diastereoselectivity (better than
99%).21 Under the same conditions, (+)-syn-7 was obtained
from (+)-syn-3 with 91% yield (dr better than to 99%). After
a
The anti/syn ratio was determined by analysis of 19F NMR spectra of
b
the crude. Isolated yields.
flash column chromatography on silica gel, with the anti-
isomer being the major compound (Table 1).16−18
B
DOI: 10.1021/acs.orglett.8b02353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Synthesis of β-Trifluoromethyl-β-aminoalcohols
Figure 1. Structure of (+)-anti-12 by X-ray diffraction.
Treatment of anti-β-amino-α-trifluoromethyl alcohols 4−6
with DAST was performed (Table 2). The corresponding
fluorinated compounds 8−10 were obtained with good yields.
Compounds (+)-8 and (+)-9 were isolated with 77 and 95%
yields, respectively (Table 2, entries 1 and 2). However,
compound (+)-anti-6 led to the corresponding product
(+)-10 with a modest yield of 66%, probably due to the
steric hindrance of the isopropyl group (Table 2, entry 3).
To access β-amino-β-trifluoromethyl alcohols, which can be
important to produce biologically active compounds,1,2
treatment of anti-3−6 and syn-3−6 with a stoichiometric
amount of triflic anhydride (Tf2O) and 1,8-bis-
(dimethylamino)naphthalene (Proton Sponge) in dichloro-
methane (− 15 °C, 2.5 h), followed by the addition of H2O
as the nucleophile (5.6 equiv, rt, 2.5 h), has been
realized.12g,h Under these conditions, optically active anti-
3−6 were diastereoselectively converted to the corresponding
optically active β-amino-β-trifluoromethyl alcohols anti-11−
14 in good to excellent yields. Likewise, treatment of
optically active syn-3−6, under the same conditions, led to
the corresponding products syn-11−14.22 The results are
summarized in Table 3. An X-ray diffraction of (+)-anti-12
was possible and allowed us to determine the relative and
absolute configuration of the stereocenters of the rearranged
products (Figure 1).
In addition to H2O, other nucleophiles can be used to
transform amino alcohols B to trifluoromethyl amines A. As a
model substrate, β-amino-α-trifluoromethyl alcohol (+)-anti-3
was transformed into a variety of α-trifluoromethylamines 15
(Table 4). Using alcohols, alcoholates (Table 4, entries 1−3),
amines (Table 4, entries 4−6), sodium pyrazolide (Table 4,
entry 7), thiols (Table 4, entry 8), bromide (Table 4, entry
9), hydride (Table 4, entry 10), and carbanion (Table 4,
entries 11 and 12), compounds 15a−l were isolated in good
yields and excellent diastereoselectivity.
It is worth noting that a selective deprotection of the N,N-
dibenzylamines can be performed as compound (−)-16,
prepared by rearrangement of (−)-anti-5 using sodium
phenoxide as the nucleophile, was hydrogenolized (1 atm)
in the presence of a catalytic amount of Pd/C in methanol.
The corresponding free amine (+)-17 was obtained in 61%
yield and was engaged in a peptidic coupling with a natural
N-protected L-amino acid, N-Cbz-L-alanine (Scheme 5). The
reaction was performed by generating in situ a mixed
anhydride from the free carboxylic acid of N-Cbz-L-alanine
using isobutyl chloroformate,23 which produced the desired
dipeptide (−)-18 in 58% yield.
In summary, the rearrangement of β-amino-α-trifluoro-
methyl alcohols by activation of the hydroxy group, followed
by the addition of nucleophiles, led to various β-amino-β-
trifluoromethyl alcohols and diversely functionalized α-
trifluoromethylamines in high yields. The reaction is regio-
and diastereoselective. In addition, we demonstrated that the
a
Isolated yields.
activation of the hydroxy group of (+)-anti-3 by DAST,
intermediate D is formed, producing the aziridinium ion E.
Due to electrostatic repulsion of the CF3 group toward
nucleophiles, the regioselective nucleophilic attack by the
fluoride on the nontrifluoromethylated carbon of the
aziridinium ion gives (−)-anti-7. Similarly, (+)-syn-3 is
transformed into (+)-syn-7 via the aziridinium ion E′.
C
DOI: 10.1021/acs.orglett.8b02353
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 4. Synthesis of α-Trifluoromethylamines
Scheme 5. Application of α-Trifluoromethylamines
N-deprotected α-trifluoromethylamines can be involved in a
peptidic coupling. The synthesized optically active β-amino-β-
trifluoromethyl alcohols and substituted α-trifluoromethyl-
amines can be useful building blocks in medicinal chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02353.
1
Experimental procedures, characterization, H, 13C, and
19F NMR spectra of isolated compounds, supercritical
fluid chromatography chromatograms of the products
(PDF)
Accession Codes
CCDC 1848221 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by sending an e-
mail to data_request@ccdc.cam.uk, or by contacting The
Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: domingo.gomez-pardo@espci.fr.
*E-mail: janine.cossy@espci.fr.
ORCID
Domingo Gomez Pardo: 0000-0003-0540-0321
Notes
The authors declare no competing financial interest.
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