α-Ketiminophosphonates: Synthesis and applications

Article abstract of DOI:10.1080/10426507.2010.521211

The synthesis of α-iminophosphonates derived from ketones has been achieved by aza-Wittig reaction of P-trimethylphosphazenes with acylphosphonates. These unstable compounds can be used for the synthesis of chiral α-aminophosphonate derivatives through ad

Full text of DOI:10.1080/10426507.2010.521211

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Phosphorus, Sulfur, and Silicon and the
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α-Ketiminophosphonates: Synthesis and
Applications
Javier Vicario a , Domitila Aparicio a & Francisco Palacios a
a Departamento de Química Orgánica I, Facultad de Farmacia,
Universidad del País Vasco, Vitoria, Spain
Published online: 25 Apr 2011.
To cite this article: Javier Vicario , Domitila Aparicio & Francisco Palacios (2011): α-
Ketiminophosphonates: Synthesis and Applications, Phosphorus, Sulfur, and Silicon and the Related
Elements, 186:4, 638-643
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Phosphorus, Sulfur, and Silicon, 186:638–643, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.521211
α-KETIMINOPHOSPHONATES:
SYNTHESIS AND APPLICATIONS
Javier Vicario, Domitila Aparicio, and Francisco Palacios
Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia,
Universidad del Pa´ıs Vasco, Vitoria, Spain
Abstract The synthesis of α-iminophosphonates derived from ketones has been achieved
by aza-Wittig reaction of P-trimethylphosphazenes with acylphosphonates. These unstable
compounds can be used for the synthesis of chiral α-aminophosphonate derivatives through
addition of nucleophiles to the C-N iminic double bond. Moreover, if α,β-unsaturated imines
are used, regioselective Michael addition to the conjugated bond yields α-dehydroamino-
phosphonic acid derivatives functionalized at the γ -position.
Keywords α-Aminophosphonates; α-dehydroaminophosphonates; α-iminophosphonates;
α,β-unsaturated imines
INTRODUCTION
α-Aminophosphonic acids1 I are structurally analogous to α-amino acids II, obtained
by isosteric substitution of the carboxylic acid by a phosphonate moiety (Figure 1). As ex-
pected from this analogy, the single α-aminophosphonic acid molecules or their phosphonic
esters as well as phosphapeptides containing α-aminophosphonic units show an assorted
biological activity2 as haptens of catalytic antibodies,3a peptide mimetics,3b enzyme in-
hibitors,3c–e and antibacterial agents.3f Moreover they are key compounds in agrochemistry
and have found several applications as fungicides4a or herbicides.4b
α-Iminophosphonate derivatives III are direct precursors of α-aminophosphonic acid
derivatives IV through the conversion of the imine moiety into amine through simple reduc-
tion of the C-N double bond or addition of nucleophiles to the electophilic imine carbon. In
addition, α-iminophosphonates holding a β,γ -unsaturated double bond III (R CH CH-
Rꢁ) are versatile compounds, which, owing to their ambident electrophilic character, can be
excellent substrates for the preparation of a variety of cyclic and acyclic α-aminophosphorus
derivatives.
Received 21 July 2010; accepted 1 September 2010.
The present work has been supported by the Direccio´n General de Investigacio´n del Ministerio de Ciencia e
Innovacio´n (MICINN, Madrid DGI, CTQ2009-12156) and by the Departamento de Educacio´n, Universidades e
Investigacio´n del Gobierno Vasco and Universidad del Pa´ıs Vasco (GV, IT 422-10; UPV, GIU-09/57). J. V. thanks
the Ministerio de Ciencia e Innovacio´n for a “Ramo´n y Cajal” contract.
Address correspondence to Francisco Palacios, Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia,
Universidad del Pa´ıs Vasco, P. O. Box 450, Vitoria-Gasteiz 01080, Spain. E-mail: Francisco.palacios@ehu.es
638

α-KETIMINOPHOSPHONATES: SYNTHESIS AND APPLICATIONS
639
R′
R′
R′
NH
NH
NH2
N
R″O
R″O
HO
HO
HO
R″O
R″O
R
P
R
P
R
P
R
Nu
O
O
O
IV
O
III
I
II
Figure 1 α-Aminoacids and their isosters α-aminophosphonates.
The simplest method for the synthesis of imines employs condensation of carbonyl
compounds with amines. This condensation reaction becomes more complicated when
electron-poor imines are sought, given the difficulty for the nucleophilic attack of the re-
quired deactivated amine to the carbonyl group. Besides, if α,β-unsaturated imines are the
objective, this method is also often complicated by Michael addition reaction, especially
when α,β-unsaturated ketones are used.5 These preparative drawbacks can be sometimes
avoided either by olefination reaction of β-phosphorylated imines or enamines with alde-
hydes to generate the conjugated C-C double bond,6 or by the Aza-Wittig reaction7,8 of
phosphazenes, a strategy recently applied for the construction of α,β-unsaturated imines
derived from α-aminoester derivatives.9 In the past we have been involved in the synthesis
and reactivity of phosphorylated oximes,10 hydrazones,11 and imines/enamines6,12 and their
transformation into different cyclic and acyclic aminophosphorus derivatives. In this article,
we report the results on the synthesis and reactivity of α-ketiminophosphonate derivatives.
RESULTS AND DISCUSSION
Initially we attempted the direct condensation reaction between amines and
carbonyl compounds. This reaction is proved successful for the synthesis of α-
oxyminophosphonates13 and α-hydrazonophosphonates,14 but, in our case, the starting
materials were recovered intact when the poorly nucleophilic amides, sulfonamides, or
phosphinamides were heated with acylphosphonates in the presence of a dehydrating agent.
The use of more nucleophilic amines is discarded in this case, since alkylamines have
already been shown to afford amides through nucleophilic attack to the acylphosphonate
followed by elimination of the phosphonate group.15 For this reason, we explored the
preparation of imines 4 by construction of the carbon-nitrogen double bond by aza-Wittig
reaction of phosphazenes and carbonyl compounds (Scheme 1). The usefulness of phosp-
hazenes species in the selective formation of imine bonds,7,8 and the increased reactivity
of phosphazenes when aromatic substituents at the phosphorus are replaced by alkyl
substituents,16 are well documented. Therefore, the synthesis of α-iminophosphonates 4
O
(R3O)2P
R2
R1
O
3
R1
N
PMe3
R1
N
(R3O)2P
R2
N3
Toluene
(0 ºC)
PMe3
O
4
1
2
Scheme 1 Synthesis of α-iminophosphonates 4 through aza-Wittig reaction.

640
J. VICARIO ET AL.
Table 1 Synthesis of α-iminophosphonates 4
Entry
Compound
R1
R2
R3
Conv. (%)
Yielda (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
p-Me-C6H4
p-NO2-C6H4
p-MeO-C6H4
Ph
CH3
PhCH CH
2-furyl CH CH
EtOCH CH
MeCH CH
MeCH CH
Me
Me
Me
Me
Me
Et
100
100
100
100
100
100
100
N.d.
N.d.
89
89
85
75
73
4g
Et
aIsolated yield.
was achieved by the aza-Wittig reaction of the very reactive phosphazenes 2 derived from
trimethyl phosphine and α-ketophosphonates 3 (Scheme 1).17
Phosphazenes 2 were readily prepared in situ by the addition of trimethylphosphine
to azides 1 in dichloromethane, and, given the unstability of P-trialkyl phosphazene species
2, their formation was monitored by 31P NMR; they were used without purification for
the following purposes. The formation of phosphazenes is evident from the visible nitro-
gen gas formation. The subsequent direct addition of the α-ketophosphonates 3 afforded,
in a few minutes, α-iminophosphonates 4 in good yields (Scheme 1, Table 1). Simple
α-iminophosphonates 4a,b (Scheme 1, Table 1, entries 1 and 2) derived from benzoylphos-
phonate or acetylphosphonate showed very low stability. α-Iminophosphonates 4a,b can
be characterized in situ by 1H, 13C, and 31P NMR, and they can be used from the resulting
solution in the further steps. The reaction was successfully applied to the synthesis of aro-
matic (Scheme 1, Table 1, entry 1) aliphatic (Scheme 1, Table 1, entry 2) and unsaturated
(Scheme 1, Table 1, entries 3–7) α-ketophosphonates 4a–g.
With this successful methodology in hand, we tried to use α-ketiminophosphonates
as substrates for the synthesis of several α-aminophosphonic acid derivatives. First, the
selective reduction of α,β-unsaturated imines was explored. The synthesis of the saturated
α-aminophosphonates 5 can be achieved in excellent yields (91–95%) by catalytic hydro-
genation of the β,γ -unsaturated α-iminophosphonates 4c–g (Scheme 2) in methanol at
80 psi.
R1
H2(80 psi), Pd-C
(25 °C)
NH
(R3O)2P
R2
O
5
R1
N
H2 (80 psi), Pd-C
(25 °C)
(R3O)2P
O
R2
R1
4
NH
BH3.SMe2
(-78 °C)
(R3O)2P
R2
O
6
Scheme 2 Selective reduction of β,γ -unsaturated α-iminophosphonates 4.

α-KETIMINOPHOSPHONATES: SYNTHESIS AND APPLICATIONS
641
Table 2 γ -Amino α-dehydroaminophosphonates 7 synthesized by aza-Michael reaction
Entry
Compound
HNR2R3
E/Za
Yieldb
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
NH3
100/0
100/0
100/0
62/38
0/100
0/100
100/0
100/0
82%
83%
88%
86%
79%
85%
79%
81%
p-Me-C6H4-NH2
Me-NH2
nPr-NH2
Bn-NH2
CH2 CH CH2 NH2
Pyrrolidine
(S)-Pseudoephedrinec
7g
7h
aDetermined by integration of 31P NMR signals of the crude.
bYield after chromatography.
cD.r. = 1:1.
On the other hand, treatment of β,γ -unsaturated α-iminophosphonates 4c–g
with BH3·SMe2 in toluene or THF at –78◦C afforded exclusively vinylogous α-
aminophosphonates 6 in very good yields (84–88%, Scheme 2) through selective reduction
of the imine bond. It is remarkable that both reductions can be performed in a one-pot
procedure directly with similar yields from the solutions generated after the aza-Wittig
reaction, that is, starting from α-ketophosphonates 3. This last aspect is of special
importance, since this avoids problems of handling associated to the susceptibility of
imines to undergo hydrolysis. Finally, the conversion of vinylogous α-aminophosphonates
6 into saturated α-aminophosphonates 5 is easily accomplished by simple catalytic
hydrogenation (Scheme 2).
Moreover, aza-Michael reaction of amines with β,γ -unsaturated α-
iminophosphonates 4f affords α-dehydro aminophosphonates 7 in very good yields
with a γ -stereogenic center bearing an amino group (Scheme 3, Table 2). It is remarkable
that the conjugate addition of amines proceeds without any additional activation. The
reaction of β,γ -unsaturated α-iminophosphonates 4f with amines in dichloromethane at
room temperature affords in a few minutes α-dehydroaminophosphonates 7 in good yields
(Scheme 3, Table 2). The scope of the reaction is especially wide, since it tolerates the
use of ammonia (Table 2, entry 1), aromatic amines (Table 2, entry 2), and primary and
secondary aliphatic amines (Table 2, entries 3–8), including β-amino alcohol derivatives
(Table 2, entry 8).
The resulting γ -amino enamines can be used for the preparation of phosphory-
lated pyrimidine derivatives. Thus, treatment of enamines 7e–f at room temperature with
O2N
R1
HN
O2N
R2
CH2Cl2
NH
N
R1
(EtO)2P
N
R2
(EtO)2P
O
O
4f
7
Scheme 3 Synthesis of α-dehydroaminophosphonates 7.

642
J. VICARIO ET AL.
triphosgene and two equivalents of triethylamine afforded phosporylated 3,4-dihydro-2-
pyrimidones 8a,b in very good yield (Scheme 4, 87–90%).
O2N
O2N
O
O
Cl3CO
OCCl3
NH
N
N
R
TEA,CH2Cl2
(EtO)2P
O
N
H
R
(EtO)2P
O
7e: R = Ph
7f: R = CH = CH2
8a: R = Ph,87%
8b: R = CH = CH2,90%
Scheme 4 Synthesis of pyrimidone derivatives 8a,b.
CONCLUSION
The very reactive phosphazene species derived from trimethylphosphine constitute
an excellent alternative for condensation (1,2-addition) with carbonyl groups, especially
with α,β-unsaturated ketones avoiding undesirable Michael addition products. This
methodology applied to α-ketophosphonates provides access to α-iminophosphonates
and β,γ -unsaturated-α-iminophosphonates. Regioselective reduction of the imine
carbon–nitrogen double bond of phosphorylated α,β-unsaturated imines provides access
to vinylogous α-aminophosphonates, while total reduction of α,β-unsaturated imines
gives saturated α-aminophosphonates. β,γ -Unsaturated-α-iminophosphonates can be
also used as Michael acceptors in aza-Michael or conjugate addition of amines to give
γ -amino-α-dehydroaminophosphonates. These amino α-dehydroaminophosphonates are
also starting materials for the synthesis of phosphorylated pyrimidone derivatives.
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17. General procedure for the synthesis of β,γ -unsaturated α-iminophosphonates 4. To a so-
lution of the corresponding azide 1 (2.0 mmol) in CH2Cl2 (10 mL) at 0◦C, a 1.0 M solution of
trimethylphosphine in toluene (2 mL) was added. The resulting solution was stirred for 30 min.
until N2 evolution stopped, which indicates the completion of the reaction, and phosphazene
2 formation and can be monitored by 31P NMR. The corresponding neat β,γ -unsaturated α-
ketophosphonate 3 (2.0 mmol) was then added, and the reaction was stirred for an additional 30
min at r.t. The solution was diluted with CH2Cl2 (40 mL) and washed with water (3 × 20 mL),
dried over MgSO4, and concentrated under reduced pressure to afford a yellow oily crude that
was purified by chromatography (SiO2, AcOEt:pentane 3:1).