Aza-Wittig reaction of N-phosphorylalkyl phosphazenes with carbonyl compounds and phenylisocyanate. Synthesis of 4-amino-3-phosphoryl-2-azadienes and pyrazine-phosphonates

Article abstract of DOI:10.1016/S0040-4020(03)00337-5

Simple and functionalized N-phosphorylalkyl imines and N-phosphorylalkyl-N′-phenyl-carbodiimides are obtained by aza-Wittig reaction of phosphazenes derived from aminophosphonates with carbonyl compounds and phenyl isocyanate. The reaction with dimethylformamide diethyl acetal (DMF-DEA) of these functionalized imines leads to the synthesis of 4-amino-3-phosphoryl-2-azadienes. N-Phosphorylmethyl imine derived from benzaldehyde can be used for the preparation of substituted pyrrole-phosphonates, while acid treatment of 4-dimethylamino-3-diethylphosphoryl-1-phenyl-2-azadiene gives diethyl 5-diethylphosphorylpyrazin-2-ylphosphonate.

Full text of DOI:10.1016/S0040-4020(03)00337-5

Tetrahedron 59 (2003) 2617–2623
Aza-Wittig reaction of N-phosphorylalkyl phosphazenes with
carbonyl compounds and phenylisocyanate. Synthesis of 4-amino-
3-phosphoryl-2-azadienes and pyrazine-phosphonates
*
Francisco Palacios, Ana Marıa Ochoa de Retana, Eduardo Martınez de Marigorta,
´
Marta Rodriguez and Jaione Pagalday
´
´ ´ ´
Departamento de Quımica Organica I, Facultad de Farmacia, Universidad del Paıs Vasco. Apartado 450, VitoriaGasteiz 01080, Spain
Received 10 January 2003; revised 20 February 2003; accepted 4 March 2003
Abstract—Simple and functionalized N-phosphorylalkyl imines and N-phosphorylalkyl-N0-phenyl-carbodiimides are obtained by aza-
Wittig reaction of phosphazenes derived from aminophosphonates with carbonyl compounds and phenyl isocyanate. The reaction with
dimethylformamide diethyl acetal (DMF–DEA) of these functionalized imines leads to the synthesis of 4-amino-3-phosphoryl-2-azadienes.
N-Phosphorylmethyl imine derived from benzaldehyde can be used for the preparation of substituted pyrrole-phosphonates, while acid
treatment of 4-dimethylamino-3-diethylphosphoryl-1-phenyl-2-azadiene gives diethyl 5-diethylphosphorylpyrazin-2-ylphosphonate. q 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
preparation of heterocycles.13 In this context, we have
been involved in the study of simple and functionalized
phosphazenes10e as well as their use in the construction
of carbon–nitrogen double bonds (aza-Wittig reaction)4,5
and in the preparation of acyclic14 and heterocyclic
compounds.15 Following our previous studies on the
reactivity and synthetic utility of phosphazenes, here we
aim to explore a new and effective strategy for the
preparation of 2-azadienes containing an electron-with-
drawing and an electron-donating group (I, Scheme 1) from
functionalized imines II, easily prepared by aza-Wittig
reaction of N-phosphonylalkyl phosphazenes IV and
carbonyl compounds V. The use of functionalized imines
and azadienes for the preparation of phosphorylated
pyrroles and pyrazines is also explored.
Substituted 2-azabutadiene systems have proved to be
efficient key intermediates in organic synthesis for the
construction of heterocycles.1 The great majority of
2-azadienes studied are substituted with strong electron-
donating groups,1,2 while the chemistry of neutral3,4 and
electron-poor 2-azadienes have received much less atten-
tion.5,6 Furthermore, a-aminophosphonates can be con-
sidered as surrogates for a-aminoacids,7a and have been
used as haptens for the generation of catalytic antibodies,7b
as enzyme inhibitors7c,d as well as antibacterial agents.7e
Therefore, the introduction of organophosphorus function-
alities in azadienes may be very interesting8 because
molecular modifications involving these substrates could
afford new aminophosphorus derivatives. However, only
the synthesis of 2-azadienes containing a phosphine oxide
group in position 49a and a phosphonate group in positions
2. Results and discussion
1
9b and 39c,d have been reported and, as far as we know, the
preparation of azadienes containing a phosphorus sub-
stituent and an electron-donating group such an amino
group has not been described.
2.1. Synthesis of N-phosphorylalkyl imines
Imines are obtained by aza-Wittig reaction of phosphazenes
On the other side, phosphazenes10,11 represent an important
class of compounds and have attracted a great deal of
attention in recent years because of their broad range of uses
in the building of acyclic compounds12 and in the
Keywords: phosphazenes; aza-Wittig; aminophosphonates; azadienes;
pyrroles; pyrazines.
*
Corresponding author. Tel.: þ34-945013103; fax: þ34-945013049;
e-mail: qoppagaf@vf.ehu.es
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00337-5

2618
F. Palacios et al. / Tetrahedron 59 (2003) 2617–2623
Scheme 2.
Scheme 3.
and carbonyl compounds.4,5,10 In our case, the required
phosphazenes 2 are very unstable compounds.10e,16 There-
fore, phosphazene 2a (R¼C6H5) was generated in situ by
Staudinger reaction of diethyl azidomethylphosphonate17 1
with triphenylphosphine (Scheme 2) and the crude reaction
mixture, without further purification, was heated with
aldehydes in THF at 608C to give N-phosphorylalkyl-
aldimines 4a–d in good yields (Scheme 2, Table 1, entries
1–4). The presence of phosphazene 2a in the crude reaction
mixture was monitored by 31P NMR spectroscopy.†
Compounds 4 were characterized on the basis of their
spectroscopic data. Thus, the 31P NMR spectrum of
compound 4a showed an absorption at dP¼21.6 ppm,
also be extended to isocyanates. Thus, treatment of the in
situ generated phosphazene 2a with phenyl isocyanate 5 at
room temperature led to the formation of N-phosphoryl-
methyl carbodiimide 6 in 75% yield (Scheme 2, Table 1,
entry 8).
2.2. Synthesis of 3-phosphoryl-2-azadienes
With these results in hand, we next tried to study whether
functionalized imines containing a phosphonate group 4
could be used as intermediates in the preparation of
phosphorylated azadienes.18 We thought that the reaction
of imines 4 with acetylenic esters could be used for this goal
and azadienes 7 could be obtained (Scheme 3) through
a similar pathway to that observed in the case of
N-alkoxycarbonylalkylimines.19 However, the expected
azadiene 7 was not formed when imine 4a (R1¼p-CH3–
C6H4, R2¼H) reacted with dimethyl acetylenedicarboxylate
in the presence of methyl lithium at 2788C, and the
substituted pyrrole 8 was obtained instead. Spectroscopic
data were in agreement with the structure of compound 8.
The formation of pyrrole 8 suggests that the process could
begin by conjugated addition of the carbanion derived from
the imine to the acetylenic ester followed by intramolecular
cyclization. Therefore, the first synthesis of a pyrrole-
phosphonate with carboxylate groups is described. In this
context, as far as we know, the synthesis of this kind of
compounds has been limited to the preparation of 3,4-
disubstituted pyrrole-phosphonates from nitroalkenes and
1
while the H NMR showed a doublet for the methylene
group (dH¼4.1 ppm; 2JPH¼16.0 Hz) and another doublet at
dH¼8.36 ppm with a long-range coupling constant
4JHP¼4.0 Hz for the imine proton.
The reaction was not limited to simple aldehydes as
N-phosphorylalkyl phosphazene 2a also reacted with
piruvonitrile 3e (R1¼CH3, R2¼CN) and ethyl cyanoformate
3f (R1¼OC2H5, R2¼CN) in THF at 608C to afford
functionalized imines 4e (R1¼CH3, R2¼CN) and 4f
(R1¼OC2H5, R2¼CN), respectively (Scheme 2, Table 1,
entries 5, 6). The use of a more reactive phosphazene 2b
(R¼CH3) derived from trimethylphosphine and generated
in situ allowed to perform the process in milder reaction
conditions (258C) when this phosphazene 2b reacted with
piruvonitrile 3e (Scheme 2, Table 1, entry 7). The aza-
Wittig reaction of these phosphorylated phosphazenes 2 can
Table 1. Imines 4 and carbodiimide 6 obtained
Entry
Compound
R1
R2
Conditions
THF, reflux, 10 h
THF, reflux, 10 h
THF, reflux, 10 h
THF, reflux, 10 h
THF, reflux, 10 h
THF, reflux, 23 h
THF, room temperature, 12 h
THF, room temperature, 42 h
Yield (%)a
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
H
H
H
H
p-CH3-C6H4
p-NO2-C6H4
p-CH3O-C6H4
o-CH2vCHCH2OC6H4
85
70
61
70
76
80
70
75
CH3
OC2H5
CH3
CN
CN
CN
4eb
6
a
Yield after purification by flash chromatography.
Prepared from the phosphazene derived from trimethylphosphine.
b
†
The reaction was monitored by 31P NMR showing the disappearance of triphenylphosphine (dP¼26.00 ppm) and the formation of phosphazene 2a (dP¼22.6
and 40.5 ppm, 3JPP¼14.1 Hz), which disappeared after the addition of aldehydes with the formation of the triphenylphosphine oxide (dP¼29.50 ppm).

F. Palacios et al. / Tetrahedron 59 (2003) 2617–2623
2619
Table 2. Heterodienes 9 and pyrazine 11 obtained
Entry
Compound
R1
R2
Conditions
Yield (%)a
1
2
3
4
5
9a
9b
9c
9d
11
H
H
H
CN
p-CH3-C6H4
p-NO2-C6H4
o-CH2vCHCH2OC6H4
OC2H5
THF, reflux, 5 d
THF, reflux, 3 d
THF, reflux, 48 h
THF, reflux, 12 h
HCl (dil), room temperature, 10 h
60
70
50
60
40
a
Yield after purification by flash chromatography.
isocyanates20 and 5-ketopyrrolephosphonates from alkenes
and nitrile ylides.21
Continuing with our interest in the chemistry of new three,24
five25 and six26 membered phosphorus substituted hetero-
cyclic compounds, we explored the use of the functionalized
imine 9a as an intermediate in the preparation of
phosphorylated pyrazines, since compound 9a may be
considered as a synthetic equivalent of phosphorylated
aminoaldehyde 10 (Scheme 4). Pyrazines are widely used
intermediates in Medicinal Chemistry.27,28 In addition,
pyrazines which are biosynthesized from amino acids, are
common units in a wide variety of marine natural products
showing cytostatic and antitumor properties,29 while
pyrazinamides30 and more recently pyrazinesters31 have
been successfully evaluated ‘in vitro’ and ‘in vivo’ for
antituberculosis activity. Therefore, the development of new
methods of synthesis of pyrazines acquired relevance in
recent years. However, although it is known that phosphorus
substituents regulate important biological functions,7 only
very recently the first synthesis of pyrazine-phosphonates by
dimerization of azirines has been disclosed.26b
A second alternative for the preparation of azadienes from
imines 4 could be also explored, for instance the
condensation reaction of these imines with dimethylforma-
mide diethyl acetal (DMF–DEA). A related reaction in
which some imines react with this reagent (DMF–DEA) has
been recently used for the preparation of quinolines22a or
imidazoles.22b In addition, this process could introduce an
electron-releasing amino group in the azadiene. Therefore,
thermal treatment of aldimines 4 (R1¼H) with dimethyl-
formamide diethyl acetal (DMF–DEA) in refluxing toluene
was carried out to give the 4-dimethylamino-3-phosphoryl
heterodienes 9 (Scheme 3, Table 2, entries 1–3) as
expected. Compounds 9 were purified by flash chromatog-
raphy and characterized on the basis of their spectroscopic
data. Thus, the 31P NMR spectrum of compound 9a showed
an absorption at dP¼20.6 ppm whereas, the 1H NMR
spectrum gave doublets for the imine and the olefinic
proton at dH¼8.17 (4JHP¼4.0 Hz) and at dH¼6.85
(3JHP¼9.3 Hz). This coupling constant is consistent with
the cis configuration of the vinylic proton and the
phosphonate group,23 and therefore, with the trans con-
figuration of the enamine double bond. The formation of
azadienes 9 could be explained by a condensation reaction
of the imines with DMF–DEA with the loss of two
molecules of ethanol and construction of the carbon–carbon
double bond. This process is not restricted to phosphoryl-
ated aldimines 4 (R1¼H) and can also be extended to
iminoester 4f (R1¼CN, R2¼OC2H5) to give azadiene 9d
(R1¼CN, R2¼OC2H5) which contains two electron-donor
(OC2H5, (NCH3)2) and two electron-withdrawing (CN,
PO(OC2H5)2) substituents (Scheme 3, Table 2, entry 4).
Then, a pyrazine containing two phosphonate groups 11 was
obtained by acid treatment (2N HCl) of functionalized imine
9a (Scheme 4, Table 2, entry 5). Spectroscopic data were
in agreement with the assigned structure 11. Mass
spectrometry of the compound showed the molecular ion
peak (m/z 352, 2%), while in the 31P NMR spectrum the
phosphonate groups resonated at dP¼7.3 ppm. The 1H NMR
spectrum of pyrazine 11 displayed a singlet at dH¼9.15 ppm
corresponding to protons in position 2 and 5, whereas, the
13C NMR spectrum of 11 showed a triplet at dC¼147.4 ppm
(JCP¼22.2 Hz) for C-3 and C-6 and a doublet at dC¼
150.1 ppm (1JCP¼220.1 Hz) for C-2 and C-5. The formation
of pyrazine 11 can be rationalized by an acid hydrolysis of
both enamine and imine groups of compound 9a, followed
by the dimerization-condensation of the aminoaldehyde
intermediate 10 with loss of two molecules of water and
formation of dihydropyrazine 12. Oxidation of this hetero-
cycle in the reaction medium would give pyrazine 11
(Scheme 4). As far as we know, this method is the first
synthesis of pyrazine-phosphonates without substituents in
the carbon atom adjacent to the heteroatom.
In conclusion, functionalized imines 4 and carbodiimides
derived from aminophosphonates 6 can be prepared,
respectively, by the aza-Wittig reaction of N-phosphoryl-
alkylphosphazenes 2 and carbonyl compounds or isocya-
nates. Thermal treatment of phosphorylated imines 4 with
DMF–DEA provides an efficient and easy access to
azadienes 9 containing both electron-withdrawing and
electron-releasing groups, which have been used for the
preparation of pyrazine-phosphonates. Azadienes1–5 and
pyrazines27–31 are important synthons in organic synthesis
Scheme 4.

2620
F. Palacios et al. / Tetrahedron 59 (2003) 2617–2623
and in the preparation of biologically active compounds of
interest in Medicinal Chemistry.
2JHP¼17.7 Hz, NCH2), 2.31 (3H, s, CH3Tolyl), 1.26 (6H, t,
3
3JHH¼7.0 Hz, 2£CH3); 13C NMR d: 165.3 (d, JCP
¼
16.6 Hz, CHvN), 141.3 (Carom–C), 133.0 (Carom–C),
129.1–128.1 (Carom), 62.4 (OCH2), 62.3 (OCH2), 57.3 (d,
1JCP¼154.1 Hz, NCH2), 21.3 (CH3tolyl), 16.3 (CH3), 16.2
(CH3); 31P NMR d: 22.6. IR (NaCl, nmax): 1633 (CvN),
1241 (PvO), 1036 (P–O); EIMS, (m/z): 269 (Mþ, 2). Anal.
calcd for C13H20NO3P: C, 57.99; H, 7.49; N, 5.20. Found:
C, 57.95; H, 7.40; N, 5.15.
3. Experimental
3.1. General
Chemicals were purchased from Aldrich Chemical
Company. Solvents for extraction and chromatography
were of technical grade. All solvents used in reactions were
freshly distilled from appropriate drying agents before use.
All other reagents were recrystallized or distilled as
necessary. All reactions were performed under an atmos-
phere of dry nitrogen. Analytical TLC was performed with
Merck silica gel 60 F254 plates. Visualization was
accomplished by UV light. Flash chromatography was
carried out using Merck silica gel 60 (230–400 mesh
ASTM). Melting points were determined with a Electro-
thermal IA9100 Digital Melting Point Apparatus and are
3.2.2. Diethyl (E)-N-(4-nitrobenzyliden)aminomethyl-
phosphonate (4b). According to the general procedure,
p-nitrobenzaldehyde 3 (1.61 g, 10 mmol) was used. The
crude residue was purified by chromatography eluting with
hexane/ethyl acetate 3:1 and 2.1 g (70%) of 4b were
1
4
obtained as a yellow oil. H NMR d: 8.36 (1H, d, JHP
3
¼
4.0 Hz, CHvN), 8.20 (2H, d, JHH¼6.8 Hz, Harom), 7.88
(2H, d, 3JHH¼6.8 Hz, Harom), 4.16 (4H, m, 2£OCH2), 4.10
2
3
(2H, d, JHP¼16.0 Hz, NCH2), 1.26 (6H, t, JHH¼7.0 Hz,
2£CH3); 13C NMR d: 163.2 (d, JCP¼16.6 Hz, CHvN),
3
1
uncorrected. H (300 MHz), 13C (75 MHz) and 31P NMR
149.3 (Carom–C), 140.8 (Carom–C), 129.8–123.6
1
(Carom), 62.6 (OCH2), 62.5 (OCH2), 57.4 (d, JCP
¼
(120 MHz) spectra were recorded on a Varian Unity Plus
300 MHz spectrometer using CDCl3 or CD3OD solutions
with TMS as internal reference for 1H and 13C NMR spectra
and phosphoric acid (85%) for 31P NMR spectra. Chemical
shifts (d) are reported in ppm. Coupling constants (J) are
reported in Hertz. Low-resolution mass spectra (MS) were
obtained at 50–70 eV by electron impact (EIMS) on a
Hewlett Packard 5971 or 5973 spectrometer. Data are
reported in the form m/z (intensity relative to base¼100).
Infrared spectra (IR) were taken on a Nicolet IRFT Magna
550 spectrometer, and were obtained as solids in KBr or as
neat oils. IR absorptions are reported in cm21. Elemental
analyses were performed in a LECO CHNS-932 apparatus.
Diethyl azidomethylphosphonate 1 was synthesized
according to literature procedures.17
153.6 Hz, NCH2), 16.3 (CH3), 16.2 (CH3); 31P NMR d:
21.6. IR (NaCl, nmax): 1520 (CvN), 1347 (PvO), 1029
(P–O); EIMS, (m/z): 163 (Mþ2 P(O)(OCH2CH3)2), 7).
Anal. calcd for C12H17N2O5P: C, 48.00; H, 5.71; N, 9.33.
Found: 48.30; H, 5.45; N, 9.65.
3.2.3. Diethyl (E)-N-(4-methoxybenzyliden)amino-
methyl-phosphonate (4c). According to the general
procedure, p-methoxybenzaldehyde 3 (1.4 g, 10 mmol)
was used. The crude residue was purified by chromatog-
raphy eluting with hexane/ethyl acetate 3:1 and 1.8 g (61%)
of 4c were obtained as a yellow oil. 1H NMR d: 8.16 (1H, d,
4JHP¼4.5 Hz, CHvN), 7.63 (2H, d, 3JHH¼8.2 Hz, Harom),
6.87 (2H, d, 3JHH¼8.3 Hz, Harom), 4.12 (4H, m, 2£OCH2),
2
4.04 (2H, d, JHP¼17.5 Hz, NCH2), 3.77 (3H, s, OCH3),
3
1.27 (6H, t, JHH¼7.0 Hz, 2£CH3); 13C NMR d: 164.7 (d,
3.2. General procedure for the synthesis of
phosphorylalkyl aldimines 4
3JCP¼16.1 Hz, CHvN), 161.8 (Carom–C), 131.7–129.6
1
(Carom), 128.2 (Carom–C), 62.3 (OCH2), 57.3 (d, JCP
¼
154.1 Hz, NCH2), 55.1 (OCH3), 16.2 (CH3); 31P NMR d:
22.8. IR (NaCl, nmax): 1599 (CvN), 1255 (PvO), 1023 (P–
O); EIMS, (m/z): 285 (Mþ, 1). Anal. calcd for C13H20NO4P:
C, 54.73; H, 7.07; N, 4.91. Found: C, 54.45; H, 7.15; N,
4.85.
Diethyl azidomethylphosphonate 1 (0.95 g, 5 mmol) in THF
(5 mL) was added dropwise to a solution of triphenyl-
phosphine (1.18 g, 4.5 mmol) in THF (10 mL) at 08C. The
formation of the phosphazene 2a was monitored by 31P
NMR spectroscopy (see Section 2.1). After stirring the
mixture at room temperature for 10 h, carbonyl derivatives 3
or 5 (5 mmol) were added and the solution stirred at room
temperature or under reflux for 10–23 h. The solvent was
removed at reduced pressure and the residue containing
imines 4 or 6 and triphenylphosphine oxide was extracted
with cool diethyl ether (4£15 mL). The combined organic
extracts were evaporated under reduced pressure and the
residue was purified by column chromatography to afford
compounds 4.
3.2.4. Diethyl (E)-N-(2-allyloxybenzyliden)aminomethyl-
phosphonate (4d). According to the general procedure,
o-allyloxybenzaldehyde 3 (1.6 g, 10 mmol) was used. The
crude residue was purified by chromatography eluting with
hexane/ethyl acetate 3:1 and 2.2 g (70%) of 4d were
1
4
obtained as a yellow oil. H NMR d: 8.72 (1H, d, JHP
4.8 Hz, CHvN), 7.91–6.80 (4H, m, Harom), 6.01 (1H, m,
¼
3
4
CH2vCH), 5.37 (1H, dd, JHH¼17.2 Hz, JHH¼1.3 Hz,
CHvCHtrans), 5.26 (1H, dd, 3JHH¼10.5 Hz, 4JHH¼1.3 Hz,
3
4
CHvCHcis), 4.53 (2H, dd, JHH¼5.2 Hz, JHH¼1.3 Hz,
3.2.1. Diethyl (E)-N-(4-methylbenzyliden)aminomethyl-
phosphonate (4a). According to the general procedure,
p-tolylaldehyde 3 (0.54 g, 4.5 mmol) was used. The crude
residue was purified by chromatography eluting with
hexane/ethyl acetate 3:1 to yield 1.03 g (85%) of 4a as a
yellow oil. 1H NMR d: 8.21 (1H, d, 4JHP¼4.7 Hz, CHvN),
OCH2), 4.15 (4H, m, 2£OCH2), 4.05 (2H, d, 2JHP¼14.2 Hz,
NCH2), 1.27 (6H, t, JHH¼7.0 Hz, 2£CH3); 13C NMR d:
3
3
161.4 (d, JCP¼16.6 Hz, CHvN), 132.2 (vCH), 157.8,
124.4 (Carom–C), 128.3, 127.3, 120.8, 112.2 (Carom),
117.6 (vCH2), 69.0 (OCH2), 62.4 (OCH2), 57.7 (d, JCP
1
¼
153.6 Hz, NCH2), 16.4 (CH3); 31P NMR d: 22.7. IR (NaCl,
max): 1593 (CvN), 1241 (PvO), 1023 (P–O); EIMS,
3
3
7.57 (2H, d, JHH¼7.9 Hz, Harom), 7.14 (2H, d, JHH
¼
n
7.9 Hz, Harom), 4.10 (4H, m, 2£OCH2), 4.03 (2H, d,

F. Palacios et al. / Tetrahedron 59 (2003) 2617–2623
2621
(m/z): 311 (Mþ, 13). Anal. calcd for C15H22NO4P: C, 57.87;
H, 7.12; N, 4.50. Found: C, 57.65; H, 7.25; N, 4.65.
3JCP¼11.5 Hz, Tol-C–NH), 63.0 (OCH2), 62.1 (OCH2),
52.0 (CH3), 51.7 (CH3), 21.2 (CH3tolyl), 16.5 (CH3); 31P
NMR d: 6.85. IR (NaCl, nmax): 1650 (CvN), 1241 (PvO),
1023 (P–O); EIMS, (m/z): 409 (Mþ, 100). Anal. calcd for
C19H24NO7P: C, 55.74; H, 5.91; N, 3.42. Found: C, 55.65;
H, 5.55; N, 3.55.
3.2.5. Diethyl N-(1-cyanoethyliden)aminomethylphos-
phonate (4e). According to the general procedure, piruvo-
nitrile 3 (0.31 g, 4.5 mmol) was used. The crude residue was
purified by chromatography eluting with hexane/ethyl
acetate 3:1 and 0.75 g (76%) of 4e were obtained as a
3.3. General procedure for the synthesis of
3-phosphoryl-2-azadienes 9
1
yellow oil. H NMR d: 4.08 (4H, m, 2£OCH2), 3.65 (2H,
dd, 2JHP¼12.0 Hz, 2JHH¼5.9 Hz, NCH2), 1.97 (3H, s, CH3),
3
1.31 (6H, t, JHH¼7.0 Hz, 2£CH3); 13C NMR d: 170.5
Dimethylformamide diethyl acetal was added to an
equimolecular amount of imine 4 (5 mmol) in toluene
(20 mL) and the mixture was heated at reflux until the
starting imine was not detected (TLC). The solvent was
removed at reduced pressure and the residue was purified by
flash chromatography eluting with hexane/ethyl acetate to
yield compounds 9.
(CvN), 115.1 (CuN), 62.4 (OCH2), 62.3 (OCH2), 34.3 (d,
1JCP¼158 Hz, NCH2), 22.3 (CH3), 16.2 (CH3), 16.1 (CH3);
31P NMR d: 23.8. IR (NaCl, nmax): 2236 (CuN), 1228
(PvO), 1023 (P–O); EIMS, (m/z): 218 (Mþ, 3%). Anal.
calcd for C8H15N2O3P: C, 44.04, H, 6.93, N, 12.84. Found:
C, 43.95, H, 6.80, N, 12.95.
3.2.6. Diethyl N-(1-cyano-1-ethoxymethyliden)amino-
methyl-phosphonate (4f). According to the general pro-
cedure, ethyl cyanoformiate 3 (0.45 g, 4.5 mmol) was used.
The crude residue was purified by chromatography eluting
with hexane/ethyl acetate 3:1 and 0.90 g (80%) of 4f
3.3.1. Diethyl (E,E)-{2-dimethylamino-1-[(4-methyl ben-
zylidene)amino]vinyl}phosphonate (9a). According to the
general procedure, imine 4a (1.3 g, 4.8 mmol) was used.
The crude residue was purified by flash chromatography
eluting with hexane/ethyl acetate 1:1 to yield a yellow solid
that was crystallized from hexane yielding 0.93 g (60%) of
9a as a yellow solid; mp 90–958C. 1H NMR d: 8.17 (1H, d,
4JHP¼4.0 Hz, CHvN), 7.47–7.10 (4H, m, Harom), 6.85
1
were obtained as a yellow oil. H NMR d: 4.17 (2H, q,
3JHH¼7.1 Hz, OCH2), 4.09 (4H, m, 2£OCH2), 3.91 (2H, d,
2JHP¼17.2 Hz, NCH2), 1.26 (9H, s, 3£CH3); 13C NMR d:
3
4
3
139.8 (d, JCP¼15.8 Hz, CvN), 106.5 (d, JCP¼3.2 Hz,
CuN), 64.3 (OCH2), 62.3 (OCH2), 47.3 (d, 1JCP¼158.5 Hz,
NCH2), 16.0 (CH3), 15.9 (CH3), 13.2 (CH3); 31P NMR d:
20.9. IR (NaCl, nmax): 2238 (CuN), 1255 (PvO); EIMS,
(m/z): 248 (Mþ, 10%). Anal. calcd for C9H17N2O4P: C,
43.55, H, 6.90, N, 11.29. Found: C, 43.50, H, 6.80, N, 11.20.
(1H, d, JHP¼9.3 Hz, PCvCH), 4.03 (4H, m, 2£OCH2),
3.26 (6H, s, (NCH3)2), 2.31 (3H, s, CH3Tolyl), 1.22 (6H, t,
3JHH¼7.0 Hz, 2£CH3); 13C NMR d: 149.0 (d, 3JCP¼9.5 Hz,
CHvN), 147.6 (d, 2JCP¼41.3 Hz, PCvC), 138.8 (Carom–
C), 135.7 (Carom–C), 129.0–126.7 (Carom), 103.8 (d,
1JCP¼181.3 Hz, PCvC), 60.7 (OCH2), 43.5 (NCH3), 21.3
(CH3tolyl), 16.1 (CH3); 31P NMR d: 20.6. IR (NaCl, nmax):
3144 (NMe2), 1633 (CvN), 1414 (PvO), 1029 (P–O);
EIMS, (m/z): 324 (Mþ, 100). Anal. calcd for C16H25N2O3P:
C, 59.25; H, 7.77; N, 8.64. Found: C, 59.30; H, 7.55; N,
8.90.
3.2.7. N-Diethoxyphosphorylmethyl-N0-phenylcarbo-
diimide (6). According to the general procedure, phenyl-
isocyanate 5 (0.54 g, 4.5 mmol) was used. The crude residue
was purified by chromatography eluting with hexane/ethyl
ether 3:1 and 0.90 g (75%) of 6 were obtained as a yellow
1
oil. H NMR d: 7.24–7.01 (5H, m, arom), 4.14 (4H, m,
2
3.3.2. Diethyl (E,E)-{2-dimethylamino-1-[(4-nitrobenzyl-
idene)amino]vinyl}phosphonate (9b). According to the
general procedure, imine 4b (1.5 g, 5 mmol) was used. The
crude residue was purified by flash chromatography eluting
with hexane/ethyl acetate 2:1 to yield a yellow solid that
was crystallized from hexane yielding 1.25 g (70%) of 9b as
OCH2), 3.59 (2H, d, JHP¼13.3 Hz, NCH2), 1.17 (6H, m,
CH3); 13C NMR d: 142.9 (Cv), 129.3–124.2 (CNarom),
1
62.9 (OCH2), 62.8 (OCH2), 41.5 (d, JCP¼151.7 Hz,
NCH2), 16.4 (CH3), 16.3 (CH3); 31P NMR (CDCl3)d:
24.5. IR (NaCl, nmax): 2094, 1221 (PvO); EIMS, (m/z): 268
(Mþ, 24%). Anal. calcd for C12H17N2O3P: C, 53.73, H,
6.39, N, 10.44. Found: C, 53.70, H, 6.35, N, 10.30.
1
a yellow solid; mp 108–1098C. H NMR d: 8.19 (1H, d,
4JHP¼3.6 Hz, CHvN), 8.27–7.60 (4H, m, Harom), 7.03
2
(1H, d, JHP¼8.8 Hz, PCvCH), 4.03 (4H, m, 2£OCH2),
3
3.2.8. Dimethyl 2-(diethoxyphosphoryl)-5-p-tolyl-1H-
pyrrole-3,4-dicarboxylate 8. Methyl lithium (1.8 mmol)
was added to a solution of the imine 4a (0.3 g, 1.1 mmol) in
THF (5 mL) at 2788C. After stirring 1 h at 2788C,
dimethylacetylenedicarboxylate (1.8 mmol) was added,
the mixture was allowed to warm to room temperature
and stirred overnight. The solvent was removed at reduced
pressure and the residue was purified by flash chroma-
tography eluting with hexane/ethyl acetate 3:1 to yield
3.30 (6H, s, (NCH3)2), 1.27 (6H, t, JHH¼7.0 Hz, 2£CH3);
2
13C NMR d: 149.3 (d, JCP¼41.5 Hz, PCvC), 147.0
3
(Carom–C), 145.1 (d, JCP¼8.5 Hz, CvN), 144.0
1
(Carom–C), 126.8–123.7 (Carom), 104.8 (d, JCP
¼
183.3 Hz, PCvC), 60.7 (OCH2), 43.5 (NCH3), 16.1
(CH3); 31P NMR d: 18.8. IR (NaCl, nmax): 3137 (NMe2),
1619 (CvN), 1394 (PvO), 1029 (P–O); EIMS, (m/z): 355
(Mþ, 100). Anal. calcd for C15H22N3O5P: C, 50.70; H, 6.24;
N, 11.83. Found: 50.90; H, 6.05; N, 11.45.
1
0.16 g (36%) of 8 as a yellow oil. H NMR d: 10.8 (1H, s,
NH), 7.20–711 (4H, m, Harom), 4.00 (4H, m, 2£OCH2),
3.3.3. Diethyl (E,E)-{2-dimethylamino-1-[(2-allyloxy-
benzylidene)amino]vinyl}phosphonate (9c). According
to the general procedure, imine 4c (1.6 g, 5 mmol) was
used. The crude residue was purified by flash chroma-
tography eluting with hexane/ethyl acetate 2:1 to yield 0.9 g
3.78 (3H, s, OCH3), 3.68 (3H, s, OCH3), 2.31 (3H, s,
3
CH3Tolyl), 1.28 (6H, t, JHH¼7.0 Hz, 2£CH3); 13C NMR
d: 164.6 (Carom–C), 138.8 (Carom–C), 128.8, 128.7
(Carom), 127.2 (Carom–C), 125.8 (d, JCP¼21.6 Hz,
2
1
1
P–CvC), 118.7 (d, JCP¼224 Hz, P–C–NH), 114.2 (d,
(50%) of 9c as a yellow oil. H NMR d: 8.68 (1H, d,

2622
F. Palacios et al. / Tetrahedron 59 (2003) 2617–2623
4JHP¼4.8 Hz, CHvN), 7.75–6.90 (4H, m, Harom), 6.81
Kettschau, G. Top. Curr. Chem. 1997, 189, 1–120. (c) Ghosez,
L. Stereocontrolled Organic Synthesis; Backwell: Oxford,
´
1994; pp 193–233. (d) Barluenga, J.; Tomas, M. Adv.
3
(1H, d, JHP¼8.4 Hz, PCvCH), 6.02 (1H, m, CH2vCH),
5.40 (1H, dd, 3JHH¼17.2 Hz, 4JHH¼1.5 Hz, CHvCHtrans),
3
4
Heterocycl. Chem. 1993, 57, 1–78. (e) Boger, D. L.
Comprehensive Organic Synthesis B; Trost, M., Paquete,
L. A., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 451–512.
2. For recent contributions see: (a) Nicolau, K. C.; Nevalainen,
M.; Safina, B. S.; Zak, M.; Bulat, S. Angew. Chem., Int. Ed.
2002, 41, 1941–1945. (b) Moody, C. J.; Hughes, R. A.;
Thompson, S. P.; Alcaraz, L. Chem. Commun. 2002,
1760–1761. (c) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc.
1999, 121, 2617–2618.
5.19 (1H, dd, JHH¼9.0 Hz, JHH¼1.3 Hz, CHvCHcis),
3
4
4.50 (2H, dd, JHH¼6.3 Hz, JHH¼1.6 Hz, OCH2), 4.05
(4H, m, 2£OCH2), 3.30 (6H, s, (NCH3)2), 1.27 (6H, t,
2
3JHH¼7.0 Hz, 2£CH3); 13C NMR d: 148.0 (d, JCP
¼
3
41.8 Hz, PCvC), 145.5 (d, JCP¼9.0 Hz, CHvN), 133.1
(vCH), 129.9 (Carom), 127.5 (Carom–C), 125.7, 120.8
1
(Carom), 116.9 (vCH2), 112.6 (Carom), 104.0 (d, JCP
¼
182.8 Hz, PCvC), 69.0 (OCH2), 61.4 (CH2), 43.8 (NCH3),
16.4 (CH3); 31P NMR d: 20.4. IR (NaCl, nmax): 3400
(NMe2), 1745 (CvN), 1241 (PvO), 1023 (P–O); EIMS,
(m/z): 366 (Mþ, 45). Anal. calcd for C18H27N2O4P: C,
59.01; H, 7.43; N, 7.65. Found: C, 59.25; H, 7.25; N, 7.50.
3. (a) Cheng, Y.; Ho, E.; Mariano, P. S.; Ammon, H. L. J. Org.
Chem. 1985, 50, 5678–5686. (b) Venturini, A.; Joglar, J.;
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4. (a) Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org.
Chem. 2002, 67, 1941–1946. (b) Palacios, F.; Alonso, C.;
Rubiales, G.; Ezpeleta, J. M. Eur. J. Org. Chem. 2001,
2115–2122. (c) Palacios, F.; Alonso, C.; Rubiales, G. J. Org.
Chem. 1997, 62, 1146–1152.
3.3.4. Ethyl N-[1-(diethoxyphosphoryl)-2-dimethyl-
amino-vinyl]cyanoformimidate (9d). According to the
general procedure, imine 4f (1.25 g, 5 mmol) was used. The
crude residue was purified by flash chromatography eluting
with ethyl acetate to yield 0.9 g (50%) of 9d as a yellow-
´
5. (a) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M.
´
J. Org. Chem. 2002, 67, 2131–2135. (b) Palacios, F.; Herran,
3
brown oil. 1H NMR d: 6.49 (1H, d, JHP¼11.1 Hz,
PCvCH), 4.13 (2H, m, OCH2), 3.93 (4H, m, 2£OCH2),
E.; Rubiales, G. J. Org. Chem. 1999, 64, 6239–6246.
2.79 (6H, s, (NCH3)2), 1.20 (6H, m, 3£CH3); 13C NMR d:
´
(c) Palacios, F.; Perez de Heredia, I.; Rubiales, G. J. Org.
Chem. 1995, 60, 2384–2390. (d) Barluenga, J.; Ferrero, M.;
Palacios, F. Tetrahedron Lett. 1988, 29, 4863–4864.
2
139.5 (d, JCP¼27.7 Hz, PCvC), 131.7 (CuN), 128.2 (d,
1
3JCP¼12.0 Hz, CHvN), 98.5 (d, JCP¼219.0 Hz, PCvC),
62.1 (OCH2), 61.2 (OCH2), 42.4 (NCH3), 16.1 (CH3), 16.0
(CH3); 31P NMR d: 18.6. IR (NaCl, nmax): 2250 (CuN),
1626 (CvN), 1241 (PvO), 1023 (P–O); EIMS, (m/z): 303
(Mþ, 60). Anal. calcd for C12H22N3O4P: C, 47.52; H, 7.31;
N, 13.85. Found: C, 47.75; H, 7.05; N, 13.55.
6. (a) Pinho e Melo, T. M. V. D.; Fausto, R.; d’A Rocha
Gonsalves, A. M.; Gilchrist, A. M. J. Org. Chem. 1998, 63,
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3.3.5. 2,5-Bis(diethoxyphosphoryl)pyrazine (11). 2 M
HCl (1 mL) was added to a solution of azadiene 9a (0.2 g,
0.6 mmol) in THF (5 mL) and the mixture was stirred
15 min at room temperature. After removing the solvent at
reduced pressure, the crude residue was purified by flash
chromatography eluting with ethyl acetate to yield 0.085 g
¨
13709–13724. (d) Wulff, G.; Bohnke, H. Angew. Chem., Int.
Ed. 1986, 25, 90–92.
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(40%) of 11 as a yellow oil. 1H NMR d: 9.15 (1H, s,
3
Hpyrazine), 4.24 (4H, m, 2£OCH2), 1.32 (6H, t, JHH
¼
1
7.1 Hz, 2£CH3); 13C NMR d: 150.1 (d, JCP¼220.1 Hz,
CP), 147.4 (t, JCP¼22.2 Hz, CHpyrazine), 63.7 (OCH2),
16.2 (CH3), 16.0 (CH3); 31P NMR d: 7.4. IR (NaCl, nmax):
1635 (CvN), 1235 (PvO), 1026 (P–O); EIMS, (m/z): 352
(Mþ, 2). Anal. calcd for C12H22N2O6P2: C, 40.92; H, 6.30;
N, 7.95. Found: C, 40.65; H, 6.55; N, 7.60.
8. (a) Toy, A. D. F.; Walsh, E. N. Phosphorus Chemistry in
Everyday Living; American Chemical Society: Washington
DC, 1987. (b) Engel, R. Handbook of Organophosphorus
Chemistry; Marcel Dekker: New York, 1992.
9. (a) Palacios, F.; Aparicio, D.; de los Santos, J. M. Tetrahedron
1996, 52, 4857–4866. (b) Stevens, C.; Gallant, M.; De Kimpe,
N. Tetrahedron Lett. 1999, 40, 3457–3460. (c) Palacios, F.;
Gil, M. J.; Martinez de Marigorta, E.; Rodriguez, M.
Tetrahedron 2000, 56, 6319–6330. (d) Palacios, F.; Gil,
M. J.; Martinez de Marigorta, E.; Rodriguez, M. Tetrahedron
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Acknowledgements
´
The present work has been supported by the Direccion
General de Investigacion del Ministerio de Ciencia y
´
´
Tecnologıa (MCYT, Madrid DGI, BQU2000-0217) and
by the Universidad del Paıs Vasco (UPV, G11/ 99). M. R.
´
¨
10. For reviews see: (a) Wamhoff, H.; Richardt, G.; Stolben, S.
´
thanks the Ministerio de Ciencia y Tecnologıa (MCYT,
Madrid) for a predoctoral fellowship.
Adv. Heterocycl. Chem. 1995, 64, 159–249. (b) Molina, P.;
Vilaplana, M. J. Synthesis 1994, 1197–1218. (c) Eguchi, S.;
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24, 209–243. (d) Gololobov, Y. G.; Kaskhin, L. F.
Tetrahedron 1992, 48, 1353–1406. (e) Barluenga, J.; Palacios,
F. Org. Prep. Proced. Int. 1991, 23, 1–59.
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