Practical and reliable synthesis of dialkyl N-arylphosphoramidates with nitroarenes as substrates

Article abstract of DOI:10.1016/j.tetlet.2009.09.037

A new single-step transformation of readily available nitroarenes with trialkyl phosphites, which can be performed both under thermal and microwave conditions, delivers dialkyl N-arylphosphoramidates in good yields and short reaction times.

Full text of DOI:10.1016/j.tetlet.2009.09.037

Tetrahedron Letters 50 (2009) 6627–6630
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Practical and reliable synthesis of dialkyl N-arylphosphoramidates
with nitroarenes as substrates
*
Reda Haggam, Jürgen Conrad, Uwe Beifuss
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstraße 30, D-70599 Stuttgart, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A new single-step transformation of readily available nitroarenes with trialkyl phosphites, which can be
performed both under thermal and microwave conditions, delivers dialkyl N-arylphosphoramidates in
good yields and short reaction times.
Received 18 August 2009
Accepted 8 September 2009
Available online 19 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Nitroarenes
Deoxygenation
Phosphoramidates
Microwaves
Phosporamidate oligonucleotides are among the most promi-
nent synthetic derivatives that have been considered for diagnostic
and therapeutic applications within the scope of the antisense con-
cept.1,2 The development of phosphoramidate-substituted nucleo-
side analogs has also become an area of intense interest due to the
anticancer, antiviral (anti-HIV), and spermicidal activities of the
nucleoside analogs.3
In addition, phosphoramidates play a significant role in synthe-
sis. One of the most important fields for dialkyl-, dibenzyl-, and di-
phenyl phosphoramidates is the protection of amino groups.4
Many synthetic applications of N-arylphosphoramidates rely on
the properties of their stabilized anions. For example, N-aryl-
phosphoramidates have been used for the preparation of imines
by aza-Wittig reactions.5 Another example is the alkylation of
diethyl phosphoramidates as a simple method for the synthesis
of secondary amines.6 Other applications come from the field of
heterocycles and include the preparation of 2,4-(1H,3H)-quinazol-
inediones.7 Recently N-arylphosphoramidates have been used to
synthesize functionalized aziridines by means of nucleophile-in-
duced cyclization.8 Baylis–Hillman adducts have been reacted with
N-arylphosphoramidates to afford 1,2-disubstituted azetidines in a
highly diastereoselective manner.9 Treatment of aza-Michael ad-
ducts with N-arylphosphoramidates yielded 1,2,4-trisubstituted
azetidines in a one-pot procedure.10
mary and secondary amines with a dialkyl or dibenzyl phosphite
and a halogen source like CCl4 (Scheme 1).11 Weak bases like ani-
line can be phosphorylated only if an extra equivalent of a strong
base like a tertiary amine is added. Valuable modifications of the
original method have been introduced that are based on the use
of alternative halogen sources12 and phase transfer catalysts.13
Other methods for the synthesis of phosphoramidates include
the phosphorylation of amines by condensation with phosphate
diesters in the presence of PPh3 and CCl4,14 the nucleophilic substi-
tution of phosphate diesters by alkylamines,15 and the oxidation of
phosphite triesters with I2 in the presence of alkylamines.16 All
methods for the synthesis of phosphoramidates mentioned so far
have in common that amines are used as starting materials and
that they are subjected to phosphorylation.
Recently we needed to convert nitroarenes into N-arylphosph-
oramidates. Much to our astonishment we found that the number
of synthetic methods for this kind of transformation is rather lim-
ited and that the reports in the literature are inconsistent. Cadogan
et al. reported that they obtained mixtures of the corresponding
dialkyl N-arylphosphoramidates (RO)2P(@O)NHAr (5–26%), dialkyl
N-alkyl-N-arylphosphoramidates (RO)2P(@O)NRAr (8–30%), dialkyl
O
OR
OR
R'
H
P
CCl4
2
N H
Despite this interest in phosphoramidates the number of known
synthetic approaches is limited. The standard method dates back to
Todd and Atherton who published the reaction of ammonia, pri-
R''
O
P
R'
R''
R'
R''
OR
OR
Cl
NH2
N
CHCl3
* Corresponding author. Tel.: +49 711 459 22171; fax: +49 711 459 22951.
E-mail address: ubeifuss@uni-hohenheim.de (U. Beifuss).
Scheme 1. Synthesis of phosphoramidates according to Todd and Atherton.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.037

6628
R. Haggam et al. / Tetrahedron Letters 50 (2009) 6627–6630
Table 2
N-alkyl-3H-azepin-7-ylphosphonates (0–18%) and dialkyl aryl-
phosphonates (RO)2P(@O)Ar (0–7%) when substituted nitroarenes
were refluxed with an excess of a trialkyl phosphite (RO)3P.17,18
In contrast to these findings, Sundberg isolated triethyl N-aryl-
phosphorimidates (EtO)3P@NAr instead of diethyl N-arylphosph-
oramidates (EtO)2P(@O)NHAr as the main products when o-
alkylnitrobenzenes were boiled with excess (EtO)3P.19,20 A report
on the two-step transformation of nitroarenes to anilines with
diethyl chlorophosphite as a reagent21 seemed to be a promising
alternative since the corresponding phosphoramidates had been
identified as intermediates. Although the scope of this method is
quite limited and the reagent is very expensive we repeated some
of the reactions reported by Fischer and Sheihet. However, we
were unable to reproduce their yields. With p-nitrotoluene as the
substrate the corresponding aniline was isolated with only 45% in-
stead of >95%. Without the second step, that is, the hydrolysis, it
was possible to isolate the corresponding N-arylphosphoramidate
(RO)2P(@O)NHAr; the yield, however, amounted to only 49%. With
these results in mind we were certain that there is no practical and
reliable method available yet for the transformation of nitroarenes
into N-arylphosphoramidates (RO)2P(@O)NHAr.
The influence of the reaction time on the transformation of 1a into 3aa
Entry
Equiv (EtO)3P
Time (min)
Yield 3a (%)
1
2
3
4
5
6
7
6.0
6.0
6.0
6.0
6.0
6.0
6.0
3
5
—
—
—
78
78
76
75
10
15
20
30
40
aMicrowave irradiations were performed at 300 W/200 °C/20 bar.
Further experiments revealed that the power of the microwave
irradiation affects the transformation outcome (Scheme 2, Table 3).
With microwave irradiation of up to 200 W no product formation
was observed after 15 min (Table 3, entries 1–3). With 250 W a
mixture of 35% N-arylphosphoramidate 3a and starting material
1a was isolated (Table 3, entry 4). It was found that it takes
300 W to ensure complete conversion of 1a within 15 min and a
high yield of N-arylphosphoramidate 3a (Table 3, entry 5).
Last but not least the influence of the reaction temperature on
the formation of 3a was studied. It could be established that no
reaction between 1a and 2a could be observed until 200 °C
(Scheme 2, Table 4, entries 1–4).
Here we demonstrate that the reaction of nitroarenes with ter-
valent phosphorous reagents can be used for the efficient synthesis
of dialkyl N-arylphosphoramidates in a single step if performed un-
der suitable conditions.
Optimizing the reaction of 1a and 2a resulted in a practical and
efficient procedure for the synthesis of 3a in a high yield. The
workup was very easy. First the volatiles were removed by distilla-
tion in vacuo and then the dichloromethane soluble residue was
washed with water and purified by flash chromatography.22
Triethyl phosphite (2a) could be replaced by other trialkyl phos-
phites like trimethyl phosphite (2b). Under the optimized reaction
conditions described above the transformation of nitrobenzene
(1a) with trimethyl phosphite (2b) delivered the dimethyl N-phen-
ylphosphoramidate (4a), which was isolated with 58% after col-
umn chromatography (Scheme 3).
To begin with, nitrobenzene (1a) and triethyl phosphite (2a)
were reacted under different reaction conditions (Scheme 2, Table
1). Under microwave conditions at 200 °C (300 W) in toluene as a
solvent the formation of 3a was observed only if an excess of 2a
was employed. With 2.5 or 3.0 equiv of 2a the starting material
was consumed only partially. Thus mixtures of the substrate 1a
and diethyl N-phenylphosphoramidate (3a) were isolated after col-
umn chromatography. With an excess of 6 equiv 2a the reaction
could be forced into completion and the product 3a was exclu-
sively formed in 78% yield (Table 1, entries 1–3). Comparable re-
sults were observed when the transformations were performed
in a sealed tube under thermal conditions (Table 1, entries 4–6).
Since the microwave transformation resulted in slightly higher
yields than the sealed tube reaction all further transformations
were run in a microwave oven.
Table 3
The influence of the microwave power on the transformation of 1a into 3aa
Entry
Equiv (EtO)3P
Time (min)
Power (W)
Yield 3a (%)
Then the reaction time of the transformation 1a?3a was opti-
mized (Scheme 2, Table 2). The highest yields were obtained when
the microwave-assisted reactions were run for 15–20 min (Table 2,
entries 4 and 5). With shorter reaction times (3–10 min) no prod-
uct was formed (Table 2, entries 1–3); with longer reaction times
the yields dropped slightly (Table 2, entries 6 and 7).
1
2
3
4
5
6.0
6.0
6.0
6.0
6.0
15
15
15
15
15
50
150
200
250
300
—
—
—
35
78
aMicrowave irradiations were performed at 200 °C/20 bar.
Table 4
O
The influence of the temperature on the transformation of 1a into 3aa
toluene
OEt
OEt
(EtO)3P
P
N
NO2
Entry
Equiv (EtO)3P
Time (min)
Temp (°C)
Yield 3a (%)
H
1a
2a
3a
1
2
3
4
6.0
6.0
6.0
6.0
15
15
15
15
50
100
150
200
—
—
—
78
Scheme 2. Reaction of 1a with (EtO)3P 2a in toluene.
aMicrowave irradiations were performed at 300 W/20 bar.
Table 1
The influence of the amount of (EtO)3P (2a) on the transformation of 1a into 3a
Entry
Equiv (EtO)3P
Reaction conditions;
temp (°C)/time (min)
Yield 3a (%)
toluene
MW / 300 W
MWa; 200/15
38
43
78
34
51
71
O
1
2
3
4
5
6
2.5
3.0
6.0
2.0
4.0
6.0
200 °C, 15 min
OMe
P
MWa; 200/15
(MeO)3P
58%
MWa; 200/15
N
H
OMe
NO2
Sealed tube; 200/15
Sealed tube; 200/15
Sealed tube; 200/15
1a
2b
4a
Scheme 3. Reaction of nitrobenzene (1a) with (MeO)3P 2b in toluene under
a
Microwave irradiations were performed at 300 W/20 bar.
microwave conditions.

R. Haggam et al. / Tetrahedron Letters 50 (2009) 6627–6630
6629
To evaluate the scope of the transformation of nitroarenes into
(EtO)3P=O
Ar NO2
(EtO)3P
Ar NO
+
+
+
+
+
phosphoramidates we examined the effects of substitution on the
aromatic ring. A range of substituents at different positions of the
aromatic ring was tested. To this end the transformation was per-
formed with a number of mono-, di- and trisubstituted nitroarenes
using the optimized protocol (Scheme 4, Table 5). It could be estab-
lished that a number of nitroarenes carrying one or two methyl
groups can be successfully transformed into the corresponding
N-arylphosphoramidates 3b–g. However, the method is not re-
stricted to methyl-substituted nitroarenes. It is also possible to
successfully convert substrates with methoxy-, halide-, methoxy-
carbonyl-, and cyano-substituents (1h–o) into the corresponding
N-arylphosphoramidates 3h–o.23 Yields were in the range between
52% and 79%; side product formation was negligible.
1
2a
5
6a
(EtO)3P
Ar NO
Ar
N
(EtO)3P=O
5
7
6a
2a
(EtO)3P
Ar
N
Ar-N=P(OEt)3
2a
7
8
Ar-N=P(OEt)3
ArNHP(O)(OEt)2
8
3
The structures of diethyl N-arylphosphoramidates 3a–o
described here have been elucidated unambiguously by NMR-
spectroscopic methods including HH-COSY, HMBC, and HSQC
experiments.
Scheme 5. Proposal for the reaction mechanism.
Acknowledgments
We assume that in the first step of the reaction cascade the
nitroarene 1 is reduced with triethyl phosphite (2a) to the corre-
sponding nitrosoarene 5 and triethyl phosphate (6a) (Scheme
5).24 Further reduction with triethyl phosphite (2a) gives the aryl-
nitrene 7 which reacts with 2a to yield the N-arylphosphorimidate
8 as an intermediate. The latter undergoes hydrolysis under the
conditions of workup/purification by chromatography to afford
the N-arylphosphoramidate 3. In accordance with this proposal
the N-arylphosphoramidates 3 could not be obtained when aniline
(9) was treated with an excess of either triethyl phosphite (2a) or
triethyl phosphate (6a) under various reaction conditions.
Our results demonstrate that—in contrast to previous reports—
the reaction of nitroarenes with trialkyl phosphites is a practical
and reliable method for the selective preparation of dialkyl N-aryl-
phosphoramidates if performed under suitable reaction conditions.
R. Haggam is grateful to the Ministry of Higher Education,
Egypt, for the award of a Ph.D. fellowship. We thank Ms. S. Mika,
Dr. H. Leutbecher, and Dipl.-Chem. F. Mert-Balci for the recording
of NMR and mass spectra.
References and notes
1. For selected reviews on antisense oligonucleotides, see for example: (a) De
Mesmaeker, A.; Häner, R.; Martin, P.; Moser, H. E. Acc. Chem. Res. 1995, 28, 366;
(b) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
2. (a) Awad, A. M.; Sobkowski, M.; Seliger, H. Nucleosides, Nucleotides, Nucleic Acids
2004, 23, 777; (b) Faria, M.; Spiller, D. G.; Dubertret, C.; Nelson, J. S.; White, M.
R. H.; Scherman, D.; Hélène, C.; Giovannangeli, C. Nat. Biotechnol. 2001, 19, 40;
(c) Skorski, T.; Perrotti, D.; Nieborowska-Skorska, M.; Gryaznov, S.; Calabretta,
B. Proc. Natl. Acad. U.S.A. 1997, 94, 3966; (d) Heidenreich, O.; Gryaznov, S.;
Nerenberg, M. Nucleic Acids Res. 1997, 25, 776; (e) Gryaznov, S.; Skorski, T.;
Cucco, C.; Nieborowska-Skorska, M.; Chiu, C. Y.; Lloyd, D.; Chen, J. K.;
Koziolkiewicz, M.; Calabretta, B. Nucleic Acids Res. 1996, 24, 1508; (f)
Gryaznov, S. M.; Chen, J. K. J. Am. Chem. Soc. 1994, 116, 3143.
R2
R2
´
3. For a review, see: (a) Venkatachalam, T. K.; Goodman, P. A.; Qazi, S.; DCruz, O.;
toluene
MW / 300 W
200 °C
Uckun, F. M. Curr. Pharm. Design 2004, 10, 1713; (b) Venkatachalam, T. K.;
Samuel, P.; Qazi, S.; Uckun, F. M. Bioorg. Med. Chem. 2005, 13, 5408; (c) Uckun,
F. M.; Samuel, P.; Qazi, S.; Chen, C.; Pendergrass, S.; Venkatachalam, T. K.
Antiviral Chem. Chemother. 2002, 13, 197; (d) Freel Meyers, C. L.; Borch, R. F. J.
Med. Chem. 2000, 43, 4319.
R3
R4
R1
R3
R4
R1
O
P
OEt
OEt
(EtO)3P
N
H
NO2
4. Wuts, P. G. M.; Greene, T. W. Green´es Protective Groups in Organic Synthesis, 4th
R5
R5
ed.; Wiley: New Jersey, 2006. pp 844–847.
1
2a
3
5. Ciufolini, M. A.; Spencer, G. O. J. Org. Chem. 1989, 54, 4739.
6. Zwierzak, A.; Brylikowska-Piotrowicz, J. Angew. Chem., Int. Ed. 1977, 16, 107.
7. Minami, T.; Ogata, M.; Hirao, I.; Tanaka, M.; Agawa, T. Synthesis 1982, 231.
8. Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron Lett. 2008, 49, 687.
9. Yadav, L. D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2008, 49, 5652.
10. Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A. Tetrahedron Lett. 2007, 48, 8037.
11. Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc. 1945, 660.
12. (a) Mielniczak, G.; Łopusin´ ski, A. J. Synth. Commun. 2003, 33, 3851. and
references cited therein; (b) Atherton, F. R.; Todd, A. R. J. Chem. Soc. 1947, 674.
13. (a) Zwierzak, A.; Osowska, K. Synthesis 1984, 223; (b) Zwierzak, A. Synthesis
1975, 507.
Scheme 4. Reaction of nitroarenes 1 with (EtO)3P 2a in toluene under microwave
conditions.
Table 5
Synthesis of diethyl N-arylphosphoramidates 3a–o in a single step reaction of 1a–o
with 2a under microwave conditions
14. (a) Appel, R.; Einig, H. Z. Anorg. Allg. Chem. 1975, 414, 241; (b) Appel, R. Angew.
Chem., Int. Ed. 1977, 14, 801.
15. Meyer, R. B.; Shuman, D. A.; Robins, R. K. Tetrahedron Lett. 1973, 269.
16. (a) Jäger, A.; Levy, M. J.; Hecht, S. M. Biochemistry 1988, 27, 7237; (b) Nemer, M.
J.; Ogilvie, K. K. Tetrahedron Lett. 1980, 21, 4149.
17. Cadogan, J. I. G.; Marshall, R.; Smith, D. M.; Todd, M. J. J. Chem. Soc. (C) 1970,
2441.
18. Cadogan, J. I. G.; Sears, D. J.; Smith, D. M.; Todd, M. J. J. Chem. Soc. (C) 1969,
2813.
Entry
1
R1
R2
R3
R4
R5 Time
(min)
3
Yield 3a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
H
Me
H
H
Me
H
Me
H
H
Br
I
H
H
H
Me
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
15
15
15
15
15
15
15
15
10
10
10
10
10
10
10
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
78
68
73
66
75
79
77
71
52
68
56
62
63
73
57
H
19. Sundberg, R. J. J. Org. Chem. 1965, 30, 3604.
20. Sundberg, R. J. J. Am. Chem. Soc. 1966, 88, 3781.
21. Fischer, B.; Sheihet, L. J. Org. Chem. 1998, 63, 393.
Me
OMe
Cl
H
H
CO2Me
CN
H
22. General procedure for the synthesis of diethyl N-arylphosphoramidates
3
under microwave conditions: A mixture of 1 (1 mmol), triethyl phosphite (2a)
(6 mmol) and toluene (3 mL) was sealed in a 10 mL septum reaction vial and
irradiated with microwaves (DiscoverTM by CEM, 2450 MHz, 300 W, 200 °C).
After removal of triethyl phosphite (2a) and triethyl phosphate (6a) at reduced
pressure (10À1 mbar) and temperatures between 40 and 70 °C the residue was
diluted with CH2Cl2 (30 mL), and washed with water (2 Â 50 mL) and brine
(3 Â 20 mL). After drying over anhydrous MgSO4 and concentration in vacuo
the resulting residue was purified by flash chromatography over silica gel.
H
H
H
H
H
Br
Cl
Me Cl
a
Isolated yields.

6630
R. Haggam et al. / Tetrahedron Letters 50 (2009) 6627–6630
23. Diethyl N-2-bromo-5-methoxyphenylphosphoramidate (3n) According to the
general procedure 4-bromo-3-nitroanisole (1n) (232 mg, 1 mmol) was reacted
with triethyl phosphite (2a) (995 mg, 6 mmol). After column chromatography
(SiO2; cyclohexane/ethyl acetate = 1:2) the title compound was isolated
(247 mg, 73% yield). Rf = 0.41(ethyl acetate–cyclohexane, 2:1). Mp = 58 °C. IR
(ATR): 3221, 2986, 1600, 1577, 1493, 1398, 1301, 1254, 1060, 1014, 973,
3J = 8.80 Hz, 5J = 1.17 Hz, 1H, 3-H). 13C NMR (75 MHz, CDCl3): d (ppm) = 16.37
(3JP–C = 6.88 Hz, 2 Â CH3), 55.72 (OCH3), 63.46 (2JP–C = 5.09 Hz, 2 Â OCH2),
103.39 (3JP–C = 12.56 Hz, C-2), 104.03 (3JP–C = 1.50 Hz, C-6), 108.89 (C-4),
132.99 (C-3), 138.55 (2JP–C = 2.99 Hz, C-1), 160.11 (C-5). MS (EI, 70 eV): m/z
(%) = 339 (30) [M+], 337 (32) [M+], 258 (80) [M+ÀBr], 230 (61), 202 (100), 184
(17), 138 (19). HRMS (EI) m/z calcd for C11H17NPBrO4: 337.0080; found:
337.0080 [M+]. Elem. Anal. Calcd for C11H17NPBrO4: C, 39.17; H, 5.08; N, 4.16.
Found: C, 39.13; H, 4.94; N, 3.91.
777 cmÀ1. UV–vis (MeCN): kmax (log ) = 275 nm (3.15), 209 nm (3.36). 1H NMR
e
(300 MHz, CDCl3): d (ppm) = 1.34 (t, 3J = 7.03 Hz, 6H, 2 Â CH3), 3.77 (s, 3H,
OCH3), 4.02–4.24 (m, 4H, 2 Â OCH2), 5.60 (d, 2JP-H = 8.50 Hz, 1H, NH), 6.43 (dd,
3J = 8.87 Hz, 4J = 2.79 Hz, 1H, 4-H), 6.94 (d, 4J = 2.79 Hz, 1H, 6-H), 7.36 (dd,
24. Cadogan, J. I. G. J. Chem. Soc., Quart. Rev. 1968, 222. and references cited therein.