Regioselective synthesis of fluoroalkylated β-aminophosphorus derivatives and aziridines from phosphorylated oximes and nucleophilic reagents

Article abstract of DOI:10.1021/jo060865g

A simple and efficient stereoselective synthesis of fluoroalkyl substituted aziridine-2-phosphine oxides and -phosphonates by diastereoselective addition of methoxide, imidazole, benzenethiol, and Grignard reagents to functionalized ketoxime-phosphine oxi

Full text of DOI:10.1021/jo060865g

Regioselective Synthesis of Fluoroalkylated â-Aminophosphorus
Derivatives and Aziridines from Phosphorylated Oximes and
Nucleophilic Reagents
Francisco Palacios,* Ana M. Ochoa de Retana, and Jose´ M. Alonso
Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia, UniVersidad del Pa´ıs Vasco, Apartado 450,
01080, Vitoria, Spain
francisco.palacios@ehu.es
ReceiVed April 25, 2006
A simple and efficient stereoselective synthesis of fluoroalkyl substituted aziridine-2-phosphine oxides
and -phosphonates by diastereoselective addition of methoxide, imidazole, benzenethiol, and Grignard
reagents to functionalized ketoxime-phosphine oxides and -phosphonates is described. Aziridines are
used as intermediates for the regioselective synthesis of fluorine containing â-amino phosphine oxides
and â-amino phosphonates. Amino phosphorus derivatives can also be obtained from ketoximes derived
from phosphine oxides and phosphonates with sodium borohydride.
Introduction
be used for the efficient and/or selective preparation of fluorine-
containing molecules with biological activity and commercial
applications.4 For these reason, the development of new methods
for the preparation of fluorine substituted aminophosphonates
is an interesting goal in synthetic organic chemistry, not only
because of their use in medicinal chemistry as ligands for
phosphoglycerate kinase5a or antibacterials,5b but also for the
preparation of fluorinated peptidomimetics.6 However, only the
addition of amines to unsaturated phosphonates5b or the addition
of fluorinated phosphonate carbanions to N-protected R-halo-
amines5a or imines7 for the synthesis of fluorine substituted
aminophosphonates have been described.
Organophosphorus compounds are important substrates in the
study of biochemical processes, and â-aminophosphonates, as
isosteres of â-amino acids, occupy an important place and reveal
diverse and interesting biological and biochemical properties
in their role as enzyme inhibitors, agrochemicals, or pharma-
ceuticals.1 On the other hand, in the field of bioactive molecules,
fluoroorganic compounds have received a great deal of attention
since the incorporation of a fluorine containing group into an
organic molecule dramatically alters its physical, chemical, and
biological properties.2 These changes in properties make them
suitable for diverse applications in synthetic, agricultural and
medicinal chemistry as well as in material science.3 Special
interest has been focused on developing synthetic methods for
the preparation of fluorinated building blocks since they can
(4) (a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds:
Stereochemical Chalenges and Biomedical Targets; Soloshonok, V. A., Ed.;
Wiley: New York, 1999. (b) Fluorine-Containing Amino Acids: Synthesis
and Applications; Kukhar, V. P., Soloshonok, V. A., Eds.; Wiley: New
York, 1995.
(5) (a) Jakeman, D. L.; Wiliamson, M. P.; Blackburn, G. M. J. Med.
Chem. 1998, 41, 4439-4452. (b) Herczegh, P.; Buxton, T. B.; McPherson,
J. C.; Kova´cs-Kulyassa, A.; Brewer, P. D.; Sztaricskai, F.; Stroebel, G. G.;
Plowman, K. M.; Farcasiu, D.; Hartmann, J. F. J. Med. Chem. 2002, 45,
2338-2341.
(6) (a) Binkert, C.; Frigerio, M.; Jones, A.; Meyer, S.; Pesenti, C.; Prade,
L.; Viani, F.; Zanda, M. ChemBioChem 2006, 7, 181-186. (b) Lazzaro,
F.; Crucianelli, M.; De Angelis, F.; Frigerio, M.; Malpezzi, L.; Volonterio,
A.; Zanda, M. Tetrahedron: Asymmetry 2004, 15, 889-893. (c) Volonterio,
A.; Bellosta, S.; Bravin, F.; Bellucci, M. C.; Bruche, L.; Colombo, G.;
Malpezzi, L.; Mazzini, S.; Meille, S. V.; Meli, M.; Ramirez de Arellano,
C.; Zanda, M. Chem.sEur. J. 2003, 9, 4510-4522. (d) Molteni, M.;
Volonterio, A.; Zanda, M. Org. Lett. 2003, 5, 3887-3890.
* To whom correspondence should be addressed. Telephone: (+34) 945-
013103. Fax: (+34) 945-013049.
(1) For recent reviews see the following: (a) Palacios, F.; Alonso, C.;
de los Santos, J. M. Chem. ReV. 2005, 105, 899-931. (b) Palacios, F.;
Alonso, C.; de los Santos, J. M. In EnantioselectiVe Synthesis of â-Amino
Acids, 2nd ed.; Juaristi, E., Soloshonok, V. A., Eds; Wiley: New York,
2005; pp 277-317.
(2) (a) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan,
S., Eds.; Wiley: New York, 1991. (b) SelectiVe Fluorination in Organic
and Bioorganic Chemistry; Welch, J. T., Ed.; American Chemical Society:
Washington, DC, 1991.
(3) (a) Chambers, R. D. Fluorine in Organic Chemistry, 2nd ed.;
Blackwell: London, 2004. (b) Organofluorine Compounds: Chemistry and
Applications; Hiyama, T., Ed.; Springer: Berlin, Germany, 2000.
10.1021/jo060865g CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/04/2006
J. Org. Chem. 2006, 71, 6141-6148
6141

Palacios et al.
SCHEME 2. Synthesis of Ketones 3 and 7, and Oximes
SCHEME 1. Retrosynthetical Pathway for Fluoroalkyl
Substituted â-Aminophosphorus Derivatives
9-12
Phosphorylated heterocycles have been acquiring increasing
interest,8 and we described new methods for the preparation of
acyclic compounds9 and phosphorylated nitrogen heterocycles.10
Likewise, we reported the preparation11 of 2H-azirine-phosphine
oxides and -phosphonates from p-toluenesulfonyl-oximes12 and
their use for the synthesis of aminophosphorus derivatives13 and
phosphorylated pyrazines,14a or oxazoles.14b,c Continuing with
our interest in the chemistry of aminophosphorus derivatives1
and of small strained nitrogen heterocycles,11-14 here we report
the regioselective preparation of fluorine containing â-amino-
phosphorus derivatives I (R ) Ph, OEt; Scheme 1) and
fluoroalkyl substituted aziridines II from fluorinated p-toluene-
sulfonyl oximes IV, probably by means of the nonisolated
fluorine containing 2H-azirines III generated in situ (Scheme
1).
TABLE 1. â-Phosphorylated Ketones 3/7, gem-Diols 5/8, and Enols
4
entry
compd
R
R1
RF
yield(%)a
1
2
3
4
5
6
7
4a
4b
Ph
Ph
Ph
Ph
OEt
OEt
OEt
H
H
H
CH3
H
CF3
74
75
Results and Discussion
CHF2
C7F15
CF3
CF3
C2F5
CF3
3c/4c
3d/5d
7a/8a
7b/8b
7c/8c
58b
75c
78d
75d
73d
Synthesis of Fluoroalkyl Substituted Aziridines. The
synthesis of 2H-azirine-phosphine oxides and -phosphonates has
been described using the modified Neber reaction15 of p-
toluenesulfonyl oximes derived from phosphine oxides and
H
CH3
a Yield of isolated purified compounds. b Obtained as mixture of deriva-
tives 3/4. c Obtained as a mixture of derivatives 3/5. d Obtained as a variable
mixture of derivatives 7/8.
(7) (a) Ro¨schenthaler, G. V.; Kukhar, V.; Barten, N.; Gvozdovska, N.;
Belik, M.; Sorochinsky, A. Tetrahedron Lett. 2004, 45, 6665-6667. (b)
Sergeeva, N. N.; Golubev, A. S.; Henning, L.; Burger, K. Synthesis 2003,
915-919. (c) Nieschalk, J.; Batsanov, A. S.; O’Hagan, D.; Howard, J.
Tetrahedron 1996, 52, 165-176.
phosphonates with alkaloids and solid supported amines.11 Now
we wish to extend the process to the preparation of azirines III
(Scheme 1) and aziridines derived from phosphine oxides and
phosphonates II (Scheme 1). With this objective, we first
explored the synthesis of â-keto-phosphine oxides and -phos-
phonates required for the preparation of the p-toluenesulfonyl
oximes. The reaction of methyldiphenyl-phosphine oxide 1a (R1
) H) with ethyl trifluoromethyl acetate 2a (RF ) CF3) or ethyl
2,2-difluoromethyl acetate 2b (RF ) CHF2) in the presence of
LDA in an inert atmosphere gave, after workup, fluorine-
substituted enol-phosphine oxides 4a and 4b in good yield
(Scheme 2, Table 1, entries 1 and 2). Whereas, when ethyl
perfluoroalkyl octanoate 2c (RF ) C7F15) was used, a mixture
of both keto 3c and enol 4c tautomers (Table 1, entry 3) was
obtained. Formation of compound 4 could be explained by initial
formation of â-ketophosphine oxide 3 followed by prototropic
tautometization to enol 4.
(8) For a recent review see the following: Moonen, K.; Laureyn, F.;
Stevens, C. V. Chem. ReV. 2004, 104, 6177-6215.
(9) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarza´bal, J.
J. Org. Chem. 2004, 69, 8767-8774. (b) Palacios, F.; Herra´n, E.; Rubiales,
G.; Ezpeleta, J. M. J. Org. Chem. 2002, 67, 2131-2135.
(10) (a) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M.;
Ezpeleta, J. M. Tetrahedron 2006, 62, 1095-1101. (b) Palacios, F.; Aparicio,
D.; Lo´pez, Y.; de los Santos, J. M.; Alonso, C. Eur. J. Org. Chem. 2005,
1142-1147.
(11) (a) Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.; de los Santos,
J. M.; Gil, J. I.; Alonso, J. M. J. Org. Chem. 2002, 67, 7283-7288. (b)
Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta, J. M. J. Org.
Chem. 2000, 65, 3213-3217.
(12) For recent reviews on azirines see the following: (a) Pinho e Melo,
T. M. V. D.; d’A Rocha Gonsalves, A. M. Curr. Org. Synth. 2004, 1, 275-
292. (b) Palacios, F.; Ochoa de Retana, A. M.; Mart´ınez de Marigorta, E.;
de los Santos, J. M. Org. Prep. Proced. Int. 2002, 34, 219-269. (c) Gilchrist,
T. L. Aldrichimica Acta 2001, 34, 51-55.
(13) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2005, 70, 8895-8901. (b) Palacios, F.; Aparicio, D.; Ochoa de
Retana, A. M.; de los Santos, J. M.; Gil, J. I.; Lo´pez de Muna´in, R.
Tetrahedron: Asymmetry 2003, 14, 689-700.
(14) (a) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Lo´pez de Muna´in,
R. Org. Lett. 2002, 4, 2405-2408. (b) Palacios, F.; Ochoa de Retana, A.
M.; Gil, J. I.; Alonso, J. M. Tetrahedron: Asymmetry 2002, 13, 2525-
2541. (c) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M.
Tetrahedron 2004, 60, 8937-8947.
(15) (a) Neber, P. W.; Friedolsheim, A. J. Liebigs Ann. Chem. 1926,
449, 109-114. (b) Neber, P. W.; Burgard, A.; Their, W. J. Liebigs Ann.
Chem. 1936, 526, 277-294.
However, when ethyldiphenylphosphine oxide 1b (R1 ) Me)
was used, fluorinated â-keto-phosphine oxide 3d, initially
formed, can undergo addition of water to provide the hydrate
form 5d, and therefore a mixture of â-keto-phosphine oxide
3d and its hydrate 5d (Scheme 2, Table 1, entry 4) was obtained.
The use of high vacuum allows one to dehydrate gem-diol 5d
(R ) Ph) to obtain â-keto-phosphine oxides 3d. The electrophic
6142 J. Org. Chem., Vol. 71, No. 16, 2006

â-Aminophosphorus DeriVatiVes and Aziridines
TABLE 2. Phosphorus Substituted Ketoximes 9-12
SCHEME 3. Preparation of Aziridines 14-17
entry
compd
R
R1
RF
E/Z (%)a
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
9a
9b
9c
9d
10a
10b
10c
11a
11b
11c
12a
12b
12c
Ph
Ph
Ph
Ph
OEt
OEt
OEt
Ph
Ph
Ph
H
H
H
CH3
H
H
CH3
H
H
H
CF3
0/100
0/100
0/100
58/42
0/100
5/95
100/0
0/100
0/100
0/100
0/100
5/95
73
77
84
60
45
46
40
84
59
64
48
43
45
CHF2
C7F15
CF3
CF3
C2F5
CF3
CF3
CHF2
C7F15
CF3
C2F5
CF3
OEt
OEt
OEt
H
H
CH3
100/0
a Ratio of E/Z isomers determined by 31P NMR. a Yield of isolated
purified compounds 9-12.
character of the carbonyl group of 3d is increased16 because of
the high electronegativity of the fluorine atoms, and then water
was easily added with the formation of hydrate 5, in a similar
way to that previously reported for fluorine containing carbonyl
compounds.17 The process was extended to alkyl phosphonates
6 (R ) OEt), and their reaction with fluoroalkylesters 2 in the
presence of LDA gave, after workup, fluorine-substituted
mixtures of â-keto-phosphonates 7 and their hydrates 8 (Scheme
2, Table 1, entries 5-7). As before, the dehydration of gem-
diols 8 (R ) OEt) to obtain â-keto-phosphonates 7 can be
performed by using high vacuum. Moreover, enols 4 can be
used directly for further synthetic purposes, and it is not
necessary to separate ketones 3 and 7 and enol 4 or hydrates 5
and 8 for further synthetic purposes.
Next we accomplished the synthesis of oximes 9 (R ) Ph)
and 10 (R ) OEt) by condensation of hydroxylamine with
â-keto-phosphine oxides 3 and -phosphonates 7. â-Ketoximes
9 (R ) Ph) and 10 (R) OEt) were isolated as a varible mixture
of E and Z isomers (Scheme 2, Table 2, entries 1-7). The E/Z
assigment of derivatives 9 (R ) Ph) and 10 (R ) OEt) was
based on NOE experiments. Irradiating the methylene protons
(CH2) at δ ) 3.63 ppm of oxime 9a showed an enhancement
(0.12%) of the hydroxyl -O-H proton at δ ) 12.90 ppm, and
this result is consistent with the Z configuration of oxime 9a.
Subsequent tosylation of â-ketoxime-phosphine oxides 9 and
-phosphonates 10 gave functionalized â-p-toluenesulfonyloxime
phosphine oxides 11 and phosphonates 12 (Scheme 2, Table 2,
entries 8-13) in the same proportion of E and Z isomers as the
â-ketoxime-precursors 9 (R ) Ph) and 10 (R ) OEt).
TABLE 3. Functionalized Aziridines 14-17 Obtained
entry
compd
R
R1
RF
yield(%)a
1
2
3
4
5
6
7
14a
14b
14c
14d
15a
16
Ph
Ph
Ph
Ph
OEt
Ph
Ph
H
H
H
CH3
H
CF3
52b (85)c
74c
CHF2
C7F15
CF3
CF3
CF3
70c
44d
47 b
45e
H
H
17
CF3
69c
a Yield of isolated purified compounds. b Yield obtained by using NaOMe
as base. c Yield obtained by using Et3N as base. d Yield obtained by using
NaH as base from oxime 9d. e Yield obtained by using imidazole as base.
leading exclusively to the formation of trans-3-methoxy-3-
trifluoromethylaziridin-2-yl diphenylphosphine oxide 14a (R )
Ph, R1 ) H, RF ) CF3) (Scheme 3, Table 3, entry 1). No trace
of the cis-aziridine could be observed by 31P NMR. Spectro-
scopic data were in agreement with the assigned structure of
compound 14a. Well-resolved doublets at δH ) 2.62 ppm (2JPH
) 17.4 Hz) for H2 in the 1H NMR spectrum as well as at δC )
40.5 ppm (1JPC ) 84.1 Hz), and at δC ) 72.4 ppm (2JFC ) 42.3
Hz) for C2 and C3 in the 13C NMR spectrum were observed.
The stereochemical assignment was based on NOESY 1D
experiments. Irradiating the methoxy protons (CH3-O-) at δ
) 3.52 ppm showed an enhancement (0.20%) of -C2-H proton
of the azirine ring at δ ) 2.80 ppm. Moreover irradiating the
-C2-H proton of the azirine ring at δ ) 2.80 ppm showed an
enhancement (0.41%) of the (CH3-O-) proton signal at δ )
3.52 ppm.
The exclusive formation of trans-aziridine phosphine oxide
14a (R ) Ph, R1 ) H, RF ) CF3) could be explained by base-
mediated (NaOMe) ring-closure of p-toluenesulfonyl oxime
phosphine oxide 11a to azirine 13 (R ) Ph, R1 ) H, RF )
CF3). This 2H-azirine 13 is probably unstable owing to the effect
of the high electron withdrawing trifluoromethyl group. Then,
azirine 13 readily undergoes addition of methoxide to the Cd
N bond from the least hindered face (see Figure 1) to give trans-
aziridine 14a, in a similar way to that observed in the case of
other nucleophiles such as hydride.11b
The base-mediated Neber reaction15 of fluoroalkyl p-tolu-
enesulfonyl oximes 11 (R ) Ph) and 12 (R ) OEt) was then
explored. Reaction of p-toluenesulfonyl oxime phosphine oxide
11a (R ) Ph, R1 ) H, RF ) CF3) with a base such as pyridine
did not give 2H-azirine 13 (RF ) CF3, R1 ) H, R ) Ph) and
starting material was recovered (Scheme 3). On the other hand,
the use of bases such as DBU, NaH, or MeLi did not lead to
the formation of fluoroalkyl 2H-azirine phosphine oxide 13 (RF
) CF3, R1 ) H, R ) Ph), but a complex mixture of products
was obtained instead. Therefore, the use of alkoxides as bases
was studied; p-toluenesulfonyl oxime phosphine oxide 11a (R
) Ph, R1 ) H, RF ) CF3) was treated with NaOMe/MeOH
(16) (a) Mikami, K.; Yajima, Y.; Terada, M.; Uchimaru, T. Tetrahedron
Lett. 1993, 34, 7591. (b) Paderes, G. D.; Jorgensen, W. L. J. Org. Chem.
1992, 57, 1904. (c) Linderman, R. J.; Jamois, E. A. J. Fluorine Chem. 1991,
53, 79.
(17) Guthrie, J. P. Can. J. Chem. 1975, 53, 898.
J. Org. Chem, Vol. 71, No. 16, 2006 6143

Palacios et al.
SCHEME 4. Preparation of Aziridines 19-22
FIGURE 1. Nucleophilic attack of MeO- (X-) to azirine 13.
The use of NEt3 as base in MeOH as a solvent, gave the
same adduct 14a (R ) Ph, R1 ) H, RF ) CF3) (Scheme 3,
Table 3, entry 1) and supported the proposed reaction mecha-
nism. Likewise, fluoroalkyl trans-aziridine phosphine oxide 14b
(R ) Ph, R1 ) H, RF ) CHF2) and 14c (R ) Ph, R1 ) H, RF
) C7F15) (Scheme 3, Table 3, entries 2 and 3) were prepared.
Aziridines 14 can also be obtained in a “one pot” reaction from
ketoximes. Thus, when oxime 9d was treated with 2 equiv of
base (NaH), followed by addition of p-toluenesulfonyl chloride
(1 equiv) and subsequent addition of MeOH, trans-aziridine
phosphine oxide 14d (R ) Ph, R1 ) CH3, RF ) CF3, Scheme
3, Table 3, entry 4) was obtained in a stereoselective fashion.
This process could also be extended to p-toluenesulfonyl oxime
phosphonate 12a (R ) OEt, R1 ) H, RF ) CF3). In this case,
formation of aziridine phosphonate 15a (R ) OEt, R1 ) H, RF
) CF3) was achieved employing NaOMe/MeOH as base
(Scheme 3, Table 3, entry 5).
TABLE 4. Aziridines 19-22 Obtained
yield
(%)b
entry compd
R
R1
RF
R2
cis/transa
1
2
3
4
5
6
7
8
9
19/20a Ph
19/20b Ph
19/20c Ph
19/20d Ph
19/20e Ph
21/22a OEt
21/22b OEt
21/22c OEt
H
CF3
CF3
CF3
CF3
CH3
C2H5
CH2-CHdCH2
C6H5
75/25
84/16
66/34
95/5
76/24
71/29
55/45
100/0
60/40
58
69
H
H
H
H
H
H
H
63 (44)c
73
CHF2 C6H5
55
57
56
60
CF3
CF3
CF3
C2H5
C6H5-CH2
C6H5
21/22d OEt CH3 CF3
CH2-CHdCH2
59
a The ratio of cis/trans isomers was determined by 31P NMR. b Yield of
isolated purified compounds. c Yield of isolated purified compounds from
oxime 9a.
Subsequently, the use of some nitrogen and sulfur nucleo-
philes to trap generated trifluoroalkyl substituted 2H-azirine 13
and thus to prepare new functionalized aziridines was studied.
Reaction of p-toluenesulfonyl oxime phosphine oxide 11a (R1
) H, RF ) CF3) with imidazole (XH ) imidazole, Scheme 3)
led exclusively to the formation of trans-3-imidazolyl-3-
trifluoromethylaziridin-2-yl diphenylphosphine oxide 16 (Scheme
3, Table 3, entry 6). No trace of the cis-aziridine was observed
by 31P NMR. In this case imidazole acts not only as a
nucleophile reagents but also as base. The exclusive formation
of trans-aziridine phosphine oxide 16 could be explained by
the base-mediated (imidazole) ring-closure of p-toluenesulfonyl
oxime phosphine oxide 11a, and the subsequent addition of the
second molecule of imidazole from the least hindered face of
the reactive trifluoromethyl substituted 2H-azirine intermediate
13a (R ) Ph, R1 ) H, RF ) CF3, Figure 1). A similar behavior
was observed when benzenethiol (X) SPh, Scheme 3) reacted
with p-toluenesulfonyl oxime phosphine oxide 11a in the
presence of triethylamine as base to give exclusively trans-3-
benzothio-3-trifluoromethylaziridin-2-yl diphenylphosphine ox-
ide 17 (Scheme 3, Table 3, entry 7).
These results prompted us to explore whether Grignard
reagents could produce a similar effect to that observed in the
case of imidazole. If so, the reaction of Grignard reagents with
fluoroalkyl substituted ketoximes 11 and 12 could afford
functionalized aziridines containing phosphorus and fluorine
substituents. Treatment of p-toluenesulfonyl oxime phosphine
oxide 11a (R ) Ph, R1 ) H, RF ) CF3) with methylmagnesium
bromide 18a (R2 ) CH3) in THF at -78 °C led to the formation
of a mixture of cis-3-methyl-3-trifluoromethylaziridin-2-yl di-
phenyl phosphine oxide 19a (R ) Ph, R1 ) H, RF ) CF3, R2
) CH3) as the major component along with the corresponding
trans-isomer 20a (R ) Ph, R1 ) H, RF ) CF3, R2 ) CH3) in
a 75:25 ratio of both isomers (Scheme 4, Table 4, entry 1).
Spectroscopic data were in agreement with the assigned structure
of compounds 19/20a. In the 31P NMR spectrum the phosphine
FIGURE 2. Nucleophilic attack of Grignard reagents to azirine 13.
oxide group of these aziridines 19 and 20a resonated at δP )
24.2 and 23.2 ppm, while 19F NMR spectrum showed singlets
for trifluoromethyl group at δF ) -68.8 and -70.6 ppm. The
stereochemical assignment was based on HOESY (19F-1H) 2D
experiments, which showed for compound 19a (cis configura-
tion) a correlation between the signal of the trifluoromethyl
group (δF ) -70.6 ppm) with the aromatic protons (1H) of the
diphenylphosphine oxide group.
The formation of the major isomer cis-aziridine 19a suggests
that the approach of the methylmagnesium bromide 18a to
azirine 13 from the opposite position to the bulky phosphine
oxide group is more favorable. However, in this case trans-
aziridine 20a, corresponding to the approach of the methyl-
magnesium bromide 18a to the most hindered face of the azirine
13, is also obtained as the minor isomer. Formation of this trans-
aziridine 20a could be explained (see Figure 2) as a consequence
of prechelation of the Grignard reagent with the fluorine atoms
of the fluoroalkyl substituents of azirine 13. A prechelation of
the Grignard reagent with the carboxyl ester group has been
previously observed by Davis et al when azirine-carboxylates
were treated with Grignard reagent.18
The scope of the reaction was not limited to methylmagne-
sium bromide 18a (R2 ) CH3), but ethylmagnesium bromide
18b (R2 ) C2H5), allylmagnesium bromide 18c (R2 ) CH2-
6144 J. Org. Chem., Vol. 71, No. 16, 2006

â-Aminophosphorus DeriVatiVes and Aziridines
CHdCH2), or phenylmagnesium bromide 18d (R2 ) C6H5)
reacted with p-toluenesulfonyl oxime phosphine oxide 11 (R
) Ph) to give mixtures of cis-19 (major component) and the
corresponding fluoroalkyl substituted trans-aziridin-2-yl di-
phenyl phosphine oxide 20 (minor isomer) (Scheme 4, Table
4, entries 2-5).
SCHEME 5. Ring Opening of Aziridines 14 and 15
Aziridines 19/20c can also be obtained in one pot reaction
from ketoxime 9a. When oxime 9a was heated with 3 equiv of
allylmagnesium bromide 18c (R2 ) CH2-CHdCH2), a mixture
(66/34 ratio) of cis-19c (major component) and the correspond-
ing fluorine substituted trans-aziridin-2-yl diphenyl phosphine
oxide 20c (minor isomer) (Table 4, entry 3) was obtained.
This process could also be extended to p-toluenesulfonyl
oximes derived from phosphonates 12 (R ) OEt). Treatment
of these ketoximes 12 (Scheme 4) with ethylmagnesium bromide
18b (R2 ) C2H5), allylmagnesium bromide 18c (R2 ) CH2-
CHdCH2), phenylmagnesium bromide 18d (R2 ) C6H5), and
benzylmagnesium bromide 18e (R2 ) CH2-C6H5) gave mix-
tures of cis-21 (major component) and the corresponding
fluoroalkyl substituted trans-aziridin-2-yl diphenyl phosphine
oxide 22 (minor isomer) (Scheme 4, Table 3, entries 6-9). This
strategy describes the first synthesis of aziridine-phosphorus
derivatives containing fluoroalkyl substituents.
Ring Opening of Aziridines. Synthesis of â-Aminophos-
phorus Derivatives. Amino phosphorus derivatives19 in general,
and â-amino compounds in particular,1,20 have acquired in-
creased interest in recent years because of their application in
organic and medicinal chemistry. For this reason we tried to
study if phosphorylated aziridines containing fluoroalkyl sub-
stituents could be used for the preparation of â-aminophosphorus
derivatives. Catalytic hydrogenation of aziridines bearing phos-
phorus functional groups produces the corresponding amino
phosphorus derivatives with highly controlled regioselectivity.13a,21
Therefore, we explored the regioselective ring opening of
phosphorylated aziridines obtained here, to obtain fluoroalkyl
substituted N-unprotected â-amino phosphine oxides or -phos-
phonates.
SCHEME 6. Synthesis of Fluorine Containing
â-Aminophosphorus Derivatives 27 and 28
TABLE 5. â-Amino Phosphine Oxides 27 and 29 and â-Amino
Phosphonates 28 and 30 Obtained
entry
compd
R
R1
RF
R2
yield (%)a
1
2
3
4
5
6
7
8
9
27a
27b
27c
27d
28a
28b
29
Ph
Ph
Ph
Ph
OEt
OEt
Ph
OEt
OEt
H
H
H
H
H
CH3
CH3
C2H5
n-C3H7
C6H5
C2H5
73
59
53
65
64
57b
74
72
45
n-C3H7
CF3
CF3
C2F5
30a
30b
a Yield of isolated purified compounds. b Obtained as a mixture of two
diastereoisomers (50:50) and determined by 31P NMR.
ethanol to give a mixture of imine 25 (R ) OEt) and tautomeric
primary enamine 26 (R ) OEt) with 65% yield (ratio 1:1).
Afterward, we explored the regioselective ring opening of
3-alkyl or 3-aryl substituted phosphorylated aziridines 19-22,
because the absence of a methoxy group could avoid the
â-elimination and therefore N-unprotected â-amino phosphine
oxides or -phosphonates could be obtained. Ring opening of
the mixture of both isomers cis- and trans-aziridine-2-phosphine
oxides 19/20 (R ) Ph) was accomplished by catalytic transfer
hydrogenation with palladium. Reduction of 3-alkyl- and 3-aryl-
aziridine-2-phosphine oxides 19/20 with ammonium formate and
palladium on carbon in refluxing ethanol gave â-amino phos-
phine oxides 27 (Scheme 6, Table 5, entries 1-4). The formation
of these compounds 27 (R ) Ph) could be explained by
regioselective ring opening of the N-C2 single bond of the
ring. Reaction conditions are strong enough to achieve also the
hydrogenation of the allyl group (R2 ) CH2-CHdCH2) to
n-propyl substituent (R2 ) n-C3H7) (Scheme 6, Table 4, entry
3).
However, in this case, when the reaction of 3-methoxy-3-
trifluoromethyl aziridine-2-phosphine oxides 14a with am-
monium formate and palladium on carbon in refluxing ethanol
was performed, primary enamine 23 (R ) Ph) was obtained in
50% yield, instead of the expected â-amino phosphine oxides
24 (Scheme 5). The formation of this compound 23 (R ) Ph)
could be explained by regioselective ring opening of the N-C2
single bond of the ring followed by â-elimination of MeOH to
form imine 25 (R ) Ph) followed by tautomerization to enamine
23 (R ) Ph). The presence of a methoxy group in the R-position
to the amino group seems to favor the â-elimination of MeOH.
This reduction could also be extended to the ring opening of
3-methoxy-3-trifluoromethyl aziridine-2-phosphonate 15a with
ammonium formate and palladium on carbon in refluxing
(18) (a) Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem. 1997, 62,
3796-3797. (b) Davis, F. A.; Deng, J.; Zhang, Y.; Haltiwanger, R. C.
Tetrahedron 2002, 58, 7135-7143.
(19) For reviews, see the following: (a) Berrlicki, L.; Kafarski, P. Curr.
Org. Chem. 2005, 9, 1829-1850. (b) Kafarski, P.; Lejczak, B. Curr. Med.
Chem.-Anti-Cancer Agents 2001, 1, 301-312. (c) Aminophosphonic and
Aminophosphinic Acids. Chemistry and Biological ActiVity; Kukhar, V. P.,
Hudson, H. R., Eds.; Wiley: Chichester, U.K., 2000.
(20) For a review of â-phosphapeptidomimetics see Palacios, F.; Alonso,
C.; de los Santos, J. M. Cur. Org. Chem. 2004, 8, 1491-1496.
(21) (a) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J.
Org. Chem. 2003, 68, 2410-2419. (b) Palacios, F.; Ochoa de Retana, A.
M.; Gil, J. I. Tetrahedron Lett. 2000, 41, 5363-5366.
This process could be extended to aziridines derived from
phosphonates 21/22. Catalytic transfer hydrogenation in the
presence of Pd(0)/C and ammonium formate of diethyl cis- and
trans-3-ethyl-3-trifluoromethylaziridin-2-ylphosphonate 21/22a
(R ) OEt, R1 ) H, R2 ) C2H5) gave â-amino phosphonate
28a (R ) OEt, R2 ) C2H5) (Scheme 6, Table 5, entry 5) by
regioselective ring opening of the N-C2 single bond of the
J. Org. Chem, Vol. 71, No. 16, 2006 6145

Palacios et al.
SCHEME 7. Preparation of â-Aminophosphorus Derivatives
29 and 30 from Oximes 11 and 12
(route b, Scheme 7) with formation of p-toluelesulfonyl amino
derivative 33 followed by â-elimination of p-toluelesulfonic acid
and subsequent reduction of imine 34 cannot be discounted.
Conclusion
In conclusion, this account describes a simple, mild and
convenient strategy for the stereoselective addition of nucleo-
phile reagents such as alkoxides, imidazole, benzenethiol,
Grignard reagents, and hydrides to fluoroalkyl substituted
ketoxime phosphine oxides and phosphonates to give function-
alized aziridine phosphine oxides and phosphonates containing
fluorine. Fluoroalkyl substituted â-amino phosphine oxides and
â-amino phosphonates were obtained by catalytic hydrogenation
of aziridines, while the reaction of ketoximes derived from
phosphine oxides and phosphonates with sodium borohydride
gives directly fluoroalkyl substituted â-amino phosphine oxides
and â-amino phosphonates. Substituted azirines12 and aziri-
dines,23 as well as â-amino phosphorus derivatives,1,20 are
important building blocks in organic synthesis and in the
preparation of biologically active compounds of interest in
medicinal chemistry.
ring. Likewise, ring opening of 2-methyl substituted diethyl cis-
and trans-3-ethyl-3-trifluoromethylaziridin-2-ylphosphonate 21/
22d (R ) OEt, R1 ) CH3, R2 ) CH2-CHdCH2), by
hydrogenolysis with ammonium formate and palladium on
carbon, gave â-amino phosphonate 28b (R ) OEt, R1 ) CH3,
R2 ) n-C3H7) as a mixture of syn/anti isomers in 50:50
proportion (Scheme 6, Table 5, entry 6). The formation of these
compounds could be explained, as before, by regioselective ring
opening of the N-C2 single bond of the ring.13,21b As far as
we know, this strategy reports the first synthesis of fluorine
containing â-disubstituted â-aminophosphorus derivatives, and
allowed us to prepare â-fluoroalkyl â-amino phosphine oxides
27, and â-fluoroalkyl â-amino phosphonates 28 from readily
available aziridine-phosphine oxides and -phosphonates.
Finally, we explored the preparation of fluorine containing
â-amino phosphine oxides or -phosphonates with only a
substituent in position â directly from phosphorylated ketoximes.
For this objective, we thought that the use of hydrides could be
appropriate, because hydrides could act as base and nucleophilic
reagents in a similar behavior to that observed in organometallic
reagents (vide supra). Oximes22a,b and p-toluenesulfonyl oximes22c
have been reduced by lithium aluminum hydride, and the
reduction of oximes with sodium borohydride in the presence
of transition metal compounds has been reported.22d Treatment
of fluorine containing p-toluenesulfonyl oxime phosphine oxide
11a (R ) Ph, RF ) CF3) and p-toluenesulfonyl oxime
phosphonates 12a (R ) OEt, RF ) CF3) or 12b (R ) OEt, RF
) C2F5) with NaBH4 at low temperature (-30 °C) gave fluorine
containing â-amino phosphine oxide 29 (R ) Ph, RF ) CF3)
and â-amino phosphonates 30a (R ) OEt, RF ) CF3) and 30b
(R ) OEt, RF ) C2F5) (Scheme 7, Table 5, entries 7-9) in a
regioselective fashion.
Experimental Section
General Procedure for the Preparation of â-Phosphorylated
Ketones 3/7, gem-Diols 5/8, and Enols 4. To a solution of LDA
(6 mmol) in THF (25 mL) was added a solution of alkylphosphine
oxide 1 or alkylphosphonate 6 (5 mmol) in THF (15 mL) cooled
at -78 °C under nitrogen atmosphere. The mixture was stirred for
1 h at -78 °C. Next a solution of the corresponding ester was added
(6 mmol) in THF (12 mL) at the same temperature, and then the
mixture was allowed to warm at room temperature (15 h). After
the reaction was complete, the solvent was evaporated under
vacuum. The crude residue was treated with HCl to 10% (5 mL)
during 30 min. The crude reaction was extracted three times with
CH2Cl2 (3 × 15 mL). The organic layer was dried over anhydrous
MgSO4 and filtered, and the solvent was evaporated under vacuum.
The crude product was purified by vacuum distillation or by
chromatography using silica gel eluting with 2:1 hexane/ethyl
acetate to afford, according to the cases, â-phosphorylated ketones
3/7, gem-diols 5/8, or enols 4.
3,3,3-Trifluoro-2-hydroxypropenyldiphenylphosphine Oxide
4a. The general procedure was followed using diphenylmethylphos-
phine oxide 1a (1.01 g, 5 mmol) and ethyl trifluoromethyl acetate
2a (0.86 g, 6 mmol). Chromatographic purification eluting with
2:1 hexane/ethyl acetate afforded 1.15 g (74%) of compound 4a
1
as a yellow solid: mp 114-115 °C. H NMR (CDCl3): δ 7.79-
7.42 (m, 12H) ppm. 13C NMR (CDCl3): δ 134.8-129.3 (m), 125.9
1
3
(dq, JFC ) 289.6 Hz, JPC ) 11.6 Hz), 210.0 ppm. 31P NMR
(CDCl3): δ 36.5 ppm.19F NMR (CDCl3): δ -83.4 ppm. IR
(KBr): 3201, 3060, 1568, 1239, 1162, 759 cm-1. MS (EI): m/z
312 (M+, 20). Anal. Calcd for C15H12F3O2P: C, 57.70; H, 3.87.
Found: C, 57.90; H, 3.90.
General Procedure for the Preparation of (Z) and (E)-â-
Phosphorylated Ketoximes 9 and 10. To a solution of the â-keto-
phosphine oxides 3 or -phosphonate 7 (5 mmol) and hydroxylamine
hydrochloride (0. 42 g, 6 mmol) in ethanol (15 mL) was added
pyridine (0. 75 mL, 9. 3 mmol) at 0 °C. The reaction mixture was
kept at reflux for 6 h until the disappearance of the starting material.
Solvent was removed under reduced pressure, and the residue was
Formation of these â-amino phosphorus derivatives 29 and
30 could be explained (route a, Scheme 7) by the initial
formation of azirine 31 followed by nucleophilic addition of
hydride and subsequent regioselective ring opening of the
aziridine 32. However, a direct reduction of the oxime group
(23) For reviews of aziridines see the following: (a) Watson, I. D. G.;
Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194-206. (b) Padwa, A.;
Murphree, S. S. ArkiVok 2006, iii, 6-33. (c) Hu, X. E. Tetrahedron 2004,
60, 2701-2743. (d) Padwa, A.; Murphree, S. S. Prog. Heterocycl. Chem.
2003, 15, 75-99-33. (e) Chemla, F.; Ferreira, F. Curr. Org. Chem. 2002,
6, 539-570. (f) Sweeney, J. B. Chem. Soc. ReV. 2002, 31, 247-258.
(22) (a) Wang, S. S.; Sukenik, C. N. J. Org. Chem. 1985, 50, 5448-
5450. (b) Iida, H.; Yamazaki, N.; Kibayashi, C. Chem. Commun. 1987,
746-748. (c) Kocovsky, P. Synlett. 1990, 677-679. (d) Ipaktschi, Chem.
Ber. 1984, 117, 856-858.
6146 J. Org. Chem., Vol. 71, No. 16, 2006

â-Aminophosphorus DeriVatiVes and Aziridines
diluted in CH2Cl2 and washed twice with HCl 2 N (2 × 10 mL)
and then with water (10 mL). The organic layer was dried with
MgSO4 anhydrous and filtered, and the solvent was evaporated
under reduced pressure. The crude product was purified by
chromatography using silica gel eluting with 1:1 hexane/ethyl
acetate to afford â-ketoximes 9 or 10 as a variable mixture of E
and Z isomers.
Hz, 1H), 2.41 (s, 1H) ppm. 13C NMR (CDCl3): δ 132.6-128.6,
1 2
122.7 (q, JFC ) 281.0 Hz), 72.4 (q, JFC ) 42.3 Hz), 55.2, 40.5
(d, 1JPC ) 84.1 Hz) ppm. 31P NMR (CDCl3): δ 22.1 ppm. 19F NMR
(CDCl3): δ -70.6 ppm. IR (KBr): 3111, 1434, 1189 cm-1. MS
(EI): m/z 341 (M+, 10). Anal. Calcd for C16H15F3NO2P: C, 56.31;
H, 4.43; N: 4.10. Found: C, 56.40; H, 4.45; N: 4.07.
Procedure for the Preparation of trans-3-Imidazolyl-3-tri-
fluoromethylaziridin-2-yldiphenylphosphine Oxide 16. To a
solution of fluorinated p-toluenesulfonyl oximes 11a (2.40 g, 5
mmol) in THF (15 mL) was added slowly at 0 °C, under nitrogen
atmosphere, imidazole (0.76 g, 11 mmol). Then, the mixture was
allowed to warm at room temperature until TLC indicated the
disappearance of oxime. The solvent was evaporated under reduced
pressure, and the mixture was diluted in CH2Cl2 (15 mL) and
washed with water. The organic phase was dried with anhydrous
MgSO4 and filtered, and the solvent was evaporated under reduced
pressure. The crude residue was purified by flash chromatography
on silica gel (hexane/AcOEt 1/1) to afford 0.85 g (45%) of
compound 16 as a white solid: mp 150-151 °C. 1H NMR
(CDCl3): δ 7.79-7.20 (m, 11H), 6.77 (d, 3JHH ) 7.0 Hz, 2H), 3.29
(Z)-3,3,3-Trifluoro-2-N-hydroxyiminopropyldiphenylphos-
phine Oxide 9a. The general procedure was followed using the
enol 4a (1.56 g, 5 mmol). Chromatographic purification eluting
with 1:1 hexane/ethyl acetate afforded 1.12 g (73%) of compound
9a as a yellow solid: mp 156-157 °C. 1H NMR (CDCl3): δ 12.9
2
(s,1H), 7.81-7.40 (m, 10H), 3.63 (d, JPH ) 13.6 Hz, 2H) ppm.
13C NMR (CDCl3): δ 140.2 (dq, 1JFC ) 33.7 Hz, 2JPC ) 9.6 Hz),
132.6-128.6 (m), 119.6 (q, 1JFC ) 273.5 Hz, 3JPC ) 2.0 Hz), 27.9
(d, 1JPC ) 64.5 Hz) ppm. 31P NMR (CDCl3): δ 28.0 ppm. 19F NMR
(CDCl3): δ -68.7 ppm. IR (KBr): 3151, 3059, 1590, 1122 cm-1
.
MS (EI): m/z 328 (M+ + 1, 55). Anal. Calcd for C15H13F3NO2P:
C, 55.05; H, 4.00; N: 4.28. Found: C, 54.90; H, 3.90; N: 4.25.
General Procedure for the Preparation of Phosphorylated
â-p-Toluenesulfonyloximes 11 and 12. To a solution of NaH (5.5
mmol) in THF (15 mL) was added, at 0 °C under nitrogen
atmosphere, the oxime 9 or 10, and the mixture was allowed to
react at room temperature during 30 min. Then, to the mixture was
added, in portions at 0 °C, tosyl chloride (1. 05 g, 5. 5 mmol) freshly
recrystallized from hexane. The mixture was allowed to warm at
room temperature, and the reaction mixture was stirred for 2 h.
The NaH remainder was neutralized with methanol, and the solvent
was evaporated under vacuum. The crude reaction was extracted
with CH2Cl2 (15 mL) and washed with water (3 × 10 mL). The
organic layer was dried over anhydrous MgSO4 and filtered, and
the solvent was evaporated under vacuum. The crude product was
purified by chromatography using silica gel eluting with 2:1 hexane/
ethyl acetate to yield the compounds 11 as a white solid and 12 as
a pale yellow oil.
3
(s, 1H), 2.88 (t, JHH ) 12.7 Hz, 1H) ppm. 13C NMR (CDCl3): δ
137.5, 132.9-128.2 (m), 126.0, 121.7 (q, 1JFC ) 279.3 Hz), 119.4,
54.2 (q, 2JFC ) 39.3 Hz), 37.2 (d, 1JFC ) 98.7 Hz) ppm. 31P NMR
(CDCl3): δ 21.8 ppm. 19F NMR (CDCl3): δ -77.1 ppm. IR
(KBr): 3116, 3003, 1620, 1491, 1189 cm-1. MS (EI): m/z 378
(M+ + 1, 100). Anal. Calcd for C18H15 N3F3OP: C, 57.30; H, 4.01;
N: 11.14. Found: C, 57.30; H, 4.01; N: 11.14.
General Procedure for the Preparation of Aziridines 19-
22. To a solution of fluorinated p-toluenesulfonyl oximes 11 or 12
(5 mmol) in THF (15 mL) cooled at -78 °C, was added a solution
of Grignard reagent 18 (15 mmol) in diethyl ether under nitrogen
atmosphere. The mixture was stirred for 1 h at -78 °C and then
was allowed to warm at room temperature (15 h). After the reaction
was complete, the mixture was quenched with a saturated NH4Cl
solution (15 mL). The crude reaction was extracted three times with
CH2Cl2 (3 × 15 mL). The organic layer was dried over anhydrous
MgSO4 and filtered, and the solvent was evaporated under vacuum.
The crude residue was then purified by flash chromatography on
silica gel (hexane/AcOEt 2/1) affording mixtures of cis and trans
isomers: derivatives 19/20 as white solids and derivatives 21/22
as pale yellow oils.
(Z)-3,3,3-Trifluoro-2-(N-p-toluenesulfonyloxyimino)propyl-
diphenylphosphine Oxide 11a. The general procedure was fol-
lowed using the â-ketoxime-phosphine oxide 9a (1.63 g, 5 mmol).
Chromatographic purification eluting with 2:1 hexane/ethyl acetate
afforded 2.02 g (84%) of compound 11a as a white solid: mp 109-
110 °C. 1H NMR (CDCl3): δ 7.81-7.20 (m, 14H), 3.64 (d, 2JPH
)
14.5 Hz, 2H), 2.38 (s, 3H) ppm. 13C NMR (CDCl3): δ 150.2 (dq,
3-Methyl-3-trifluoromethylaziridin-2-yldiphenylphosphine Ox-
ide 19/20a. The general procedure was followed using (Z)-3,3,3-
trifluoro-2-(N-p-toluenesulfonyloxyimino) propyldiphenylphosphine
oxide 11a (2.40 g, 5 mmol) and methylmagnesium bromide 18a 3
M (5 mL, 15 mmol). Chromatographic purification eluting with
2:1 hexane/ethyl acetate afforded 0.94 g (58%) of a mixture (75/
25) of cis-19a (major component) and trans-20a (minor component)
as a white solid: mp 177-179 °C.
2
2JFC ) 35.2 Hz, JPC ) 9.0 Hz), 146.1, 132.7-126.5 (m), 119.0
(q, 1JFC ) 277.0 Hz, 3JP), 30.5 (d, 1JPC ) 57.9 Hz), 21.7 ppm. 31
P
NMR (CDCl3): δ 24.8 ppm. 19F NMR (CDCl3): δ -68.2 ppm.
IR (KBr): 3070, 1590, 1122 cm-1. MS (EI): m/z 482 (M+ + 1,
53). Anal. Calcd for C22H19F3NO4PS: C, 54.89; H, 3.98; N: 2.91;
S: 6.66. Found: C, 54.80; H, 3.94; N: 2.93; S: 6.64.
General Procedure for the Preparation of Aziridines 14-
17. To a solution of fluorinated p-toluenesulfonyl oximes 11 or 12
(5 mmol) in MeOH (15 mL) was added slowly at 0 °C, under
nitrogen atmosphere, the corresponding base (5.5 mmol). Then, the
mixture was allowed to warm at room temperature until TLC
indicated the disappearance of oxime. The solvent was evaporated
under reduced pressure, and the mixture was diluted in CH2Cl2 (15
mL) and washed with water. The organic phase was dried with
anhydrous MgSO4 and filtered, and the solvent was evaporated
under reduced pressure. The crude residue was purified by flash
chromatography on silica gel (hexane/AcOEt 1/1) to yield the
aziridines 14 or 15.
trans-3-Methoxy-3-trifluoromethylaziridin-2-yldiphenylphos-
phine Oxide 14a. The general procedure was followed using (Z)-
3,3,3-trifluoro-2-(N-p-toluenesulfonyloxyimino) propyldiphenyl-
phosphine oxide 11a (2.40 g, 5 mmol) and triethylamine (0.76 mL,
5.5 mmol) or NaOMe (0.28 g, 5.5 mmol). Chromatographic
purification eluting with 1:1 hexane/ethyl acetate afforded 1.45 g
(85%) (using triethylamine) or 0.88 g (52%) (using NaOMe) of
compound 11a as a white solid: mp 110-111 °C. 1H NMR
(CDCl3): δ 7.78-7.30 (m, 10H), 3.37 (s, 3H), 2.62 (d, 2JPH) 17.4
1
cis-19a. H NMR (CDCl3): δ 7.77-7.40 (m, 10H), 2.30 (dd,
2JPH ) 17.9 Hz, 3JHH ) 8.7 Hz 1H), 2.07 (dd, 2JPH ) 17.1 Hz, 3JHH
) 9.6 Hz 1H), 1.44 (s, 3H) ppm. 13C NMR (CDCl3): δ 134.4-
1
2
129.6, 124.9 (q, JFC ) 277.0 Hz), 43.2 (q, JFC ) 37.8 Hz), 41.3
(d, JPC ) 84.6 Hz), 19.5 ppm. 31P NMR (CDCl3): δ 24.2 ppm.
1
19F NMR (CDCl3): δ -68.8 ppm.
trans-20a. 1H NMR (CDCl3): δ 7.77-7.40 (m, 10H), 2.61 (dd,
2JPH ) 15.6 Hz, 3JHH ) 8.7 Hz 1H), 2.07 (dd, 2JPH ) 17.1 Hz, 3JHH
) 9.6 Hz 1H), 1.59 (s, 3H) ppm. 13C NMR (CDCl3): δ 133.1-
1
2
128.8, 124.4 (q, JFC ) 277.0 Hz), 40.8 (q, JFC ) 35.3 Hz), 34.0
(d, JPC ) 91.6 Hz), 11.9 ppm. 31P NMR (CDCl3): δ 23.2 ppm.
1
19F NMR (CDCl3): δ -70.7 ppm. IR (KBr): 3184, 3078, 1434,
1387, 1175 cm-1. MS (EI): m/z 326 (M+ + 1, 100). Anal. Calcd
for C16H15F3NOP: C, 59.08; H, 4.65; N: 4.31. Found: C, 59.17;
H, 4.66; N: 4.30.
General Procedure for Ring Opening of Aziridines. To a
solution of aziridine-2-phosphine oxides 14 or 19/20 or aziridine-
2-phosphonate 15 or 21/22 (5 mmol) in EtOH (15 mL) was added,
under nitrogen atmosphere, Pd/C (20%) and then ammonium
formate (4.74 g, 75 mmol). The mixture was kept at reflux for 18
J. Org. Chem, Vol. 71, No. 16, 2006 6147

Palacios et al.
h, until TLC indicated the disappearance of azirine. The solvent
was evaporated under reduced pressure, and the mixture was diluted
in water. Then, NH4OH solution (25%) was added until pH 8, and
the aqueous layer was extracted three times with CH2Cl2. The
combined organic layers were dried over anhydrous MgSO4, and
the solvent was evaporated. The crude mixture was purified by flash
column chromathography on silica gel (hexane/AcOEt 1/1) to afford
amino phosphorus derivatives 23 or 25-30 as white solids or
colorless oils.
added NaBH4 (15 mmol) at -30 °C under nitrogen atmosphere.
The mixture was stirred at -30 °C until TLC indicated the
disappearance of p-toluenesulfonyloxime. After the reaction was
complete, the mixture was quenched with a saturated NH4Cl
solution (15 mL). The crude reaction was extracted three times with
CH2Cl2 (3 × 15 mL). Organic layer was dried over anhydrous
MgSO4 and filtered, and the solvent was evaporated under vacuum.
The crude residue was then purified by flash chromatography on
silica gel (hexane/AcOEt 2/1) to yield the compounds 29 and 30
as a pale yellow oil.
2-Amino-3,3,3-trifluoropropen-1-yldiphenylphosphine Oxide
23. The general procedure was followed using trans-3-methoxy-
3-trifluoromethylaziridin-2-yldiphenylphosphine oxide 14a (1.71 g,
5 mmol). Chromatographic purification eluting with 1:1 hexane/
ethyl acetate afforded 0.78 g (50%) of compound 23 as a white
solid: mp 162-163 °C. 1H NMR (CDCl3): δ 7.70-7.23 (m, 10H),
2-Amino-3,3,3-trifluoropropyldiphenylphosphine Oxide 29.
The general procedure was followed using (Z)-3,3,3-trifluoro-2-
(N-p-toluenesulfonyloxyimino) propyldiphenylphosphine oxide 11a
(2.40 g, 5 mmol). Chromatographic purification eluting with 2:1
hexane/ethyl acetate afforded 1.15 g (74%) of compound 29 as a
2
5.82 (s, 2H), 4.86 (d, JPH ) 17.9 Hz, 1H) ppm. 13C NMR
1
pale yellow oil: Rf ) 0.41 (ethyl acetate). H NMR (CDCl3): δ
2
2
(CDCl3): δ 148.8 (q, JFC ) 33.2 Hz), 134.6-128.5, 120.4 (dq,
7.82-7.45 (m, 10H), 3.71 (m, 1H), 2.62 (ddd, JPH ) 10.4 Hz,
1JFC ) 276.5 Hz, 3JPC ) 27.7 Hz), 86.2 (dd, 1JPC ) 108.8 Hz, 3JFC
) 2.5 Hz) ppm. 31P NMR (CDCl3): δ 29.3 ppm. 19F NMR
(CDCl3): δ -72.4 ppm. IR (KBr): 3370, 3298, 3056, 1648, 1434,
1259, 1174 cm-1. MS (EI): m/z 311 (M+, 10), 310 (M+ - 1, 100).
Anal. Calcd for C15H13F3NOP: C, 57.88; H, 4.21; N: 4.50.
Found: C, 58.00; H, 4.22; N: 4.48.
2JHHgem ) 15.1 Hz, 2JHH ) 2.0 Hz 1H), 2.46 (ddd, 2JPH ) 11.4 Hz,
2
2JHHgem ) 15.1 Hz, JHH ) 12.1 Hz 1H), 1.94 (s, 2H) ppm. 13C
1
NMR (CDCl3): δ 134.7-128.7 (m), 127.1 (dq, JFC ) 280.5 Hz,
2
2
3JPC ) 17.6 Hz), 49.8 (dq, JFC ) 30.7 Hz, JPC ) 3.5 Hz), 30.3
(d, 1JPC ) 72.5 Hz) ppm. 31P NMR (CDCl3): δ 30.6 ppm. 19F NMR
(CDCl3): δ -80.0 ppm. IR (KBr): 3396, 3306, 3058, 1160, 1122
cm-1. MS (EI): m/z 313 (M+, 7), 215 (CH2P(O)Ph2+, 100). Anal.
Calcd for C15H15F3NOP: C, 57.51; H, 4.83; N: 4.47. Found: C,
57.45; H, 4.82; N: 4.48.
2-Amino-2-trifluoromethylpropyldiphenylphosphine Oxide
27a. The general procedure was followed using 3-methyl-3-
trifluoromethylaziridin-2-yldiphenylphosphine oxide 19/20a (1.63
g, 5 mmol). Chromatographic purification eluting with 1:1 hexane/
ethyl acetate afforded 1.19 g (73%) of compound 27a as a white
Acknowledgment. The authors thank the Direccio´n General
de Investigacio´n del Ministerio de Ciencia y Tecnolog´ıa
(MCYT, Madrid DGI, Grant PPQ2003-00910) and the Univer-
sidad del Pa´ıs Vasco (UPV, Grant GC/2002) for supporting this
work. J.M.A. thanks the Ministerio de Educacio´n (Madrid) for
a predoctoral fellowship.
1
solid: mp 65-66 °C. H NMR (CDCl3): δ 7.82-7.45 (m, 10H),
2.73 (dd, 2JPH ) 11.9 Hz, 2JHHgem ) 15.4 Hz, 1H), 2.59 (dd, 2JPH
)
2
11.2 Hz, JHHgem ) 15.4 Hz, 1H), 1.89 (s, 2H), 1.40 (s, 3H) ppm.
1
13C NMR (CDCl3): δ 134.7-128.7 (m), 126.9 (dq, JFC ) 281.7
3
2
2
Hz, JPC ) 14.2 Hz), 56.8 (dq, JFC ) 27.7 Hz, JPC ) 4.0 Hz),
34.5 (d, JPC ) 73.0 Hz), 23.0 ppm. 31P NMR (CDCl3): δ 28.4
1
ppm. 19F NMR (CDCl3): δ -84.4 ppm. IR (KBr): 3396, 3371,
3224, 1626, 1434, 1176, 1122 cm-1. MS (EI): m/z 327 (M+, 7),
215 (CH2P(O)Ph2+, 100). Anal. Calcd for C16H17F3NOP: C, 58.72;
H, 5.24; N: 4.28. Found: C, 58.78; H, 5.25; N: 4.29.
Supporting Information Available: Experimental procedures
and characterization data (1H NMR, 13C NMR, 31P NMR, IR, and
elemental analysis) for compounds 4b, 3c/4c, 3d/5d, 7a/8a, 7b/
8b, 7c/8c, 9b-d, 10a-c, 11b,c, 12a-c, 14b-d, 15a, 17, 19/20b,
19/20c, 19/20d, 19/20e, 21/22a, 21/22c, 21/22b, 21/22d, 25/26,
27b-d, 28a,b, 30a,b. This material is available free of charge via
the Internet at http://pubs.acs.org.
Procedure for the Preparation of Fluorine Containing
â-Aminophosphine Oxide 29 or â-Aminophosphonate 30 from
p-Toluenesulfonyloxime 11 or 12. To a solution of fluorinated
p-toluenesulfonyloxime phosphine oxide 11 (5 mmol) or p-
toluenesulfonyloxime phosphate 12 (5 mmol) in THF (15 mL) was
JO060865G
6148 J. Org. Chem., Vol. 71, No. 16, 2006