Synthesis of α-Trifluoromethylamines by Cu-Catalyzed Regio- and Enantioselective Hydroamination of 1-Trifluoromethylalkenes

Article abstract of DOI:10.1021/acs.orglett.9b01471

A copper-catalyzed regioselective net hydroamination of 1-trifluoromethylalkenes with hydrosilanes and hydroxylamines has been developed. The judicious choice of ligand and additive suppresses the conceivable but undesired β-F elimination of an α-CF₃

Full text of DOI:10.1021/acs.orglett.9b01471

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α‑Trifluoromethylamines by Cu-Catalyzed Regio- and
Enantioselective Hydroamination of 1‑Trifluoromethylalkenes
Tatsuaki Takata, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A copper-catalyzed regioselective net hydro-
amination of 1-trifluoromethylalkenes with hydrosilanes and
hydroxylamines has been developed. The judicious choice of
ligand and additive suppresses the conceivable but undesired
β-F elimination of an α-CF3-substituted organocopper
intermediate, leading to targeted α-trifluoromethylamines in
good yields with excellent regioselectivity. Additionally, with an appropriate chiral bisphosphine ligand, the enantioselective
reaction is also possible to deliver optically active α-trifluoromethylamines of high potential in medicinal and pharmaceutical
chemistry.
he introduction of fluorine into organic molecules can
increase the lipophilicity and metabolic stability, and
Scheme 1. Working Hypothesis: Net Hydroamination
versus Hydrodefluorination of 1-Trifluoromethylalkene 1
a
T
organofluorine compounds thus have received significant
attention in the design of new drug candidates and
agrochemicals.1 Among them, α-trifluoromethylamines are
proposed to be amide isosteres and frequently occur in
biologically active compounds.2 Thus, the development of
their efficient synthetic methods, particularly catalytic asym-
metric synthesis, has been a long-standing topic in the
synthetic community. The most common approaches to the
above α-trifluoromethylamine structure include the reduction3
or carbon nucleophile addition4 of trifluoromethyl-substituted
imines and nucleophilic trifluoromethylation5 of simple
imines.6 Herein, we report an alternative strategy using a 1-
trifluoromethylalkene as a starting platform: A copper-
catalyzed regio- and enantioselective hydroamination7 of
trifluoromethylalkenes with hydrosilanes and hydroxylamines
is described. The copper catalysis relies on an umpolung,
electrophilic amination strategy8 and thus delivers the α-
trifluoromethylamines with excellent regioselectivity, which
can be difficult to achieve under conventional nucleophilic
hydroamination catalysis due to the Michael acceptor nature of
trifluoromethylalkene. Additionally, the asymmetric catalysis
ligated with an appropriate chiral bisphosphine enables the
enantioselective synthesis of chiral alkyl-substituted α-trifluor-
omethylamines, which are still challenging by means of
reported methods.9
Our working scenario is shown in Scheme 1, which is based
on the recent success of net hydroamination of relatively
electronically neutral alkenes, originally and independently
developed by our group10 and the Buchwald research group.11
A LnCu−H species A, which is initially generated from a Cu
salt, ancillary ligand, and hydrosilane,12 undergoes the
hydrocupration with the 1-trifluoromethylalkene 1 to form
the organocopper intermediate B; where the CF3 group works
as the strong electron-withdrawing group, and thus B would be
formed as the preferable regioisomer.13 Subsequent electro-
a
Bz = benzoyl, L = ligand.
philic amination with the hydroxylamine derivative 2 occurs to
deliver the desired α-trifluoromethylamine 3 regioselectively.14
The concurrently formed LnCuOBz is converted to the starting
copper hydride A with the second hydrosilane to complete the
catalytic cycle. If the enantioselectivity is also controlled by an
appropriate chiral ligand in the insertion step (A to B), then
the stereodefined α-CF3-substituted organocopper is formed,
leading to the corresponding optically active 3 catalytically
through the stereoretentive electrophilic amination.15 How-
ever, the intermediate B contains the fluorine atom at position
β to Cu and thus can easily decompose via β-F elimination to
afford the undesired gem-difluoroalkene 4. Actually, such an
elementary step is reported in several transition-metal-
catalyzed reactions with fluoroalkene substrates.13,16 Therefore,
suppression of the undesired β-F elimination is the most
important and challenging task for the development of regio-
and stereoselective net hydroamination of 1-trifluoromethy-
lalkene.
On the basis of the aforementioned hypothesis, we began
our optimization studies by using 1-trifluoromethylalkene 1a
(0.25 mmol), N,N-dibenzylhydroxylamine 2a (1.5 equiv), and
polymethylhydrosiloxane (PMHS) to identify the appropriate
Received: April 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ligand in the presence of Cu(OAc)2 catalyst and CsOAc base
(Table 1). An initial experiment with 1,2-bis-
effect of the base was critical: Weaker acetate bases such as
LiOAc and NaOAc gave poor conversion (entries 10 and 11),
whereas the defluorinated 4a was predominantly formed with
LiOtBu and NaOtBu (entries 12 and 13), which are usually
optimal bases in our previous net hydroamination of alkenes.10
The observed trend apparently indicates that the Lewis acidic
alkali cations with smaller ionic radius promoted the undesired
β-F elimination because of their higher fluorine affinity, as
illustrated in Figure 1.18 On the other hand, no reaction
Table 1. Optimization Studies for Copper-Catalyzed
Regioselective Net Hydroamination of 1-
Trifluoromethylalkene 1a with N,N-Dibenzylhydroxylamine
a
2a
b
yield (%)
Figure 1. Possible mechanism of the undesired β-F elimination
promoted by Lewis acidic metals.
entry
ligand
dppbz
CF3-dppbz
p-CF3-dppbz
F3-dppbz
DTBM-dppbz
TMS-dppbz
MeO-dppbz
p-tBu-dppbz
o-Me-dppbz
p-tBu-dppbz
p-tBu-dppbz
p-tBu-dppbz
p-tBu-dppbz
p-tBu-dppbz
p-tBu-dppbz
base
3aa
4a
5a
1
2
3
4
5
6
7
8
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
LiOAc
NaOAc
LiOtBu
NaOtBu
none
29
0
0
35
0
0
0
0
0
0
0
0
0
0
37
36
0
0
0
0
occurred without any external bases (entry 14); the exact
reason was not clear, but in our catalyst system with the p-tBu-
dppbz ligand, the external base might be essential for
generation of the copper hydride species. After additional
0
0
68
71
36
76
0
0
0
34
10
0
20
11
0
<10
0
0
0
0
0
1
fine-tuning, we finally obtained the desired 3aa in 85% H
NMR yield (70% isolated yield) with Cu(OAc)2·H2O/p-tBu-
dppbz catalyst, CsOAc base, and (EtO)2MeSiH (entry 15).19
The reaction could also be conducted on a 1.0 mmol scale,
thus indicating the good reproducibility of this process.
With the optimal conditions in hand (Table 1, entry 15), we
examined the substrate scope of the catalytic hydroamination
(Scheme 2). In addition to 2a, some acyclic hydroxylamines
9
10
11
12
13
14
0
0
c
d
15
CsOAc
85 (70, 61 )
0
Scheme 2. Copper-Catalyzed Regioselective Net
Hydroamination of Various 1-Trifluoromethylalkenes 1 and
Hydroxylamines 2
a
Conditions: 1a (0.25 mmol), 2a (0.38 mmol), PMHS (0.75 mmol
based on Si−H), Cu(OAc)2 (0.025 mmol), ligand (0.025 mmol),
b
base (0.50 mmol), and 1,4-dioxane (1.5 mL), rt, 4 h, N2. Estimated
c
by 1H NMR. Isolated yield in parentheses. With Cu(OAc)2·H2O and
d
(EtO)2MeSiH instead of Cu(OAc)2 and PMHS. On a 1.0 mmol
scale. Bn = benzyl, Bz = benzoyl.
(diphenylphosphino)benzene (dppbz) afforded the targeted
α-trifluoromethylamine 3aa regioselectively, but expectedly the
gem-difluoroalkene 4a was preferably formed (entry 1).
Notably, the substituent on the phosphorus of dppbz ligand
gave a significant impact on the product selectivity. While the
electron-withdrawing CF3-, p-CF3-, and F3-dppbzs resulted in
almost no conversion (entries 2−4), electron-donating
substituents at the meta- or para-position suppressed the
undesired β-F elimination to furnish the desired 3aa with
better chemoselectivity (entries 5−8). Particularly, the para-
tert-butyl-substituted p-tBu-dppbz ligand proved to be best,
delivering 3aa in 76% 1H NMR yield, albeit with 10%
concomitant formation of the over-reduced monofluoroalkene
5a (entry 8).16c On the other hand, the more sterically
hindered o-Me-dppbz showed no activity (entry 9), thus
suggesting the important role of remote steric hindrance in the
chemoselective net hydroamination of 1a.17 Additionally, the
a
Conditions: 1 (0.25 mmol), 2 (0.38 mmol), (EtO)2MeSiH (0.75
mmol), Cu(OAc)2·H2O (0.025 mmol), p-tBu-dppbz (0.025 mmol),
CsOAc (0.50 mmol), and 1,4-dioxane (1.5 mL), rt, 4 h, N2. Yields of
b
isolated products are given. With PMHS instead of (EtO)2MeSiH.
c
d
Without CsOAc. With TMS-dppbz instead of p-tBu-dppbz.
Starting from 9:1 E/Z mixture. Boc = tert-butoxycarbonyl.
e
B
DOI: 10.1021/acs.orglett.9b01471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bearing N,N-diethyl, N-benzyl-N-methyl, and N,N-diallyl
groups could be coupled with 1a to form the corresponding
α-trifluoromethylamines 3ab−3ad in good yields as the single
regioisomers. In the case of 3ad, the CF3-substituted alkene
moiety was preferably hydroaminated over the allylic
system.11g The copper catalysis was also compatible with
cyclic amines, including piperidine, morpholine, thiomorpho-
line, Boc-protected piperazine, and tetrahydroisoquinoline
(3ae−3ai). The acetal-protected piperidone could also be
employed (3aj); the protecting group of which can be readily
removed to form the corresponding NH2 amine.20 The
reactions of several 1-trifluoromethylalkenes 1 with 2a were
also performed. The aliphatic primary and secondary alkyl-
substituted substrates underwent the regioselective hydro-
amination to afford the corresponding amines 3ba and 3ca in
acceptable yields. Additionally, the ether, ester, and phthali-
mide functional groups were tolerated under the standard
conditions (3da−3fa). Notably, the reaction system also
accommodated the trisubstituted 1-trifluoromethylalkene to
deliver 3gf as the single diastereomer.21 On the other hand, the
styrenyl-type substrate gave a 3:2 regiomixture of 3ha and
3ha′, which can be attributed to the competitive Ph-vinyl
conjugation22 in the hydrocupration step (A to B in Scheme
1). In some cases, the yield of the desired 3 was relatively low;
no full conversion of 1 was observed, and sometimes simply
reduced trifluoromethylalkanes were also detected as the side
products.
As mentioned in Scheme 1, an appropriate chiral bi-
sphosphine ligand can successfully induce the enantioselectiv-
ity. After the extensive screening (see the Supporting
Information for detail), we were pleased to find that the
Cu(OAc)2·H2O/(R)-DTBM-BINAP complex catalyzed the
enantioselective hydroamination of 1a with 2a to provide the
enantioenriched 3aa in 56% yield with a 98:2 enantiomeric
ratio (e.r.; Scheme 3). The observed high stereoinduction and
acceptable reactivity were unique to the (R)-DTBM-BINAP;
attempts to apply related (R)-DTBM-SEGPHOS and (R)-
DTBM-MeO-BIPHEP remained unsuccessful. Regardless of
steric and electronic nature of hydroxylamine used, the
Cu(OAc)2·H2O/(R)-DTBM-BINAP asymmetric catalysis uni-
formly produced the corresponding optically active α-
trifluoromethylamines 3ae−3ah with excellent enantioselectiv-
ity (98:2−99:1 e.r.). Other 1-trifluoromethylalkenes 1c and 1d
were also successfully converted to the chiral amines 3ch and
3da with 98:2 and 96:4 e.r., respectively. The absolute
configuration was assigned to be R by the preparation of
known compound 3ia (40%, 98:2 e.r.) under the present
Cu(OAc)2·H2O/(R)-DTBM-BINAP catalysis (see the Sup-
porting Information for details).
Finally, we derivatized the optically active N,N-dibenzyl-
amine 3aa (Scheme 4). The hydrogenolysis of benzyl
Scheme 4. Derivatization of Optically Active 3aa
protection readily afforded the corresponding primary amine
3aa-H in 77% yield without loss of enantiomeric excess. The
product obtained can be an important building block for more
complicated and chiral CF3-containing amino compounds.
In conclusion, we have developed an umpolung-enabled
copper-catalyzed regio- and enantioselective net hydroamina-
tion of 1-trifluoromethylalkenes with hydrosilanes and
hydroxylamines. By the judicious choice of an ancillary ligand
and additive, the undesired β-F elimination process is
effectively suppressed to deliver the optically active α-
trifluoromethylamines of great interest in medicinal applica-
tion. In particular, the copper catalysis successfully produces
the alkyl-substituted α-trifluoromethylamines, which are still
challenging by means of reported methods, and thus
complements the precedented strategies.9 The newly devel-
oped protocol, particularly for the generation of stereodefined
α-CF3-substituted organocopper species, will find wide
applications in further development of related copper-catalyzed
multicomponent coupling reactions with 1-trifluoromethylal-
kenes for the synthesis of versatile CF3-containing complex
molecules, which are of great importance in medicinal and
pharmaceutical research fields.
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 3. Copper-Catalyzed Regio- and Enantioselective
Net Hydroamination of 1-Trifluoromethylalkenes 1 and
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01471.
a
Hydroxylamines 2
1H, 13C{1H}, and 19F{1H} NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
ORCID
Koji Hirano: 0000-0001-9752-1985
Masahiro Miura: 0000-0001-8288-6439
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI grant nos. JP
15H05485 (Grant-in-Aid for Young Scientists (A)) and
a
■
Conditions: 1 (0.25 mmol), 2 (0.38 mmol), (EtO)2MeSiH (0.75
mmol), Cu(OAc)2·H2O (0.025 mmol), (R)-DTBM-BINAP (0.025
mmol), CsOAc (0.50 mmol), and 1,4-dioxane (1.5 mL), rt, 4 h, N2.
C
DOI: 10.1021/acs.orglett.9b01471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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̈
amination, see: (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.;
Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (b) Fukumoto,
Y. Yuki Gosei Kagaku Kyokaishi 2009, 67, 735. (c) Hesp, K. D.;
Stradiotto, M. ChemCatChem 2010, 2, 1192. (d) Huang, L.; Arndt,
M.; Gooβen, K.; Heydt, H.; Gooβen, L. Chem. Rev. 2015, 115, 2596.
(e) Coman, S. M.; Parvulescu, V. I. Org. Process Res. Dev. 2015, 19,
1327. Also see the organocatalytic approach: (f) MacDonald, M. J.;
Hesp, C. R.; Schipper, D. J.; Pesant, M.; Beauchemin, A. M. Chem. -
Eur. J. 2013, 19, 2597.
(8) For pioneering work on the electrophilic amination using the
hydroxylamines, see: (a) Tsutsui, H.; Hayashi, Y.; Narasaka, K. Chem.
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(21) The relative stereochemistry of 3gf was assigned by the
reported stereochemistry of hydrocupration and electrophilic
amination, see refs 12 and 15.
(22) For a related study on the insertion to borylcopper species, see:
Dang, L.; Zhao, H.; Lin, Z.; Marder, T. B. Organometallics 2007, 26,
2824.
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DOI: 10.1021/acs.orglett.9b01471
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