A general synthesis of ethyl 4-aminophenyl and ethyl 4-[amino(hydroxyimino)methyl]phenyl phosphonates

Article abstract of DOI:10.1016/S0040-4039(01)02100-1

Diethyl phosphonates were conveniently converted into ethyl 4-aminophenyl and ethyl 4-[amino(hydroxyimino)methyl]phenyl phosphonates as potentially useful intermediates for the preparation of functionalized phenyl phosphonates.

Full text of DOI:10.1016/S0040-4039(01)02100-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 167–170
A general synthesis of ethyl 4-aminophenyl and ethyl
4-[amino(hydroxyimino)methyl]phenyl phosphonates
a,
a
a,b
&
Stanislav Gobec, * Katja Strancar and Urosˇ Urleb
aUniversity of Ljubljana, Faculty of Pharmacy, Asˇkercˇeva 7, 1000 Ljubljana, Slovenia
bLek d.d., Verovsˇkova 57, 1000 Ljubljana, Slovenia
Received 30 August 2001; revised 25 October 2001; accepted 5 November 2001
Abstract—Diethyl phosphonates were conveniently converted into ethyl 4-aminophenyl and ethyl 4-[amino(hydroxy-
imino)methyl]phenyl phosphonates as potentially useful intermediates for the preparation of functionalized phenyl phosphonates.
© 2001 Elsevier Science Ltd. All rights reserved.
intermediates for the DBU-catalyzed transesterification
by various alcohols.13 a-Aminoalkyl phosphonate
di(chlorophenyl) esters were prepared as inhibitors of
serine proteases,14 while di(2-methylphenyl) and di(2-
methoxyphenyl) phosphonates were developed as pro-
drugs of fosmidomycin derivative FR900098.15 A series
of diaryl phosphonates with different substituents on
the phenyl rings (hydroxyl, methoxy, acylamino, sul-
fonylamino, ureyl, methoxycarbonyl, and alkyl-
aminocarbonyl) were synthesized to develop irreversible
dipeptidyl peptidase(IV) inhibitors.16
Organophosphorus(V) derivatives like phosphonates,
phosphinates or phosphonamidates, find great utility as
transition-state analog enzyme inhibitors. Phosphonate
(mono)ester containing molecules include potent
inhibitors of many proteases and other enzymes.1 In the
last decade, the synthesis of complex phosphonate
esters as haptens for the generation of catalytic anti-
bodies has become very important.2 Generally, mixed
phosphonate esters are synthesized through phospho-
nochloridates, obtained either from phosphonate
diesters with phosphorus pentachloride,3,4 from phos-
phonate monoesters with thionyl or oxalyl chloride,1a,4
or from phosphinate esters with carbon tetrachloride.5
They have also been prepared from phosphonate
monoesters using BOP-Cl,6 BOP and PyBOP7 reagents,
and by modified Mitsunobu reactions.8 Landry has
synthesized mixed phosphonic diesters from phospho-
nic dichlorides with tetrazole as the catalyst.9
Although a variety of phenyl phosphonates with substi-
tuted phenyl rings have already been described,10–16 no
synthesis of aminophenyl and [amino(imino)methyl]-
phenyl phosphonate ester derivatives has been reported
in the literature. We wanted to synthesize ethyl 4-
aminophenyl and ethyl 4-[amino(hydroxyimino)-
methyl]phenyl phosphonates, a new type of substituted
phenyl phosphonate derivatives that allow facile further
derivatization of the phenyl substituent. Aromatic
amines are widely used as intermediates in the prepara-
tion of important chemicals such as pharmaceuticals,
dyes, and agrochemicals.17 Some benzamines are active
as serine protease inhibitors, for example 4-
aminophenyl based thrombin inhibitors.18 The benza-
midoxime motif on the other hand is an important
constituent of ribonucleotide reductase inhibitors with
antitumor activity19 and NO donors20 with antithrom-
botic and antihypertensive activities.21 The amidoxime
group can serve as a prodrug functionality for an
amidino group22 and the amidoxime prodrug strategy
has been used for improved oral bioavailability for
During the course of our investigations aimed at devel-
oping new serine protease inhibitors, we became inter-
ested in synthesizing mixed alkyl phenyl phosphonates
with a functionalized phenyl moiety. Many phenyl
phosphonate ester derivatives synthesized to date con-
tain a substituted phenyl ring. Nitrophenyl and car-
boxyphenyl monophosphonates were reported to
inhibit
serine
b-lactamase,10
while
alkyl
4-
nitrophenyl11,12 and di(4-nitrophenyl)12 phosphonates
were active as inhibitors of lipase. Furthermore, di(4-
nitrophenyl) phosphonates were also used as activated
Keywords: phosphonates; benzamines; benzamidoximes.
* Corresponding author. Tel.: +386-1-4769-500; fax: +386-1-4258-031;
e-mail: gobecs@ffa.uni-lj.si
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02100-1

168
S. Gobec et al. / Tetrahedron Letters 43 (2002) 167–170
fibrinogen antagonists,23 pentamidine22,24 and other
anti-Pneumocystis carinii pneumonia agents.22,25 From
the synthetic point of view, amidoxime derivatives have
been employed as key intermediates for the synthesis of
a wide variety of valuable compounds, such as 4,5-dihy-
dro-1,2,4-oxadiazoles,26,27 2-oxo-1,2,3,5-oxathiadiazole
derivatives,27 oxadiazolone28,29 and the thiadiazolone
ring.27,29
Similarly, ethyl 4-cyanophenyl phosphonates 7a–c were
obtained after the reaction of phosphonochloridates
4a–c with sodium 4-cyanophenolate. Finally, the reac-
tion of the aromatic nitriles 7a–c with hydroxylamine36
in absolute ethanol gave novel organophosphorus(V)
derivatives of benzamidoximes 8a–c.37 Both ethyl 4-
nitrophenyl phosphonates 5a–c and ethyl 4-cyanophenyl
phosphonates 7a–c are activated phosphonate species
and we were unable to purify them by silica-gel column
chromatography. Due to their instability, crude acti-
vated phosphonates were used immediately in the next
reaction steps.
We started the synthesis with the preparation of the
known diethyl alkylphosphonates 2a–b30,31 and a novel
diethyl 2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-
ethoxy] ethylphosphonate 2c from the appropriate bro-
mides 1a–c,32 using the Arbuzov reaction with neat
triethyl phosphite (Scheme 1). After selective cleavage of
C-substituted phosphonic acid diesters 2a–c with
sodium azide35 to the corresponding monoesters 3a–c,
the latter were reacted with 2 equiv. of oxalyl chloride
in the presence of 0.1 equiv. of DMF for the formation
of the key intermediate phosphonochloridates 4a–c.4
Following the precedent of Buono and co-workers,12 the
crude chloridates were then reacted with sodium 4-nitro-
phenolate to form ethyl 4-nitrophenyl phosphonates
5a–c. As an extension of the method, the aromatic nitro
compounds were hydrogenated over 10% Pd/C at nor-
mal pressure to afford the desired ethyl 4-aminophenyl
phosphonates 6a–c in satisfactory yields.
To summarize, we report here an expeditious synthesis
of hitherto unknown ethyl 4-aminophenyl and ethyl
4-[amino(hydroxyimino)methyl]phenyl phosphonates.
In the crucial synthetic steps, ethyl 4-nitrophenyl phos-
phonates 5a–c were reduced to ethyl 4-aminophenyl
phosphonates 6a–c by catalytic hydrogenation, and
ethyl 4-cyanophenyl phosphonates 7a–c were converted
to the corresponding benzamidoximes 8a–c with
hydroxylamine. The resulting functionalized phenyl
phosphonates are valuable intermediates for further
derivatization of the phenyl substituent. Furthermore,
they represent an interesting type of mixed phosphonate
derivative with possible applications in the development
of new serine protease inhibitors.
O
O
O
O
O
P
OEt
OEt
OEt
Br
b
P
c
a
OH
N
N
N
Z
Z
Z
O
O
O
Z
Z
Z
1a: (CH2)2
2a: (CH2)2
3a: (CH2)2
1b: (CH2)4
2b: (CH2)4
3b: (CH2)4
1c: (CH2)2O(CH2)2
2c: (CH2)2O(CH2)2
3c: (CH2)2O(CH2)2
O
O
O
P
O
P
OEt
O
OEt
O
d
e
N
N
Z
Z
O
O
NO2
NH2
O
Z
Z
O
P
OEt
Cl
5a: (CH2)2
6a: (CH2)2
N
Z
5b: (CH2)4
6b: (CH2)4
O
5c: (CH2)2O(CH2)2
6c: (CH2)2O(CH2)2
Z
4a: (CH2)2
4b: (CH2)4
O
O
O
O
OEt
O
OEt
O
P
P
g
f
N
N
Z
Z
4c: (CH2)2O(CH2)2
O
O
CN
H2N NOH
Z
Z
7a: (CH2)2
7b: (CH2)4
8a: (CH2)2
8b: (CH2)4
7c: (CH2)2O(CH2)2
8c: (CH2)2O(CH2)2
Scheme 1. (a) P(OEt)3, reflux, 16 h (56–77%); (b) NaN3, DMF, 100°C, 16 h (59–69%); (c) (COCl)2, DMF, CH2Cl2, 0°C, 0.5 h,
then rt, 1.5 h; (d) sodium p-nitrophenolate, THF, CH2Cl2, −15°C, 0.5 h, then rt, 16 h (44–50%, three steps); (e) H2, Pd/C, MeOH,
rt, 1.5–6 h (85%); (f) sodium p-cyanophenolate, THF, CH2Cl2, −15°C, 0.5 h, then rt, 16 h (40–51%, three steps); (g) NH2OH, abs.
EtOH, rt, 16 h, then 80°C, 4 h (60–96%).

S. Gobec et al. / Tetrahedron Letters 43 (2002) 167–170
169
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170
S. Gobec et al. / Tetrahedron Letters 43 (2002) 167–170
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washed with 10% K2CO3 (3×20 mL) and brine (2×20 mL),
dried (anh. Na2SO4) and concentrated to afford 1.188 g
(40%, three steps) of the desired product, 4-cyanophenyl
ethyl
4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl-
phosphonate 7b. The latter (1.188 g, 2.88 mmol) was
immediately dissolved in absolute ethanol (15 mL).
Hydroxylamine (0.206 g, 6.24 mmol) was added, the
reaction mixture was stirred overnight at rt, and then
heated under reflux for 4 h. The solution was cooled, the
solvents removed in vacuo and the residue purified by
silica-gel column chromatography (eluent EtOAc/MeOH
(30/1)) to give 4-[amino(hydroxyimino)methyl]phenyl ethyl
4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butylphos-
phonate 8b (yield: 60%); IR (KBr): 3345, 2931, 1768, 1706,
1644, 1514, 1397, 1207, 1115, 1037, 928, 719, 530 cm−1; 1H
NMR (300 MHz, CDCl3): l 1.30 (t, J=7.00 Hz, 3H,
35. Holy´, A. Synthesis 1998, 381–385.
36. Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
Sardharwala, T. E. Synth. Commun. 1996, 26, 4351–4367.
37. A typical procedure for preparing compounds 8a–c is as
follows: ethyl phosphonate 3b (2.254 g, 7.24 mmol) was
dissolved in CH2Cl2 (50 mL) and the mixture was cooled
to 0°C. DMF (56 mL, 0.724 mmol) was added, followed
by dropwise addition of oxalyl chloride (1.26 ml, 14.48
mmol). The reaction was stirred at 0°C for 30 min, and then
allowed to warm to rt and stirred for 1.5 h. The reaction
mixture was then concentrated in vacuo and the resulting
phosphonochloridate 4b immediately reacted with sodium
4-cyanophenolate, which was prepared in the following
way. 4-Cyanophenol (0.826 g, 7.24 mmol), dissolved in dry
THF (4–6 mL), was added dropwise to a mixture of sodium
hydride (0.217 g, 7.24 mmol) in dry THF (3–5 mL). After
1 h, the reaction mixture was cooled to −15°C and a
solution of phosphonochloridate 4b in CH2Cl2 was slowly
added dropwise. The reaction was stirred for 30 min, then
allowed to warm to rt and stirred overnight. The solvent
was removed in vacuo, diluted with EtOAc, filtered,
P-O-CH2-CH3
P), 3.72 (t, J=6.79 Hz, 2H, N-CH
2H, P-O-CH2-CH3), 4.89 (broad s, 2H, C(NOH)NH2
(d, J=7.53 Hz, 2H, Ar-H), 7.61 (d, J=9.04 Hz, 2H, Ar-H
7.71–7.74 (m, 2H, Pht-H), 7.84–7.87 (m, 2H, Pht-H) ppm;
6
), 1.70–2.06 (m, 6H, N-CH2 CH2
2-CH2-), 4.07–4.29 (m,
), 7.26
),
6 -CH6 2-CH6 2-
6
6
6
6
6
6
6
31P NMR (121 MHz CDCl3): l 30.01 ppm; MS (FAB): m/z
446 (M+H)+; Anal. calcd for C21H24N3O6P: C, 56.63; H,
5.43; N, 9.43. Found: C, 56.31; H, 5.54; N, 9.07; mp:
138–142°C.
.