Reaction of 2H-azirine phosphine oxide and -phosphonates with nucleophiles. Stereoselective synthesis of functionalized aziridines and α- and β-aminophosphorus derivatives

Article abstract of DOI:10.1021/jo051404i

A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 3, and -phosphine oxide 5 by diastereoselective addition of Grignard reagents to 2H-azirine phosphonate 1 and -phosphine oxide 4 is reported. Similarly, the addition of heterocycl

Full text of DOI:10.1021/jo051404i

Reaction of 2H-Azirine Phosphine Oxide and -Phosphonates with
Nucleophiles. Stereoselective Synthesis of Functionalized
Aziridines and r- and â-Aminophosphorus Derivatives†
Francisco Palacios,* Ana M. Ochoa de Retana, and Jose´ M. Alonso
Departamento de Quı´mica Orga´nica I, Facultad de Farmacia, Universidad del Pa´ıs Vasco, Apartado 450,
01080 - Vitoria, Spain
francisco.palacios@ehu.es
Received July 7, 2005
A simple and efficient stereoselective synthesis of aziridine-2-phosphonate 3, and -phosphine oxide
5 by diastereoselective addition of Grignard reagents to 2H-azirine phosphonate 1 and -phosphine
oxide 4 is reported. Similarly, the addition of heterocyclic amines and benzenethiol to aziridines 1
and 4 yielded functionalized aziridines 10, 11, and 18. These aziridines are used as intermediates
for the regioselective synthesis of â-aminophosphine oxides 6 and â-aminophosphonates 7, as well
as R- aminophosphonates 8. Phenylsulfenyl-substituted R-aminophosphorus derivatives 15 and 19
are obtained directly from benzenethiol and 2H-azirine phosphonates 1 and -phosphine oxides 4.
Introduction
conditions used. In particular, 2H-azirines containing a
carboxylic ester group I (Scheme 1) are constituents of
naturally occurring antibiotics1d and are excellent re-
agents for the preparation of functionalized aziridines1,2b,c,3
and R-2c,3b,4a-c and â-amino acid derivatives.2c,3b,4d,e 2H-
Azirine phosphine oxides IIa and -phosphonates IIb
(Scheme 1) may represent an important tool in organic
synthesis because these small strained heterocycles are
expected to play a role similar to that of their isosteric
analogues I and therefore could be used as starting
materials for the preparation of phosphorus-substituted
aziridines and R- or â-aminophosphorus derivatives.
R-Aminophosphonates5 can be considered as surrogates
2H-Azirine ring systems represent an important class
of compounds because of their high reactivity.1 They can
be used as key intermediates in organic synthesis in the
preparation of heterocycles2a-e and acyclic functionalized
amino derivatives,2f,g since all three bonds of the azirine
ring can be cleaved, depending on the experimental
* Corresponding author. Phone: (+34) 945-013103. Fax: (+34) 945-
013049.
† Dedicated to Prof. Jose´ Barluenga on the occasion of his 65th
birthday.
(1) For recent reviews on azirines, see: (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. (d) Palacios, F.;
Ochoa de Retana, A. M.; Mart´ınez de Marigorta, E.; de los Santos, J.
M. Eur. J. Org. Chem. 2001, 2401-2414.
(3) (a) Osborn, H. M. I.; Sweeney, J. B. Tetrahedron: Asymmetry
1997, 8, 1693-1715. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 599-619.
(4) (a) Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002,
67, 1399-1402. (b) Filigheddu, S. N.; Taddei, M. Tetrahedron Lett.
1998, 39, 3857-3860. (c) Zwanenburg, B.; Thijs, L. Pure Appl. Chem.
1996, 68, 735-738. (d) Righi, G.; D’Achielle, R. Tetrahedron Lett. 1996,
37, 6893-6896. (e) Lim, Y.; Lee, W. K. Tetrahedron Lett. 1995, 36,
8431-8434.
(5) For reviews, see: (a) Kafarski, P.; Lejczak, B. Curr. Med.
Chem.: Anti-Cancer Agents 2001, 1, 301-312. (b) Aminophosphonic
and Aminophosphinic Acids. Chemistry and Biological Activity; Kukhar,
V. P., Hudson, H. R., Eds.; Wiley: Chichester, 2000.
(2) For recent contributions, see: (a) Padwa, A.; Stengel, T. Tetra-
hedron Lett. 2004, 45, 5991-5993. (b) Moneen, K.; Laureyn, I.; Stevens,
C. V. Chem. Rev. 2004, 104, 6177-6215. (c) Zhou, P.; Chen, B.-C.;
Davis, F. A. Tetrahedron 2004, 60, 8003-8030. (d) Pinho e Melo, T.
M. V. D.; Cardoso, A. L.; d’A Rocha Gonsalves, A. M. Tetrahedron 2003,
59, 2345-2351. (e) Timen, S.; Somfai, P. J. Org. Chem. 2003, 68, 9958-
9963. (f) Hilty, F. M.; Brun, K. A.; Heimgartner, H. Helv. Chim. Acta
2004, 87, 2539-2548. (g) Stamm, S.; Heimgartner, H. Eur. J. Org.
Chem. 2004, 3820-3827.
10.1021/jo051404i CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/29/2005
J. Org. Chem. 2005, 70, 8895-8901
8895

Palacios et al.
SCHEME 1
SCHEME 2
for R-amino acids6a and have been used as haptens for
the generation of catalytic antibodies6b,c or biologically
active compounds,6c-f whereas â-aminophosphonate de-
rivatives7 have been used for the preparation of enzyme
inhibitors, agrochemicals, or pharmaceuticals.
TABLE 1. 3,3-Disubstituted Aziridines 3 and 5 Obtained
entry compound
R
R1
R2
yield (%)a
1
2
3
4
5
6
7
3aa
3ab
3bc
5aa
5ac
5ad
5bc
OEt CH3 C2H5
60
66
87
57
68
65
63
In this context, we described new methods for the
preparation of phosphorus-substituted nitrogen hetero-
cycles8 from functionalized phosphine oxides and phos-
phonates and the synthetic uses of aminophosphorus de-
rivatives as starting materials for the synthesis of acyclic
compounds9a and phosphorus-containing heterocycles.9b,c
Likewise, we reported the preparation of 2H-azirine
phosphine oxides IIa and -phosphonates IIb (Scheme 1)
through base-mediated Neber reaction of â-ketoxime
tosylates and their use for the synthesis of aminophos-
phorus derivatives11 and phosphorylated pyrazines12a or
oxazoles.12b,c Continuing with our interest in the chem-
istry of small strained nitrogen heterocycles, we report
here the stereoselective addition of some nucleophilic
reagents to phosphorylated azirines and the use of
functionalized aziridines as key intermediates for the
preparation of new â-substituted R- or â-aminophosphine
oxides and phosphonates in a regioselective fashion.
OEt CH3 CH2-Ph
OEt Ph CH2-CHdCH2
Ph CH3 C2H5
Ph CH3 CH2-CHdCH2
Ph CH3 2-ethyl-[1,3]-dioxolanyl
Ph Ph CH2-CHdCH2
a Yield of isolated purified compounds 3 and 5.
to produce aziridines.1 The few reports of the addition of
Grignard reagents to 2H-azirines reveal that the aziri-
dine product is formed by attack at the least hindered
face,13 in a way similar to that reported for other
nucleophiles such as hydrides.1,10b However, the presence
of carboxylic esters in the azirine ring favors the attack
of Grignard reagent to the more hindered face (the same
of the carboxylic ester) as a consequence of prechelation
of the Grignard reagent with the carboxyl ester group.14
These reports prompted us to explore whether phosphine
oxide and phosphonate group, phosphorus isosteric analo-
gous of the carboxylic group, directly bonded to the
azirine ring could produce a similar effect to that
observed in the case of carboxylic ester and therefore to
explore if the reaction of Grignard reagents with phos-
phorylated azirines takes place through the more or least
hindered face of the azirine ring system.
Results and Discussion
Diastereoselective Addition of Grignard Re-
agents to 2H-Azirines. Due to the strain of the three-
membered ring, the electrophilic character of the C-N
double bond is higher than that in a normal imine and
azirines react with nucleophiles at the N-C3 double bond
Reaction of 2H-azirine phosphonate 1a (R ) OEt, R1
) CH3) with ethylmagnesium bromide 2a (R2 ) C2H5) in
THF at -78 °C led exclusively to the formation of diethyl
trans-3-ethyl-3-methylaziridin-2-yl phosphonate 3aa (R
) OEt, R1 ) CH3, R2 ) C2H5) (Scheme 2, Table 1, entry
(6) (a) Smith, A. B.; Yager, K. M.; Taylor, C. M. J. Am. Chem. Soc.
1995, 117, 10879-10888. (b) Smithrud, D. B.; Benkovic, P. A.;
Benkovic, S. J.; Taylor, C. M.; Yager, K. M.; Witherington, J.; Phillips,
B. W.; Sprengler, P. A.; Smith, A. B.; Hirschmann, R. J. Am. Chem.
Soc. 1997, 119, 278-282. (c) Steere, J. A.; Sampson, P. B.; Honek, J.
F. Bioorg. Med. Chem. Lett. 2002, 12, 457-460. (d) Cristau, H. J.;
Coulombeau, A.; Genevis-Borella, A.; Pirat, J. L. Tetrahedron Lett.
2001, 42, 4491-4494. (e) Georgiadis, D.; Dive, V.; Yiotakis, A. J. Org.
Chem. 2001, 66, 6604-6610. (f) Christensen, B. G.; Beattie, T. R. Ger.
Offen. 2.011.092; Chem Abstr. 1971, 74, 42491.
(7) For a recent review, see: Palacios, F.; Alonso, C.; de los Santos,
J. M. Chem. Rev. 2005, 105, 899-931.
(8) (a) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M.;
Alonso, C. Eur. J. Org. Chem. 2005, 1142-1147. (b) Palacios, F.; Ochoa
de Retana, A. M.; Mart´ınez de Marigorta, E.; Rodr´ıguez, M.; Pagalday,
J. Tetrahedron 2003, 59, 2617-2623. (c) Palacios, F.; Ochoa de Retana,
A. M.; Pagalday, J. Eur. J. Org. Chem. 2003, 913-919.
(9) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarza´bal,
J. J. Org. Chem. 2004, 69, 8767-8774. (b) Palacios, F.; Ochoa de
Retana, A. M.; Pascual, S.; Lo´pez de Muna´in, R.; Oyarza´bal, J.;
Ezpeleta, J. M. Tetrahedron 2005, 61, 1087-1094. (c) Palacios, F.;
Alonso, C.; Rodr´ıguez, M.; Mart´ınez de Marigorta, E.; Rubiales G. Eur.
J. Org. Chem. 2005, 1795-1804.
(10) (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.
(11) 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.
1). No trace of the cis-aziridine could be observed by 31
P
NMR. In the 31P NMR spectrum, the diethyl phosphonate
group of this aziridine 3aa resonated at δP ) 25.5 ppm,
while well-resolved doublets at δH ) 1.66 ppm (2JPH
)
1
14.7 Hz) for H2 in the H NMR spectrum as well as at
δC ) 34.7 ppm (1JPC ) 191.9 Hz) and at δC ) 41.6 ppm
for C2 and C3 in the 13C NMR spectrum were observed.
Spectroscopic data were in agreement with the assigned
structure of compound 3aa, and the stereochemical
assigment of derivative 3 was based on NOESY 1D
experiments. Irradiating the -C2-H proton of the aziri-
dine ring at 1.66 ppm showed an enhancement (1.32%)
of the methylene group protons (CH3CH2-C3) signal at
1.32 ppm (see Figure 1). On the other hand, the irradia-
tion of methyl protons (CH3-C3) at 1.43 ppm showed an
influence in the ethoxy groups bounded to the phosphorus
atom with an enhancement (0.30%) of the -OCH2-
(12) (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.
(13) Carlson, R. M.; Lee, S. Y. Tetrahedron Lett. 1969, 10, 4001-
4004.
(14) (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.
8896 J. Org. Chem., Vol. 70, No. 22, 2005

2H-Azirine Phosphine Oxide and -Phosphonates
SCHEME 3
TABLE 2. r- and â-Aminophosphorus Derivatives 6-8
Obtained
FIGURE 1.
entry starting material compound R1
R2
yield (%)a
1
2
3
4
5
6
5aa
5ac
5bc
3aa
3ab
3bc
6aa
6ac
6bc
7aa
8ab
8bc
CH3 C2H5
67
58
65
58
73
54
proton signal at 4.10 ppm as well as an enhancement
(0.61%) of the -OCH2CH3 proton signal at 1.30 ppm. The
exclusive formation of trans-aziridine 3aa suggests that
the approach of the ethylmagnesium bromide 2a to cyclic
compound from the position opposite the phosphine oxide
group is more favorable, due to the high exocyclic
dihedral angle of the saturated carbon and to the pres-
ence of the bulky phosphorus group, in a way similar to
that observed in the case of other nuchelophiles such as
hydride.10b The scope of the reaction was not limited to
ethylmagnesium bromide 2a (R2 ) C2H5), but also
Grignard reagents containing benzyl substituent 2b (R2
) CH2-Ph) as well as olefine groups 2c (R2 ) CH2-CHd
CH2) reacted with azirines 1a (R ) OEt, R1 ) CH3) and
1b (R ) OEt, R1 ) Ph) to give functionalized trans-
aziridine phosphonates 3ab and 3bc (Scheme 2, Table
1, entries 2 and 3) in a regioselective fashion. Aziridine
phosphonates have been also obtained by reaction of R-
lithiated halomethylphosphonates15a,b with imines, by
addition of diethyl phosphite anion to 1-nitro-2,2-diphen-
ylethylene15c and by cyclization of R-mesyl â-aminophos-
phonates.15d However, our strategy describes, as far as
we know, the first addition of Grignard reagents to 2H-
azirine-phosphonates, and aziridine derivatives 3 (R )
OEt) are formed diastereoselectively by attack of the
Grignard reagents at the least hindered face.
This process could also be extended to 2H-azirines
derived from diphenylphosphine oxide 4. Treatment of
3-methyl 4a (R ) Ph, R1 ) CH3) and 3-phenyl-2H-azirine
4b (R ) Ph, R1 ) Ph) with ethylmagnesium bromide 2a
(R2 ) C2H5), allylmagnesium bromide 2c (R2 ) CH2-
CHdCH2), and 2-ethyl-[1,3]-dioxolanylmagnesium bro-
mide 2d gave diastereoselectively 3,3-disubstituted azir-
idines 5aa, 5ac, 5ad, and 5bc (Scheme 2, Table 1, entries
4-7).
Ring Opening of Aziridines. Synthesis of r- and
â-Aminophosphorus Derivatives. Aminophosphorus
derivatives5,7 have acquired increased interest in recent
years because of their application in organic and medici-
nal chemistry. For this reason we tried to study if
phosphorylated aziridines obtained above by nucleophilic
attack of Grignard reagents to azirines could be used for
the preparation of R- and â-aminophosphorus derivatives.
Catalytic hydrogenation of N-substituted and non-N-
substituted aziridines bearing phosphorus functional
groups produces the corresponding aminophosphorus
derivatives with highly controlled regioselectivity.15a,16
CH3 n-C3H7
Ph
n-C3H7
CH3 C2H5
CH3 CH2-Ph
Ph
n-C3H7
a Yield of isolated purified compounds 6, 7, and 8.
SCHEME 4
Therefore, we explored the regioselective ring opening
of aziridines 3 and 5 to obtain N-unprotected R- or
â-aminophosphonates or -phosphine oxides. Ring opening
of aziridine-2-phosphine oxides 5 was accomplished by
catalytic transfer hydrogenation with palladium. Reduc-
tion of 3-disubstituted aziridine-2-phosphine oxides 5
with ammonium formate and palladium on carbon in
refluxing ethanol gave â-aminophosphine oxides 6 (Scheme
3, Table 2, entries 1-3). The formation of these com-
pounds 6 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 hydro-
genation of the allyl group (R2 ) CH2-CHdCH2) to
n-propyl substituent (R2 ) n-C3H7) (Scheme 3, Table 2,
entries 2 and 3).
This process could be extended to aziridines derived
from phosphonates 3. Catalytic transfer hydrogenation
in the presence of Pd(0)/C and ammonium formate of
diethyl 3-ethyl-3-methylaziridin-2-yl phosphonate 3aa
(R1 ) CH3, R2 ) C2H5) gave â-amino phosphonate 7aa
(R1 ) CH3, R2 ) C2H5) (Scheme 4, Table 2, entry 4) by
regioselective ring opening of the N-C2 single bond of
the ring in a way similar to that previously observed for
3-monosubstituted aziridine phosphonates.16 However, in
a manner similar to that reported for aziridine phospho-
(15) (a) Davis, F. A.; Wu, Y.; Yan, H.; McCoull, W.; Prasad, K. R. J.
Org. Chem. 2003, 68, 2410-2419. (b) Coutrot, P.; Abdelaziz, E.; Grison
C. Heterocycles 1989, 28, 1179-1192. (c) Russell, G. A.; Yao, C.-F.;
Tashtoush, H. I.; Russell, J. E.; Dedolph, D. F. J. Org. Chem. 1991,
56, 663-669. (d) Thomas, A. D.; Sharpless, K. B. J. Org. Chem. 1999,
64, 8379-8385.
nates with aryl substituents in the 3-position,11,15a
different behavior was observed by the hydrogenolysis
of diethyl 3-benzyl-3-methylaziridin-2-yl phosphonate
3ab (R1 ) CH3, R2 ) CH2-Ph) and diethyl 3-allyl-3-
a
(16) Palacios, F.; Ochoa de Retana, A. M.; Gil, J. I. Tetrahedron Lett.
2000, 41, 5363-5366.
J. Org. Chem, Vol. 70, No. 22, 2005 8897

Palacios et al.
TABLE 3. Functionalized Aziridine Derivatives
SCHEME 5
10 and 11
entry
compound
R
yield (%)a
1
2
3
10aa
10ab
11aa
Ph
87
83
69
Ph
OEt
a Yield of isolated purified compounds 10 and 11.
in the case of Grignard reagents, the exclusive formation
of trans-aziridine 11aa suggests that the approach of the
phthalimide to the 2H-azirine ring takes place from the
least hindered face.
Likewise, the reaction of other heterocyclic amine such
as imidazole 9b with 3-methyl-2H-azirine phosphine
oxide 4a (R ) Ph) at room temperature gave diastereo-
selectively functionalized trans-aziridine phosphine oxide
10ab (Scheme 5, Table 3, entry 2). Next, we studied the
hydrogenolysis of aziridine 10aa and 11aa, but unfor-
tunately this gave a complex mixture of products, while
hydrogenation of imidazolyl-substituted aziridine phos-
phine oxide 10ab led to the formation of 2-oxopropyl-
diphenylphosphine oxide 13 (X ) O). Formation of this
â-ketophosphine oxide 13 could be explained by ring
opening of the azirine followed by â-elimination of
imidazole with formation of imine 12 (X ) NH) and
hydrolysis of the imine to carbonyl compound 13 (X )
O).
phenylaziridin-2-yl phosphonate 3bc (R1 ) Ph, R2
)
CH2-CHdCH2), to afford R-amino phosphonate 8ad (R1
) CH3, R2 ) CH2-Ph) as a single anti isomer17,18 (Scheme
4, Table 2, entry 5) and 8bb (R1 ) Ph, R2 ) n-C3H7) as a
mixture of syn/anti isomers in 50:50 proportion (Scheme
4, Table 2, entry 6). The formation of these compounds
could be explained by regioselective ring opening of the
N-C3 single bond of the ring as an example of benzyl-
amine-type reduction.11,19 This strategy allowed us to
prepare â-disubstituted â-aminophosphine oxides 6, R-
and â-aminophosphonates 8 and 7 from readily available
aziridine phosphonates 3 and aziridine phosphine oxides
5.
Addition of Benzenethiol to 2H-Azirines. Reaction
of sulfur nucleophiles to 2H-azirines was also studied to
test if these nucleophiles could give a new entry to
functionalized aminophosphorus derivatives. For this
reason, we explored the reaction of 2H-azirine phosphine
oxides 4 and -phosphonates 1 with benzenethiol 14.
Treatment of 3-methyl-2H-azirin-2-yldiphenylphosphine
oxide 4a (R ) Ph, R1 ) CH3) with benzenethiol 14 at room
temperature led exclusively to the formation of 1-amine-
2-phenylsulfanylprop-2-en-1-yldiphenylphosphine oxide
15 (R ) Ph) (Scheme 6, Table 4, entry 1), instead of the
expected functionalized aziridine intermediate 16. Spec-
troscopic data were in agreement with the assigned
structure of compound 15 (R ) Ph). In the 31P NMR
spectrum, the phosphine oxide group of this acyclic
R-aminophosphorus derivative resonated at δP ) 30.5
ppm, while well-resolved doublets at δH ) 4.16 ppm (2JPH
) 6.1 Hz) for H-C1 as well as at δH ) 5.02 ppm (2JHHgem
) 3.4 Hz) and at δH ) 5.65 ppm (2JHHgem ) 3.4 Hz) for
Addition of Phthalimide and Imidazole to 2H-
Azirines. The behavior of 2H-azirine phosphine oxides
and -phosphonates toward some nitrogen nucleophiles
was also studied. Thus, we explored the behavior of
phosphorus-substituted 2H-azirines with heterocyclic
amines such as phthalimide and imidazole. Treatment
of 2H-azirine phosphine oxide 4a (R ) Ph) with phthal-
imide 9a at room temperature and in the presence of
NEt3 led regioselectively to the formation of trans-3-
methyl-3-phthalimidylaziridin-2-yldiphenylphosphine ox-
ide 10aa (R ) Ph) as a single product (Scheme 5, Table
3, entry 1). Azirine phosphonates 1 showed a similar
behavior: 3-methyl-2H-azirine phosphonate 1a (R ) OEt)
reacted with phthalimide 9a to yield exclusively trans-
aziridinyl phosphonate 11aa (R ) OEt) (Scheme 5, Table
3, entry 3). The stereochemical assigment of aducts 11aa
was based on NOESY 1D experiments,20 and as before
1
vinylic protons (dCH2) were observed in the H NMR
spectrum. The 13C NMR spectrum showed doublets at δC
) 56.1 ppm (1JPC ) 72.1 Hz) for C1 and at δC ) 116.8
ppm (3JPC ) 6.6 Hz) for C3. The formation of derivative
15 (R ) Ph) could be explained by addition of ben-
zenethiol 14 to the imine bond, followed by formation of
the carbon-carbon double bond and ring opening of the
aziridine intermediate 16 (Scheme 6). The instability of
compound 15 (R ) Ph) forced us to convert it into the
R-aminophosphine oxide hydrochloride 17 (R ) Ph) with
hydrogen chloride in CH2Cl2 (Table 4, entry 2). To verify
the reaction mechanism, we accomplished the addition
of benzenethiol 14 to 3-phenyl-2H-azirin-2-yldiphenylphos-
phine oxide 4b (R ) Ph, R1 ) Ph) to trap the aziridine
intermediate and to avoid the formation of the carbon-
carbon double bond. Effectively, the reaction of 3-phenyl-
2H-azirin-2-yldiphenylphosphine oxide 4b (R ) Ph, R1
(17) Determination of anti configuration was established according
to vicinal 3JHH ) 9.7 Hz coupling constant between H-C1 and H-C2,18
as well as by comparison with R-aminoesters (3JHH ) 7.5 Hz) obtained
by ring opening of aziridine esters.14a
(18) (a) Gaudemar, A.; Golfrer, M.; Mandelbaum, A.; Parthasarathy,
R. Determination of Configuration by Spectroscopic Methods; Kagan,
H. B., Ed.; G. Thieme: Stuttgart, 1977; Vol. 1.
(19) Hu, X. E. Tetrahedron 2004, 60, 2701-2743.
(20) Irradiating -CH2- protons of diethyl phosphonate moiety at
4.25 ppm showed an enhancement (1.14%) of the CH3-C3 proton signal
at 1.96 ppm, while irradiating H-C2 proton at 2.35 ppm showed no
enhancement of the CH3-C3 proton signal at 1.96 ppm
8898 J. Org. Chem., Vol. 70, No. 22, 2005

2H-Azirine Phosphine Oxide and -Phosphonates
SCHEME 6
TABLE 4. Sulfur-Containing Aminophosphorus
Derivatives 15, 17, 18, and 19
sphere. The mixture was stirred for 1 h at -78 °C and then
was allowed to warm to 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). Organic layer
was dried over anhydrous MgSO4 and filtered, and the solvent
was evaporated under vacuum. The crude residue was then
purified by flash cromatography (silica gel, AcOEt), affording
derivatives 5 as white solids and derivatives 3 as pale yellow
oils.
entry
compound
R
yield (%)a
1
2
3
4
15
17
18
19
Ph
74
56
58
58
Ph
Ph
OEt
a Yield of isolated purified compounds 15, 17, 18, and 19.
Diethyl trans-3-Ethyl-3-methylaziridin-2-ylphospho-
nate 3aa. The general procedure was followed using 2H-
azirine-2-phosphonate 1a (0.96 g, 5 mmol) and ethylmagne-
sium bromide 3 M 2a (5 mL, 15 mmol). Chromatographic
purification eluting with AcOEt afforded 0.66 g, (60%) of
compound 3aa as a pale yellow oil: Rf 0.61 (AcOEt/MeOH 5/1);
1H NMR (CDCl3) δ 4.17 (m, 4H), 1.66 (d, 2JPH ) 14.7 Hz, 1H),
1.55 (m, 2H), 1.50 (s, 3H), 1.36 (m, 7H), 0.98 (t, 3JHH ) 7.5 Hz,
) Ph) with benzenethiol 14 at room temperature followed
by purification of the crude reaction allowed us to obtain
the trans-aziridine phosphine oxide 18 (R ) Ph, R1 ) Ph)
as a single product (Scheme 6, Table 4, entry 3) in a
stereoselective fashion. 3-Methyl-2H-azirine phosphonate
1a (R ) OEt, R1 ) CH3) also reacted with benzenethiol
14 to afford regioselectively diethyl 1-amine-2-phenyl-
sulfanylprop-2-en-1-ylphosphonate 19 (R ) OEt) (Scheme
6, Table 4, entry 4). This process describes, as far as we
know, the first addition of sulfur nucleophiles to phos-
phorylated 2H-azirines and the synthesis of novel sulfur-
containing R-aminophosphine oxides and -phosphonates.
2
3H) ppm; 13C NMR (CDCl3) δ 62.0 (d, JPC ) 6.0 Hz), 61.9 (d,
1
2JPC ) 7.0 Hz), 41.6, 34.7 (d, JPC ) 191.9 Hz), 31.2, 17.5 (d,
3JPC ) 2.0 Hz), 16.4, 16.3, 9.8 ppm; 31P NMR (CDCl3) δ 25.5
ppm; IR (NaCl) 3244, 1679, 1454, 1394, 1248 cm-1; MS (EI)
m/z 221 (M+, 7), 84 (M+ - P(O)(OEt)2, 100); Anal. Calcd for
C9H20NO3P: C, 48.86; H, 9.11; N, 6.33. Found: C, 48.97; H,
9.13; N, 6.31.
trans-3-Ethyl-3-methylaziridin-2-yldiphenylphosphine
Oxide 5aa. The general procedure was followed using 2H-
azirine-2-diphenylphosphine oxide 4a (1.28 g, 5 mmol) and
ethylmagnesium bromide 3 M 2a (5 mL, 15 mmol). Chromato-
graphic purification eluting with AcOEt afforded 0.82 g (57%)
Conclusion
In conclusion, this account describes a simple, mild,
and convenient strategy for the stereoselective addition
of Grignard reagents, phthalimide, imidazole, and ben-
zenethiol to 2H-azirines phosphonates 1 and -phosphine
oxides 4 to give trans-functionalized aziridine phospho-
nates 3, 11, and -phosphine oxides 5, 10, 18. â-Amino-
phosphine oxides 6 and R- and â-aminophosphonates 8
and 7 were obtained by catalytic hydrogenation of aziri-
dines 5 and 3, while reaction of azirine phosphine oxides
4 and -phosphonates 1 with benzenethiol allowed us to
obtain sulfur-substituted aziridine 18 as well as R-ami-
nophosphine oxides 15, 17, and R-aminophosphonate 19
with a thioolefine in â-position. Substituted aziridines as
well as R- and â-aminophosphorus derivatives are im-
portant building blocks in organic synthesis3,5-7 and in
the preparation of biologically active compounds of inter-
est in medicinal chemistry.5-7
1
of compound 4aa as a white solid: mp 119-118 °C; H NMR
(CDCl3) δ 7.83-7.41 (m, 10), 2.11 (d, 2JPH ) 23.2 Hz, 1H), 1.80
3
(s, 1H), 1.59 (m, 1H), 1.42 (s, 3H), 1.38 (m, 1H), 0.92 (t, JHH
) 7.5 Hz, 3H) ppm; 13C NMR (CDCl3) δ 134.2-128.6 (m), 42.9
2
1
3
(d, JPC ) 1.3 Hz), 38.1 (d, JPC ) 95.4 Hz), 33.6, 17.1 (d, JPC
) 2.1 Hz), 10.1 ppm; 31P NMR (CDCl3) δ 28.2 ppm; IR (KBr)
3224, 3051, 1434, 1374, 1188 cm-1; MS (EI) m/z 285 (M+, 12),
84 (M+ - P(O)Ph2, 100); Anal. Calcd for C17H20NOP: C, 71.56;
H, 7.07; N, 4.91. Found: C, 71.74; H, 7.08; N, 4.89.
General Procedure for Hydrogenation Ring Opening
of Aziridines 3 and 5. To a solution of aziridine 3 or 5 (5
mmol) in EtOH (15 mL) was added under nitrogen atmosphere
Pd/C (20%) and then ammonium formate (75 mmol). The
mixture was kept at reflux for 8 h. 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 to afford amino phosphorus derivatives 6,
7, or 8 as white solids or colorless oils.
2-Amino-2-methylbuthyldiphenylphosphine Oxide 6aa.
The general procedure was followed using aziridine-2-diphe-
nylphoshine oxide 5aa (1.43 g, 5 mmol). Chromatographic
purification eluting with AcOEt afforded 0.96 g (67%) of
compound 6aa as a colorless oil: Rf 0.15 (AcOEt/MeOH 5/1);
1H NMR (CDCl3) δ 7.82-7.26 (m, 10H), 2.73 (s, 2H), 2.53 (d,
Experimental Section
General Procedure for the Preparation of Aziridines
3 and 5. To a solution of 2H-azirine 1 or 4 (5 mmol) in THF
(15 mL) cooled to -78 °C, was added a solution of Grignard
reagent 2 (15 mmol) in diethyl ether under nitrogen atmo-
J. Org. Chem, Vol. 70, No. 22, 2005 8899

Palacios et al.
2JPH ) 10.4 Hz, 2H), 1.57 (q, 3JHH ) 7.3 Hz, 2H), 1.15 (s, 3H),
(M+ + 1, 92); Anal. Calcd for C15H19N2O5P: C, 53.26; H, 5.66;
N, 8.28. Found: C, 53.39; H, 5.68; N, 8.27.
3
0.82 (t, JHH ) 7.3 Hz, 3H) ppm; 13C NMR (CDCl3) δ 135.3-
2
1
128.6 (m), 54.0 (d, JPC ) 5.0 Hz), 40.1 (d, JPC ) 70.4 Hz),
Procedure for Hydrogenation Ring Opening of Aziri-
dine 10ab. Synthesis of 2-Oxopropyldiphenylphosphine
Oxide 13. To a solution of aziridine 10ab (1.62 g, 5 mmol) in
EtOH (15 mL) was added under nitrogen atmosphere Pd/C
(20%) and then ammonium formate (75 mmol). The reaction
was kept at reflux for 8 h. 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
eluting with AcOEt to afford derivative 13 (0.62 g, 48%) as a
white solid: mp 125-126 °C. Spectroscopic data were in
agreement with the literature.21
Procedure for the Synthesis of Sulfur-Substituted
Aminophosphorus Derivatives 15, 18, and 19. Benzeneth-
iol 14 (0.61 g, 5.5 mmol) was added to a solution of 2H-azirine
1 or 4 (5 mmol) in CH2Cl2 (15 mL) cooled to 0 °C under a
nitrogen atmosphere. The mixture was stirred at room tem-
perature until TLC indicated the disappearance of azirine (48
h). The crude reaction was washed three times with H2O (3 ×
10 mL), and the organic layer was dried over anhydrous
MgSO4 and filtered. Evaporation of solvent under reduced
pressure and chromatographic purification by flash column
chromatography with hexane/AcOEt 1:1 afforded the corre-
sponding derivatives 15, 18, and 19 as pale yellow oils or
yellow solids.
1-Amino-2-phenylsulfanylpro-2-en-1-yldiphenylphos-
phine Oxide 15. The general procedure was followed using
2H-azirine-2-diphenylphosphine oxide 4a (1.28 g, 5 mmol).
Chromatographic purification eluting with hexane/AcOEt 1:1
afforded 1.29 g (74%) of compound 15 as a pale yellow oil: Rf
0.21 (AcOEt); 1H NMR (CDCl3) δ 8.08-7.18 (m, 15H), 5.65 (d,
2JHHgem ) 3.5 Hz, 1H), 5.02 (d, 2JHHgem ) 3.4 Hz, 1H), 4.16 (d,
2JPH ) 6.1 Hz, 1H), 2.28 (s, 2H) ppm; 13C NMR (CDCl3) δ
133.2-128.1 (m), 116.8 (d, 3JPC ) 6.6 Hz), 56.1 (d, 1JPC ) 72.1
Hz) ppm; 31P NMR (CDCl3) δ 30.5 ppm; IR (NaCl) 3383, 3051,
1725, 1672, 1633, 1434, 1182 cm-1; MS (CI) m/z 366 (M+ + 1,
100); Anal. Calcd for C21H20NOPS: C, 69.02; H, 5.52; N, 3.83;
S, 8.77. Found: C, 68.91; H, 5.50; N, 3.84; S, 8.76.
Preparation of trans-3-Phenyl-3-phenylsulfanylaziri-
din-2-yldiphenylphosphine Oxide 18. The general proce-
dure was followed using 2H-azirine-2-diphenylphosphine oxide
4b (1.59 g, 5 mmol). Chromatographic purification eluting with
hexane/AcOEt 1:1 afforded 1.03 g (58%) of compound 18 as a
yellow solid: mp 74-73 °C; 1H NMR (CDCl3) δ 7.95-6.89 (m,
15H), 3.22 (d, 2JPH ) 17.1 Hz, 1H), 2.17 (s, 1H) ppm; 13C NMR
(CDCl3) δ 134.8-125.3 (m), 51.8, 40.6 (d, 1JPC ) 102.7 Hz) ppm;
31P NMR (CDCl3) δ 25.4 ppm; IR (KBr) 3158, 3051, 1626, 1580,
1434, 1175, 1122 cm-1; MS (CI) m/z 428 (M+ + 1, 100); Anal.
Calcd for C26H22NOPS: C, 73.05; H, 5.19; N, 3.28; S, 7.50.
Found: C, 73.18; H, 5.20; N, 3.27; S, 7.48.
37.0 (d, JPC ) 8.6 Hz), 28.2 (d, JPC ) 6.6 Hz), 8.2 ppm; 31P
NMR (CDCl3) δ 29.5 ppm; IR (NaCl) 3434, 3045, 1583, 1434,
1180 cm-1; MS (EI) m/z 288 (M+ + 1, 90), 271 (M+ - NH2,
100); Anal. Calcd for C17H22NOP: C, 71.06; H, 7.72; N, 4.87.
Found: C, 71.15; H, 7.74; N, 4.86.
3
3
Diethyl 2-Amino-2-methylbuthylphosphonate 7aa. The
general procedure was followed using aziridine-2-phosphonate
3aa (1.11 g, 5 mmol). Chromatographic purification eluting
with AcOEt afforded 0.65 g (58%) of compound 7aa as a
1
colorless oil: Rf 0.60 (AcOEt/MeOH 5/1); H NMR (CDCl3) δ
2
4.11 (m, 4H), 1.91 (d, JPH ) 18.5 Hz, 2H), 1.88 (s, 2H),1.54
3
2
3
(dq, JHH ) 7.5 Hz, JHHgem ) 3.7 Hz, 2H), 1.33 (t, JHH ) 7.2
4
3
Hz, 7.0 Hz, 6H), 1.22 (d, JPH ) 0.8 Hz, 3H), 0.92 (t, JHH
)
7.5 Hz, 3H) ppm; 13C NMR (CDCl3) δ 61.3, 61.2, 50.9 (d, JPC
2
1
3
) 4.5 Hz), 37.9 (d, JPC ) 136.5 Hz), 37.0 (d, JPC ) 11.6 Hz),
28.4 (d, 3JPC ) 8.6 Hz), 16.4, 16.3, 8.4 ppm; 31P NMR (CDCl3)
δ 30.1 ppm; IR (NaCl) 3423, 1633, 1454, 1381, 1241 cm-1; MS
(EI) m/z 223 (M+, 10), 222 (M+ - 1, 100); Anal. Calcd for C9H22-
NO3P: C, 48.42; H, 9.93; N, 6.27. Found: C, 48.34; H, 9.91;
N, 6.28.
Diethyl 1-Amino-2-methyl-3-phenylpenthylphospho-
nate 8ab. The general procedure was followed using aziridine-
2-phosphonate 3ab (1.42 g, 5 mmol). Chromatographic puri-
fication eluting AcOEt afforded 1.04 g (73%) of compound 8ab
1
as a colorless oil: Rf 0.26 (AcOEt); H NMR (CDCl3) δ 7.23-
3
7.05 (m, 5H), 4.18 (m, 4H), 3.42 (dq, JHHanti ) 9.5 Hz, 1H),
3
2
3.31 (dd, JHHanti ) 9.5 Hz, JPH) 10.5 Hz, 1H), 2.40 (s, 2H),
1.70 (s, 2H), 1.21 (m, 9H) ppm; 13C NMR (CDCl3) δ 137.6-
125.6 (m), 62.1, 54.3 (d, 1JPC ) 153.2 Hz), 36.9, 29.7, 20.0, 16.5
(d, 5JPC ) 5.7 Hz) ppm; 31P NMR (CDCl3) δ 28.7 ppm; IR (NaCl)
3384, 1467, 1223, 1064 cm-1; MS (EI) m/z 285 (M+, 7), 148
(M+ - P(O)(OEt)2, 100); Anal. Calcd for C14H24NO3P: C, 58.93;
H, 8.48; N, 4.91. Found: C, 59.08; H, 8.50; N, 4.92.
General Procedure for the Synthesis of Functional-
ized Aziridines 10 and 11. To a solution of 2H-azirine 1 and
4 (5 mmol) in benzene (15 mL) cooled to 0 °C, triethylamine
(5.5 mmol) was added slowly under a nitrogen atmosphere and
with continuous stirring. Then phthalimide (0.81 g, 5 mmol)
was added, and the reaction mixture was stirred at room
temperature for 48 h. The crude reaction was then washed
three times with H2O (3 × 5 mL). The organic layer was dried
over anhydrous MgSO4 and filtered, and the solvent was
evaporated under reduced pressure. Crude reaction was puri-
fied by crystallization from diethyl ether/hexane 2:1 for aziri-
dine-2-diphenylphosphine oxide derivatives 10, while aziridine-
2-phosphonate derivatives 11 were purified by column chromato-
graphy eluting hexane/AcOEt 2:1.
trans-3-Methyl-3-phthalimidylaziridin-2-yldiphenylphos-
phine Oxide 10aa. The general procedure was followed using
2H-azirine-2-diphenylphosphine oxide 4a (1.28 g, 5 mmol).
Crystallization of the crude from diethyl ether/hexane 2:1
afforded 2.31 g (87%) of compound 10aa as a white solid: mp
94-93 °C; 1H NMR (CDCl3) δ 8.27-7.42 (m, 14H), 2.92 (d, 2JPH
) 21.1 Hz, 1H), 2.37 (s, 1H), 1.80 (s, 3H) ppm; 13C NMR
Diethyl 1-Amino-2-phenylsulfanylpro-2-en-1-ylphos-
phonate 19. The general procedure was followed using 2H-
azirine-2-phosphonate 4a (0.96 g, 5 mmol). Chromatographic
purification eluting with hexane/AcOEt 1:1 afforded 0.88 g
(58%) of compound 19 as a pale yellow oil: Rf 0.19 (AcOEt);
1H NMR (CDCl3) δ 7.48-7.20 (m, 5H), 5.65 (d, 4JPH ) 4.4 Hz,
1
(CDCl3) δ 167.1, 134.2-123.2 (m), 48.9, 37.0 (d, JPC ) 89.6
Hz), 18.4 (d, 3JPC ) 1.0 Hz) ppm; 31P NMR (CDCl3) δ 26.8 ppm;
IR (KBr) 3429, 3191, 3051, 1719, 1374, 1195 cm-1; MS (CI)
m/z 403 (M+ + 1, 60); Anal. Calcd for C23H19N2O3P: C, 68.75;
H, 4.76; N, 6.96. Found: C, 68.89; H, 4.77; N, 6.95.
1H), 5.15 (d, 4JPH ) 4.0 Hz, 1H), 4.19 (m, 4H), 3.76 (d, 2JPH
)
19.1 Hz, 1H), 1.90 (s, 2H), 1.35 (m, 6H) ppm; 13C NMR (CDCl3)
δ 143.3-126.5 (m), 116.3 (d, 3JPC ) 8.6 Hz), 62.8 (d, 2JPC ) 7.1
Diethyl trans-3-Methyl-3-phthalimidylaziridin-2-ylphos-
phonate 11aa. The general procedure was followed using 2H-
azirine-2-phosphonate 1a (0.96 g, 5 mmol). Chromatographic
purification eluting with hexane/AcOEt 2:1 afforded 1.17 g
2
1
Hz), 62.7 (d, JPC ) 7.1 Hz), 54.1 (d, JPC ) 151.1 Hz), 16.3,
16.2 ppm; 31P NMR (CDCl3) δ 24.1 ppm; IR (NaCl) 3456, 3376,
3297, 1732, 1606, 1480, 1434, 1241 cm-1; MS (CI) m/z 302 (M+
+ 1, 100); Anal. Calcd for C13H20NO3PS: C, 51.81; H, 6.69; N,
4.65; S, 10.64. Found: C, 51.95; H, 6.70; N, 4.64; S, 10.65.
Preparation of 1-Diphenylphosphinyl-2-phenylsulfa-
nylallylammonium Chloride 17. A solution of the sulfur-
substituted amino phosphorus derivative 15 (1.83 g, 5 mmol)
1
(69%) of compound 11aa as a white solid: mp 85-84 °C; H
NMR (CDCl3) δ 7.86-7.34 (m, 4H), 4.31 (m, 4H), 2.40 (d, 2JPH
3
) 13.8 Hz, 1H), 1.96 (s, 3H), 1.68 (s, 1H), 1.43 (q, JHH ) 6.9
Hz, 6H) ppm; 13C NMR (CDCl3) δ 167.0, 134.3, 123.4, 63.0 (d,
2
1
2JPC ) 6.0 Hz), 62.6 (d, JPC ) 5.5 Hz), 47.8, 34.1 (d, JPC
)
184.8 Hz), 18.9, 16.4, 16.3 ppm; 31P NMR (CDCl3) δ 21.4 ppm;
IR (KBr) 3436, 3260, 1725, 1387, 1023 cm-1; MS (CI) m/z 339
(21) Corbel, B. Synthesis 1985, 1048-1051.
8900 J. Org. Chem., Vol. 70, No. 22, 2005

2H-Azirine Phosphine Oxide and -Phosphonates
in CH2Cl2 (15 mL) was saturated with hydrogen chloride, and
the mixture was stirred at room temperature under nitrogen
atmosphere until the disappearance of the starting material.
Evaporation of solvent under reduced pressure and crystal-
lization from diethyl ether afforded 1.12 g (56%) of compound
Acknowledgment. We thank the Direccio´n General
de Investigacio´n del Ministerio de Ciencia y Tecnolog´ıa
(MCYT, Madrid DGI, PPQ2003-00910) and the Univer-
sidad del Pa´ıs Vasco (UPV, GC/ 2002) for supporting
this work. J.M.A. thanks the Ministerio de Educacio´n
(Madrid) for a predoctoral fellowship.
1
17 as a yellow solid: mp 74-73 °C; H NMR (CDCl3) δ 9.49
4
(s, 3H), 7.98-7.09 (m, 15H), 5.65 (s, 1H), 5.16 (d, JPH ) 1.5
Hz, 1H), 5.06 (d, 2JPH ) 6.9 Hz, 1H) ppm; 13C NMR (CDCl3) δ
137.1-126.4 (m), 117.8 (d, 3JPC ) 6.6 Hz), 52.7 (d, 1JPC ) 67.0
Hz) ppm; 31P NMR (CDCl3) δ 31.9 ppm; IR (KBr) 3429, 3151,
3058, 1732, 1679, 1586, 1440, 1175 cm-1; MS (CI) m/z 402 (M+
Supporting Information Available: Experimental pro-
cedures and characterization data (1H NMR, 13C NMR, 31P
NMR, IR, and elemental analysis) for compounds 3ab, 3bc,
5ac, 5ad, 5bc, 6ac, 6bc, 8bc, and 10ab. This material is
available free of charge via the Internet at http://pubs.acs.org.
+
+ 1, 7), 203 (P(O)Ph2 + 2, 100); Anal. Calcd for C21H21-
ClNOPS: C, 62.76; H, 5.27; N, 3.49; S, 7.98. Found: C, 62.63;
H, 5.26; N, 3.49; S, 7.99.
JO051404I
J. Org. Chem, Vol. 70, No. 22, 2005 8901