Stereoselective access to substituted [(E)- or (Z)-1-(trifluoromethyl)- allyl]amines

Article abstract of DOI:10.1002/ejoc.200701090

Hydrometallation reactions, for example, hydroboration and hydroalumination, on [1-(trifluoromethyl)propargyl]amines lead stereoselectively to the corresponding [(Z)- and (E)-1-(trifluoromethyl)allyl]amines in good yields; (Z)- and (E)-allylamines with a free amino group can be obtained in good yields and excellent enantioselectivities from the chiral propargylamines. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701090

FULL PAPER
DOI: 10.1002/ejoc.200701090
Stereoselective Access to Substituted [(E)- or (Z)-1-(Trifluoromethyl)-
allyl]amines
Guillaume Magueur,[a] Benoit Crousse,*[a] and Danièle Bonnet-Delpon[a]
Keywords: Propargylamines / Allylamines / Fluorine / Hydroboration / Hydroalumination
Hydrometallation reactions, for example, hydroboration and
hydroalumination, on [1-(trifluoromethyl)propargyl]amines
lead stereoselectively to the corresponding [(Z)- and (E)-1-
(trifluoromethyl)allyl]amines in good yields; (Z)- and (E)-
allylamines with a free amino group can be obtained in good
yields and excellent enantioselectivities from the chiral pro-
pargylamines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
by the addition of lithium acetylides in toluene to non-acti-
Introduction
vated CF3-substituted aldimines 1–3 (Table 1).[9]
Allylamines are highly functionalizable compounds and
are thus the focus of numerous studies. The functionaliza-
tion of the double bond opens the way to a wide range
of useful products such as α- and β-amino acids, various
alkaloids and carbohydrate derivatives.[1] Many methods
have been developed for their asymmetric preparation. Sur-
prisingly, despite the fact that the introduction of fluorine
can bring about profound changes in bioactive molecules,
only a few methods for the preparation of trifluoromethyl-
ated allylamines have been reported. [1-(Trifluoromethyl)-
allyl]amines can be obtained in different ways: by trifluoro-
methylation of unsaturated nitrones,[2] N-sulfinimines or N-
tosylaldimines,[3] or by olefination of fluorinated β-amino
sulfones[4] or fluorinated enamine phosphonates.[5] More re-
cently we have shown that the addition of a vinyl Grignard
reagent to CF3-N-aryl- and -N-alkylaldimines was efficient
and did not require an activating N-substituent.[6] Similar
approaches involving the addition of a vinyl Grignard rea-
gent to activated CF3-sulfinimine[7] and vinyl trifluorobor-
ate to (trifluoromethyl)iminium species[8] have also been re-
ported. Although different routes to fluorinated allylamines
have been reported, a simple and selective access to substi-
tuted allylamines is not known. This paper focuses on the
partial and stereocontrolled reduction of propargylamines
to CF3-substituted (Z)- or (E)-allylamines.
Table 1. Preparation of propargylamines.
Entry
Imine
RЈ
Product
Yield
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
3
3
3
SiMe3
Bu
Ph
SiMe3
Bu
Ph
SiMe3
Bu
Ph
4a
4b
4c
5a
5b
5c
6a
6b
6c
83%
94%
87%
84%
71%
78%
95%
77%
90%
The propargylamines were obtained in good to excellent
yields. From the imine 3, with the methyl ether of (R)-phen-
ylglycinol as a chiral N-substituent, [1-(trifluoromethyl)-
propargyl]amines 6 were obtained in good yields and with
excellent diastereoselectivities (de Ͼ 98%). In all cases, only
one diastereoisomer was detected in the H and 19F NMR
1
spectra of the crude product. The isomer is assumed to have
(R) configuration by comparison with the results of our
previous vinylation reactions.[6]
With [1-(trifluoromethyl)propargyl]amines 4–6 in hand,
the partial reduction of the triple bond to give (Z)-allyl-
amines was first investigated. Under classical conditions
using the Lindlar reagent, a mixture of compounds was
obtained. Faced with this failure, hydrometallation of the
triple bond was investigated, particularly hydroboration.
Results and Discussion
[1-(Trifluoromethyl)propargyl]amines have previously
been synthesized by our group. They were easily prepared
[a] Faculty of Pharmacy, BioCIS-CNRS UMR 8076,
92296 Chatenay-Malabry, France
Fax: +33-1-46835740
E-mail: Benoit.crousse@u-psud.fr
Eur. J. Org. Chem. 2008, 1527–1534
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Magueur, B. Crousse, D. Bonnet-Delpon
FULL PAPER
The reaction of propargylamines 4 with the active BH3 rea- Table 3. Reduction of propargylamines with LAH at room tem-
perature.
gent led to the degradation of the starting material. Conse-
quently, the hydroboration reaction was investigated with
less reactive borane reagents such as dicyclohexylborane
(Table 2).
Table 2. Hydroboration of propargylamines 4–6.
Entry Amine Time CF2H amine,[a] yield Allylamine,[a] yield
1
2
3
4
5
6
4a
4b
4c
5a
5b
5c
11 h
13 h
12 h
1 h
10 h
3 h
10a, –
10b, –
12a, 100%
12b, 100%
12c, 100%
13a, –
13b, 100%
13c, 64%
10c, –
11a, Ͼ90%
11b, –
11c, 36%
[a] NMR signal ratio of the crude product.
Entry
Imine
RЈ
Product
Yield
The N-benzylpropargylamines 4 were exclusively con-
verted into [1-(trifluoromethyl)allyl]amines 12 in good
yields and with excellent stereoselectivity [(E)/(Z) = 100:0].
Surprisingly, the reactivity of the N-(p-methoxyphenyl)pro-
pargylamines 5 depended on the nature of the RЈ group.
With the butyl group, only the allylamine 13b was obtained.
With the phenyl group, a 36:64 mixture of [1-(difluoro-
methyl)propargyl]amine 11c and [1-(trifluoromethyl)allyl]-
amine 13c was formed, whereas with a TMS group (En-
try 4) only the [1-(difluoromethyl)propargyl]amine was ob-
tained. The formation of the CF2H amines can be com-
pared with the results obtained with Red-Al®. This latter
reaction takes place presumably by deprotonation at C1
and successive elimination of a fluoride ion (Figure 1).
1
2
3
4
5
6
4a
4b
5a
5c
6b
6c
SiMe3
Bu
SiMe3
Ph
Bu
Ph
7a
7b
8a
8c
9b
9c
92%
93%
35%
32%
86%
85%
Under these conditions propargylamines 4a and 4b were
quantitatively reduced to the corresponding allylamines 7a
and 7b with excellent stereoselectivity [100% (Z)]. However,
with propargylamines 5, the yields were lower (only 32–
35%). Interestingly, hydroboration of the chiral CF3-substi-
tuted propargylamines 6b and 6c provided the correspond-
ing allylamines 9b and 9c in excellent yields without loss of
stereoselectivity (de Ͼ98%). It is worth noting that in all
cases (Entries 1–6) excellent stereoselectivity of the re-
duction reaction was obtained [signals of the (E) isomer
were not observed in the NMR spectra].
In the same way, in order to obtain the corresponding
[(E)-1-(trifluoromethyl)allyl]amines, partial and selective re-
duction was attempted by hydrometallation with, in this
case, hydroalumination reagents. The use of DIBAL-H at
room temperature or at reflux in THF led to the recovery
of the starting amines 4 and 5. Use of the more reactive
Red-Al® afforded a complex mixture of compounds when
the reaction was performed at 0 °C. 1H and 19F NMR
analyses of this mixture highlighted the presence of triple
and double bonds as well as the presence of CF2H, CFH2
and CH3 groups.
Figure 1. Intermediate A.
At a higher temperature the reaction would be expected
to favour one pathway more than the other. The reaction
was therefore investigated at reflux in order to gain an un-
derstanding of the reduction mechanism. The results are
reported in Table 4.
Table 4. Reduction of propargylamines with LAH at reflux in THF.
Faced with these disappointing results, we investigated
the reduction of the triple bond with LiAlH4 (LAH). Only
a few examples of the reduction of non-fluorinated propar-
gylamines to the corresponding (E)-allylamines have been
described,[10] and there is no precedent for the reduction of
a fluorinated propargylamine. The first attempts were real-
ized on amines 4a and 5a with 4 equiv. of LAH at low tem-
perature in THF, but only the starting materials were reco-
vered. However, at room temperature, either [1-(trifluoro-
methyl)allyl]amine or [1-(difluoromethyl)propargyl]amine
were obtained depending on the starting propargylamine.
The results are presented in Table 3.
Entry
Amine
RЈ
Time
Product
Yield
1
2
3
4
5
6
7
4b
4c
5a
5b
5c
6a
6c
Bu
Ph
SiMe3
Bu
Ph
SiMe3
Ph
1 h
1.5 h
1 h
1.5 h
1 h
1.5 h
2 h
12b
12c
13a
13b
13c
14a
14c
94%
90%
88%
89%
90%
88%
90%
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1527–1534

Stereoselectively Substituted [(E)-or (Z)-1-(Trifluoromethyl)allyl]amines
Under these conditions, the reaction was not only faster
but also completely chemo- and stereoselective and gave a
good yield irrespective of the nature of the substituents on
the triple bond and the nitrogen atom. [1-(Trifluoromethyl)-
propargyl]amines 4–6 were selectively reduced to [(E)-1(-tri-
fluoromethyl)allyl]amines 12–14 in excellent yields. Under
these conditions the reaction of 5a with LAH (Entry 3)
led to a considerable reduction of the proportion of [1-(di-
fluoromethyl)propargyl]amine 11a (8 vs. Ͼ90% at room
temperature). CF2 compounds were not observed in any
other case.
Interestingly, hydroalumination of the chiral CF3-substi-
tuted propargylamines 3a and 3c provided the correspond-
ing allylamines 14a and 14c without any stereochemical loss
[de Ͼ98 and 100% (Z), respectively] in excellent yields.
Despite these excellent results obtained at high tempera-
ture, we decided to investigate in more detail the course of
the two reductive pathways. Such a difference in reactivity
induced by temperature, reflected in the reaction times (En-
try 4 vs. Entry 5 in Table 3), highlights the fact that 11 and
13 are obtained by two different reaction pathways. To gain
a better understanding of the reaction mechanisms, the re-
actions were carried out with isotopic labelling. Amine 5a
was treated with LiAlD4 (LAD) at room temperature and
at reflux in THF, and the mixtures were hydrolysed with
either H2O or D2O. The results obtained at reflux in THF
(Scheme 1) are in accordance with the classical mechanism
Scheme 2. Reaction of 5a with LAD at room temperature.
niently achieved first by demethylation with BBr3 in
[12]
[13]
CH2Cl2
and then by the standard Pb(OAc)4
method
described in the literature.[11]
to give the corresponding novel free allylamines in good
yields (Scheme 3). The (R) configuration of the CF3-substi-
tuted allylamine obtained was assigned by comparison with
the optical rotation data reported in the literature: [α]D25
=
–50 (c = 0.2, MeOH) {ref.[3] [α]2D0 = +51.4 [c = 1.0, MeOH,
for the (S) enantiomer]}.
Scheme 1. Reaction of 5a with LAD at reflux.
When the reaction was conducted at room temperature,
5a was converted into compound 16 after hydrolysis with
H2O and D2O (Scheme 2). First, deuterium was introduced
at C1, indicating an addition of D– to an imine intermedi-
ate. Secondly, hydrolysis with water or D2O produced the
same compound 16, indicating that the last intermediate F
is an amide (NAl and not CF2Al but CF2H). Thus, the
mechanism of the reduction can be explained by Scheme 2.
Difluoro enamine B is expected after deprotonation of E at
the C1 carbon atom and subsequent loss of a fluoride ion
Scheme 3. Synthesis of free [1-(trifluoromethyl)allyl]amines.
Conclusions
This paper describes the stereoselective access to func-
from intermediate A; B then quickly rearranges to the more tionalized [(Z)- and (E)-1-(trifluoromethyl)allyl]amines.
stable difluoromethyl imine C which is immediately reduced These were obtained by partial and selective hydroboration
by LAD to afford D. This latter deprotonates E at C1 to or hydroalumination reduction of [1-(trifluoromethyl)pro-
afford F and to regenerate A which starts the cycle again.
pargyl]amines. In the case of hydroalumination, the com-
Interestingly, the (Z)- or (E)-allylamines could be depro- petitive formation of allylamine and CF2H-substituted pro-
tected in order to obtain the free amino group. For example, pargylamine was observed at room temperature. When the
for compounds 9c or 14c, removal of the methyl ether moi- reaction was conducted at reflux, only the reduction to (E)-
ety of the (R)-phenylglycinol side-chain was very conve- allylamines was observed. Isotopic labelling reactions were
Eur. J. Org. Chem. 2008, 1527–1534
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1529

G. Magueur, B. Crousse, D. Bonnet-Delpon
FULL PAPER
(400 µL, 3.6 mmol) and nBuLi (1.6 , 2.3 mL, 3.6 mmol). The
crude material was purified on silica gel to give 4c (760 mg, 87%)
as an orange oil. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 1.74 (br.
s, 1 H, NH), 3.91 (d, J = 13.1 Hz, 1 H, CH2Ph), 4.03 (q, J = 6.7 Hz,
1 H, CHCF3), 4.04 (d, J = 13.1 Hz, 1 H, CH2Ph), 7.06–7.44 (m,
10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 50.9
(CH2), 52.5 (q, J = 33 Hz, CHCF3), 81.3 (C), 86.3 (C), 121.7 (CAr),
124.0 (q, J = 281 Hz, CF3), 127.4 (CHAr), 128.2 (CHAr), 128.3
also realized in order to gain information on the mechan-
istic pathways of these reactions. Free [(Z)- or (E)-1-(tri-
fluoromethyl)allyl]amines were easily obtained with excel-
lent enantioselectivity.
Experimental Section
(CHAr), 128.5 (CHAr), 128.9 (CHAr), 131.8 (CHAr), 138.5 (CAr
)
General Methods: Experiments were carried out under dry argon.
All moisture-sensitive reactants were handled under argon. Tetra-
hydrofuran was distilled from sodium/benzophenone and toluene
from calcium hydride. Column chromatography was carried out on
Merck SiO2 (70–230 mesh). NMR spectra were recorded with a
Bruker AC 200 spectrometer (1H: 200 MHz; 19F: 188 MHz; 13C:
75 MHz) in CDCl3 solutions. Chemical shifts are reported in ppm
relative to Me4Si and CFCl3 [for 19F NMR (188 MHz, CDCl3,
25 °C)] as internal standards. For the 13C NMR data, reported sig-
nal multiplicities were measured relative to C–F coupling. Optical
rotations were measured at 589 nm with a Polartronic E-Schmidt-
Haensch apparatus. Melting points were determined with a Kofler
block melting point apparatus and are uncorrected.
ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.4 (d, J =
6.7 Hz, 3 F) ppm. C17H14F3N (289.30): calcd. C 70.58, H 4.88, N
4.84; found C 70.64, H 4.92, N 4.72.
(4-Methoxyphenyl)[1-(trifluoromethyl)-3-(trimethylsilyl)prop-2-ynyl]-
amine (5a): Compound 2 (2.4 g, 12 mmol) was treated with (tri-
methylsilyl)acetylene (2.0 mL, 14 mmol) and nBuLi (2.5 , 5.7 mL,
14 mmol). The crude material was purified on silica gel to give
5a (2.6 g, 84%) as brown crystals. M.p. 60 °C (Et2O). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 0.17 [s, 9 H, Si(CH3)3], 3.66 (d, J =
9.7 Hz, 1 H, NH), 3.75 (s, 3 H, OCH3), 4.52 (dq, J = 9.7, 6.5 Hz,
1 H, CHCF3), 6.50–6.67 (m, 4 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = –0.5 [Si(CH3)3], 52.2 (q, J = 34 Hz, CHCF3),
55.6 (OCH3), 92.2 (C), 96.7 (C), 114.8 (CHAr), 116.8 (CHAr), 123.6
(q, J = 282 Hz, CF3), 139.0 (CAr), 154.1 (CAr) ppm. 19F NMR
(188 MHz, CDCl3, 25 °C): δ = –76.2 (d, J = 6.5 Hz, 3 F) ppm.
C14H18F3NOSi (301.38): calcd. C 55.79, H 6.02, N 4.65; found C
56.05, H 6.24, N 4.62.
General Procedure for the Alkynylation Reaction: n-Butyllithium
[1.6  (hexane), 6 mmol] was added under argon to a cooled
(–78 °C) solution of alkyne (6 mmol) in toluene (50 mL). The reac-
tion mixture was stirred for 30 min, and then the (trifluoromethyl)-
aldimine (5 mmol) in toluene (5 mL) was added dropwise. The bath
was warmed to room temperature overnight. After 15 h, the reac-
tion was quenched with an aqueous solution of NH4Cl (10 mL)
and the mixture extracted with AcOEt (15 mL). The organic layers
were dried with MgSO4 and concentrated under vacuum. The
crude product was purified on silica gel (petroleum ether/AcOEt,
90:10) to give the corresponding propargylamine.
(4-Methoxyphenyl)[1-(trifluoromethyl)hept-2-ynyl]amine (5b): Com-
pound 2 (1.0 g, 5.1 mmol) was treated with hexyne (700 µL,
6.1 mmol) and nBuLi (1.6 , 5.4 mL, 6.1 mmol). The crude mate-
rial was purified on silica gel to give 5b (982 mg, 71%) as a brown
1
oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 0.90 (t, J = 7.0 Hz, 3
H, CH3), 1.25–1.60 (m, 4 H, 2 CH2), 2.20 (td, J = 6.9, 1.9 Hz, 2
H, CH2C), 3.60 (br. s, 1 H, NH), 3.76 (s, 3 H, OCH3), 4.50 (br. q,
J = 6.2 Hz, 1 H, CHCF3), 6.88–7.07 (m, 4 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 13.1 (CH3), 18.0 (CH2), 21.6 (CH2),
30.1 (CH2), 51.3 (q, J = 34 Hz, CHCF3), 55.2 (OCH3), 72.1 (C),
87.1 (C), 114.6 (CHAr), 116.4 (CHAr), 123.9 (q, J = 283 Hz, CF3),
139.1 (CAr), 153.9 (CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C):
δ = –76.6 (d, J = 6.4 Hz, 3 F) ppm. C15H18F3NO (285.30): calcd.
C 63.15, H 6.36, N 4.91; found C 62.95, H 6.49, N 4.82.
Benzyl[1-(trifluoromethyl)-3-(trimethylsilyl)prop-2-ynyl]amine (4a):
Compound 1 (1.1 g, 6.0 mmol) was treated with (trimethylsilyl)-
acetylene (1.0 mL, 7.2 mmol) and nBuLi (1.6 , 4.5 mL, 7.2 mmol).
The crude material was purified on silica gel to give 4a (1.1 g, 83%)
1
as a brown oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 0.14 [s, 9
H, Si(CH3)3], 3.79 (q, J = 6.7 Hz, 1 H, CHCF3), 3.83 (d, J =
12.9 Hz, 1 H, CH2Ph), 3.97 (d, J = 12.9 Hz, 1 H, CH2Ph), 7.04–
7.32 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
–0.44 [Si(CH3)3], 50.8 (CH2Ph), 52.5 (q, J = 33 Hz, CHCF3), 92.1
(C), 97.3 (C), 123.8 (q, J = 281 Hz, CF3), 127.4 (CH), 128.3 (CH),
128.5 (CH), 138.5 (C) ppm. 19F NMR (188 MHz, CDCl3, 25 °C):
δ = –75.5 (d, J = 6.7 Hz, 3 F) ppm. C14H18F3NSi (285.38): calcd.
C 58.92, H 6.36, N 4.91; found C 59.01, H 6.35, N 5.15.
(4-Methoxyphenyl)[3-phenyl-1-(trifluoromethyl)prop-2-ynyl]amine
(5c): Compound 2 (4.0 g, 20 mmol) was treated with phenylacetyl-
ene (2.6 mL, 24 mmol) and nBuLi (1.6 , 14.8 mL, 24 mmol). The
crude material was purified on silica gel to give 5c (4.7 g, 78%) as
1
a brown oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 3.76 (s, 3 H,
OCH3), 3.91 (d, J = 9.7 Hz, 1 H, NH), 4.75 (dq, J = 9.7, 6.3 Hz,
1 H, CHCF3), 6.75–6.86 (m, 4 H, Ar), 7.15–7.49 (m, 5 H, Ar) ppm.
13C NMR (75 MHz, CDCl3, 25 °C): δ = 51.9 (q, J = 34 Hz,
CHCF3), 55.2 (OCH3), 80.8 (C), 86.2 (C), 114.7 (CHAr), 116.7
(CHAr), 121.3 (CAr), 123.8 (q, J = 282 Hz, CF3), 128.2 (CHAr),
129.0 (CHAr), 131.8 (CHAr), 138.8 (CAr), 154.1 (CAr) ppm. 19F
NMR (188 MHz, CDCl3, 25 °C): δ = –76.1 (d, J = 6.3 Hz, 3 F)
ppm. C17H14F3NO (305.30): calcd. C 68.88, H 4.62, N 4.59; found
C 68.51, H 4.65, N 4.24.
Benzyl[1-(trifluoromethyl)hept-2-ynyl]amine (4b): Compound
1
(611 mg, 3.3 mmol) was treated with hexyne (450 µL, 3.9 mmol)
and nBuLi (1.6 , 2.45 mL, 3.9 mmol). The crude material was
purified on silica gel to give 4b (830 mg, 94%) as an orange oil. 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 1.20 (t, J = 7.1 Hz, 3 H,
CH3), 1.60–1.97 (m, 5 H, CH2), 2.52 (td, J = 6.8, 2.0 Hz, 2 H,
1
CH2C), 4.12 (q, J = 6.7 Hz, 1 H, CHCF3), 4.17 (d, J = 13.0 Hz,
1 H, CH2Ph), 4.31 (d, J = 13.0 Hz, 1 H, CH2Ph), 7.50–7.67 (m, 5
H, Ar) ppm. 13H NMR (75 MHz, CDCl3, 25 °C): δ = 13.3 (CH3),
18.1 (CH2), 21.8 (CH2), 30.4 (CH2), 50.8 (CH2), 52.0 (q, J = 32 Hz,
CHCF3), 72.5 (C), 87.2 (C), 124.1 (q, J = 281 Hz, CF3), 127.3
(CHAr), 128.2 (CHAr), 128.4 (CHAr), 138.8 (CAr) ppm. 19F NMR
(188 MHz, CDCl3, 25 °C): δ = –75.9 (d, J = 6.7 Hz, 3 F) ppm.
C15H18F3N (269.31): calcd. C 66.90, H 6.74, N 5.20; found C 66.93,
H 6.88, N 5.14.
(–)-[(R)-2-Methoxy-1-phenylethyl][(R)-1-(trifluoromethyl)-3-(tri-
methylsilyl)prop-2-ynyl]amine (6a): Compound 3 (1.1 g, 4.6 mmol)
was treated with (trimethylsilyl)acetylene (780 µL, 5.5 mmol) and
nBuLi (1.6 , 3.5 mL, 5.5 mmol). The crude material was purified
on silica gel to give 6a (1.4 g, 95%) as an orange oil. [α]2D2 = –6 (c
1
= 0.31, MeOH). H NMR (200 MHz, CDCl3, 25 °C): δ = 0.23 [s,
Benzyl[3-phenyl-1-(trifluoromethyl)prop-2-ynyl]amine (4c): Com- 9 H, Si(CH3)3], 2.44 (d, J = 12 Hz, 1 H, NH), 3.41 (s, 3 H, OCH3),
pound 1 (568 mg, 3.0 mmol) was treated with phenylacetylene 3.46 (d, J = 6.3 Hz, 1 H, CH2O), 3.46 (d, J = 7.6 Hz, 1 H, CH2O),
1530
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Stereoselectively Substituted [(E)-or (Z)-1-(Trifluoromethyl)allyl]amines
3.67 (dq, J = 12, 6.7 Hz, 1 H, CHCF3), 4.29 (dd, J = 7.6, 6.3 Hz,
CDCl3, 25 °C): δ = –0.2 [Si(CH3)3], 50.8 (CH2Ph), 60.6 (q, J =
1 H, CHAr), 7.17–7.47 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, 28 Hz, CHCF3), 125.7 (q, J = 295 Hz, CF3), 127.3 (CHAr), 128.1
CDCl3, 25 °C): δ = –0.36 (CH3), 50.9 (q, J = 33 Hz, CHCF3), 58.2
(CHAr), 128.5 (CHAr), 138.6 (CH=CHSi), 139.1 (d, J = 1.7 Hz,
(OCH3), 59.1 (CHAr), 77.1 (OCH2), 91.6 (C), 97.7 (C), 123.6 (q, J CH=CHSi), 139.2 (CAr) ppm. 19F NMR (188 MHz, CDCl3,
= 280 Hz, CF3), 127.8 (CAr), 128.1 (CHAr), 128.7 (CHAr), 138.2
25 °C): δ = –74.7 (d, J = 7.0 Hz, 3 F) ppm. C14H20F3NSi (287.40):
(CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.7 (d, J = calcd. C 58.51, H 7.01, N 4.87; found C 58.71, H 7.21, N 4.57.
6.7 Hz, 3 F) ppm. C16H22F3NOSi (329.43): calcd. C 58.33, H 6.73,
Benzyl[(Z)-1-(trifluoromethyl)hept-2-enyl]amine (7b): Compound 4b
N 4.25; found C 58.18, H 7.05, N 3.96.
(270 mg, 1 mmol) was treated with BH3·Me2S (2.5 mL, 5 mmol)
(–)-[(R)-2-Methoxy-1-phenylethyl][(R)-1-(trifluoromethyl)hept-2- and cyclohexene (1 mL, 10 mmol). The crude material was purified
ynyl]amine (6b): Compound 3 (807 mg, 3.5 mmol) was treated with
hexyne (480 µL, 4.2 mmol) and nBuLi (1.6 , 2.6 mL, 3.9 mmol).
The crude material was purified on silica gel to give 6b (830 mg,
on silica gel to give 7a (253 mg, 93%) as a yellow oil. 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 0.80 (t, J = 7.0 Hz, 3 H, CH3), 1.09–
1.97 (m, 6 H, 2 CH2), 3.70 (d, J = 13.4 Hz, 1 H, CH2Ph), 3.84 (d,
J = 13.4 Hz, 1 H, CH2Ph), 3.81 (dq, J = 9.6, 7.2 Hz, 1 H, CHCF3),
5.20 (dd, J = 11.0, 9.6 Hz, 1 H, CH=CHCH2), 5.73 (dt, J = 11.0,
1
77%) as an orange oil. [α]2D2 = –185 (c = 0.55, MeOH). H NMR
(200 MHz, CDCl3, 25 °C): δ = 0.83 (t, J = 7.2 Hz, 3 H, CH3), 1.24–
1.51 (m, 4 H, 2 CH2), 2.14 (td, J = 6.8, 1.9 Hz, 2 H, CH2C), 2.32 7.5 Hz, 1 H, CH=CHCH2), 7.16–7.31 (m, 5 H, Ar) ppm. 13C NMR
(br. s, 1 H, NH), 3.29 (s, 3 H, OCH3), 3.29–3.37 (m, 2 H, CH2O), (75 MHz, CDCl3, 25 °C): δ = 13.7 (CH3), 22.2 (CH3CH2), 27.6
3.51 (qt, J = 6.9, 2.0 Hz, 1 H, CHCF3), 4.16 (dd, J = 7.5, 5.9 Hz,
(CH2), 31.3 (CHCH2), 50.8 (CH2Ph), 55.7 (q, J = 29 Hz, CHCF3),
1 H, CHAr), 7.12–7.37 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, 122.2 (CH=CHCH2), 125.8 (q, J = 281 Hz, CF3), 127.2 (CHAr),
CDCl3, 25 °C): δ = 13.3 (CH3), 18.1 (CH2), 21.7 (CH2), 30.4
(CCH2), 50.3 (q, J = 32 Hz, CHCF3), 58.2 (OCH3), 59.3 (CHAr),
72.7 (C), 77.1 (OCH2), 86.7 (C), 123.9 (q, J = 280 Hz, CF3), 127.7
128.1 (CHAr), 128.4 (CHAr), 137.9 (CH=CHCH2), 139.2 (CAr)
ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.4 (d, J =
7.2 Hz, 3 F) ppm. C15H20F3N (271.32): calcd. C 66.40, H 7.43, N
(CHAr), 128.0 (CHAr), 128.5 (CHAr), 138.4 (CAr) ppm. 19F NMR 5.16; found C 66.19, H 7.58, N 5.02.
(188 MHz, CDCl3, 25 °C): δ = –76.2 (d, J = 6.9 Hz, 3 F) ppm.
C17H22F3NO (313.36): calcd. C 65.16, H 7.08, N 4.47; found C
65.33, H 7.25, N 4.39.
(4-Methoxyphenyl)[(Z)-1-(trifluoromethyl)-3-(trimethylsilyl)allyl]-
amine (8a): Compound 5a (283 mg, 0.9 mmol) was treated with
BH3·Me2S (2.3 mL, 4.7 mmol) and cyclohexene (950 µL,
9.4 mmol). The crude material was purified on silica gel to give 8a
(101 mg, 35 %) as an orange oil. 1H NMR (200 MHz, CDCl3,
25 °C): δ = 0.11 [s, 9 H, Si(CH3)3], 3.75 (s, 3 H, OCH3), 4.29 (dq,
J = 8.5, 6.8 Hz, 1 H, CHCF3), 5.88 (d, J = 14.2 Hz, 1 H,
CH=CHSi), 6.07 (dd, J = 14.2, 8.5 Hz, 1 H, CH=CHSi), 6.50–6.74
(m, 4 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –0.2
[Si(CH3)3], 55.6 (OCH3), 59.6 (q, J = 30 Hz, CHCF3), 114.8
(CHAr), 116.3 (q, J = 0.8 Hz, CHAr), 125.4 (q, J = 283 Hz, CAr),
(–)-[(R)-2-Methoxy-1-phenylethyl][(R)-3-phenyl-1-(trifluoromethyl)-
prop-2-ynyl]amine (6c): Compound 3 (654 mg, 2.8 mmol) was
treated with phenylacetylene (375 µL, 3.4 mmol) and nBuLi (1.6 ,
2.1 mL, 3.4 mmol). The crude material was purified on silica gel to
give 6c (848 mg, 90%) as white crystals. M.p. 57 °C (Et2O). [α]2D2
–302 (c = 0.65, MeOH). H NMR (200 MHz, CDCl3, 25 °C): δ =
2.54 (d, J = 12.6 Hz, 1 H, NH), 3.41 (s, 3 H, OCH3), 3.47 (d, J =
7.3 Hz, 1 H, OCH2), 3.47 (d, J = 6.3 Hz, 1 H, OCH2), 3.88 (dq, J
=
1
= 12.6, 6.8 Hz, 1 H, CHCF3), 4.34 (t, J = 6.8 Hz, 1 H, CHAr), 138.0 (q, J = 2.0 Hz, CH=CHSi), 138.4 (CH=CHSi), 139.6 (CAr),
7.08–7.78 (m, 10 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 50.9 (q, J = 33 Hz, CHCF3), 58.4 (OCH3), 59.5 (CHAr), 77.2
153.5 (CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.4
(d, J = 6.8 Hz, 3 F) ppm. C14H20F3NOSi (303.37): calcd. C 55.42,
(CH2), 81.7 (C), 86.1 (C), 121.9 (CAr), 123.8 (q, J = 280 Hz, CF3), H 6.64, N 4.62; found C 55.23, H 6.53, N 4.51.
127.9 (CHAr), 128.2 (CHAr), 128.3 (CHAr), 128.7 (CHAr), 128.8
(4-Methoxyphenyl)[(Z)-3-phenyl-1-(trifluoromethyl)allyl]amine (8c):
(CHAr), 132.0 (CHAr), 138.3 (CAr) ppm. 19F NMR (188 MHz,
CDCl3, 25 °C): δ = –75.7 (d, J = 6.8 Hz, 3 F) ppm. C19H18F3NO
(333.34): calcd. C 68.46, H 5.44, N 4.20; found C 68.38, H 5.52, N
4.14.
Compound 5c (263 mg, 0.9 mmol) was treated with BH3·Me2S
(2.2 mL, 4.3 mmol) and cyclohexene (870 µL, 8.6 mmol). The crude
material was purified on silica gel to give 8c (85 mg, 32%) as a
1
yellow oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 3.72 (s, 3 H,
General Procedure for the Hydroboration Reaction: BH3·Me2S (2 
in THF, 5 mmol) was added under argon to cyclohexene (10 mmol)
at 0 °C. The mixture was stirred for 45 min, and then the propar-
gylamine (1 mmol) in THF (7 mL) was added dropwise. After
2.5 h, acetic acid (1 mL) was added to the mixture, and the solution
OCH3), 4.73 (dq, J = 9.8, 6.6 Hz, 1 H, CHCF3), 5.64 (dd, J = 11.3,
9.8 Hz, 1 H, CH=CHPh), 6.41–6.75 (m, 4 H, Ar), 6.88 (d, J =
11.3 Hz, 1 H, CH=CHPh), 7.14–7.39 (m, 5 H, Ph) ppm. 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 55.0 (q, J = 30 Hz, CHCF3), 55.6
(OCH3), 114.8 (CHAr), 115.7 (CHAr), 123.3 (CH=CHPh), 126.1 (q,
was stirred at room temperature for 10 h. The reaction mixture was J = 282 Hz, CF3), 127.9 (CHAr), 128.4 (CHAr), 128.5 (CHAr), 135.5
then successively washed with aqueous solutions of NaCl (10 mL)
and NaHCO3 (10 mL), and extracted with AcOEt (15 mL). The
organic layers were dried with MgSO4 and concentrated under vac-
uum. The crude product was purified on silica gel (petroleum ether/
AcOEt, 90:10) to give the corresponding (Z)-allylamine.
(CAr), 136.1 (CH=CHPh), 139.0 (CAr), 153.3 (CAr) ppm. 19F NMR
(188 MHz, CDCl3, 25 °C): δ = –75.1 (d, J = 6.6 Hz, 3 F) ppm.
C17H16F3NO (307.31): calcd. C 66.44, H 5.25, N 5.56; found C
66.56, H 5.43, N 5.37.
(–)-[(R)-2-Methoxy-1-phenylethyl][(R,Z)-1-(trifluoromethyl)hept-2-
enyl]amine (9b): Compound 6b (211 mg, 0.7 mmol) was treated
Benzyl[(Z)-1-(trifluoromethyl)-3-(trimethylsilyl)allyl]amine (7a):
Compound 4a (248 mg, 0.9 mmol) was treated with BH3·Me2S with BH3·Me2S (1.7 mL, 3.4 mmol) and cyclohexene (680 µL,
(2.2 mL, 4.3 mmol) and cyclohexene (880 µL, 8.7 mmol). The crude
material was purified on silica gel to give 7a (230 mg, 92%) as an
orange oil. H NMR (200 MHz, CDCl3, 25 °C): δ = 0.06 [s, 9 H,
6.7 mmol). The crude material was purified on silica gel to give 9b
1
(182 mg, 86%) as a colorless oil. [α]2D2 = –6 (c = 0.80, MeOH). H
1
NMR (200 MHz, CDCl3, 25 °C): δ = 0.73 (t, J = 7.1 Hz, 3 H,
Si(CH3)3], 3.77 (dq, J = 8.3, 7.0 Hz, 1 H, CHCF3), 3.79 (d, J = CH3), 1.01–1.38 (m, 4 H, 2 CH2), 1.46–1.80 (m, 2 H, CH2CH=),
13.5 Hz, 1 H, CH2Ph), 3.92 (d, J = 13.5 Hz, 1 H, CH2Ph), 5.98 (d, 3.22–3.33 (m, 2 H, CH2CHPh), 3.25 (s, 3 H, OCH3), 3.56 (dq, J =
J = 14.2 Hz, 1 H, CH=CHSi), 6.10 (dd, J = 14.2, 8.3 Hz, 1 H,
9.5, 7.6 Hz, 1 H, CHCF3), 3.86 (dd, J = 8.5, 4.8 Hz, 1 H, CHPh),
5.13 (br. t, J = 10.4 Hz, 1 H, CH=CHCH2), 5.72 (dt, J = 10.9,
CH=CHSi), 7.27–7.35 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
Eur. J. Org. Chem. 2008, 1527–1534
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1531

G. Magueur, B. Crousse, D. Bonnet-Delpon
FULL PAPER
7.4 Hz, 1 H, CH=CHCH2), 7.08–7.38 (m, 5 H, Ar) ppm. 13C NMR 135.7 (CAr), 136.3 (CH=CHPh), 139.1 (CAr) ppm. 19F NMR
(75 MHz, CDCl3, 25 °C): δ = 13.7 (CH3), 22.1 (CH2CH3), 27.3 (188 MHz, CDCl3, 25 °C): δ = –75.3 (t, J = 7.4 Hz, 3 F) ppm.
(CH2), 31.5 (CH2CH=), 53.9 (q, J = 29 Hz, CHCF3), 58.5 (OCH3), C17H16F3N (291.31): calcd. C 70.09, H 5.54, N 4.81; found C 69.97,
58.7 (CHPh), 77.5 (OCH2), 122.4 (CH=CHCH2), 125.5 (q, J =
280 Hz, CF3), 127.8 (CHAr), 128.5 (CHAr), 137.8 (CH=CHCH2),
139.2 (CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.7
(d, J = 7.6 Hz, 3 F) ppm. C17H24F3NO (315.37): calcd. C 64.74, H
7.67, N 4.44; found C 64.49, H 7.92, N 4.32.
H 5.86, N 4.72.
(4-Methoxyphenyl)[(E)-1-(trifluoromethyl)-3-(trimethylsilyl)allyl]-
amine (13a): Compound 5a (68 mg, 0.2 mmol) was treated with Li-
AlH4 (34 mg, 0.9 mmol). The crude material was purified on silica
1
gel to give 13a (60 mg, 88%) as a brown oil. H NMR (200 MHz,
(–)-[(R)-2-Methoxy-1-phenylethyl][(R,Z)-3-phenyl-1-(trifluorometh- CDCl3, 25 °C): δ = 0.09 [s, 9 H, Si(CH3)3], 3.61 (br. d, J = 9.7 Hz,
yl)allyl]amine (9c): Compound 6c (337 mg, 1 mmol) was treated 1 H, NH), 3.75 (s, 3 H, OCH3), 4.24–4.42 (m, 1 H, CHCF3), 6.02
with BH3·Me2S (205 mL, 5 mmol) and cyclohexene (1 mL, (dd, J = 18.7, 4.6 Hz, 1 H, CH=CHSi), 6.21 (d, J = 18.7 Hz, 1 H,
10 mmol). The crude material was purified on silica gel to give 9c
CH=CHSi), 6.60–6.90 (m, 4 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = –1.6 [Si(CH3)3], 55.7 (OCH3), 60.9 (q, J =
(285 mg, 85%) as a yellow solid. M.p. 72 °C. [α]2D2 = –21 (c = 0.24,
MeOH). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 2.2 (s, 1 H, NH), 29 Hz, CHCF3), 114.9 (CHAr), 115.5 (CHAr), 125.3 (q, J = 282 Hz,
3.47–3.52 (m, 2 H, OCH2), 3.51 (s, 3 H, OCH3), 3.9 (dd, J = 8.6,
4.8 Hz, 1 H, NHCH), 4.0 (qd, J = 10.3, 7.5 Hz, 1 H, CHCF3), 5.7
(t, J = 11.0 Hz, 1 H, CH=CHPh), 7.0–7.4 (m, CH=CHPh, 11 H,
2 Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 53.9 (q, J =
29 Hz, CHCF3), 58.5 (OCH3), 58.7 (CHPh), 77.0 (OCH2), 124.2
(CH=CHPh), 125.6 (q, J = 280 Hz, CF3), 127.3, (CAr) 127.4 (CAr),
128.0 (CAr), 128.18 (CAr), 128.2 (CAr), 135.6 (CAr), 135.9
(CH=CHPh), 138.4 (CAr) ppm. 19F NMR (188 MHz, CDCl3,
25 °C): δ = –74.86 (d, J = 7.6 Hz, 3 F) ppm. C19H20F3NO (335.37):
calcd. C 68.05, H 6.01, N 4.18; found C 67.90, H 6.12, N 4.22.
CF3), 136.4 (CH=CHSi), 136.7 (CH=CHSi), 140.0 (CAr), 153.2
(CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.6 (d, J =
7.4 Hz, 3 F) ppm. C14H20F3NOSi (303.40): calcd. C 55.42, H 6.64,
N 4.62; found C 55.61, H 6.31, N 4.32.
(4-Methoxyphenyl)[(E)-1-(trifluoromethyl)hept-2-enyl]amine (13b):
Compound 5b (289 mg, 1.1 mmol) was treated with LiAlH4
(168 mg, 4.3 mmol). The crude material was purified on silica gel
to give 13b (259 mg, 89%) as a brown oil. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.18–1.51 (m, 4
H, 2 CH2), 2.08 (q, J = 6.7 Hz, 2 H, CH2CH=), 3.75 (s, 3 H,
OCH3), 4.26 (q, J = 6.9 Hz, 1 H, CHCF3), 5.44 (dd, J = 15.5,
6.5 Hz, 1 H, CH=CHBu), 5.88 (dt, J = 15.5, 6.7 Hz, 1 H,
CH=CHBu), 6.61–6.82 (m, 4 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 13.6 (CH3), 21.9 (CH2), 30.7 (CH2), 31.8
(CH2CH=), 55.4 (OCH3), 59.3 (q, J = 30 Hz, CHCF3), 114.7
(CHAr), 115.6 (CHAr), 121.8 (CH=CHBu), 125.4 (q, J = 282 Hz,
CF3), 137.6 (CH=CHBu), 139.8 (CAr), 153.1 (CAr) ppm. 19F NMR
(188 MHz, CDCl3, 25 °C): δ = –76.0 (d, J = 7.1 Hz, 3 F) ppm.
C15H20F3NO (287.32): calcd. C 62.70, H 7.02, N 4.87; found C
62.96, H 7.29, N 4.71.
General Procedure for the Hydroalumination Reaction: LiAlH4
(4 mmol) was added in one portion to a solution of the propar-
gylamine (1 mmol) in THF (10 mL) at room temperature. The reac-
tion mixture was immediately heated to reflux in THF (oil bath
preheated) and stirred for 2 h. The solution was cooled to room
temperature, diluted with AcOEt (10 mL) and filtered through Ce-
lite. The solution was washed with an aqueous solution of NH4Cl
(10 mL), dried with MgSO4 and concentrated under vacuum. The
crude product was purified on silica gel (cyclohexane/AcOEt,
90:10) to give the corresponding (E)-allylamine.
Benzyl[(E)-1-(trifluoromethyl)hept-2-enyl]amine (12b): Compound
(4-Methoxyphenyl)[(E)-3-phenyl-1-(trifluoromethyl)allyl]amine
4a (271 mg, 1.0 mmol) was treated with LiAlH4 (153 mg, (13c): Compound 5c (321 mg, 1.0 mmol) was treated with LiAlH4
4.0 mmol). The crude material was purified on silica gel to give 12b
(160 mg, 4.2 mmol). The crude material was purified on silica gel
(257 mg, 94%) as a yellow oil. 1H NMR (200 MHz, CDCl3, 25 °C): to give 13c (291 mg, 90%) as a brown oil. 1H NMR (200 MHz,
δ = 0.91 (t, J = 7.0 Hz, 3 H, CH3), 1.22–1.49 (m, 4 H, 2 CH2), 1.67 CDCl3, 25 °C): δ = 2.1 (br. s, 1 H, NH), 3.72 (s, 3 H, OCH3), 4.48
(br. m, 1 H, NH), 2.11 (q, J = 7.0 Hz, 2 H, CH2CH=), 3.51 (q, J
= 7.6 Hz, 1 H, CHCF3), 3.77 (d, J = 13.5 Hz, 1 H, CH2Ph), 3.91
(d, J = 13.5 Hz, 1 H, CH2Ph), 5.33 (dd, J = 15.5, 7.9 Hz, 1 H,
CH=CHBu), 5.77 (dt, J = 15.5, 6.7 Hz, 1 H, CH=CHBu), 7.21–
7.40 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ =
(m, 1 H, CHCF3), 6.17 (dd, J = 15.9, 6.4 Hz, 1 H, CH=CHPh),
6.66–6.82 (m, 5 H, Ar and CH=CHPh), 7.21–7.41 (m, 5 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 55.2 (OCH3), 59.3
(q, J = 30 Hz, CHCF3), 114.7 (CHAr), 115.5 (CHAr), 120.9
(CH=CHPh), 125.3 (q, J = 282 Hz, CF3), 126.5 (CHAr), 128.2
13.7 (CH3), 22.1 (CH2), 31.0 (CH2), 32.0 (CH2CH=), 50.6 (CHAr), 128.4 (CHAr), 135.2 (CH=CHPh), 135.5 (CAr), 139.7 (CAr),
(CH2Ph), 61.3 (q, J = 29 Hz, CHCF3), 122.4 (CH=CHBu), 125.7 153.1 (CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ = –75.5
(q, J = 281 Hz, CF3), 127.2 (CHAr), 128.1 (CHAr), 128.4 (CHAr), (d, J = 7.1 Hz, 3 F) ppm. C17H16F3NO (307.31): calcd. C 66.44, H
138.6 (q, J = 2.0 Hz, CH=CHBu), 139.4 (CAr) ppm. 19F NMR 5.25, N 4.56; found C 66.53, H 5.05, N 4.19.
(188 MHz, CDCl3, 25 °C): δ = –75.5 (d, J = 7.4 Hz, 3 F) ppm.
(–)-[(R)-2-Methoxy-1-phenylethyl][(E)-1-(trifluoromethyl)-3-(tri-
C15H20F3N (271.32): calcd. C 66.40, H 7.43, N 5.16; found C 66.59,
methylsilyl)allyl]amine (14a): Compound 6a (387 mg, 1.2 mmol)
H 7.15, N 4.83.
was treated with LiAlH4 (177 mg, 4.6 mmol). The crude material
Benzyl[(E)-3-phenyl-1-(trifluoromethyl)allyl]amine (12c): Com-
was purified on silica gel to give 14a (343 mg, 88%) as a brown oil.
pound 4c (289 mg, 1.1 mmol) was treated with LiAlH4 (168 mg, [α]2D2 = –95 (c = 0.63, MeOH). 1H NMR (200 MHz, CDCl3, 25 °C):
4.3 mmol). The crude material was purified on silica gel to give 12c
(262 mg, 90%) as a brown oil. 1H NMR (200 MHz, CDCl3, 25 °C):
δ = 3.69 (q, J = 7.4 Hz, 1 H, CHCF3), 3.80 (d, J = 13.3 Hz, 1 H,
CH2Ph), 3.93 (d, J = 13.3 Hz, 1 H, CH2Ph), 6.04 (dd, J = 16.0,
7.0 Hz, 1 H, CH=CHPh), 6.63 (d, J = 16.0 Hz, 1 H, CH=CHPh),
7.19–7.44 (m, 10 H, 2 Ar) ppm. 13H NMR (75 MHz, CDCl3,
25 °C): δ = 50.6 (CH2Ph), 61.3 (q, J = 29 Hz, CHCF3), 121.6
δ = 0.00 [s, 9 H, Si(CH3)3], 2.07 (br. s, 1 H, NH), 3.20 (qd, J = 7.8,
5.8 Hz, 1 H, CHCF3), 3.24 (s, 3 H, OCH3), 3.29 (d, J = 5.4 Hz, 1
H, CH2CH), 3.30 (d, J = 8.0 Hz, 1 H, CH2CH), 3.83 (dd, J = 8.0,
5.4 Hz, 1 H, CHCH2), 5.67 (dd, J = 18.5, 5.8 Hz, 1 H, CH=CHSi),
5.80 (d, J = 18.5 Hz, 1 H, CH=CHSi), 7.10–7.29 (m, 5 H, Ar)
ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –1.6 [Si(CH3)3], 58.3
(OCH3), 58.6 (CHPh), 61.6 (q, J = 29 Hz, CHCF3), 77.5 (OCH2),
(CH=CHPh), 125.6 (q, J = 282 Hz, CF3), 126.6 (CHAr), 127.2 125.3 (q, J = 280 Hz, CF3), 127.8 (CHAr), 128.5 (CHAr), 136.9
(CHAr), 128.0 (CHAr), 128.3 (CHAr), 128.4 (CHAr), 128.6 (CHAr), (CH=CHSi), 137.8 (CH=CHSi), 139.1 (CAr) ppm. 19F NMR
1532
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1527–1534

Stereoselectively Substituted [(E)-or (Z)-1-(Trifluoromethyl)allyl]amines
(188 MHz, CDCl3, 25 °C): δ = –75.4 (d, J = 7.8 Hz, 3 F) ppm.
C16H24F3NOSi (331.45): calcd. C 57.98, H 7.30, N 4.23; found C
58.14, H 7.43, N 3.97.
6.67–6.87 (m, 4 H, Ar) ppm. 19F NMR (188 MHz, CDCl3, 25 °C):
δ = –127.1 (dd, J = 279, 56 Hz, 1 F), –125.1 (dd, J = 279, 56 Hz,
1 F) ppm.
(–)-[(R)-2-Methoxy-1-phenylethyl][(E)-3-phenyl-1-(trifluoromethyl)-
allyl]amine (14c): Compound 6c (300 mg, 0.89 mmol) was treated
with LiAlH4 (129 mg, 3.4 mmol). The crude material was purified
on silica gel to give 14c (272 mg, 90%) as a yellow oil. [α]2D2 = –200
(c = 0.4, MeOH). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 3.37 (s,
3 H, OCH3), 3.41 (d, J = 6.5 Hz, 2 H, OCH2), 3.5 (m, 1 H,
CHCF3), 4.0 (t, J = 6.7 Hz, 1 H, CHPh), 6.0 (dd, J = 16.0, 8.5 Hz,
1 H, CH=CHPh), 6.47 (d, J = 16.0 Hz, 1 H, CH=CHPh), 7.28–
7.45 (m, 10 H, 2 Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ
= 58.6 (OCH3), 58.7 (CHPh), 59.4 (q, J = 29 Hz, CHCF3), 77.4
(OCH2), 121.35 (CH=CHPh), 126.7 (CAr), 127.8 (CAr), 127.9 (CAr),
128.3 (CAr), 128.6 (CAr), 128.7 (CAr), 135.7 (CAr), 136.2
(CH=CHPh), 139.0 (CAr) ppm; CF3 signal not observed. 19F NMR
(188 MHz, CDCl3, 25 °C): δ = –75.4 (d, J = 7.6 Hz, 3 F) ppm.
C19H20F3NO (336.22): calcd. C 68.05, H 6.01, N 4.18; found C
68.21, H 5.95, N 4.11.
General Procedure for the Deprotection of the Chiral Auxiliary
(–)-[(E,R)-3-Phenyl-1-(trifluoromethyl)allyl]amine Hydrochloride
(17c): Boron tribromide (1.5 mL, 1  in CH2Cl2, 1.5 mmol) was
added dropwise to a solution of 14c (160 mg, 0.5 mmol) in dry
CH2Cl2 (6 mL) at –20 °C under argon. After stirring at –20 °C for
45 min, the reaction was quenched with a saturated aqueous solu-
tion of NaHCO3 (10 mL) and the mixture extracted with ethyl ace-
tate (3ϫ10 mL). The combined organic layers were washed with
brine, dried with anhydrous MgSO4, filtered and concentrated un-
der reduced pressure to give a clean crude product of the corre-
sponding alcohol (160 mg, 96%) which was used directly in the
next reaction. Pb(OAc)4 (310 mg, 0.7 mmol) was added to a solu-
tion of the alcohol (160 mg, 0.5 mmol) in a 2:1 mixture of MeOH/
CH2Cl2 (10 mL) at 0 °C. After 30 min of stirring at 0 °C, the reac-
tion mixture was poured into an aqueous buffer solution (pH = 7,
10 mL) at room temperature and then filtered through Celite. The
aqueous layer was extracted with dichloromethane (4ϫ10 mL),
and the combined organic extracts were dried with Na2SO4, filtered
and concentrated under reduced pressure. HCl (3 , 5 mL) was
then added. After 24 h at room temperature, the reaction mixture
was extracted with diethyl ether (3 ϫ5 mL), and the combined
aqueous extracts were concentrated under reduced pressure to af-
ford (R)-allylamine 17c. The hydrochloride was dissolved in propyl-
ene oxide (10 mL) and stirred at room temperature for 1 h. The
crude mixture was concentrated under reduced pressure, and pure
17c (94 mg, 80%) was obtained after recrystallization in methanol/
diethyl ether. [α]2D5 = –50 (c = 0.2, MeOH). 1H NMR (200 MHz,
CD3OH, 25 °C): δ = 4.95 (quint, 1 H, CHCF3), 5.5 (br. s, 3 H,
NH3), 6.2 (dd, J = 8.8, 15.8 Hz, 1 H, CH=CHPh), 7.14 (d, J =
15.8 Hz, 1 H, CH=CHPh), 7.4 (m, 3 H, Ar), 7.54 (m, 2 H, Ar)
ppm. 13H NMR (75 MHz, CD3OD, 25 °C): δ = 55.8 (q, J = 33 Hz,
CHCF3), 115.0 (CH=CHPh), 124.8 (q, J = 280 Hz, CF3), 128.3
(CHAr), 130.0 (CHAr), 130.7 (CHAr), 135.9 (CAr), 143.1
(CH=CHPh) ppm. 19F NMR (188 MHz, CD3OD, 25 °C): δ =
–75.5 (d, J = 6.7 Hz, 3 F) ppm. C10H11ClF3N (237.65): calcd. C
50.75, H 4.26, N 5.92; found C 50.62, H 4.10, N 6.14.
[(E)-2-Deuterio-1-(trifluoromethyl)-3-(trimethylsilyl)allyl](4-meth-
oxyphenyl)amine (15-H): Compound 5a (126 mg, 0.4 mmol) was
treated with LiAlD4 (70 mg, 1.7 mmol). Once the starting material
had been consumed (GC), a part of the solution was hydrolyzed
1
with H2O to give 15-H. H NMR (200 MHz, CDCl3, 25 °C): δ =
0.09 [s, 9 H, Si(CH3)3], 3.58 (br. d, J = 8.0 Hz, 1 H, NH), 3.75 (s,
3 H, OCH3), 4.33 (q, J = 7.6 Hz, 1 H, CHCF3), 6.18 (s, 1 H,
CD=CHSi), 6.60–6.90 (m, 4 H, Ar) ppm. 19F NMR (188 MHz,
CDCl3, 25 °C): δ = –75.6 (d, J = 7.4 Hz, 3 F) ppm.
[(E)-2,3-Dideuterio-1-(trifluoromethyl)-3-(trimethylsilyl)allyl](4-
methoxyphenyl)amine (15-D): Compound 5a (126 mg, 0.4 mmol)
was treated with LiAlD4 (70 mg, 1.7 mmol). Once the starting ma-
terial had been consumed (GC), a part of the solution was hy-
drolyzed with D2O to give 15-D. 1H NMR (200 MHz, CDCl3,
25 °C): δ = 0.09 [s, 9 H, Si(CH3)3], 3.61 (br. d, J = 8.9 Hz, 1 H,
NH), 3.75 (s, 3 H, OCH3), 4.33 (q, J = 7.6 Hz, 1 H, CHCF3), 6.60–
6.90 (m, 4 H, Ar) ppm. 19F NMR (188 MHz, CDCl3, 25 °C): δ =
–75.6 (d, J = 7.4 Hz, 3 F) ppm.
[1-(Difluoromethyl)-3-(trimethylsilyl)prop-2-ynyl](4-methoxyphen-
yl)amine (11a): LiAlH4 (67 mg, 1.8 mmol) was added in one por-
tion to a solution of propargylamine 5a (133 mg, 0.4 mmol) in
THF (5 mL) at room temperature. After stirring at this temperature
for 1 h, the reaction was quenched with an aqueous solution of
NH4Cl (10 mL), the mixture extracted with AcOEt (10 mL), dried
with MgSO4 and concentrated under vacuum. The crude product
was purified on silica gel (cyclohexane/AcOEt, 95:5) to give 11a
(+)-[(R,Z)-3-Phenyl-1-(trifluoromethyl)allyl]amine Hydrochloride
(18c): Boron tribromide (1.35 mL, 1  in CH2Cl2, 1.34 mmol) was
added dropwise to a solution of 9c (150 mg, 0.45 mmol) in dry
CH2Cl2 (6 mL) at –20 °C under argon. After stirring at –20 °C for
45 min, the reaction was quenched with a saturated aqueous
solution of NaHCO3 (10 mL) and extracted with ethyl acetate
(3ϫ10 mL). The combined organic layers were washed with brine,
dried with anhydrous MgSO4, filtered and concentrated under re-
duced pressure to give a clean crude product of the corresponding
alcohol (154 mg) which was used directly in the next reaction.
Pb(OAc)4 (300 mg, 0.67 mmol) was added to a solution of the
alcohol (154 mg, 0.48 mmol) in a 2:1 mixture of MeOH/CH2Cl2
(10 mL) at 0 °C. After 30 min of stirring at 0 °C, the reaction mix-
ture was poured into an aqueous buffer solution (pH = 7, 10 mL)
at room temperature and then filtered through Celite. The aqueous
1
(110 mg, 88%). H NMR (200 MHz, CDCl3, 25 °C): δ = 0.17 [s, 9
H, Si(CH3)3], 3.76 (s, 3 H, OCH3), 4.34 (ddd, J = 13.0, 10.0, 3.0 Hz,
1 H, HF2CCH), 5.85 (td, J = 55.0, 3.0 Hz, 1 H, CF2H), 6.69–6.87
(m, 4 H, Ar) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = –0.39
[Si(CH3)3], 51.4 (t, J = 25 Hz, CHCF2H), 55.5 (OCH3), 91.6 (C),
98.5 (C), 113.8 (t, J = 248 Hz, CF2H), 114.7 (CHAr), 116.7 (CHAr),
139.3 (CAr), 153.8 (CAr) ppm. 19F NMR (188 MHz, CDCl3, 25 °C):
δ = –126.9 (ddd, J = 278, 55, 13 Hz, 1 F), –124.9 (ddd, J = 278,
55, 10 Hz, 1 F) ppm.
[1-Deuterio-1-(difluoromethyl)-3-(trimethylsilyl)prop-2-ynyl](4-meth- layer was extracted with dichloromethane (4 ϫ 10 mL), and the
oxyphenyl)amine (16): According to the previous procedure, 5a combined organic extracts were dried with Na2SO4, filtered and
(191 mg, 0.6 mmol) in THF (6 mL) was treated with LiAlD4 concentrated under reduced pressure. HCl (3 , 5 mL) was then
(27 mg, 0.6 mmol) at room temperature. After 2 h at this tempera-
ture, in a part of the mixture the reaction was quenched with H2O
and in the rest with D2O. In both cases, compound 16 was ob-
tained. 1H NMR (200 MHz, CDCl3, 25 °C): δ = 0.16 [s, 9 H,
added. After 24 h at room temperature, the reaction mixture was
extracted with diethyl ether (3ϫ5 mL), and the combined aqueous
extracts were concentrated under reduced pressure to afford (R)-
allylamine 18c. The hydrochloride was dissolved in propylene oxide
Si(CH3)3], 3.76 (s, 3 H, OCH3), 5.84 (t, J = 56 Hz, 1 H, CF2H), (10 mL) and stirred at room temperature for 1 h. The crude mixture
Eur. J. Org. Chem. 2008, 1527–1534
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1533

G. Magueur, B. Crousse, D. Bonnet-Delpon
FULL PAPER
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was concentrated under reduced pressure and pure 18c (116 mg,
77%) was obtained after recrystallization in methanol/ether. [α]2D5
= +20 (c = 0.1, MeOH). H NMR (200 MHz, CD3OD, 25 °C): δ
1
= 4.8–5.1 (m, 4 H, NH3, CHCF3), 5.75 (t, J = 11.0 Hz, 1 H,
CH=CHPh), 7.28 (d, J = 11.0 Hz, 1 H, CH=CHPh), 7.34–7.50 (m,
5 H, Ar) ppm. 13C NMR (75 MHz, CD3OD, 25 °C): δ = 51.3 (q,
J = 33 Hz, CHCF3), 117.3 (CH=CHPh), 124.8 (q, J = 280 Hz,
CF3), 129.4 (CHAr), 130.0 (CHAr), 130.1 (CAr), 135.5 (CAr), 143.1
(CH=CHPh) ppm. 19F NMR (188 MHz, CD3OD, 25 °C): δ =
–75.4 (d, J = 6.7 Hz, 3 F) ppm. C10H11ClF3N (237.65): calcd. C
50.75, H 4.26, N 5.92; found C 50.94, H 4.35, N 6.03.
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Received: November 19, 2007
Published Online: February 5, 2008
1534
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1527–1534