Synthesis of 1,2-dihydro-1,3-diaza-2λ5,4λ5-2,4- diphosphorine 2-oxides

Article abstract of DOI:10.1016/S0040-4020(02)00144-8

The reaction of lithium (N-diphenylphosphoryl)phosphazenes with nitriles afforded 1,2-dihydro-1,3-diaza-2λ⁵,4λ⁵-2,4- diphosphorine 2-oxides through a C-regioselective addition to the cyano linkage followed by in situ cyclocondensation. The new heterocycles were designed to mimic thymine and are promising chemotherapeutic anticancer agents. As an exception, for p-nitrobenzonitrile a S_NAr reaction was exclusively observed with the nucleophile entering in the ortho position of the nitro substituent in a process directed by the strong electron withdrawing effect of the NO₂ group.

Full text of DOI:10.1016/S0040-4020(02)00144-8

TETRAHEDRON
Pergamon
Tetrahedron 58 +2002) 2569±2575
Synthesis of
1,2-dihydro-1,3-diaza-2l5,4l5-2,4-diphosphorine 2-oxides
p
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Carmen M. Andujar, Isidro Perez Alvarez and Fernando Lopez Ortiz
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Area de Quõmica Organica, Universidad de Almerõa, Carretera de Sacramento s/n, 04120 Almerõa, Spain
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Received 12 September 2001; revised 21 December 2001; accepted 5 February 2002
AbstractÐThe reaction of lithium +N-diphenylphosphoryl)phosphazenes with nitriles afforded 1,2-dihydro-1,3-diaza-2l5,4l5-2,4-di-
phosphorine 2-oxides through a C-regioselective addition to the cyano linkage followed by in situ cyclocondensation. The new heterocycles
were designed to mimic thymine and are promising chemotherapeutic anticancer agents. As an exception, for p-nitrobenzonitrile a SNAr
reaction was exclusively observed with the nucleophile entering in the ortho position of the nitro substituent in a process directed by the
strong electron withdrawing effect of the NO2 group. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
phosphorus atoms in the ring.8 The ring structures known
include 1,4-diaza-2,5-diphosphorines9 1, 1,5-diaza-2,4-
diphosphorines10 2, as well as a series of polychlorinated
1,3-diaza-2,4-diphosphorines 3 obtained by reaction of
nitriles with hexachlorodiphosphazonium chloride11
+Scheme 1). To the best of our knowledge, there are no
reports on 1,3-diaza-2,4-diphosphorines with a substituents
pattern formed by carbon containing groups which could
mimic the thymine system.
Phosphorus heterocycles continue attracting a great interest
because of the diversity of structures and the biological
properties they present.1,2 In many cases, the phosphorus
atom is linked to other heteroatoms such as oxygen or
nitrogen and the biological activity of the heterocyclic
compound may be associated to the particular arrangement
of heteroatoms and size of the ring.3 As part of an ongoing
project devoted to the synthesis of antitumour agents we
were interested in the preparation of thymine analogues
where the trigonal carbonyl groups are replaced by tetra-
coordinated phosphorus atoms. Phosphorus-containing
anticancer agents are well known. Cyclophosphamide,
2-bis+2-chloroethyl)amino-1,3,2-oxazaphosphorine 2-oxide,
an anticancer prodrug in use for over 20 years is the best
example. It is a nitrogen mustard with effect as alkylating
agent of DNA. In principle, phosphorus analogues of
thymine may act as drugs interfering with DNA synthesis
either by blocking pyrimidine synthesis or through inhibi-
tion of speci®c enzymes involved in the synthesis of DNA.4
Phosphonic and phosphinic acid derivatives are known to
mimic the transition state of the hydrolysis of a peptide bond
and compounds containing these functionalities have been
utilized as enzyme inhibitors.5
We have very recently described the synthesis of 1,2,5,6-
tetrahydro 1,3-oxaza-2,4-diphosphorine 2-oxides 5±7
through reaction of lithium N-phosphorylphosphazenes 4
with aldehydes and ketones +Scheme 1).12 We reasoned
that the target 1,3-diaza-2,4-diphosphorines 8 could be
obtained in a similar manner by using nitriles as electro-
philes instead of the carbonyl reagents. The retrosynthetic
pathway is shown in Scheme 2.
Several synthesis of 1,3,2-6 and 1,5,2-diazaphosphorines7
have been described. A literature search revealed that
there are very few reports on the preparation of six-
membered heterocycles containing two nitrogen and two
The reaction of nitriles with phosphazenyl stabilized
carbanions is precedented. The addition of nitriles to
Keywords: phosphazenes; diphosphorines; carbanions; phosphorus hetero-
cycles; SNAr.
p
Corresponding author. Tel.: 134-950-015478; fax: 134-950-015481;
e-mail: ¯ortiz@ual.es
Scheme 1. +i) BunLi, 2358C, THF, 30 min; +ii) R3R4CO, 2958C to rt, 8 h.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+02)00144-8

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C. M. Andujar et al. / Tetrahedron 58 *2002) 2569±2575
2570
Scheme 2.
Scheme 4. +i) R1CH2Br, THF, 270 to 258C, 3 h; +ii) N3P+O)+OPh)2, THF,
258C, 30 min; +iii) +a) 2.5 equiv. BunLi, 2308C, THF, 30 min, +b) 2.5 equiv.
R2CN, 2858C, THF, 48 h.
Table 1. d31P +ppm), 2JPP +Hz), and melting points +8C) of phosphazenes 4
Product
R1
R2
d
31P +PN/PO)
2JPP
Mp
4a
4b
4c
4d
H
CH3
CH3+CH2)2
PhCH2
H
H
H
H
16.17/25.06
21.77/25.71
19.75/25.74
18.68/25.61
31.2
31.2
32.7
32.3
70±71
118±119
85±86
93±94
Scheme 3. +i) BunLi, 2358C, THF, 30 min; +ii) R2CN, 270 to 258C, 12 h.
metalated alkyl+N-phenyl)phosphazenes affords Z-b-
enamino+N-phenyl)phosphazenes 9 in reasonable yields.13
However, in the analogous reaction of phosphazenes with
the nitrogen linked to an alkoxycarbonyl and benzoyl group
the initial adduct is unstable under the reaction conditions
used and rearranges to form iminophosphazenes 10 quanti-
tatively +Scheme 3).14 A similar behavior has been recently
observed in the reaction of lithium phosphonates with
amidines.15 In these processes, the tendency of the phos-
phazenyl moiety to migrate increases with increasing the
electron withdrawing strength of the group bonded to the
nitrogen, which produces an increase in the electrophilic
character of the phosphorus.16
alkyl halide. Overall yields were generally higher than
80% +Scheme 4). The phosphazenes 4 used in this study
and their 31P NMR data are shown in Table 1.
Lithiation of 4 is quantitatively achieved in 30 min by treat-
ment with BunLi at 2308C in THF. The ®rst attempts of
obtaining 1,3-diaza-2,4-diphosphorine 2-oxides 8 were
disappointing. The standard conditions for the reaction of
electrophiles with lithium phosphazenes: addition of the
nitrile at 2808C, slow increase of the temperature to
ambient, and stirring the mixture for 8 h, were unsuccessful
and the starting materials were recovered unaltered. New
signals, eventually assigned to the adduct, were observed
in the 1H and 31P NMR spectra of crude reactions mixtures
when the temperature was maintained at 2808C for a few
hours. After some experimentation the best results were
obtained when the reaction was stirred at 2808C during
48 h using a stoichiometry phosphorylphosphazene/BunLi/
nitrile 1:2.5:2.5 +Scheme 4). Aqueous workup afforded
the expected heterocycles 1,3-diaza-2,4-diphosphorine 2-
oxides 8. Due to the excess of base and electrophile, the
adduct was contaminated with the ketone arising from the
addition of BunLi to the cyano group of the nitrile. Column
chromatography allowed the isolation of the 1,3-diaza-2,4-
diphosphorine 2-oxides 8 indicated in Table 2.
We describe here the reaction of lithium phosphoryl-
phosphazenes with aryl- and alkyl-nitriles. At 2808C the
addition proceeds cleanly without the formation of
rearranged products affording 1,3-diaza-2,4-diphosphorine
2-oxides 8. In the particular case of p-nitrobenzonitrile the
reaction is driven by the NO2 group and the adducts
obtained derived from the addition of the anion to the
aromatic ring in b position relative to the nitro substituent.
This is the ®rst synthesis of a heterocyclic system with a
P±N±P±N structural fragment without halide substituents
linked to the phosphorus atoms.
The mass spectra of 8 are consistent with a mass balance
arising from the addition of one molecule of nitrile to
lithiated phosphazenes 4 and the lost of one molecule of
phenol from the initial adduct. Formation of heterocycles
8 is clearly detected in the 31P NMR spectra. In all cases, the
phosphorus atom of the PvN linkage were shifted
down ®eld with respect to phosphazenes 4 +average Dd
+8±4)ˆ25.3 ppm, see Tables 1 and 2). The phosphorus of
the PvO moiety were less sensitive to the cyclocondensa-
tion reaction. Generally, they appeared slightly shifted to
higher ®eld +Dd +8±4)<1.2 ppm, see Tables 1 and 2),
2. Results and discussion
Phosphorylphosphazenes 4 were easily accessible through
the Staudinger reaction of diphenylphosphorylazide with
the appropriate phosphine.17 Diphenylphosphorylazide is a
commercial compound scarcely used in phosphazene
chemistry.18 Phosphazenes derived from phosphines not
available commercially were synthesized by in situ addition
of diphenylphosphorylazide to the phosphine prepared by
alkylation of diphenylphosphide +generated by reductive
lithiation of triphenylphosphine)19 with the appropriate

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C. M. Andujar et al. / Tetrahedron 58 *2002) 2569±2575
2571
Table 2. 31P NMR data, melting point and yield of the 13-diaza-2l5,4l5-2,4-diphosphorine 2-oxides 8 and +phosphazenylalkyl)nitriles 11 obtained
Product
R1
R2
d
31P +PN/PO) +ppm)
2JPP +Hz)
Mp +8C)
Yielda +%)
8a
8b
8c
8d
8d
8e
11a
11b
CH3
CH3
CH3
CH3
CH3CH2CH2
PhCH2
H
C6H11
C6H5
p-Cl-C6H4
p-F-C6H4
C6H11
26.58/25.57
25.57/26.9
25.43/26.95
25.35/27.01
25.77/25.2
24.82/27.21
17.58/25.86
19.65/27.65
8.9
8.9
8.9
8.9
8.9
8.9
31.1
35.6
254±255
214±215
256±257
253±254
246±247
256±257
Oil
97
40
63
68
15
13
26
63
p-Cl-C6H4
CH3
Oil
a
Isolated yield.
although for 8e a down ®eld shift of 0.4 ppm was observed.
The most dramatic effect is observed on the geminal 31P±31P
coupling constant. Its magnitude decreased notably with the
cyclization20 with D2JPP +8±4) ranging from 222.3 to
223.8 Hz. The presence of the enamino moiety in 8 was
easily deduced from the 1H and 13C NMR spectra: the NH of
the series of compounds appeared at d 5.31±5.6321 as a
broad doublet +2JPHˆ2±4.4 Hz) and the corresponding
carbon atoms were assigned according to their chemical
shifts and the magnitude of the 31P±13C coupling constants:
the carbon a to the phosphorus showed a double doublet in
p-nitrobenzonitrile, which could lead to either a primary
imine +the enamine tautomer was discarded because of the
presence of the methylene group) or the corresponding
ketone formed by hydrolysis of the CvN moiety
+Scheme 5).
1
the range d 80.6±86.57 ppm +average JPCˆ89.6 Hz,
3JPCˆ8.9 Hz), while the carbon linked to the nitrogen
absorbed at d 151.78±155.07 and was coupled only to one
2
phosphorus +average JPCˆ8.5 Hz).
The formation of heterocycles 8 can be explained by the
nucleophilic addition of the metallated phosphazene to the
cyano group followed by cyclocondensation with loss of a
lithium phenolate. Finally, the imine linkage of the inter-
mediate heterocycle thus obtained stabilized as the corre-
sponding enamine tautomer +Scheme 4). The results in
Table 2 indicate that the reaction is very sensitive to rela-
tively small changes in the alkyl substituent of phosphazene
4. Thus, for cyclohexylcarbonitrile yields dropped from
almost quantitative to 15% by increasing the chain length
from methyl to n-propyl +entries 1, 5). Curiously, no
reaction was observed for the simplest phosphazene
4a +R1ˆH). This behavior is analogous to the lack of
P-diphenyl+methyl)+N-
Scheme 5. +i) 2.5 equiv. BunLi, 2308C, THF, 30 min; +ii) 2.5 equiv.
p-nitrobenzonitrile, THF, 2858C, 48 h.
However, the 13C NMR spectrum showed no signals in the
expected range for a CvX +XˆO, N) carbon. Moreover, the
IR spectrum showed the C;N stretching absorption at
2219 cm21, implying that the cyano group remained
unreacted and the attack of the anion had to take place on
the aromatic ring of the nitrile. The analysis of the 2D
HMBC spectrum con®rmed this conclusion and allowed
to establish the structure of the compound. The correlation
between the methylene protons and the quaternary carbon at
reaction
between
lithium
3
methoxycarbonyl)phosphazene and dimethyl acetylendicar-
boxylate22 and may be explained through the lower nucleo-
philicity of the primary carbanion derived from 4a
compared to the secondary carbanion generated from phos-
phazenes 4b±d. As expected, yields increased with increas-
ing electrophilic character of the nitrile, cf. benzonitrile with
p-chlorobenzonitrile or p-¯uoronitrile +entries 2±4, Table
2). On the contrary, the reaction with p-nitrobenzonitrile
followed a different course yielding acyclic products 11.
d 150.54 +d, JPCˆ5.4 Hz), corresponding to the C-ipso
bonded to the nitro group, indicated that the phosphazenyl
substituent is located ortho to the NO2.23 The two high ®eld
quaternary carbons at d 116.51 and 116.67 +d, 4JPCˆ3.0 Hz)
were assigned to the cyano group and the ipso-carbon next
to the CN, respectively. The C-ipso correlated via 3JCH with
the proton ortho to the NO2 group +doublet at d 7.79), while
the cyano group showed correlations with the adjacent
protons at d 7.57 and 8.26. Therefore, the regioselective
addition of the lithium phosphazene to the aromatic ring is
directed by the strong electron withdrawing effect of the
nitro substituent. The addition reaction is followed by a
rearomatizing step leading to 11.
1
Focusing on 11a, the H, and 31P NMR spectra show that
the lithium phosphazene added to the electrophile C-regio-
selectively. This conclusion is supported by the doublet
observed for the methylene protons at
d
4.59
+2JPHˆ14.5 Hz) and the fact that the new compound retained
the phosphazene moiety of the starting material, as deduced
from the magnitudes of the 31P chemical shifts +cf. entries 1,
2 in Table 1 and entries 6, 7 in Table 2) and homonuclear
geminal coupling +2JPPˆ31.2 Hz). A priori, these data
would be consistent with a structure derived from the 1,2
addition of lithium phosphazene to the cyano group of
The formal nucleophilic substitution of one hydrogen ortho
to the nitro group in substituted nitroarenes is prece-
dented.24±26 The substituents present in the nitroaromatic
compound include halogen, nitro, cyano, methoxy, phenoxy
dimethylamino, etc. The reaction proceeds by an addition±
elimination mechanism, which is the same for the

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C. M. Andujar et al. / Tetrahedron 58 *2002) 2569±2575
2572
nucleophilic replacement of either hydrogen or other
nucleophugal group located ortho or para to the nitro
group. Hydrogen substitution is the main process if there
is a fast step, which transforms the initial adduct into
products. This transformation has been carried out through
oxidation +with oxidizing substituents24 or with external
pellets using a Mattson Genesis II FT spectrometer. Mass
spectra were determined by APCI +Atmospheric Pressure
Chemical Ionization) on a Hewlett±Packard 1100. Micro-
analysis were performed on a Perkin±Elmer 2400. NMR
spectra were measured on a Bruker Avance 300 DPX spec-
trometer. Chemical shifts are referred to internal tetra-
1
oxidants25) or via vicarious nucleophilic substitution,26
a
methylsilane for H, the deuterated solvent for 13C, and to
reaction scheme where the rearomatization involves the
elimination of a leaving group linked to the carbanion
center. In our case, the phosphazenyl moiety may serve as
transient hydride acceptor27 and this hydride is ®nally
converted into molecular hydrogen in the aqueous workup.
external 85% H3PO4 for 31P. 2D NMR Correlation spectra
+HMQC and HMBC) were acquired using standard Bruker
software and processing routines. Anticancer assays were
carried by the NCI on 3-cell line panel consisting of MCF7
+breast), NCI-H460 +lung) and SF-268 +CNS). The respec-
tive growth inhibition percentages found for a 1.1£1024 M
dose were 64, 68 and 53.
Primary dose assays of compound 8c as anticancer agent
against three human tumour cell lines +lung, breast, CNS)
showed growth inhibition factors higher than 50% and
passed on for further evaluation of additional cell lines.28
4.2. Synthesis of phosphazenes 4
N-+Diphenylphosphoryl)phosphazenes were prepared by
addition of diphenylphosphorylazide to the appropriate
phosphine following the same methodology previously
reported for the synthesis of N-+alkoxycarbonyl)phospha-
zenes.29 All compounds precipitated from diethyl ether
solutions as white solids. They were ®ltered, dried, and
characterized through their spectral data. The purity deter-
mined by 1H and 31P NMR was in all cases higher than 95%
and the compounds were used without further puri®cation.
3. Conclusions
N-+Diphenylphosphoryl)phosphazenes were prepared in
high yield through the Staudinger reaction of diphenyl-
phosphoryl azide with a series of phosphines. Metallation
of the phosphazenes was easily achieved with BunLi in THF
at 2308C. The reaction of the lithium phosphazenes with
aliphatic and aromatic nitriles afforded 1,2-dihydro-1,3-
diaza-2l5,4l5-2,4-diphosphorine 2-oxides. Yields varied
as a function of the reactivity of the nitrile and the steric
crowding around the metalated center. Thus, high yields of
phosphorus heterocycles were obtained in the reaction of
P-diphenyl+ethyl)+N-diphenylphosphoryl)phosphazene with
cyclohexylcarbonitrile and p-chlorobenzonitrile, whereas
increasing the chain length of the aliphatic moiety of the
phosphazene reduced signi®cantly the yield of the hetero-
cycle formed. However, for p-nitrobenzonitrile the regio-
selective alkylation at the ortho position of the NO2
substituent of the aromatic ring was exclusively observed.
The SNAr reaction is promoted by the strong electron with-
drawing nature of the nitro group. Preliminary assays as
antitumour agents of the new type of heterocycles are
promising.
4.2.1. P, P-Diphenyl-P-*methyl)*N-diphenylphosphoryl)-
phosphazene *4a). White solid. Yield: 95%. Mp: 70±718C.
IR +KBr), n +cm21): 3053, 1300, 1188. 1H NMR
2
+300.13 MHz, CDCl3), d +ppm): 2.14 +d, JPHˆ13.3 Hz,
3H), 7.08 +m, 2H, Har), 7.25 +m, 8H, Har), 7.43 +m, 4H,
Har), 7.54 +m, 2H, Har), 7.63 +m, 4H, Har). 13C NMR
1
+75.46 MHz, CDCl3), d +ppm): 15.37 +d, JPCˆ67.9 Hz),
3
3
120.67 +d, JPCˆ5.4 Hz), 123.67, 128.72 +d, JPCˆ
12.6 Hz), 129.13, 130.65 +dd, 3JPCˆ6.0 Hz, 1JPC
2
4
107.3 Hz), 130.85 +d, JPCˆ10.8 Hz), 132.19 +d, JPCˆ
2.9 Hz), 152.31 +d, JPCˆ7.2 Hz). 31P NMR +121.49 MHz,
2
2
CDCl3), d +ppm): 25.06 +d, JPPˆ31.2 Hz), 16.17 +d,
2JPPˆ31.2 Hz). Anal. Calcd for C25H23NO3P2 +447.41): C,
67.04; H, 5.13; N, 3.12. Found: C, 66.89; H, 5.01; N, 2.98.
MS, m/z +%): 447 +70).
4.2.2. P, P-Diphenyl-P-*ethyl)*N-diphenylphosphoryl)-
phosphazene *4b). White solid. Yield: 95%. Mp: 118±
4. Experimental
4.1. General
1
1198C. IR +KBr), n +cm21): 3061, 1293, 1185. H NMR
3
+300.13 MHz, CDCl3), d +ppm): 1.14 +dt, JHHˆ7.3 Hz,
3
2
3JPHˆ18.9 Hz, 3H), 2.48 +dq, JHHˆ7.3 Hz, JPHˆ13.6 Hz,
2H), 7.08 +m, 2H, Har), 7.25 +m, 8H, Har), 7.44 +m, 4H, Har),
7.55 +m, 2H, Har), 7.65 +m, 4H, Har). 13C NMR +75.46 MHz,
All reactions were carried out under an atmosphere of
nitrogen using dried glassware. Solvents were distilled
before use. THF was dried with sodium and distilled
under nitrogen. Commercial starting materials were
2
CDCl3), d +ppm): 5.70 +d, JPCˆ4.8 Hz), 21.92 +d,
3
1JPCˆ67.9 Hz), 120.64 +d, JPCˆ4.8 Hz), 123.56, 128.70
3
3
Â
purchased from Aldrich or Quõmica ID Asturias S.L.
+d, JPCˆ12.0 Hz), 129.10, 129.48 +dd, JPCˆ5.4 Hz,
1JPCˆ106.5 Hz), 131.32 +d, JPC2ˆ10.2 Hz), 132.14 +d,
2
+methyldiphenyl- and ethyldiphenylphosphine). Liquids,
except BunLi, were distilled prior to use. Non commercial
phosphines were prepared by reacting the appropriate alkyl
halide with lithium diphenylphosphide.18 TLC was
performed on Merck plates with aluminum backing and
silica gel 60 F254. For column chromatography silica gel
60 +40±63 mm) from Scharlau was used.
4JPCˆ2.4 Hz, C-12), 152.43 +d, JPCˆ7.2 Hz). 31P NMR
2
+121.49 MHz, CDCl3), d +ppm): 25.71 +d, JPPˆ32.3 Hz,
P-4), 21.77 +d, 2JPPˆ32.3 Hz). Anal. Calcd for C26H25NO3P2
+461.44): C, 67.60; H, 5.41; N, 3.02. Found: C, 67.44; H,
5.31; N, 2.98. MS, m/z +%): 461 +70).
4.2.3. P, P-Diphenyl-P-*butyl)*N-diphenylphosphoryl)-
phosphazene *4c). White solid. Yield: 83%. Mp: 85±
868C. IR +KBr), n +cm21): 1203, 1179. 1H NMR
Melting points were recorded on a BuÈchi B-540 apparatus
and are uncorrected. Infrared spectra were obtained in KBr

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C. M. Andujar et al. / Tetrahedron 58 *2002) 2569±2575
2573
+300.13 MHz, CDCl3), d +ppm): 0.85 +t, 3JHHˆ7.1 Hz, 3H),
1.39 +m, 2H), 1.46 +m, 2H), 2.42 +m, 2H), 7.08 +m, 2H, Har),
7.23 +m, 8H, Har), 7.45 +m, 4H, Har), 7.54 +m, 2H, Har), 7.65
+m, 4H, Har). 13C NMR +75.46 MHz, CDCl3), d +ppm):
+476.49): C, 67.99; H, 6.29; N, 5.87. Found: C, 67.88; H,
6.21; N, 5.79. MS, m/z +%): 477 +90).
4.3.2. 1,2-Dihydro-P, P-diphenyl-5-methyl-6-phenyl-1,3-
diaza-2l5,4l5-2,4-diphosphorine 2-oxide *8b). White
solid. Yield: 40%. Mp: 214±2158C. IR +KBr), n +cm21):
3
2
13.51, 23.41 +d, JPCˆ3.6 Hz), 23.84 +d, JPCˆ16.3 Hz),
1
3
28.45 +d, JPCˆ68.1 Hz), 120.69 +d, JPCˆ5.1 Hz), 123.60,
128.72 +d, 3JPCˆ12.7 Hz), 129.12, 129.68 +dd, 3JPCˆ5.1 Hz,
3103, 1266, 1165. H NMR +300.13 MHz, DMSO-d6), d
1
1JPCˆ103.2 Hz), 131.26 +d, JPCˆ10.7 Hz), 132.14 +d,
+ppm): 1.56 +d, JPHˆ13.2 Hz, 3H), 7.08 +m, 2H, Har),
2
3
4JPCˆ2.0 Hz), 152.47 +d, JPCˆ7.6 Hz). 31P NMR
7.27 +m, 4H, Har), 7.32 +m, 4H, Har), 7.52 +m, 3H, Har),
2
2
2
+121.49 MHz, CDCl3), d +ppm): 25.74 +d, JPPˆ32.7 Hz),
7.7 +m, 7H, Har), 8.1 +d, JPHˆ4.4 Hz, NH). 13C NMR
2
2
19.75 +d, JPPˆ32.7 Hz). Anal. Calcd for C28H29NO3P2
+75.46 MHz, CDCl3), d +ppm): 14.6 +d, JPCˆ9.8 Hz),
3
1
+489.49): C, 68.64; H, 5.92; N, 2.85. Found: C, 68.44; H,
5.76; N, 2.76. MS, m/z +%): 489 +100).
84.79 +dd, JPCˆ8.1 Hz, JPCˆ89 Hz,), 121.15 +d,
4
2JPCˆ4.6 Hz), 123.79, 127.69, 128.56 +d, JPCˆ2.9 Hz),
3
3
128.63 +d, JPCˆ13.3 Hz), 128.66 +d, JPCˆ12.7 Hz),
1
4.2.4. P, P-Diphenyl-P-*2-phenylethyl)*N-diphenylphos-
phoryl)phosphazene *4d). White solid. Yield: 85%. Mp:
93±948C. IR +KBr), n +cm21): 3053, 1308, 1170. 1H
NMR +300.13 MHz, CDCl3), d +ppm): 2.8 +m, 4H), 7.15
+m, 5H, Har), 7.27 +m, 10H, Har), 7.45 +m, 4H, Har), 7.54
+m, 2H, Har), 7.72 +m, 4H, Har). 13C NMR +75.46 MHz,
128.77 +d, JPCˆ113.4 Hz), 128.84, 129.16, 129.43,
2
4
132.06 +d, JPCˆ11.3 Hz), 132.4 +d, JPCˆ3 Hz), 132.41
2
3
+d, JPCˆ11.1 Hz), 137.82 +dd, JPCˆ9.3, 12.7 Hz), 151.99
+d, JPCˆ8.1 Hz), 155.91 +d, JPCˆ 6.4 Hz). 31P NMR
2
2
2
+121.49 MHz, CDCl3), d +ppm): 26.9 +d, JPPˆ8.9 Hz),
2
25.57 +d, JPPˆ8.9 Hz). Anal. Calcd for C27H24N2O2P2
2
1
CDCl3), d +ppm): 27.47 +d, JPCˆ3 Hz), 30.87 +d, JPCˆ
+470.44): C, 68.86; H, 5.12; N, 5.95. Found: C, 68.79; H,
5.05; N, 5.83. MS, m/z +%): 471 +100).
3
4
64.9 Hz), 120.74 +d, JPCˆ5 Hz), 123.74 +d, JPCˆ1.2 Hz),
3
126.36, 128.16, 128.54, 128.75 +d, JPCˆ12.6 Hz), 129.21,
3
1
2
129.55 +dd, JPCˆ5.4, JPCˆ107.6 Hz), 131.25 +d, JPCˆ
4.3.3. 1,2-Dihydro-P, P-diphenyl-6-*p-chlorophenyl)-5-
methyl-1,3-diaza-2l5,4l5-2,4-diphosphorine 2-oxide *8c).
White solid. Yield: 63%. Mp: 256±2578C. IR +KBr), n
4
3
10.3 Hz), 132.32 +d, JPCˆ3.5 Hz), 140.56 +d, JPCˆ
16.2 Hz), 152.41 +d, 2JPCˆ7.8 Hz). 31P NMR
2
1
+cm21): 3127, 3051, 1263, 1116. H NMR +300.13 MHz,
+121.49 MHz, CDCl3), d +ppm): 25.61 +d, JPPˆ32.3 Hz),
2
3
18.68 +d, JPPˆ32.3 Hz). Anal. Calcd for C32H29NO3P2
CDCl3), d +ppm): 1.56 +d, JPHˆ13.7 Hz, 2H), 5.33 +d,
2JPHˆ4.1 Hz, NH), 7.1 +m, 3H, Har), 7.19 +m, 2H, Har),
7.25 +m, 2H, Har), 7.41 +m, 2H, Har), 7.52 +m, 8H, Har),
7.85 +m, 2H, Har). 13C NMR +75.46 MHz, DMSO-d6), d
+537.53): C, 71.44; H, 5.4; N, 2.61. Found: C, 71.31; H,
5.29; N, 2.49. MS, m/z +%): 537 +100).
2
3
+ppm): 14.66 +d, JPCˆ10.2 Hz), 83.57 +dd, JPCˆ9 Hz,
4.3. General procedure for the synthesis of 1,2-dihydro-
1JPCˆ89.5 Hz), 121.29 +d, JPCˆ4.8 Hz), 123.92, 128.87,
3
1,3-diaza-2l5,4l5-2,4-diphosphinina-2-oxides 8
3
3
129.24 +d, JPCˆ12.6 Hz), 129.44 +d, JPCˆ12.6 Hz),
3
1
129.63, 129.61, 129.73 +dd, JPCˆ3 Hz, JPCˆ110.5 Hz),
To a solution of 0.5 mmol of the appropriate phosphazene in
THF +25 mL) was added a solution of BunLi +0.8 mL of a
1.6 M solution in hexane, 1.25 mmol) at 2308C. After
30 min of metalation, the temperature was lowered to
2858C and the corresponding nitrile +1.25 mmol) was
added. The reaction mixture was stirred for 48 h at this
temperature. Addition of water +25 mL) followed by extrac-
tion with ethyl acetate +3£15 mL) and solvent evaporation
under vacuum afforded a crude product, which was puri®ed
by precipitation from diethyl ether.
1
2
129.81 +d, JPCˆ112.1 Hz), 130.56, 132.14 +d, JPCˆ
2
4
10.8 Hz), 132.19 +d, JPCˆ10.8 Hz), 132.77 +d, JPCˆ
4
3
3 Hz), 132.99 +d, JPCˆ2.4 Hz), 134.01, 136.13 +dd, JPCˆ
2
2
9.2, 13.8 Hz), 152.5 +d, JPCˆ8.4 Hz), 156.47 +d, JPCˆ
7.2 Hz). 31P NMR +121.49 MHz, CDCl3), d +ppm): 26.95
2
2
+d, JPPˆ8.9 Hz), 25.43 +d, JPPˆ8.9 Hz). Anal. Calcd for
C27H23N2O2P2Cl +504.93): C, 64.16; H, 4.54; N, 5.54.
Found: C, 64.01; H, 4.40; N, 5.39. MS, m/z +%): 505 +90).
4.3.4. P, P-Diphenyl-5-methyl-6-*p-¯uorophenyl)-1,2-di-
hydro-1,3-diaza-2l5,4l5-2,4-diphosphinina-2-oxide *8d).
White solid. Yield: 68%. Mp: 253±2548C. IR +KBr), n
4.3.1. 1,2-Dihydro-P, P-diphenyl-6-cyclohexyl-5-methyl-
1,3-diaza-2l5,4l5-2,4-diphosphorine 2-oxide *8a). White
solid. Yield: 95%. Mp: 254±2558C. IR +KBr), n +cm21):
3170, 1250, 1173. 1H NMR +300.13 MHz, CDCl3), d
1
+cm21): 3114, 1169. H NMR +300.13 MHz, CDCl3), d
3
2
+ppm): 1.54 +d, JPHˆ13.1 Hz, 3H), 5.63 +d, JPHˆ4.4 Hz,
1H, NH), 7.00±7.64 +m, 15Har), 7.83 +m, 2Har), 7.86 +m,
2Har). 13C NMR +75.46 MHz, CDCl3), d +ppm): 14.59 +d,
3
+ppm): 1.32 +m, 4H), 1.65 +d, JPHˆ13.4 Hz, 3H), 1.73 +m,
4H), 1.85 +m, 2H), 2.69 +m, 1H), 5.31 +d, 2JPHˆ2.8 Hz, 1H,
NH), 7.03 +m, 3H, Har), 7.18 +m, 2H, Har), 7.49 +m, 6H, Har),
7.76 +m, 4H, Har). 13C NMR +75.46 MHz, CDCl3), d +ppm):
3
1
2JPCˆ9.6 Hz), 85.65 +dd, JPCˆ7.2 Hz, JPCˆ89.5 Hz),
2
2
114.61 +d, JFCˆ22.2 Hz), 116.41 +d, JFCˆ21 Hz), 121.15
3
3
2
4
+d, JPCˆ4.2 Hz), 123.55 +d, JFCˆ3 Hz), 123.92, 128.46
12.69 +d, JPCˆ10.8 Hz), 25.57, 26.11 +d, JPCˆ5.4 Hz),
3
1
3
3
+dd, JPCˆ7.8 Hz, JP3Cˆ109.3 Hz), 128.73 +d, JPCˆ
26.17, 29.5, 30.2, 41.64 +dd, JPCˆ7.8, 9.6 Hz), 80.6 +dd,
4
3JPCˆ9 Hz, JPCˆ89.5 Hz), 121.26 +d, JPCˆ4.8 Hz),
1
3
12.6 Hz), 128.76 +d, JPCˆ13.2 Hz), 129.24 +d, JPCˆ
3
2
3
3
1.5 Hz), 130.75 +d, JFCˆ7.8 Hz), 132.07 +d, JPCˆ11.4 Hz),
123.77, 128.54 +d, JPCˆ12.5 Hz), 128.58 +d, JPCˆ
132.32 +d, 4JPCˆ2.4 Hz), 132.45 +d, 2JPCˆ10.8 Hz), 132.57 +d,
3
1
12.5 Hz), 129.06, 129.17 +dd, JPCˆ7.2 Hz, JPCˆ
4JPCˆ3 Hz), 139.62 +ddd, JFCˆ7.2 Hz, JPCˆ9.0, 13.2 Hz),
4
3
1
4
111.1 Hz), 129.8 +d, JPCˆ105.2 Hz), 131.98 +d, JPCˆ
2
2
4
2
151.93 +d, JPCˆ8.4 Hz), 154.43 +d, JPCˆ7.2 Hz), 162.58
5.1 Hz), 132.23 +d, JPCˆ4.4 Hz), 132.32 +d, JPCˆ11 Hz),
+d, JFCˆ248.7 Hz). 31P NMR +121.49 MHz, CDCl3), d
1
151.79 +d, 2JPCˆ8.4 Hz), 161.09 +d, 2JPCˆ4.3 Hz). 31P NMR
2
2
2
+ppm): 27.01 +d, JPPˆ8.9 Hz), 25.35 +d, JPPˆ8.9 Hz).
+121.49 MHz, CDCl3), d +ppm): 25.57 +d, JPPˆ8.9 Hz),
2
Anal. Calcd for C27H23N2O2FP2 +488.43): C, 66.39; H, 4.74;
26.58 +d, JPPˆ8.9 Hz). Anal. Calcd for C27H30N2O2P2

Â
C. M. Andujar et al. / Tetrahedron 58 *2002) 2569±2575
2574
N, 5.73. Found: C, 66.27; H, 4.59; N, 5.67. MS, m/z +%): 488
+100).
2H), 7.07 +m, 2H, Har), 7.19 +m, 4H, Har), 7.25 +m, 5H,
Har), 7.42 +m, 4H, Har), 7.57 +m, 6H, Har), 7.79 +d,
4
3JHHˆ8.9 Hz, 1Har), 8.26 +t, JHHˆ4JPHˆ1.6 Hz, 1Har). 13C
1
4.3.5. 1,2-Dihydro-P, P-diphenyl-6-cyclohexyl-5-propyl-
1,3-diaza-2l5,4l5-2,4-diphosphorine 2-oxide *8e). White
solid. Yield: 15%. Mp: 246±2478C. IR +KBr), n +cm21):
3167, 1252, 1213. 1H NMR +300.13 MHz, CDCl3), d
+ppm): 0.58 +m, 4H, CH31CH), 0.78 +m, 1H), 1.3 +m,
5H), 1.7 +m, 3H), 1.85 +m, 2H), 2.0 +m, 2H), 2.63 +m,
NMR +75.46 MHz, CDCl3), d +ppm): 32.79 +d, JPCˆ
4
61.6 Hz), 116.51, 116.67 +d, JPCˆ3 Hz), 120.48 +d,
3
3JPCˆ4.8 Hz), 123.99, 125.74, 126.99 +dd, JPCˆ4.2 Hz,
2
3
1JPCˆ93 Hz), 127.89 +d, JPCˆ9 Hz), 128.97 +d, JPCˆ
2
13.2 Hz), 129.32, 131.68 +d, JPCˆ10.3 Hz), 131.89 +d,
4
3
4JPCˆ3 Hz), 133.08 +d, JPCˆ3 Hz), 137.76 +d, JPCˆ
2
1H), 5.48 +d, JPHˆ2.4 Hz, NH), 7.01 +m, 3H, Har), 7.12
2
2
4.2 Hz), 150.54 +d, JPCˆ5.4 Hz), 151.97 +d, JPCˆ
7.2 Hz). 31P NMR +121.49 MHz, CDCl3), d +ppm): 25.86
+d, 2JPPˆ31.1 Hz), 17.58 +d, 2JPPˆ31.1 Hz). Anal. Calcd for
C32H25N3O5P2 +593.53): C, 64.75; H, 4.24; N, 7.07. Found:
C, 64.62; H, 4.32; N, 6.98. MS, m/z +%): 593 +90).
+m, 2H, Har), 7.48 +m, 8H, Har), 7.72 +m, 2H, Har). 13C
NMR +75.46 MHz, CDCl3), d +ppm): 13.85, 23.95 +d,
4
3JPCˆ1.2 Hz), 25.52, 26.19 +d, JPCˆ1.2 Hz), 29.61 +d,
3
2JPCˆ10.2 Hz), 30.24, 30.7, 41.72 +dd, JPCˆ7.2, 10.8 Hz),
3
1
3
86.57 +dd, JPCˆ9.6 Hz, JPCˆ90.1 Hz), 121.16 +d, JPCˆ
5
3
4.8 Hz), 123.49, +d, JPCˆ1.2 Hz), 128.44 +d, JPCˆ
4.4.2. 3-{[1-[*P-Diphenyl)*N-diphenylphosphoryl)phos-
phazenyl]ethyl}-4-nitrobenzonitrile *11b). Oil. Yield:
3
4
12.6 Hz), 128.48 +d, JPCˆ13.2 Hz), 128.91 +d, JPCˆ
3
1
1
1.2 Hz), 130.11 +dd, JPCˆ7.2 Hz, JPCˆ111.7 Hz), 130.53
63%. IR +KBr), n +cm21): 2230, 1261, 1022. H NMR
3
1
4
3
+dd, JPCˆ2.4 Hz, JPCˆ105.7 Hz), 131.91 +d, JPCˆ
+300.13 MHz, CDCl3), d +ppm): 1.64 +dd, JHHˆ7.3,
2
3
4
2.2 Hz), 132.07 +d, JPCˆ10.8 Hz), 132.1, 132.26 +d,
17.2 Hz, 3H), 4.83 +dq, JHHˆ2JPHˆ7.3 Hz, JPHˆ2.6 Hz,
1H), 7.12 +m, 7H, Har), 7.32 +m, 8H, Har), 7.63 +m, 5H,
Har), 8.0 +m, 2H, Har), 8.32 +s, 1Har). 13C NMR
2JPCˆ11 Hz), 152.05 +d, JPCˆ8.4 Hz), 162.1 +d, JPCˆ
2
2
4.8 Hz). 31P NMR +121.49 MHz, CDCl3), d +ppm): 25.2
2
2
2
+d, JPPˆ8.9 Hz), 25.77 +d, JPPˆ8.9 Hz). Anal. Calcd for
C29H34N2O2P2 +504.54): C, 68.97; H, 6.73; N, 5.55. Found:
C, 68.82; H, 6.62; N, 5.39. MS, m/z +%): 505 +100).
+75.46 MHz, CDCl3), d +ppm): 15.3 +d, JPCˆ3 Hz), 34.08
+dd, 3JPCˆ3.8 Hz, 1JPCˆ68.5 Hz), 116.55, 116.85 +d, 4JPCˆ
2.8 Hz), 120.48 +d, JPCˆ5.4 Hz), 120.71 +d, 3JPCˆ4.8 Hz),
3
124 +d, 3JPCˆ11.1 Hz), 124.98 +d, 5JPCˆ2.1 Hz), 126.56 +d,
1JPCˆ97.1 Hz), 127.56 +dd, JPCˆ4.8 Hz, JPCˆ104.7 Hz),
3
1
4.3.6. 1,2-Dihydro-P, P-diphenyl-5-benzyl-6-*p-chloro-
2-oxide
phenyl)-1,3-diaza-2l5,4l5-2,4-diphosphorine
*8f). White solid. Yield: 13%. Mp: 256±2578C. IR +KBr),
2
129.22, 129.41, 129.44, 130.96 +d, JPCˆ10.4 Hz), 131.64
4
2
+d, JPCˆ2.8 Hz), 132.06 +d, JPCˆ9.7 Hz), 132.52 +d,
n +cm21): 3130, 1261, 1094. 1H NMR +300.13 MHz,
4JPCˆ3.5 Hz), 133.13 +d, JPCˆ2.8 Hz), 133.67 +d, JPCˆ
4
4
3
2
3
3
CDCl3), d +ppm): 3.38 +dd, JPHˆ9.5 Hz, JHHˆ17.7 Hz,
5.6 Hz), 135.35 +d, JPCˆ4.2 Hz), 150.98 +d, JPCˆ7 Hz),
3
2
152.28 +dd, JPCˆ7.6 Hz, JPCˆ5.5 Hz). 31P NMR
2
4
1H), 3.46 +dd, JPHˆ9.3 Hz, JHHˆ17.7 Hz, 1H), 5.52 +1H,
2JPHˆ2 Hz, NH), 6.4 +m, 2H, Har), 6.82 +m, 3H, Har), 7.12
+m, 2H, Har), 7.3 +m, 5H, Har), 7.47 +m, 6H, Har), 7.78 +m,
2H, Har). 13C NMR +75.46 MHz, CDCl3), d +ppm): 29.58,
2
+121.49 MHz, CDCl3), d +ppm): 27.65 +d, JPPˆ35.6 Hz),
2
19.65 +d, JPPˆ35.6 Hz). Anal. Calcd for C33H27N3O5P2
+607.53): C, 65.24; H, 4.47; N, 6.91. Found: C, 65.1; H,
4.53; N, 6.8. MS, m/z +%): 607 +40).
3
1
3
80.3 +dd, JPCˆ10.2 Hz, JPCˆ90 Hz), 121.15 +d, JPCˆ
3
4.8 Hz), 123.89, 125.54, 127.5 +d, JPCˆ12.2 Hz), 127.64±
132.41 +16Car), 135.49 +dd, JPCˆ9.2, 13.6 Hz), 138.74 +d,
3
3JPCˆ1.8 Hz), 155.07 +d, JPCˆ9.0 Hz), 157.77 +d,
2
Acknowledgements
2JPCˆ7.8 Hz). 31P NMR +121.49 MHz, CDCl3), d +ppm):
2
2
27.21 +d, JPPˆ8.9 Hz), 24.82 +d, JPPˆ8.9 Hz). Anal.
Calcd for C33H27N2O2P2Cl +581.02): C, 68.21; H, 4.65; N,
4.82. Found: C, 68.03; H, 4.49; N, 4.72. MS, m/z +%): 581
+100).
Â
Financial support through Direccion General de EnsenÄanza
Superior +project PB97-0587-C02-01) is gratefully
Â
acknowledged. C. A. thanks Ministerio de Educacion y
Cultura for a doctoral fellowship. We thank the NCI for
the bioassays performed.
4.4. Synthesis of nitriles 11
References
To a solution of 0.5 mmol of the appropiate phosphazene in
THF +25 mL) was added a solution of BunLi +0.8 mL of a
1.6 M solution in hexane, 1.25 mmol) at 2308C. After
30 min of metallation, the temperature was lowered to
2858C and p-nitrobenzonitrile +1.25 mmol) was added.
The reaction mixture was stirred for 48 h at this tempera-
ture. Addition of water +25 mL) followed by extraction with
ethyl acetate +3£15 mL) and solvent evaporation under
vacuum afforded a crude product, which was puri®ed by
column cromatography using a mixture of ethyl acetate/hex-
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1
26%. IR +KBr), n +cm21): 2219, 1261, 1023. H NMR
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Â
Tetrahedron 1996, 52, 12323. +c) Barluenga, J.; Jardon, J.;
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Â
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2
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3
NO2 group +d 7.79, doublet, JHHˆ8.9 Hz).
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