Phosphorated 1,2-oxazabuta-1,3-dienes as synthetic tools for the preparation of a-amino phosphorus derivatives and functionalized nitrogen-containing heterocycles

Article abstract of DOI:10.1080/10426507.2010.522632

An efficient method for the synthesis of phosphorated 1,2-oxazabuta-1,3- dienes derived from phosphine oxides and phosphonates has been developed by means of base-mediated dehydrohalogenation of readily available a-halooximes. New functionalized a-amino p

Full text of DOI:10.1080/10426507.2010.522632

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Phosphorated 1,2-Oxazabuta-1,3-dienes
as Synthetic Tools for the Preparation
of α-Amino Phosphorus Derivatives and
Functionalized Nitrogen-Containing
Heterocycles
Jesús M. de los Santos a , Roberto Ignacio a , Domitila Aparicio a &
Francisco Palacios a
a Department of Organic Chemistry I, Faculty of Pharmacy ,
University of the Basque Country , Vitoria-Gasteiz , Spain
Published online: 25 Apr 2011.
To cite this article: Jesús M. de los Santos , Roberto Ignacio , Domitila Aparicio & Francisco Palacios
(2011) Phosphorated 1,2-Oxazabuta-1,3-dienes as Synthetic Tools for the Preparation of α-Amino
Phosphorus Derivatives and Functionalized Nitrogen-Containing Heterocycles, Phosphorus, Sulfur, and
Silicon and the Related Elements, 186:4, 735-741, DOI: 10.1080/10426507.2010.522632
To link to this article: http://dx.doi.org/10.1080/10426507.2010.522632
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Phosphorus, Sulfur, and Silicon, 186:735–741, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.522632
PHOSPHORATED 1,2-OXAZABUTA-1,3-DIENES AS
SYNTHETIC TOOLS FOR THE PREPARATION OF α-AMINO
PHOSPHORUS DERIVATIVES AND FUNCTIONALIZED
NITROGEN-CONTAINING HETEROCYCLES
Jesu´s M. de los Santos, Roberto Ignacio, Domitila Aparicio, and
Francisco Palacios
Department of Organic Chemistry I, Faculty of Pharmacy, University of the Basque
Country, Vitoria-Gasteiz, Spain
Abstract An efficient method for the synthesis of phosphorated 1,2-oxazabuta-1,3-dienes de-
rived from phosphine oxides and phosphonates has been developed by means of base-mediated
dehydrohalogenation of readily available α-halooximes. New functionalized α-amino phos-
phorus derivatives are easily available, in a regioselective way, through conjugate addition of
amino nucleophilic reagents such as ammonia, primary or secondary amines, and optically
active amino esters to these highly reactive nitroso derivative Michael acceptors. Phosphorated
1,2-oxazabuta-1,3-dienes also react with enamines in a formal [3 + 2] cycloaddition to afford
highly functionalized phosphorated N-hydroxypyrrole derivatives.
Keywords α-Amino phosphorus derivatives; conjugate addition; α-halooxime; Michael ac-
ceptor; nitrone; phosphorated N-hydroxypyrrole; phosphorated 1,2-oxazabuta-1,3-diene
INTRODUCTION
1,2-Oxazabuta-1,3-dienes1 are highly reactive functionalized nitroso derivatives and
generally unstable species. Over recent years, many researchers have investigated their use
in nucleophilic addition2 and cycloaddition reactions.3 Due to the high reactivity connected
with these nitroso compounds, only a few examples have been isolated and character-
ized. Mainly, bulky alkyl4a or aryl substituents4b at the terminal carbon atom (C–4) or
heteroatoms4c–e directly bonded to the heterodienic system enhance the stability of these
1,2-oxazabuta-1,3-dienes.
We have previously described the generation of phosphinyl I (R = Ph) and phospho-
nyl 1,2-diazabuta-1,3-dienes I (R = OEt) (Scheme 1) and their application in the synthesis
of new α-amino phosphorus derivatives5 and five-6 and six-membered7 nitrogen-containing
heterocycles. It is known that phosphorus substituents regulate important biological func-
tions,8 and the introduction of organophosphorus functionalities in simple synthons may
Received 21 July 2010; accepted 2 September 2010.
This work was financially supported by the Universidad del Pa´ıs Vasco–Departamento de Educacio´n, Uni-
versidades e Investigacio´n del Gobierno Vasco (GIU-07/114; IT-422-10), and Direccio´n General de Investigacio´n
del Ministerio de Ciencia y e Innovacio´n (Madrid DGI, CTQ2009-12156 BQU).
Address correspondence to Francisco Palacios, Department of Organic Chemistry I, Faculty of Pharmacy,
University of the Basque Country, P. O. Box 450, 01080 Vitoria-Gasteiz, Spain. E-mail: francisco.palacios@ehu.es
735

736
J. M. DE LOS SANTOS ET AL.
Scheme 1 Phosphorated 1,2-diazabuta- (I) and 1,2-oxazabuta-1,3-dienes (II).
afford the development of new strategies for the preparation of phosphorated azahete-
rocycles.9 As a continuation of our work on the preparation of new amino phosphorus
compounds,10,11 in this article we disclose the preparation of new 1,2-oxazabuta-1,3-dienes
derived from phosphine oxides (II, R = Ph, Scheme 1) or phosphonates (II, R = OEt,
Scheme 1). We also describe in this article the use of these phosphorus-substituted nitroso
derivatives for the preparation of acyclic and cyclic amino phosphorus compounds.
RESULTS AND DISCUSSION
As outlined in Scheme 2, for the preparation of phosphorated 1,2-oxazabutadienes
the required α-halooxime 3a derived from phosphine oxide (R = Ph) is easily accessi-
ble from the reaction of functionalized oxime 2 with a base followed by the addition of
bromine. Functionalized oxime 2 derived from phosphine oxide was obtained by the re-
action of allenic phoshine oxide 1 with hydroxylamine hydrochloride in the presence of
a base and in refluxing chloroform.12 A different approach was applied to the preparation
of the α-bromooxime phosphonate 3b, which was synthesized in two steps starting from
β-ketophosphonate 4 (X = H). Treatment of 4 with a base such as EtONa in EtOH at room
temperature followed by the addition of bromine at 0 ◦C gave α-bromo-β-ketophosphonate
5 (X = Br) in excellent yield.13 Condensation reaction of 5 with hydroxylamine hydrochlo-
ride led to the formation of α-bromooxime phosphonate 3b (Scheme 2).
1. MeONa (2.3 eq),
MeOH, reflux, 1h.
Br
NH2OH·HCl
N
N
HO
PR2
HO
PPh2
PPh2
2. Br2 (1 eq), 0ºC
Et3N
CHCl3, reflux
O
O
O
3a R = Ph, 73%
3b R = OEt, 82%
1
2
H2NOH·HCl (1 eq),
Et3N, MeOH, rt
Et3N (1 eq)
CH2Cl2
X
N
O
O
PR2
P(OEt)2
O
O
1. EtONa (1 eq),
EtOH, rt, 1h.
2. Br2 (1 eq), 0ºC
4
5
X = H
X = Br
6a R = Ph, > 99%
6b R = OEt, > 99%
Scheme 2 Preparation of highly reactive 1,2-oxazabuta-1,3-dienes 6 through base-mediated dehydrohalogena-
tion.

PREPARATION OF α-AMINO PHOSPHORUS DERIVATIVES
737
The addition of 1 eq of a base such as triethylamine to a solution of phosphorated α-
bromooxime 3 in dichloromethane caused 1,4-elimination of HBr and led to the formation of
the highly colored 1,2-oxaza-1,3-butadiene 6 in almost quantitative yield (>99%) (Scheme
2). The E-sterochemistry of the carbon–carbon double bond on 6 was evident since the 13C
◦
NMR spectrum at −40 C of 6a showed an absorption at δC 7.65 ppm as a doublet with
a coupling constant (3JPC = 2.8 Hz) for the methyl group, indicating that the phosphorus
atom and the methyl group are related cis.14 The highly reactive compounds 6 proved to be
unstable, and they were used in situ without isolation in subsequent reactions.
1,2-Oxazabuta-1,3-dienes 6 possess a highly electrophilic carbon center (C−4), and
the presence of an electron-withdrawing group on the terminal carbon atom may enhance
the electrophilic character of this atom. We first explored the addition of ammonia to nitroso
derivative 6a (R = Ph) generated in situ from α-bromooxime 3a (Scheme 2, vide supra).
When ammonia gas was bubbled through a solution of α-bromooxime 3a in CH2Cl2 (the
ammonia gas was used as the base), the reaction mixture became deep green, due to the
formation of 1,2-oxazadiene 6a. The green color disappeared very quickly, showing the end
of the reaction with the formation of only one stereoisomer corresponding to the α-amino
phosphine oxide 8a in good yield. Similarly, the addition of ammonia to 6b (R = OEt)
led to an unstable α-amino phosphonate 8b (R = OEt) isolated as a mixture of syn- and
anti-isomers (Scheme 3, Table 1).
H
CO2R3
R2 10
N
R1
O
Br
PR2 R2
Et3N
N
N
N
HO
PR2
O
HO
N
R1
11
CO2R3
O
PR2
O
CH2Cl2
3
6
R1
NH3 (gas)
CH2Cl2
NH3 (gas)
CH2Cl2
HN
CH2Cl2
R2
7
R1
R2
NH2
N
N
N
HO
PR2
O
HO
PR2
O
8
9
Scheme 3 Michael addition of amino nucleophiles to phosphorated 1,2-oxazabutadienes 6.
Functionalized nitroso derivatives 6 can also act as Michael acceptors toward pri-
mary and secondary amines. The addition of primary or secondary amines 7 to com-
pounds 6 led to the formation of functionalized anti15-α-amino-phosphine oxide 9 (R =
Ph) and -phosphonate 9 (R = OEt) derivatives in moderate to excellent yields16 (Scheme 3,
Table 1).
The diastereoselective conjugate addition of optically active α-amino esters has also
been studied, because this strategy could afford a new alternative for the preparation of
phospha-depsipeptide derivatives.17 The addition of ethyl glycinate 10a (R1 = R2 = H, R3 =
Et) to 1,2-oxazabuta-1,3-diene-phosphine oxide 6a led to the formation of functionalized

738
J. M. DE LOS SANTOS ET AL.
Table 1 α-Amino phosphorus compounds 8, 9, and 11 obtained through conjugate addition of amino nucleophiles
to nitroso compounds 6
Yielda
(%)
Yielda
(%)
Yielda
(%)
deb
(%)
6
R
7
R1
R2
8
9
10
R1
R2
R3
11
6a
6b
6a
6a
Ph
OEt
Ph
7a
7a
7b
7c
H
H
H
H
H
H
8a
8b
71
66
p-MeOC6H4
9a
9b
90
95
Ph
6a
6b
6b
6b
6a
6a
6a
6b
6b
Ph
7d
7b
7e
7d
Et
Et
H
H
9c
9d
9e
9f
94
89
90
88
OEt
OEt
OEt
Ph
Ph
Ph
p-MeOC6H4
Et
Et
10a
10b
10c
10b
10d
H
H
H
Et
Et
11a
11b
11c
11d
11e
58
90
87
82
80
iPr
51
0
30
64
(CH2)3− Me
OEt
OEt
H
H
iPr
Bn
Et
Me
aYields of pure compounds are based on 1,2-oxazadienes 6.
bde was determined by 31P NMR on the crude reaction mixture.
anti-α-amino-phosphine oxide derivative 11a in 58% yield. A slight diastereoselection was
i
observed when L-valine ethyl ester hydrochloride 10b (R1 = H, R2 = Pr, R3 = Et) or
L-phenylalanine methyl ester hydrochloride 10d (R1 = H, R2 = Bn, R3 = Me) was used in
the 1,4-addition to derivatives 6. In these cases, α-amino phosphorus derivatives 11b, 11d,
and 11e were obtained as nonseparable diastereomeric mixtures (Scheme 3, Table 1). Total
absence of diastereoselectivity was observed when L-proline methyl ester hydrochloride
10c [R1R2 = (CH2)3 , R3 = Me] was treated with 1,2-oxazadiene-phosphine oxide 6a
(R = Ph). However, in this case, both diastereoisomers could be separated and isolated
from the diastereomeric mixture (Scheme 3, Table 1). This new family of functionalized
α-aminophosphorate compounds 11 derived from α-amino esters can be considered as
“phospha-depsipeptides” and could be interesting substrates in medicinal chemistry.
The reactivity of 1,2-oxazabuta-1,3-dienes toward enamines was also studied. Addi-
tion of enamines 12 to the highly reactive systems 6 generated in situ from bromooximes
3 in CH2Cl2 at room temperature afforded, rather than the expected six-membered 1,2-
oxazine 13, the phosphorated N-hydroxypyrrole 1418 in good yields and in a regioselective
way (Scheme 4, Table 2).
It was necessary to obtain evidences for the structure 14, because it is known that
1,2-oxazabuta-1,3-dienes mainly react with dienophiles according to [4+2]-cycloaddition
processes. In the latter case, compound 13 could be expected and produced instead of the
N-hydroxypyrrole 14. The choice between structures 13 and 14 was based upon the 2D
NMR and mass spectral data. Namely, the HMBC spectrum showed a cross signal between
the vinylic proton (H–5) with the signal at down-field corresponding to the carbon (C–2)
of 14d. This cross signal unambiguously confirms the presence of the N-hydroxypyrrole
14d and not the oxazine ring 13 (four bonds distance between H–6 and C–3 in the oxazine
ring). In addition, two cross-signals were observed between the vinylic proton (H–5) with
the quaternary carbons C–3 and C–4 of the N-hydroxypyrrole 14d. Moreover, the high
resolution mass spectra for compound 14d showed an ion peak for the fragment [M+ OH]
typical loss corresponding to these structures.
The mechanism for the formation of the N-hydroxypyrroles 14 most likely involves
an initial conjugate addition of enamine 12 at the terminal carbon atom of 6 to give adduct

PREPARATION OF α-AMINO PHOSPHORUS DERIVATIVES
739
R2
N
N
+
O
N
H
R2
R1
R1
N
O
CH2Cl2
R2
N
+
O
PR2
R1
N
O
O
PR2
PR2
12
O
6a R = Ph
6b
13
15
R = OEt
CH2Cl2
R2
N
R2
−
HN
O
R1
HO
R1
N
N
∆
PR2
PR2
O
O
16
14
Scheme 4 Michael addition of enamines 12 to phosphorated 1,2-oxazabutadienes 6.
15, which promptly affords nitrone 16 by ring closure (formally a [3+2] cycloaddition).
Elimination of the pyrrolidine residue in nitrones 16 leads to substituted pyrroles 14. 1,2-
Oxazabuta-1,3-dienes have been shown to add themselves to the C−N double bond of some
1,2-oxazines,19 1,3-diazabuta-1,3-dienes,20 and imines,21 as well as to the C C double bond
attached to a pyrimidinone ring,22 with the formation of unusual [3+2] cycloadducts.
Further evidence for the mechanism for the formation of N-hydroxypyrrole deriva-
tives 14 is confirmed by the isolation of nitrone intermediates 16. The nitrones 16 have
shown a tendency to aromatize to afford the corresponding N-hydroxypyrroles 14. However,
in some cases, when the process was performed at 0 ◦C, some nitrones (Scheme 4, Table 2)
Table 2 Phosphorated N-hydroxypyrroles 14 and nitrones 16 obtained through addition of enamines 12 to nitroso
derivatives 6
Yielda
(%)
Yielda
(%)
6
R
12
R1
iPr
R2
14
16
6a
6a
6a
Ph
Ph
Ph
12a
12b
12c
H
Ph
14a
14b
14c
89 (81)b
89
70
16a
83
CO2Et
6b
6b
6b
6b
6b
6b
OEt
OEt
OEt
OEt
OEt
OEt
12a
12d
12e
12f
12b
12g
iPr
Bn
Pr
Ph
H
H
H
H
Ph
14d
14e
14f
14g
14h
14i
89
81
(82)b
(71)b
94
16f
16g
85
87
CO2Et
(CH2)3
83
aYields of pure compounds 14 and 16 are based on 1,2-oxazabuta-1,3-dienes 6.
bYields of compounds 14 based on isolated nitrones 16.

740
J. M. DE LOS SANTOS ET AL.
proved to be stable enough to the reaction conditions and even to flash-chromatography,
and it was possible to isolate and characterize them on the basis of analytical and spectral
data.
CONCLUSION
In conclusion, we report a general and highly efficient method for the synthesis of
functionalized α-amino phosphorus compounds through conjugate addition of ammonia,
amines, and optically active amino esters to phosphorated dienes 6 containing a phosphine
oxide group or a phosphonate group at the C−4 position of the heterodienic system. Also,
phosphorus-substituted N-hydroxypyrroles containing a phosphine oxide or phosphonate
group at C−3 position of the heterocyclic system have been obtained by means of a [3+2]
formal cycloaddition reaction of phosphorated 1,2-oxazabuta-1,3-dienes and enamines. It
should be also emphasized that the use of these very reactive phosphorated systems also
opens a novel route to other functionalized cyclic and acyclic phosphorus compounds due
to the marked ability of 1,2-oxazabutadienes to add nucleophiles.
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741
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16. Representative procedure for the synthesis of α-amino-phosphine oxide 9a: To an ice-cooled
solution of α-bromooxime 3a (352 mg, 1.0 mmol) in dichlorometane (5 mL), triethylamine
(140 µL, 1.0 mmol) was added. Then p-anisidine (123 mg, 1.0 mmol) was added all at once.
The reaction was allowed to stir at room temperature for 30 min. The solvent was removed by
rotary evaporation, and the residue was stirred with diethyl ether; 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 α-amino-phosphine oxide 9a (354 mg, 90%)
obtained as a colorless oil. IR (NaCl) λmax 3341, 2929, 2673, 1514, 1434, 1242, 1167, 1028 cm-1;
1H NMR (400 MHz, CDCl3) δ 9.84 (1H, br s), 7.80–7.31 (10H, m), 6.60 (4H, s), 4.94–4.89 (1H,
m), 4.82 (1H, dd, 3JPH = 9.9 Hz, 3JHH = 7.0 Hz), 3.62 (3H, s), 1.78 (3H, d, 4JPH = 2.1 Hz); 13
C
NMR (75 MHz, CDCl3) 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, 1JPC = 76.1 Hz),
55.5, 11.4; 31P NMR (120 MHz, 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.
17. (a) Palacios, F.; Alonso, C.; de los Santos, J. M. Curr. Org. Chem. 2004, 8, 1481–1496; (b) Na-
sopoulou, M.; Matziari, M.; Dive, V.; Yiotakis, A. J. Org. Chem. 2006, 71, 9525–9527; (c) Van
Der Donk, W. A. J. Org. Chem. 2006, 71, 9561–9571.
18. Representative procedure for the synthesis of N-hydroxypyrrole 14a: To a stirred solution of
α-bromooxime 3a (352 mg, 1.0 mmol) in CH2Cl2 (5 mL), triethylamine (1.2 mmol) was added.
Then (E)-1-(3-methylbut-1-enyl)pyrrolidine 12a (167 mg, 1.2 mmol) was added all at once
at room temperature under a nitrogen atmosphere. The reaction was allowed to stir at room
temperature for 20 min. The solvent was removed by rotary evaporation, and the residue was
stirred with diethyl ether. The triethyl amine hydrobromic salt 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 to get N-hydroxypyrrole 14a (245 mg, 89%) obtained as a
brown oil. IR (NaCl) obtained as a brown oil. IR (NaCl) λmax 3423, 2961, 1214, 1031, 963 cm-1;
1H NMR (300 MHz, CDCl3) δ 11.16 (bs, 1H), 6.53 (d, 4JPH = 6.0 Hz, 1H), 4.02-3.92 (m, 4H),
3.00 (m, 1H), 1.98 (s, 3H), 1.29 (t, 3JHH = 7.2 Hz, 6H), 1.13 (d, 3JPH = 6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3) δ 133.6 (d, 2JPC = 26.0 Hz), 129.8 (d, 2JPC = 12.5 Hz), 114.1 (d, 3JPC = 13.5
Hz), 94.7 (d, 1JPC = 218.4 Hz), 61.3 (d, 2JPC = 5.6 Hz), 25.5, 24.5, 16.1 (d, 3JPC = 7.0 Hz), 9.2;
31P NMR (120 MHz, CDCl3) δ 21.9; MS (EI) m/z 275 (M+, 10), 258 (100), 202 (40); HRMS
(EI) m/z Calcd. for C12H22NO4P [M+] 275.1286, found: [M+] 275.1263.
19. Zimmer, R.; Collas, M.; Czerwonka, R.; Hain, U.; Reissig, H.-U. Synthesis 2008, 237–244.
20. Sharma, A. K.; Hundal, G.; Obrai, S.; Mahajan, M. P. J. Chem. Soc., Perkin Trans. 1 1999,
615–619.
21. Marwaha, A.; Singh, P.; Mahajan, M. P. Tetrahedron 2006, 62, 5474–5486.
22. Sharma, A. K.; Mahajan, M. P. Heterocycles 1995, 40, 787–800.