Enantioselective synthesis of α-trifluoromethyl arylmethylamines by ruthenium-catalyzed transfer hydrogenation reaction

Article abstract of DOI:10.1002/adsc.201301115

A simple combination of dichloro(para-cymene)ruthenium(II) dimer, a chiral amino alcohol and isopropyl alcohol allowed for in-situ generation of the bifunctional catalyst responsible for the transfer hydrogenation reaction of trifluoromethyl ketimines in excellent yields with high enantioselectivities (up to 93% ee). Herein, we describe the optimization, scope, limitations, and applications of the method.

Full text of DOI:10.1002/adsc.201301115

FULL PAPERS
DOI: 10.1002/adsc.201301115
Enantioselective Synthesis of a-Trifluoromethyl
Arylmethylamines by Ruthenium-Catalyzed Transfer
Hydrogenation Reaction
Xiaoyang Daia and Dominique Caharda,*
a
UMR 6014 COBRA et FR 3038 INC3M, Normandie Universitꢀ, INSA de Rouen, CNRS, rue Tesniꢁre, 76821
Mont-Saint-Aignan, France
E-mail: dominique.cahard@univ-rouen.fr
Received: December 10, 2013; Published online: March 27, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301115.
Abstract: A simple combination of dichloro(para- ties (up to 93% ee). Herein, we describe the optimi-
cymene)ruthenium(II) dimer, a chiral amino alcohol zation, scope, limitations, and applications of the
and isopropyl alcohol allowed for in-situ generation method.
of the bifunctional catalyst responsible for the trans-
fer hydrogenation reaction of trifluoromethyl ket- Keywords: amines; enantioselectivity; fluorine;
ACHTUNGTRENNUNGimines in excellent yields with high enantioselectivi- ruthenium; transfer hydrogenation
Introduction
while retaining its ability to act as an H-bond donor.
À À
À
À
The C N C bond angle of (CF3)CH NH CH is
À
The trifluoromethyl group has been increasingly em- close to the 1208 observed with an amide, and the C
ployed in the organic synthesis of pharmaceutical and CF3 bond is isopolar with a carbonyl function.[8] In ad-
agrochemical compounds, and outstanding results dition, the replacement of the planar amide bond by
have recently emerged for the trifluoromethylation of the CHACTHNUTRGNE(UNG CF3)NH motif presents structural analogy
arenes and heteroarenes.[1] Concurrently, innovation with the tetrahedral proteolytic transition state associ-
in methods for the construction of sp3 carbons featur- ated with peptides.
ing a CF3 group is steadily progressing.[2] In this con-
The asymmetric construction of the stereogenic
text, and emphasizing chiral species, a-trifluoromethyl carbon centre in a-trifluoromethyl amines has been
amines hold great potential in diversifying the family achieved through three key disconnections as depict-
of chiral amines. Indeed, chiral amines have a broad ed in Figure 1. In view of the simple preparation of
application, being prevalent motifs in natural products ketimines from the corresponding trifluoromethyl ke-
and in synthetic biologically active compounds. Chiral tones, it is not surprising that several approaches were
amines also find widespread application in asymmet- based on the C=N bond reduction. Notably, this was
ric synthesis as chiral auxiliaries, organocatalysts, and achieved by enantioselective palladium-catalyzed hy-
as chiral bases.[3] In addition, the trifluoroethylamine drogenation of either a-trifluoromethyl imino esters,[9]
motif RCHACHTUNGTRENNUNG(CF3)NH has emerged as a remarkable
surrogate of the natural peptide bond in the area of
peptide mimics.[4] Peptide analogues featuring this flu-
orinated motif display both retarded proteolytic deg-
radation and enhanced permeability through biologi-
cal barriers. Furthermore, a number of drug candi-
dates feature the trifluoroethylamine motif such as
the cathepsin K inhibitor Odanacatib,[5] the anticancer
agent CF3-Ac-Docetaxel,[6] as well as others.[7] Several
characteristic effects of fluorine can account for the
importance of biologically active a-trifluoromethyl
amino compounds. Indeed, the trifluoromethyl group
Figure 1. Key disconnections to access enantioenriched a-
reduces the basicity of an adjacent amine function trifluoromethyl amines.
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Xiaoyang Dai and Dominique Cahard
or from aryl and alkyl ketimines[10] under high pres-
sure of hydrogen in up to 91 and 94% ee, respectively.
To avoid handling high pressure H2 gas, Akiyamaꢃs
group reported a highly enantioselective Brçnsted
acid-organocatalyzed transfer hydrogenation of aro-
matic and heteroaromatic trifluoromethyl ketimines
(up to 98% ee). This group used benzothiazoline as
a source of hydride and chiral phosphoric acid as
a source of chirality.[11] More recently, Benagliaꢃs
group proposed the enantioselective Lewis base-orga-
nocatalyzed hydrosilylation of not only aryl but also
alkyl ketimines by means of trichlorosilane in up to
98% ee.[12] Diastereoselective reductive aminations
were also reported exploiting either simple amino
Scheme 1. Our approach towards optically enriched a-tri-
fluoromethyl amines.
acids[13] or N-tert-butanesulfinamide[14] as chiral auxil- Results and Discussion
iaries to get high dr values. In addition, N-benzyl tri-
fluoromethyl ketimines were catalytically isomerized The first series of experiments examined the asym-
into a-trifluoromethyl amines with the aid of chiral metric transfer hydrogenation of ketimine 1a
bases.[15] As an alternative, the C C bond disconnec- (Scheme 1, R=C6H5) in a 5:2 formic acid-triethyl-
À
tion has also been investigated through direct nucleo-
ACHUTGTNRENNUGamine azeotropic mixture with {RuClACHTUNGTRENNUNG[(S,S)-
philic trifluoromethylation of aldimines with the Rup- TsDPEN](h6-para-cymene)} (TsDPEN=N-para-tosyl-
pert–Prakash reagent.[16] The other C C bond could 1,2-diphenylethylenediamine) under Noyoriꢃs condi-
À
be constructed starting from trifluoroacetaldehyde tions.[21] The reaction proceeded in moderate to good
imines, hydrazones, or N,O-acetals of trifluoroacetal- enantioselectivities (ee up to 81%); however, the
dehyde;[17] for example, the reaction of the acetal with yield of the expected chiral a-CF3 amine 2a did not
arylboroxines and a Pd(II)/chiral pyridine-oxazolidine exceed 58% because of the formation of 2,2,2-tri-
complex afforded enantioenriched secondary a-tri- fluoro-1-phenylethanol as a side product. To avoid
fluoromethyl amines.[18] Although some of these the ketimine hydrolysis we modified the reaction pa-
methods allowed high stereoselectivities, some draw- rameters, in particular the ratio formic acid:triethyl-
backs still limit scalability and transfer to other appli-
ACHTUNGTRENaNGNU mine and the use of isopropyl alcohol as an alterna-
cations (of concern are the use of toxic reagents, and tive hydrogen source; however, again, the yield in 2a
expensive sources of chirality). In addition, a method was not enhanced. Thus, we turned our attention to
applicable to non-fluorinated substrates may prove in- a catalytic transfer hydrogenation system using N,O-
effective on fluorinated analogues as observed in the type ligands to perform the reduction of the trifluoro-
hydrogenation of N-arylimines catalyzed by iridium methyl ketimine 1a. For this purpose, we were in-
bis(phosphine) complexes.[19]
spired by the independent works of Noyori,[22]
Of the different approaches for the reduction of Wills,[23] Pꢄntener,[24] and Guijarro and Yus[25] on re-
imines, the asymmetric transfer hydrogenation (ATH) lated ATH of non-fluorinated ketones and ketimines.
has attracted considerable attention due to its opera- Specifically, this latter work described the diastereose-
tional simplicity in not requiring the handling of haz- lective transfer hydrogenation of optically pure N-
ardous hydrogen gas, metallic hydrides, or silanes. (tert-butylsulfinyl)imines in the presence of an achiral
Other advantages are that a low loading of metal cat- amino alcohol ligand, or a chiral ligand with matched
alyst can be used, and purification of products is fa- effect.[25a,b] With regard to this work, we decided to
cilitated thanks to the formation of volatile by-prod- examine an enantioselective version by means of pro-
ucts, such as acetone or carbon dioxide. In this con- chiral ketimines and chiral ruthenium complexes fea-
text, Akiyamaꢃs pioneering work on chiral phosphoric turing an optically pure amino alcohol ligand. Be-
acid-catalyzed transfer hydrogenation paved a new cause N,O-type ligands are incompatible with the
route for chiral a-trifluoromethyl amines.[11] Recently, formic acid-triethylamine reduction system,[26] we
our group illustrated an efficient ruthenium-catalyzed used isopropyl alcohol as hydrogen donor. We first se-
hydride transfer in the isomerization of trifluorometh- lected a simple achiral ligand, 2-amino-2-methylpro-
yl allylic alcohols.[20] As a new example of hydride pan-1-ol, in combination with [{RuCl2(para-
transfer applied to fluorinated molecules, we herein cymene)}2] at room temperature in isopropyl alcohol.
disclose the first enantioselective ruthenium-catalyzed Pleasingly, the expected a-trifluoromethyl amine was
transfer hydrogenation of trifluoromethyl ketimines obtained in 88% yield without 2,2,2-trifluoro-1-phe-
that has the advantage of both using isopropyl alcohol nylethanol side product. The next step was obviously
as a simple source of hydride and an inexpensive to evaluate a chiral non-racemic amino alcohol
amino alcohol as a source of chirality (Scheme 1).
ligand; to this end, we selected (1S,2R)-1-amino-2-in-
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Enantioselective Synthesis of a-Trifluoromethyl Arylmethylamines
Table 1. Optimization of reaction conditions for the enantioselective transfer hydrogenation of ketimine 1a.
Run
Base
Ratio Ru dimer/L[a]/base
Temperature [8C]
Time [h]
Yield[b] [%]
ee [%]
1
2
3
4
5
6
7
8
KOH
1:2:5
1:2:5
1:2:5
1:2:5
1:2:5
1:2:5
1:2:5
25
25
25
25
25
0
40
80
25
40
25
25
25
25–90
14
14
14
14
14
21
5
>98
>98
>98
0
0
59
>98
>98
79
>98
87
>98
>98
0[f]
92
93
93
-
t-BuOK
i-PrONa
Cs2CO3
K2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
-
94
93
92
93
91
93
93
87
-
1:2:5
5
9
1:2:5[c]
1:2:5[c]
1:4:5
14
14
22
14
14
18
10
11
12
13
14
1:2:10
1:2:5[d]
1:2:5[e]
[a]
L=ligand.
[b]
[c]
[d]
[e]
[f]
Yields were determined by 19F NMR using trifluorotoluene as internal standard.
3 mol% of ruthenium dimer was used.
[{RuCl2ACHTUNGTRENNUNG(benzene)}2] was used.
[RuCp*ACHTUNGTRENNUNG
(ACN)3]+PF6 was used.
À
Only 2,2,2-trifluoro-1-phenylethanol was obtained.
danol that gave an excellent 93% ee value. With these the quantity of ligand was doubled. Moreover, twice
suitable conditions in hand, we next conducted the the amount of base did not improve the reaction. It is
optimization of the reaction conditions by scrutinizing important to note that these changes had a very small
the nature of the base, the ratio of the reagents, the impact on the enantioselectivities (Table 1, runs 9–
imine concentration, the temperature, and the source 12). The concentration of ketimine 1a in isopropyl al-
of ruthenium (Table 1).
cohol was fixed at 0.06M and variations were con-
A base was essential for the reaction and its nature ducted in the range 0.01–0.2M; but, here again, no
appeared crucial for the reactivity with a strong re- perceptible effect was observed on the enantioselec-
quirement for alkoxides over carbonates; indeed, tivity. These experiments were conducted with the aid
K2CO3 and Cs2CO3 did not allow the reaction where- of a catalyst prepared in-situ by heating, at reflux,
as KOH, i-PrONa and t-BuOK gave full conversions
a mixture of [{RuCl2(para-cymene)}2], (1S,2R)-1-
of the starting ketimine 1a (Table 1, runs 1–5). We amino-2-indanol, and 4ꢅ molecular sieves in isopro-
chose to keep t-BuOK as the base to study the effect pyl alcohol. We found that changing the ruthenium
of the temperature on the course of the reaction. At source to [{RuCl2ACTHNUTRGNEU(GN benzene)}2], showing a less bulky
08C, the reaction was not complete, even after a pro- arene moiety, lowered the ee value of 2a to 87%
longed reaction time, whereas an increase of the tem- (Table 1, run 13). Alkylated h6-arene such as the h6-
perature allowed us to significantly reduce the reac- para-cymene enhanced stabilization of the transition
tion time without impacting the enantioselectivity; in state due to the increased p-donation of the arene as
the range 0–608C the ee value difference was only 2% well as contributing to
a
favourable secondary
(sp ) H/p interaction with the aryl moietÀy of the
was established at 5 mol% with a ratio Ru dimer/ substrate.[27] The use of [RuCp*(ACN)3]+PF6 (Cp*=
ligand/base of 1:2:5. A lower loading of catalyst had h5-pentamethylcyclopentadienyl,
ACN=CH3CN)
3
À
(Table 1, runs 6–8). The optimal amount of catalyst
CACHTUNGTRENNUNG
AHCTUNGTRENNUNG
the effect of lowering the conversion for a fixed reac- showed no efficiency, yielding the 2,2,2-trifluoro-1-
tion time. The same tendency was also observed when phenylethanol as the sole product (Table 1, run 14).
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Xiaoyang Dai and Dominique Cahard
Table 2. Screening of chiral ligands in the transfer hydroge-
nation of 1a.[a]
fects. In the major part, our results were in agreement
with these previous observations. Surprisingly, howev-
er, we observed an inversion of the main enantiomer
configuration caused by a simple change in the nature
of the substituent, alkyl or aryl at the amine-substitut-
ed carbon, while keeping the same absolute configu-
ration at this carbon (Table 2, runs 2–6). Indeed, with
L5, (S)-2-amino-2-phenylethanol, the (R) enantiomer
of 2a was obtained, in an identical way to the use of
L1, but the use of L2, L3, or L4, which have the 2-
phenyl group replaced by a 2-alkyl chain, gave the op-
posite (S) enantiomer of 2a. This is a quite unique ob-
servation for which we could not find a precedent in
the literature. A case was reported in ATH of keto-
AHCTUNGTREGiNNUN sophorone with ligands having both a 2-alkyl chain:
(S)-prolinol gave the (R) alcohol while (S)-tert-leuci-
nol gave the (S) alcohol. Unfortunately, the required
data were not detailed.[24] Otherwise, L5 and L6 pro-
vided opposite enantiomers of 2a, as expected. Re-
versing the position of alkyl and aryl groups on the li-
gands, while retaining the same absolute configura-
tions at the two centres such as in L7 compared to
L1, led to a lower enantioselectivity for the R enan-
tiomer of 2a (Table 2, runs 1 and 7). N-Alkylated de-
rivative L8, having a secondary amino group, exhibit-
ed a lower reactivity and a slightly increased enantio-
selectivity by comparison with L7. (S)-Diphenylproli-
nol L9 as ligand was unsuccessful in the reaction, pos-
sibly due to bulkiness.[29] We also considered
a ruthenium aminocarboxylate complex with the
amino acid L10 that has found application in the
transfer hydrogenation of ketones[30] but not of ket-
Run
Ligand
Yield [%][b]
ee [%] (Configuration)[c]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
>98
53
92
96
85
69
>98
72
0
93 (R)
42 (S)
26 (S)
48 (S)
23 (R)
20 (S)
67 (R)
69 (R)
-
10
0
-
[a]
Reactions were run under optimized conditions (see
Table 1, run 2).
AHCTUNGTRENNUNG
[b]
[c]
Yields were determined by 19F NMR using trifluoroto-
luene as internal standard.
complex bearing L1 as ligand was the most efficient
in terms of reactivity and stereodiscrimination, we
then went on to a series of ketimines in the enantiose-
lective transfer hydrogenation reaction. This work in-
cluded aryl and alkyl ketimines with various protect-
The absolute configuration was determined by compari-
son with data reported in the literature.[11,16f]
Ethanol was also examined as an alternative source of ing groups (PG) for the nitrogen atom (Table 3). It is
hydrogen donor but the reaction resulted only in important to mention that all the aryl ketimines de-
a moderate yield.
scribed hereafter were obtained as a single E isomer.
The effect of the b-amino alcohol ligand was ad- It was essential that the ketimine geometry was clear-
dressed by evaluating various structures having either ly established because it has a strong impact on the
one or two stereogenic centres. A series of ten ligands stereochemical course of the reaction (see later in the
L1–L10 was studied and the results are reported in text). For aryl ketimines 1a–m, excellent yields and
Table 2. At first sight, ruthenium complex with L1 high ee values were obtained, irrespective of the elec-
ligand, (1S,2R)-1-amino-2-indanol, was the most effi- tronic nature and position of the substituents on the
cient and stereodiscriminating catalyst; however, the benzene ring, except for the 2-MeO substituted ket-
results obtained with other ligands also deserved spe-
ACHTUNGTRENiNGNU mine 1l (Table 3, runs 1–13). This substrate did not
cial attention. In the literature, it was reported that react, even at 908C, possibly because of the steric
the outcome of asymmetric induction in asymmetric demand next to the imine function. The absolute con-
transfer hydrogenation of ketones is determined pri- figuration of the amine 2a was determined by polar-
marily by the configuration of the hydroxy-bearing imetry and comparison with published data.[11,16f] The
carbon.[22,24,28] These studies also reported that the absolute configurations of the other aryl methyl-
amine-substituted carbon affects the enantioselection
ACHTUNGTRENaNGNU mines were assigned by analogy. The scope of the re-
but to a lesser extent and mainly through steric ef- action was further explored with benzyl and n-hexyl
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Enantioselective Synthesis of a-Trifluoromethyl Arylmethylamines
Table 3. Variation of substrates and protecting groups.
a base-mediated 1,3-hydrogen shift. Indeed, this iso-
merization reaction led to the regioisomeric imine,
which, after transfer hydrogenation, gave an amine
not possessing a stereogenic centre (Table 3, run
17).[32] In addition, three bulky N-aryl-protected ket-
AHCTUNGTREGUNiNN mines 1r, 1s, and 1t were employed in the ATH reac-
tion; in outcomes, we got the corresponding imines in
high yields but lower ee values were obtained com-
pared the N-PMP ketimines (Table 3, runs 18–20). A
À
step-economic synthetic plan would be to utilize N H
imines to avoid a deprotection step after ATH reac-
Run
R
PG
2
Yield ee
[%][a] [%]
tion.[33] By chance the 2,2,2-trifluoro-1-phenylethan-
AHCTUNGTREGiNNUN mine 1u was reported to be a stable, readily isolable
1
2
3
4
5
6
7
8
C6H5
4-BrC6H4
4-MeOC6H4 PMP
4-ClC6H4
PMP
PMP
2a 98
2b 94
2c 99
2d 98
2e 99
2f 99
2g 99
2h 99
2i 98
2j 81
2k 94
93 (R)
90 (R)
91 (R)
90 (R)
92 (R)
92 (R)
89 (R)
89 (R)
91 (R)
84 (R)
90 (R)
–
À
N H ketimine existing as a dynamic mixture of Z and
E isomers.[34] However, the existence of two imine ge-
ometries could cause the multiplication of transition
states and a poor enantiodiscrimination during the
course of enantioselective additions to these imines.
In our study, ketimine 1u gave full conversion into
the expected free amino product 2u but with only
32% ee (Table 3, run 21). Although the investigation
PMP
PMP
PMP
PMP
PMP
PMP
4-MeC6H4
4-t-BuC6H4
3-ClC6H4
4-CF3C6H4
3-i-PrC6H4
3,4-Cl2C6H3 PMP
3,4-Me2C6H3 PMP
2-MeOC6H4 PMP
2-naphthyl
Bn
hexyl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
9
10
11
12
13
14
15
16
17
18
19
20
21
À
of N H ketimines is a very important area to explore,
no attempt was done to screen other amino alcohol li-
gands.
2l
2m 99
2n
2o 52
0
PMP
91 (R)
–
PMP[b]
PMP[c]
–
The difluoromethyl group has received less atten-
tion than the CF3 group due to synthetic difficulties
associated with this motif. Nevertheless, it is a motif
of great interest in modern organofluorine chemis-
try.[35] Difluoromethyl ketimine 1v was prepared fol-
lowing a literature procedure that gave a mixture of
inseparable geometric isomers in a ratio 36:64.[10,36]
This mixture was subjected to our ATH conditions.
Amine 2v was obtained in a good yield and a moder-
ate ee value that we reasonably ascribed to the start-
ing mixture of stereoisomers (Scheme 2, top). In
order to provide a comparison of the behaviour of
fluorinated versus non-fluorinated ketimines and to
highlight the effect of fluorine, we conducted the
22 (nd[e])
–
t-BuSO[c]
Bn
2p
–
[d]
2q 86
2r 99
2s 99
0
1-naphthyl
2-naphthyl
72 (+)
84 (À)
90 (À)
32 (nd[e])
2,4-(MeO)2C6H3 2t 80
H[c]
2u 99
[a]
Yields of isolated pure products.
Mixture of imine–enamine tautomers (1:1).
Mixture of diastereoisomers.
Only 2,2,2-trifluoro-1-phenylethanol was obtained.
nd=not determined.
[b]
[c]
[d]
[e]
ketimines. Ketimine 1n with a benzyl group showed ATH reaction on phenyl methyl ketimine 1w (E
imine–enamine tautomerization (1:1) and failed to isomer). We only obtained an 8% yield of the expect-
react under our ATH conditions. In the case of n- ed amine 2w (Scheme 2, bottom), clearly indicating
hexyl ketimine 1o, the desired amine was obtained in
a moderate yield and a low ee value of 22% (Table 3,
run 15). Apart from the PMP group, other protecting
groups were also examined to evaluate their steric
and electronic effects on reactivity and enantioselec-
tivity. The ketimine 1p, with N-(tert-butylsulfinyl) pro-
tecting and activating group, is significantly more
electrophilic than its N-PMP analogue, albeit with
a greater instability and tendency to hydrolysis.
Hence, 1p was fully converted into 2,2,2-trifluoro-1-
phenylethanol under our ATH conditions (Table 3,
run 16). This result indicated that the conditions re-
ported by Guijarro, Yus and co-workers[25a] could not
be transposed to trifluoromethyl aryl ketimines.[31]
Benzyl-protected ketimine 1q gave the desired
Scheme 2. A comparative study with a-difluoromethylated
amine in the form of a racemic compound because of amine 1v and non-fluorinated ketimine 1w.
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Xiaoyang Dai and Dominique Cahard
Scheme 3. Catalytic cycle for the ATH reaction of ketimine 1a.
that the presence of the electron-withdrawing CF3 sition state models of the enantiodiscriminating step.
group in 1a significantly enhanced the electrophilic Indeed, in reactions involving ketimine 1a, mecha-
character of the iminic carbon and thus the ketimine nisms were proposed employing either the E or the Z
reactivity. This result confirmed, one more time, that configuration of the ketimine C=N bond.[10–12,39] We
the chemistry developed for fluorinated substrates therefore conducted a comprehensive study to ascer-
cannot be simply transposed to non-fluorinated mole- tain the geometry of aryl trifluoromethyl ketimines.
cules and vice versa.[31]
Imine 1m featuring a 2-naphthyl moiety was crystal-
The mechanism of ATH reaction as well as the lized and studied by X-ray diffraction to show the E
origin of the stereoselectivity are well documented in configuration.[40] Next, the 19F,1H-HOESY NMR spec-
the literature, although the C=N bond reduction was trum of ketimine 1a was recorded; it showed an inter-
less investigated than the C=O bond reduction.[25d,28,37] action with an aromatic C H of the phenyl group but
À
À
The pre-catalyst I was generated by reaction of the not with the aromatic C H of the PMP group, con-
ruthenium dimer with the amino alcohol and further firming the E configuration. In addition, DFT calcula-
reacted, in presence of the base, to provide the active tions were realized. The geometries of the E and Z
catalyst II (Scheme 3). This 16 electron deficient isomers were first optimized at the B3LYP/6-311+ +
ruthenium complex dehydrogenated the isopropyl al-
cohol to form the ruthenium hydride complex III with stabilize the E isomer, we also performed calculations
the release of acetone. The bifunctional complex III at the wB97X-D/6-311+ +G(d,p) level of theory. The
GACTHUNGTERNNU(G d,p) level of theory. As stacking interactions could
AHCTUNGTRENNUNG
transferred a hydride to the ketimine, together with use of the latter functional indicated that the E
a proton, in a stepwise process to end up with the isomer was 4.5 kcalmolÀ1 more stable than the Z
amine and regeneration of the active catalyst II.
isomer whereas the difference was only 2 kcalmolÀ1
Upon formation of the pre-catalyst, the complex with the widespread B3LYP functional. In the light of
became chiral-at-metal with the possibility of forma- our own observations together with published infor-
tion of diastereomers owing to the chirality of the mation this led us to propose a transition state to
amino alcohol ligand. An X-ray diffraction study deduce the origin of the enantioselectivity (Figure 2).
along with NMR spectroscopic data showed that the Transfer of the hydride to the iminic carbon took
pre-catalyst exists as a single diastereoisomer.[38] In place through the Si-face of the ketimine, followed by
order to rationalize the enantiofacial discrimination a proton transfer to the iminic nitrogen, to produce
of the prochiral ketimines, we needed to know their the R enantiomer of the amine.
precise structures that is, E or Z configuration. Al-
As an illustration of the utility of these chiral tri-
though the geometry of the trifluoromethyl ketimines fluoromethyl amines, (R)-2d was readily converted
is a parameter of prime importance, it was not often into the corresponding free amine 3d without loss of
properly taken into account in the literature for tran- the stereochemical integrity at the stereogenic centre.
1322
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Adv. Synth. Catal. 2014, 356, 1317 – 1328

FULL PAPERS
Enantioselective Synthesis of a-Trifluoromethyl Arylmethylamines
method is remarkable for its simplicity using isopro-
pyl alcohol and an inexpensive chiral amino alcohol.
It contributes a suitable alternative to asymmetric hy-
drogenation using molecular hydrogen and chiral
ruthenium-bisphosphine catalysts. Furthermore, the
E-configuration of aryl trifluoromethyl ketimines was
ascertained and the origin of the enantioselectivity
was rationalized. Finally, we showed how the PMP
protecting group could be easily cleaved and the free
amine engaged in the synthesis of a trifluoro analogue
of an active compound.
Figure 2. Transition state for hydrogen transfer via metal–
ligand bifunctional catalysis.
Next, the imine formation with 2,6-dichloroisonicotin- Experimental Section
ACHTUNGTRENNUNGaldehyde followed by reduction by means of sodium
borohydride provided compound 4 that is a trifluoro General Information
analogue of a potent plant disease control agent
1H (300 MHz), 13C (75.5 MHz) and 19F (282 MHz) NMR
(Scheme 4).[41] Erosion of the ee value was noticed
but will hopefully be avoided by testing other condi-
tions for the reductive amination step. We believe
that our asymmetric transfer hydrogenation reaction
should be readily applicable to compounds such as
Odanacatib or CF3-Ac-Docetaxel (see earlier in the
text).
spectra were recorded on a Bruker AVANCE 300. Chemical
shifts in NMR spectra are reported in parts per million from
TMS or CFCl3 resonance as the internal standard. IR spec-
tra were recorded on a Perkin–Elmer IR-FT 1650 spectrom-
eter. The wave numbers (n) of recorded IR signals are
quoted in cmÀ1. The conversion and ratio of the correspond-
ing products were determined by 19F NMR analysis adopting
a,a,a-trifluorotoluene as internal standard with D1 value=
5 s. The enantiomeric excesses were determined by HPLC
analysis. HPLC analysis were performed on Agilent HPLC
1100 Series system, column Daicel Chiralcel OD-H, OJ-H
or AD-H, mobile phase n-heptane/isopropyl alcohol, UV
detector at 254 or 210 nm. High-resolution mass spectrome-
try was carried out on an electrospray ionization mass spec-
trometer with a micro-TOF analyzer. Unless otherwise
noted, all reagents were purchased from commercial sources
and were used without further purification. Isopropyl alco-
hol was dried over molecular sieves under an argon atmos-
phere. Trifluoromethyl ketimines 1a–u were prepared
through the corresponding trifluoromethyl ketones[42] ac-
cording to literature procedures.[11,43] Some of the ketimines
employed in this work are known: 1a,[39b,44] 1b,[39b,45] 1c,[10]
1d,[39b] 1e,[39b] 1h,[39b] 1l,[39b] 1m,[11,39a] 1n (mixture of tauto-
mers),[12,46] 1o,[39b] 1p,[14,47] 1q,[32] 1s,[44] 1u,[34] 1v,[10,39a,46] 1w.[48]
Typical Procedure for the Synthesis of CF3 Ketimines
Scheme 4. Synthesis of the trifluoro analogue of a plant dis- (1)
ease control agent.
(E)-N-[1-(4-tert-Butylphenyl)-2,2,2-trifluoroethylidene]-4-
methoxyaniline (1f): To a 50-mL round-bottom flask fitted
with a Dean–Stark water trap and reflux condenser were
added 1-(4-tert-butylphenyl)-2,2,2-trifluoroethanone (2.30 g,
10 mmol) and p-anisidine (1.48 g, 12 mmol), along with dry
toluene (25 mL) and p-toluenesulfonic acid (51.66 mg,
0.3 mmol). The mixture was refluxed until the theoretical
amount of water had collected into the trap. The reaction
was also monitored by 19F NMR. After completion, the reac-
tion mixture was quenched with a saturated aqueous solu-
tion of NaHCO3 and extracted with ethyl acetate. The com-
bined organic layers were dried over MgSO4 and concentrat-
ed under vacuum. The residue was purified by silica gel
column chromatography to give the ketimine as a yellow
Conclusions
We have investigated an enantioselective ruthenium-
catalyzed transfer hydrogenation of CF3 ketimines
that allows the synthesis of optically enriched a-tri-
fluoromethyl amines in high yields and enantioselec-
tivities. Aryl ketimines led to high ee values for the
corresponding aryl trifluoromethyl amines; however,
the most challenging aliphatic ketimines gave much
lower enantioselectivities, presumably caused by dia-
stereomeric mixtures of the starting ketimines. The oil; yield: 99%. 1H NMR (CDCl3): d=7.31–7.34 (m, 2H),
Adv. Synth. Catal. 2014, 356, 1317 – 1328
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1323

FULL PAPERS
Xiaoyang Dai and Dominique Cahard
7.15–7.18 (m, 2H), 6.70–6.78 (m, 4H), 3.76 (s, 3H), 1.29 (s,
13C NMR (CDCl3): d=158.8, 157.3, 150.7, 131.4, 130.1,
128.4, 128.1, 122.0, 120.1 (q, JC,F =276.8 Hz), 104.2, 99.4,
55.5; 19F NMR (CDCl3): d=À69.9; IR (neat): n=2966,
1601, 1438, 1333, 1311, 1211, 1129, 1030, 971, 856 cmÀ1; HR-
MS: m/z=310.1057, calcd. for C16H15NF3O2 ([M+H]+):
310.1055.
9H); 13C NMR (CDCl3): d=157.7, 155.6 (q, JC,F =33 Hz),
153.6, 140.1, 128.6, 127.5, 125.8, 123.4, 120.3 (q, JC,F
=
277 Hz), 114.1, 55.5, 35.0, 31.2; 19F NMR (CDCl3): d=
À70.2; IR (neat): n=2965, 1602, 1503, 1463, 1329, 1233,
1189, 1124, 1033, 971, 830 cmÀ1; HR-MS: m/z=336.1569,
calcd. for C19H21NF3O ([M+H]+): 336.1575.
(E)-N-[1-(3-Chlorophenyl)-2,2,2-trifluoroethylidene]-4-
methoxyaniline (1g): Yellow oil; yield: 65%. 1H NMR
(CDCl3): d=7.28–7.29 (m, 1H), 7.17–7.20 (m, 2H), 7.28–
7.29 (m, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.67 (m, 4H), 3.68 (s,
3H); 13C NMR (CDCl3): d=158.2, 153.6 (q, JC,F =33.8 Hz),
139.2, 135.0, 132.5, 130.5, 130.3, 128.6, 127.0, 123.6, 120.0 (q,
General Procedure for the Synthesis of CF3 Imines
(2) by ATH of CF3 Ketimines (1)
A mixture of [{RuCl2ACHTNUGRTNE(NUG p-cymene)}2] (6.1 mg, 0.01 mmol),
J
C,F =277 Hz), 114.3, 55.5; 19F NMR (CDCl3): d=À70.4; IR
(1S,2R)-1-amino-2-indanol (3 mg, 0.02 mmol), 4ꢅ molecular
sieves and anhydrous isopropyl alcohol (0.5 mL) was heated
at 908C for 20 min. During this heating period, the initially
orange reaction mixture turned dark red in colour. The reac-
tion was then cooled to room temperature and a solution of
trifluoromethyl ketimine (0.2 mmol) in isopropyl alcohol
(2 mL) and a solution of t-BuOK (5.5 mg, 0.05 mmol) in
0.5 mL isopropyl alcohol were successively added. After
14 h, the reaction went to completion (monitoring by
19F NMR). The reaction mixture was filtered through
a small amount of silica gel and washed with ethyl acetate.
The combined organic phase was concentrated under re-
duced pressure and purified by column chromatography on
silica gel (petroleum ether/ethyl acetate: 30:1) to give the
corresponding trifluoromethylamine 2.
(neat): n=2958, 1602, 1503, 1293, 1231, 1193, 1125, 982, 835,
759 cmÀ1
;
HR-MS:
m/z=314.0552,
calcd.
for
C15H12NF3O35Cl ([M+H]+): 314.0560.
(E)-N-[1-(3-Isopropylphenyl)-2,2,2-trifluoroethylidene]-4-
methoxyaniline (1i): Yellow oil; yield: 99%. 1H NMR
(CDCl3): d=7.28–7.31 (m, 2H), 7.15 (d, J=7.0 Hz, 1H),
7.07 (s, 1H), 6.74–6.80 (m, 4H), 3.78 (s, 3H), 2.85 (m, 1H),
1.17 (s, 3H), 1.15 (s, 3H); 13C NMR (CDCl3): d=157.8,
156.0 (q, JC,F =33 Hz), 149.4, 140.1, 130.5, 128.8, 128.5, 127.1,
126.0, 123.3, 120.2 (q, JC,F =277.5 Hz), 114.1, 55.5, 34.0, 23.8;
19F NMR (CDCl3): d=À70.2; IR (neat): n=2963, 1602,
1503, 1465, 1325, 1237, 1186, 1125, 1118, 1033, 988, 835, 763,
700 cmÀ1; HR-MS: m/z=322.1413, calcd. for C18H19NF3O
([M+H]+): 322.1419.
(E)-N-[1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethylidene)-
4-methoxyaniline (1j): Yellow oil; yield: 99%. 1H NMR
(CDCl3): d=7.39–7.42 (m, 2H), 7.01–7.04 (m, 1H), 6.72–
6.79 (m, 4H), 3.76 (s, 3H); 13C NMR (CDCl3): d=158.4,
152.5 (q, JC,F =34.5 Hz), 139.0, 135.0, 133.6, 131.1, 130.6,
130.5, 128.2, 123.5, 119.8 (q, JC,F =276.8 Hz), 114.4, 55.5;
19F NMR (CDCl3): d=À70.3; IR (neat): n=2967, 1601,
1503, 1470, 1326, 1247, 1195, 1126, 1033, 984, 839, 763,
732 cmÀ1; HR-MS: m/z=348.0176, calcd. for C15H11Cl2F3NO
([M+H]+): 348.0170.
(E)-N-[1-(3,4-dimethylphenyl)-2,2,2-trifluoroethylidene]-
4-methoxyaniline (1k): Yellow oil; yield: 89%. 1H NMR
(CDCl3): d=7.03–7.08 (m, 2H), 6.93 (d, J=7.8 Hz, 1H),
6.71–6.78 (m, 4H), 3.75 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H);
13C NMR (CDCl3): d=157.7, 155.8 (q, JC,F =33.8 Hz), 140.1,
(R)-N-(1-Phenyl-2,2,2-trifluoroethyl)-4-methoxyaniline
(2a):[11] Colorless oil; yield: 99%; 93% ee; [a]2D0: À64.5 (c
1.40, CHCl3); 1H NMR (CDCl3): d=7.37–7.46 (m, 5H),
6.71–6.77 (m, 2H), 6.58–6.63 (m, 2H), 4.78–4.83 (m, 1H),
4.08 (d, J=7.1 Hz, 1H), 3.72 (s, 3H); 13C NMR (CDCl3): d=
153.9, 140.1, 134.9, 129.6, 129.5, 128.5, 125.7 (q, JC,F
=
280.5 Hz), 116.3, 115.4, 62.3 (q,
JC,F =29.2 Hz), 56.2;
19F NMR (CDCl3): d=À74.6 (d, J=7.3 Hz); HPLC (Chiral-
cel OD-H column, heptane/isopropyl alcohol=95:5, flow
rate=0.5 mLminÀ1, l=254 nm): tR =16.0 min (S), tR =
16.8 min (R).
(R)-N-[1-(4-Bromophenyl)-2,2,2-trifluoroethyl]-4-meth-
AHCTUNGTRENNUNG
oxyaniline (2b):[11] White solid; yield: 94%; 90% ee;
1H NMR (CDCl3): d=7.50–7.54 (m, 2H), 7.34 (d, J=8.4 Hz,
2H), 6.72–6.77 (m, 2H), 6.54–6.59 (m, 2H), 4.73–4.83 (m,
1H), 4.06 (d, J=7.0 Hz, 1H), 3.72 (s, 3H); 13C NMR
139.2, 137.3, 130.0, 129.5, 128.1, 126.3, 123.4, 120.3 (q, JC,F
=
276.8 Hz), 114.1, 55.4, 19.9; 19F NMR (CDCl3): d=À70.3;
IR (neat): n=2954, 1651, 1602, 1503, 1442, 1328, 1239, 1203,
1153, 1123, 1032, 980, 871, 766, 733 cmÀ1; HR-MS; m/z=
308.1264, calcd. for C17H17NF3O ([M+H]+): 308.1262.
(E)-N-(1-Phenyl-2,2,2-trifluoroethylidene)naphthalen-1-
(CDCl3): d=153.6, 139.1, 133.4, 132.2, 129.8, 124.9 (q, JC,F =
280.0 Hz), 123.4, 115.9, 115.0, 61.4 (q, JC,F =29.5 Hz), 55.8;
19F NMR (CDCl3): d=À74.7 (d, J=7.2 Hz); HPLC (Chiral-
cel OD-H column, heptane/isopropyl alcohol=95:5, flow
rate=0.5 mLminÀ1, l=254 nm): tR =25.2 min (minor enan-
tiomer), tR =29.2 min (major enantiomer).
1
amine (1r): Yellow oil; yield: 45%. H NMR (CDCl3): d=
8.01–8.04 (m, 1H), 7.81–7.84 (m, 1H), 7.52–7.58 (m, 3H),
7.28–7.32 (m, 1H), 7.15–7.24 (m, 5H), 6.46 (d, J=7.3 Hz,
1H); 13C NMR (CDCl3): d=157.9 (q, JC,F =34.5 Hz), 143.9,
133.9, 130.5, 130.1, 128.6, 128.3, 128.2, 127.0, 126.7, 126.4,
123.3, 120.0 (q, JC,F =277.5 Hz), 114.1; 19F NMR (CDCl3):
d=À70.0; IR (neat): n=3065, 1661, 1392, 1328, 1190, 1127,
968, 780, 772, 696 cmÀ1; HR-MS: m/z=300.0988, calcd. for
C18H13NF3O ([M+H]+): 300.1000.
(R)-N-[1-(4-Methoxyphenyl)-2,2,2-trifluoroethyl]-4-me-
thoxyaniline (2c):[11] White solid; yield: 99%; 91% ee;
1H NMR (CDCl3): d=7.38 (d, J=8.6 Hz, 2H), 6.91–6.94 (m,
2H), 6.74–6.79 (m, 2H), 6.59–6.65 (m, 2H), 4.76–4.81 (m,
1H), 4.08 (d, J=6.5 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H);
13C NMR (CDCl3): d=160.0, 153.2, 139.6, 129.1, 126.2, 125.2
(q,
JC,F =279.8 Hz), 115.7, 114.8, 114.3, 61.0 (q, JC,F =
29.2 Hz), 55.6, 55.2; 19F NMR (CDCl3): d=À74.8 (d, J=
7.4 Hz); HPLC (Chiralcel OD-H column, heptane/isopropyl
alcohol=95:5, flow rate=0.5 mLminÀ1, l=254 nm): tR =
27.8 min (major enantiomer), tR =30.4 min (minor enantio-
mer).
(E)-N-(1-Phenyl-2,2,2-trifluoroethylidene)-2,4-dimethoxy-
1
N
(CDCl3): d=7.22–7.37 (m, 5H), 6.55–6.58 (m, 1H), 6.34–
6.36 (m, 1H), 6.27–6.31 (m, 1H), 3.73 (s, 3H), 3.62 (s, 3H);
1324
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Adv. Synth. Catal. 2014, 356, 1317 – 1328

FULL PAPERS
Enantioselective Synthesis of a-Trifluoromethyl Arylmethylamines
(R)-N-[1-(4-Chlorophenyl)-2,2,2-trifluoroethyl]-4-meth-
tR =21.6 min (minor enantiomer), tR =28.0 min (major
enantiomer).
ACHTUNGTRENNUNG
(R)-N-[1-(3-Isopropylphenyl)-2,2,2-trifluoroethyl]-4-me-
thoxyaniline (2i): Yellow oil; yield: 98%; 91% ee; [a]2D0:
1
À55.7 (c 1.08, CHCl3); H NMR (CDCl3): d=7.21–7.32 (m,
4H), 6.72–6.76 (m, 2H), 6.60–6.63 (m, 2H), 4.73–4.83 (m,
1H), 4.05 (d, J=7.3 Hz, 1H), 3.70 (s, 3H), 2.83–2.97 (m,
1H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (CDCl3): d=153.3,
149.7, 139.8, 134.4, 129.0, 127.2, 126.4, 125.3, 125.4 (q, JC,F
=
280.5 Hz), 115.8, 114.9, 61.9 (q, JC,F =29.2 Hz), 55.7, 34.2,
24.0; 19F NMR (CDCl3): d=À74.4 (d, J=7.3 Hz); IR (neat):
n=3379, 2961, 1608, 1512, 1443, 1347, 1234, 1164, 1118,
1118, 1035, 818, 708 cmÀ1; HR-MS: m/z=324.1568, calcd.
for C18H21NF3O ([M+H]+): 324.1575; HPLC (Chiralcel OJ-
H column, heptane/isopropyl alcohol=95:5, flow rate=
0.5 mLminÀ1, l=254 nm): tR =20.2 min (minor enantiomer),
tR =24.5 min (major enantiomer).
(R)-N-(1-para-Tolyl-2,2,2-trifluoroethyl)-4-methoxyaniline
(2e):[11] Colourless oil; yield: 99%; 92% ee; 1H NMR
(CDCl3): d=7.38 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz,
2H), 6.73–6.78 (m, 2H), 6.60–6.65 (m, 2H), 4.75–4.84 (m,
1H), 4.08 (d, J=7.3 Hz, 1H), 3.73 (s, 3H), 2.36 (s, 3H);
13C NMR (CDCl3): d=153.3, 139.7, 139.1, 131.4, 129.7,
127.9, 125.3 (q, JC,F =279.8 Hz), 115.8, 114.9, 61.6 (q, JC,F
=
(R)-N-[1-(3,4-Dichlorophenyl)-2,2,2-trifluoroethyl]-4-me-
29.2 Hz), 55.7, 21.3; 19F NMR (CDCl3): d=À74.6 (d, J=
7.4 Hz); HPLC (Chiralcel OJ-H column, heptane/isopropyl
alcohol=95:5, flow rate=0.5 mLminÀ1, l=254 nm): tR =
52.5 min (minor enantiomer), tR =58.7 min (major enantio-
mer).
thoxyaniline (2j): Yellow oil; yield: 81%; 84% ee; [a]2D0:
1
À42.4 (c 1.12, CHCl3); H NMR (CDCl3): d=7.57–7.58 (m,
1H), 7.47 (d, J=8.3 Hz, 1H), 7.30–7.33 (m, 1H), 6.73–6.79
(m, 2H), 6.54–6.59 (m, 2H), 4.74–4.83 (m, 1H), 4.09 (d, J=
6.5 Hz, 1H), 3.73 (s, 3H); 13C NMR (CDCl3): d=153.7,
(R)-N-[1-(4-tert-Butylphenyl)-2,2,2-trifluoroethyl]-4-me-
138.8, 134.6, 133.6, 133.3, 131.0, 130.1, 127.4, 124.7 (q, JC,F =
thoxyaniline (2f): Colourless oil; yield: 99%; 92% ee; [a]2D0:
280.5 Hz), 115.9, 115.0, 60.9 (q, JC,F =30 Hz), 55.7; 19F NMR
(CDCl3): d=À74.6 (d, J=7.1 Hz); IR (neat): n=3378, 2941,
1512, 1470, 1401, 1347, 1234, 1175, 1122, 1032, 917, 816, 769,
711 cmÀ1; HR-MS: m/z=350.0322, calcd. for C15H13NF3Cl2O
([M+H]+): 350.0326; HPLC (Chiralcel OD-H column, hep-
tane/isopropyl alcohol=95:5, flow rate=0.5 mLminÀ1, l=
254 nm): tR =27.8 min (minor enantiomer), tR =34.1 min
(major enantiomer).
1
À85.6 (c 1.22, CHCl3); H NMR (CDCl3): d=7.37–7.44 (m,
4H), 6.75–6.79 (m, 2H), 6.63–6.67 (m, 2H), 4.77–4.86 (m,
1H), 4.08 (d, J=7.5 Hz, 1H), 3.74 (s, 3H), 1.34 (s, 9H);
13C NMR (CDCl3): d=153.3, 152.2, 139.8, 131.4, 127.6, 125.4
(q,
JC,F =280.5 Hz), 126.0, 115.7, 114.9, 61.4 (q, JC,F =
29.2 Hz), 55.7, 34.7, 31.4; 19F NMR (CDCl3): d=À74.5 (d,
J=7.4 Hz); IR (neat): n=3394, 2968, 1513, 1233, 1182, 1177,
1118, 1028, 825, 684 cmÀ1; HR-MS: m/z=337.1653, calcd.
for C19H22NF3O (M+): 337.1653; HPLC (Chiralcel OD-H
column, heptane/isopropyl alcohol=95:5, flow rate=
0.5 mLminÀ1, l=254 nm): tR =13.4 min (minor enantiomer),
tR =15.2 min (major enantiomer).
(R)-N-[1-(3,4-Dimethylphenyl)-2,2,2-trifluoroethyl]-4-me-
thoxyaniline (2k): Colourless oil; yield: 94%; 90% ee; [a]2D0:
1
À85.8 (c 1.50, CHCl3); H NMR (CDCl3): d=7.14–7.20 (m,
3H), 6.73–6.79 (m, 2H), 6.60–6.66 (m, 2H), 4.70–4.80 (m,
1H), 4.07 (d, J=6.5 Hz, 1H), 3.73 (s, 3H), 2.28 (s, 3H), 2.26
(s, 3H); 13C NMR (CDCl3): d=153.3, 139.8, 137.8, 137.3,
131.8, 130.2, 129.2, 125.4, 125.4 (q, JC,F =280.5 Hz), 115.7,
114.9, 61.6 (q, JC,F =29.2 Hz), 55.8, 20.0, 19.6; 19F NMR
(CDCl3): d=À74.6 (d, J=7.4 Hz); IR (neat): n=3372, 2923,
1511, 1455, 1348, 1233, 1179, 1158, 1115, 1035, 816, 757,
689 cmÀ1; HR-MS: m/z=310.1411, calcd. for C17H19NF3O
([M+H]+): 310.1419; HPLC (Chiralcel OJ-H column, hep-
tane/isopropyl alcohol=95:5, flow rate=0.5 mLminÀ1, l=
254 nm): tR =36.8 min (minor enantiomer), tR =49.1 min
(major enantiomer).
(R)-N-[1-(3-Chlorophenyl)-2,2,2-trifluoroethyl)-4-
methoxyACHTUNGTRENNUNGaniline (2g): Pale yellow oil; yield: 99%; 89% ee;
1
[a]2D0: À52.7 (c 0.84, CHCl3); H NMR (CDCl3): d=7.47 (s,
1H), 7.32–7.38 (m, 3H), 6.73–6.78 (m, 2H), 6.56–6.61 (m,
2H), 4.75–4.85 (m, 1H), 4.10 (d, J=7.1 Hz, 1H), 3.72 (s,
3H); 13C NMR (CDCl3): d=153.5, 139.1, 136.4, 135.0, 130.3,
129.5, 128.3, 126.3, 124.9 (q, JC,F =280.5 Hz), 115.8, 115.8,
61.4 (q, JC,F =30 Hz), 55.7; 19F NMR (CDCl3): d=À74.5 (d,
J=7.2 Hz); IR (neat): n=3372, 2936, 1575, 1512, 1233, 1172,
1119, 1033, 818, 785, 697 cmÀ1; HR-MS: m/z=315.0635,
calcd. for C15H13NF3O (M+): 315.0638; HPLC (Chiralcel
OD-H column, heptane/isopropyl alcohol=95:5, flow rate=
0.5 mLminÀ1, l=254 nm): tR =26.0 min (minor enantiomer),
tR =29.5 min (major enantiomer).
(R)-N-[1-(Naphthalen-2-yl)-2,2,2-trifluoroethyl]-4-meth-
AHCTUNGTRENNUNG
oxyaniline (2m):[11] White solid; yield: 99%; 91% ee;
1H NMR (CDCl3): d=7.70–7.81 (m, 4H), 7.35–7.44 (m,
3H), 6.60–6.63 (m, 2H), 6.51–6.54 (m, 2H), 4.82–4.92 (m,
1H), 4.09 (d, J=6.4 Hz, 1H), 3.57 (s, 3H); 13C NMR
(CDCl3): d=153.5, 139.6, 133.6, 133.3, 131.8, 129.0, 128.2,
127.8, 126.8, 126.7, 125.4 (q, JC,F =280.3 Hz), 115.9, 115.0,
62.0 (q, JC,F =29.4 Hz), 55.7; 19F NMR (CDCl3): d=À74.2
(d, J=7.3 Hz); HPLC (Chiralcel AD-H column, heptane/
isopropyl alcohol=95:5, flow rate=0.5 mLminÀ1, l=
254 nm): tR =26.4 min (major enantiomer), tR =30.3 min
(minor enantiomer).
(R)-N-{1-[4-(Trifluoromethyl)phenyl]-2,2,2-trifluoroethyl}-
4-methoxyaniline (2h):[11] Pale yellow oil; yield: 99%; 89%
1
ee; H NMR (CDCl3): d=7.66 (d, J=8.4 Hz, 2H), 7.60 (d,
J=8.3 Hz, 2H), 6.73–6.78 (m, 2H), 6.55–6.60 (m, 2H), 4.85–
4.95 (m, 1H), 4.14 (d, J=7.0 Hz, 1H), 3.72 (s, 3H);
13C NMR (CDCl3): d=153.7, 139.0, 138.4, 131.5 (q, JC,F
32.2 Hz), 128.6, 126.0 (q, JC,F =3.8 Hz), 124.9 (q, JC,F
=
=
280.5 Hz), 124.0 (q, JC,F =270.8 Hz), 115.9, 115.0, 61.6 (q,
J
C,F =29.2 Hz), 55.7; 19F NMR (CDCl3): d=À63.3, À74.4 (d,
N-(1,1,1-Trifluorooctan-2-yl)-4-methoxyaniline
Yellow oil; yield: 52%; 22% ee; H NMR (CDCl3): d=6.76–
(2o):
1
J=7.2 Hz); HPLC (Chiralcel OD-H column, heptane/iso-
propyl alcohol=95:5, flow rate=0.5 mLminÀ1, l=254 nm):
6.81 (m, 2H), 6.60–6.65 (m, 2H), 3.75 (s, 3H), 3.65–3.72 (m,
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Xiaoyang Dai and Dominique Cahard
1H), 3.26 (d, J=9.0 Hz, 1H), 1.81–1.92 (m, 1H), 1.11–1.59
(m, 8H), 0.87–0.92 (m, 4H); 13C NMR (CDCl3): d=151.7,
column, heptane/isopropyl alcohol=95:5, flow rate=
0.5 mLminÀ1, l=254 nm): tR =12.0 min (minor enantiomer),
tR =15.2 min (major enantiomer).
139.9, 125.4 (q, JC,F =282 Hz), 113.8, 113.7, 55.8 (q, JC,F
=
(R)-1-Phenyl-2,2,2-trifluoroethanamine (2u):[15c,16f] Yellow
oil; yield: 99%; 32% ee; 1H NMR (CDCl3): d=7.38–7.44
(m, 5H), 4.36–4.43 (m, 1H), 1.78 (br s, 2H); 13C NMR
28.5 Hz), 54.6, 50.9, 30.7, 28.3, 26.6, 21.3, 12.8; 19F NMR
(CDCl3): d=À76.6 (d, J=6.9 Hz); IR (neat): n=3389, 2957,
1619, 1511, 1465, 1234, 1167, 1130, 1037, 818, 691 cmÀ1; HR-
MS: m/z=290.1724, calcd. for C15H23NF3O ([M+H]+):
290.1732; HPLC (Chiralcel OJ-H column, heptane/isopropyl
alcohol=95:5, flow rate=0.5 mLminÀ1, l=254 nm): tR =
15.3 min (minor enantiomer), tR =16.7 min (major enantio-
mer).
(CDCl3): d=135.6, 131.4, 129.1, 128.8, 125.8 (q, JC,F
=
279.8 Hz), 58.1 (q, JC,F =30 Hz); 19F NMR (CDCl3,: d=
À77.2 (d, 7.5 Hz); HPLC (Chiralcel OD-H column, heptane/
isopropyl alcohol=95:5, flow rate=0.5 mLminÀ1, l=
210 nm): tR =22.4 min (minor enantiomer), tR =26.7 min
(major enantiomer).
N-Benzyl-1-phenyl-2,2,2-trifluoroethanamine
(2q):[49]
N-(1-Phenyl-2,2-difluoroethyl)-4-methoxyaniline (2v):[50]
1
Yellow oil; yield: 86%; 0% ee; H NMR (CDCl3): d=7.40–
7.45 (m, 5H), 7.29–7.35 (m, 5H), 4.11–4.19 (m, 1H), 3.85 (d,
J=13.4 Hz, 1H), 3.68 (d, J=13.4 Hz, 1H), 2.06 (br s, 1H);
13C NMR (CDCl3): d=139.1, 134.3, 129.2, 128.9, 128.8,
1
Pale yellow oil; yield: 82%; 57% ee; H NMR (CDCl3): d=
7.34–7.44 (m, 5H), 6.70–6.76 (m, 2H), 6.55–6.60 (m, 2H),
5.99 (td, J=55.9 Hz, 3.2 Hz, 1H), 4.63 (td, J=13.2 Hz,
2.9 Hz, 1H), 4.16 (br s, 1H), 3.71 (s, 3H); 13C NMR
(CDCl3): d=153.0, 140.1, 135.7, 129.0, 128.7, 127.9, 116.0 (t,
128.7, 128.3, 127.5, 125.6 (q, JC,F =284.2 Hz), 63.5 (q, JC,F
=
28.5 Hz), 51.1; 19F NMR (CDCl3): d=À74.4 (d, J=7.4 Hz);
HPLC (Chiralcel OJ-H column, heptane/isopropyl alcohol=
95:5, flow rate=0.5 mLminÀ1, l=254 nm): tR =17.3 min,
tR =23.5 min.
J
C,F =245.2 Hz), 115.6, 114.9, 61.3 (t, JC,F =21 Hz), 55.8;
19F NMR (CDCl3): d=À126.4 (d, J=7.5 Hz); HPLC (Chir-
alcel OD-H column, heptane/isopropyl alcohol=95:5, flow
rate=0.5 mLminÀ1, l=254 nm): tR =26.6 min (minor enan-
tiomer), tR =31.2 min (major enantiomer).
(+)-N-(1-Phenyl-2,2,2-trifluoroethyl)naphthalen-1-amine
(2r): Pale yellow oil; yield: 99%; 72% ee; [a]2D0: +171.7 (c
0.82, CHCl3); 1H NMR (CDCl3): d=7.90–7.93 (m, 1H),
7.75–7.78 (m, 1H), 7.42–7.50 (m, 4H), 7.31–7.38 (m, 3H),
7.26–7.29 (m, 1H), 7.15–7.20 (m, 1H), 6.47 (d, J=7.5 Hz,
1H), 5.03–5.13 (m, 1H), 4.98 (d, J=6.6 Hz, 1H); 13C NMR
(CDCl3): d=140.6, 134.4, 133.9, 129.3, 129.1, 129.0, 128.0,
126.2, 125.6, 124.2, 125.3 (q, JC,F =280.5 Hz), 119.9, 119.7,
107.3, 60.8 (q, JC,F =29.2 Hz); 19F NMR (CDCl3): d=À74.4
(d, J=7.0 Hz); IR (neat): n=3425, 3064, 1583, 1527, 1407,
1245, 1168, 1119, 888, 766 cmÀ1; HR-MS: m/z=302.1159,
(R)-1-(4-Chlorophenyl)-2,2,2-trifluoroethanamine
(3d)[11]
(R)-N-[1-(4-Chlorophenyl)-2,2,2-trifluoroethyl]-4-methoxya-
niline 2d (52.6 mg, 0.17 mmol) was dissolved in 4 mL of
MeCN/H2O (1:1). Periodic acid (38 mg, 0.17 mmol) and con-
centrated H2SO4 (16.7 mg, 0.17 mmol) were subsequently
added into the solution. After 24 h, the reaction went to
completion (monitoring by 19F NMR analysis). The aqueous
solution was made alkaline by adding 10% aqueous NaOH
to pH 8 and then extracted with ethyl acetate. The com-
bined organic solution was washed with brine and dried
over MgSO4. The solvent was removed under vacuum and
the residue purified by column chromatography on silica gel
(petroleum ether/ethyl acetate 5:1) to afford the chiral pri-
mary amine 3d as a pale yellow oil; yield: 76%; 94% ee;
1H NMR (CDCl3): d=7.34–7.40 (m, 4H), 4.37–4.40 (m,
1H), 1.76 (br s, 2H); 13C NMR (CDCl3): d=135.1, 134.0,
calcd. for C18H15NF3OACHTNURTGENUNG
([M+H]+): 302.1157; HPLC (Chiral-
cel OD-H column, heptane/isopropyl alcohol=95:5, flow
rate=0.5 mLminÀ1, l=254 nm): tR =15.3 min (major enan-
tiomer), tR =19.3 min (minor enantiomer).
(À)-N-(1-Phenyl-2,2,2-trifluoroethyl)naphthalen-2-amine
(2s): White solid; mp 838C; yield: 99%; 84% ee; [a]2D0:
1
À14.8 (c 1.14, CHCl3); H NMR (CDCl3): d=7.53–7.58 (m,
2H), 7.38–7.46 (m, 3H), 7.22–7.32 (m, 4H), 7.10–7.15 (m,
1H), 6.83 (dd, J=8.8 Hz, 2.4 Hz, 1H), 6.70–6.71 (m, 1H),
4.91–5.00 (m, 1H), 4.39 (d, J=7.4 Hz, 1H); 13C NMR
(CDCl3): d=143.2, 134.8, 134.0, 129.4, 129.3, 129.1, 128.3,
128.0, 127.7, 126.7, 126.4, 125.2 (q, JC,F =280.5 Hz), 123.1,
118.0, 106.9, 60.6 (q, JC,F =29.2 Hz); 19F NMR (CDCl3): d=
À74.3 (d, J=7.2 Hz); IR (neat): n=3397, 2923, 1722, 1632,
1497, 1248, 1169, 1121, 844, 800, 747 cmÀ1; HR-MS: m/z=
302.1171, calcd. for C18H15NF3 ([M+H]+): 302.1157; HPLC
(Chiralcel AD-H column, heptane/isopropyl alcohol=95:5,
flow rate=0.5 mLminÀ1, l=254 nm): tR =18.0 min (minor
enantiomer), tR =28.9 min (major enantiomer).
129.3, 129.0, 125.5 (q,
JC,F =279.8 Hz), 57.5 (q, JC,F =
29.1 Hz); 19F NMR (CDCl3): d=À77.3 (d, J=7.3 Hz); IR
(neat): n=3402, 1598, 1494, 1257, 1116, 1091, 1015, 889,
830 cmÀ1; HR-MS: m/z=210.0294, calcd. for C8H8NF3Cl
([M+H]+): 210.0297; HPLC (Chiralcel OD-H column, hep-
tane/isopropyl alcohol=95:5, flow rate=0.5 mLminÀ1, l=
210 nm): tR =22.5 min (minor enantiomer), tR =24.2 min
(major enantiomer).
(À)-N-(1-Phenyl-2,2,2-trifluoroethyl)-2,4-dimethoxyaniline
(R)-1-(4-Chlorophenyl)-N-[(2,6-dichloropyridin-4-
yl)methyl]-2,2,2-trifluoroethanamine (4)
(2t): White solid; mp 868C; yield: 80%; 90% ee; [a]2D0: À31.4
1
(c 0.55, CHCl3); H NMR (CDCl3): d=7.37–7.48 (m, 5H),
6.43–6.47 (m, 2H), 6.30–6.32 (m, 1H), 4.80–4.89 (m, 1H),
4.73 (d, J=6.2 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H); 13C NMR
(CDCl3): d=153.2, 148.5, 134.6, 129.7, 129.1, 128.9, 128.1,
(R)-1-(4-Chlorophenyl)-2,2,2-trifluoroethanamine
3d
(18.9 mg, 0.09 mmol) and 2,6-dichloroisonicotinaldehyde
(17.6 mg, 0.1 mmol) were dissolved in MeOH (3 mL) and re-
fluxed for 7 h until the reaction went to completion (moni-
toring by 19F NMR analysis). The reaction mixture was al-
lowed to cool down to room temperature and was then
treated with NaBH4 portionwise (34 mg, 0.9 mmol,
10 equiv.). Then, the mixture was quenched with NH4Cl so-
125.4 (q, JC,F =279.8 Hz), 112.1, 103.8, 99.4, 61.4 (q, JC,F
=
29.2 Hz), 55.8; 19F NMR (CDCl3): d=À74.6 (d, J=7.2 Hz);
IR (neat): n=3408, 2957, 1598, 1512, 1457, 1268, 1206, 1119,
1025, 840, 762 cmÀ1; HR-MS: m/z=312.1217, calcd. for
C16H17NF3O2 ([M+H]+): 312.1211; HPLC (Chiralcel AD-H
1326
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Adv. Synth. Catal. 2014, 356, 1317 – 1328

FULL PAPERS
Enantioselective Synthesis of a-Trifluoromethyl Arylmethylamines
lution and extracted with ethyl acetate. The combined or-
ganic phase was dried over MgSO4, concentrated under re-
duced pressure and the residue purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate 10:1)
to give the desired product 4 as white solid; mp938C; yields:
Med. Chem. 2007, 50, 319–327; b) Y. Kohno, K. Awano,
M. Miyashita, T. Ishizaki, K. Kuriyama, Y. Sakoe, S.
Kudoh, K. Saito, E. Kojima, Bioorg. Med. Chem. Lett.
1997, 7, 1519–1524.
[8] a) M. Molteni, M. C. Bellucci, S. Bigotti, S. Mazzini, A.
Volonterio, M. Zanda, Org. Biomol. Chem. 2009, 7,
2286–2296; b) M. Zanda, New J. Chem. 2004, 28, 1401–
1411; c) A. Volonterio, S. Bellosta, F. Bravin, M. C.
Bellucci, L. Bruchꢀ, G. Colombo, L. Malpezzi, S. Maz-
zini, S. V. Meille, M. Meli, C. Ramirez de Arellano, M.
Zanda, Chem. Eur. J. 2003, 9, 4510–4522.
1
82%; 90% ee; H NMR (CDCl3): d=7.32–7.41 (m, 4H), 7.22
(s, 2H), 4.11 (q, J=7.1 Hz, 1H), 3.75 (q, J=12.9 Hz, 1H),
2.14 (s, 1H); 13C NMR (CDCl3): d=154.4, 150.9, 135.6,
131.9, 129.9, 129.4, 124.9 (q, JC,F =279.8 Hz), 121.9, 63.4 (q,
J
C,F =29.2 Hz), 49.1; 19F NMR (CDCl3): d=À74.5 (d, J=
7.1 Hz); IR (neat): u=3352, 1544, 1492, 1365, 1258, 1164,
1121, 1015, 813, 610 cmÀ1; HR-MS: m/z=312.1217, calcd.
for C16H17NF3O2 ([M+H]+): 312.1211; HPLC (Chiralcel
OD-H column, heptane/isopropyl alcohol=99:1, flow rate=
0.4 mLminÀ1, l=210 nm): tR =37.2 min (major enantiomer),
tR =41.3 min (minor enantiomer).
[9] H. Abe, H. Amii, K. Uneyama, Org. Lett. 2001, 3, 313–
315.
[10] M.-W. Chen, Y. Duan, Q.-A. Chen, D.-S. Wang, C.-B.
Yu, Y.-G. Zhou, Org. Lett. 2010, 12, 5075–5077.
[11] A. Henseler, M. Kato, K. Mori, T. Akiyama, Angew.
Chem. 2011, 123, 8330–8333; Angew. Chem. Int. Ed.
2011, 50, 8180–8183.
[12] A. Genoni, M. Benaglia, E. Massolo, S. Rossi, Chem.
Acknowledgements
Commun. 2013, 49, 8365–8367.
[13] G. Hughes, P. N. Devine, J. R. Naber, P. D. OꢃShea,
B. S. Foster, D. J. McKay, R. P. Volante, Angew. Chem.
2007, 119, 1871–1874; Angew. Chem. Int. Ed. 2007, 46,
1839–1842.
[14] J. Xu, Z.-J. Liu, X.-J. Yang, L.-M. Wang, G.-L. Chen, J.-
T. Liu, Tetrahedron 2010, 66, 8933–8937.
X.D. thanks the China Scholarship Council for a PhD fel-
lowship. This work was supported by Normandie Universitꢀ,
CNRS, CRUNCH and LABEX SYNORG (ANR-11-LABX-
0029). The authors thank Professor Georges Dupas for DFT
calculations on ketimine geometries.
[15] a) Y. Wu, L. Deng, J. Am. Chem. Soc. 2012, 134,
14334–14337; b) V. A. Soloshonok, A. G. Kirilenko,
S. V. Galushko, V. P. Kukhar, Tetrahedron Lett. 1993,
34, 3621–3624; c) V. A. Soloshonok, T. Ono, J. Org.
Chem. 1997, 62, 3030–3031; d) V. A. Soloshonok, M.
Yasumoto, J. Fluorine Chem. 2007, 128, 170–173; e) V.
Michaut, F. Metz, J.-M. Paris, J.-C. Plaquevent, J. Fluo-
rine Chem. 2007, 128, 500–506.
[16] a) L. Bernardi, E. Indrigo, S. Pollicino, A. Ricci, Chem.
Commun. 2012, 48, 1428–1430; b) G. K. S. Prakash, M.
Mandal, G. A. Olah, Angew. Chem. 2001, 113, 609–610;
Angew. Chem. Int. Ed. 2001, 40, 589–590; c) G. K. S.
Prakash, M. Mandal, G. A. Olah, Org. Lett. 2001, 3,
2847–2850; d) Y. Kawano, T. Mukaiyama, Chem. Lett.
2005, 34, 894–895; e) W. Xu, W. R. Dolbier Jr, J. Org.
Chem. 2005, 70, 4741–4745; f) I. Fernꢆndez, V. Valdivia,
A. Alcudia, A. Chelouan, N. Khiar, Eur. J. Org. Chem.
2010, 1502–1509; g) H. Kawai, A. Kusuda, S. Naka-
mura, M. Shiro, N. Shibata, Angew. Chem. 2009, 121,
6442–6445; Angew. Chem. Int. Ed. 2009, 48, 6324–6327.
[17] For an exhaustive treatment of this disconnection, see
ref.[2a]
References
[1] a) T. Besset, C. Schneider, D. Cahard, Angew. Chem.
2012, 124, 5134–5136; Angew. Chem. Int. Ed. 2012, 51,
5048–5050; b) G. Landelle, A. Panossian, S. Pazenok,
J.-P. Vors, F. R. Leroux, Beilstein J. Org. Chem. 2013, 9,
2476–2536; c) H. Liu, Z. Gu, X. Jiang, Adv. Synth.
Catal. 2013, 355, 617–626; d) X.-F. Wu, H. Neumann,
M. Beller, Chem. Asian J. 2012, 7, 1744–1754.
[2] a) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev.
2011, 111, 455–529; b) J.-A. Ma, D. Cahard, Chem. Rev.
2008, 108, PR1–PR43.
[3] a) T. C. Nugent, (Ed.), Chiral Amine Synthesis: Meth-
ods, Developments and Applications, Wiley-VCH,
Weinheim, 2010; b) T. C. Nugent, M. El-Shazly, Adv.
Synth. Catal. 2010, 352, 753–819.
[4] a) M. Piras, I. N. Fleming, W. T. A. Harrison, M.
Zanda, Synlett 2012, 23, 2899–2902; b) M. Sani, A. Vo-
lonterio, M. Zanda, ChemMedChem 2007, 2, 1693–
1700.
[5] J. Y. Gauthier, N. Chauret, W. Cromlish, S. Desmarais,
L. T. Duong, J.-P. Falgueyret, D. B. Kimmel, S. Lamon-
tagne, S. Lꢀger, T. LeRiche, C. S. Li, F. Massꢀ, D. J.
McKay, D. A. Nicoll-Griffith, R. M. Oballa, J. T.
Palmer, M. D. Percival, D. Riendeau, J. Robichaud,
G. A. Rodan, S. B. Rodan, C. Seto, M. Thꢀrien, V.-L.
Truong, M. C. Venuti, G. Wesolowski, R. N. Young, R.
Zamboni, W. C. Black, Bioorg. Med. Chem. Lett. 2008,
18, 923–928.
[18] T. Johnson, M. Lautens, Org. Lett. 2013, 15, 4043–4045.
[19] T. Imamoto, N. Iwadate, K. Yoshida, Org. Lett. 2006, 8,
2289–2292.
[20] a) V. Bizet, X. Pannecoucke, J.-L. Renaud, D. Cahard,
Angew. Chem. 2012, 124, 6573–6576; Angew. Chem.
Int. Ed. 2012, 51, 6467–6470; b) V. Bizet, X. Panne-
coucke, J.-L. Renaud, D. Cahard, J. Fluorine Chem.
2013, 152, 56–61; c) V. Bizet, X. Pannecoucke, J.-L.
Renaud, D. Cahard, Adv. Synth. Catal. 2013, 355, 1394–
1402; d) D. Cahard, V. Bizet, X. Dai, S. Gaillard, J.-L.
Renaud, J. Fluorine Chem. 2013, 155, 78–82.
[6] I. Ojima, J. C. Slater, P. Pera, J. M. Veith, A. Abouab-
dellah, J.-P. Bꢀguꢀ, R. J. Bernacki, Bioorg. Med. Chem.
Lett. 1997, 7, 133–138.
[21] N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R.
[7] a) N. Zhang, S. Ayral-Kaloustian, T. Nguyen, J. Afrago-
Noyori, J. Am. Chem. Soc. 1996, 118, 4916–4917.
la, R. Hernandez, J. Lucas, J. Gibbons, C. Beyer, J.
Adv. Synth. Catal. 2014, 356, 1317 – 1328
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1327

FULL PAPERS
Xiaoyang Dai and Dominique Cahard
[22] J. Takehara, S. Hashiguchi, A. Fujii, S.-i. Inoue, T. Ikar-
iya, R. Noyori, Chem. Commun. 1996, 233–234.
[23] M. Palmer, T. Walsgrove, M. Wills, J. Org. Chem. 1997,
62, 5226–5228.
[24] M. Hennig, K. Pꢄntener, M. Scalone, Tetrahedron:
Asymmetry 2000, 11, 1849–1858.
[25] a) D. Guijarro, ꢇ. Pablo, M. Yus, Tetrahedron Lett.
2009, 50, 5386–5388; b) D. Guijarro, ꢇ. Pablo, M. Yus,
J. Org. Chem. 2010, 75, 5265–5270; c) D. Guijarro, ꢇ.
Pablo, M. Yus, Tetrahedron Lett. 2011, 52, 789–791;
d) ꢇ. Pablo, D. Guijarro, G. Kovꢆcs, A. Lledꢈs, G.
Ujaque, M. Yus, Chem. Eur. J. 2012, 18, 1969–1983;
e) D. Guijarro, ꢇ. Pablo, M. Yus, J. Org. Chem. 2013,
78, 3647–3654; f) ꢇ. Pablo, D. Guijarro, M. Yus, J. Org.
Chem. 2013, 78, 9181–9189.
[26] M. J. Palmer, M. Wills, Tetrahedron: Asymmetry 1999,
10, 2045–2061.
[27] S. Gladiali, E. Alberico, Chem. Soc. Rev. 2006, 35, 226–
236.
[28] D. G. I. Petra, J. N. H. Reek, J.-W. Handgraaf, E. J.
Meijer, P. Dierkes, P. C. J. Kamer, J. Brussee, H. E.
Schoemaker, P. W. N. M. van Leeuwen, Chem. Eur. J.
2000, 6, 2818–2829.
[29] ꢇ. Pablo, D. Guijarro, M. Yus, Appl. Sci. 2012, 2, 1–12.
[30] D. Carmona, F. Viguri, M. Pilar Lamata, J. Ferrer, E.
Bardaji, F. J. Lahoz, P. Garcia-Orduna, L. A. Oro,
Dalton Trans. 2012, 41, 10298–10308.
[37] a) K. Everaere, A. Mortreux, J.-F. Carpentier, Adv.
Synth. Catal. 2003, 345, 67–77; b) R. Noyori, M. Yama-
kawa, S. Hashiguchi, J. Org. Chem. 2001, 66, 7931–
7944; c) R. Noyori, T. Ohkuma, Angew. Chem. 2001,
113, 40–75; Angew. Chem. Int. Ed. 2001, 40, 40–73;
d) K. MuÇiz, Angew. Chem. 2005, 117, 6780–6785;
Angew. Chem. Int. Ed. 2005, 44, 6622–6627.
[38] K. Everaere, A. Mortreux, M. Bulliard, J. Brussee, A.
van der Gen, G. Nowogrocki, J.-F. Carpentier, Eur. J.
Org. Chem. 2001, 2001, 275–291.
[39] a) Y.-L. Liu, T.-D. Shi, F. Zhou, X.-L. Zhao, X. Wang,
J. Zhou, Org. Lett. 2011, 13, 3826–3829; b) D. Enders,
K. Gottfried, G. Raabe, Adv. Synth. Catal. 2010, 352,
3147–3152.
[40] CCDC 976479 contains the supplementary crystallo-
graphic data for 1m. These data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[41] N. Kusano, Y. Kokaji, Y. Niizeki, (Kureha Corporation,
Japan) Patent WO 2006/004062A1, 2006.
[42] a) H. A. Schenck, P. W. Lenkowski, I. Choudhury-Mu-
kherjee, S.-H. Ko, J. P. Stables, M. K. Patel, M. L.
Brown, Bioorg. Med. Chem. 2004, 12, 979–993; b) T.
Konno, T. Takehana, M. Mishima, T. Ishihara, J. Org.
Chem. 2006, 71, 3545–3550.
[43] W. H. Pirkle, J. R. Hauske, J. Org. Chem. 1977, 42,
2436–2439.
[31] D. Cahard, V. Bizet, Chem. Soc. Rev. 2014, 43, 135–147.
[32] a) D. O. Berbasov, I. D. Ojemaye, V. A. Soloshonok, J.
Fluorine Chem. 2004, 125, 603–607; b) T. Ono, V. P.
Kukhar, V. A. Soloshonok, J. Org. Chem. 1996, 61,
6563–6569.
[44] M. Abid, M. Savolainen, S. Landge, J. Hu, G. K. S. Pra-
kash, G. A. Olah, B. Tçrçk, J. Fluorine Chem. 2007,
128, 587–594.
[45] D. Enders, A. Henseler, S. Lowins, Synthesis 2009,
4125–4128.
[33] G. Hou, F. Gosselin, W. Li, J. C. McWilliams, Y. Sun,
M. Weisel, P. D. OꢃShea, C.-y. Chen, I. W. Davies, X.
Zhang, J. Am. Chem. Soc. 2009, 131, 9882–9883.
[34] F. Gosselin, P. D. OꢃShea, S. Roy, R. A. Reamer, C.-Y.
Chen, R. P. Volante, Org. Lett. 2005, 7, 355–358.
[35] a) V. Gouverneur, O. Lozano, in: Science of Synthesis,
Vol. 3, Georg Thieme Verlag, Stuttgart, 2011, pp 851–
930; b) J. Hu, W. Zhang, F. Wang, Chem. Commun.
2009, 45, 7465–7478.
[46] Y.-L. Liu, X.-P. Zeng, J. Zhou, Chem. Asian J. 2012, 7,
1759–1763.
[47] H. Wang, X. Zhao, Y. Li, L. Lu, Org. Lett. 2006, 8,
1379–1381.
[48] N. Mrsic, A. J. Minnaard, B. L. Feringa, J. G. d. Vries, J.
Am. Chem. Soc. 2009, 131, 8358–8359.
[49] V. V. Levin, A. D. Dilman, P. A. Belyakov, M. I. Struch-
kova, V. A. Tartakovsky, Eur. J. Org. Chem. 2008, 2008,
5226–5230.
[36] T. Sakamoto, K. Horiguchi, K. Saito, K. Mori, T.
[50] G. K. S. Prakash, R. Mogi, G. A. Olah, Org. Lett. 2006,
8, 3589–3592.
Akiyama, Asian J. Org. Chem. 2013, 2, 943–946.
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