Direct access to CF3-propargyl amines and conversion to difluoromethyl imines

Article abstract of DOI:10.1016/j.tetlet.2005.02.030

Trifluoromethyl aldimines reacted with acetylides in toluene at -78°C to provide propargyl amines in good yields. From a chiral trifluoromethyl aldimine, the propargyl amines were obtained with excellent diastereoselectivities (de >98%). Trifluoromethyl p

Full text of DOI:10.1016/j.tetlet.2005.02.030

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2219–2221
Direct access to CF3-propargyl amines and
conversion to difluoromethyl imines
*
Guillaume Magueur, Benoit Crousse and Daniele Bonnet-Delpon
`
´ ´ ˆ
BioCIS-CNRS, Faculte de Pharmacie-Paris Sud, rue J. B. Clement, F-92296 Chatenay-Malabry, France
Received 7 January 2005; revised 31 January 2005; accepted 4 February 2005
Abstract—Trifluoromethyl aldimines reacted with acetylides in toluene at ꢀ78 ꢀC to provide propargyl amines in good yields. From
a chiral trifluoromethyl aldimine, the propargyl amines were obtained with excellent diastereoselectivities (de >98%). Trifluoro-
methyl propargyl amines could be further converted into difluoromethyl imines under basic conditions.
ꢁ 2005 Elsevier Ltd. All rights reserved.
Propargyl alcohols and propargyl amines can serve as
important building blocks for organic synthesis.1 While
propargyl alcohols can be prepared through a variety of
transformations, reliable methods that provide direct ac-
cess to propargyl amines are far fewer. Classical carban-
ion addition to N-alkyl aldimines prescribes the use of
Lewis acidic additives for activating the aldimine sub-
strate. By contrast, reactions of activated aldimines pro-
ceed without necessary additional activation.1
acetylene (1.2 equiv), generated in situ with n-BuLi
(1.2 equiv), in usual various solvents. The reaction was
carried out at ꢀ78 ꢀC for 1 h, and then temperature
was allowed to rise to room temperature. Results are
summarized in Table 1.
In THF, the reaction led to a complex mixture with only
traces of the propargyl amine 3a. Maintaining the reac-
tion medium at ꢀ50 ꢀC or at 0 ꢀC did not improve the
addition reaction. When the reaction was conducted in
ether, the propargyl trifluoromethyl amine 3a was iso-
lated in 64% yield, together with 25% of starting mate-
rial and 11% of an unknown side product. The best
selectivity was obtained in toluene, and the propargyl
amine 3a could be isolated in high yield (83%). The
scope of this process towards starting aldimines 1, 4
and acetylenic reagents, was then examined under im-
proved reaction conditions (Table 2). In all cases, reac-
tions were clean, and yields were good to excellent
(71–95%).6
Despite the potential interest of fluorinated com-
pounds,2 the preparation of propargyl trifluoromethyl
amines has not been intensively studied so far.
The addition of trimethylsilylacetylenes to trifluoro-
methyl iminium ions, generated from corresponding
oxazolidines3 or aminal4 in the presence of Lewis acids,
has been described. Another preparation has also been
reported by addition of acetylides on more reactive
CF3-imines prepared from trifluoromethylated pyru-
vate.5 However, to our knowledge the addition of acet-
ylides on trifluoromethylated N-aryl and N-alkyl
aldimines has not been reported so far. Herein, we
describe the addition of acetylenic reagents on aldimines
derived from fluoral.
Table 1. Addition of trimethylsilyl acetylide on the N-benzyl-imine 16
SiMe3
CF3
solvent
CF3
-78°C to r.t.
+
Li
SiMe3
First, the reaction has been explored with the N-benzyl-
aldimine 1 and the lithium acetylide 2a of trimethylsilyl-
N
NHBn
3a
2a
Bn
1
Entry
Solvent
Yield (%)
Keywords: Trifluoromethyl aldimines; CF3-propargyl amines; Difluo-
romethyl imines; Difluoromethyl propargyl amines.
1
2
3
THF
Ether
Toluene
Traces
64
83
*
Corresponding author. Tel.: +33 1 46 83 57 39; fax: +33 1 46 83 57
40; e-mail: benoit.crousse@cep.u-psud.fr
0040-4039/$ - see front matter ꢁ 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.030

2220
G. Magueur et al. / Tetrahedron Letters 46 (2005) 2219–2221
Table 2. Addition reaction of acetylides to aldimines6
Ph
CF3
Toluene
+
Li
Ph
HCF2
R'
-78 °C to r.t.
CF3
N
2c
(3 eq.)
Toluene
CF3
-78°C to r.t.
R
+
Li
R'
NR
Bn
N
2
1
Bn
R=
8c
NHR
R =
R
4
PMP
PMP 9c
1
3
5
Bn
R=
4
PMP
(R) Ph(CH)CH2OMe6
7 (d.e. > 98%)
Scheme 1.
Entry
Imine
2 R0
Products
Yields (%)
4 provided the difluoromethyl imine 9c (60%). The
amount of difluoromethyl imines could not be improved
by changing conditions of the acetylide generation (Na,
MgX salts) (Scheme 1).
1
2
3
4
5
6
7
8
9
1
1
1
4
4
4
6
6
6
2a SiMe3
2b Bu
2c Ph
2a
3a
3b
3c
5a
5b
5c
7a
7b
7c
83
94
87
84
71
78
90
77
95
2b
2c
Like CF3 substituted compounds, difluoromethyl con-
taining compounds could exhibit interesting specific bio-
logical activities.9 However, the difluoromethyl starting
materials are less available than trifluoromethyl parent
compounds.
2a
2b
2c
Recently, we have reported that using the imine 6 (pre-
pared from the hemiacetal of fluoral and the methyl
ether of the (R)-phenylglycinol as chiral N-substituent)
in the vinylation reaction7 and in the allylation reaction8
yielded products with remarkable de. We then investi-
gated the propargylation reaction from this chiral trifluo-
romethyl aldimine 6. Under the optimized conditions,
different trifluoromethyl homopropargyl amines 7 were
obtained in good yield, and in excellent diastereoselecti-
vities (de >98%). In all cases only one diastereoisomer
Assuming that the imines 8, 9 could result from a depro-
tonation of 3 or 5, the access to CF2H imines has then
been attempted from CF3-propargyl amines 3 and 5 un-
der basic conditions (BuLi, LDA, LiHMDS, etc.). With
amine 3, no reaction occurred or decomposition was ob-
served. With amine 5 the best result into difluoromethyl
imine 9 could be obtained with 1.2 equiv of NaOH in
THF (Scheme 2). With the amine 5c, a total conversion
was observed leading to the imine derivative 9c, which
was obtained in good yield. The preliminary studies to
reduce the new difluoromethyl imine 9c have been at-
tempted with NaBH4 in EtOH. Difluoropropargyl
amine 10c was obtained in good yield (Scheme 2).
1
was detected in H and 19F NMR of the crude.
Since the vinylation of the aldimine 6 provided the allyl
amine with creation of an R centre confirmed by X-ray,7
we assumed that propargyl amines had also the R con-
figuration with the hypothesis of a chelation controlled
mechanism with an attack opposite to the phenyl group
(Fig. 1).
Despite our efforts, the mechanism of the conversion of
5 or 4 to 9 could not be yet elucidated. Generation of a
CF2 moiety strongly suggests a deprotonation at the C1
carbon, probably favoured by the presence of an alkynyl
substituent,10 followed by a loss of fluoride anion, then
tautomerization. However, the reaction requires only
1.2 equiv of base, which normally should deprotonate
the amine first. The fact that N-acyl amine 11 remained
unchanged with NaOH, led us to believe that the NH
function could be involved in the latter process (Scheme
3).
R
CF3
CF3
*
N
Ph
H
N
Ph
R
Met
H
(R)
O
MeO
7
Me
Figure 1.
Ph
An interesting result emerged during investigations on
these propargylations. When the reaction was per-
formed with the aldimine 1 and an excess of acetylide
2c (3 equiv) in toluene under the above described condi-
tions, the propargyl amine 3c was accompanied with
60% of difluoromethyl imine 8c. Similarly, the aldimine
CF3
Ac
NaOH / THF
0°C
Starting Material
N
PMP
11
Scheme 3.
Ph
Ph
Ph
CF3
NaBH4 / EtOH
HCF2
NaOH / THF
HCF2
r.t.
96%
0°C
69%
NHPMP
5c
NPMP
9c
NHPMP
10c
Scheme 2.

G. Magueur et al. / Tetrahedron Letters 46 (2005) 2219–2221
2221
sium Series 456; American Chemical Society: Washington,
DC, 1991.
3. Lebouvier, N.; Laroche, C.; Huguenot, F.; Brigaud, T.
Tetrahedron Lett. 2002, 43, 2827–2830.
4. Xu, Y.; Dolbier, W. R., Jr. J. Org. Chem. 2000, 65, 2134–
2137.
In summary, this letter describes a new use of aldimines
derived from fluoral for an access to various fluorinated
nitrogen containing compounds.11 Trifluoromethyl
propargyl amines were prepared from trifluoromethyl
aldimines and various acetylides, and were obtained in
good yield. Some of these trifluoromethyl amines are
precursors of interesting difluoromethyl imines, which
can further be easily reduced into difluoromethyl prop-
argyl amines.
5. (a) Burger, K.; Sewald, N. Synthesis 1990, 115–118; (b)
´
ˆ
Semeril, D.; Le Notre, J.; Bruneau, C.; Dixneuf, P. H.;
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6. Experimental procedure: to a solution of trimethylsilyl-
acetylene (1.2 mmol, 170 lL) in toluene (10 mL) was
dropped at ꢀ78 ꢀC, n-BuLi (1.2 equiv, 1.6 N). After 1 h,
the imine 1 (1.0 mmol, 187 mg) diluted in toluene (2 mL)
was added slowly at this temperature and warmed at room
temperature. Then, the mixture was hydrolyzed with a
solution of saturated NH4Cl (20 mL). The aqueous phase
was extracted with ether (2 · 10 mL) and the combined
organic layers dried on MgSO4, were filtered and evapo-
rated. The crude product was purified on silica gel to
afford the propargyl amine 3a (236 mg, 83%).
Acknowledgments
G.M. thanks MENRT for a fellowship. The authors
´
´
thank Dr. J.-P. Begue for fruitful discussions. We thank
Central Glass Co., Ltd for a kind gift of fluoral, DSM
Company for the donation of (R)-phenylglycine.
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´
´
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