A one-pot synthesis of doubly unsaturated trifluoromethyl amines: Easy access to CF3-substituted piperidines

Article abstract of DOI:10.1002/ejoc.200400719

A straightforward route to trifluoromethyl analogs of piperidines is described. These syntheses involve a Barbier-type allylation reaction of trifluoroacetaldimines, followed by N-allylation (one-pot), and ring-closing metathesis. An efficient asymmetric

Full text of DOI:10.1002/ejoc.200400719

FULL PAPER
A One-Pot Synthesis of Doubly Unsaturated Trifluoromethyl Amines:
Easy Access to CF3-Substituted Piperidines
Guillaume Magueur,[a] Julien Legros,[a] Franck Meyer,[a] Michèle Ourévitch,[a]
Benoit Crousse,[a] and Danièle Bonnet-Delpon*[a]
Keywords: Allylation / Cyclization / Fluoral / Nitrogen heterocycles / Trifluoromethyl group
A straightforward route to trifluoromethyl analogs of piperi-
dines is described. These syntheses involve a Barbier-type
allylation reaction of trifluoroacetaldimines, followed by N-
allylation (one-pot), and ring-closing metathesis. An efficient
asymmetric version is also reported (Ͼ98% de). Function-
alized heterobicyclic compounds can also be obtained by a
Pauson–Khand reaction.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Piperidines are an important class of compounds, and Barbier-type allylation of trifluoromethyl aldimines 1 and
this heterocycle pattern is found in many therapeutic 2, respectively (Scheme 1).[10,11] This reaction proceeds (75–
agents.[1] In this frame, the introduction of novel substitu- 97% yields) under mild conditions (at room temperature in
ents on these heterocycles has been the focus of many in- DMF, or at reflux in THF) with allyl bromides as reaction
vestigations.[2] Among them, trifluoromethyl groups can partners and activated zinc (Zn*) as promoter.[12] Moreover,
greatly modify the biological properties of the target mole- starting from the enantiopure aldimine 3, the correspond-
cule.[3] The building-block strategy is a general approach ing homoallylamines 4–6 were obtained with high de (up to
to trifluoromethylated target compounds. Thus, aldimines 98%).[13] We also found that the propargylation reaction
derived from fluoral[4] in cycloaddition reactions have been was successful under the same conditions (4d, 5d).[14] Con-
shown to be a rich source of nitrogen heterocycles bearing sequently, this approach allows the synthesis of a great di-
a CF3 group, especially β-lactams,[5] aziridines,[6] quinolines, versity of substituted homoallyl (and homopropargyl)
and piperidinones.[7] An alternative route to the piperidine amines.
pattern involves ring-closing metathesis (RCM)[8] of doubly
In order to access to doubly unsaturated amines, we
unsaturated amines. Recently, Billard and Langlois have
successfully applied RCM to the preparation of nonchiral,
CF3-substituted piperidines.[9] However, a limitation of the
methodology stemmed from the protection/deprotection
steps required to access the substrates. In this context, a
fast and general methodology to give the starting doubly
unsaturated trifluoromethylamines would be highly desir-
able. Along these lines, we report here our investigations on
a simple, one-pot methodology leading to doubly unsatu-
rated trifluoromethylated amines, and their subsequent cyc-
lization in RCM and Pauson–Khand reactions. The asym-
metric synthesis of a nonracemic CF3-containing piperidine
(Ͼ98% de) is also described.
studied the N-allylation reaction of homoallylamines 4a–d
and 5a. Previous examples of N-allylation of α-trifluorome-
thylamines concerned only substrates with the nitrogen
atom activated by an acyl group.[9] Nevertheless, the direct
N-allylation of 4a–d and 5a was investigated under simple
conditions: NaHCO3 and allyl bromides, in refluxing aceto-
nitrile, in the presence of a catalytic amount of KI (Table 1).
Despite the fact that very long reaction times were required
(3–5 days), very good yields of the expected products 7, 9,
and 10 (79–80%) were obtained. The reaction was less ef-
ficient with the bulkier amine 4b, yielding 42% of 8, and
even less so with aromatic amine 5a (30% conversion after
10 days). In this latter case, replacing the previous base by
NaH and performing the reaction overnight in DMF
(100 °C) provided the corresponding product 11 in good
yield (83%).
Results and Discussion
In a previous communication we disclosed the efficient
synthesis of homoallyl trifluoromethylamines 4 and 5 by
According to the mechanism of the Barbier-type reac-
tion, a zinc amide should be the primary product of the
Barbier allylation of aldimines. Such a species should exhi-
bit a pronounced nucleophilic character. The N-allylation
was thus attempted in situ (Table 2). This one-pot, Zn-me-
diated C-allylation/N-allylation sequence was performed
[a] Laboratoire BioCIS associé au CNRS, Centre d’Etudes Pharma-
ceutiques
Rue J.-B. Clément, 92296 Châtenay-Malabry, France
Fax: +33-1-4683-5740
E-mail: daniele.bonnet-delpon@cep.u-psud.fr
1258
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400719
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Doubly Unsaturated Trifluoromethyl Amines
FULL PAPER
Scheme 1. Allylation and propargylation reaction of CF3-containing aldimines 1–3.
Table 1. Synthesis of doubly unsaturated amines 7–11.
allyl bromide and 1.5 equiv. of zinc, then the second allyl
bromide (4 equiv.) was added to the mixture and the reac-
tion was heated at reflux. With both methallyl bromide/allyl
bromide (entry 2) and allyl bromide/propargyl bromide (en-
try 3), the corresponding amines 9 and 12 were obtained,
after five hours, in good yields (63% and 65%, respec-
tively). However, with other pairs of allyl bromides (en-
tries 4–8) the reaction times were longer (12–18 h) and de-
composition of both starting materials and expected ad-
ducts occurred, leading to a mixture of products. Neverthe-
less, we found that the reaction could be easily improved by
simple addition of copper iodide (20 mol-%): the reaction
times were shorter (1–3 h) and the corresponding amines
were obtained in moderate to good yields (56–86%). To our
delight, the reaction also gave good results with the chiral
aldimine 3. In this case, 1.5 equivalents of CuI was required,
and the reaction had to be stopped before the total conver-
sion of the homoallylamine intermediate in order to avoid
complete decomposition of the product 16. Nevertheless, 16
was obtained in 54% yield and with an excellent 98% de
(entry 9).
This process exhibits significant advantages over pre-
vious examples since various doubly unsaturated CF3-con-
taining amines can be prepared in a one-pot procedure and
isolated in good yields (54–86% over 2 steps). Moreover,
the reaction can be performed with commercially available
allyl partners, which makes it suitable for larger scale prepa-
ration.
The products of the bis-allylation reaction 7–16 were
[a] Measured by GC analyses. [b] Yield of isolated product. [c] Re-
action performed with NaH in DMF (100 °C).
then subjected to
a ring-closing metathesis reaction
(Table 3).
with aldimines 1–3 in DMF. In a preliminary experiment,
In the presence of Grubbs catalyst(5–10 mol-%), the allyl
the aldimine 1 was treated at room temperature in the pres- homoallyl adducts easily reacted, at room temperature, to
ence of activated Zn (1.3 equiv.) with an excess of allyl bro- afford the expected CF3-containing dehydropiperidine de-
mide (5 equiv.), and the reaction medium was heated to re- rivatives in excellent yields (Ͼ89% in most cases). However,
flux. Under these conditions, the allyl homoallylamine 7 with the N-methallylamines 13 and 14, the reaction re-
was obtained in 70% yield (entry 1). Interestingly, this pro- quired solvent reflux and longer reaction times to proceed
cedure also allowed the introduction of two different allyl (entries 4 and 6). The diastereo-enriched substrate 16
substituents (entries 2–5, 7, and 8). The first step was per- underwent the cyclization reaction to yield the correspond-
formed at room temperature in DMF with 1.4 equiv. of ing dihydropiperidine derivative 24 (98% yield, 98% de).
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G. Magueur, J. Legros, F. Meyer, M. Ourévitch, B. Crousse, D. Bonnet-Delpon
FULL PAPER
Table 2. One-pot synthesis of doubly unsaturated amines 7–16.[a]
Table 3. Cyclization of 7–16 by ring-closing metathesis.
[a] Catalyst was added in three portions over the time indicated.
[b] Reaction performed at reflux. [c] de Ͼ 98%.
[a] Reactions performed on a 2 mmol scale. [b] 20 mol-% of CuI.
[c] 1.5 equiv. of CuI. [d] 30% of homoallylamine 6c was recovered.
[e] 98% de.
The enynes 10 and 12 can also be considered as good
substrates for a Pauson–Khand reaction.[15] Under classical
The RCM was also studied with enynes as substrates, under stoichiometric conditions [Co2(CO)8, followed by the ad-
similar conditions. Unfortunately, the homopropargyl al- dition of N-methylmorpholine oxide], both substrates 10
lylamine 10 did not undergo cyclization, and starting mate- and 12 reacted very well, and in a similar fashion. The bicy-
rial was recovered unchanged (entry 8). Heating the reac- clic products 25 and 26 resulting from the formal [2+2+1]
tion to reflux or use of a second-generation Grubbs cata- cycloaddition were obtained in 68% (85:15 ratio of trans/
lyst, also failed to give satisfactory results. Surprisingly, its cis stereoisomers) and in 80% yield (18:82 ratio of trans/cis
isomer, the homoallyl propargylamine 12, provided the pi- stereoisomers), respectively (Scheme 2).[16] This transforma-
peridine 21 quantitatively (95% yield), leading to a dienic tion allows access to new, functionalized heterobicyclic
molecule (entry 9).
molecules bearing a CF3 group.
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Doubly Unsaturated Trifluoromethyl Amines
FULL PAPER
Scheme 2. Syntheses of CF3-containing heterobicyclic compounds 25 and 26 by a Pauson–Khand reaction.
cooled to 0 °C, then coarse zinc powder (467 mg, 7.16 mmol) was
added, followed by 2 drops of TMSCl. The reaction was then
slowly warmed to room temperature. After 45 min (the reaction
Conclusions
In summary, we have set up a simple and straightforward
route to various trifluoromethyl-containing nitrogen hetero- was monitored by GC), the mixture was cooled to 0 °C and hy-
drolyzed with a saturated aqueous solution of NH4Cl (20 mL),
then extracted with Et2O (3×20 mL). The organic layer was
washed with brine (30 mL), dried with MgSO4, filtered, and the
solvents were evaporated. The residue was then purified by flash
chromatography over silica gel (petroleum ether/AcOEt, 9:1) to af-
ford compound 5d as a colorless liquid (1.06 g, 79%).1H NMR: δ
= 2.1 (t, J = 2.6 Hz, 1 H), 2.6 (ddd, J = 17.0, 6.4, 2.6 Hz, 1 H),
2.8 (ddd, J = 17.0, 5.2, 2.8 Hz, 1 H), 3.7 (s, 3 H), 3.9 (m, 1 H), 6.7
(d, J = 9.2 Hz, 2 H), 6.8 (d, J = 9.2 Hz, 2 H) ppm; NH not ob-
cycles by ring-closing metathesis and Pauson–Khand reac-
tions, including an asymmetric version (98% de). One of the
strong features of this synthesis is the simple preparation of
the substrates (doubly unsaturated trifluoromethylamines)
by an original C-allylation/N-allylation one-pot procedure
starting from easily accessible materials (CF3-containing
aldimines and allyl bromides).
3
served. 13C NMR: δ = 19.6 (q, JC,F = 2.5 Hz, CF3CHCH2), 55.4,
2
Experimental Section
55.9 (q, JC,F = 29 Hz, CF3CH), 71.7, 77.9, 114.8, 116.0, 125.5 (q,
1JC,F = 283 Hz, CF3), 139.9, 153.5 ppm. 19F NMR: δ = –69.5 (d,
JH,F = 8.7 Hz, CF3) ppm. C12H22F3NO (243.23): calcd. C 59.26,
H 4.97, N 5.76; found C 58.95, H 4.81, N 5.52.
General Remarks: All reactions were performed in oven-dried glass-
1
ware under an inert atmosphere of argon. H, 13C, and 19F NMR
spectra were recorded in CDCl3 on a 200 or a 400 MHz multinu-
clear spectrometer. 19F NMR spectra are referenced to external
General Procedure for the N-Allylation Reaction. Synthesis of Com-
pounds 7–11: The allyl bromide (3 mmol), NaHCO3 (5 mmol), and
KI (0.1 mmol) were added to a solution of homoallylic or homo-
propargylic amine 4/5 (1 mmol) in MeCN (3 mL), and the reaction
mixture was heated at reflux (the reaction was monitored by GC).
The mixture was then cooled to room temperature, brine was added
(10 mL), and the mixture extracted with Et2O (3×10 mL). The
combined organic phases were dried with MgSO4, and the solvents
evaporated. The crude product was purified over silica gel (petro-
leum ether) to afford di-ω-unsaturated amine.
1
CFCl3, and H and 13C NMR spectra to TMS. In all NMR mea-
surements CDCl3 was used as a solvent. Elemental analyses were
performed by the Service de Microanalyses at the Faculté de Phar-
macie, Châtenay-Malabry. Diastereomeric ratios and dia-
stereomeric excesses were determined by 19F NMR spectroscopy
and GC analysis.
Synthesis of Benzyl[1-(trifluoromethyl)but-3-ynyl]amine (4d):[17] The
imine
1 (1.03 g, 5.5 mmol) and propargyl bromide (1.06 g,
7.16 mmol) were dissolved in DMF (10 mL). The solution was
cooled to 0 °C, then coarse zinc powder[18] (467 mg, 7.16 mmol)
was added, followed by 2 drops of TMSCl. The reaction mixture
was then slowly warmed to room temperature. After 45 min (the
reaction was monitored by GC) the medium was cooled to 0 °C
and hydrolyzed with a saturated aqueous solution of NH4Cl
(20 mL), then extracted with Et2O (3×20 mL). The combined or-
ganic layers were washed with brine (30 mL), dried with MgSO4,
filtered, and the solvents were evaporated. The residue was purified
by flash chromatography over silica gel (petroleum ether/AcOEt,
9:1) to afford compound 4d as a colorless liquid (944 mg, 76%).
1H NMR: δ = 2.0 (br. s, 1 H), 2.3 (t, J = 2.6 Hz, 1 H), 2.7 (ddd, J
= 17.0, 7.6, 2.6 Hz, 1 H), 2.9 (ddd, J = 17.0, 4.8, 2.8 Hz, 1 H), 3.5
(m, 1 H), 4.2 (d, J = 13.0 Hz, 1 H), 4.3 (d, J = 13.0 Hz, 1 H), 7.4–
N-Allyl-N-benzyl[1-(trifluoromethyl)but-3-enyl]amine (7): Amine 4a
(229 mg, 1 mmol), allyl bromide (363 mg, 3 mmol), NaHCO3
(420 mg, 5 mmol), and KI (17 mg, 0.1 mmol) in MeCN (3 mL)
were heated at reflux for 3 d. After purification, compound 7 was
obtained as a colorless liquid (215 mg, 80%). 1H NMR: δ = 2.6
(m, 2 H), 3.5 (m, 3 H), 3.9 (d, J = 14.0 Hz, 1 H), 4.2 (d, J =
14.0 Hz, 1 H), 5.3 (m, 4 H), 5.9 (m, 2 H), 7.3–7.5 (m, 5 H) ppm.
3
2
13C NMR: δ = 30.9 (q, JC,F = 1.6 Hz), 53.1, 53.8, 59.3 (q, JC,F
=
1
25.0 Hz), 117.2, 117.6, 127.0, 127.6 (q, JC,F = 291.0 Hz, CF3),
128.2, 128.7, 134.5, 136.3, 139.3 ppm. 19F NMR: δ = –69.5 (d, JH,F
= 8.7 Hz, CF3) ppm. C15H18F3N (269.31): calcd. C 66.90, H 6.74,
N 5.20; found C 67.06, H 6.82, N 5.32.
N-Allyl-N-benzyl[2,2-dimethyl-1-(trifluoromethyl)but-3-enyl]amine
(8): Amine 4b (257 mg, 1 mmol), allyl bromide (363 mg, 3 mmol),
NaHCO3 (420 mg, 5 mmol), and KI (17 mg, 0.1 mmol) in MeCN
(3 mL) were heated at reflux for 5.5 d. After purification, com-
pound 8 was obtained as a colorless liquid (124 mg, 42%). 1H
NMR: δ = 1.1 (m, 6 H), 3.1 (m, 2 H), 3.5 (q, JH,F = 8.0 Hz, 1 H),
3.7 (dq, J = 14, 1.5 Hz, 1 H), 4.1 (m, 1 H), 4.9 (dd, J = 15.2, 1.3 Hz,
2 H), 5.2 (dd, J = 15, 8 Hz, 2 H), 5.9 (m, 2 H), 7.2–7.4 (m, 5 H)
3
7.6 (m, 5 H) ppm. 13C NMR: δ = 19.3 (q, JC,F = 3.2 Hz,
CF3CHCH2), 51.9, 57.1 (q, 2JC,F = 28.0, CF3CH), 71.2, 78.6, 126.0
1
(q, JC,F = 284.0 Hz, CF3), 127.3, 128.2, 128.4, 139.2 ppm. 19F
NMR: δ = –75.1 (d, JH,F = 7.0 Hz, CF3) ppm. C12H12F3N (227.23):
calcd. C 63.43, H 5.32, N 6.16; found C 63.80, H 5.52, N 6.01.
Synthesis of 4-Methoxyphenyl[1-(trifluoromethyl)but-3-ynyl]amine
(5d): The imine 2 (1.12 g, 5.5 mmol) and propargyl bromide (1.06 g,
7.16 mmol) were dissolved in DMF (10 mL). The solution was
2
ppm. 13C NMR: δ = 25.7, 26.1, 29.6, 40.3, 66.7 (q, JC,F = 22 Hz),
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1
112.2, 117.6, 125.2, 128.1, 128.4 (q, JC,F = 294 Hz), 136.6,
amine (9): Methallyl bromide (378 mg, 0.25 mL, 2.8 mmol), coarse
144.4 ppm. 19F NMR: δ = –59.5 (d, JH,F = 8.0 Hz, CF3) ppm. zinc powder (195 mg, 3 mmol), and two drops of TMSCl were
C17H22F3N (297.37): calcd. C 68.67, H 7.46, N 4.71; found C 68.80,
H 7.54, N 4.88.
added to a solution of imine 1 (374 mg, 2 mmol) in DMF (3 mL).
After 1 h, allyl bromide (968 mg, 8 mmol) was added. The mixture
was then refluxed for 5 h, the solution was hydrolyzed with a satu-
rated aqueous solution of NH4Cl (30 mL), and extracted with Et2O
(3×20 mL). The combined organic layers were dried with MgSO4,
the solvents were evaporated, and the residue was purified by
chromatography over silica gel (petroleum ether/CH2Cl2, 3:1) to
afford amine 9 as a colorless liquid (356 mg, 63%).
N-Allyl-N-benzyl[3-methyl-1-(trifluoromethyl)but-3-enyl]amine (9):
Amine 4c (243 mg, 1 mmol), allyl bromide (363 mg, 3 mmol),
NaHCO3 (420 mg, 5 mmol), and KI (17 mg, 0.1 mmol) in MeCN
(3 mL) were heated at reflux for 3.5 d. After purification, com-
pound 9 was obtained as a colorless liquid (226 mg, 80%). 1H
NMR:δ = 1.7 (s, 3 H), 2.4 (dd, J = 14.5, 4.8 Hz, 1 H), 2.6 (dd, J
= 14.5, 10 Hz, 1 H), 3.4 (m, 3 H), 3.7 (d, J = 14.0 Hz, 1 H), 4.1
(d, J = 14.0 Hz, 1 H), 4.85 (s, 1 H), 4.94 (s, 1 H), 5.20 (dq, J =
10.0, 1.3 Hz, 1 H), 5.24 (dq, J = 14.0, 1.3 Hz, 1 H), 5.7 (m, 1 H),
7.2–7.5 (m, 5 H) ppm. 13C NMR: δ = 21.5, 34.9 (q, 3JC,F = 1.6 Hz),
N-Allyl-N-benzyl[2,2-dimethyl-1-(trifluomethyl)but-3-enyl]amine
(8): From imine 1 (374 mg, 2 mmol), dimethylallyl bromide
(417 mg, 2.8 mmol), allyl bromide (968 mg, 8 mmol), and CuI
(76 mg, 0.4 mmol), 8 was obtained as a brown oil (338 mg, 57%).
2
53.0, 53.8, 57.3 (q, JC,F = 25 Hz), 114.1, 117.7, 127.1, 127.8 (q,
N-Allyl-N-(4-methoxyphenyl)[1-(trifluoromethyl)but-3-enyl]amine
(11): From imine 2 (406 mg, 2 mmol), allyl bromide (1.3 g,
10.8 mmol), and CuI (76 mg, 0.4 mmol), 11 was obtained as a
brown oil (347 mg, 61%).
1JC,F = 291 Hz), 128.2, 128.8, 136.5, 139.4, 141.0 ppm. 19F NMR:
δ = –69.1 (d, JH,F = 8.3 Hz, CF3) ppm. C16H20F3N (283.34): calcd.
C 67.83, H 7.11, N 4.94; found C 68.05, H 7.20, N 5.02.
N-Allyl-N-benzyl[1-(trifluoromethyl)but-3-ynyl]amine (10): Amine
4d (227 mg, 1 mmol), allyl bromide (363 mg, 3 mmol), NaHCO3
(420 mg, 5 mmol), and KI (17 mg, 0.1 mmol) in MeCN (3 mL)
were heated at reflux for 4.5 d. After purification, compound 10
was obtained as a colorless liquid (211 mg, 79%). 1H NMR: δ =
1.9 (t, J = 2.6 Hz, 1 H), 2.38 (ddd, J = 17.3, 5.4, 2.6 Hz, 1 H),2.5
(dd, J = 17.3, 2.6 Hz, 1 H), 3.2 (m, 2 H), 3.4 (m, 1 H), 3.6 (d, J =
13.8 Hz, 1 H), 3.8 (d, J = 13.8 Hz, 1 H), 5.0 (dq, J = 10.0, 1.5 Hz,
1 H), 5.05 (dq, J = 14.0, 1.5 Hz, 1 H), 5.6 (m, 1 H), 7.0–7.3 (m, 5
N-Benzyl-N-prop-2-ynyl[1-(trifluoromethyl)but-3-enyl]amine (12):
From imine 1 (374 mg, 2 mmol), allyl bromide (339 mg, 2.8 mmol),
and propargyl bromide (952 mg, 8 mmol), 12 was obtained as a
1
brown oil (347 mg, 65%). H NMR:δ = 2.2 (t, J = 2.4 Hz, 1 H),
2.4 (m, 1 H), 3.4 (d, J = 2 Hz, 2 H), 3.5 (m, 1 H), 3.7 (d, J =
13.6 Hz, 1 H), 4.0 (d, J = 13.6 Hz, 1 H), 5.1 (m, 2 H), 5.8 (m, 1
H), 7.1–7.3 (m, 5 H) ppm. 13C NMR: δ = 30.7 (q, J = 1.7 Hz), 39.7
2
(q, J = 1.4 Hz), 53.6 (q, J = 1.2 Hz), 61 (q, JC,F = 26 Hz), 72.5,
1
117.5, 127.1 (q, JC,F = 289 Hz), 127.3, 128.4, 128.6, 134.2, 138.2
3
H) ppm. 13C NMR: δ = 16.8 (q, JC,F = 2.2 Hz), 53.4, 53.9, 58.6
(q, J = 0.6 Hz) ppm. 19F NMR: δ = –70.2 (d, J = 8.1 Hz, CF3)
ppm. C15H16F3N (267.30): calcd. C 67.40, H 6.03, N 5.24; found
C 67.55, H 6.10, N 5.32.
2
1
(q, JC,F = 26 Hz), 70.6, 80.0, 117.9, 126.5 (q, JC,F = 289 Hz),
127.1, 128.2, 128.6, 136.1, 139.0 ppm. 19F NMR: δ = –71.0 (d, JH,F
= 7.9 Hz, CF3) ppm. C15H16F3N (267.30): calcd. C 67.40, H 6.03,
N 5.24; found C 67.62, H 6.11, N 5.33.
N-Benzyl-N-(2-methylallyl)[1-(trifluoromethyl)but-3-enyl]amine
(13): From imine 1 (374 mg, 2 mmol), allyl bromide (339 mg,
2.8 mmol), methallyl bromide (1.08 g, 8 mmol), and CuI (76 mg,
0.4 mmol), 13 was obtained as a brown oil (317 mg, 56 %). 1H
NMR: δ = 1.9 (s, 3 H), 2.6 (m, 2 H), 3.4 (s, 2 H), 3.5 (m, 1 H), 3.9
(d, J = 14.0 Hz, 1 H), 4.1 (d, J = 14.0 Hz, 1 H), 4.8 (m, 1 H), 4.9
(m, 1 H), 5.02 (d, J = 8.8 Hz, 1 H), 5.04 (d, J = 17.0 Hz, 1 H), 6.0
(m, 1 H), 7.4–7.5 (m, 5 H) ppm. 13C NMR: δ = 20.3, 30.8, 54.0,
N-Allyl-N-(4-methoxyphenyl)[1-(trifluoromethyl)but-3-enyl]amine
(11): NaH 60% (245 mg, 6.12 mmol) was slowly added to a solu-
tion of allyl bromide (987 mg, 8.16 mmol) and amine 5a (500 mg,
2.05 mmol) in DMF (2 mL), under an argon atmosphere, at 0 °C
in a sealed tube. The reaction was then heated to 100 °C. After
17 h, the solution was cooled to 0 °C, hydrolyzed with a saturated
aq. NH4Cl solution (30 mL), and extracted with Et2O (3×30 mL).
The combined organic phases were dried (MgSO4) and the solvents
evaporated. The crude product was purified over silica gel (petro-
leum ether/AcOEt, 70:30) to afford compound 11 as a brown oil
2
1
56.7, 58.6 (q, JC,F = 25 Hz), 114.3, 117.3, 127.1, 127.5 (q, JC,F
=
291 Hz), 128.3, 129.0, 134.7, 139.0, 142.9 ppm. 19F NMR: δ = –
68.8 (d, J = 8.5 Hz, CF3) ppm. C16H20F3N (283.34): calcd. C 67.83,
H, 7.11, N 4.94; found C 67.76, H 7.17, N 4.85.
1
(487 mg, 83%). H NMR: δ = 2.5 (m, 2 H), 3.7 (s, 3 H), 3.9 (d, J
= 5.4 Hz, 2 H), 4.1 (m, 1 H), 5.1 (m, 4 H), 5.8 (m, 2 H), 6.9 (m, 4
N-(4-Methoxyphenyl)-N-(2-methylallyl)[1-(trifluoromethyl)but-3-en-
yl]amine (14): From imine 2 (406 mg, 2 mmol), allyl bromide
(339 mg, 2.8 mmol), methallyl bromide (1.08 g, 8 mmol), and CuI
(76 mg, 0.4 mmol), 14 was obtained as a brown oil (335 mg, 56%).
1H NMR:δ = 1.7 (s, 3 H), 2.6 (m, 2 H), 3.76 (s, 3 H), 3.83 (s, 2 H),
4.1 (m, 1 H), 4.8 (m, 1 H), 4.9 (m, 1 H), 5.1 (dq, J = 9.2, 1.4 Hz,
1 H), 5.2 (dq, J = 17.1, 1.5 Hz, 1 H), 5.8 (m, 1 H), 6.8 (d, J =
9.4 Hz, 2 H), 6.9 (d, J = 9.4 Hz, 2 H) ppm. 13C NMR: δ = 20.0,
2
H) ppm. 13C NMR: δ = 34.6, 48.2, 55.3, 62.7 (q, JC,F = 30 Hz),
1
114.2, 116.6, 118.0, 119.2, 126.4 (q, JC,F = 290 Hz), 133.3, 135.5,
143.9, 153.5 ppm. 19F NMR: δ = –72.1 (d, JH,F = 7.9 Hz, CF3)
ppm. C15H18F3NO (285.30): calcd. C 63.15, H 6.36, N 4.91; found
C 64.03, H, 6.21, N 4.95.
One-Pot Double Allylation Reaction. Synthesis of N-Allyl-N-ben-
zyl[1-(trifluoromethyl)but-3-enyl]amine (7): Allyl bromide (1.3 g,
10.8 mmol), coarse zinc powder (196 mg, 3.0 mmol), and two drops
of TMSCl were addedto a solution of imine 1 (374 mg, 2 mmol) in
DMF (4 mL). After 1 h at room temperature, the mixture was re-
fluxed for 3 h, then treated with a saturated aq. NH4Cl solu-
tion(30 mL) and extracted with Et2O (3×10 mL). The combined
organic layers were washed with brine (20 mL), dried with MgSO4,
filtered, and the solvents were evaporated. The residue was purified
by chromatography over silica gel (petroleum ether/CH2Cl2, 8:2) to
afford the amine 7 as a colorless liquid (377 mg, 70%).
2
31.4, 51.8, 55.3, 64.0 (q, JC,F = 27 Hz), 112.8, 114.1, 118.1, 120.1,
1
126.5 (q, JC,F = 288 Hz), 133.7, 141.7, 142.6, 153.9 ppm. 19F
NMR: δ = –71.7 (d, J = 7.6 Hz, CF3) ppm. C16H20F3NO (299.33):
calcd. C 64.20, H 6.73, N 4.68; found C 64.17, H 6.88, N 4.57.
N-Allyl-N-(4-methoxyphenyl)[3-methyl-1-(trifluoromethyl)but-3-en-
yl]amine (15): From imine 2 (406 mg, 2 mmol), methallyl bromide
(378 mg, 2.8 mmol), allyl bromide (968 mg, 8 mmol), and CuI
(76 mg, 0.4 mmol), 15 was obtained as a brown oil (514 mg, 86%).
1H NMR: δ = 1.6 (s, 3 H), 2.3 (dd, J = 15.2, 4.1 Hz, 1 H), 2.6 (dd,
J = 15.2, 10.4 Hz, 1 H), 3.7 (s, 3 H), 3.9 (m, 2 H), 4.2 (dqd, J =
10.4, 8.0, 4.1 Hz, 1 H), 4.7 (m, 1 H), 4.8 (m, 1 H), 5.0 (d, J =
Typical Procedure for the One-Pot Double Allylation Reaction. Syn-
thesis of N-Allyl-N-benzyl[3-methyl-1-(trifluoromethyl)but-3-enyl]-
1262
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1258–1265

Doubly Unsaturated Trifluoromethyl Amines
FULL PAPER
10.2 Hz, 1 H), 5.1 (d, J = 17.3 Hz, 1 H), 5.7 (m, 1 H), 6.8 (m, 4 H) 17.8 Hz, 1 H), 2.4 (d, J = 17.8 Hz, 1 H), 2.9 (d, J = 15.9 Hz, 1 H),
ppm. 13C NMR: δ = 21.9, 34.9, 47.9, 55.1, 61.0 (q, 2JC,F = 27.0 Hz), 3.1 (d, J = 15.9 Hz, 1 H), 3.3 (qt, J = 9.1, 2.3 Hz, 1 H), 3.8 (dq, J
1
114.0, 114.2, 116.4, 118.6, 126.7 (q, JC,F = 288 Hz), 135.6, 140.3,
142.3, 153.3 ppm. 19F NMR: δ = –72.2 (d, J = 8.0 Hz, CF3) ppm.
C16H20F3NO (299.33): calcd. C 64.20, H 6.73, N 4.68; found C
63.98, H 6.91, N 4.52.
= 13.6, 1.6 Hz, 1 H), 3.9 (d, J = 13.6 Hz, 1 H), 5.3 (s, 1 H), 7.1–
2
7.3 (m, 5 H) ppm. 13C NMR: δ = 20.6, 24.1, 51.4, 55.9 (q, JC,F
=
25.0 Hz), 58.9, 115.8, 127.2, 127.8 (q, 1JC,F = 292 Hz), 128.4, 128.5,
132.1, 138.8 ppm. 19F NMR: δ = –68.5 (d, J = 9.0 Hz, CF3) ppm.
C14H16F3N (255.29): calcd. C 65.87, H 6.32, N 5.49; found C 65.80,
H 6.66, N 5.41.
(–)-N-Allyl-N-(2-methoxy-1-phenylethyl)[1-(trifluoromethyl)but-3-en-
yl]amine (16): From imine 3 (462 mg, 2 mmol), allyl bromide (1.3 g,
10.8 mmol), and CuI (571 mg, 3 mmol), 16 was obtained as a
brown oil (338 mg, 54%). [α]2D5 = –32.4 (c = 1.02 in MeOH). 1H
NMR: δ = 2.1 (m, 2 H) 3.2 (s, 3 H), 3.3 (m, 3 H), 3.6 (d, J =
6.4 Hz, 2 H), 4.1 (t, J = 6.4 Hz, 1 H), 4.80 (d, J = 16.7 Hz, 1 H),
4.83 (d, J = 10.3 Hz, 1 H), 5.0 (d, J = 10.0 Hz, 1 H), 5.1 (d, J =
17.0 Hz, 1 H), 5.4 (ddt, J = 17.0, 10.3, 6.9 Hz, 1 H), 5.7 (ddt, J =
16.8, 10.0, 6.2 Hz, 1 H), 7.2 (m, 5 H) ppm. 13C NMR: δ = 31.5,
50.2, 58.7, 59.1 (q, J = 27.0 Hz), 61.7, 73.8, 116.8, 117.0, 127.1 (q,
J = 287.0 Hz), 127.4, 128.3, 128.4, 134.4, 137.3, 139.7 ppm. 19F
NMR: δ = –71.7 (d, J = 8.3 Hz, CF3) ppm. C17H22F3NO (313.36):
calcd. C 65.16, H 7.08, N 4.47; found C 65.22, H 7.09, N 4.21.
1-Benzyl-2-trifluoromethyl-5-vinyl-1,2,3,6-tetrahydropyridine (21):
Starting from 12 (267 mg, 1 mmol) and the Grubbs catalyst (44 mg,
10 mol-%), compound 21 was obtained as a clear, brown liquid
1
(253 mg, 95%). H NMR: δ = 2.3 (d, J = 19.0 Hz, 1 H), 2.6 (d, J
= 19.0 Hz, 1 H), 3.3 (dq, J = 9.0, 2.2 Hz, 1 H), 3.8 (d, J = 13.6 Hz,
1 H), 4.0 (d, J = 13.6 Hz, 1 H), 4.83 (d, J = 17.6 Hz, 1 H), 4.84 (d,
J = 11.0 Hz, 1 H), 5.7 (s, 1 H), 6.2 (dd, J = 17.6, 11.0 Hz, 1 H),
7.4–7.5 (m, 5 H) ppm. 13C NMR: δ = 24.5 (q, 3JC,F = 2.0 Hz), 46.5
3
2
(q, JC,F = 0.6 Hz), 56.0 (q, JC,F = 25.8 Hz), 59.1, 110.8, 123.1,
127.3, 127.6 (q, 1JC,F = 292 Hz), 128.4, 128.5, 134.2 (q, J = 0.7 Hz),
136.9, 138.5 (q, J = 0.5 Hz) ppm. 19F NMR: δ = –68.8 (d, J =
9.0 Hz, CF3) ppm. C15H16F3N (267.29): calcd. C 67.40, H 6.03, N
5.23; found C 67.38, H 6.02, N 5.32.
General Procedure for the Ring-Closing Metathesis. Synthesis of
Compounds 17–24: Di-ω-dienes 7–16 and the Grubbs catalyst (5–
10 mol-%) were dissolved in CH2Cl2 under an argon atmosphere.
After 2–48 h (monitored by GC), the solvent was evaporated and
the crude mixture was purified over silica gel (petroleum ether/Ac-
OEt, 9:1) to afford 17–24.
1-(4-Methoxyphenyl)-2-trifluoromethyl-1,2,3,6-tetrahydropyridine
(22): Starting from 11 (57 mg, 0.45 mmol) and the Grubbs catalyst
(18 mg, 5 mol-%), compound 22 was obtained as a clear, brown
liquid (104 mg, 90%). 1H NMR: δ = 2.3 (m, 2 H), 2.6 (m, 2 H),
3.7 (s, 3 H), 4.3 (quint, J = 9.0 Hz, 1 H), 5.8 (s, 2 H), 6.8 (m, 4 H)
1-Benzyl-2-trifluoromethyl-1,2,3,6-tetrahydropyridine (17): Starting
from 7 (121 mg, 0.45 mmol) and the Grubbs catalyst (18 mg, 5 mol-
%), compound 17 was obtained as a clear, brown liquid (103 mg,
95%). 1H NMR: δ = 2.2 (m, 1 H), 2.5 (m, 1 H), 3.1 (d, J = 16 Hz,
1 H), 3.3 (d, J = 16 Hz, 1 H), 3.4 (m, 1 H), 3.7 (d, J = 14 Hz, 1
H), 3.9 (d, J = 14 Hz, 1 H), 5.7 (d, J = 2.0 Hz, 2 H), 7.2–7.4 (m, 5
2
ppm. 13C NMR: δ = 24.0, 44.2, 54.4 (q, JC,F = 30.0 Hz), 55.4,
1
114.5, 116.7, 121.1, 124.4, 126.7 (q, JC,F = 290 Hz), 143.5,
153.2 ppm. 19F NMR: δ = –70.8 (d, JH,F = 8.5 Hz, CF3) ppm.
C13H14F3NO (257.29): calcd. C 60.70, H 5.49, N 5.44; found C
60.59, H 5.51, N 5.45.
1-(4-Methoxyphenyl)-5-methyl-2-trifluoromethyl-1,2,3,6-tetrahydro-
pyridine (23): Starting from 14 (136 mg, 0.45 mmol) and the
Grubbs catalyst (21 mg, 7 mol-%), compound 23 was obtained as
H) ppm. 13C NMR: δ = 24.2 (q, JC,F = 2.0 Hz), 44.1, 56.1 (q,
3
2JC,F = 26 Hz), 59.1, 121.5, 125.1, 125.3 (q, 1JC,F = 293 Hz), 127.1,
128.3, 128.4, 138.7 ppm. 19F NMR: δ = –68.6 (d, JH,F = 9.0 Hz,
CF3) ppm. C13H14F3N (241.26): calcd. C 64.72, H 5.85, N 5.81;
found C 64.99, H, 5.78, N 5.88.
1
a brown liquid (47 mg, 41%). H NMR: δ = 1.8 (s, 3 H), 2.4 (d, J
= 17.9 Hz, 1 H), 2.7 (d, J = 17.9 Hz, 1 H), 3.5 (d, J = 16.9 Hz, 1
H), 3.7 (d, J = 16.9 Hz, 1 H), 3.8 (s, 3 H), 4.4 (q, J = 8.3 Hz, 1 H),
5.5 (m, 1 H), 6.8–6.9 (m, 4 H) ppm. 13C NMR: δ = 20.6, 24.1 (q,
1-Benzyl-3,3-dimethyl-2-trifluoromethyl-1,2,3,6-tetrahydropyridine
(18): Starting from 8 (134 mg, 0.45 mmol) and the Grubbs catalyst
(18 mg, 5 mol-%), compound 18 was obtained as a clear, brown
2
3JC,F = 1.6 Hz), 48.3, 54.1 (q, JC,F = 27.0 Hz), 55.5, 114.6, 115.7,
1
116.9, 126.9 (q, JC,F = 292 Hz), 131.4, 143.4, 153.3 ppm. 19F
1
liquid (116 mg, 96%). H NMR: δ = 1.1–1.3 (m, 6 H), 3.0 (q, J =
NMR: δ = –70.8 (d, J = 8.3 Hz, CF3) ppm. C14H16F3NO (271.28):
calcd. C 61.98, H 5.94, N, 5.16; found C 61.82, H 6.06, N 5.04.
9.0 Hz, 1 H), 3.2 (m, 2 H), 4.0 (m, 2 H), 5.4 (m, 1 H), 5.6 (td, J =
3.1, 10 Hz, 1 H), 7.3–7.4 (m, 5 H) ppm. 13C NMR: δ = 24.8, 31.4,
(–)-1-(2-Methoxy-1-phenylethyl)-2-trifluoromethyl-1,2,3,6-tetrahy-
dropyridine (24): Starting from 16 (258 mg, 0.82 mmol) and the
Grubbs catalyst (56 mg, 7 mol-%), compound 24 was obtained as
a brown liquid (214 mg, 98%). [α]2D5–26.4 (c = 0.265 in MeOH). 1H
NMR: δ = 2.1 (d, J = 18.0 Hz, 1 H), 2.5 (d, J = 18.0 Hz, 1 H), 3.0
(d, J = 17.6 Hz, 1 H), 3.1 (d, J = 17.6 Hz, 1 H), 3.2 (s, 3 H), 3.62
(d, J = 5.7 Hz, 1 H), 3.63 (d, J = 4.4 Hz, 1 H), 3.7 (m, 1 H), 4.0
(t, J = 5.2 Hz, 1 H), 5.5–5.7 (m, 2 H), 7.2–7.4 (m, 5 H) ppm. 13C
2
1
46.3, 60.4, 66.7 (q, JC,F = 23 Hz), 122.3, 127.1, 128.0 (q, JC,F
=
297 Hz), 128.2, 128.5, 133.1, 139.0 ppm. 19F NMR: δ = –62.2 (d,
JH,F = 9.0 Hz, CF3) ppm. C15H18F3N (269.31): calcd. C 66.90, H
6.74, N 5.20; found C 66.58, H, 6.69, N 5.31.
1-Benzyl-4-methyl-2-trifluoromethyl-1,2,3,6-tetrahydropyridine (19):
Starting from diene 9 (127 mg, 0.45 mmol) and the Grubbs catalyst
(18 mg, 5 mol-%), compound 19 was obtained as a clear, brown
1
2
liquid (107 mg, 93%). H NMR: δ = 1.4 (s, 3 H), 2.0 (m, 1 H), 2.4
NMR: δ = 24.1, 44.8, 53.8 (q, JC,F = 27.0 Hz), 58.8, 66.0, 75.0,
1
(m, 1 H), 3.1 (m, 2 H), 3.5 (m, 1 H), 3.9 (qd, J = 14.0, 1.6 Hz, 1
H), 4.0 (d, J = 14.0 Hz, 1 H), 5.4 (m, 1 H), 7.2–7.4 (m, 5 H) ppm.
121.7, 125.5, 127.4, 127.9 (q, JC,F = 292 Hz), 127.9, 128.3, 141.0
ppm. 19F NMR: δ = –69.6 (d, J = 9.0 Hz, CF3) ppm. C15H18F3NO
(285.30): calcd. C 63.15, H 6.36, N 4.91; found C 63.26, H 6.52, N
4.98.
13C NMR: δ = 22.7, 28.6 (q, JC,F = 2.0 Hz), 47.3, 56.7 (q, JC,F
=
3
2
26.0 Hz), 58.7, 119.9, 127.1, 127.7 (q, 1JC,F = 292 Hz), 128.3, 128.4,
128.9, 138.7 ppm. 19F NMR (CDCl3): δ = –68.8 (d, JH,F = 9.0 Hz,
CF3) ppm. C14H16F3N (255.29): calcd. C 65.87, H 6.32, N 5.49;
found C 65.06, H 6.25, N 5.58.
Synthesis of 2-Benzyl-3-trifluoromethyl-1,2,3,6,7,7a-hexahydro-
[2]pyrindin-6-one (25): Co2(CO)8 (261 mg, 0.76 mmol) was added to
a solution of 10 (170 mg, 0.64 mmol) in CH2Cl2 (4 mL) under an
1-Benzyl-5-methyl-2-trifluoromethyl-1,2,3,6-tetrahydropyridine (20): argon atmosphere. After disappearance of the starting material
Starting from 13 (160 mg, 0.6 mmol) and the Grubbs catalyst
(44 mg, 20 mol-%), compound 20 was obtained as a clear, brown
liquid (128 mg, 89 %). 1H NMR: δ = 1.5 (s, 3 H), 2.1 (d, J =
(0.5 h; monitored by TLC), the reaction mixture was cooled to
0 °C, and N-methylmorpholine N-oxide monohydrate (774 mg,
5.7 mmol) was added in several portions over 15 min. The reaction
Eur. J. Org. Chem. 2005, 1258–1265
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Magueur, J. Legros, F. Meyer, M. Ourévitch, B. Crousse, D. Bonnet-Delpon
FULL PAPER
mixture was then allowed to warm to room temp. After 3 h (moni-
tored by TLC), the mixture was filtered through silica gel. The
solvent was then evaporated and the crude product was purified by
chromatography over silica gel (petroleum ether/AcOEt, 1.5:1) to
afford compound 25 (109 mg, 58% of trans and 19 mg, 10% of cis)
as yellow oils.
1 H, CH2Bn), 5.94 [m, 1 H, C(7)-H], 7.2–7.4 (m, 5 H, Ar) ppm.
13C NMR: δ = 29.5 [C(4)], 38.0 [C(4a)], 41.5 [C(5)], 50.5 [C(1)],
54.7 (CH2Ph), 60.5 [C(3)], 125.5 [q, JC,F = 290 Hz, C(9)], 128.45
[C(7)], 128.5 (×3, Ar), 137.0 (Ph), 176.5 [C(8)], 207.5 [C(6)] ppm.
19F NMR: δ = –70.1 (d, J = 8.2 Hz, CF3) ppm. C16H16F3NO
(295.31): calcd. C 65.08, H 5.46, N 4.74; found C 65.10, H 5.47, N
1
trans-25 (major): 1H NMR: δ = 1.96 [dd, J = 19.0, 2.5 Hz, 1 H, 4.68.
C(7)-H], 2.47 [dd, J = 19.0, 6.4 Hz, 1 H, C(7)-H], 2.71 [tq, J = 11.0,
2.4 Hz, 1 H, C(1)-H], 2.84 [ddd, J = 15.0, 7.0, 0.4 Hz, 1 H, C(4)-
Acknowledgments
H], 2.98 [m, 1 H, C(7a)-H], 3.04 [d, J = 15 Hz, 1 H, C(4)-H], 3.12
[dd, J = 11.0, 6.6 Hz, 1 H, C(1)-H], 3.64 [m, 1 H, C(3)-H], 3.93
(dq, J = 14.0, 1.7 Hz, 1 H, CH2Ph), 4.07 (d, J = 14 Hz, 1 H,
CH2Ph), 6.01 [m, 1 H, C(5)-H], 7.2–7.4 (m, 5 H, Ph) ppm. 13C
The authors thank Central Glass Co., Ltd., for a kind gift of fluo-
ral, DSM Co. for the donation of (R)-phenylglycine, and Rhodia
Chimie for financial support. Serge Ratton and Jean-Marc Paris
(Rhodia Chimie) are acknowledged for fruitful discussions. S. Mai-
resse-Lebrun is thanked for elemental analyses.
3
NMR: δ = 28.6 [q, JC,F = 2.0 Hz, C(4)], 38.7 C(7), 38.8 C(7a),
2
52.2 C(1), 58.8 [q, JC,F = 26 Hz, C(2)], 59.3 (CH2Ph), 127.2 (q,
1JC,F = 293 Hz), 127.5 (Ph), 128.1 (Ph), 128.7 (Ph), 138.3 (Ph),
177.0 (C=CH), 207.2 (CO) ppm. 19F NMR: δ = –65.9, (d, J =
8.6 Hz, CF3) ppm. C16H16F3NO (295.31): calcd. C 65.08, H 5.46,
N 4.74; found C 65.22, H 5.52, N 4.79.
[1] P. S. Watson, B. Jiang, B. Scott, Org. Lett. 2000, 2, 3679–3681,
and references cited therein.
[2] For a review, see: P. M. Weintraub, J. S. Sabol, J. M. Kane,
D. R. Borcherding, Tetrahedron 2003, 59, 2953–2989.
[3] a) J.-P. Bégué, D. Bonnet-Delpon, Chimie Bioorganique et
Médicinale du Fluor, Edisciences-CNRS Publishers, in press; b)
Organofluorine Compounds in Medicinal Chemistry and Bio-
chemical Applications (Eds.: R. Filler, Y. Kobayashi, L. Yagu-
polskii), Elsevier, Amsterdam, 1993; c) Biomedical Frontiers of
Fluorine Chemistry (Eds.: I. Ojima, J. R. McCarthy, J. T.
Welch), ACS, Washington, 1996; d) P. N. Edwards, in Organ-
ofluorine Chemistry: Principles and Commercial Applications
(Eds.: R. E. Banks, J. C. Tatlow), Plenum Press, New York,
1994, p. 501.
cis-25 (minor): 1H NMR: δ = 1.84 [dd, J = 18.7, 2.4 Hz, 1 H, C(7)-
H], 1.96 [t, J = 12 Hz, 1 H, C(1)-H], 2.46 [dd, J = 18.7, 6.6 Hz, 1
H, C(7)-H], 2.77 [m, 1 H, C(4)-H], 2.95 [m, 1 H, C(7a)-H], 3.07
[m, 1 H, C(4)-H], 3.24 [m, 1 H, C(3)-H], 3.25 [m, 1 H, C(1)-H],
3.54 (d, J = 13.5 Hz, 1 H, CH2Ph), 4.16 (d, J = 13.5 Hz, 1 H,
CH2Ph), 6.00 [s, 1 H, C(5)-H], 7.2–7.4 (m, 5 H, Ar) ppm. 13C
NMR: δ = 28.5 [q, 3J = 2.0 Hz, C(4)], 38.1 [C(7)], 38.2 [C(7a)], 55.0
2
(CH2Ph), 56.5 [C(1)], 62.8 [q, JC,F = 26 Hz, C(2)], 128.5 (×2, Ph),
1
129.2 (×2, Ph), 129.3 [q, JC,F = 293 Hz, C(9)), 138.3 (Ph), 178.0
[C(8)], 208.0 [C(6)] ppm. 19F NMR: δ = –69.2, (d, J = 7.3 Hz, CF3)
ppm. C16H16F3NO (295.31): calcd. C 65.08, H 5.46, N 4.74; found
C 65.11, H 5.47, N 4.77.
[4] For a review, see: J.-P. Bégué, D. Bonnet-Delpon, B. Crousse,
J. Legros, manuscript submitted.
[5] a) A. Abouabdellah, J.-P. Bégué, D. Bonnet-Delpon, Synlett
1996, 399–400; b) A. Abouabdellah, J.-P. Bégué, D. Bonnet-
Delpon, T. T. T. Nga, J. Org. Chem. 1997, 62, 8826–8833.
[6] B. Crousse, S. Narizuka, D. Bonnet-Delpon, J.-P. Bégué, Syn-
lett 2001, 679–681.
[7] a) B. Crousse, J.-P. Bégué, D. Bonnet-Delpon, Tetrahedron Lett.
1998, 39, 5765–5768; b) B. Crousse, J.-P. Bégué, D. Bonnet-
Delpon, J. Org. Chem. 2000, 65, 5009–5013.
Synthesis of 2-Benzyl-3-trifluoromethyl-1,2,3,4,4a,5-hexahydro-
[2]pyrindin-6-one (26): Co2(CO)8 (261 mg, 0.76 mmol) was added to
a solution of 12 (170 mg, 0.64 mmol) in CH2Cl2 (4 mL) under an
argon atmosphere. After disappearance of the starting material
(0.5 h; monitored by TLC), the reaction mixture was cooled to
0 °C, and N-methylmorpholine N-oxide monohydrate (774 mg,
5.7 mmol) was added in several portions over 15 min. The reaction
mixture was then allowed to warm to room temp. After 3 h (moni-
tored by TLC), the mixture was filtered through silica gel. The
solvent was then evaporated and the crude product was purified by
chromatography over silica gel (petroleum ether/AcOEt, 1.5:1) to
afford compound 26 (193 mg, 65.6% of cis and 42 mg, 14.4% of
trans) as yellow oils.
[8] For reviews on RCM, see: a) S. K. Armstrong, J. Chem. Soc.,
Perkin Trans. 1 1998, 371–388; b) A. Fürstner, Angew. Chem.
2000, 112, 3140–3172; Angew. Chem. Int. Ed. 2000, 39, 3012–
3043; c) T. M. Trnka, R. H. Grubbs, Acc. Chem. Res. 2001, 34,
18–29; d) F.-X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003,
3693–3712; e) A. Deiters, S. F. Martin, Chem. Rev. 2004, 104,
2199–2238.
cis-26 (major): 1H NMR: δ = 1.74 [td, J = 13.6, 5.7 Hz, 1 H, C(4)- [9] S. Gille, A. Ferry, T. Billard, B. R. Langlois, J. Org. Chem.
2003, 68, 8932–8935.
H], 2.04 [dd, J = 18.7, 2.6 Hz, 1 H, C(5)-H], 2.42 [ddd, J = 12.6,
6.0, 4.6 Hz, 1 H, C(4)-H], 2.67 [dd, J = 18.6, 6.4 Hz, 1 H, C(5)-H],
3.13 [d, J = 13.0 Hz, 1 H, C(4a)-H], 3.45 [qdd, J = 9.5, 5.7, 1.4 Hz,
1 H, C(3)-H], 3.65 [d, J = 14.2 Hz, 1 H, C(1)-H], 3.80 [d, J =
14.2 Hz, 1 H, C(1)-H], 3.88 (d, J = 13.8 Hz, 1 H, CH2Ph), 4.04 (d,
J = 13.8 Hz, 1 H, CH2Ph), 5.9 [m, 1 H, C(7)-H], 7.2–7.4 (m, 5 H,
Ph) ppm. 13C NMR: δ = 30.5 [C(4)], 36.0 [C(4a)], 42.0 [C(5)], 48.0
[10] a) J. Legros, F. Meyer, M. Coliboeuf, B. Crousse, D. Bonnet-
Delpon, J.-P.Bégué, J. Org. Chem. 2003, 68, 6444–6446. See
also: b) D. Bonnet-Delpon, J.-P. Bégué, J. Legros, B. Crousse,
F. Meyer (Rhodia Chimie, Fr.) PCT Int. Appl., 2003, WO
2003095415.
[11] For a review of the allylation reaction of fluoral and its deriva-
tives, see: D. Bonnet-Delpon, J.-P. Bégué, B. Crousse, in Fluori-
nated Synthons (Ed.: V. Soloshonok), Oxford University Press,
accepted for publication.
2
1
[C(1)], 57.5 [q, JC,F = 26 Hz, C(3)], 59.0 (CH2Ph), 125.4 [q, JC,F
= 293 Hz, C(9)], 128.3 [C(7)], 128.5 (×3, Ph), 137.5 (Ph), 175.3
[C(8)], 207.5 [C(6)] ppm. 19F NMR: δ = –65.2 (d, J = 9.5 Hz, CF3)
ppm. C16H16F3NO (295.31): calcd. C 65.08, H 5.46, N 4.74; found
C 65.20, H 5.50, N 4.69.
[12] Magnesium and indium are also efficient promoters in some
cases; see ref.[10]
[13] Diastereoselective allylation of trifluoromethyl aldimines has
also been described with allyltin derivatives as allyl donors and
SAMP or RAMP as chiral auxiliaries: K. Funabiki, M. Naga-
mori, M. Matsui, D. Enders, Synthesis 2002, 2585–2588.
[14] Homopropargylamine was accompanied by traces of allenyl
product.
1
trans-26 (minor): H NMR: δ = 1.70 [td, J = 12.7, 10.1 Hz, 1 H,
C(4)-H], 2.13 [dd, J = 18.6, 2.1 Hz, 1 H, C(5)-H], 2.44 [dt, J = 13.0,
5.8 Hz, 1 H, C(4)-H], 2.69 [dd, J = 18.6, 6.6 Hz, 1 H, C(5)-H], 3.03
[m, 1 H, C(4a)-H], 3.47 [d, J = 16.4 Hz, 1 H, C(1)-H], 3.65 [dqd,
J = 10.1, 8.2, 5.1 Hz, 1 H, C(3)-H], 3.76 (d, J = 13.4 Hz, 1 H,
CH2Bn), 3.80 [d, J = 16.4 Hz, 1 H, C(1)-H], 3.89 (d, J = 13.4 Hz,
[15] a) I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts, M. I.
Foreman, J. Chem. Soc., Perkin Trans. 1 1973, 977–981; b) For
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1258–1265

Doubly Unsaturated Trifluoromethyl Amines
FULL PAPER
a review, see: K. M. Brummond, J. L. Kent, Tetrahedron 2000,
56, 3263–3283.
TMSCl, no reaction occurred. As an alternative, zinc dust
could be activated by aq. HCl prior to the reaction. However,
the results obtained by this latter procedure are not always re-
producible.
[16] The configurations of 25 and 26 were attributed according to
homo- and hetero-nOe data.
[17] For the description of homoallylamines, see ref.[10a]
[18] It is imperative to use zinc as coarse powder. Parallel experi-
ments showed that when using zinc dust in combination with
Received October 11, 2004
Eur. J. Org. Chem. 2005, 1258–1265
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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