Synthesis of N-diphenylphosphinoylimines using the Kresze reaction

Article abstract of DOI:10.1021/jo051491e

The synthesis of N-diphenylphosphinoylimines involving the treatment of aldehydes with P,P-diphenyl N-sulfmylphosphoramidate (Ph₂P(O)NSO) is described. The reagent is prepared from P,P-diphenylphosphinic amide, thionyl chloride, and imidazole.

Full text of DOI:10.1021/jo051491e

tion of the sulfinic acid adduct of the imine that decom-
poses to the imine under basic treatment.9 This method
is particularly effective for the preparation of N-diphe-
nylphosphinoylimines derived from alkyl-substituted al-
dehydes. Inspired by the Kresze reaction,10 this paper
describes a new approach for the synthesis of N-phos-
phinoylimines.
Synthesis of N-Diphenylphosphinoylimines
Using the Kresze Reaction
Caroline Lauzon, Jean-Nicolas Desrosiers, and
Andre´ B. Charette*
De´partement de Chimie, Universite´ de Montre´al, P.O. Box
6128, Station Downtown, Montre´al, QC, Canada H3C 3J7
The Kresze reaction is described as the reaction of
aldehydes with N-sulfinylamines (RNSO)11 in the pres-
ence of a Lewis acid to generate N-tosylimines. Using this
methodology, Weinreb12 has reported that the addition
of Grignard and organolithium reagents to in situ gener-
ated N-tosylimines led to protected R-chiral amines
(Scheme 1). This transformation involves a [2 + 2]
cycloaddition process followed by a SO2 extrusion.
Given this precedent, we envisioned that this approach
should be perfectly amenable to the synthesis of N-
phosphinoylimines. The Kresze reaction is now applied
to the synthesis of N-phosphinoylimines 3 using in situ
andre.charette@umontreal.ca
Received July 18, 2005
generated P,P-diphenyl N-sulfinylphosphoramidate13
and an aldehyde as starting materials (Scheme 2).
2
The solvent and reaction temperature were optimized
using benzaldehyde as starting material (Table 1). Al-
though several solvents can be used for this reaction,
toluene provided the best conversions (entry 3).
The synthesis of N-diphenylphosphinoylimines involving the
treatment of aldehydes with P,P-diphenyl N-sulfinylphos-
phoramidate (Ph2P(O)NSO) is described. The reagent is
prepared from P,P-diphenylphosphinic amide, thionyl chlo-
ride, and imidazole.
The methodology was then applied to a variety of aryl-
substituted aldehydes. The significant advantage of this
procedure is its simplicity: imidazole and freshly distilled
thionyl chloride were mixed at -10 °C and stirred at 20
°C for 10 min, and then the imidazolium chloride was
filtered off through a fritted glass funnel.11 A second
treatment with thionyl chloride and P,P-diphenylphos-
phinic amide 1/filtration led to a filtrate that was
concentrated to give the crude N-sulfinylphosphorami-
date. The N-sulfinylphosphoramidate was dissolved in
toluene, and the aldehyde was added. The solution was
stirred typically for 16 h, and evaporation followed by a
quick filtration over a small plug of silica gel led to the
corresponding N-phosphinoylimine with a purity higher
In the past few years, N-phosphinoylimines have been
extensively exploited in many reactions.1 Shibasaki has
reported the first catalytic asymmetric nitro-Mannich-
type,2 Mannich,3 and Strecker4 reactions using these good
electrophiles. The phosphinoyl group is also used as a
protecting group for amines owing to its facile cleavage
under mild acidic conditions.5 Although the direct con-
densation of phosphinic amides with highly electrophilic
aldehydes constitute a viable entry to N-phosphi-
noylimines, titanium tetrachloride and titanium tetrai-
sopropoxide are usually used as dehydrating reagents to
facilitate this condensation.6,7 In this last procedure,
however, the removal of titanium salts can be tedious,
and long reaction times (up to 1 day) are sometimes
required. Heating the reaction mixture to shorten the
reaction times generally led to some degradation of the
imines. Stec described the reaction of ketoximes or
aldoximes with chlorodiphenylphosphine at low temper-
ature to produce unstable O-phosphinyloximes that
undergo a rearrangement to give N-phosphinoylimines.8
Our group has reported a method involving the prepara-
1
than 95% by H NMR. The workup is straightforward
and the starting materials are readily available. This
procedure is particularly advantageous over the TiCl4 (or
Ti(OEt)4) method that requires removal of the titanium
derived byproducts through tedious extractions. As shown
in Table 2, the reaction occurs well with several aryl-
substituted aldehydes. Thus far, we have not been able
to extend that reaction to alkyl-substituted aldehydes.
In summary, a new methodology for the synthesis of
N-phosphinoylimines has been developed. The isolated
yields are similar to the methodologies previously devel-
oped for the preparation of these compounds. The main
advantage of this new procedure is that a straightforward
workup is required to isolate the corresponding imine.
* To whom correspondence should be addressed.
(1) Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205-1227.
(2) Yamada, K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 3504-3506.
(3) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 4712-4713.
(4) Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2003, 125, 5634-5635.
(9) Coˆte´, A.; Boezio, A. A.; Charette, A. B. Proc. Natl Acad. Sci.
U.S.A. 2004, 101, 5405-5410.
(5) Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270-273.
(6) (a) Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29,
3725-3728. (b) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47,
5561-5568.
(10) (a) Albrecht, R.; Kresze, G.; Mlakar, B. Chem. Ber. 1964, 97,
483-489. (b) Albrecht, R.; Kresze, G. Chem. Ber. 1965, 98, 1431-1434.
(c) Kresze, G.; Wucherpfennig, W. Angew. Chem., Int. Ed. Engl. 1967,
6, 109-123.
(11) Kim, Y. H.; Shin, J. M. Tetrahedron Lett. 1985, 26, 3821-3821.
(12) Sisko, J.; Weinreb, S. M. J. Org. Chem. 1990, 55, 393-395.
(13) Zhang, Y.; Flann, C. J. J. Org. Chem. 1998, 63, 1372-1378.
(7) Hayase, T.; Osanai, S.; Shibata, T.; Soai, K. Heterocycles 1998,
48, 139-144.
(8) Krzyzanowska, B.; Stec, W. J. Synthesis 1978, 521-524.
10.1021/jo051491e CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/11/2005
J. Org. Chem. 2005, 70, 10579-10580
10579

SCHEME 1. Application of the Kresze Reaction toward the Preparation of r-Chiral Aminesa
a Key: (a) TsNSO (1.5 equiv), RCHO (1.0 equiv), 1-2 h; (b) R′M (3.0 equiv), 1 h (32-93%).
SCHEME 2. Synthesis of P,P-Diphenylphosphinoyl Imines 3 from Aryl Aldehydesa
a Key: (a) imidazole (2 equiv), SOCl2 (2 × 0.5 equiv), CH2Cl2, -10 °C to rt, then NH2P(O)Ph2 (1 equiv); (b) RCHO (1.35 equiv), rt, 16
h, toluene.
TABLE 1. Optimization for the Synthesis of
mixture was stirred at 20 °C for 10 min to form imidazolium
chloride, which was filtered off through a fine fritted glass
funnel. A second portion of thionyl chloride (134 µL, 219 mg,
1.84 mmol) was added to the filtrate at -10 °C, and the mixture
was stirred at 20 °C for 10 min. This solution of N-(chlorosulfi-
nyl)imidazole (3.68 mmol) was added via cannula to a solution
of P,P-diphenylphosphinic amide 1 (800 mg, 3.68 mmol) in
dichloromethane (5 mL) at -40 °C. After the reaction was stirred
at 20 °C for 6 h, imidazolium chloride was removed by filtration
through a fine fritted glass funnel, and the filter cake was
washed with dichloromethane (2.0 mL). The filtrate was con-
centrated to give the crude N-sulfinylphosphoramidate 2 as a
brown oil which was thermally unstable and moisture sensitive
so it was used without further purification.
N-Phosphinoylimine 3a (R ) Ph)
entry
solvent
T (°C)
conva (%)
1
2
3
4
THF
rt
rt
57
52
64
60
CH2Cl2
toluene
CH2Cl2
rt
55
a Conversions were determined by 1H NMR and are based on
aldehyde consumption.
TABLE 2. Application of Kresze’s Reaction to the
Synthesis of Different N-Phosphinoylimines 3a
General Procedure for the Preparation of N-Phosphi-
noylimines 3a-i. The P,P-diphenyl N-sulfinylphosphoramidate
2 (3.68 mmol) was dissolved in toluene (7.5 mL), and the
aldehyde (4.97 mmol) was added. After the solution was stirred
at 20 °C for 16 h, the solvent was removed under reduced
pressure and the residue filtered through silica gel eluting with
100% AcOEt to afford 3 as a solid, with a purity greater than
95% (1H NMR).
R
yield (%)
Ph (3a)
52
48
44
54
61
58
58
48
52
1-naphthyl (3b)
2-BrC6H4 (3c)
3-MeOC6H4 (3d)
4-MeC6H4 (3e)
4-ClC6H4 (3f)
4-CF3C6H4 (3g)
2-furyl (3h)
2,4,6-MeC6H2 (3i)
Acknowledgment. This work was supported by
NSERC, Astra Zeneca R&D Montre´al, Boehringer In-
gelheim (Canada), Merck Frosst Canada, and the Uni-
versite´ de Montre´al. J.N.D. is grateful to NSERC,
SSHRC, and CIHR (CGS D) for a graduate fellowship.
a Key: (a) RCHO (1.35 equiv), toluene, 16 h, rt.
Experimental Section
Supporting Information Available: General information
and NMR spectra for compounds described in this work. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Procedure for the Preparation of P,P-Diphenyl N-
Sulfinylphosphoramidate (2). Compound 2 was prepared
according to the literature.13 Thionyl chloride (134 µL, 219 mg,
1.84 mmol) was added to a solution of imidazole (501 mg, 7.36
mmol) in dichloromethane (7.5 mL) at -10 °C. The reaction
JO051491E
10580 J. Org. Chem., Vol. 70, No. 25, 2005