Synthesis of diethyl α-(o-nitroaryl)phosphoglycines via oxidative nucleophilic substitution of hydrogen in nitroarenes

Article abstract of DOI:10.1055/s-0029-1219956

The carbanion of protected diethyl phosphoglycinate adds to nitroarenes in liquid ammonia in ortho position to the nitro group. Subsequent oxidation of the resulting adduct σ^H with potassium permanganate gave N-protected diethyl α-(o-nitroaryl)phosphoglycinates. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219956

1666
LETTER
Synthesis of Diethyl a-(o-Nitroaryl)phosphoglycines via Oxidative
Nucleophilic Substitution of Hydrogen in Nitroarenes
Synthesis of
o
-Nitroary
i
lated P
e
hosphogly
c
D
eriva
z
tives ysław Mąkosza,* Daniel Sulikowski
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: icho-s@icho.edu.pl
Received 15 April 2010
Dedicated to Prof. Bernd Giese on the occasion of his 70th birthday.
Results of preliminary attempts of ONSH in nitrobenzene
2 with 1a and 1b were disappointing, thus we have tested
a variety of conditions and have found that only genera-
tion of carbanion 1b– in the presence of nitrobenzene 2 in
liquid ammonia at –78 °C and subsequent oxidation with
KMnO4 gave desired product 2b in 57% yield.17
Abstract: The carbanion of protected diethyl phosphoglycinate
adds to nitroarenes in liquid ammonia in ortho position to the nitro
group. Subsequent oxidation of the resulting adduct sH with potas-
sium permanganate gave N-protected diethyl a-(o-nitroaryl)phos-
phoglycinates.
Key words: amino acids, carbanions, oxidation, arylation
O
a-Aminophosphonic acid analogoues of a-amino acids
have found a widespread applicability.1 For example, they
are used as enzyme inhibitors2 or for the generation of cat-
alytic antibodies,3 as antibacterial,4 antiviral,5 antifungal,6
herbicides,7 and antitumor agents.8 The potential utility of
a-aminophosphonic acid and their derivatives has strong-
ly stimulated research in synthesis of these compounds.
O
N
OEt
OEt
P
Na2SO4
PhMe
Ph
1a 97%
O
OEt
OEt
P
H2N
O
OEt
OEt
1. CS2, Et3N
S
P
2. (CH2Br)2
chloroform
Several approaches to construction of a-aminophos-
ponates have been described.9 The three-component reac-
tion between amine, carbonyl compounds (or imine
equivalents), and dialkyl phosphite – Kabachnik–Fields
reaction – is one of the oldest and the most important pro-
cesses.10 This reaction has already seen a number of vari-
ants that allow to carry out the reactions also in
asymmetric manner.10c–g An analogous route was devel-
oped by Mikołajczyk, in which imines were reacted with
lithiated phosphites or its derivatives.11
S
N
1b 51%
Scheme 1 Synthesis of protected phosphoglycine esters carbanion
precursors
This result indicates that, at low temperature in liquid am-
monia, oxidation of sH adduct proceeds faster than oxida-
tion of the sulfur in 1,3-dithiolane group.
We suppose that the negative result in the reaction of ni-
trobenzene 2 with 1a might be connected with insufficient
nuclepophilicity of 1a–, thus adduct sH is formed in a low
degree. It is worth to mention that carbanions stabilized by
phosphonate group exhibit much lower nucleophilicity
than one could expect on the basis of their basicity. This
was confirmed by quantitative measurements by Mayr.18
In this communication we present a novel approach to
synthesis of a-aryl-a-aminophosphonic acid using oxida-
tive nucleophilic substitution of hydrogen in nitroarenes
(ONSH). We have already shown that this reaction is of
general character. On this way it is possible to introduce
into electron-deficient arenes a variety of substituents
such as: OH,12 NH2,13 POPh2, 14 and a wide range of car-
bon substituents.15 Recently we have shown that ONSH in
nitroarenes with carbanion of protected amino acids is an
efficient way for the synthesis of amino acids containing
nitroaryl substituent.15a,b Furthermore, we have also prov-
en that carbanions stabilized with phosphonate group en-
ter the ONSH reaction with nitroarenes giving
nitroarylated phosphonates.15k On this basis we expected
that similar ONSH procedure can be used to synthesis of
a-aryl-a-aminophosphonic acid, particularly a-aryl-phos-
phoglycine derivatives. As the carbanion precursors we
have chosen imino derivatives of diethyl phosphoglyci-
nate 1a and 1b, prepared according to literature proce-
dures (Scheme 1).16
Although ONSH in nitrobenzene 2 with 1b could give two
isomeric products, the 1H NMR spectrum of the reaction
mixture indicated that only one isomer was formed. Anal-
ysis of the spin system of 1H NMR and 13C NMR spectra
allowed to deduce that substitution of hydrogen in ni-
troarene proceeds exclusively in ortho position to the nitro
group. So far, such behavior has been reported only for the
reaction of potassium salts of carbanions in THF,19 where-
as reactions carried out in liquid ammonia give mostly
product of substitution of hydrogen in para position to the
nitro group.15k
Under identical conditions17 other nitroarenes were react-
ed with 1b to give the expected products (Scheme 2), the
results are presented in Table 1.20
SYNLETT 2010, No. x, pp 1666–1668
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Advanced online publication: 04.06.2010
DOI: 10.1055/s-0029-1219956; Art ID: G09710ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of o-Nitroarylated Phosphoglycine Derivatives
1667
In summary, in this communication we have presented a
new approach to the synthesis of a-(o-nitroaryl)phospho-
glycine derivatives using the oxidative nucleophilic sub-
stitution of hyrogen in nitroarenes with carbanion of
protected phosphoglycine 1b.
NO2
Z
NO2
2–9
H
S
KMnO4
KOt-Bu
N
Z
+
NH3 (liq)
–78 °C
S
OEt
P
EtO
EtO
P
O
Acknowledgment
S
O
OEt
This work was partially supported by Ministerium of Science and
Higher Education, Grant N204 0304 33.
S
N
1b
NO2
Cl
S
S
EtO
N
NO2
References and Notes
Cl
+
S
OEt
P
(1) (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 193. (b) De Lombaert, S.; Blanchard,
L.; Stamfort, L. B.; Tan, J.; Wallace, E. M.; Satoh, Y.; Fitt,
J.; Hoyer, D.; Simonsbergen, D.; Moliterni, J.; Marcopoulos,
N.; Savage, P.; Chou, M.; Trapani, A. J.; Jeng, A. Y. J. Med.
Chem. 2000, 43, 488. (c) Aminophosphonic and
S
N
P
EtO
Z
O
O
EtO
8b'
2b–9b
Scheme 2 ONSH in nitroarenes with carbanion of 1b
Aminophosphinic Acids; Kukhar, V. P.; Hudson, H. R., Eds.;
John Wiley and Sons: Chichester, 2000. (d) Vassiliou, S.;
Xeilari, M.; Yiotakis, A.; Germbecka, J.; Pawełczak, M.;
Kafarski, P.; Mucha, A. Bioorg. Med. Chem. Lett. 2007, 15,
3187.
Table 1 The results of the Reaction of Carbanion 1b– with Nitro-
arenes in Liquid Ammonia
No
ZC6H4NO2
Z
Products Yield (%)
(2) Hirschmann, R.; Smith, A. B. III.; Taylor, C. M.; Benkovic,
P. A.; Taylor, S. D.; Yager, K. M.; Sprengler, P. A.;
Benkovic, S. J. Science 1994, 265, 234.
1
2
3
4
5
6
7
8
H
2
3
4
5
6
7
8
9
2b
3b
4b
5b
6b
7b
8ba
9b
57
76
23
68
52
24
15
53
(3) Smith, A. B. III.; Taylor, C. M.; Bencovic, S. J.;
Hirschmann, R. Tetrahedron Lett. 1994, 35, 6853.
(4) (a) Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P.
J. Med. Chem. 2003, 46, 2641. (b) Moore, J. D.; Sprott, K.
T.; Hanson, P. R. J. Org. Chem. 2002, 67, 8123. (c) Liu,
W.; Rogers, C. J.; Fisher, A. J.; Toney, M. D. Biochemistry
2002, 41, 12320. (d) Osipov, S. N.; Artyushin, O. I.;
Kolomiets, A. F.; Bruneau, C.; Dixneuf, P. H. Synlett 2000,
1031. (e) Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1,
1141.
4-F
2-Cl
3-Cl
4-Cl
2-MeO
2,3-Cl2
(5) Huang, J.; Chen, R. Heteroat. Chem. 2000, 11, 480.
(6) Maier, L.; Diel, P. J. Phosphorous, Sulfur Silicon Relat.
Elem. 1994, 90, 259.
1-nitronaphthalene
a Mixture of ortho and para isomers was obtained (5.7:1.0); the regio-
(7) Yager, K. M.; Taylor, C. M.; Smith, A. B. III. J. Am. Chem.
isomeric ratio was established using the 31P NMR spectrum.
Soc. 1994, 116, 9377.
(8) Lavielle, G.; Hautefaye, P.; Schaeffer, C.; Boutin, J. A.;
Cudennec, C. A.; Pierre, A. J. Med. Chem. 1991, 34, 1998.
(9) (a) Schmidt, U.; Krause, H. W.; Oehme, G.; Michalik, M.;
Fischer, K. Chirality 1998, 10, 564. (b) Ordonez, M.;
Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17.
(10) (a) Kabachnik, M. J.; Medvev, T. Y. Dokl. Akad. Nauk SSSR
1952, 83, 689. (b) Fields, E. K. J. Am. Chem. Soc. 1952, 74,
1528. (c) Lee, S.-G.; Lee, J. K.; Song, C. E.; Kim, D.-C.
Bull. Korean Chem. Soc. 2002, 667. (d) Matveeva, E. D.;
Podrugina, T. A.; Tishkovskaja, E. V.; Tomilova, L. G.;
Zefirov, N. S. Synlett 2003, 2311. (e) Joly, G. D.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 4102. (f) Wu, J.; Sun,
W.; Xia, H.-G.; Sun, X. Org. Biomol. Chem. 2006, 4, 1663.
(g) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72,
1263.
(11) (a) Mikołajczyk, M.; Łyżwa, P.; Drabowicz, J. Tetrahedron:
Asymmetry 1997, 8, 3991. (b) Mikołajczyk, M.; Łyżwa, P.;
Drabowicz, J. Tetrahedron: Asymmetry 2002, 13, 2571.
(c) Mikołajczyk, M. J. Organomet. Chem. 2005, 690, 2488.
(12) Kolesnichenko, G. A.; Malykhin, E. V.; Shteingarts, V. D.
Zh. Org. Khim. 1986, 22, 806.
O
O2N
O
S
H2O2, p-TsOH
HCO2H, MeCN
N
P
HN
O
NO2
EtO
S
0–20 °C
48 h
P
EtO
EtO
Z
Z
EtO
3b
5b
3c 94%
5c 86%
Scheme 3 Hydrolysis of ONSH products
All products were obtained as single ortho regioisomers,
except the reaction of 2,3-dichloronitrobenzene 8, where
ortho and para isomer were formed in ratio 5.7:1.0. It
should be stressed that even when 4-fluoronitrobenzene
was used as a starting material, we did not observe forma-
tion of substitution product of fluorine in SNAr reaction.
Products of ONSH reaction can be further deporotected to
give N-formyl derivative in very good yield under condi-
tions presented in Scheme 3.21
Synlett 2010, No. x, 1666–1668 © Thieme Stuttgart · New York

1668
M. Mąkosza, D. Sulikowski
LETTER
(19) (a) Mąkosza, M.; Glinka, T.; Kinowski, A. Tetrahedron
1984, 40, 1863. (b) Mąkosza, M.; Wenall, M.; Goliński, J.;
Kinowski, A. Bull. Pol. Acad. Chem. 1985, 33, 427.
(20) Selected Analytical Data
(13) (a) Counotte-Potman, A.; van der Plas, H. C. J. Heterocycl.
Chem. 1981, 18, 123. (b) Van der Plas, H. C.; Woźniak, M.
Croat. Chim. Acta 1986, 59, 33. (c) Woźniak, M.;
van der Plas, H. C. Acta Chem. Scand. 1993, 47, 95.
(d) Stern, K. M.; Cheng, B. K.; Hilman, F. D.; Allman, J. M.
J. Org. Chem. 1994, 59, 5627.
Diethyl N-(1,3-Ditiholan-2-ylidene)-a-(2-nitrophenyl)-
phosphoglycinate (2a)
(14) Mąkosza, M.; Paszewski, M.; Sulikowski, D. Synlett 2008,
2938.
(15) (a) Mąkosza, M.; Surowiec, M.; Szczepańska, A.;
Sulikowski, D.; Maltsev, O. Synlett 2007, 470.
Solidifying oil. IR (film, CH2Cl2): nmax = 2986, 2905, 1589,
1534, 1355, 1245, 1026, 572 cm–1. 1H NMR (400 MHz,
CDCl3): d = 8.00 (m, 1 H), 7.90 (m, 1 H), 7.61 (m, 1 H), 7.41
(m, 1 H), 4.50 (s, 1 H), 5.96 (d, J = 18.8 Hz), 4.11–4.00 (m,
4 H), 3.64–3.40 (m, 4 H), 1.26–1.21 (m, 6 H). 13C NMR (100
MHz, CDCl3): d = 175.6 (d, J = 19 Hz), 148.4 (d, J = 7 Hz),
132.9 (d, J = 4 Hz), 130.9 (d, J = 7 Hz), 130.7 (d, J = 4 Hz),
128.1 (d, J = 4 Hz), 124 (d, J = 3 Hz), 65.9 (d, J = 156 Hz),
63.4 (d, J = 15 Hz), 63.3 (d, J = 15 Hz), 38.1, 35.0, 16.3 (d,
J = 10 Hz), 16.2 (d, J = 10 Hz). 31P NMR (162 MHz,
CDCl3): d = 18.1. ESI-LRMS (+): m/z 391 [M + H]+. Anal.
Calcd for C14H19N2O5S2P: C, 43.07; H, 4.91; N, 7.18; S,
16.43. Found: C, 42.85; H, 4.90; N, 7.17; S, 16.55.
Diethyl N-(1,3-Dithiolan-2-ylidene)-a-(1-nitro-2-naphthyl)-
phosphoglycinate (9b)
Oil. IR (film, CH2Cl2): nmax = 2983, 1581, 1528, 1254, 1049,
1020, 563 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.05–7.95
(m, 2 H), 7.90–7.85 (m, 1 H), 7.76–7.71 (m, 1 H), 7.63–7.54
(m, 2 H), 5.15 (d, J = 18.0 Hz), 4.20–4.00 (m, 4 H), 3.65–
3.51 (m, 2 H), 3.49–3.35 (m, 2 H), 1.28 (dt, J = 0.4, 7.1 Hz,
3 H), 1.22 (dt, J = 0.4, 7.1 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 175.7 (d, J = 19 Hz), 146.8 (d, J = 9 Hz), 133.0
(d, J = 2 Hz), 130.6 (d, J = 3 Hz), 128.4, 127.9 (d, J = 2 Hz),
127.4, 126.2 (d, J = 4 Hz), 126.0 (d, J = 6 Hz), 124.2 (d,
J = 2 Hz), 121.8, 66.9 (d, J = 161 Hz), 63.6 (d, J = 8 Hz),
63.5 (d, J = 8 Hz), 38.2, 34.9, 16.2 (d, J = 6 Hz), 16.1 (d,
J = 6 Hz). 31P NMR (162 MHz, CDCl3): d = 17.6. ESI-
LRMS (+): m/z 463 [M + H]+. Anal. Calcd for
(b) Mąkosza, M.; Sulikowski, D.; Maltsev, O. Synlett 2008,
1711. (c) Mąkosza, M.; Staliński, K. Chem. Eur. J. 1997, 3,
2025. (d) Mąkosza, M.; Staliński, K. Synthesis 1998, 1631.
(e) Mąkosza, M.; Staliński, K. Tetrahedron 1998, 54, 8797.
(f) Mąkosza, M.; Staliński, K. Pol. J. Chem. 1999, 73, 151.
(g) Mąkosza, M.; Kamieńska-Trela, K.; Paszewski, M.;
Bechcicka, M. Tetrahedron 2005, 61, 11952. (h) Bartoli, G.
Acc. Chem. Res. 1984, 17, 109. (i) Mąkosza, M.;
Sypniewski, M. Tetrahedron 1994, 50, 4913. (j) Mąkosza,
M.; Paszewski, M. Synthesis 2002, 2203. (k) Mąkosza, M.;
Sulikowski, D. J. Org. Chem. 2009, 74, 3827. (l) Bartoli,
G.; Bosco, M.; Melandri, A.; Boicelli, C. J. Org. Chem.
1979, 44, 2087.
(16) (a) Oberhauser, T.; Meduna, V. Tetrahedron 1996, 52,
7691. (b) Modified Literature Procedure16c
To the solution of diethyl phosphoglycinate (4.55 g, 27.2
mmol) in CHCl3 (100 mL) Et3N (3 equiv, 81.6 mmol, 12.5
mL) was added followed by CS2 (1.5 equiv, 40.8 mmol, 2.43
mL). The resulting mixture was stirred at r.t. for 24 h, and
then ethylene bromide (1.2 equiv, 32.6 mmol, 6.07 g) was
added. The solution was stirred for further 24 h at 60 °C.
After cooling to r.t., the mixture was washed with H2O, dried
with anhyd Na2SO4, and evaporated. The residue was
purified by column chromatography (CHCl3–MeOH, 30:1,
v/v). The N-protected phosphoglycinate was obtained as an
oil, 3.73 g, 51% yield. (c) Hoppe, D.; Beckmann, L. Liebigs
Ann. Chem. 1979, 2066.
C18H21N2O5S2P: C, 49.08; H, 4.91; N, 6.36; S, 14.56. Found:
C, 48.62; H, 4.93; N, 6.34; S, 14.45.
(21) The hydrolysis reactions were performed according to
literature procedure, see ref. 15a.
(17) General Procedure
To liquid NH3 (15 mL) at –78 °C a solution of nitroarene
(2.0 mmol) and 1b (269 mg, 1.0 mmol) was added followed
by dropwise addition of KOt-Bu in THF (1.05 mL, 1.00 M,
1.05 mmol) over 5 min. The reaction mixture was stirred at
this temperature for 30 min and then solid KMNO4 (156 mg,
1.0 mmol) was added. After 5 min reaction was quenched by
addition of NH4Cl (500 mg), and the mixture was left to
evaporation of NH3. The residue was treated with H2O (50
mL) and EtOAc (50 mL) and filtered through a pad of Celite.
The organic layer was separated, dried, and evaporated.
Products were isolated by column chromatography (EtOAc–
hexane).
Selected Analytical Data
Diethyl a-(5-Fluoro-2-nitrophenyl)phosphoglycinate (3c)
Oil. IR (film, CH2Cl2): nmax = 3250, 2987, 1689, 1589, 1532,
1351, 1236 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.27 (s,
1 H), 8.00 (ddd, J = 0.4, 5.1, 9.0 Hz, 1 H), 7.64 (dt, J = 2.7,
9.5 Hz, 1 H), 7.13–7.09 (m, 1 H), 5.52 (d, J = 21.5 Hz),
4.26–4.00 (m, 4 H), 2.95 (br s, 1 H), 1.29 (t, J = 7.0 Hz, 3 H),
1.17 (t, J = 7.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 164.9 (d, J = 204 Hz), 160.9 (d, J = 7.4 Hz), 144.7 (dd,
J = 2.3, 5.0 Hz), 137.0 (d, J = 6.6 Hz), 127.9 (dd, J = 1.6, 7.8
Hz), 116.5 (dd, J = 2.4, 3.5 Hz), 115.4 (dd, J = 2.3, 18.6 Hz),
63.6 (d, J = 5.5 Hz), 63.5 (d, J = 5.5 Hz), 47.8 (d, J = 118
Hz), 16.3 (d, J = 2.5 Hz), 16.2 (d, J = 2.5 Hz). 31P NMR (162
MHz, CDCl3): d = 22.0. ESI-LRMS (+): 357 [M + Na]+.
Anal. Calcd for C12H16N2O6PF: C, 43.12; H, 4.83; N, 8.38.
Found: C, 43.16; H, 4.83; N, 8.30.
(18) Appel, R.; Loos, H.; Mayr, H. J. Am. Chem. Soc. 2009, 131,
704.
Synlett 2010, No. x, 1666–1668 © Thieme Stuttgart · New York