N-(Diethoxyphosphoryl)-O-benzylhydroxylamine - A convenient substrate for the synthesis of N-substituted O-benzylhydroxylamines

Article abstract of DOI:10.1016/j.tet.2003.10.056

Easily available N-(diethoxyphosphoryl)-O-benzylhydroxylamine was shown to be convenient, orthogonally protected substrate for regioselective N-alkylation by means of diverse halides under basic conditions (sodium hydride/ tetrabutylammonium bromide). An

Full text of DOI:10.1016/j.tet.2003.10.056

Tetrahedron 59 (2003) 10249–10254
N-(Diethoxyphosphoryl)-O-benzylhydroxylamine—
a convenient substrate for the synthesis
of N-substituted O-benzylhydroxylamines
*
Katarzyna Bl⁄az˙ewska and Tadeusz Gajda
˙
Institute of Organic Chemistry, Technical University of Lodz (Politechnika), Zeromskiego Street 116, 90-924 Lodz, Poland
Received 13 August 2003; revised 23 September 2003; accepted 16 October 2003
Abstract—Easily available N-(diethoxyphosphoryl)-O-benzylhydroxylamine was shown to be convenient, orthogonally protected substrate
for regioselective N-alkylation by means of diverse halides under basic conditions (sodium hydride/tetrabutylammonium bromide).
An efficient procedure for dephosphorylation of N-substituted N-(diethoxyphosphoryl)-O-benzylhydroxylamine to provide N-substituted
O-benzylhydroxylamines was also established.
q 2003 Elsevier Ltd. All rights reserved.
Compounds with N–O linkage in their substructure are
important class of chemical species due to their biological
activity. Such derivatives are found, to name but a few,
among iron sequestering siderophores,1 inhibitors of
5-lipoxygenase,2–4 inhibitors of DXP reductoisomerase,5–7
and inhibitors of metalloproteinase.8
attractive substrate for the preparation of N-substituted
hydroxylamines.
To the best of our knowledge N-phosphorylated hydroxyl-
amines have not yet been applied for this purpose.15,16
In this paper we disclose our results on the use of the easily
available, orthogonally protected N-(diethoxyphosphoryl)-
O-benzylhydroxylamine17 1 in the synthesis of N-substi-
tuted O-benzylhydroxylamines.
Among a plethora of different routes9 leading to N-substi-
tuted hydroxylamines, a prominent position takes strategy in
which N-alkylation of N,O-bis protected hydroxylamines
provides a desired product as N-substituted N,O-bis
protected hydroxylamines.10 Generally, the presence of
protecting groups on hydroxylamine template enhances the
N–H acidity of the N,O-bis protected hydroxylamine,
allows its chemoselective N-alkylation and, for orthogonal
protection, gives also the chance for further chemoselective
deprotection, after alkylation. N-Alkylation of such N,O-bis
protected hydroxylamines can be accomplished by a range
of alkylating agents under standard basic conditions10 or
alternatively Mitsunobu protocol can be applied.10,11 There
is a range of N,O-bis protected hydroxylamines commonly
used for those purposes.10,11
1. Results and discussion
The starting N-(diethoxyphosphoryl)-O-benzylhydroxyl-
amine 1 was prepared according to the literature pro-
cedure17 from N-benzylhydroxylamine hydrochloride and
diethyl phosphonate using Atherton–Todd method.18
In order to optimize reaction conditions for N-alkylation we
conducted our preliminary studies using different bases for
metallation of 1 and bromoethane or ethanol as a model-
alkylating agent, according to Scheme 1. The results are
presented in Table 1
On the other hand, an easy acidic cleavage of P–N bond in
dialkyl phosphoramidates which depends on the steric and
electronic factors around phosphorus atom is well known.12,13
Therefore dialkyl phosphoryl groups may be regarded as
convenient protecting groups for amines.14 These features
make N-(diethoxyphosphoryl)-O-benzylhydroxylamine 1 an
No progress of the reaction was observed when the solid–
liquid two-phase system19 was applied, in which a mixture
Keywords: hydroxylamines; N-alkylation; N-(diethoxyphosphoryl)-O-
benzylhydroxylamine.
*
Corresponding author. Tel.: þ48-42-631-3146; fax: þ48-42-636-5530;
e-mail: tmgajda@p.lodz.pl
Scheme 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.056

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K. Bl⁄az˙ewska, T. Gajda / Tetrahedron 59 (2003) 10249–10254
Table 1. N-Ethyl-N-(diethoxyphosphoryl)-O-benzylhydroxylamine 2a
Entry
R
Alkylating agent RX
Reaction conditions
Isolated yield (%)
1
2
3
4
5
Et
EtBr (1.5 equiv.)
EtOH (1.2 equiv.)
EtBr (1.5 equiv.)
EtBr (1.5 equiv.)
EtBr (1.5 equiv.)
K2CO3 (2 equiv.)/KHCO3 (2 equiv.)/TBABr (5 mol%), 5 h, rt
Ph3P (1.5 equiv.)/DEAD (1.5 equiv.)/THF, 24 h, rt
NaH/THF/TBABr (5 mol%), 3 h, rt
NaH/THF/TBABr (5 mol%), 3 h, reflux
NaH/THF, 4 h, reflux
–
–
92
73
75
of potassium carbonate and potassium hydrogen carbonate
acts as the base, and tetrabutylammonium bromide is used
as phase-transfer catalyst (Table 1, entry 1). The same
outcome was achieved when the reaction was carried out
under standard Mitsunobu20 conditions (triphenylphos-
phine/dietyl azodicarboxylate) using ethanol as alkylating
agent (Table 1, entry 2). Those results suggest that
compound 1 is too weak NH-acid for such reaction
conditions.
amine 1 in tetrahydrofuran, followed by the addition of
tetrabutylammonium bromide (5 mol%) and organic halide
at room temperature.
Progress of the alkylation was monitored by 31P NMR
spectroscopy (the signal of 1 at d¼7.72 ppm disappeared,
while new peak of the N-alkylated product 2 was observed
within the range 7.71–9.24 ppm). All of the reactions were
completed in three up to 6 h at room temperature, or at
reflux, depending on the halide used. Diverse halides were
applied for alkylations (for details, see Table 2).
Positive results were obtained only when stronger base such
as sodium hydride in tetrahydrofuran was applied for
metallation. The best chemical efficiency was obtained at
room temperature when sodium hydride in the presence of
catalytic amounts of tetrabutylammonium bromide
(TBABr) was used (Table 1, entry 3). Conducting reaction
at reflux with or without phase-transfer catalyst led to
decreased yields (Table 1, entries 4 and 5, respectively).
For primary, allyl and benzyl halides reactions occurred
at room temperature (Table 2, entries 1, 3, 8, 4 and 7,
respectively). All of the products were isolated with good to
excellent yields (56–95%) and with good analytical purity,
except for the benzyl bromide for which ‘bulb-to-bulb’
distillation was necessary to obtain analytically pure
product (Table 2, entry 7). Also alkylation of 1 by means
of diethyl 3-bromopropylphosphonate21 gave product 2k
with high 79% yield, after chromatography (Table 2, entry
10).
All of the other alkylations were executed in compliance
with this optimized protocol. Thus, according to Scheme 2,
an excess of sodium hydride was added at 08C to the
solution of N-(diethoxyphosphoryl)-O-benzylhydroxyl-
For isopropyl bromide, it was necessary to carry out the
alkylation under reflux to obtain completion (Table 2, entry
2). Otherwise compound 2c was obtained with low yield
(10%).
Next, v,v0-dihalides were used as electrophilic reagents.
We found that alkylation of 1 with 1,4-dibromobutane
occurred completely regioselectively to give only mono-
alkylated product 2g with 68% yield after flash chroma-
tography (Table 2, entry 6). Contrary to the above-
mentioned reaction, substitution of 1,3-dibromopropane by
metallated 1 led to the mixture of mono- and bis-alkylated
products 2f and 2j in ratio 100:2, respectively. Major
product 2f was isolated from crude reaction mixture with
Scheme 2.
Table 2. N-Substituted-N-(diethoxyphosphoryl)-O-benzylhydroxylamines 2b-k prepared
Entry
Compound
R
Alkylating agent RX
Reaction conditions (time (h), temp. (8C))
Yield (%)a
1
2
3
4
5
6
7
8
9
10
2b
2c
2d
2e
2f
2g
2h
2i
Me
i-Pr
i-Bu
MeI (2 equiv.)
i-PrBr (2 equiv.)
i-BuBr (2 equiv.)
AllylBr (1.3 equiv.)
Br(CH2)3Br (20 equiv.)
Br(CH2)4Br (20 equiv.)
BnBr (1.05 equiv.)
BuBr (1.5 equiv.)
5, rt
91
6, reflux
6, rt
4, rt
4, rt
5, rt
6, rt
6, rt
5, rt
3, rt
64b
56
Allyl
(CH2)3Br
(CH2)4Br
Bn
Bu
(CH2)3N(OBn) P(O)(OEt)2
(CH2)3P(O)(OEt)2
88
63c,d
68c
79e
95
2j
2k
2f (1 equiv.)
Br(CH2)3P(O)(OEt)2 (1.3 equiv.)
73c
79c
a
Yields of pure 2, based on 1.
2c was formed in 10% yield after 24 h at room temperature.
After flash chromatography.
b
c
d
e
Crude product consists of the mixture of mono 2f and bis-alkylated product 2j in ratio 100:2, respectively. Isomer ratios measured by 31P NMR.
After bulb-to-bulb distillation.

K. Bl⁄az˙ewska, T. Gajda / Tetrahedron 59 (2003) 10249–10254
10251
Table 3. N-Substituted-O-benzylhydroxylamine hydrochlorides 3a-i, k
prepared
dephosphorylation was conducted at reflux temperature.
The progress of the reaction was controlled by 31P NMR
spectroscopy. The completion of dephosphorylation was
observed as the decay of the signal of starting 2 (d¼7.71–
9.24 ppm). It appeared that the shorter reaction time, the
better the reaction yield (Table 3, footnote d). Eventually,
treatment of N-alkylated O-benzylhydroxylamines 2 with
4 M hydrogen chloride in ethanol under reflux for 5 min
gave the corresponding products of dephosphorylation 3 in
good yields (61–92%). This optimized procedure allowed
direct isolation of 3 as crystalline hydrochlorides or, in case
when the latter were oils, as hemioxalates (3b, 3i), or as a
free amine (3k). The results were summarized in Table 3.
Entry Compound
R
Reaction conditions Yield
(time (min), temp. (8C)) (%)
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
Et
Me
i-Pr
i-Bu
Allyl
(CH2)3Br
(CH2)4Br
Bn
5, reflux
5, reflux
5, reflux
5, reflux
5, reflux
5, reflux
5, reflux
5, reflux
5, reflux
77a
90
71b
61c,d
75
92
74
66
Bu
73a
66e
3k
(CH2)3P(O)(OEt)2 5, reflux
a
Isolated as hemioxalate.
Compound 3c was obtained in 40% yield when 30% HBr in AcOEt was
used at room temperature for 24 h.
Compound 3b was obtained in 16% yield when 4 M HCl in AcOEt was
applied at room temperature for 30 days.
Compound 3d was obtained in 61 and 56% yields when the mixture of
4 M HCl/EtOH and 2d were heated at reflux for 15 and 90 min,
respectively.
Finally, N-(diethoxyphosphoryl)-O-benzylhydroxylamine 1
was applied to the synthesis of 3-(N-hydroxyamino)propyl-
phosphonic acid, the core precursor of fosmidomycin5,22
[3-(N-formyl-N-hydroxyamino)propylphosphonic acid,
FR-31564], which is an antibiotic, that specifically inhibits
1-deoxy-D-xylulose 5-phosphate reductoisomerase, which
in turn, is indispensable for several bacteria, green algae and
chloroplasts of higher plants in the non-mevalonate pathway
for terpenoid biosynthesis.5–7 Recently, derivatives of
3-(N-hydroxyamino)propylphosphonic acid were also
found to act as potent antimalarial agents.23
b
c
d
e
Isolated as free amine.
63% yield, after flash chromatography (Table 2, entry 5).
Attempts to improve the regioselectivity of alkylation by
increasing the amount of 1,3-dibromopropane in relation to
1 have failed. The structure of the side, bis-substituted
product 2j, was confirmed on independent route, by
alkylation of 1 by means of 2f (Table 2, entry 9).
Thus, according to Scheme 4, heating compound 3k,
obtained in 52% overall yield from 1, under reflux for
14 h with concentrated HCl and acetic acid (2:1, v/v) gave,
after work up5 3-(N-hydroxyamino)propylphosphonic
acid5,24 4 in 82% yield.
Having elaborated the efficient synthesis of N-substituted-
O-benzylhydroxylamines 2, we proceeded with their
dephosphorylation, taking advantage of mentioned earlier
acidic lability of the P–N bond in phosphoramidates.12,13
2. Conclusions
Our preliminary studies on chemoselective dephosphoryla-
tion were conducted by means of different acidic reagents.
Application of 4 M HCl in ethyl acetate as well as 30% HBr
in acetic acid led to divergent results, with long reaction
times and poor yields (Table 3, footnotes b and c,
respectively). Next, according to Scheme 3, 4 M HCl in
ethanol was used for cleavage of the P–N bond in 2. The
In summary, the protocol described here provides new
and simple access to N-alkyl-O-benzylhydroxylamines.
N-Alkylation of easily available, orthogonally protected
N-(diethoxyphosphoryl)-O-benzylhydroxylamine 1 with
primary and secondary halides as well as bis-halides
occurred under mild conditions and led to N-alkylated
derivatives of high purity with good to excellent yields.
Next, N-substituted N-(diethoxyphosphoryl)-O-benzyl-
hydroxylamines were easily dephosphorylated under acidic
conditions to afford appropriate N-substituted O-benzyl-
hydroxylamines in good yields.
3. Experimental
NMR spectra were recorded on a Bruker Avance DPX 250
1
instrument at 250.13 MHz for H and 101.3 MHz for 31P
NMR, respectively, in CDCl3 or D2O solution, using
tetramethylsilane as internal and 85% H3PO4 as external
standard. Positive chemical shifts are downfield from
Scheme 3.
Scheme 4.

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K. Bl⁄az˙ewska, T. Gajda / Tetrahedron 59 (2003) 10249–10254
4
external 85% H3PO4 for 31P NMR spectra. Chemical shifts
(d) are indicated in ppm and coupling constants (J) in Hz.
FAB/MS were recorded on a APO Electron (Ukraine)
model MI 12001E mass spectrometer equipped with a FAB
ion source (thioglycerol matrix). IR spectra were measured
on a Specord M80 (Zeiss) instrument and are reported in
wavenumbers (cm21). Flash chromatography was per-
formed with glass column packed with Baker silica gel
(30–60 mm). Eluents: AcOEt (A); AcOEt/hexane 30:1 (B).
Melting points were determined in open capillaries and are
uncorrected. All reagents were purchased from Fluka and
used without further purification. Diethyl 3-bromopropyl-
phosphonate was obtained according to the literature
procedure via an Arbuzov reaction of 1,3-dibromopropane
with triethyl phosphite.21
7.0 Hz, JHP¼0.5 Hz, 6H, 2CH3), 3.72–3.85 (dheptet,
3JHH¼6.75 Hz, JHP¼4.5 Hz, 1H, CH), 4.11–4.28 (m, 4H,
3
2CH2), 4.86 (s, 2H, CH2Ph,), 7.30–7.40 (m, 5Harom); 31P
NMR: d¼7.71; IR (film): n¼2976, 1456, 1368, 1264, 1024;
FAB/MS m/z (%): 302 (78). Anal. calcd for C14H24NO4P
(301.31): C: 55.80; H: 8.03; N: 4.65. Found: C: 55.69; H:
7.98; N: 4.60.
3.1.4. N-Isobutyl-(N-diethoxyphosphoryl)-O-benzyl-
1
hydroxylamine (2d). Yield: 56%; colorless oil; H NMR:
3
3
d¼0.97 (d, JHH¼6.75 Hz, 6H, 2CH3), 1.35 (dt, JHH
¼
7.0 Hz, 4JHP¼0.75 Hz, 6H, 2CH3), 1.95–2.06 (m, 1H, CH),
3
3
2.97 (dd, JHH¼7.25 Hz, JHP¼5.0 Hz, 2H, CH2N), 4.08–
4.28 (m, 4H, 2CH2), 4.89 (s, 2H, CH2Ph,), 7.31–7.38 (m,
5Harom); 31P NMR: d¼9.13; IR (film): n¼2960, 1452, 1368,
1264, 1028; FAB/MS m/z (%): 316 (54). Anal. calcd for
C15H26NO4P (315.34): C: 57.13; H: 8.31; N: 4.44. Found:
C: 56.99; H: 8.20; N: 4.36.
3.1. N-Substituted-N-(diethoxyphosphoryl)-O-benzyl-
hydroxylamines (2a-k)—general procedure
A solution of N-(diethoxyphosphoryl)-O-benzylhydroxyl-
amine 1 (6 mmol, 1.55 g) in dry THF (2 mL) was added
dropwise to a cooled to 08C suspension of NaH (9 mmol,
0.22 g) in THF (15 mL). Then, the reaction mixture was
allowed to warm to the room temperature and tetrabutyl-
ammonium bromide (TBABr) (5 mol%, 0.1 g) followed by
alkylating agent (6.3–120 mmol) was added. The reaction
was carried out at room temperature or at reflux for 3–6 h.
Then the solvent was evaporated under reduced pressure,
and the solid residue was partitioned between diethyl ether
(150 mL) and water (5 mL). The organic layer was
separated, washed with water (3£2 mL), and dried over
anhydrous Na2SO4. The solvent was evaporated under
reduced pressure and the rest of the volatile material
was removed at 308C/0.1 Torr to give analytically pure
N-substituted-N-(diethoxyphosphoryl)-O-benzylhydroxyl-
amine 2 as a colorless or yellow oils. In some cases flash
chromatography or bulb-to-bulb distillation was necessary
to obtain pure product (for details, see Table 2).
3.1.5. N-Allyl-N-(diethoxyphosphoryl)-O-benzylhydroxyl-
amine (2e). Yield: 88%; colorless oil; 1H NMR: d¼1.36 (dt,
4
3
3JHH¼7.0 Hz, JHP¼0.75 Hz, 6H, 2CH3), 3.80 (tt, JHH
¼
4
6.5 Hz, JHP¼4JHH¼1.25 Hz, 2H, CH2N), 4.82 (s, 2H,
CH2Ph), 5.17–5.31 (m, 2H, CH2¼), 5.88–6.04 (10 lines,
3JHH¼6.5 Hz, 3Jcis¼10.25 Hz, 3Jtrans¼17.12 Hz, 1H,
CHv), 7.32–7.37 (m, 5Harom); 31P NMR: d¼8.19; IR
(film): n¼3416, 2984, 1648, 1368, 1264, 1028; FAB/MS
m/z (%): 300 (47). Anal. calcd for C14H22NO4P (299.30): C:
56.18; H: 7.41; N: 4.68. Found: C: 56.01; H: 7.34; N: 4.61.
3.1.6. N-(3-Bromopropyl)-N-(diethoxyphosphoryl)-O-
benzylhydroxylamine (2f). Yield: 63%; colorless oil;
1
3
4
Rf¼0.51 (B); H NMR: d¼1.36 (dt, JHH¼7.0 Hz, JHP
¼
0.75 Hz, 6H, 2CH3), 2.12 (qu, 3JHH¼6.5 Hz, 2H, CH2), 3.31
(q, JHH¼3JHP¼6.5 Hz, 2H, CH2N), 3.41 (t, JHH¼6.5 Hz,
2H, CH2Br), 4.12–4.26 (m, 4H, 2CH2), 4.85 (s, 2H,
CH2Ph), 7.27–7.38 (m, 5Harom); 31P NMR: d¼8.26; IR
(film): n¼2976, 1440, 1368, 1264, 1028; FAB/MS m/z (%):
380 (51), 382 (43.8). Anal. calcd for C14H23BrNO4P
(380.21): C: 44.22; H: 6.10; N: 3.68. Found: C: 44.03; H:
5.99; N: 3.58.
3
3
3.1.1. N-Ethyl-N-(diethoxyphosphoryl)-O-benzyl-
1
hydroxylamine (2a). Yield: 92%, colorless oil; H NMR:
d¼1.21 (dt, 3JHH¼7.0 Hz, 4JHP¼0.5 Hz, 3H, CH3), 1.35 (dt,
3
3JHH¼7.0 Hz, 4JHP¼0.75 Hz, 6H, 2CH3), 3.25 (dq, JHH
¼
3.1.7. N-(4-Bromobutyl)-N-(diethoxyphosphoryl)-O-
benzylhydroxylamine (2g). Yield: 68%; colorless oil;
3
7.0 Hz, JHP¼1.25 Hz, 2H, CH2N,), 4.13–4.24 (m, 4H,
2CH2), 4.84 (s, 2H, CH2Ph,), 7.32–7.40 (m, 5Harom); 31P
NMR: d¼7.71; IR (film): n¼2984, 1452, 1368, 1264, 1024;
FAB/MS m/z (%): 288 (87). Anal. calcd for C13H22NO4P
(287.28): C: 54.35; H: 7.72; N: 4.88. Found: C: 54.24; H:
7.61; N: 4.81.
1
3
4
Rf¼0.5 (A); H NMR: d¼1.36 (dt, JHH¼7.0 Hz, JHP
¼
0.75 Hz, 6H, 2CH3), 1.70–1.96 (m, 4H, 2CH2), 3.19 (q,
3JHH¼3JHP¼7.0 Hz, 2H, CH2N), 3.39 (t, 3JHH¼6.5 Hz, 2H,
CH2Br), 4.08–4.31 (m, 4H, 2CH2), 4.86 (s, 2H, CH2Ph),
7.33–7.39 (m, 5Harom); 31P NMR: d¼8.59; IR (film):
n¼2928, 1444, 1368, 1164, 1264, 1028; FAB/MS m/z (%):
394 (55), 396 (49.9). Anal. calcd for C15H25BrNO4P
(394.23): C: 45.70; H: 6.39; N: 3.55. Found: C: 45.55; H:
6.29; N: 3.47.
3.1.2. N-Methyl-N-(diethoxyphosphoryl)-O-benzyl-
1
hydroxylamine (2b). Yield: 91%, colorless oil; H NMR:
3
4
d¼1.35 (dt, JHH¼7.0 Hz, JHP¼0.75 Hz, 6H, 2CH3), 2.85
3
(d, JHP¼12.75 Hz, 3H, CH3), 4.04–4.29 (m, 4H, 2CH2),
4.80 (s, 2H, CH2Ph,), 7.30–7.42 (m, 5Harom); 31P NMR:
d¼9.24; IR (film): n¼2984, 1456, 1368, 1268, 1024; FAB/
MS m/z (%) 274 (42). Anal. calcd for C12H20NO4P
(273.26): C: 52.74; H: 7.38; N: 5.13. Found: C: 52.57; H:
7.29; N: 5.07.
3.1.8. N-Benzyl-N-(diethoxyphosphoryl)-O-benzyl-
1
hydroxylamine (2h). Yield: 79%; colorless oil; H NMR:
d¼1.35 (dt, 3JHH¼7.0 Hz, 4JHP¼0.75 Hz, 6H, 2CH3), 4.01–
4.29 (m, 4H, 2CH2), 4.32 (d, 3JHP¼5.5 Hz, 2H, CH2N), 4.49
(s, 2H, CH2Ph), 7.12–7.43 (m, 10Harom); 31P NMR: d¼
8.12; IR (film): n¼2984, 1496, 1488, 1368, 1260, 1164,
1028; FAB/MS m/z (%):350 (100). Anal. calcd for
C18H24NO4P (349.35): C: 61.88; H: 6.92; N: 4.01. Found:
C: 61.68; H: 6.79; N: 3.89.
3.1.3. N-Isopropyl-N-(diethoxyphosphoryl)-O-benzyl-
1
hydroxylamine (2c). Yield: 64%, colorless oil; H NMR:
3
3
d¼1.26 (d, JHH¼6.75 Hz, 6H, 2CH3,), 1.35 (dt, JHH
¼

K. Bl⁄az˙ewska, T. Gajda / Tetrahedron 59 (2003) 10249–10254
10253
3.1.9. N-Butyl-N-(diethoxyphosphoryl)-O-benzylhydroxyl-
amine (2i). Yield: 95%; colorless oil; 1H NMR: d¼0.92 (t,
3.2.3. N-Isopropyl-O-benzylhydroxylamine hydro-
chloride (3c). Yield: 71%; colorless needles; mp 107–
3
4
1
3
3JHH¼7.5 Hz, 3H, CH3), 1.35 (dt, JHH¼7.0 Hz, JHP
¼
1088C; H NMR: d¼1.34 (d, JHH¼6.75 Hz, 6H, 2CH3),
3
0.75 Hz, 6H, 2CH3), 1.31–1.40 (m, 2H, CH2), 1.57–1.69
3.74 (hp, JHH¼6.75 Hz, 1H, CHN), 5.14 (s, 2H, CH2Ph),
3
(m, 2H, CH2), 3.17 (q, JHH¼3JHP¼7.5 Hz, 2H, CH2N,),
7.51 (s, 5Harom); IR (KBr): n¼2648, 2432, 1460, 1392;
FAB/MS m/z (%): 166 (100). Anal. calcd for C10H16ClNO
(201.69): C: 59.55; H:8.00; N: 6.94. Found: C: 59.40; H:
7.87; N: 6.83.
4.11–4.30 (m, 4H, 2CH2), 4.85 (s, 2H, CH2Ph), 7.32–7.38
(m, 5Harom); 31P NMR: d¼8.78; IR (film): n¼2960, 1456,
1368, 1260, 1164, 1028; FAB/MS m/z (%): 316 (55). Anal.
calcd for C15H26NO4P (315.34): C: 57.13; H: 8.31; N: 4.44.
Found: C: 57.01; H: 8.23; N: 4.38.
3.2.4. N-Isobutyl-O-benzylhydroxylamine hydrochloride
(3d). Yield: 61%; colorless prisms; mp 119–1218C; 1H
3
3.1.10. 1,3-Bis-(O-benzyloxy-N-diethoxyphosphoryl-
amino)propane (2j). Yield: 73%; colorless oil; Rf¼0.21
NMR: d¼1.00 (d, JHH¼6.75 Hz, 6H, 2CH3), 2.22–2.08
3
(m, 1H, CH), 3.22 (d, JHH¼6.75 Hz, 2H, CH2N), 5.14 (s,
1
3
4
(B); H NMR: d¼1.34 (dt, JHH¼7.0 Hz, JHP¼0.75 Hz,
2H, CH2Ph), 7.50 (s, 5Harom); IR (KBr): n¼2968, 2672,
2560, 1456, 1168; FAB/MS m/z (%): 180 (100). Anal. calcd
for C11H18ClNO (215.71): C: 61.24; H: 8.41; N: 6.49.
Found: C: 61.00; H: 8.22; N: 6.32.
3
12H, 4CH3), 2.03 (bqu, JHH¼7.25 Hz, 2H, CH2), 3.26
3
(bq, JHH¼3JHP¼7.25 Hz, 4H, CH2N), 4.09–4.27 (m, 8H,
4CH2), 4.85 (s, 4H, 2CH2Ph), 7.29–7.34 (m, 10Harom); 31
P
NMR: d¼8.51; IR (film): n¼2984, 2936, 1368, 1264, 1164,
1024; FAB/MS m/z (%): 559 (41). Anal. calcd for
C25H40N2O8P2 (558.53): C: 53.76; H: 7.22; N: 5.02.
Found: 53.51; H: 7.09; N: 4.87.
3.2.5. N-Allyl-O-benzylhydroxylamine hydrochloride
(3e). Yield: 75%; colorless needles; mp 112.5–113.58C;
1H NMR: d¼3.98 (d, 3JHH¼6.75 Hz, 2H, CH2), 5.15 (s, 2H,
CH2Ph), 5.53–5.62 (m, 2H, CH2v), 5.88–5.99 (m, 1H,
CHv), 7.51 (s, 5Harom); IR (KBr): n¼2864, 2896, 2576,
2440, 1464, 1384; FAB/MS m/z (%): 164 (4). Anal. calcd
for C10H14ClNO (199.67): C: 60.15; H: 7.07; N: 7.02.
Found: C: 59.93; H: 6.92; N: 7.03.
3.1.11. Diethyl 3-[N-(diethoxyphosphoryl)-N-(benzyloxy-
amino)propylphosphonate (2k). Yield: 79%; colorless oil;
Rf¼0.4 (A); 1H NMR: d¼1.32 (t, 3JHH¼7.0 Hz, 6H, 2CH3),
3
4
1.36 (dt, JHH¼7.0 Hz, JHP¼0.75 Hz, 6H, 2CH3) 1.72–
3
2.04 (m, 4H, 2CH2,), 3.24 (bq, JHH¼2JHP¼7.0 Hz, 2H,
CH2P), 3.99–4.31 (m, 8H, 4CH2), 4.85 (s, 2H, 2CH2Ph),
7.28–7.38 (m, 5Harom); 31P NMR: d¼8.34, 32.30; IR (film):
n¼2984, 2936, 1452, 1368, 1260, 1164, 1032; FAB/MS m/z
(%): 438 (68). Anal. calcd for C18H33NO7P2 (437.40): C:
49.42; H: 7.61; N: 3.20. Found: C: 49.29; H: 7.50; N: 3.11.
3.2.6. N-(3-Bromopropyl)-O-benzylhydroxylamine
hydrochloride (3f). Yield: 92%; colorless solid; mp 104–
1058C; 1H NMR: d¼2.24–2.38 (m, 2H, CH2), 3.52 (t,
3
3JHH¼7.25 Hz, 2H, CH2N), 3.55 (t, JHH¼6.25 Hz, 2H,
CH2Br), 5.15 (s, 2H, CH2Ph), 7.51 (s, 5Harom); IR (KBr):
n¼2960, 2872, 2664, 1448, 1240; FAB/MS m/z (%): 244
(100), 246 (95.6). Anal. calcd for C10H15BrClNO (280.58):
C: 42.80; H: 5.39; N: 4.99. Found: C: 42.60; H: 5.27; N:
4.96.
3.2. N-Substituted-O-benzylhydroxylamines (3a-i, k)—
general procedure
A solution of N-substituted N-(diethoxyphosphoryl)-O-
benzylhydroxylamine 3 (1.5 mmol) in 4 M HCl in anhy-
drous EtOH (8 mL) was heated under reflux for 5 min. Then
the solvent was evaporated under reduced pressure, and
diethyl ether (35 mL) was added to the oil residue. The
crystalline precipitates was washed with diethyl ether
(2£10 mL) and dried in vacuum over P2O5 to afford
analytically pure 3 as a colorless or cream crystals. In
some cases products 3 were isolated as a hemioxalate, or
free amine (for details, see Table 3).
3.2.7. N-(4-Bromobutyl)-O-benzylhydroxylamine hydro-
chloride (3g). Yield: 74%; colorless needles; mp 82–848C;
1H NMR: d¼1.87–1.94 (m, 4H, 2CH2), 3.37–3.43 (m, 2H,
CH2N), 3.49–3.54 (m, 2H, CH2Br), 5.15 (s, 2H, CH2Ph),
7.51 (s, 5Harom); IR (KBr): n¼2952, 2600, 1484, 1296;
FAB/MS m/z (%): 258 (100), 260 (99.4). Anal. calcd for
C11H17BrClNO (294.61): C: 44.84; H: 5.82; N: 4.75. Found:
C: 44.62; H: 5.67; N: 4.76.
3.2.8. N-Benzyl-O-benzylhydroxylamine hydrochloride
(3h).27 Yield: 66%; colorless needles; mp 166–1688C,
3.2.1. N-Ethyl-O-benzylhydroxylamine hemioxalate
(3a).25 Yield: 77%; colorless flakes; mp 85–868C, (lit.,26
1
(lit.,27 mp 174–1768C); H NMR: d¼4.40 (s, 2H, CH2Ph),
1
3
mp 92–948C); H NMR: d¼1.30 (t, JHH¼7.25 Hz, 2H,
5.08 (s, 2H, CH2N), 7.27–7.57 (m, 10Harom); IR (KBr):
n¼3008, 2944, 1488, 1448; FAB/MS m/z (%): 214 (8.06).
Anal. calcd for C14H16ClNO (249.73): C: 67.33; H: 6.46; N:
5.61. Found: C: 67.21; H: 6.40; N: 5.59.
3
CH3), 3.39 (q, JHH¼7.25 Hz, 2H, CH2N), 5.13 (s, 2H,
CH2Ph,), 7.50 (s, 5Harom); IR (KBr): n¼3408, 2664, 1720,
1636, 1456, 1280; FAB/MS m/z (%): 152 (17). Anal. calcd
for C11H15NO5 (241.23): C: 54.76; H: 6.27; N: 5.81. Found:
C: 54.59; H: 6.16; N: 5.72.
3.2.9. N-Butyl-O-benzylhydroxylamine hemioxalate (3i).
Yield: 73%; colorless solid; mp 122–1248C; 1H NMR:
3
3
3.2.2. N-Methyl-O-benzylhydroxylamine hydrochloride
(3b).26 Yield: 90%; cream needles; mp 90–938C, (lit.,25 mp
958C) 1H NMR: d¼3.02 (s, 3H, CH3N,), 5.14 (s, 2H,
CH2Ph,), 7.51 (s, 5Harom); IR (KBr): n¼3040, 2920, 2632,
2432, 1464; FAB/MS m/z (%): 138 (2). Anal. calcd for
C8H12ClNO (173.64): C: 55.33; H: 6.97; N: 8.07. Found: C:
55.18; H: 6.81; N: 7.96.
d¼0.91 (t, JHH¼7.25 Hz, 3H, CH3), 1.38 (bsextet, JHH
¼
7.25 Hz, 2H, CH2), 1.63–1.76 (m, 2H, CH2), 3.34 (t, 3JHH
¼
7.75 Hz, 2H, CH2N), 5.13 (s, 2H, CH2Ph), 7.50 (s, 5Harom);
IR (KBr): n¼2960, 2696, 1696, 1640, 1456, 1128; FAB/MS
m/z (%): 180 (100). Anal. calcd for C13H19NO5 (269.29):
C: 57.98; H: 7.11; N: 5.20. Found: C: 57.72; H: 7.02; N:
5.21.

10254
K. Bl⁄az˙ewska, T. Gajda / Tetrahedron 59 (2003) 10249–10254
409–410. (e) Pandya, S. U.; Garcon, C.; Chavant, P. Y.;
Sandrine, P.; Vallee, Y. Chem. Commun. 2001, 1806–1807.
(f) Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Tetrahedron Lett.
2001, 42, 7883–7886. (g) Yanada, R.; Bessho, K.; Yanada, K.
Synlett 1995, 443–444. (h) Brown, D. S.; Gallagher, P. T.;
Lightfoot, A. P.; Moody, C. J.; Slawin, A. M. Z.; Swann, E.
Tetrahedron 1995, 51, 11473–11488. (i) Hunt, J. C. A.; Lloyd,
C.; Moody, C. J.; Slavin, M. Z.; Takle, A. K. J. Chem. Soc.,
Perkin Trans. 1 1999, 3443–3454. (j) Pan, S.; Wang, J.; Zhao,
K. J. Org. Chem. 1999, 64, 4–5. (k) O’Neil, I. A.; Cleator, E.;
Southern, J. M.; Bickley, J. F.; Tapolczay, D. J. Tetrahedron
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3.2.10. Diethyl 3-(N-benzyloxyamino)propylphospho-
1
nate (3k). Yield: 66%; colorless oil; H NMR: d¼1.24 (t,
3JHH¼7.0 Hz, 6H, 2CH3); 1.64–1.83 (m, 4H, 2CH2), 2.88–
2.93 (m, 2H, CH2N), 3.94–4.08 (m, 4H, 2CH2), 4.62 (s, 2H,
CH2Ph), 7.21–7.28 (m, 5Harom); IR (KBr): n¼3448, 2984,
1456, 1368, 1240, 1028; FAB/MS m/z (%): 302 (100). Anal.
calcd for C14H24NO4P (301.31): C: 55.80; H: 8.03; N: 4.65.
Found: C: 55.59; H: 7.91; N: 4.60.
3.2.11. 3-(N-hydroxyamino)propylphosphonic acid (4).5,
22d,24 The mixture of amine 3k (2.8 mmol, 0.85 g), 36% HCl
aq. (15 mL) and acetic acid (7.5 mL) was heated under
reflux for 14 h. Then the solution was evaporated under
reduced pressure, and the residue was dissolved in ethanol
(17 mL). Pyridine was added to the solution until pH 5 was
reached. The precipitate was washed with ethanol, and
crystallized from water-ethanol to give 0.43 g (82% yield)
of 3-(N-hydroxyamino)propylphosphonic acid 4 as a color-
less solid, mp 157–1598C (lit.24 mp 158–1608C). 1H NMR
(D2O): d¼1.63–1.76 (m., 2H, CH2P), 1.89–2.06 (m., 2H,
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Acknowledgements
Financial support by a grant 3T 09A 103 14 from the Polish
State Committee for Scientific Research is gratefully
acknowledged.
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