Synthesis of α-(nitroaryl)benzylphosphonates via oxidative nucleophilic substitution of hydrogen in nitroarenes

Article abstract of DOI:10.1021/jo900204e

(Chemical Equation Presented) Carbanions of diethyl benzylphosphonate and diethyl 1-phenylethylphosphonate add to nitroarenes to form relatively long-lived σ^H adducts that can be oxidized to products of oxidative nucleophilic substitution of hy

Full text of DOI:10.1021/jo900204e

Synthesis of r-(Nitroaryl)benzylphosphonates via Oxidative
Nucleophilic Substitution of Hydrogen in Nitroarenes†
Mieczysław Ma¸kosza* and Daniel Sulikowski
Institute of Organic Chemistry PAS, Kasprzaka 44/52, 00-224 Warszawa, Poland
icho-s@icho.edu.pl
ReceiVed February 2, 2009
Carbanions of diethyl benzylphosphonate and diethyl 1-phenylethylphosphonate add to nitroarenes to
form relatively long-lived σH adducts that can be oxidized to products of oxidative nucleophilic substitution
of hydrogen. By variation of the conditions, o- and p-nitroarylated derivatives of the starting phosphonates
can be synthesized regioselectively. It has been proven that addition of carbanions of diethyl
benzylphosphonate and diethyl 1-phenylethylphosphonate to nitroarenes is a fast process and the respective
σH adducts are formed almost quantitatively.
Introduction
many methods that can be used for modification or extension
of the carbon skeleton of phosphonates. Perhaps the most
common and versatile of the latter approach are reactions of
carbanions stabilized by phosphonate groups with a variety of
electrophilic partners.8b,9 Despite substantial interest in substi-
tuted phosphonates and a great variety of available methods of
synthesis of these compounds, very little is known about
phosphonates containing nitroaryl moieties. On the other hand,
nitroaryl substituents offer interesting properties and possibilities
of further transformations.
Esters of substituted phosphonic acids have found wide
application in chemistry, medicine, and other fields. They are
key intermediates in a variety of synthetically important
reactions1,2 and are widely used as agents in treatment of
osteoporosis3 or as chelating agents for many metals,4 etc.5
Because of such wide applications there is continuous interest
in efficient methods of synthesis of substituted phosphonates.2
Methods of synthesis of these compounds can be divided into
two major groups: synthesis of desired phosphonates from
precursors that do not contain phosphorus via formation of new
C-P bonds and modification of the carbon skeleton of the
simpler phosphonates. There is a plethora of methods for
introduction of phosphorus moiety into organic molecules that
produce phosphonates such as Michaelis-Arbuzov6 and
Michaelis-Becker7 reactions, among others.8a,b Also there are
To our knowledge, R-nitrophenyl benzyl phosphonates have
been obtained via Michaelis-Arbuzov reaction of o- and
p-nitrobenzhydryl chlorides with trialkyl phosphites; however,
because of steric hindrances yields of the phosphonates were
low.5 An alternative, general method of synthesis of such
nitrobenzyl phosphonates was reported in our early paper via
vicarious nucleophilic substitution of hydrogen (VNS) of dialkyl
† Dedicated to Professor O. N. Chupakhin on the occasion of his 75th birthday.
(1) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; John Wiley &
Sons: New York, 2000. (b) The Chemistry of Organophosphorus Compounds;
John Wiley & Sons: New York, 1992; Vols. 1 and 2.
(2) Savignac, P.; Iorga, B. Modern Phoshphonate Chemistry; CRC Press:
Boca Raton, 2003.
(3) (a) Fleisch, H. Breast Cancer Res. 2002, 4, 30. (b) Cabanela, M. E.;
Jowsey, J. Calc. Tiss. ReV. 1971, 8, 114.
(4) (a) Wang, Y.; Stone, A. T. EnViron. Sci. Technol. 2008, 14, 4397. (b)
Anderson, P. M.; Wiseman, G. A.; Dispenzieri, A.; Arndt, C. A. S.; Hartmann,
L. C.; Smithson, W. A.; Mullan, B. P.; Bruland, O. S. J. Clin. Oncol. 2002,
189.
(6) (a) Michaelis, A.; Kaehne, R. Berichte 1898, 31, 1048. (b) Arbuzov, A. E.
J. Russ. Phys. Chem. Soc. 1906, 38, 687. (c) Arbuzov, A. E. Pure Appl. Chem.
1964, 9, 307. (d) Bhattacharya, A. K.; Thyagarajan, G. Chem. ReV. 1981, 81,
415.
(7) Fakhraian, H.; Akbar, M. Phosphorus, Sulfur Silicon Relat. Elem. 2006,
181, 511.
(8) (a) Walker, B. J. In Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I. G., Ed.; Academic Press: London, 1979; p 155. (b) Johnson, A. W.
Ylides and Imines of Phosphorus; John Wiley & Sons: New York, 1993.
(9) Smith, D. J. H. In Organophosphorus Reagents in Organic Synthesis;
Cadogan, J. I. G., Ed.; Academic Press: London, 1979; p 2007.
(5) Schwender, C. F.; Beers, S. A.; Malloy, E. A.; Cinicola, J. J.; Wustrow,
D. J.; Demarest, K. D.; Jordan, J. Bioorg. Med. Chem. Lett. 1996, 6, 311.
10.1021/jo900204e CCC: $40.75
Published on Web 04/07/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3827–3832 3827

Ma¸kosza and Sulikowski
R-chlorobenzyl phosphonates with nitroarenes.10a,b VNS with
carbanions of chloromethyl-diphenylphosphinoxide was also
used in synthesis of nitrobenzyl diphenyl phosphinoxides.10c,d
Results and Discussion
In one of our preceding papers we reported ONSH reaction
in nitroarenes with carbanions of alkyl phenylacetates.15e Taking
into account the similarity of these carbanions to that of diethyl
benzylphosphonate 1, we expected that ONSH with this
carbanion should be a feasible process. Because the acidity of
1 (pKa 27.5)18a is substantially lower than that of ethyl
phenylacetate (pKa 23),18b carbanion 1- should exhibit higher
nucleophilicity and form relatively long-lived σH adducts to
nitroarenes that could be oxidized with appropriate oxidants.
Indeed in the first experiments in which the carbanion of 1
generated in THF/DMF by treatment of 1 with t-BuOK was
reacted with nitrobenzene 2 at low temperature and the resulting
mixture was treated with DDQ, we observed formation of a
mixture of diethyl R-(o- and p-nitrophenyl)benzyl phosphonates
2a and 2b in moderate overall yield. Because we have
encountered significant difficulties in chromatographic separa-
tion of the isomers, the mixture was not separated, and its
Here we present a new and general method of synthesis of
R-(o- and p-nitroaryl) benzyl phosphonates via oxidative nu-
cleophilic substitution of hydrogen, ONSH, in nitroarenes with
the carbanion of diethyl benzylphosphonate. Oxidative nucleo-
philic substitution of hydrogen in nitroarenes proceeds via
addition of nucleophilic agents to the electron-deficient aromatic
rings in positions occupied by hydrogen followed by oxidation
of the produced σH adducts with external oxidants.11-15 The
final outcome of this reaction is a replacement of the ring
hydrogen with the nucleophile moiety. It should be stressed that
addition of nucleophiles to electron-deficient aromatic rings
proceeds faster in positions occupied by hydrogen than those
similarly activated occupied by halogens, and thus ONSH should
be a dominant process even in the reaction of halonitrobenzenes
with nucleophiles. This protocol can be used for introduction
of OH,12 NH2,13 PAr2,14 and particularly carbon substituents
into nitroaromatic rings.15 For instance, addition of the alkyl
Grignard reagents to the nitroaromatic ring followed by oxida-
tion of the formed σH adducts with KMnO4 or other oxidants is
1
composition was estimated on the basis of H NMR spectra.
Full analysis and identification of the individual o- and
p-nitroisomers 2a and 2b were done using samples obtained
under conditions that assured selective substitution in positions
ortho and para to the nitro group. Spectra of products 2a and
2b possess a characteristic signal of a benzylic proton observed
as a doublet with the largest coupling constant (1JHP ≈ 25-26
Hz) at 5.41 and 4.53 ppm, respectively. The direct integration
of both doublets allows determining the ratio of ortho/para
isomers. Further identification of isomers was performed by
an efficient method of oxidative nucleophilic alkylation.15f,i
A
variety of carbanions enter similar reaction with nitroarenes
provided they are sufficiently nucleophilic to form long-lived
σH adducts.15,16
Oxidation of σH adducts of nucleophilic agents to substituted
nitroarenes can be effected by a variety of oxidants such as
DDQ,15e-h,16 bromine,16 KMnO4,15a,b oxygen,17 cerium am-
monium nitrate,19 etc. There are also many examples of anodic
oxidation of σH adducts.20 On the other hand, σH adducts of
some carbanions to nitroarenes oxidized with dimethyl dioxirane
produce substituted phenols. This oxidant directs its action on
the negatively charged nitro group of the σH adducts.21
analysis of spin system of H NMR spectra or by 13C NMR
1
spectra, based in the case of ortho isomer on observation of
coupling between the carbon bonded to the nitro group (the most
deshielded) and phosphorus (3JCP ≈ 8-10 Hz); in the case of
the para isomer this coupling was not observed. This methodol-
ogy was fully adopted to other products.
In a similar way 1 was reacted with a series of nitroarenes,
usually giving the expected products of ONSH reactions as
individual isomers or mixtures of o- and p-nitro isomers. Results
are given in Table 1, conditions A. It should be stressed that
2-fluoronitrobenzene 3, which is known to rapidly enter SNAr
of fluorine with a variety of nucleophiles,11a reacted exclusively
along the ONSH pathway via fast formation of σH adducts
predominantly in position 4, giving a mixture of 2-nitro-3-fluoro-
and 4-nitro-3-fluoro-phenyl derivatives 3a and 3b. ONSH in
nitroarenes with the carbanion of 1 and DDQ oxidant, although
generally giving good yields of the desired products, suffers
some drawbacks. The oxidant, DDQ, is a relatively expensive
compound of rather high molecular weight, and often we
experienced difficulties in purification of the products from
the reduced form of DDQ. Thus, the conditions presented in
Table 1, column A are not attractive in practical use, and
moreover they do not provide possibilities for the control of
the orientation of the substitution. We have already shown that
the most convenient conditions for ONSH in nitroarenes with
carbanions of arylacetonitriles and esters of arylacetic acids is
liquid ammonia with KMnO4 oxidant.15a,b,e Here we have found
that these conditions are also very convenient for ONSH reaction
of 1 with nitroarenes. Thus, the reaction of 1 with a variety of
nitroarenes carried out in liquid ammonia in the presence of
(10) (a) Ma¸kosza, M.; Golin´ski, J. Angew. Chem. 1982, 94, 468. (b) Ma¸kosza,
M.; Baran, J.; Dziewon´ska-Baran, D.; Golin´ski, J. Liebigs Ann. Chem. 1989,
825. (c) Jackson, D. A.; Lawrence, N. J.; Liddle, J. Tetrahedron Lett. 1995, 36,
8477. (d) Jackson, D. A.; Lawrence, N. J.; Liddle, J. Synlett 1996, 55.
(11) (a) Terrier, F. Nucleophilic Aromatic Displacement: The Influence of
the Nitro Group; VCH: New York, 1991. (b) Chupakhin, O. N.; Charushin,
V. N.; van der Plas, H. C. Nucleophilic Aromatic Substitution of Hydrogen;
Academic Press: San Diego, 1994. (c) Ma¸kosza, M.; Wojciechowski, K. Chem.
ReV. 2004, 104, 2631. (d) Ma¸kosza, M.; Paszewski, M. Pol. J. Chem. 2005, 79,
163.
(12) Kolesnichenko, G. A.; Malykhin, E. V.; Shteingarts, V. D. Zh. Org.
Khim. 1986, 22, 806.
(13) (a) Counotte-Potman, A.; van der Plas, H. C. J. Heterocycl. Chem. 1981,
18, 123. (b) Van der Plas, H. C.; Woz´niak, M. Croat. Chim. Acta 1986, 59, 33.
(c) Woz´niak, 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.
(14) Ma¸kosza, M.; Paszewski, M.; Sulikowski, D. Synlett 2008, 2938.
(15) (a) Ma¸kosza, M.; Stalin´ski, K. Chem.-Eur. J. 1997, 3, 2025. (b)
Ma¸kosza, M.; Stalin´ski, K. Synthesis 1998, 1631. (c) Ma¸kosza, M.; Stalin´ski,
K. Tetrahedron 1998, 54, 8797. (d) Ma¸kosza, M.; Stalin´ski, K. Pol. J. Chem.
1999, 73, 151. (e) Ma¸kosza, M.; Kamien´ska-Trela, K.; Paszewski, M.; Bechcicka,
M. Tetrahedron 2005, 61, 11952. (f) Ma¸kosza, M.; Surowiec, M. J. Organomet.
Chem. 2001, 624, 167. (g) Ma¸kosza, M.; Surowiec, M.; Szczepan´ska, A.;
Sulikowski, D. Synlett 2007, 420. (h) Ma¸kosza, M.; Sulikowski, D.; Maltsev,
O. Synlett 2008, 1711. (i) Bartoli, G. Acc. Chem. Res. 1984, 17, 109.
(16) (a) Kienzle, F. HelV. Chim. Acta 1978, 61, 449. (b) RajanBabu, T. V.;
Reddy, G. S.; Fukunaga, T. J. Am. Chem. Soc. 1985, 107, 5437. (c) Rege, P. D.;
Johnson, F. J. Org. Chem. 2003, 68, 6133.
(17) (a) Ma¸kosza, M.; Sypniewski, M. Tetrahedron 1994, 50, 4913. (b)
Ma¸kosza, M.; Paszewski, M. Synthesis 2002, 15, 2203.
(18) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) Bordwell, F. G.;
Fried, H. E. J. Org. Chem. 1981, 46, 4327.
(19) Kraus, G. A.; Selvakumar, N. J. Org. Chem. 1998, 63, 9846.
(20) (a) Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2002, 67, 2548.
(b) Gallardo, I.; Guirado, G.; Marquet, J. Eur. J. Org. Chem. 2002, 251, 261.
(c) Gallardo, I.; Guirado, G.; Marquet, J. J. Org. Chem. 2003, 68, 7334.
(21) (a) Adam, W.; Ma¸kosza, M.; Stalin´ski, K.; Zhao, C. G. J. Org. Chem.
1998, 63, 4390. (b) Adam, W.; Ma¸kosza, M.; Zhao, C. G.; Surowiec, M. J.
Org. Chem. 2000, 65, 1099. (c) Surowiec, M.; Ma¸kosza, M. Tetrahedron 2004,
60, 5019.
3828 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of R-(Nitroaryl)benzylphosphonates
SCHEME 1. Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes 2-18 with Carbanion of 1 under Various
Conditionsa
a Conditions: (A) THF/DMF, -78 °C, addition of DDQ; (B) liquid ammonia, -78 °C, addition of KMnO4; (C) THF, -78 °C, addition of KMnO4 and
liquid ammonia; (D) DMSO, rt, dry air.
TABLE 1. Results of ONSH in Nitroarenes with Carbanion of 1 under Various Conditions (Scheme 1)
conditions
nitroarenes
A
B
C
D
entry
1
Z
no.
products
yield %
37
ratioa
yield %
70
ratioa
yield %
68
ratioa
yield %
H
2
2a
2b
3a
3b
4a
4b
5a
6a
6b
7a
7b
8a
2
1
1
9
1
1
1
9
30
46
78
2
3
2-F
3-F
3
4
66
58
0
0
29
39
63
77
4
5
4-F
2-Cl
5
6
1
1
37
31
39
47
74
6
3-Cl
7
1b
1.2
66
60
66
80
7
8
4-Cl
8
9
3-MeO
9a
0
9b
72
73
55
9
10
11
4-MeO
3-Me
3-CN
10
11
12
10a
11b
12a
12b
13a
13b
14a
15a
16b
17a
18a
80
3b
2
55
43
57
2b
1
48
12
3-CF3
13
34
32
1b
3.5
13
14
15
16
17
4-CF3
3-NO2
2,3-Cl2
3-NO2-4-Cl
1-NNc
14
15
16
17
18
56
69
56
95
a Ratio of isomeric products established on the basis of 1H NMR or/and 31P NMR spectra. b Substitution in position 6- of 3-Z-nitrobenzene. c 1-NN:
1-nitronaphthalene.
t-BuOK, for generation of the carbanion, and subsequent
oxidation of the σH adducts with KMnO4 gave better yields of
the nitroarylated products compared with that presented in Table
1, column A. Results of the reaction carried out in liquid
ammonia with KMnO4 as an oxidant are presented in Table 1,
column B. Additionally in some cases better selectively in sense
of formation of p-nitro isomers was observed. As we have
reported in early papers oxidation of the anionic σH adducts is
sensitive to steric hindrance by substituents located in the
vicinity of the addition site. For instance, in the case of tertiary
(methinic) carbanion of 2-phenylpropionitrile only σH adducts
in the position para to the nitro groups were oxidized with
KMnO4. Oxidation of these para σH adducts is decelerated or
totally inhibited by additional substituents located in the vicinity
of the addition site. Thus ONSH with 2-phenylpropionitrile
carbanion in 3-iodonitrobenzene proceeds in low yield and not
at all in 3,5-dichloronitrobenzene. By independent experiments
it was shown that this carbanion forms quantitatively σH adducts
with these nitroarenes in para positions as well as with
4-chloronitrobenzene in ortho position, but they are not oxidized
with KMnO4.15a Addition of the secondary (methylenic) car-
banion of 1 to nitroarenes and oxidation of the formed σH
adducts is less sensitive to steric hindrances; thus the reaction
with nitrobenzene carried out in liquid ammonia and KMnO4
oxidant produces a mixture of o- and p-nitrophenyl isomers 2a
and 2b in equal amounts. One should particularly stress that
the reaction of 1 with 4-chloro- and even 4-fluoronitrobenzenes
8 and 5 proceeded exclusively as ONSH in the position ortho
to the nitro group without even traces of the conventional
nucleophilic substitution of halogen (SNAr). This is a very clear-
cut proof that the addition in positions occupied by hydrogen
proceeds much faster and that at low temperature dissociation
of the initially formed σH adducts is a slow process, so no
equilibration of the addition takes place.
Despite bulkiness of the diethoxyphosphoryl group, tendency
for para substitution in the ONSH with the carbanion of 1 in
J. Org. Chem. Vol. 74, No. 10, 2009 3829

Ma¸kosza and Sulikowski
SCHEME 2. Estimation of Degree of Conversion of 1- into
nitroarenes that can form σH adducts in ortho and para positions
is not strongly pronounced (Table 1, entries 1, 2, and 12)
Although is some cases we could obtain selectively one of the
isomeric products containing an o- or p-nitroaryl ring, the
problem of selectivity of the substitution was not solved.
In one of our early papers we reported that the VNS reaction
in nitroarenes with secondary carbanion of chloromethyl phenyl
sulfone proceeds selectively ortho to the nitro group when
carried out under action of potassium butoxide in neat THF.
The selective addition of the carbanion in vicinity of NO2 group
was due to interaction of the potassium cation of the tight ion
pair carbanion-potassium cation that exists in THF with the
oxygen atoms of the nitro group.22 We thus expected that the
ONSH reaction carried out via addition of the carbanion of 1
to nitroarenes in neat THF followed by oxidation of the
produced σH adducts with a solution of KMnO4 in liquid
ammonia or tetraalkylammonium permanganate that is soluble
in THF should proceed selectively or preferentially ortho to
the nitro group. Indeed under these conditions we observed
preferential or selective ONSH ortho to the nitro group, although
yields of the products were rather moderate (Table 1, column
C).
We have already shown that orientation of the VNS reaction
that also proceeds via formation of the σH adduct depends on
the conditions. Under conditions assuring equilibration of the
σH adducts formation, substitution proceeds mostly in the para
position (thermodynamic control).23 Thus, in order to afford
selectively or dominantly substitution in the para position it is
necessary to create conditions that ensure equilibration of the
σH adducts formation. Upon some experimentation we have
found that treatment of mixtures of nitroarenes, 1, and t-BuOK
in DMSO at room temperature with air or oxygen resulted in
exclusive formation of p-nitroarylated derivatives of 1 usually
in good yields (Table 1, column D). Thus, we have elaborated
a method of synthesis of R-(o- and p-nitroaryl)benzylphospho-
nates by a simple one-pot process that consists of generation
of carbanion of 1, its addition to nitroarenes followed by
oxidation of the produced σH adducts.
In the case when the substitution can produce isomeric
products containing o- or p-nitroaryl moieties, we can control
orientation of the substitution by proper selection of the
conditions, thus in majority of cases individual ortho- and para-
nitroarylated products can be obtained. The results presented
in Table 1 indicate that in the majority of cases yields of the
desired products are good, particularly taking into account that
they are overall yields of three consecutive reactions. Neverthe-
less in some instances the ONSH products were obtained in
moderate or low yields or no desired products were obtained at
all. Taking into account that the reactions were carried out under
standard conditions A, B, C or D, we could suppose that
elaboration of optimal procedures for a given case should
increase yields and possibly selectivity. We should nevertheless
clarify which step of the overall process is responsible for the
failure of the ONSH: addition resulting in formation of the σH
adducts or oxidation of the σH adducts. For this purpose we
should determine (estimate) degree of conversion of 1- and
ArNO2 in the σH adducts. Since direct measurements of amount
(conc.) of the σH adducts in the reaction mixtures are infeasible,
we have applied the method that was already used in our
σH Adducts
previous paper for a clarification of similar question, alkylation
of the carbanion with methyl iodide. Addition of the carbanion
of 1 to nitroarenes is a reversible process, and thus when the
anionic σH adducts formed in liquid ammonia are neutralized
with NH4Cl (equivalent of HCl in liquid ammonia) they are
quantitatively converted into starting nitroarenes and 1. On the
other hand, treatment of 1- under identical conditions in the
absence of nitroarene with methyl iodide results in quantita-
tive methylation. Thus when equimolar amounts of the carbanion
of 1 and a nitroarene were mixed and after a few minutes the
mixture was exposed to an excess of methyl iodide and the
whole subsequently treated with NH4Cl, full recovery of 1 and
absence of the product of its methylation, diethyl 1-phenyleth-
ylphosphonate 1a, indicates that no free carbanion was present
in the system. Thus, all carbanions were engaged in reversible
formation of the σH adducts, which when acidified with the weak
acid NH4Cl dissociate to nitroarenes and 1. To confirm this
supposition we have made experiments in which 1 mol of a
nitroarene in liquid ammonia was treated with 2 mol of the
carbanion of diethyl benzylphosphinate 1 and after a few
minutes an excess of methyl iodide was added. In this case,
after quenching of the mixture with NH4Cl, GLC analysis of
the product indicated the presence of 1 and its methylation
product in a ratio of ca. 1:1. On the basis of these experiments
we can believe that this simple method gives reliable information
concerning the degree of conversion of the carbanion of 1 into
σH adducts. This method of estimation of degree of conversion
is shown in Scheme 2.
It should be noted that in all cases when yields of the ONSH
products were low or the reaction did not proceed, the σH
adducts of 1- to nitroarenes were formed quantitatively. No free
carbanions 1- were detected in the reaction mixtures by the
methylation method. Thus, the failure of the ONSH reaction
was due to problems with the oxidation and not with the addition
step. It is not clear why in some cases oxidation of the σH
adducts was inefficient or did not proceed at all. Raising the
temperature of the oxidation step did not improve the results.
Quantitative formation of the σH adducts indicates that selection
of a more efficient oxidant could overcome the failure observed
for the ONSH in some cases.
Replacement of hydrogen atom in the methylenic group of 1
with o- or p-nitroaryl substituents results in substantial increase
of CH acidity of the produced ONSH products 2a-17b and
18a. This effect, however, does not result in complication of
the reaction course. During the reaction we have not observed
deprotonation of the products and formation of the nitrobenzyl-
(22) Ma¸kosza, M.; Glinka, T.; Kinowski, J. Tetrahedron 1984, 40, 1863.
(23) (a) Blaz˙ej, S.; Ma¸kosza, M. Chem.-Eur. J. 2008, 14, 11113. (b)
Ma¸kosza, M.; Kwast, A. J. Phys. Org. Chem. 1998, 11, 391.
3830 J. Org. Chem. Vol. 74, No. 10, 2009

Synthesis of R-(Nitroaryl)benzylphosphonates
SCHEME 3. Conversion of Carbanion of 10a into
Nitrobenzophenone and 2,1-Benzisoxazole Derivatives
SCHEME 4. Oxidative Nucleophilic Substitution of
Hydrogen in Nitroarenes with Carbanion of 1aa
a Conditions: (A) THF/DMF, -78 °C, addition of DDQ; (B) liquid
ammonia, -78 °C, addition of KMnO4.
TABLE 2. Results of ONSH in Nitroarenes with Carbanion of 1a
nitroarene
no.
yields (%)
Z
products
condition A
condition B
H
2-F
3-F
2-Cl
3-Cl
3-CN
2
3
4
6
7
8
2c
3c
4c
6c
7c
8c
70
99
97
95
94
type carbanion that could react further. On the other hand,
isolated ONSH products, when treated with moderately strong
base, undergo rapid deprotonation giving deep-colored nitroben-
zylic carbanions. This behavior can be used in TLC analysis of
the products that can be detected as strongly colored spots by
treatment with solution of a base (e.g., ethanolic solution of
NaOH).
The nitrobenzylic carbanions of 10a are readily oxidized with
air oxygen to give respective substituted nitrobenzophenone.
The reaction apparently proceeds via hydroxylation followed
by dissociation of the C-P bond. Thus, when a solution of 10a
in THF was treated with t-BuOK and dry air, 2-nitro-5-
methoxybenzophenone was formed in nearly quantitative yield.
On the other hand, when carbanions of R-(o-nitroaryl)ben-
zylphoshonates are kept protected from air, spontaneous conver-
sion into substituted 3-phenyl-2,1-benzisoxazoles (anthranils)
takes place (Scheme 3). This interesting transformation is a
subject of a separate publication.24
Continuing our work, we have studied ONSH reaction in
nitroarenes with carbanion diethyl 1-phenylethylphosphonate 1a.
Due to the tertiary (methinic) character of this carbanion, its
reaction with nitroarenes will be much more sensitive to steric
effects of the nitro group and other substituents in the ring. On
the other hand, one should expect that higher nucleophilicity
of the carbanion of 1a will increase the rate of the nucleophilic
addition and stability of σH adducts. Indeed, addition of the
carbanion of 1a to nitroarenes proceeds exclusively in position
para to the nitro group giving σH adducts that can be oxidized
to expected products of ONSH, diethyl 1-(p-nitroaryl)-1-
phenylethylphosphonate. For this reaction two conditions were
tested, generation of the carbanion by action of t-BuOK on 1a
and nitroarene in THF/DMF mixture at low temperature
followed by oxidation with DDQ (conditions A) and treatment
of a mixture of 1a and nitroarene in liquid ammonia at -78 °C
with t-BuOK followed by oxidation of the produced σH adducts
with potassium permanganate (conditions B, Scheme 4). Results
are given in Table 2.
38
82
78
addition in the para position occupied by halogen is very slow,
so conventional SNAr does not proceed either. We can say that
chlorine in the para position of 8 protects this position against
nucleophilic addition. Also, no ONSH product was obtained in
the reaction of 1a with 3-(trifluoromethyl)nitrobenzene 13. It
appears that in this case the σH adduct was formed but because
of the steric hindrance the oxidation was inhibited.
Conclusion
We have found that carbanions of diethyl benzylphosphonate
1 and diethyl 1-phenylethylphosphonate 1a add to nitroarenes
at low temperature to form relatively long-lived σH adducts that
can be oxidized to respective R-nitroarylbenzylphosphonates.
These interesting compounds were synthesized in generally good
yields. We have also shown that in the cases of low yields or
total failure of ONSH reaction the σH adducts were formed but
not oxidized with the used oxidants. This observation suggests
that σH adducts can be used as intermediates in other reactions.
Experimental Section
Procedures for the reaction under conditions A, B, C, and D:
Conditions A. To a stirred solution of carbanion precursor 1 or
1a (1 mmol) and nitroarene 2-18 (2 mmol) in THF/DMF (10 mL/2
mL) cooled to -78 °C was added dropwise a solution of t-BuOK
in THF (1.05 mmol, 1.05 mL, 1.00 M) during 5 min. After 30 min
of stirring at the same temperature the reaction mixture was treated
with DDQ (272 mg, 1.2 mmol) in THF (1 mL). The resulted dark
thick solution was stirred for a further 5 min, and the reaction was
quenched by adding 5% aq solution of NH4Cl (5 mL). After
reaching rt, the mixture was extracted with ethyl acetate (2 × 50
mL). The organic phase was washed twice with water (100 mL)
and then with brine (100 mL). After drying with anhydrous sodium
sulfate and evaporation, crude product was purified by column
chromatography on silica gel using ethyl acetate/hexane as eluent
(1:4 to 1:1).
Conditions B. To liquid ammonia (15 mL) kept at -78 °C was
added a solution of proper nitroarene 2-14 (2 mmol) and carbanion
precursor 1 or 1a (1 mmol) in THF (2 mL) followed by dropwise
addition of solution of t-BuOK in THF (1.05 mmol, 1.05 mL, 1.00
M). After stirring for 30 min, solid potassium permanganate (174
mg, 1.1 mmol) was added. The dark solution was stirred for further
Yields of the ONSH products are usually high or excellent.
Conditions B are not only simpler and more convenient, they
also ensure much higher yields. The reaction with 4-chloroni-
trobenzene 8 gave negative results, and the starting materials
were fully recovered. It seems that the addition of the bulky
carbanion 1a in the position ortho to the nitro group does not
proceed, whereas under these mild conditions (low temp)
(24) Sulikowski, D.; Ma¸kosza, M. Acta. Chim. SloV. 2009, in press.
J. Org. Chem. Vol. 74, No. 10, 2009 3831

Ma¸kosza and Sulikowski
5 min and treated with excess of solid NH4Cl. After evaporation
of ammonia, the residue was partitioned between water and ethyl
acetate and filtered trough a small pad of cellite, and the organic
phase was separated. The purification was performed in the same
way as in procedure A.
Conditions C. To a solution of carbanion precursor 1 (1.0 mmol)
and nitroarene 2-14 (2.0 mmol) in THF (10 mL) cooled to -78
°C was added dropwise a solution of t-BuOK in THF (1.05 mmol,
1.05 mL, 1.00 M) during 5 min. Then, the reaction mixture was
stirred 30 min at this temperature. After this time, solid potassium
permanganate (174 mg, 1.1 mmol) was added in one portion,
followed by addition of liquid ammonia (10 mL). After 5 min, the
reaction was quenched by addition of solid NH4Cl. Further workup
was performed as described in procedure B.
Conditions D. To a solution of carbanion precursor 1 (1.0 mmol)
and nitroarene 2-12 (2.0 mmol) in DMSO (10 mL) at room
temperature was added dropwise a solution of t-BuOK in THF (1.5
mmol, 1.5 mL, 1.00 M) during 1 min, and dry air was passed
through this dark-colored mixture for 15 min. Then, a 5% aq
solution of NH4Cl was added and after standard aqueous workup,
as in procedure A, products were isolated by column chromatog-
raphy on silica gel using ethyl acetate/hexane (1:1 to 1:4).
Analytical and Spectral Data for Representative Compounds.
Diethyl r-(2-Nitrophenyl)-benzylphosphonate (2a). Oil; IR (film,
CH2Cl2) νmax 2982, 1528, 1355, 1252, 1051, 1025 cm-1; 1H NMR
(500 MHz, CDCl3) δ 8.14-8.05 (m, 1H), 7.80 (d, J ) 8.1 Hz,
1H), 7.64-7.52 (m, 3H), 7.41-7.22 (m, 4H), 5.41 (d, J ) 25.6
Hz, 1H), 4.14-3.66 (m, 4H), 1.11 (t, J ) 7.2 Hz, 3H), 1.10 (t, J
) 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 149.7 (d, J ) 9.8
Hz), 135.0 (d, J ) 5.1 Hz), 132.6 (d, J ) 2.0 Hz), 131.8 (d, J )
5.6 Hz), 131.0 (d, J ) 3.8 Hz), 129.8 (d, J ) 8.2 Hz), 128.6, 127.9
(d, J ) 2.0 Hz), 127.6 (d, J ) 1.8 Hz), 124.6, 62.9 (d, J ) 85.1
Hz), 62.8 (d, J ) 75.2 Hz), 43.6 (d, J ) 137.3 Hz), 16.1 (d, J )
10.5), 16.0 (d, J ) 5.7 Hz); 31P NMR (202 MHz, CDCl3) δ 25.0
(s); LRMS-EI m/z (%) 349 (M, 4), 212 (100), 195 (54), 167 (65).
Anal. Calcd for C17H20NO5P: C, 58.45; H, 5.77; N, 4.01. Found:
C, 58.29; H, 5.98; N, 3.81.
Diethyl r-(4-Nitrophenyl)-benzylphosphonate (2b). Oil; IR
(film, CH2Cl2) νmax 2983, 1595, 1520, 1348, 1250, 1049, 1025 cm-1
;
1H NMR (500 MHz, CDCl3) δ 8.17 (d, J ) 8.7 Hz, 2H), 7.71 (dd,
J ) 8.8 Hz, 1.8 Hz, 2H), 7.51 (dd, J ) 5.3 Hz, 3.6 Hz, 2H),
7.38-7.27 (m, 3H), 4.53 (d, J ) 25.1 Hz, 1H), 4.07-3.88 (m,
3H), 3.83 (m, 1H), 1.16 (t, J ) 7.1 Hz, 3H), 1.11 (t, J ) 7.1 Hz,
3H); 13C NMR (126 MHz, CDCl3) δ 147.0, 144.6 (d, J ) 5.1 Hz),
135.4 (d, J ) 5.7 Hz), 130.3 (d, J ) 7.8 Hz), 129.5 (d, J ) 7.9
Hz), 128.9, 127.8, 123.7, 63.1 (d, J ) 70.1 Hz), 63.0 (d, J ) 70.3
Hz), 51.1 (d, J ) 139.0 Hz), 16.3 (d, J ) 6.2 Hz), 16.2 (d, J )
6.2 Hz); 31P NMR (202 MHz, CDCl3) δ 24.8 (s); LRMS-EI m/z
(%): 349 (M, 31), 319 (17), 303 (20), 212 (94), 196 (63), 165 (100),
109 (32). Anal. Calcd for C17H20NO5P: C, 58.45; H, 5.71 N, 4.01.
Found: C, 58.59; H, 6.03; N, 4.31.
Diethyl r-(4-Nitrophenyl)-r-methylbenzylphosphonate (2c).
Oil; IR (film, CH2Cl2) νmax 2983, 1519, 1349, 1253, 1049, 1024
1
cm-1; H NMR (500 MHz, CDCl3) δ 8.13 (d, J ) 8.5 Hz, 2H),
7.75-7.55 (m, 2H), 7.48-7.38 (m, 2H), 7.38-7.21 (m, 3H),
4.19-3.88 (m, 3H), 3.79 (m, 1H), 2.00 (d, J ) 15.8 Hz, 3H), 1.23
(t, J ) 7.1 Hz, 3H), 1.17 (t, J ) 7.1 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 151.2 (d, J ) 3.9 Hz), 146.4, 141.4 (d, J ) 4.9 Hz),
129.9 (d, J ) 6.9 Hz), 128.9 (d, J ) 6.6 Hz), 128.2 (d, J ) 1.0
Hz), 127.2 (d, J ) 1.8 Hz), 122.9, 62.9 (d, J ) 35.5 Hz), 62.8 (d,
J ) 35.5 Hz), 50.4 (d, J ) 139.1 Hz), 25.0 (d, J ) 5.3 Hz), 16.2
(d, J ) 5.4 Hz), 16.1 (d, J ) 5.4 Hz); 31P NMR (202 MHz, CDCl3)
δ 28.1 (s); LRMS-EI m/z (%): 363 (M, 15), 317 (5), 226 (100),
209 (73), 178 (28), 165 (35). Anal. Calcd for C18H22NO5P: C, 59.50;
H, 6.10; N, 3.85. Found: C, 59.32; H, 5.37; N, 3.87.
Acknowledgment. This work was partially supported by
Ministerium of Science and Higher Education, Grant N204 0304
33.
Supporting Information Available: Analytical and spectral
characterization data and 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO900204E
3832 J. Org. Chem. Vol. 74, No. 10, 2009