Diethyl Chlorophosphite: A Mild Reagent for Efficient Reduction of Nitro Compounds to Amines

Full text of DOI:10.1021/jo971525l

J . Org. Chem. 1998, 63, 393-395
393
Sch em e 1
Sch em e 2
Dieth yl Ch lor op h osp h ite: A Mild Rea gen t
for Efficien t Red u ction of Nitr o
Com p ou n d s to Am in es
Bilha Fischer* and Larisa Sheihet
Department of Chemistry, Bar-Ilan University,
Ramat-Gan 52900, Israel
Received August 13, 1997
Phosphorus reagents are well established as deoxy-
genating agents in various important reactions such as
Wittig,1 Mitsunobu,2 Arbuzov,3 etc. The driving force in
all these reactions is the high energy, ranging from 120
to 150 kcal/mol, released upon formation of phosphine
oxide or phosphate products.4
Cadogan and others reported the abstraction of oxygen
from aromatic nitro and nitroso compounds by triethyl
phosphites and related reagents to form various hetero-
cyclic compounds (Scheme 1).5 The mechanism of these
reactions probably involves a nucleophilic attack of the
phosphorus atom on the nitro oxygen with the formation
of a nitrene intermediate that, if generated in proximity
to a suitable side chain, gives a nitrogen-containing
heterocycle.5b Alternatively, the nitrene intermediate can
undergo reaction with electronegative atoms.5a This
provides a general route to a wide variety of heterocyclic
compounds including carbazoles, indoles, 3H-azepines,
benzoxazoles, etc., described in numerous reports by
Cadogan and others.5
The scope of the reaction is illustrated in Table 1.
Whereas nitroalkanes are known not to react with
P(OEt)3 and in general their reduction is difficult (e.g.,
it can give rise to the corresponding oxime), 1-nitrohexane
was converted smoothly and quantitatively to hexylamine
by the above procedure.
Moreover, the scope of most of the common nitro
reduction methodologies is rather limited; various func-
tional groups or substituents do not survive the reaction
conditions. For example, hydride or hydrazine reductions
are not applicable to carbonyl-containing nitro com-
pounds.7 Even under the mild conditions of catalytic
hydrogenation, halogenated aromatic nitro compounds
often suffer dehalogenation.7
6
In this new procedure, groups commonly sensitive to
reduction such as aldehyde or ketone not only survived
but even promoted the reaction, when present at the para
position; thus, p-nitrobenzaldehyde and p-nitroacetophe-
none (entries 3 and 7) were reduced completely. The
former reacted after 0.5 h even at -10 °C. Nitrosoben-
We have exploited the highly efficient driving force of
phosphate formation from the corresponding phosphite
derivative, to devise a quantitative reduction of various
nitro compounds to amines in a one-pot synthesis under
mild conditions.
zene was reduced efficiently at room temperature.
A
m-chloro substitution (entry 4) did not lower the yield;
however, a p-cyano group (entry 5), or a p-methoxy group
(entry 8) decreased the yield to 20%.
In a typical experiment, 3 equiv of diethyl chlorophos-
phite and 3 equiv of a tertiary amine are added (no
reaction takes place in the absence of a tertiary amine,
and lower yields are obtained when only 2 equiv of diethyl
chlorophosphite are used) to 1 equiv of the nitro com-
pound in CHCl3 under a nitrogen atmosphere. After
0.5-5 h at room temperature, excess HCl(g) in MeOH is
added and the mixture is stirred at 50 °C for 6-10 h.
Workup with 10% NaOH affords the free amine, usually
in a quantitative yield (Scheme 2).
In the course of this process, substituents such as
chloro, nitrile, aldehyde, or ketone are not affected. The
procedure is applicable to the reduction of nitroso com-
pounds as well, but not to compounds containing hydroxyl
or primary and secondary amine functions, which under
these conditions are converted into phosphite derivatives.
In addition to diethyl chlorophosphite, we evaluated
the efficiency of other tervalent phosphorus compounds
in this respect. Thus, when trimethyl phosphite, P(OMe)3,
was added under the above reaction conditions, at room
temperature, no product formation was observed. Like-
wise, no reaction took place with either PCl3 or bis-
(diisopropylamino) chlorophosphite.
Diethyl chlorophosphite is responsible for the high
efficiency of this reaction as reflected in reaction rate,
mild temperature (e.g., room-temperature instead of ca.
150 °C in P(OR)3-induced reductive cyclizations,5 Scheme
1), and quantitative yields. By comparison, reaction of
p-nitrotoluene with an excess of P(OEt)3 at 156 °C was
reported to produce a mixture of four products, which
were isolated in low yields and were identified as diethyl
toluene-p-phosphonate (5%), diethyl 4-methyl-3H-azepine-
7-phosphonate (6%), diethyl N-ethyl-N-p-tolylphospho-
ramidate (24%), and diethyl N-p-tolylphosphoramidate
(26%).8,9 Under our conditions, the reductive step (step
* Author to whom correspondence should be addressed Tel: 972-
3-5318303. Fax: 972-3-5351250. e-mail: bfischer@ashur.cc.biu.ac.il.
(1) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. (Washington, D.C.)
1989, 89, 863.
(2) Mitsunobu, O. Synthesis 1981, 1.
(3) Brill, T. B.; Landon, S. J . Chem. Rev. (Washington, D.C.) 1984,
84, 577.
(4) Hartley, S. B.; Holmes, W. S.; J acques, J . K.; Mole, M. F.;
McCoubrey, J . C. Quart. Rev. 1963, 17, 204.
(5) (a) Cadogan, J . I. G. Synthesis 1969, 11, and references therein.
(b) Cadogan, J . I. G.; Todd, M. J . J . Chem. Soc., Chem. Commun. 1967,
178. (c) Cadogan, J . I. G. Quart. Rev. 1968, 22, 222.
(6) Trippett, S.; Walker, B. J .; Hoffmann, J . J . Chem. Soc. 1965,
7140.
(7) Boyer J . H. In The Chemistry of the Nitro and Nitroso groups.
Part 1; Feuer, H., Patai, S., Eds.; J ohn Wiley: New York, 1969; pp
244-248.
(8) Emerson, T. R.; Rees, C. W. J . Chem. Soc. 1964, 2319.
(9) Cadogan, J . I. G.; Sears, D. J .; Smith, D. M. J . Chem. Soc., Chem.
Commun. 1968, 1107.
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394 J . Org. Chem., Vol. 63, No. 2, 1998
Notes
Sch em e 3. Su ggested Mech a n ism of th e Title
Ta ble 1. Red u ction of Nitr o Com p ou n d s to
Cor r esp on d in g Am in es
Rea ction
I, Scheme 2) of p-nitrotoluene took place at 20 °C within
4 h to afford a quantitative yield of the reduced product,
diethyl N-p-tolylphosphoramidate, 1.
To characterize the special role of ClP(OEt)2 here, we
need to compare it with literature reports illustrating the
nucleophilic character of P(OEt)3 and the electrophilic
nature of PCl3, used for deoxygenation of nitro- (nitroso)
and N-oxide functions, respectively. The fact that reduc-
tive cyclizations of aromatic nitro compounds require
trialkyl phosphite or triphenylphosphine, whereas PCl3
does not react at all under these conditions, suggests a
nucleophilic attack of triethyl phosphite on the nitro (or
nitroso) oxygen.5c It is known, however, that pyridine
N-oxide and related compounds undergo rapid reduction
with PCl3 which is accelerated in the presence of 2,6-
lutidine.8 In this case, the qualitative evidence is in
agreement with PCl3 acting as an electrophile, which is
attacked by the N-oxide oxygen atom. This is further
supported by the observation that with 4-nitropyridine
N-oxide, the reaction rate is markedly decreased.8 In
contrast, in nitroso reductions induced by trialkyl phos-
phite, electron-donating groups at the para position of a
nitrosoarene increase the electron density on the nitroso
oxygen and make reduction to N-arylphosphorimidate
much slower.5c
NMR.10 In the first deoxygenating step, reactive species
2 acts as an electrophile to reduce the nitro to a nitroso
compound, possibly via the intermediacy of a four-
membered ring 4, common in phosphorus chemistry. One
equivalent of diethyl chlorophosphate is released in this
step. A supporting evidence for the intermediacy of a
nitroso compound was suggested by reacting nitrosoben-
zene (entry 6) under the same reaction conditions to give
a phosphoramidate 1, in a quantitative yield.
The second deoxygenating step requires a nucleophilic
tervalent phosphorus reagent, which attacks at the
nitroso oxygen with the probable formation of intermedi-
ate 6. Supporting evidence for this mechanistic step is
the fact that an electron-poor nitroso (p-chloronitrosoben-
Diethyl chlorophosphite represents a “biphilic” reagent,
a hybrid of triethyl phosphite and phosphorus trichloride,
which could play both an electrophilic and a nucleophilic
role. This is illustrated in the suggested mechanism
shown in Scheme 3.
(10) Diethyl chlorophosphite was mixed with an equimolar amount
of diisopropylethylamine in CDCl3. After 10 min at rt, the 1H NMR
spectrum showed a new set of signals which are downfield shifted,
relative to those of the phosphite and the amine. The downfield shift,
as well as the more complex splitting pattern, indicates the formation
of a quaternary ammonium as described for reactive species 2. On the
basis of the 1H NMR spectrum taken after 10 min at 25 °C, a 40%
conversion to species 2 had taken place. 1H NMR (200 MHz, CDCl3) δ
3.95 (m, 4H), 3.67 (septet d, J ) 5, 3 Hz, 2H), 3.09 (dqd, J ) 15, 5, 3
Hz, 2H), 1.33 (td, J ) 5, 0.3 Hz, 6H), 0.96 (t, J ) 5 Hz, 3H), 0.95 (d, J
) 5 Hz, 12H).
Since a tertiary amine is essential for the reaction, we
suggest that the reactive species at the first deoxygen-
ation step is [R3NsP(OEt)2]+ Cl-, 2, formed from the
1
amine and diethyl chlorophosphite as evidenced by H

Notes
J . Org. Chem., Vol. 63, No. 2, 1998 395
zene, entry 9) reacted rapidly (within 40 min) under the
reaction conditions to form phosphoramidate 1 in high
yield. Moreover, as expected, p-cyanonitrobenzene (entry
5) reacted sluggishly, probably due to the rate-limiting
step, which is the reaction of the electron poor nitro
compound with the electrophilic reagent 2. The possibil-
ity of intermediate 6 decomposing to produce a nitrene
is unlikely, since we observed no reductive cyclization
products, e.g. diethyl-4-methyl-3H-azepine-7-phospho-
nate,9 due to nitrene insertion and ring expansion. By
comparison, a reaction of nitrobenzene with diethyl
methylphosphonite in a large excess of diethylamine at
55 °C for 5 days was reported to give 2-diethylamino-
3H-azepine (83%).11
ternary ammonium product (from which the free amine
is liberated by neutralization with 10% NaOH) and a
third equivalent of phosphate ester.
The new methodology for reduction of nitro compounds
into amines is a versatile procedure enabling a one-pot
quantitative transformation, under mild conditions, of
aliphatic and aromatic nitro compounds to the corre-
sponding amines. The “biphilic” character of the reagent,
diethyl chlorophosphite, is responsible for the high ef-
ficiency of the reaction. Further applications of this
reagent for deoxygenating various functions is currently
under investigation.
Exp er im en ta l Section
Gen er a l. 1H NMR and 31P NMR spectra were recorded at
300 and 200 MHz, respectively, in CDCl3. Mass spectra were
recorded on AutoSpec-E-Fision VG high-resolution mass spec-
trometer. Moisture sensitive reactions were carried out in two-
necked flasks, flame-dried under nitrogen. Chloroform was
distilled from CaH2. Commercial nitro compounds were recrys-
tallized. Nitroso compounds were prepared according to litera-
ture.15 Diethyl chlorophosphite was used as received without
additional purification.
R ed u ct ion of Nit r o Com p ou n d s t o Am in es. Typ ica l
P r oced u r e. To a solution of p-nitrotoluene (0.25 g, 1.82 mmol)
in dry CHCl3 (10 mL) under a nitrogen atmosphere were added
diisopropylethylamine (0.95 mL, 5.47 mmol) and diethyl chlo-
rophosphite (0.79 mL, 5.47 mmol). The solution was stirred at
room temperature for 4 h. MeOH (7.4 mL, 100 equiv) was added
until complete dissolution. The flask was immersed in an ice
bath, and acetyl chloride (6.5 mL, 50 equiv) was added dropwise.
The reaction mixture was then stirred at 50 °C for 6 h. The
solvent was removed under reduced pressure, and the residue
was dissolved in CHCl3, washed with 10% NaOH (3 × 25 mL),
dried over MgSO4, and evaporated. Traces of diisopropylethyl-
amine and phosphate ester were removed by chromatography
(silica gel, CHCl3:MeOH 10:1) to give the free amine (p-toluidine)
in quantitative yield; spectroscopic data (1H NMR and MS) were
consistent with the given structure.
Intermediate 6 probably reacts subsequently with an
additional molecule of reagent 2, acting as an electrophile,
leading to 7. The isolated product 1, characterized by
31P NMR,12 is most probably obtained by hydrolysis of
intermediate 8. A release of a second phosphate ester is
concomitant. When the reaction was run with 4 equiv
of ClP(OEt)2, product 9 was isolated in trace amounts
1
and was characterized by MS, H and 31P NMR.13 The
low yields of reduction products obtained with strong
electron-donating (entry 8) or -withdrawing (entry 5)
substituents further support the biphilic nature of the
reagent.
In step II (Scheme 2), the phosphoramidate moiety is
cleaved by treatment with HCl(g)/MeOH14 to yield a qua-
(11) (a) Cadogan, J . I. G.; Todd, M. J . J . Chem. Soc. C 1969, 2808.
(b) Cadogan, J . I. G.; Mackie, R. K. Ibid. 2819.
(12) Compound 1: 31P NMR (200 MHz, CDCl3) δ 2.70 (d, J ) 10
Hz). 1H NMR (300 MHz, CDCl3): δ 7.05 (d, J ) 7.5 Hz, 2H), 6.88 (d,
J ) 7.5 Hz, 2H), 5.15 (d, J ) 10 Hz, 1H), 4.2 (m, 4H), 2.30 (s, 3H), 1.31
(td, J ) 6, 0.5 Hz, 6H). MS (CI/NH3): 243 (M+), 244 (M + H+).
(13) Compound 9: 1H NMR (300 MHz, CDCl3) δ 7.17 (ABq, 4H),
4.2 (m, 4H), 2.28 (s, 3H), 1.31 (td, J ) 6, 0.5 Hz, 6H). 31P NMR (200
MHz, CDCl3): 2.68 (s). MS (CI/NH3): 380 (M + H+).
J O971525L
(14) (a) Zhao, Y.-F.; J i, G.-J .; Xi, S.-K.; Tang, H.-G.; Song, A.-T.; Wei,
S.-Z. Phosphorus Sulfur 1983, 18, 155-158. (b) Zwierzak, A.; Bry-
likowska-Piotrowicz, J . Angew. Chem., Int. Ed. Engl. 1977, 16, 107.
(15) Coleman, G. H.; McCloskey, C. M.; Stuart, F. A. Organic
Syntheses; Wiley-New York, 1955; Collect. Vol. 3, p 668.