Diastereoselective alkynylation of chiral phosphinoylimines: preparation of optically active propargylamines

Article abstract of DOI:10.1016/j.tetlet.2009.11.091

Chiral phosphinoylimines were prepared from methylphenylphosphonamides and tested as new chiral and activated imines. The addition of aluminum acetylides was proved to be highly diastereoselective while lithium or magnesium acetylides gave poor results. T

Full text of DOI:10.1016/j.tetlet.2009.11.091

Tetrahedron Letters 51 (2010) 645–648
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Tetrahedron Letters
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Diastereoselective alkynylation of chiral phosphinoylimines: preparation
of optically active propargylamines
*
Mounira Benamer, Serge Turcaud, Jacques Royer
UMR 8638, CNRS/Université Paris Descartes, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’observatoire, 75270 Paris Cedex 06, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral phosphinoylimines were prepared from methylphenylphosphonamides and tested as new chiral
and activated imines. The addition of aluminum acetylides was proved to be highly diastereoselective
while lithium or magnesium acetylides gave poor results. The cleavage of the chiral auxiliary was done
under mild conditions and allows the recovery of the starting phosphonamide without loss of optical
purity.
Received 6 October 2009
Revised 17 November 2009
Accepted 20 November 2009
Available online 26 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Chiral phosphinoylimine
Aluminum reagents
Aluminum acetylides
Propargylamines asymmetric synthesis
Asymmetric induction
1. Introduction
We recently described the addition of alkynyl dimethyl alumi-
num compounds onto N-p-tolylsulfinylimines as a powerful meth-
Development of methodologies for the asymmetric synthesis of
optically active amines is still a very active area of research due to
the general interest of substituted amines. The addition of nucleo-
philes to imines is a one of the most important reaction used to
od for the preparation of enantiopure propargylamines.6 In
continuation to this work we wondered if chiral N-sulfoxide
groups are the only groups able to offer enhanced imine reactivity
(through an electron-withdrawing effect) as well as diastereoselec-
tive efficiency and easy deprotection. We thus envisaged to study
the activation of an imine function with a chiral phosphine oxide
and then to prepare chiral phosphinoylimines and to study their
reactivity. Phosphorus derivatives have been rarely used as chiral
auxiliary and activator of the imine function. We recently reported
the use of chiral phosphoryl derivatives as phosphoryliminium
equivalents which were found to display good reactivity and fair
to good diastereoselectivity.7 With similar idea, phosphorylimine
derivatives were quite recently studied by G. Li8 who disclosed
preliminary results for this chiral auxiliary in the reaction of Dar-
zens and particular enolates showing very interesting stereochem-
ical results. In these cases, a chiral phosphoric acid derivative is
used. To the best of our knowledge, there is only one report in
the literature dealing with chiral phosphinoylimines used for the
preparation of chiral oxaziridines.9
As a first attempt and model we have investigated the reaction
of N-(methylphenylphosphinoyl)-imines with acetylides which
could be compared with the alkynylation we described with
sulfinylimines.
We will present herein our results related to the preparation of
N-methylphenylphosphinoylimines followed by diastereoselective
addition of acetylides, particularly alkynyl dimethyl aluminum
derivatives, to give chiral propargylamines.5c,d,10
prepare a
-substituted amines.1 In order to make it a valuable pro-
cess and to attain optically active amines, the electrophilicity of the
imine function must be enhanced and the asymmetry must be
introduced in the reaction. Methods have been proposed to simul-
taneously attain these two goals from which two methods have
drawn our attention. The first method is based on the use of a
chiral appendage linked to the nitrogen atom by forming a sulfinyl-
imine.2 The N-sulfinylimines are activated chiral imines which
have been extensively used by several authors to prepare optically
active amines following the pioneering works of Davis et al.
(p-tolyl-sulfoxide group)3 and Ellman (tert-butyl-sulfoxide).4 The
second method is concerned with the activation of the imine in
combination with a chiral catalyst. The use of achiral N-diphenyl
phosphinoylimines recently emerged as a very attractive activation
of the imine function and was developed by several authors5 show-
ing the broad scope of applications with various nucleophiles and
the elaboration of several original catalysts. The method was
proved to be highly efficient in terms of activation of the imine:
the diphenylphosphynoyl group is as effective as the Boc group
while much easier to deprotect.
* Corresponding author. Tel.: +33 1 5373 9749; fax: +33 1 4329 1403.
E-mail address: jacques.royer@parisdescartes.fr (J. Royer).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.091

646
M. Benamer et al. / Tetrahedron Letters 51 (2010) 645–648
O
P
O
P
O
R1CHO
b)
ZNH2
a)
X
N
P
NH2
R1
H3C
H3C
H3C
4
3
Z = H
Z = Na
1 X = Cl
2 X = OMen
Scheme 1. Reagents and conditions: (a) from 1: NH3, CH2Cl2, À78 °C, 15 h. from 2: NaNH2, THF, À45 °C, 1 h; (b) TiCl4, CH2Cl2, 0 °C to rt.
sulfinylimines.6 As for the reaction of these aluminum derivatives
2. Results and discussion
onto sulfinylimines it was noticed that the reaction necessitated
the use of 4 equiv of organometallic reagent to reach completion
in acceptable time. The reaction was first conducted in CH2Cl2 at
rt with phenyl acetylide and phosphinoylimine derived from benz-
aldehyde (Table 1, entry 1). The reaction was rather rapid and went
to completion within 2-3 h at rt. A 88:12 diastereomeric ratio was
obtained for an acceptable 55% isolated yield. The results were
found to be better with a 70% isolated yield and a 90:10 dr when
the reaction was conducted in toluene. The reaction was also ob-
served at lower temperature (0 °C) but the diastereoselectivity
was not improved while the reaction was very slowed and not
complete after 20 h (entry 3). By the use of these aluminum deriv-
atives no reaction was obtained in diethyl ether or THF as the sol-
vent from 0 °C to rt. As a matter of comparison, the reaction of
lithium acetylide was checked but no reaction occurred. With mag-
nesium acetylide the reaction went to completion within 2 h at rt
but without any diastereoselectivity (entry 6). The addition of phe-
nylacetylides was investigated when R1 = p-tolyl. Once again the
best conditions were the use of dimethylaluminum derivatives in
toluene. While magnesium acetylide showed no selectivity (entry
9), the diastereoselectivity was raised to 95:5 dr with dimethylalu-
minum acetylide in toluene (entry 8).
2.1. Preparation of N-(P-methyl P-phenylphosphinoyl)imines
Racemic methylphenylphosphinamide ( )-3 can be easilly pre-
pared as reported11 in large scale from the corresponding and com-
mercially available phosphinyl chloride 1 while the preparation of
(S)-3 was obtained from menthyl methylphenyl phosphinate 2
using a known procedure.11 The synthesis of different phos-
phinoylimines 4 has been obtained through the methodology de-
scribed for the preparation of N-diphenylphosphinoylimines by
condensation of methylphenylphosphinamide with an aldehyde
catalyzed by TiCl4/Et3N (Scheme 1).12
It is worth noting that this method has been found to be the
only one giving rise to the formation of aldimine in a reasonable
yield. The methods using p-tolylsulfinic acid described by A. Cha-
rette13 or using activation with imidazole introduced by Kresze14
which give good results with N-diphenylphosphinamide were
checked but failed to give the reaction when applied to meth-
ylphenylphosphinamide. An apparent and unexpected lowered
nucleophily of methylphenylphosphinamide compared with diph-
enylphosphinamide should be invoked.
Whereas occurring with lowered diastereoselectivity, the use of
aliphatic aluminum acetylide derivatives was proved to be possible
and interesting results were obtained with functionalized chains
(entries 10 and 11)
2.2. Diastereoselective alkynylation of racemic
methylphenylphosphinoylimines
The reaction of methylphenylphosphinoylimines with acety-
lides and more particularly dimethyl aluminum acetylide15 was
investigated. This very first study was done with racemic material,
the results are reported in Table 1.
2.3. Alkynylation of optically active
methylphenylphosphinoylimines
Optically active (S)-methylphenylphosphinoylimine (4a),16 was
obtained from (S)-methylphenylphosphinamide (+)-317 and
We focused on the reaction of aluminum derivatives which we
found to be highly valuable nucleophiles on the addition to
Table 1
Diastereoselective alkynylation of methylphenylphoninoylimines
R2
(4 equiv.)
M
O
O
P
R1
P
N
NH
R1
H3C
Solvent
H3C
R2
4
5 - 8
Entry
R1
Imine
R2
M
Conditions
Propargyl amine
Yielda (%)
drb
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
p-Tol
p-Tol
p-Tol
Ph
4a
4a
4a
4a
4a
4a
4b
4b
4b
4a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me2Al
Me2Al
Me2Al
Me2Al
Li
CH2Cl2,3 h, rt
5
5
5
5
5
5
6
6
6
7
55
70
53
0
88:12
90:10
85:15
—
Toluene, 1 h, rt
Toluene, 20 h, 0 °C
Ether or THF, rt
Toluene, rt
Toluene, 1.5 h, rt
CH2Cl2, 1.5 h, rt
Toluene, 1.5 h, rt
Toluene, 1.5 h, rt
CH2Cl2, 15 h, rt
0
—
Mg
70
64
69
74
42
50:50
90:10
95:5
50:50
75:25
Me2Al
Me2Al
Mg
10
—(CH2)2CH2Cl
Me2Al
11
Ph
4a
Me2Al
CH2Cl2, 15 h, rt
8
50
83:17
a
Isolated yield.
b
Determined by integration of the 31P NMR and/or the 1H NMR signals of the crude reaction mixtures.

M. Benamer et al. / Tetrahedron Letters 51 (2010) 645–648
647
Ph
Ph
(4 equiv.)
Al
O
P
O
P
Ph
Ph
N
NH
Ph
b)
H3C
Ph
(de = 80% )
AcNH
H3C
(-)- 4a
5
Ph
a)
c), d)
O
PhCHO
Ph
(+)-10
( ee = 78% )
O
P
NaNH2
e)
Ph
H3C
NH2
P OMe
H3C
Ph
(+)- 3
(+)- 9
(ee = 94%)
Scheme 2. Reagents and conditions: (a) TiCl4, CH2Cl2, 0 °C to rt, 1 h; (b) toluene, 0 °C to rt, 1 h; (c) aq 3 M HCl in MeOH (1:5), 0 °C to rt, 1.5 h; (d) Ac2O, CH2Cl2, iPr2NEt, 0 °C to
rt, 1 h; (e) NaNH2, THF, À45 °C, 1 h.
Ph
Si face
addition
H
O
P
O
P
H
N
N
H
Al
Ph
Scheme 3. Proposed model for the alkynylation of phosphinoylimine.
reacted with dimethyl aluminum phenylacetylide18 to give opti-
Acknowledgment
cally active 519 as a mixture of two diastereomers in a 90:10 ratio
(Scheme 2). The separation of the diastereomers was not attempted
and the mixture was submitted to the cleavage of the chiral auxil-
iary. Treatment of 5 with HCl in MeOH, was followed by Ac2O treat-
ment and allowed the isolation of methylphosphinate (+)-920 and
The authors would like to thank ‘Groupe Saidal’ (Alger) for
financial support.
References and notes
N-acetyl propargylamine (+)-10.21 The [ D value of 1021 was con-
a]
1. Bloch, R. Chem. Rev. 1998, 98, 1407–1438.
sistent with diastereomeric excess (80%) of the alkynylation and
the enantiomeric purity of the chiral auxiliary, its sign allowed
the determination of the absolute configuration of 10 as R.6 The
model we proposed for the alkynylation of N-p-tolylsulfinylimines
can also be applied here.6 This model (Scheme 3) was based on the
necessity to use 4 equiv of organometallic reagent to attain a rea-
sonable reaction time, it was then proposed that two molecules of
the organoaluminum are complexed to the imine: one at the nitro-
gen and the other at the oxygen of the phosphoryl. The antiperipla-
nar disposition of these groups resulting from these complexations
and the addition on the less-hindered face could explain the config-
uration of the major propargylamide 5.
Eventually, it was demonstrated that the chiral auxiliary can be
recovered (Scheme 2). Methylphosphinate (+)-9 was obtained
through inversion of configuration at phosphorus from the acidic
cleavage of 5. Furthermore, treatment of (+)-9 with NaNH2 led to
phosphinamide (+)-3, resulting in a second inversion of configura-
tion, in fair yield (31%) but without loss of enantiomeric purity
(ee = 94% from chiral HPLC).
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propargylamines see: (a) Liu, B.; Liu, J.; Jia, X.; Huang, L.; Li, X.; Chan, A. S. C.
In conclusion, we have shown that chiral phosphinoylimines
are good substrates for the addition of aluminum acetylides giving
rise to propargylamines in good chemical yields and enantiomeric
excesses. The chiral inductor can be recovered without loss of opti-
cal purity.

648
M. Benamer et al. / Tetrahedron Letters 51 (2010) 645–648
Tetrahedron: Asymmetry 2007, 18, 1124–1128; (b) Taylor, A. M.; Schreiber, S. L.
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C. Chem. Commun. 2006, 4263–4275. and references cited herein.
k = 210 nm, 1 mL/min, n-Hex/i-PrOH 82:18); [
8.3 (c 2.2, MeOH).
18. Experimental procedure:
a] [a]
7.3 (c 2.2, MeOH), lit.11
D D
a 1.45 M toluene solution of dimethylaluminum
phenylacetylide15 (1.64 mmol) was added at 0 °C to N-phosphinoylimine 4a
(0.411 mmol) in anhydrous toluene (2 mL). The reaction mixture was stirred at
room temperature for 1 h. The reaction was quenched by the addition of 3 ml
of a 2 M Rochelle salt solution and the reaction mixture was stirred for 15 min
at rt. The aqueous layer was separated and extracted with ethyl acetate. The
organic layers were mixed and washed successively with water and brine.
After drying, the solvent was evaporated under reduced pressure, and the oily
residue was purified by column chromatography on silica gel (ether/n-heptane
6/4) to leave 5 as a white solid (56%).
11. Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1977, 2057–2063. The method
described in this publication was used with a slight modification: potassium
was replaced by sodium.
12. (a) Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29, 3725–3730; (b)
Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561–5568.
13. (a)Desrosiers, J.-N.;Côté,A.;Boezio,A. A.;Charette, A. B. Org. Synth. 2006, 83, 5–17;
(b)Lauzon,C.; Desrosiers, J.-N.;Charette, A. B. J. Org. Chem. 2005, 70, 10579–10580.
14. (a) Albrecht, R.; Kresze, G. Chem. Ber. 1965, 98, 1431–1434; (b) Kresze, G.;
Wucherpfennig, W. Angew. Chem., Int. Ed. Engl. 1967, 6, 109–123.
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19. Analytical data for 5: (9:1 mixture of isomers). MS: 712.81 g/mol [MNa]+; 1H
NMR (300 MHz, CDCl3) d ppm: 1.69 3Y, d, J = 14.4 Hz), 3.25 (0.1H, t, J = 9.9 Hz),
3.39 (0.9H, t, J = 9.9 Hz), 5.38 (0.9H, t, J = 9.9 Hz), 5.44 (0.1H, t, J = 9.9 Hz), 7.06
(2H, m), 7.28 (4H, m), 7.45 (5H, m), 7.53 (4H, m); 31P NMR (121 MHz, CDCl3) d
ppm): 30.64 ppm (0.1H), 30.65 ppm (0.9H); 13C NMR (75 MHz, CDCl3)
d
ppm signals of the major isomers from the mixture: 16.9 (d, JC–P = 90.5 Hz);
46.7 (d, JC–P = 2.9 Hz); 85.4; 88.5 (d, JC–P = 5.6 Hz); 122.5;127.3; 128.2; 128.5
(d, JC–P = 12.0 Hz); 128.8; 131.2, 131.6; 131.7 (d, JC–P = 9.1 Hz);131.9
(d, JC–P = 2.7 Hz); 133.2; 133.7; 140.0.
16. Analytical data for 4a: [
a
]
À17 (c 0.35, CH2Cl2); 1H NMR (300 MHz, CDCl3) d
D
ppm: 1.88 (3Y, d, J = 14.3 Hz), 7.85 (8H, m), 7.93 (4H, m), 9.20 (1H, d,
J = 33.6 Hz); 31P NMR (121 MHz, CDCl3) d ppm: 34.58 ppm; 13C NMR (75 MHz,
CDCl3) d ppm: 17.1 (d, JC–P = 93.0 Hz); 128.5 (d, JC–P = 12.0 Hz); 128.9; 130.0;
130.9 (d, JC–P = 9.3 Hz); 131.3 (d, JC–P = 10.3 Hz); 131.9 (d, JC–P = 2.7 Hz); 132.8
(d, JC–P = 126.8 Hz); 133.5; 173.2 (d, JC–P = 8.2 Hz).
20. (+)-9: [
a
]
D
42 (c 3.7, MeOH), lit.22
28 (c 0.8, CHCl3), lit.6
[a
]
D
45.2 (c 3.7, MeOH).
36.1 (c 0.82, CHCl3).
21. (+)-10: [
a
]
D
[a
]
D
22. Koizumi, T.; Yanada, R.; Tagaki, H.; Hirai, H.; Yoshii, E. Tetrahedron Lett. 1981,
571–572.