Synthesis of amidines derived from phosphonates and phosphane oxides - Amidine-mediated preparation of phosphorylated oxazolines

Article abstract of DOI:10.1002/ejoc.200390139

Alkylation of N-(phosphorylalkyl)phosphazenes 2 with methyl iodide and allyl bromide and acylation with ethyl chloroformate leads to the formation of aminophosphonium salts 4 derived from (aminoalkyl)phosphonates. N-(Phosphorylalkyl)amidines 8 were obtained by reaction of phosphazenes derived from aminophosphonates with benzoyl chloride and subsequent addition of amines. These functionalized amidines were used as key intermediates in the synthesis of oxazolin-4-ylphosphonates 9 and 10. In a similar manner, oxazolin-4-ylphosphane oxides 17 and 18 were prepared from N-(phosphanylalkyl)amidines 16, which were obtained by reaction of phosphazenes derived from phosphane oxides 15 with benzoyl chloride and amines. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390139

FULL PAPER
Synthesis of Amidines Derived from Phosphonates and Phosphane Oxides ؊
Amidine-Mediated Preparation of Phosphorylated Oxazolines
[a]
[a]
[a]
´
Francisco Palacios,* Ana Marıa Ochoa de Retana, and Jaione Pagalday
Keywords: Amidines / Oxazolines / Phosphane oxides / Phosphazenes / Phosphonates
Alkylation of N-(phosphorylalkyl)phosphazenes
2
with
synthesis of oxazolin-4-ylphosphonates 9 and 10. In a similar
manner, oxazolin-4-ylphosphane oxides 17 and 18 were pre-
pared from N-(phosphanylalkyl)amidines 16, which were ob-
tained by reaction of phosphazenes derived from phosphane
oxides 15 with benzoyl chloride and amines.
methyl iodide and allyl bromide and acylation with ethyl
chloroformate leads to the formation of aminophosphonium
salts 4 derived from (aminoalkyl)phosphonates. N-(Phos-
phorylalkyl)amidines 8 were obtained by reaction of phos-
phazenes derived from aminophosphonates with benzoyl
chloride and subsequent addition of amines. These func-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tionalized amidines were used as key intermediates in the Germany, 2003)
Introduction
volved in the study of simple and functionalized phosphaz-
enes[6e] as well as of their use in the construction of
carbonϪnitrogen double bonds[11] and in the preparation
of acyclic[12] and heterocyclic compounds.[13] Following on
from our previous studies on the reactivity and the syn-
thetic utility of phosphazenes,[6e,11Ϫ13] here we aim to ex-
plore a new and effective strategy for the preparation of
phosphorylated amidines (III, Scheme 2) from func-
tionalized phosphazenes IV, as well as their synthetic utility
in the preparation of oxazolinylphosphonates V (R ϭ OEt)
and oxazolinylphosphane oxides V (R ϭ Ph). Retrosynthet-
ically, we envisaged the preparation of amidines III by reac-
tion of phosphazenes with acyl halides and subsequent ad-
dition of amines in a similar manner to the strategy previ-
ously used for the preparation of 2-azadienes.[14]
Amidines are interesting intermediates in functional
group transformations[1] and are used widely in medicinal
chemistry.[2] Molecular modifications involving the intro-
duction of organophosphorus functionalities could increase
their biological activities.[3] Very few examples have been
described of syntheses of phosphorus-substituted amidines,
such as N-phosphoryl-[4] (I, Scheme 1) and C-phosphoryla-
midines[5] (II, Scheme 1). Moreover, as far as we know,
the preparation of N-(phosphorylalkyl)amidines (III,
Scheme 1) has not been reported.[1]
Scheme 1
On the other hand, phosphazenes[6,7] are an important
class of compounds that have attracted a great deal of atten-
tion in recent years because of their broad range of uses in
the construction of acyclic compounds[8] and in the pre-
paration of heterocycles.[9] Furthermore, α-aminophos-
phonates can be considered as surrogates for α-amino ac-
ids,[10a] and have been used as haptens for the generation of
catalytic antibodies,[10b] as enzyme inhibitors[10c,10d] and as
antibacterial agents.[10e] In this context, we have been in-
Scheme 2
Results and Discussion
Synthesis of N-(Phosphorylalkyl)amidines
The required phosphazene 2, derived from an alkylphos-
phonate, is a functionalized N-alkylphosphazene and a very
unstable compound.[6e,15] For this reason, phosphazene 2
was generated in situ by a Staudinger reaction of diethyl
azidomethylphosphonate[16] (1) with triphenylphosphane
[a]
´
´
Departamento de Quımica Organica I, Facultad de Farmacia,
´
Universidad del Paıs Vasco
Apartado 450, 01080 Vitoria, Spain
Fax: (internat.) ϩ 34-945/013049
E-mail: qoppagaf@vf.ehu.es
Eur. J. Org. Chem. 2003, 913Ϫ919  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0305Ϫ0913 $ 20.00ϩ.50/0
913

F. Palacios, A. M. Ochoa de Retana, J. Pagalday
FULL PAPER
ium salts be used as intermediates for the preparation of
amidines. When phosphazene 2 was treated with benzoyl
chloride in THF (28 h) at room temperature, however, acyl-
ated aminophosphonium salt 5 was not isolated and, in-
stead, a mixture of triphenylphosphane oxide and amide 6
was obtained after evaporation of the solvent (Scheme 4).
Formation of the amide 6 may occur via an unstable im-
idoyl chloride 7, generated from salt 5 by intramolecular
loss of triphenylphosphane oxide, and subsequent addition
of water to the imidoyl chloride, in a manner similar to that
observed in simple[8e,15a] and functionalized phosphaz-
enes.[14] We cannot exclude, however, that hydrolysis of the
phosphonium salts 5 might occur, with cleavage of the
Scheme 3
(Scheme 3), and the crude reaction mixture was used satis-
factorily in the following steps. The presence of phosphaz-
ene 2 in the crude reaction mixture was monitored by 31P
NMR spectroscopy.[17] In order to know the chemical beha-
viour of phosphazene 2, and confirm its presence in the
reaction mixture, the formation of alkyl and acyl derivatives
was explored. Thus, treatment of crude phosphazene 2 with
alkyl halides, such as methyl iodide 3a (R1 ϭ Me; X ϭ I)
or allyl bromide 3b (R1 ϭ CH2CHϭCH2; X ϭ Br), in re-
fluxing benzene gave N-alkylated aminophosphonium salts
4a (R1 ϭ Me; X ϭ I) and 4b (R1 ϭ CH2CHϭCH2; X ϭ
Br) in very good yields (Scheme 3, Table 1, Entries 1, 2).
Compounds 4a,b were characterized on the basis of their
spectroscopic data, which are consistent with reported data
of alkylated aminophosphonium salts.[12c,18] For example,
the 31P NMR spectrum shows signals at δP ϭ 22.1 and
49.3 ppm (3JP,P ϭ 9.3 Hz) for the phosphonate and the pho-
nitrogenϪphosphorus
bond,
during
the
workup
(Scheme 4).
Scheme 4
sphonium salt (4a), respectively, and the H and 13C NMR
1
Having obtained these results, we studied the synthesis of
amidines. We thought that if imidoyl chloride 7 is formed,
this reactive intermediate could be trapped in situ by the
addition of simple nucleophilic reagents such as amines.
Benzoyl chloride was added to phosphazene 2 and the
crude reaction mixture was treated with piperidine in the
presence of triethylamine to give N-(phosphorylalkyl)amid-
ine 8a [R12 ϭ (CH2)5] (Scheme 4, Table 1, Entry 4). Spectro-
scopic data are in agreement with the structure of com-
pound 8a. The mass spectrum of 8a shows the molecular
spectra displayed doublets for the N-methyl group (δH
ϭ
3
2
3.26 ppm, JPH ϭ 9.3 Hz; δC ϭ 39.6 ppm, JP,C ϭ 3.0 Hz,
respectively) of phosphonium salt 4a. Because of the high
basicity of the phosphazene linkage, formation of these de-
rivatives 4 can be explained by selective N-alkylation of the
phosphazene, in a manner similar to that of simply func-
tionalized phosphazenes.[8a,12c] A similar behaviour was ob-
served when N-(phosphorylalkyl)phosphazene 2 reacted
with ethyl chloroformate 3c (R1 ϭ CO2Et; X ϭ Cl) in THF
to afford the hygroscopic phosphonium salt 4c (R1
CO2Et; X ϭ Cl) in good yield (Scheme 3, Table 1, Entry 3).
ϭ
1
ion [m/z (%) ϭ 338 (60)], the H NMR spectrum displays a
2
doublet at δH ϭ 3.40 ppm with a coupling constant JPH ϭ
15.3 Hz for the methylene protons, and the 13C NMR spec-
trum gave well-resolved doublets at δC ϭ 47.9 ppm (1JP,C ϭ
163.3 Hz), for the methylene carbon atom bonded to the
Table 1. Aminophosphonium salts and amidines
Entry
Compd.
R1
Yield (%)
M.p. [°C]
phosphorus atom, and at δC ϭ 164.3 ppm (3JP,C
ϭ
1
2
3
4
5
6
4a
4b
4c
8a
8b
16
Me
85[a]
80[b]
70[c]
78[d]
50[d]
80[d]
125Ϫ126
55Ϫ56
107Ϫ108
oil
oil
oil
17.3 Hz), for the imidoyl carbon atom. The formation of
amidine 8a suggests that the amine could indeed trap the
unstable imidoyl chloride 7 (Scheme 4).
CH2ϭCHCH2
CO2Et
[CH2]5
CHMe2
[CH2]5
Synthesis of Oxazolinylphosphonates
[a]
Yield after purification by recrystallization from ethyl acetate.
Oxazolines are common heterocycles with a wide range
of uses as building blocks in organic synthesis and as li-
gands in organometallic chemistry.[19,20] Although it is
known, however, that phosphorus substituents regulate im-
portant biological functions,[3] and increase their biological
[b]
Yield after purification by recrystallization from diethyl ether/
[c]
dichloromethane.
from THF. Yield after purification by flash chromatography.
Yield after purification by recrystallization
[d]
Having obtained these results, we tried to explore activity, the synthesis has been described only[21,22] of 2-
whether N-(phosphorylalkyl)phosphazene 2 could be acyl- unsubstituted oxazolinylphosphonates by the reaction of
ated with acyl halides and if the corresponding phosphon- isocyanomethylphosphonates and aldehydes and, as far as
914
Eur. J. Org. Chem. 2003, 913Ϫ919

Amidine-Mediated Preparation of Phosphorylated Oxazolines
FULL PAPER
we know, no examples of 2-substituted oxazolinylphos-
phonates have been reported. In this context, we are interes-
ted in the design of new nitrogen-containing acyclic and
cyclic derivatives bearing either a phosphane oxide or a
phosphonate moiety, and previously we have described the
synthesis of three-,[23] five-,[24] and six-membered[25] phos-
phorus-substituted nitrogen heterocycles from enamines
and imines derived from phosphazenes, phosphane oxides,
or phosphonates, as well as of phosphorus-containing het-
erocycles.[26] Continuing with our interest in the chemistry
of new phosphorus-substituted heterocyclic compounds, we
thought that N-(phosphorylalkyl)amidine (III, Scheme 2)
could be used for the preparation of oxazolines containing
a phosphonate group as a substituent (V, Scheme 2).
Scheme 5
Table 2. Oxazolidines obtained from 8a
Treatment of amidine 8a with n-butyllithium followed by
the addition of p-tolylaldehyde led to the formation of di-
ethyl trans- and cis-2-phenyl-5-(p-tolyl)-2-oxazolin-4-ylpho-
sphonates (R2 ϭ p-CH3C6H4) (9a and 10a, respectively) in
good yields (Scheme 5, Table 2, Entry 1). These isomers can
be separated by flash chromatography, and spectroscopic
data are in agreement with their assigned structures. Mass
spectrometry of both derivatives showed their molecular
ions [m/z (%) ϭ 373 (2)], while in their 31P NMR spectra
the phosphonate group resonates at δP ϭ 21.5 ppm for the
trans isomer and at δP ϭ 19.1 ppm for the cis isomer. The
1H NMR spectrum of trans-oxazoline 9a displays a typical
Entry
Compd.
R2
Yield (%)[a]
M.p. [°C]
1
2
3
4
9/10a
9/10b
17/18a
17/18b
p-MeC6H4
Me
p-MeC6H4
Me
74
80
80
86
oil
oil
oil
oil
[a]
Yield after purification by flash chromatography.
Synthesis of N-(Phosphinylalkyl)amidines and
Oxazolinylphosphane Oxides
This methodology that we have used for the preparation
double doublet at δH ϭ 4.38 ppm corresponding to the pro- of amidines 8 and oxazolines derived from phosphonates 9
ton in position 4 bonded to the phosphonate group (2JPH ϭ and 10, can be extended also to the synthesis of amidines
14.1 Hz) and with a second coupling constant (3JH,H
ϭ
and oxazolines containing a phosphane oxide group. Ac-
7.5 Hz) characteristic of a trans configuration in oxazol- cording to a similar strategy to that described for the syn-
ines,[22] and the signal of the 5-H proton appears at δ ϭ thesis of amidines 8, the generation of phosphazene 15 in
3
5.80 ppm as a double doublet (2JPH ϭ 19.8, JHH
ϭ
situ is necessary for the preparation of N-[(diphenylphos-
7.5 Hz). Conversely, in the isomer 10a, the protons 4-H and phanyl)methyl]amidine 16 and, therefore, the synthesis of
5-H display a coupling constant (3JHH ϭ 10.8 Hz) that is (azidomethyl)diphenylphosphane oxide (14) is required.
in agreement with a cis arrangement between substituent in Preparation of azide 14 was achieved by reaction of (hydro-
positions 4 and 5 of the heterocycle. Also, the 13C NMR xymethyl)phosphane oxide[28] 13 with tosyl chloride and
spectra of products 9a and 10a display very characteristic subsequent addition of sodium azide in dimethyl sulfoxide.
signals for C-4 and C-5: the spectrum of oxazoline 9a shows Azide 14 was used then for the one-pot synthesis of amidine
doublets at δC ϭ 72.4 ppm (1JP,C ϭ 162.16 Hz) and at δC ϭ 16. Thus, benzoyl chloride was added to the phosphazene
81.9 ppm (2JP,C ϭ 2.4 Hz) for C-4 and C-5, respectively, 15, which was prepared easily by the Staudinger reaction of
while in the spectrum of cis-oxazoline 10a these signals ap- (azidoalkyl)phosphane oxide 14 and triphenylphosphane,
pear as a doublet at δC ϭ 69.1 ppm (1JP,C ϭ 164.68 Hz) for and the crude reaction mixture was treated with piperidine
C-4 and as a singlet at δC ϭ 82.7 ppm for C-5. The scope in the presence of triethylamine to give N-(phosphanylalkyl)-
of the reaction is not limited to aromatic aldehydes, since amidine 16 (Scheme 6, Table 1, Entry 6). Spectroscopic
the aliphatic aldehyde ethanal also reacted with amidine 8a data are consistent with the structure of compound 16.
to yield diethyl 5-methyl-2-phenyl-2-oxazolin-4-ylphos- Mass spectrometry shows the molecular ion [m/z (%) ϭ 402
1
phonates (R2 ϭ Me) 9/10b (Table 2, Entry 2). The forma- (2)], while the H and 13C NMR spectra showed well-re-
tion of oxazolines 9 and 10 can be explained by depro- solved doublets at δH ϭ 3.90 ppm (2JPH ϭ 12.4 Hz) and at
tonation of amidine 8a in the presence of the base (butylli- δC ϭ 51.9 ppm (1JP,C ϭ 87.6 Hz) for the methylene group
thium) followed by nucleophilic addition of the stabilized bonded to the phosphane oxide group.
carbanion phosphonate to the aldehyde with formation of
Amidines derived from phosphane oxides 16 were then
intermediate 11. Cyclization of this intermediate 11 with the used for the preparation of oxazolinylphosphane oxides 17
loss of piperidine would afford oxazolines 9 and 10. We and 18. Treatment of amidine 16 with butyllithium followed
cannot exclude totally, however, an alternative mechanism by the addition of aromatic (R2 ϭ p-MeC6H4) and aliphatic
involving the formation of an unstable nitrile ylide 12, from (R2 ϭ Me) aldehydes gave (2-phenyl-2-oxazolin-4-yl)phos-
the amidine and the base, and subsequent 1,3-dipolar cyclo- phane oxides, isolated as mixtures of trans (17) and cis iso-
additions[27] of this dipole to the aldehydes with the forma- mers (18), in good yields (Scheme 6, Table 2, Entries 3, 4).
tion of oxazolines (Scheme 5).
These isomers can be separated by flash chromatography
Eur. J. Org. Chem. 2003, 913Ϫ919
915

F. Palacios, A. M. Ochoa de Retana, J. Pagalday
FULL PAPER
with a Nicolet IRFT Magna 550 spectrometer, and were obtained
as solids in KBr or as neat oils. Peaks are reported in cmϪ1. Ele-
mental analyses were performed with a LECO CHNS-932 appar-
atus. Diethyl (azidomethyl)phosphonate (1) was synthesized ac-
cording to a literature procedure.[16]
General Procedure for the Synthesis of Aminophosphonium Salts 4:
To a solution of triphenylphosphane (4.5 mmol) in benzene (for 4a,
4b) or THF (for 4c) (10 mL) was added dropwise with stirring and
to a cooled (ice bath) solution of diethyl (azidomethyl)phosphonate
(1) (5 mmol). Phosphazene 2 was generated in situ and the presence
of 2 in the crude reaction mixture was monitored by 31P NMR
spectroscopy.[17] Alkyl halides 3 were added to the crude reaction
mixture, which was then stirred under reflux for 17Ϫ20 h. The mix-
ture was concentrated under vacuum and the crude residue was
purified by recrystallization.
Scheme 6
and spectroscopic data are in agreement with the assigned
structures. For 17a and 18a, their mass spectra show their
molecular ions [m/z (%) ϭ 437 2%], and in their 31P NMR
spectra the signal of the phosphane oxide group appeared
at δP ϭ 28.1 ppm for the trans isomer and at δP ϭ 22.8 ppm
for the cis isomer. The formation of oxazolines 17 and 18
can be explained, as in the case of phosphorylamidines 8,
by nucleophilic addition of the stabilized carbanion derived
from the amidine 16 to the aldehyde, followed by cyclization
with the loss of piperidine (Scheme 6). As far as we know,
this is the first synthesis of oxazolines containing a phos-
phane oxide group directly bonded to the heterocyclic ring.
In conclusion, the strategy described in this paper out-
lines an efficient and simple route to the first synthesis of
amidines containing either alkylphosphonate or alkylphos-
phane oxide groups, and makes use of readily available
starting materials. These amidines can be used for the pre-
paration of oxazolinylphosphonates and oxazolinylphos-
phane oxides, some of which have been prepared for the
first time. Functionalized amidines and oxazolines are im-
portant building blocks in organic synthesis and in the pre-
paration of biologically active compounds of interest to me-
dicinal chemistry.[1,2,18,19]
[(Diethoxyphosphorylmethyl)(methyl)amino]triphenylphosphonium
Iodide (4a): The general procedure was applied using methyl iodide
3 (6 mmol), affording 4a (2.18 g, 85%) as a white solid. M.p.
1
125Ϫ126 °C. H NMR: δ ϭ 7.67Ϫ7.33 (m, 15 H), 3.97 (m, 4 H),
3.72 (dd, 3JPH ϭ 11.4, 2JPH ϭ 8.0 Hz, 2 H) 3.26 (d, 3JHP ϭ 9.3 Hz,
3 H), 1.17 (m, 6 H) ppm. 13C NMR: δ ϭ 135.6Ϫ130.2, 119.0 (d,
1
1JP,C ϭ 103.0 Hz), 62.6, 62.5, 46.2 (d, JP,C ϭ 160.2 Hz), 39.6 (d,
3
2JP,C ϭ 3.0 Hz), 16.3, 16.2 ppm. 31P NMR: δ ϭ 22.1 (d, JP,P
ϭ
9.3 Hz), 49.3 (d, 3JP,P ϭ 9.3 Hz) ppm. IR (KBr): ν˜: 1247 cmϪ1. MS:
m/z (%) ϭ 413 (12) [M Ϫ I Ϫ Et]ϩ. C24H30INO3P2 (569): calcd. C
50.62, H 5.27, N 2.46; found C 50.58, H 5.24, N 2.39.
[(Allyl)(diethoxyphosphorylmethyl)amino]triphenylphosphonium
Bromide (4b): The general procedure was applied using allyl brom-
ide 3 (4.5 mmol), affording 4b (1.97 g, 80%) as a white solid. M.p.
55Ϫ56 °C. 1H NMR: δ ϭ 7.85Ϫ7.23 (m, 15 H), 5.60 (m, 1 H), 5.21
3
2
(m, 2 H), 4.15 (m, 4 H), 3.70 (dd, JPH ϭ 9.4, JPH ϭ 7.0 Hz, 2
H), 3.40 (m, 2 H), 1.14 (m, 6 H) ppm. 13C NMR: δ ϭ 135.1Ϫ128.3,
121.9, 60.2, 59.1, 51.4, 42.9 (d, 1JP,C ϭ 149.5 Hz), 16.6, 16.25 ppm.
3
3
31P NMR: δ ϭ 21.5 (d, JP,P ϭ 16.5 Hz), 40.8 (d, JP,P ϭ 16.5 Hz)
ppm. IR (KBr): ν˜ ϭ 1245 cmϪ1. MS: m/z (%) ϭ 468 (2) [M Ϫ
Br]ϩ. C26H32BrNO3P2 (548) calcd. C 56.93, H 5.84, N 2.55; found
C 56.98, H 5.82, N 2.60.
[(Diethoxyphosphorylmethyl)(ethoxycarbonyl)amino]triphenylphos-
phonium Chloride (4c): The general procedure was applied using
ethyl chloroformate 3 (4.5 mmol) affording 4c (1.69 g, 70%) as a
hygroscopic white solid. M.p. 107Ϫ108 °C. 1H NMR: δ ϭ
Experimental Section
General: Chemicals were purchased from Aldrich Chemical Com-
pany. Solvents for extraction and chromatography were technical
grade. All solvents used in reactions were freshly distilled from ap-
propriate drying agents before use. All other reagents were recrys-
tallised or distilled as necessary. All reactions were performed un-
der dry nitrogen. Analytical TLC was performed on Merck silica
gel 60 F254 plates. Visualization was accomplished by UV light.
Flash chromatography was carried out on Merck silica gel 60
(230Ϫ400 mesh ASTM). Melting points were determined with an
Electrothermal IA9100 Digital Melting Point Apparatus and are
3
8.05Ϫ7.26 (m, 15 H), 4.11 (m, 4 H), 3.93 (m, 4 H) 1.16 (t, JH,H ϭ
3
7.0 Hz, 6 H), 0.96 (t, JH,H ϭ 6.9 Hz, 3 H) ppm. 13C NMR: δ ϭ
1
153.1, 135.5Ϫ128.0, 117.8 (d, JP,C ϭ 103.0 Hz), 65.4, 62.5, 62.4,
1
42.8 (d, JP,C ϭ 158.1 Hz), 16.3, 15.9, 15.8, 13.1 ppm. 31P NMR:
3
3
δ ϭ 21.7 (d, JP,P ϭ 17.0 Hz), 40.7 (d, JP,P ϭ 17.0 Hz) ppm. IR
(KBr): ν˜ ϭ 1760, 1252 cmϪ1. MS: m/z (%) ϭ 500 (1) [M Ϫ Cl]ϩ.
C26H32ClNO5P2 (535.5) calcd. C 58.26, H 5.98, N 2.61; found C
58.29, H 5.90, N 2.58.
General Procedure for the Synthesis of Amidines 8: A solution of
uncorrected. 1H (300 MHz), 13C (75 MHz), and 31P NMR diethyl (azidomethyl)phosphonate (1) (5 mmol) was added drop-
(120 MHz) spectra were recorded with a Varian VXR 300 MHz
spectrometer using CDCl3 or CD3OD solutions, with TMS as an
wise with stirring to a solution of triphenylphosphane (4.5 mmol)
in THF (25 mL) cooled in an ice bath. Phosphazene 2 was gener-
internal reference (δ ϭ 0.00 ppm) for 1H and 13C NMR spectra ated in situ and the presence of 2 in the crude reaction mixture
and phosphoric acid (85%) (δ ϭ 0.00 ppm) for 31P NMR spectra.
was monitored by 31P NMR spectroscopy.[17] Benzoyl chloride was
Chemical shifts (δ) are reported in ppm. Coupling constants (J) are added to the crude reaction mixture, which was then allowed to
reported in Hz. Low-resolution mass spectra (MS) were obtained stand at room temperature for 28 h. A solution of either a second-
at 50Ϫ70 eV by electron impact (EIMS) with a HewlettϪPackard ary amine (piperidine or diisopropylamine, 6 mmol) or of triethyla-
5971 or 5973 spectrometer and by chemical ionization (CI) with a
HewlettϪPackard 1100MSD. Data are reported in the form m/z
(intensity relative to base ϭ 100). Infrared spectra (IR) were taken
mine (9 mmol) was added to the resulting mixture . The reaction
mixture was then left at room temperature for 3 d. The resulting
mixture was washed three times with water, extracted with CH2Cl2,
916
Eur. J. Org. Chem. 2003, 913Ϫ919

Amidine-Mediated Preparation of Phosphorylated Oxazolines
FULL PAPER
dried with anhydrous MgSO4, and concentrated under vacuum.
The crude residue was purified by flash column chromatography
eluting with diethyl ether/hexane (1:6).
(15 mL) stirred at Ϫ78 °C. After 1 h at Ϫ78 °C, the corresponding
aldehyde (4 mmol) was added. The reaction mixture was warmed
to room temperature and stirred until TLC showed the disappear-
ance of the amidine. The resulting mixture was washed three times
with water, extracted with CH2Cl2, dried with anhydrous MgSO4,
and concentrated under vacuum. The crude residue was purified
by flash column chromatography eluting with ethyl acetate/hexane
(1:5) to afford isomeric compounds 9 and 10 or 17 and 18.
N2-(Diethoxyphosphorylmethyl)-N1-(pentamethylene)benzamidine
(8a): The general procedure was applied using piperidine
(4.5 mmol), affording 8a (1.19 g, 78%) as an oil. 1H NMR: δ ϭ
2
7.42Ϫ7.12 (m, 5 H), 4.07 (m, 4 H), 3.40 (d, JPH ϭ 15.3 Hz, 2 H),
3.21 (m, 4 H), 1.54 (m, 2 H), 1.46 (m, 4 H), 1.26 (t, 3JH,H ϭ 7.0 Hz,
6 H) ppm. 13C NMR: δ ϭ 164.3 (d, 3JP,C ϭ 17.3 Hz), 133.3Ϫ127.3,
Diethyl [2-Phenyl-5-(p-tolyl)-2-oxazolin-4-yl]phosphonate (9/10a):
The general procedure was applied using amidine 8a (2 mmol) and
p-tolylaldehyde (4 mmol), affording a mixture of oxazolines trans-
9a and cis-10a (0.54 g, 74%) as an oil. 1H NMR: 9a: δ ϭ 8.11Ϫ7.00
1
61.9, 61.8, 47.9 (d, JP,C ϭ 163.3 Hz), 46.5, 25.6, 22.8, 16.3,
16.2 ppm. 31P NMR: δ ϭ 26.5 ppm. IR (KBr): ν˜ ϭ 1239 cmϪ1
.
MS: m/z (%) ϭ 338 (60) [Mϩ]. C17H27N2O3P (338): calcd. C 60.36,
3
2
H 7.99, N 8.28; found C 60.30, H 7.94, N 8.23.
(m, 9 H), 5.80 (dd, JH,H ϭ 7.5, JPH ϭ 19.8 Hz, 1 H), 4.38 (dd,
3JH,H ϭ 7.5, JPH ϭ 14.0 Hz, 1 H), 4.15 (m, 4 H), 2.28 (s, 3 H),
2
N2-(Diethoxyphosphorylmethyl)-N1,N1-diisopropylbenzamidine (8b):
1.25 (m, 6 H) ppm. 10a: δ ϭ 8.11Ϫ 7.00 (m, 9 H), 5.89 (dd, 3JH,H ϭ
10.8, 2JPH ϭ 23.8 Hz, 1 H), 4.78 (dd, 3JH,H ϭ 10.8, 2JPH ϭ 16.9 Hz,
1 H), 3.85 (m, 4 H), 2.27 (s, 3 H), 1.06 (m, 6 H) ppm. 13C NMR:
The general procedure was applied using diisopropylamine
(4.5 mmol), affording 8b (0.72 g, 50%) as an oil. 1H NMR: δ ϭ
2
7.38Ϫ7.06 (m, 5 H), 4.05 (m, 4 H), 3.7 (m, 2 H), 3.25 (d, JPH
ϭ
3
2
9a: δ ϭ 138.3 (d, JP,C ϭ 19.1 Hz), 133.3Ϫ125.5, 81.9 (d, JP,C
ϭ
14.6 Hz, 2 H), 1.15 (m,18 H) ppm. 13C NMR: δ ϭ 162.9 (d, 3JP,C ϭ
2.4 Hz), 72.3 (d, 1JP,C ϭ 162.1 Hz), 63.1, 63.0, 21.1, 16.5, 16.4 ppm.
1
17.6 Hz), 134.5Ϫ127.1, 76.5, 61.7, 61.6, 46.9 (d, JP,C ϭ 163.7 Hz),
3
10a: δ ϭ 137.3 (d, JP,C ϭ 11.6 Hz), 133.3Ϫ125.5, 82.6, 69.1 (d,
20.8, 16.5, 16.4 ppm. 31P NMR: δ ϭ 26.7 ppm. IR (KBr): ν˜ ϭ 1235
cmϪ1. MS: m/z (%) ϭ 354 (7) [Mϩ]. C18H31N2O3P (354) calcd. C
61.01, H 8.75, N 7.90; found C 61.08, H 8.68, N 7.92.
1JP,C ϭ 164.6 Hz), 62.5, 62.3, 21.1, 16.3, 16.2 ppm. 31P NMR: 9a:
δ ϭ 21.51 ppm; 10a: δ ϭ 19.03 ppm. IR (KBr): ν˜ ϭ 1228 cmϪ1
.
MS: m/z (%) ϭ 373 (1) [Mϩ]. C20H24NO4P (373): calcd. C 64.34,
Synthesis of (Azidomethyl)phosphane Oxide (14): Tosyl chloride
(4.5 mmol) was added with stirring to an ice-cooled solution of
(hydroxymethyl)phosphane oxide 13[28] (4.5 mmol) in THF/di-
methyl sulfoxide and the mixture stirred for 2 h. Sodium azide
(5 mmol) was added to the crude reaction mixture, which was then
heated at 70 °C for 24 h. The resulting mixture was washed three
times with water, extracted with CH2Cl2, dried with anhydrous
MgSO4, and concentrated under vacuum. The crude residue was
purified by flash column chromatography eluting with ethyl acetate
to afford 14 (0.7 g, 80%) as a white solid. M.p. 109Ϫ110 °C. 1H
H 6.43, N 3.75; found C 64.38, H 6.42, N 3.77.
Diethyl (5-Methyl-2-phenyl-2-oxazolin-4-yl)phosphonate (9/10b):
The general procedure was applied using amidine 8a (2 mmol) and
acetaldehyde (4 mmol), affording a mixture of oxazolines trans-9b
and cis-10b (0.5 g, 80%) as an oil. 1H NMR: 9b: δ ϭ 7.90Ϫ7.21
3
(m, 5 H), 4.98 (m, 1 H), 4.14 (m, 4 H), 4.03 (dd, JH,H ϭ 8.0,
2
2JPH ϭ 13.8 Hz, 1 H), 1.44 (d, JH,H ϭ 6.3 Hz, 3 H), 1.24 (m, 6 H)
ppm; 10b: δ ϭ 7.90Ϫ7.21 (m, 5 H), 5.07 (m, 1 H), 4.47 (dd, 3JH,H ϭ
10.2, 2JPH ϭ 16.0 Hz, 1 H), 4.14 (m, 4 H), 1.56 (d, 2JH,H ϭ 6.4 Hz,
3 H), 1.16 (m, 6 H) ppm. 13C NMR: 9b: δ ϭ 131.5Ϫ128.2, 77.6,
2
NMR: δ ϭ 7.75Ϫ7.37 (m, 10 H), 3.92 (d, JPH ϭ 7.3 Hz, 2 H)
1
1
70.5 (d, JP,C ϭ 163.17 Hz), 63.1, 62.9, 21.5, 16.5 ppm; 10b: δ ϭ
ppm. 13C NMR: δ ϭ 132.3Ϫ128.5, 49.3 (d, JP,C ϭ 76.0 Hz) ppm.
1
131.5Ϫ128.2, 77.9, 66.6 (d, JP,C ϭ 161.66 Hz), 62.7, 62.4, 21.4,
31P NMR: δ ϭ 27.9 ppm. IR (KBr): ν˜ ϭ 2480, 1340 cmϪ1. MS:
m/z (%) ϭ 257 (2) [Mϩ]. C13H12N3OP (257): calcd. C 60.67, H 4.70,
N 16.34; found C 60.62, H 4.69, N 16.28.
16.4 ppm. 31P NMR: 9b: δ ϭ 21.91 ppm; 10b: δ ϭ 20.27 ppm. IR
(KBr): ν˜ ϭ 1238 cmϪ1. MS: m/z (%) ϭ 297 (4) [Mϩ]. C14H20NO4P
(297): calcd. C 56.56, H 6.73, N 4.71; found C 56.59, H 6.77, N
4.75.
Synthesis of N2-(Diphenylphosphanylmethyl)-N1-(pentamethylene)b-
enzamidine (16): A solution of triphenylphosphane (4.5 mmol) was
added dropwise with stirring to a solution of (azidomethyl)phos-
phane oxide 14 (4.5 mmol) in THF (20 mL) cooled in an ice bath.
The mixture was allowed to warm to room temperature for 22 h,
phosphazene 15 was generated in situ. Benzoyl chloride was added
to the crude reaction mixture, which was allowed to stand at room
temperature for 7 h. A solution of either piperidine (6 mmol) or
triethylamine (9 mmol) was added to the resulting mixture. The
reaction mixture was then left at room temperature for 3 d. The
resulting mixture was washed three times with water, extracted with
CH2Cl2, dried with anhydrous MgSO4, and the solvents were evap-
orated under vacuum. The crude residue was purified by flash col-
umn chromatography eluting with diethyl ether/hexane (1:6) to af-
ford of 16 (0.59 g, 80%) as an oil. 1H NMR: δ ϭ 7.82Ϫ7.17 (m, 15
Diphenyl[2-phenyl-5-(p-tolyl)-2-oxazolin-4-yl]phosphane Oxides 17/
18a: The general procedure was applied using amidine 16 (2 mmol)
and p-tolualdehyde (4 mmol), affording a mixture of oxazolines
1
trans-17a and cis-18a (0.72 g, 80%) as an oil. H NMR: 17a: δ ϭ
8.05Ϫ7.04 (m, 19 H), 5.90 (dd, 3JH,H ϭ 6.5, 2JPH ϭ 18.2 Hz, 1 H),
4.92 (dd, 3JH,H ϭ 6.5, 2JPH ϭ 6.5 Hz, 1 H), 2.24 (s, 3 H) ppm; 18a:
3
δ ϭ 8.03Ϫ7.03 (m, 19 H), 6.10 (dd, JH,H ϭ 10.7, 2JPH ϭ 12.6 Hz,
3
2
1 H), 5.34 (dd, JH,H ϭ 10.7, JPH ϭ 11.4 Hz, 1 H), 2.16 (s, 3 H)
ppm. 13C NMR: 17a: δ ϭ 165.2 (d, JP,C ϭ 8.6 Hz), 138.1Ϫ125.2,
3
80.8, 76.4 (d, 1JP,C ϭ 79.6 Hz), 21.1 ppm; 18a: δ ϭ 165.8 (d, 3JP,C ϭ
1
13.6 Hz), 137.7Ϫ125.3, 83.0, 71.6 (d, JP,C ϭ 87.1 Hz), 21.1 ppm.
31P NMR: 17a: δ ϭ 28.06 ppm; 18a: δ ϭ 22.82 ppm. IR (KBr):
ν˜ ϭ 1325 cmϪ1. MS: m/z (%) ϭ 437 (2) [Mϩ]. C28H24NO2P (437):
calcd. C 76.88, H 5.49, N 3.20; found C 76.84, H 5.42, N 3.12.
2
H), 3.91 (d, JPH ϭ 12.4 Hz, 2 H), 3.10 (m, 4 H), 1.50 (m, 2 H),
3
1.34 (m, 4 H) ppm. 13C NMR: δ ϭ 164.0 (d, JP,C ϭ 12.6 Hz),
(5-Methyl-2-phenyl-2-oxazolin-4-yl)diphenylphosphane Oxides 17/
18b: The general procedure was applied using amidine 16 (2 mmol)
and acetaldehyde (4 mmol), affording a mixture of oxazolines
1
136.9Ϫ127.1, 51.9 (d, JP,C ϭ 87.6 Hz), 46.7, 25.8, 24.7 ppm. 31P
NMR: δ ϭ 30.8 ppm. IR (KBr): ν˜ ϭ 1350 cmϪ1. MS: m/z (%) ϭ
402 (2) [Mϩ]. C25H27N2OP (402): calcd. C 74.62, H 6.71, N 6.96;
found C 74.59, H 6.74, N 6.93.
1
trans-17b and cis-18b (0.61 g, 86%) as an oil. H NMR: 17b: δ ϭ
3
2
8.14Ϫ7.19 (m, 15 H), 5.26 (m, 1 H), 4.60 (dd, JH,H ϭ 7.5, JPH
ϭ
2
General Procedure for the Synthesis of Phosphorylated Oxazolines
9, 10, 17, 18: Butyllithium (1.6  in hexanes, 2.4 mmol) was added
dropwise to a solution of amidine 8a or 16 (2 mmol) in THF
7.5 Hz, 1 H), 1.44 (d, JH,H ϭ 6.6 Hz, 3 H) ppm; 18b: δ ϭ
8.14Ϫ7.19 (m, 15 H), 5.21(m, 1 H), 5.04 (dd, 3JH,H ϭ 10.4, 2JPH ϭ
2
10.4 Hz, 1 H), 1.40 (d, JH,H ϭ 6.3 Hz, 3 H) ppm. 13C NMR: 17b:
Eur. J. Org. Chem. 2003, 913Ϫ919
917

F. Palacios, A. M. Ochoa de Retana, J. Pagalday
FULL PAPER
3
1
R. Alvarez, C. Peinador, J. M. Quintela, Tetrahedron 2001, 57,
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δ ϭ 165.1 (d, JP,C ϭ 9.6 Hz), 134.4Ϫ127.2, 79.4, 73.8 (d, JP,C
ϭ
81.6 Hz), 22.09 (d, 3JP,C ϭ 10.6 Hz) ppm; 18b: δ ϭ 165.5 (d, 3JP,C ϭ
1
12.1 Hz), 134.4Ϫ127.2, 76.9, 69.8 (d, JP,C ϭ 83.6 Hz), 17.1 (d,
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24.69 ppm. IR (KBr): ν˜ ϭ 1238 cmϪ1. MS: m/z (%) ϭ 361 (1) [Mϩ].
C22H20NO2P (361): calcd. C 73.13, H 5.54, N 3.87; found C 73.19,
H 5.49, N 3.88.
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918
Eur. J. Org. Chem. 2003, 913Ϫ919

Amidine-Mediated Preparation of Phosphorylated Oxazolines
FULL PAPER
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