Highly efficient synthesis of o-(2,4-dinitrophenyl)hydroxylamine. Application to the synthesis of substituted N-benzoyliminopyridinium ylides

Article abstract of DOI:10.1021/jo034456l

An efficient two-step synthesis of O-(2,4-dinitrophenyl)hydroxylamine is described along with a comparison of its aminating efficiency with O-mesitylenesulfonylhydroxylamine (MSH). It was used in an expedient N-amination/benzoylation procedure involving various substituted pyridines, leading to polysubstituted N-benzoyliminopyridinium ylides, and the scope of its amination power was studied.

Full text of DOI:10.1021/jo034456l

High ly Efficien t Syn th esis of
O-(2,4-Din itr op h en yl)h yd r oxyla m in e.
Ap p lica tion to th e Syn th esis of Su bstitu ted
N-Ben zoylim in op yr id in iu m Ylid es
Claude Legault and Andre´ B. Charette*
De´partement de Chimie, Universite´ de Montre´al,
P.O. Box 6128, Station Downtown, Montre´al,
Que´bec, Canada H3C 3J 7
andre.charette@umontreal.ca
Received April 10, 2003
F IGURE 1. Common reagents for the synthesis of N-amino-
pyridinium ylides.
SCHEME 1
Abstr a ct: An efficient two-step synthesis of O-(2,4-dinitro-
phenyl)hydroxylamine is described along with a comparison
of its aminating efficiency with O-mesitylenesulfonylhy-
droxylamine (MSH). It was used in an expedient N-amina-
tion/benzoylation procedure involving various substituted
pyridines, leading to polysubstituted N-benzoyliminopyri-
dinium ylides, and the scope of its amination power was
studied.
however, the scope is limited since this strategy cannot
be applied to the synthesis of 2-substituted-N-amino-
pyridinium ylides.5 A review on electrophilic aminations
using MSH and related compounds has been published.6
The main drawbacks of reagent 4 are its high cost of
synthesis and instability.7 The general method of syn-
thesis of aminating reagents involves reaction of a
N-protected hydroxylamine with an electrophilic reagent
on the hydroxyl, followed by deprotection of the amine
moiety (Scheme 1). The deprotection conditions must be
compatible with the hydroxylamine functionality as well
as the R group on the oxygen.
We decided to focus on O-(2,4-dinitrophenyl)hydroxyl-
amine 5 because of increased O-aryl bond stability,
permitting a broader range of N-protecting groups. It is
reportedly more stable than O-sulfonyl hydroxylamine
derivatives.8 This aminating reagent and related ana-
logues were recently used in the synthesis of novel
antibacterial agents.9 The 3-nitro analogue was also
synthesized and used recently.10 The usual method of
synthesis involves the use of the expensive N-Boc hy-
droxylamine and either chloro- or fluoro-2,4-dinitroben-
zene (8a or 8b) as reported by Sheradsky (Scheme 2).11
We elected to start with N-hydroxyphthalimide as the
N-protected hydroxylamine source because of its low cost.
Our second goal was to use 2,4-dinitrochlorobenzene as
the starting material since it is considerably cheaper than
its fluoro analogue. In this paper, we wish to report the
highly efficient synthesis of O-(2,4-dinitrophenyl)hy-
droxylamine 5 from inexpensive starting materials, fol-
lowed by its application and scope for the amination of
various aromatic heterocycles and efficient preparation
of substituted N-benzoyliminopyridinium ylides.
In our research program directed toward the develop-
ment of new methods for the synthesis of substituted
piperidines, we recently reported a highly regioselective
addition of nucleophiles to the 2-position of N-benzoyl-
iminopyridinium ylides.1 These compounds were also
shown to be useful precursors to various novel hetero-
cyclic compounds, mainly through 1,3-dipolar cycloaddi-
tion reactions and photochemical rearrangments.2 The
common precursor for the synthesis of these compounds
is the corresponding N-aminopyridinium salt (eq 1).
These salts can be prepared by direct N-amination of
the corresponding pyridine according to the procedure of
Go¨sl, using hydroxylamine-O-sulfonic acid 3.3 The pro-
cedure has some drawbacks, including moderate yields
and the necessity to use an excess of the pyridine. Other
aminating reagents can be used for this transformation,
the most widely known being O-mesitylenesulfonyl-
hydroxylamine (MSH) 4.4 An alternative method for the
synthesis of N-benzoyliminopyridinium ylides involves
the reaction of Zincke salts 6 with benzoic hydrazide;
* To whom correspondence should be addressed. Tel: 514-343-2432.
Fax: 514-343-5900.
(1) Legault, C.; Charette, A. B. J . Am. Chem. Soc. 2003, 125, 6360.
(2) Reviews on N-iminopyridinium ylides: (a) Timpe, H.-J . Adv.
Heterocycl. Chem. 1974, 17, 213. (b) Tamura, Y.; Ikeda, M. Adv.
Heterocycl. Chem. 1981, 29, 71.
(3) (a) Go¨sl, R.; Meuwsen, A. Chem. Ber. 1959, 92, 2521. (b) Go¨sl,
R.; Meuwsen, A. Org. Synth. 1963, 43, 1. (c) Wallace, R. G. Aldrichimica
Acta 1980, 13, 3.
(4) (a) Tamura, Y.; Minamikawa, J .; Miki, Y.; Matsugashita, S.;
Ikeda, M. Tetrahedron Lett. 1972, 13, 4133. (b) Tamura, Y.; Minami-
kawa, J .; Sumoto, K.; Fujii, S.; Ikeda, M. J . Org. Chem. 1973, 38, 1239.
(c) Tamura, Y.; Matsugashita, S.; Ishibashi, H.; Ikeda, M. Tetrahedron
1973, 29, 2359.
(5) (a) Tamura, Y.; Tsujimoto, N.; Mano, M. Chem. Pharm. Bull.
1971, 19, 130. (b) Tamura, Y.; Miki, Y.; Honda, T.; Ikeda, M. J .
Heterocycl. Chem. 1972, 9, 865. (c) Knaus, E. E.; Redda, K. J .
Heterocycl. Chem. 1976, 13, 1237.
(6) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1.
(7) Ning, R. Y. Chem. Eng. News 1973, 51, 37.
(8) Erdik, E.; Ay, M. Chem. Rev. 1989, 89, 1947.
(9) Boyles, D. C.; Curran, T. T.; Parlett, R. V. Org. Proc. Res. Dev.
2002, 6, 230.
(10) Miyazama, E.; Sakamoto, T.; Kikugawa, Y. Org. Prep. Proced.
Int. 1997, 29, 594.
(11) (a) Sheradsky, T. J . Heterocycl. Chem. 1967, 4, 413. (b)
Sheradsky, T.; Salemnick, G.; Nir, Z. Tetrahedron 1972, 28, 3833.
10.1021/jo034456l CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/12/2003
J . Org. Chem. 2003, 68, 7119-7122
7119

TABLE 1. Com p a r ison of Am in a tion Yield s of Va r iou s
Ar om a tic Heter ocycles w ith 4 a n d 5
SCHEME 2
The nucleophilic aromatic substitution of chloro-2,4-
dinitrobenzene (8a ) by nucleophilic attack of N-hydroxy-
phthalimide was easily achieved in 95% yield in the
presence of triethylamine in acetone (eq 2). Under these
a
See supporting info for experiment details.
aminate various aromatic heterocycles, as can be seen
in Table 1.
We then optimized a one-pot amination/benzoylation
procedure for the synthesis of a variety of substituted
N-benzoyliminopyridinium ylides (Table 2). The amina-
tion was done in a 1:1 mixture of THF and water at 40
°C. The use of water as a cosolvent accelerated the
reaction, as shown by Yamamoto.15 It is postulated that
a stabilization of the SN2 transition state occurs by a
hydrogen bond with water. The reactions were usually
allowed to react for 12 h for reproducibility sake; how-
ever, as illustrated with pyridine (entries 1-3), the
reaction was nearly quantitative after 4 h. Following the
amination, the reaction mixture was diluted with aque-
ous sodium hydroxide and treated with 50% excess of
benzoyl chloride to effect the benzoylation of the pyri-
dinium ylide. Under these conditions, the N-benzoylimi-
nopyridinium ylides were obtained from the correspond-
ing pyridines in excellent yields. The amination is high
yielding with many substrates, including 2-alkyl-mono-
substituted and 2,6-disubstituted pyridines (entries 5-7).
The methodology is also compatible with amino-substi-
tuted pyridine (entry 9). Quinoline and isoquinoline were
also transformed in high yields (entries 12 and 13);
however, following amination, they were first treated
with benzoyl chloride for 30 min before addition of the
aqueous sodium hydroxide solution to obtain high yields.
The normal procedure led to decomposition. The modest
yield obtained for pyrazine (entry 11) is due to the low
conversion of amination. In many cases, the N-ben-
zoyliminopyridinium ylide is obtained in sufficiently high
purity that it did not require any further purification.
Synthesis of N-benzoyliminopyridinium ylide from
2-amino-substituted pyridine proved to be problematic.
However, as seen in eq 4, the amination step proceeds
with excellent yield.
reaction conditions, the N,O-disubstituted product 11 was
obtained in excellent yield, without the need for further
purification. These conditions played an important role
for the feasibility of the substitution reaction. Earlier
reports had previously shown that the potassium alkox-
ide derived from 10 led to a much lower yield for the
substitution reaction12 and that a fluoro substituent (8b)
on the electrophilic component was mandatory if triethy-
lamine was to be used as the base.13
The deprotection of N-phthalimido-O-aryl-substituted
hydroxylamines was recently reported by Sharpless.14
However, in our case, the high electrophilicity of the
resulting hydroxylamine led to a low isolated yield of the
desired compound. By using milder hydrazinolysis condi-
tions we were able to deprotect the hydroxylamine in
nearly quantitative yield (eq 3). The aminating reagent
is obtained in sufficiently high purity that it can be used
without any further purification.
With an efficient synthesis in hand, we then developed
optimal conditions for the amination reaction. A report
by Tamura et al.4b showed 5 to have low aminating power
toward pyridine, but we found that by heating at 40 °C
in acetonitrile for 12 h, 5 was as efficient as MSH to
(12) Ilvespa¨a¨, A. O.; Marxer, A. Helv. Chim. Acta 1963, 225, 2009.
(13) Rougny, A.; Daudon, M. Bull. Soc. Chim. Fr. 1976, 5, 833.
(14) Petrassi, H. M.; Sharpless, K. B.; Kelly, J . W. Org. Lett. 2001,
3, 139.
7120 J . Org. Chem., Vol. 68, No. 18, 2003

TABLE 2. Syn th esis of N-Ben zoylim in op yr id in iu m
Ylid e Der iva tives
TABLE 3. Syn th esis of N-Ben zoylim in op yr id in iu m
Ylid es fr om Electr on -P oor P yr id in es
a
See Supporting Information for experiment details.
amine. It is a good alternative to MSH for the amination
of various hetereoaromatics, being noticeably more stable
and cheaper. This aminating reagent was applied to a
one-pot amination/benzoylation procedure leading to
substituted N-benzoyliminopyridium ylides in excellent
yields. We also showed the scope of its amination ef-
ficiency. These compounds are useful starting materials
for the synthesis of polysubstituted piperidines.
Exp er im en ta l Section
2-(2,4-Din itr op h en oxy)-1H-isoin d ole-1,3(2H)-d ion e (11).
Triethylamine (21.5 mL, 0.154 mol) was added in one portion
to a suspension of N-hydroxyphthalimide (25.0 g, 0.153 mol) in
500 mL of acetone, and the mixture was stirred at room
temperature. The reaction mixture turned dark red, and the
N-hydroxyphthalimide slowly dissolved. The reaction was stirred
until it became a homogeneous solution (ca. 10 min). 2,4-
Dinitrochlorobenzene (31.0 g, 0.153 mol) was then added in one
portion, and the reaction was stirred at room temperature for 2
h. After this time, a bright yellow suspension was formed, and
the reaction mixture was poured into 500 mL of ice water. The
precipitate was filtered and washed three times with 100 mL of
cold MeOH. The solid was compressed and washed with three
100-mL portions of hexanes and dried under vacuum to afford
11 as an off white solid (48.0 g, 95% yield): Rf 0.92 (50% EtOAc/
Hexanes); mp 186 °C, lit. mp 186 °C;12 1H NMR (300 MHz,
CDCl3) δ 8.99 (d, J ) 2.6 Hz, 1H), 8.44 (dd, J ) 9.3, 2.7 Hz, 1H),
8.03-7.97 (m, 2H), 7.95-7.90 (m, 2H), 7.46 (d, J ) 9.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 162.3, 156.7, 143.4, 137.5, 136.0,
129.7, 128.9, 124.9, 122.8, 116.0; IR (neat) 3094, 1732, 1600,
1523, 1347, 870 cm-1; LRMS (APCI, Neg) m/z calcd for C14H7N3O7
[M - H]- 328.0, observed 328.0.
O-(2,4-Din itr op h en yl)h yd r oxyla m in e (5). A solution of
hydrazine hydrate (10.0 mL, 0.177 mol) in 60 mL of MeOH was
added in one portion to a solution of 11 (20.0 g, 60.7 mmol) in
400 mL of CH2Cl2 at 0 °C. The reaction mixture rapidly became
bright yellow, and a precipitate was formed. The suspension was
allowed to stand at 0 °C for 8 h, cold aqueous HCl (1 N, 400
mL) was added, and the reaction was shaken rapidly at 0 °C.
The mixture was rapidly filtered through a loose cotton plug on
a Bu¨chner funnel, and the precipitate was washed three times
with 50 mL of MeCN. The filtrate was poured into a separatory
funnel, and the organic phase was separated. The aqueous phase
was extracted twice with 100 mL of CH2Cl2. The organic phases
were combined, dried over Na2SO4, filtered, and concentrated
under reduced pressure, affording 5 (12.1 g, 99% yield, 95% pure
as determined by 1H NMR using an internal standard) as an
orange solid. An analytically pure sample can be obtained by
a
Isolated yield after work-up, recrystallization or flash chro-
matography. Reaction time is 1 h. c Reaction time is 4 h.
b
To test the scope and limitations of 5, we examined
the amination of pyridines bearing electron-withdrawing
groups at various positions; the results are summarized
in Table 3. 2-Substituted pyridines failed to react with 5
under various conditions (entries 1-3). 3-Substituted
pyridines (entries 4-7) were more difficult to aminate,
the worst case being 3-cyanopyridine (entry 5), where
only traces of amination were observed. Although the
amination of 4-substituted pyridines proceeded more
easily, we observed the same trend, that the cyano-
substituted pyridine was the most difficult to aminate.
In all cases, the yields of the pyridinium ylides were
directly related to the conversion of amination observed.
In conclusion, we have developed a highly efficient and
inexpensive synthesis of O-(2,4-dinitrophenyl)hydroxyl-
(15) Yamamoto, F.; Oae, S. Bull. Chem. Soc. J pn. 1975, 48, 77.
J . Org. Chem, Vol. 68, No. 18, 2003 7121

recrystallization from EtOH: Rf 0.39 (50% EtOAc/Hexanes); mp
112 °C, lit. mp 112 °C;4b 1H NMR (300 MHz, CDCl3) δ 8.82 (d,
J ) 2.7 Hz, 1H), 8.44 (dd, J ) 9.4, 2.7 Hz, 1H), 8.07 (d, J ) 9.4
Hz, 1H), 6.42 (s(br), 2H); 13C NMR (75 MHz, CDCl3) δ 159.9,
140.8, 136.5, 129.6, 122.2, 116.6; IR (neat) 3323, 3259, 3118,
1603, 1516, 1339, 834, 742 cm-1; LRMS (APCI, Neg) m/z calcd
for C6H5N3O5 [M - H]- 198.0, observed 198.0.
Gen er a l Am in a tion /Ben zoyla tion P r oced u r e. N-Ben -
zoylim in op yr id in iu m Ylid e (15a ). Pyridine (0.100 mL, 1.24
mmol) and 5 (272 mg, 1.36 mmol) were added to 0.5 mL of a
(1:1) mixture of H2O and THF. The reaction flask was sealed,
and the resulting suspension was stirred at 40 °C for 12 h.
During this period, the reaction mixture turned dark red. The
reaction was poured into aqueous NaOH (2.5 N, 6 mL) at room
temperature, and benzoyl chloride (0.215 mL, 1.84 mmol) was
slowly added. After 4 h, the reaction was diluted with 5 mL of
H2O and extracted three times with 10 mL of CHCl3. The
combined organic phases were washed once with 5 mL of 2.5 N
NaOH. The organic phase was dried over Na2SO4, filtered, and
concentrated under reduced pressure affording 15a as a beige
solid (236 mg, 96% yield): mp 174 °C, lit. mp 179 °C;16 1H NMR
(400 MHz, CDCl3) δ 8.81 (d, J ) 5.9 Hz, 2H), 8.16 (d, J ) 5.7
Hz, 2H), 7.87 (t, J ) 7.6 Hz, 1H), 7.62 (t, J ) 7.0 Hz, 2H), 7.48-
7.37 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 143.5, 137.4,
130.3, 128.1, 128.0, 126.1; IR (neat) 1548, 1465, 1332, 762, 710
cm-1; HRMS (MAB) m/z calcd for C12H10N2O [M] 198.0793,
observed 198.0798.
Ack n ow led gm en t. This work was supported by
NSERC (Canada)/Merck Frosst/Boehringer Ingelheim
Industrial Chair on Stereoselective Drug Synthesis and
the Universite´ de Montre´al. C.L. is grateful to NSERC
(PGF A and B) and NATEQ (B2) for postgraduate
fellowships.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures, characterization data, and 1H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034456L
(16) Epsztajn, J .; Lunt, E.; Katritzky, A. R. Tetrahedron 1970, 26,
1665.
7122 J . Org. Chem., Vol. 68, No. 18, 2003