Michael addition of amine derivatives to conjugate phosphinyl and phosphonyl nitrosoalkenes. Preparation of α-amino phosphine oxide and phosphonate derivatives

Article abstract of DOI:10.1021/jo0705521

(Chemical Equation Presented) The synthesis of nitrosoalkenes derived from phosphine oxides and phosphonates generated through base-mediated dehydrohalogenations of readily available α-halooximes is reported. These highly reactive intermediates act as Mic

Full text of DOI:10.1021/jo0705521

Michael Addition of Amine Derivatives to Conjugate Phosphinyl
and Phosphonyl Nitrosoalkenes. Preparation of r-Amino Phosphine
Oxide and Phosphonate Derivatives#
Jesu´s M. de los Santos, Roberto Ignacio, Domitila Aparicio, and Francisco Palacios*
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 March 22, 2007
The synthesis of nitrosoalkenes derived from phosphine oxides and phosphonates generated through base-
mediated dehydrohalogenations of readily available R-halooximes is reported. These highly reactive
intermediates act as Michael acceptors toward nucleophilic reagents such as ammonia, amines, and optically
active amino esters, furnishing R-amino phosphine oxides and phosphonates in a highly regioselective
fashion.
Introduction
recently renewed interest in nitroso compounds due to their
applications in catalytic or cycloaddition processes.5 Nitroso-
alkenes (I, see Figure 1) are functionalized nitroso derivatives,
and the presence of an adjacent double bond in conjugation with
the nitroso moiety introduces new reactivity centers in these
substrates and then increases the synthetic value of these
compounds. Therefore, the usefulness of nitrosoalkenes6 (I) as
conjugate addition acceptors,7 coupled with the easy conversion
of the nitroso group into other functionalities, such as oximes
and ketones,8 or their ability to act as dienes in hetero-Diels-
Alder reactions for the preparation of 1,2-oxazine derivatives,9
has been reported. Examples of nitrosoalkenes with substitution
Oximes have great potential not only as intermediates in
organic synthesis1,2 and in the preparation of natural products
such as erythromycin derivatives3a and perhydrohistrionicotoxin3b
but also for their industrial applications in the areas of
agrochemicals,4a medicinal chemistry,4b toxicology,4c,d and in
the preparation of cephalosporin derivatives with potent anti-
bacterial activity.4e Likewise, there has been a great deal of
# Dedicated to Prof. Vicente Gotor on the occasion of his 60th birthday.
(1) Preparation and the synthetic utility of oximes: (a) Unterhalt, B.
Houben-Weyl. Methoden der Organischen Chemie, Band E14b; Klamann,
D., Hagemann, H., Eds.; G. Thieme Verlag: Stuttgart, 1990; pp 287-432.
(b) Sandler, S. R.; Karo, W. Organic Functional Group Preparations, 2nd
ed.; Academic Press, Inc.: San Diego, CA, 1989; Vol. 3, pp 431-476.
(2) For recent communications, see: (a) Savarin, C. G.; Grise, C.; Murry,
J. A.; Reamer, R. A.; Hughes, D. L. Org. Lett. 2007, 9, 981-983. (b) Huang,
S.; Li, R.; Connolly, P. J.; Xu, G.; Gaul, M. D.; Emanuel, S. L.; LaMontagne,
K. R.; Greenberger, L. M. Bioorg. Med. Chem. Lett. 2006, 16, 6063-6066.
(c) Dang, T. T.; Albrecht, U.; Gerwien, K.; Siebert, M.; Langer, P. J. Org.
Chem. 2006, 71, 2293-2301.
(3) (a) Morimoto, S.; Adachi, T.; Matsunaga, T.; Kashimura, M.;
Watanabe, Y.; Sota, K. Jpn. Kokai Tokkyio Koho JP63-183597, 1988; Chem.
Abstr. 1986, 109, 6898q. (b) Corey, E. J.; Petrzilka, M.; Ueda, Y. HelV.
Chim. Acta 1977, 60, 2294-2302.
(4) (a) Toyabe, K.; Usami, T.; Taketoi, T.; Nagata, T.; Nakano, J.; Kudo,
S.; Kurihara, H. Jpn. Kokai Tokkyio Koho 96153, 491, 1996; Chem. Abstr.
1996, 125, 167543. (b) Hill, M.; Lapcik, O.; Hampl, R.; Starka, L.; Putz,
Z. Steroids 1995, 60, 615-620. (c) Karalliedde, L.; Baker, D.; Marrs, T.
C. Toxicol. ReV. 2006, 25, 1-14. (d) Petroianu, G. A.; Arafat, K.; Kuca,
K.; Kassa, J. J. Appl. Toxicol. 2006, 26, 64-71. (e) Bateson, J. H.; Burton,
G.; Fell, C. M.; Smulders, C. H. J. Antibiot. 1994, 47, 253-256.
(5) For recent reviews, see: (a) Yamamoto, Y.; Yamamoto, H. Eur. J.
Org. Chem. 2006, 2031-2043. (b) Yamamoto, H.; Nimiyama, N. Chem.
Commun. 2005, 3514-3525. (c) Gowenlock, B. G.; Richter-Addo, G. B.
Chem. ReV. 2004, 104, 3315-3340. (d) Adam, W.; Krebs, O. Chem. ReV.
2003, 103, 4131-4146.
(6) For an excellent review, see: Gilchrist, T. L. Chem. Soc. ReV. 1983,
12, 53-73.
(7) (a) Tishkov, A. A.; Lesiv, A. V.; Khomutova, Y. A.; Strelenko, Y.
A.; Nesterov, I. D.; Antipin, M. Y.; Ioffe, S. L.; Denmark, S. E. J. Org.
Chem. 2003, 68, 9477-9480. (b) Trewartha, G.; Burrows, J. N.; Barret, A.
G. M. Tetrahedron Lett. 2005, 46, 3553-3556.
(8) For a review, see: Corsaro, A.; Chiacchio, U.; Pistara, V. Synthesis
2001, 1903-1931.
(9) (a) Domingo, L. R.; Picher, M. T.; Arroyo, P. Eur. J. Org. Chem.
2006, 2570-2580. (b) Gallos, J. K.; Sarli, V. C.; Massen, Z. S.; Varvogli,
A. C.; Papadoyanni, C. Z.; Papaspyrou, S. D.; Argyropoulos, N. G.
Tetrahedron 2005, 61, 565-574. (c) Wabnitz, T. C.; Saaby, S.; Jørgensen,
K. A. Org. Biomol. Chem. 2004, 2, 828-834. (d) Zimmer, R.; Reissig,
H.-U. J. Org. Chem. 1992, 57, 339-347.
10.1021/jo0705521 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/19/2007
5202
J. Org. Chem. 2007, 72, 5202-5206

Michael Addition of Amine DeriVatiVes to Nitrosoalkenes
SCHEME 1. Umpolung Reactions at the Cr Atom of
r-Phosphorylated Oximes
FIGURE 1. Nitrosoalkenes I and azadienes II and III.
at C-3, mainly alkyl, aryl, and carboxylate groups, of the hetero-
diene system6,9 have been described. However, to the best of
our knowledge, only one report for the preparation of nitroso-
alkenes containing a carboxylate group at C-4 of the heterodiene
system (Ia, R4 ) CO2R, Figure 1) and its behavior in [4 + 2]
cycloaddition processes has been previously reported.10
We have been involved in the chemistry of functionalized 1-
(II)11 and 2-azadienes (III)12 (Figure 1) derived from amino
esters and amino phosphonates and in the application of
phosphorus-substituted oximes13 as starting materials for the
preparation of acyclic and cyclic compounds as well as in the
synthesis of R-14 and â-amino phosphonate15 derivatives.
Oximes not only serve as protecting groups for carbonyl
compounds16 but they can also be used as starting materials for
the preparation of nitrosoalkenes, and it is well-known that
molecular modifications involving the introduction of organo-
phosphorus functionalities in organic substrates could increase
their biological activity or their interest as synthetic intermediates
in organic and medicinal chemistry.17 Moreover, to date, the
synthesis of nitrosoalkenes containing phosphorus substituents
at C-4 (Ib, R4 ) P(O)R2, Figure 1) and the study of these highly
reactive intermediates as Michael acceptors toward nucleophilic
reagents remain unexplored.
The CR functionalization of ketones IV (X ) O) or oximes
IV (X ) NOH) with electrophilic reagents to obtain CR-
substituted compounds VI (X ) O, NOH) is known1 (Scheme
1). Bearing this in mind, we envisaged the use of oximinoalkyl
phosphine oxides and phosphonates (IV, X ) NOH, P ) POPh2
or PO(OEt)2, Scheme 1) as starting materials for the preparation
of functionalized oximes containing a nucleophilic substituent
(V, X ) NOH), through a sequence involving halogenation with
formation of an R-halooxime VII, subsequent formation of
nitrosoalkene VIII through base-mediated dehydrohalogenation,
and Michael addition of nucleophiles to the heterodiene system
(Scheme 1). Therefore, by means of this strategy, the umpolung
reaction in the CR of the phosphonate (phosphine oxide) moiety
could be achieved, favoring the introduction of nucleophiles in
order to prepare functionalized oximes (V, X ) NOH) or their
synthetic equivalent carbonyl compounds (V, X ) O, Scheme
1). This strategy could be of particular interest since the
introduction of amino substituents (Scheme 1, NuH ) RNH2)
at the CR carbon atom could produce R-amino phosphonates,18
which are important substrates in organic and medicinal
chemistry.19,20
(10) Tishkov, A. A.; Lyapkalo, I. M.; Ioffe, S. L.; Strelenko, Y. A.;
Tartakovsky, V. A. Org. Lett. 2000, 2, 1323-1324.
(11) (a) Palacios, F.; Vicario, J.; Aparicio, D. J. Org. Chem. 2006, 71,
7690-7696. (b) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de los Santos, J. M.;
Ezpeleta, J. M. Tetrahedron 2006, 62, 1095-1101. (c) Palacios, F.; Ochoa
de Retana, A. M.; Pascual, S.; Oyarzabal, J. J. Org. Chem. 2004, 69, 8767-
8774. (d) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J.
Org. Lett. 2002, 4, 769-772.
(12) (a) Palacios, F.; Herra´n, E.; Alonso, C.; Rubiales, G.; Lecea, B.;
Ayerbe, M.; Cossio, F. P. J. Org. Chem. 2006, 71, 6020-6030. (b) Palacios,
F.; Alonso, C.; Rubiales, G.; Villegas, M. Tetrahedron Lett. 2004, 45, 4031-
4034. (c) Palacios, F.; Herra´n, E.; Rubiales, G.; Ezpeleta, J. M. J. Org.
Chem. 2002, 67, 2131-2135. (d) Palacios, F.; Alonso, C.; Amezua, P.;
Rubiales, G. J. Org. Chem. 2002, 67, 1941-1946.
(13) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2006, 71, 6141-6148. (b) Palacios, F.; Ochoa de Retana, A. M.;
Gil, J. I.; Lo´pez de Munain, R. Org. Lett. 2002, 4, 2405-2408. (c) Palacios,
F.; Ochoa de Retana, A. M.; Gil, J. I.; Ezpeleta, J. M. J. Org. Chem. 2000,
65, 3213-3217. (d) Palacios, F.; Aparicio, D.; de los Santos, J. M.;
Rodr´ıguez, E. Tetrahedron 1998, 54, 599-614. (e) Palacios, F.; Aparicio,
D.; de los Santos, J. M.; Rodr´ıguez, E. Tetrahedron Lett. 1996, 37, 1289-
1292.
As a continuation of our work on the preparation of new
R-amino phosphorus compounds, here we disclose the prepara-
tion of new species such as 2-nitrosoprop-1-enyl phosphine
oxides (Ib, R ) Ph, Figure 1) or phosphonates (Ib, R ) OEt,
(14) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org.
Chem. 2005, 70, 8895-8901. (b) Palacios, F.; Aparicio, D.; Lo´pez, Y.; de
los Santos, J. M. Tetrahedron Lett. 2004, 45, 4345-4348. (c) Palacios, F.;
Aparicio, D.; Ochoa de Retana, A. M.; de los Santos, J. M.; Gil, J. I.; Lo´pez
de Munain, R. Tetrahedron: Asymmetry 2003, 14, 689-700. (d) Palacios,
F.; Aparicio, D.; Ochoa de Retana, A. M.; de los Santos, J. M.; Gil, J. I.;
Lo´pez de Munain, R. J. Org. Chem. 2002, 67, 7283-7288.
(15) For recent reviews, see: (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. EnantioselectiVe Synthesis of â-Amino Acids, 2nd ed.; Juaristi,
E., Soloshonok, V. A., Eds.; Wiley: New York, 2005; pp 277-317.
(16) Green, T. G.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; pp 172-223.
(17) Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in EVeryday
LiVing; American Chemical Society: Washington, DC, 1987. (b) Handbook
of Organophosphorus Chemistry; Engel, R., Ed.; Dekker: New York, 1992.
(18) For an excellent book, see: Kukhar, V. P., Hudson, H. R., Eds.;
Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological
ActiVity; Wiley: Chichester, UK, 2000.
(19) For reviews, see: (a) Kafarski, P.; Lejczak, B. Curr. Med. Chem:
Anti-Cancer Agents 2001, 1, 301-312. (b) Gambecka, J.; Kafarski, P. Mini-
ReV. Med. Chem. 2001, 1, 133-144. (c) Kafarski, P.; Lejczak, B.
Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193-215.
(20) (a) Hirschmann, R.; Smith, A. B., III; Taylor, C. M.; Benkovic, P.
A.; Taylor, S. D.; Yager, K. M.; Sprengeler, P. A.; Benkovic, S. J. Science
1994, 265, 234-237. (b) Oleksyszyn, J.; Powers, J. C. Biochemistry 1991,
30, 485-493. (c) Lejczak, B.; Kafarski, P.; Sztajer, H.; Masterlerz, P. J.
Med. Chem. 1986, 29, 2212-2217. (d) Atherton, F. R.; Hassall, C. H.;
Lambert, R. W. J. Med. Chem. 1986, 29, 29-40. (e) Allen, M. C.; Fuhrer,
W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32, 1652-
1661.
J. Org. Chem, Vol. 72, No. 14, 2007 5203

de los Santos et al.
SCHEME 3. Michael Addition of Ammonia and Amine
SCHEME 2. Preparation of Highly Reactive Nitrosoalkenes
5 through Base-Mediated Dehydrohalogenation
Reagents to Phosphorylated Nitrosoalkenes 5
bond of heterodiene 5a. Similarly, 4-phosphonyl-1,2-oxaza-1,3-
butadiene 5b was obtained in very high yield (δP 15.4 ppm).
Nitrosoalkenes 5 proved to be unstable, and they were not
isolated and but were, therefore, used in situ without isolation
in subsequent Michael additions. As far as we know, this is the
first reported example of the preparation of phosphorus-
containing nitrosoalkenes 5 using this methodology.
Figure 1), as well as the results of the conjugate addition of
nitrogen nucleophiles to these highly reactive phosphorylated
nitrosoalkenes.
Electron-withdrawing groups on the terminal carbon atom
may enhance the electrophilic character of this atom, and the
Michael addition of nucleophilic reagents on this carbon atom
(1,4-addition) may be favored. Some conjugate addition of
amines to 1,2-oxaza-1,3-butadienes have been reported.6,7
However, to date, Michael addition of nucleophilic reagents to
phosphorus-substituted nitrosoalkenes remains unexplored, and
by means of this strategy, a wide range of R-amino phosphorus
derivatives could be obtained. For this reason, we first studied
the reaction between ammonia and amines with phosphorus-
containing nitrosoalkenes 5 (Scheme 3).
Results and Discussion
As outlined in Scheme 2, for the preparation of phosphory-
lated nitrosoalkenes, the required R-halooxime 2a derived from
phosphine oxide (R ) Ph) is in turn easily accessible from the
reaction of functionalized â-oxime 113d,e with a base followed
by addition of bromine. Treatment of compound 1 with an
excess (2.3 equiv) of MeONa in MeOH at reflux and subsequent
addition of bromine at 0 °C led to the formation of R-bro-
mooxime phosphine oxide 2a (Scheme 2). A different process
was applied to the preparation of the corresponding R-bro-
mooxime phosphonate 2b, which was synthesized in two steps
from â-ketophosphonate 3 (X ) H). Treatment of compound 3
with a base such as EtONa in EtOH at rt followed by addition
of bromine at 0 °C gave R-bromoketophosphonate 4 (X ) Br)
in excellent yield.21 Condensation reaction of compound 4 with
hydroxylamine hydrochloride in MeOH and in the presence of
base (Et3N) at room temperature led to the formation of
R-bromooxime phosphonate 2b (Scheme 2).
Addition of 1 equiv of triethylamine to a solution of
functionalized R-bromooxime 2a derived from phosphine oxide
in dichloromethane caused 1,4-elimination of HBr and led to
the formation of the highly colored 4-phosphinyl-1,2-oxaza-
1,3-butadiene 5a (R ) Ph) in almost quantitative yield (>99%,
Scheme 2). The presence of nitrosoalkene 5a in the crude
reaction mixtures was confirmed by NMR spectroscopy at -40
°C. Thus, the 31P NMR spectrum of 5a showed only an
absorption at δP 23.1 ppm, and the 13C NMR spectrum of 5a
showed an absorption at δC 7.65 ppm as a doublet with a
coupling constant (3JPC ) 2.8 Hz) for the methyl group,
indicating the presence of only one isomer and that the
phosphorus atom and the methyl group are related cis22 and
confirming the E-stereochemistry of the carbon-carbon double
We explored the addition of ammonia to nitrosoalkene 5a
(R ) Ph) generated in situ from R-bromooxime 2a. When
ammonia gas was bubbled through a solution of R-bromooxime
2a in CH2Cl2, the reaction mixture became deep green, showing
the formation of 1,2-oxazadiene 5a. The green color disappeared
very fast, showing the end of the reaction with the formation
of only one stereoisomer corresponding to the R-amino phos-
phine oxide 6a in good yield (Scheme 3, Table 1, entry 1).
Compound 6a was characterized on the basis of its spectroscopic
data. Mass spectrometry of 6a supported the molecular ion peak,
while the 31P NMR spectrum of the phosphinyl group resonated
1
at δP 31.3 ppm. The H NMR spectrum showed an absorption
at δH 4.35 ppm as a doublet with coupling constant 2JPH ) 8.1
Hz for the methine proton, and the 13C NMR spectrum showed
an absorption at δC 56.7 ppm as a doublet with coupling constant
1JPC ) 73.5 Hz for the carbon atom directly bonded to the
phosphorus atom. Then, the process was extended to 4-phos-
phonyl nitrosoalkene 5b (R ) OEt). Although, in this case
R-amino phosphonate 6b (R ) OEt) was very unstable, it could
be isolated as a mixture of syn- and anti-R-amino phosphonate
6b and further characterized (Scheme 3, Table 1, entry 2).
R-Amino phosphonates18 are very interesting substrates in
medicinal chemistry,19 with a wide range of biological activities
such as haptens of catalytic antibodies,20a peptide mimetics,20b
enzyme inhibitors,20c and antibacterial20d or antihypertensive
agents.20e
(21) A modified procedure of the Sturtz method was used: Haelters, J.
P.; Corbel, B.; Sturtz, G. Phosphorus Sulfur Relat. Elem. 1988, 37, 65-
85.
(22) (a) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E. Eur. J. Org.
Chem. 1998, 1413-1423. (b) Palacios, F.; Aparicio, D.; de los Santos, J.
M. Tetrahedron 1994, 50, 12727-12742.
Functionalized nitrosoalkenes 5 can also act as Michael
acceptors toward primary and secondary amines. The addition
5204 J. Org. Chem., Vol. 72, No. 14, 2007

Michael Addition of Amine DeriVatiVes to Nitrosoalkenes
TABLE 1. r-Amino Phosphine Oxides and Phosphonates 6 and 8
Obtained through Conjugate Addition of Ammonia and Amines to
Nitrosoalkenes 5
TABLE 2. r-Amino Phosphine Oxides and Phosphonates
Obtained through Conjugate Addition of r-Amino Esters to
Nitrosoalkenes 5
entry
product
R
R1
R2
yield (%)a,b
1
2
3
4
5
6
7
10
Ph
Ph
OEt
Ph
OEt
Ph
-
Et
Et
Et
Me
Me
Me
Me
58
90
82
83
80
87
79
12a
12b
12c
12d
14ac
14bc
iPr
iPr
Bn
Bn
-
OEt
-
a After chromatography. b Yields of pure compounds 10, 12, and 14 are
based on 1,2-oxazadienes 3. c Both isomers can be separated and isolated
from the diastereomeric mixture.
at δC 61.9 ppm (1JPC ) 80.1 Hz) for the carbon bonded to the
phosphorus atom.
Then the reaction was extended to the diastereoselective
addition of optically active R-amino esters 11 to phosphorylated
nitrosoalkenes 5. A slight diastereoselection was observed when
a After chromatography. b Yields of pure compounds 6 and 8 are based
on 1,2-oxazadienes 5.
i
L-valine ethyl ester hydrochloride 11a (R1 ) Pr, R2 ) Et) or
L-phenylalanine methyl ester hydrochloride 11b (R1 ) Bn, R2
) Me) was used in the reaction with nitrosoalkenes 5. Thus,
reaction of L-valine ethyl ester hydrochloride 11a with 5a and
5b gave R-amino phosphorus derivatives 12a and 12b, respec-
tively, as nonseparable diastereomeric mixtures, and light
diastereoselective excess (51% in the case of 12a and 28% in
the case of 12b)26 was observed (Scheme 4, Table 2, entries 2
and 3). Michael addition of L-phenylalanine methyl ester
hydrochloride 11b to nitrosoalkenes 5a and 5b gave adducts
12c and 12d, respectively, obtained as before as nonseparable
diastereomeric mixtures and diastereoselective excess rising
from 13% for compound 12c and 65% for compound 12d
(Scheme 4, Table 2, entries 4 and 5).26
SCHEME 4. Michael Addition of r-Amino Esters to
Phosphorylated Nitrosoalkenes 5
However, no diastereoselection was observed when L-proline
methyl ester hydrochloride 13 was treated with nitrosoalkene
phosphine oxide 5a (R ) Ph) or when treated with nitrosoalkene
phosphonate 5b (R ) OEt). Adducts 14a and 14b were obtained
as an equimolecular mixture of both isomers.26 However, in
these cases, both isomers 14 and 14′ (see Scheme 4) could be
separated and isolated from the diastereomeric mixture (Scheme
4, Table 2, entries 6 and 7). This new family of functionalized
R-amino phosphonates 10, 12, and 14 derived from R-amino
esters can be considered as “phospha-depsipeptides” and could
be interesting substrates in medicinal chemistry.25 As far as we
know, this novel strategy is the first example of conjugate
addition of nitrogen nucleophiles to phosphorylated nitroso-
alkenes to be reported.
of primary or secondary amines 7 to functionalized nitroso-
alkenes 5 containing a phosphine oxide or a phosphonate group23
led to the formation of functionalized anti-R-amino phosphine
oxide24 8 (R ) Ph) and phosphonate 8 (R ) OEt) derivatives
in moderate to excellent yields (Scheme 3, Table 1, entries
3-10). The scope of the reaction was not limited to aliphatic
(Table 1, entries 7 and 10) and aromatic amines (Table 1, entries
3, 4, and 8) since amines containing double or triple bonds can
also be used (Table 1, entries 5, 6, and 9).
Finally, we studied the addition of R-amino esters because
this strategy could afford a new alternative for the preparation
of phospha-depsipeptide derivatives.25 The addition of ethyl
glycinate 9 (R2 ) Et) to nitrosoalkene phosphine oxide23 5a
led to the formation of functionalized R-amino phosphine oxide
derivative 10 (R ) Ph, R2 ) Et) in good yield (Scheme 4, Table
2, entry 1). Compound 10 was characterized by its spectroscopic
data, which indicated that it was isolated as the anti-oxime24
10. The 31P NMR spectrum of 10 showed one absorption at δP
Conclusion
In conclusion, the first synthesis of 1,2-oxaza-1,3-butadienes
containing a phosphine oxide group 5a or a phosphonate group
5b at the C-4 position of the heterodiene system is reported.
This is also the first example reported for the conjugate addition
of ammonia, amines, and optically active amino esters to
phosphorylated nitrosoalkenes 5 for the preparation of func-
tionalized R-amino phosphorus compounds 6, 8, 10, 12, and
14. It should be also emphasized that the use of these very
reactive phosphorylated heterodienes 5 also opens a novel route
to other functionalized phosphorus compounds due to the
1
29.5 ppm. Likewise, the H NMR spectra of 10 gave a well-
resolved doublet for the methine proton at δH 4.31 ppm (2JPH
) 11.4 Hz), while in the 13C NMR spectra, a doublet appeared
(23) In these processes, nitrosoalkenes 5 were generated in situ from
R-halooximes 2 and triethylamine.
(24) Smith, J. H.; Heidema, J. H.; Kaiser, E. T.; Wetherington, J. B.;
Moncrief, J. W. J. Am. Chem. Soc. 1972, 94, 9274-9276.
(25) For recent contributions, see; (a) Van der Donk, W. A. J. Org. Chem.
2006, 71, 9561-957. (b) Nasopoulou, M.; Matziari, M.; Dive, V.; Yiotakis,
A. J. Org. Chem. 2006, 71, 9525-9527. (c) Palacios, F.; Alonso, C.; de
los Santos, J. M. Curr. Org. Chem. 2004, 8, 1481-1496.
(26) Diastereoisomer ratios were determined by 31P NMR on the crude
reaction mixture.
J. Org. Chem, Vol. 72, No. 14, 2007 5205

de los Santos et al.
2
4
(10H, m), 4.35 (1H, d, JPH ) 8.1 Hz), 1.85 (3H, d, JPH ) 1.8
Hz); 13C NMR (75 MHz, CDCl3) δ 155.1, 132.1, 132.1, 132.0,
131.8, 131.6, 131.5, 128.7, 128.5, 128.4, 56.7 (d, 1JPC ) 73.5 Hz),
12.7; 31P NMR (120 MHz, CDCl3) δ 31.3; MS (EI) m/z 288 (M+,
12), 201 (100), 124 (30), 77 (30). Anal. Calcd for C15H17N2O2P:
C, 62.49; H, 5.94; N, 9.72. Found: C, 62.51; H, 5.97; N, 9.71.
General Procedure for the Addition of Amines to Phospho-
rylated Nitrosoalkenes. To an ice-cooled solution of R-bro-
mooxime 2a or 2b (1.0 mmol) in dichloromethane (5 mL) was
added triethylamine (140 µL, 1.0 mmol). Then the corresponding
amine (1.0 mmol) (p-anisidine, aniline, allylamine, propargylamine,
or diethylamine) was added at once. The reaction was allowed to
stir at room temperature for 30 min. The solvent was removed by
rotary evaporation, the residue was stirred with diethyl ether, and
then it was filtered through a sintered glass vacuum filtration funnel.
The solid was washed twice with ether, and the filtrate was
concentrated to dryness in vacuum. The crude products were
purified by flash-column chromatography (silica gel, AcOEt) to
afford R-amino phosphine oxides or phosphonates 8.
marked ability of compounds 5 to add nucleophiles. These
R-amino phosphorus derivatives may be important synthons in
organic synthesis for the preparation of biologically active
compounds of interest to medicinal chemistry.18-20
Experimental Section
General Methods. Reagent and solvent purification, workup
procedures, and analyses were performed in general as describe in
the Supporting Information.
General Procedure for the Preparation of 1-Bromo-1-(diphen-
ylphosphinoyl)propan-2-one Oxime (2a). To a stirred solution
of sodium methoxide (0.62 g, 11.5 mmol) in methanol (50 mL)
was added the â-oximino phosphine oxide 113d,e (1.37 g, 5.0 mmol).
The mixture was refluxed for 1 h, and then it was cooled at 0 °C.
Then bromine (256 µL, 5.0 mmol) was added with a syringe pump.
Once added, the reaction mixture was allowed to reach room
temperature and stirred for 1 h. The crude product was washed
with water and extracted twice with dichloromethane (20 mL).
Organic layers were dried over MgSO4, filtered, and the crude
product was purified by flash-column chromatography (silica gel,
AcOEt/pentane 50:50) to afford 2a (1.29 g, 73%) as a colorless
1-(Diphenylphosphinoyl)-1-(4-methoxyphenylamino)propan-
2-one Oxime (8a) (354 mg, 90%) was obtained as a colorless oil
as described in the general procedure; IR (NaCl) νmax 3341, 2929,
2673, 1514, 1434, 1242, 1167, 1028 cm-1; H NMR (400 MHz,
1
1
oil: IR (NaCl) νmax 3183, 1728, 1436, 1185 cm-1; H NMR (400
CDCl3) δ 9.84 (1H, br s), 7.80-7.31 (10H, m), 6.60 (4H, s), 4.94-
MHz, CDCl3) δ 10.40 (1H, br s), 8.09-7.27 (10H, m), 5.31 (1H,
s), 2.09 (3H, s); 13C NMR (75 MHz, CDCl3) δ 152.1, 132.9, 132.6,
132.5, 132.4, 132.3, 131.8, 131,7, 131.6, 131.5, 131.4, 131.3, 131.2,
131.0, 130.9, 130.3, 129.9, 129.5, 129.3, 128.6, 128.6, 128.6, 128.5,
128.5, 128.4, 128.2, 47.0 (d, 1JPC ) 68.8 Hz), 12.1; 31P NMR (160
MHz, CDCl3) δ 27.9; MS (CI) m/z 352 (M+, 100). Anal. Calcd for
C15H15BrNO2P: C, 51.16; H, 4.29; N, 3.98. Found: C, 51.18; H,
4.33; N, 4.00.
3
3
4.89 (1H, m), 4.82 (1H, dd, JPH ) 9.9 Hz, JHH ) 7.0 Hz), 3.62
(3H, s), 1.78 (3H, d, JPH ) 2.1 Hz); 13C NMR (75 MHz, CDCl3)
4
δ 154.2, 152.8, 140.1, 140.0, 132.2, 132.2, 132.1, 132.0, 131.7,
131.6, 131.2, 131.1, 130.4, 129.8, 128.6, 128.5, 128.4, 128.2, 115.4,
114.7, 58.3 (d, JPC ) 76.1 Hz), 55.5, 11.4; 31P NMR (120 MHz,
1
CDCl3) δ 32.1; MS (CI) m/z 395 (M+ + 1, 100). Anal. Calcd for
C22H23N2O3P: C, 67.00; H, 5.88; N, 7.10. Found: C, 67.01; H,
5.90; N, 7.09.
General Procedure for the Addition of Ammonia to Phos-
phorylated Nitrosoalkenes. To an ice-cooled solution of R-bro-
mooxime 2a or 2b (1.0 mmol) in dichloromethane (5 mL) was
bubbled ammonia gas for 1 min. The reaction was allowed to stir
at room temperature for 30 min. The solvent was removed by rotary
evaporation, the residue was stirred with diethyl ether, and then it
was filtered through a sintered glass vacuum filtration funnel. The
solid was washed twice with ether, and the filtrate was concentrated
to dryness in vacuum. The crude products were purified by flash-
column chromatography (silica gel, AcOEt) to afford R-amino
phosphine oxide 6a or R-amino phosphonate 6b.
Acknowledgment. This work was financially supported by
the University of the Basque Country (UPV, GIU 06/51) and
Direccio´n General de Investigacio´n del Ministerio de Ciencia
y Tecnolog´ıa (MCYT, Madrid DGI, CTQ2006-09323). R.I.
thanks the Ministerio de Ciencia y Tecnolog´ıa for a predoctoral
fellowship. A Ramo´n y Cajal contract to J.M.S. from MCYT
is acknowledged.
Supporting Information Available: Full characterization
data and procedures for the synthesis of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1-Amino-1-(diphenylphosphinoyl)propan-2-one Oxime (6a)
(205 mg, 71%) was obtained as a colorless oil as described in the
general procedure: IR (NaCl) νmax 3383, 3246, 1728, 1236, 1048
1
cm-1; H NMR (300 MHz, CDCl3) δ 9.14 (1H, br s), 7.43-7.88
JO0705521
5206 J. Org. Chem., Vol. 72, No. 14, 2007