A high yield procedure for the preparation of 2-hydroxynitrostyrenes: Synthesis of imines and tetracyclic 1,3-benzoxazines

Article abstract of DOI:10.1002/ejoc.201402016

Attempts to synthesize 2-hydroxynitrostyrenes by a Knoevenagel condensation of salicylaldehyde and subsequent elimination were unsuccessful because of the formation of a stable imine. This could be easily prevented by using secondary amines to catalyze the reaction, which then afforded 2-hydroxynitrostyrenes in high yields. In addition, the stable imine that was formed by employing ammonium acetate underwent a reaction with phosgene to allow the preparation of benzoxazines in good yields. Copyright

Full text of DOI:10.1002/ejoc.201402016

Job/Unit: O42016
/KAP1
Date: 21-03-14 10:31:46
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201402016
A High Yield Procedure for the Preparation of 2-Hydroxynitrostyrenes:
Synthesis of Imines and Tetracyclic 1,3-Benzoxazines
Víctor Tena Pérez,[a] Ángel L. Fuentes de Arriba,[a] Laura M. Monleón,[a] Luis Simón,*[b]
Omayra H. Rubio,[a] Francisca Sanz,[c] and Joaquín R. Morán*[a]
Keywords: Synthetic methods / Heterocycles / Schiff bases / Nucleophilic addition / Elimination
Attempts to synthesize 2-hydroxynitrostyrenes by a Knoev-
enagel condensation of salicylaldehyde and subsequent eli-
mination were unsuccessful because of the formation of a
stable imine. This could be easily prevented by using sec-
ondary amines to catalyze the reaction, which then afforded
2-hydroxynitrostyrenes in high yields. In addition, the stable
imine that was formed by employing ammonium acetate
underwent a reaction with phosgene to allow the preparation
of benzoxazines in good yields.
Introduction
amphetamine derivatives.[5] However, the procedure de-
Nitrostyrenes are synthetically useful building blocks,[1] scribed in the literature for the synthesis of 2-hydroxy-
and for years their many biological properties have been nitrostyrenes is not completely satisfactory, and poor yields
recognized.[2] They are readily prepared from nitromethane have been reported.[6] Indeed, unlike other aromatic alde-
and a suitable aldehyde by ultrasonication under Knoeven- hydes, salicylaldehyde requires high temperatures (95 °C)[7]
agel conditions.[3] Among nitrostyrenes, 2-hydroxynitrostyr- to react with nitromethane. Under these conditions, a dark
enes are of special importance because they are employed brown solid is obtained, which is indicative of the presence
as the starting material in the preparation of important of tarry materials. High temperatures facilitate side reac-
pharmacologically active compounds such as Lirinine[4] and tions and, therefore, reduce the final yield.
Scheme 1. Preparation of 2-hydroxynitrostyrenes from salicylaldehyde and nitromethane in the presence of ammonium acetate.
The conventional mechanism of the reaction between
salicylaldehyde and nitromethane to afford 2-hydroxy-
[a] Organic Chemistry Department, University of Salamanca,
nitrostyrenes involves the formation of Knoevenagel adduct
3, which is followed by an elimination reaction (see
Scheme 1). However, in our case, the Knoevenagel adduct
undergoes further reaction with another salicylaldehyde
molecule to furnish imine 5. The stability of this compound
decreases the rate of formation of 2-hydroxynitrostyrene
(4), which strongly reduces its final yield. Herein, we offer
some solutions to overcome these drawbacks, and we report
Plaza de los Caídos 1–5, 37008 Salamanca, Spain
E-mail: romoran@usal.es
[b] Chemical Engineering Department, University of Salamanca,
Plaza de los Caídos 1–5, 37008 Salamanca, Spain
E-mail: lsimon@usal.es
http://campus.usal.es/~ingquimica/
[c] X-ray diffraction service of the NUCLEUS Platform,
University of Salamanca,
Plaza de los Caídos 1–5, 37008 Salamanca, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402016.
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L. Simón, J. R. Morán et al.
FULL PAPER
a new procedure for the preparation of 2-hydroxynitrostyr-
A primary amine such as butylamine (see Table 1, En-
enes. In addition, imines 5 have been isolated and trans- try 2) yielded the desired product 4 in a higher yield (65%)
formed into benzoxazines.[8]
than ammonia (see Table 1, Entry 1), but the reaction rate
was slow. An explanation for this is that salicylaldehyde can
undergo a reaction with a primary amine such as butyl-
amine to yield the imine, which is stabilized by the presence
of a strong intramolecular hydrogen bond (see Figure 2).
Results and Discussion
Preparation of Nitrostyrenes
Under conventional conditions,[3] the reaction between
salicylaldehyde and ammonium acetate in nitromethane
yields imine 5. This compound is formed because the Knoe-
venagel adduct between aldimine 2 and nitromethane is
trapped by another aldehyde molecule (even with a low
concentration of salicylaldehyde), which reduces the rate of
formation of 2-hydroxynitrostyrene. Furthermore, imine 5
can presumably form through secondary reaction pathways,
such as further Knoevenagel condensations with additional
nitromethane molecules or polymerization reactions by
electrophilic attack of the phenolic rings. Modeling stud-
ies[9] suggest that the stability of this imine could be as-
cribed, at least partially, to the formation of two strong hy-
drogen bonds between the phenolic OH groups and the im-
ine nitrogen atom as shown in Figure 1. The formation of
imine 5 reduces the yield of 2-hydroxynitrostyrene.
Figure 2. Imine formed between salicylaldehyde and butylamine
with the intramolecular hydrogen bond shown.
The reaction of a secondary amine and salicylaldehyde
does not produce an imine, and the iminium salt that is
formed can, therefore, undergo reaction faster with nitro-
methane. Indeed, the best results were obtained with pyr-
rolidine (see Table 1, Entry 3), from which 2-hydroxy-
nitrostyrene (4) was obtained almost quantitatively (97%
yield) in only 1.5 h at room temperature. However, dieth-
ylamine afforded known molecule 6 (see Table 1, Entry 4),
as a result of the fast Michael addition between nitrometh-
ane and 2-hydroxynitrostyrene.
Because pyrrolidine offered the best results for the prepa-
ration of 2-hydroxynitrostyrene, the reaction conditions
were optimized with this amine by using different ratios of
pyrrolidine/acetic acid to accelerate the reaction. As shown
in Table 2, the best results at room temperature were ob-
tained by employing a 2:1 molar ratio of AcOH/pyrrolidine.
However, the reaction at room temperature afforded a dark
colored product. To reduce the extent of side reactions, the
reaction temperature was lowered to 0 °C, which improved
the product appearance and increased the yield (see Sup-
porting Information, Figure S36). At this temperature, the
Figure 1. Model for imine 5 generated from salicylaldehyde, nitro-
methane, and ammonium acetate under Knoevenagel conditions,
in which two intramolecular hydrogen bonds are shown.
The most obvious way to preclude the formation of the AcOH/pyrrolidine molar ratio was adjusted to 1.2:1 to ob-
imine is to replace ammonia with a catalyst that contains tain suitable reaction rates.
an alkyl-substituted nitrogen atom, because the N-alkyl-
Additionally, these mild reaction conditions are compati-
iminium ion that is formed under these conditions should ble with many substituted 2-hydroxybenzaldehydes, and all
be less stable than the imine formed from ammonia. Both the substrates that were tested (see Table 3) afforded con-
primary and secondary amines were tested in this reaction, sistently high yields. This reaction was also applicable on a
and the results are shown in Table 1.
multigram scale (see Table 3, Entry 4).
Table 1. Results of the reaction between salicylaldehyde and nitromethane catalyzed with different amines at room temperature.
Entry
R1
R2
Product
Time [h]
Yield [%]
1
2
3
4
H
Bu
H
H
4 + 5 (1:3)[a]
4
85
65
97
88
4
4
6
120
1.5
120
–(CH2)4–
Et
Et
[a] Ratio determined by spectroscopic analysis.
2
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Synthesis of 1,3-Benzoxazines
Table 2. Results of the reaction between salicylaldehyde and nitro- ment of new materials[10] and also exhibit several interesting
biological activities.[11] To improve the yield of imine 5,
methanol was added to the reaction mixture to increase the
methane catalyzed by pyrrolidine with different molar amounts of
AcOH/pyrrolidine.
solubility of ammonium acetate, which was otherwise only
sparingly soluble in nitromethane. Lowering the reaction
temperature to 5 °C was also essential, as low temperatures
hinder the elimination reaction that leads to the 2-hydroxy-
nitrostyrene. Under these latter conditions, imine 5 can be
obtained in excellent yields by simply pouring the reaction
over water and then filtering the mixture.
Nucleophiles other than nitromethane were also tested
under these reaction conditions. The results are summa-
rized in Table 4. Surprisingly, not all of the nucleophiles ex-
amined successfully led to the corresponding imine, and
other products were identified.
Entry
AcOH/
pyrrolidine
Product
Time
[min]
Yield
[%]
1
2
3
1.5:1
2:1
2.5:1
4.8:1
1.2:1
4 + 6 (7:3)[a]
5
45
180
2880
180
80
90
4
4
4
4
85
no reaction
99
4
5[b]
Dimethyl malonate (see Table 4, Entry 2) yielded similar
results as those of nitromethane (see Table 4, Entry 1) and
afforded a clean crystalline adduct after pouring the reac-
tion mixture over water. However, dibenzoyl methane (see
Table 4, Entry 3) led to a 1:1 mixture of the expected com-
pound 5g and a lactol that was obtained by its intramolecu-
lar condensation. Malononitrile (see Table 4, Entry 4) failed
to produce the expected imine and instead yielded simple
Knoevenagel adduct 8. Meldrum’s acid (see Table 4, En-
try 5) provided known chromene 9, which is of technical
interest as a rat poison[12] and was obtained with this pro-
cedure under especially mild conditions.
By using imines 5a, 5f, and 5g, we attempted to obtain
the corresponding benzoxazines by following the procedure
described by Betti[8] but, surprisingly, these experiments
failed. A modeling study (see Figure 3)[9] showed that be-
cause of the double hydrogen-bond stabilization, imine 5 is
5.6 kcalmol–1 more stable than benzoxazine 10. The imine
is the more stable compound, and this explains why the
isomerization from imine 5 to benzoxazine 10 does not take
place under the employed thermodynamic conditions. How-
ever, the σ-bonds that are present in the benzoxazine should
[a] Ratio determined by spectroscopic analysis. [b] Reaction carried
out at 0 °C.
Table 3. Results of the reaction of salicylaldehydes 1a–1e and nitro-
methane catalyzed by pyrrolidine at 0 °C.
Entry
AcOH/
pyrrolidine
R3
R4 Product Time Yield
[min]
[%]
1
2
1.2:1
1.2:1
1.2:1
1.2:1
H
Br
H
H
H
OH
H
4a
4b
4c
4d
180
120
300
270
99
95
92
90
3
4[a]
Cl
[a] Reaction carried out at 50 g scale.
Preparation of Imines and Benzoxazines
Imine 5 is an interesting molecule, as it is a potential be stronger than the imine π-bonds, and, therefore, the
source of benzoxazines, which are attractive to the develop- benzoxazine could be the most stable product if the forma-
Table 4. Products of the reaction between salicylaldehyde and different nucleophiles using ammonium acetate at 5 °C.
Entry
R5
R6
Product
Time [h]
Yield [%]
1
2
3
4
5
H
NO2
5a
8
1.5
3
1.1
270
82
80
75
82
90
CO2Me
COPh
CN
CO2Me
COPh
CN
5f
5g + 7g (1:1)[a]
8
9
–(CO)-O-C(Me)2-O-(CO)–
[a] Ratio determined by spectroscopic analysis.
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L. Simón, J. R. Morán et al.
FULL PAPER
Figure 4. Proposed structure for the iminium salt formed from im-
ine 5a (left) and energy-minimized model showing the two intramo-
lecular hydrogen bonds and the great distance between the phenolic
hydroxy group and the imine carbon atom (right).
As an alternative to the protonation of the imine nitro-
gen atom, different electrophiles that might acylate this
nitrogen were examined. The alkylated or acylated nitrogen
atom in the benzoxazine was expected to be more stable
than the corresponding alkyl or acyl imine, which should
provide the benzoxazine over the imine. The results are
summarized in Table 5.
Figure 3. Modeling study of imine 5 versus benzoxazine 10.
tion of the two intramolecular hydrogen bonds of the imine
were prevented.
Methyl iodide (see Table 5, Entry 2) only afforded the
nitrostyrene product (together with the starting aldehyde as
a byproduct), but when phosgene was tested as the electro-
phile (see Table 5, Entries 3–5), benzoxazines were gener-
ated from imines 5a, 5f, and 5g to yield the tetracyclic com-
pounds 10a, 10f, and 10g, respectively. Interestingly, the 1:1
mixture of imines 5g and 7g, which were generated from the
earlier reaction of salicylaldehyde with dibenzoylmethane,
underwent a reaction with phosgene to give a single product
(i.e., 10g; see Table 5, Entry 5) and, thus, confirmed the
structure of lactol 7g.
A final confirmation was obtained by X-ray crystal
structure analysis of benzoxazine 10g. This compound crys-
tallized with a chloroform molecule (see Figure 5) and ex-
hibited all the structural features expected for this com-
pound.
To change the thermodynamic preference for imine 5, an
acidic medium was examined (see Table 5, Entry 1). We as-
sumed that the higher basic character of the protonated sp3-
hybridized nitrogen atom of the benzoxazine compared to
the sp2-hybridized nitrogen atom of the initially formed
iminium salt should favor the protonation of the benz-
oxazine. Nevertheless, the treatment of imine 5a with tri-
fluoroacetic acid yielded the iminium salt, which did not
progress to give the desired benzoxazine but gave the corre-
sponding 2-hydroxynitrostyrene after a long reaction time
(together with the starting salicylaldehyde as a byproduct).
1
This iminium salt was characterized by H NMR analysis
by monitoring the appearance of a broad signal at δ =
12.7 ppm, which corresponds to the iminium proton at the
nitrogen atom and is coupled to the imine proton at the
carbon atom. The signal of this deshielded proton appeared
at δ = 8.6 ppm. Thus, the iminium salt proved to be surpris-
ingly stable, probably because it is stabilized by two intra-
molecular hydrogen bonds and also its phenolic hydroxy
group is far away from the imine carbon (4.1 Å according
to modeling studies) as shown in Figure 4.
Conclusions
In the present work, a study of the preparation of 2-
hydroxynitrostyrenes was carried out. The results provided
Table 5. Products of the reaction of imines 5 with several electrophiles.
Entry
Substrate
R5
R6
Electrophile
Product
Time
[h]
Yield
[%]
1
2
3
4
5
5a
H
H
H
CO2Me
COPh
NO2
NO2
NO2
CO2Me
COPh
CF3CO2H
MeI
(CO)Cl2
(CO)Cl2
(CO)Cl2
1a + 4a (1:1)[a]
0.75
16
1
2.5
2
99
99
87
80
76
5a
1a + 4a (1:1)[a]
5a
5f
10a
10f
10g
5g[b] + 7g (1:1)
[a] Ratio determined by spectroscopic analysis. [b] This imine was employed as a mixture with lactol 7g, which resulted from the intramo-
lecular condensation of the imine as described in Table 4, Entry 3.
4
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Synthesis of 1,3-Benzoxazines
(E)-2-(2-Nitrovinyl)phenol (4a): Following the general procedure
and using salicylaldehyde (5.0 g, 41 mmol) for 3 h gave 4a (6.7 g,
99% yield).
(E)-4-Bromo-2-(2-nitrovinyl)phenol (4b): Following the general pro-
cedure and using 5-bromosalicylaldehyde (1.0 g, 5 mmol) for 2 h
gave 4b (1.2 g, 95% yield).
(E)-3-(2-Nitrovinyl)benzene-1,2-diol (4c): Following the general pro-
cedure and using 2,3-dihydroxybenzaldehyde (690 mg, 5 mmol) for
5 h gave 4c (830 mg, 92% yield).
(E)-4-Chloro-2-(2-nitrovinyl)phenol (4d): Following the general pro-
cedure and using 5-chlorosalicylaldehyde (50.0 g, 0.3 mol) for 4.5 h
gave 4d (57.4 g, 90% yield).
2-(1,3-Dinitropropan-2-yl)phenol (6): This compound was prepared
from salicylaldehyde by following a variation of the general pro-
cedure. Salicylaldehyde (0.5 mL, 1.0 mmol), nitromethane (2.4 g,
5.0 mmol), and acetic acid (1.7 mL, 3.4 mmol) were added to a
two-necked round-bottomed flask that was equipped with a ther-
mometer and cooled with an ice bath. Diethylamine (2.5 mL,
2.9 mmol) was added dropwise by an addition funnel. The resulting
mixture was stirred at 0 °C for 12 h, and then it was warmed to
room temperature and stirred for an additional 108 h. The solvent
was removed under reduced pressure, and the crude product was
purified by column chromatography (CH2Cl2/AcOEt) to give 6
(1.6 g, 86% yield) as a yellow oil. The physical and spectroscopic
properties were identical to those described in the literature.[14]
Figure 5. ORTEP diagram of benzoxazine 10g.
an improvement over the previously described method for
their preparation. The reaction mechanism was elucidated
to optimize the experimental conditions for the preparation
of a series of 2-hydroxynitrostyrenes with high yields and
purities. In addition, the corresponding imines were ob-
tained and transformed into new benzoxazine compounds.
General Procedure for the Preparation of Imines: The corresponding
aldehyde (1.0 mmol), nucleophile (5.0 mmol), ammonium acetate
(2.0 mmol), acetic acid (1.0 mmol), and methanol (6.0 mLg–1 of
ammonium acetate) were added to a two-necked round-bottomed
flask, and the resulting mixture was stirred at room temperature
for 1.5–8.0 h. (When nitromethane was used as the nucleophile, the
reaction was conducted at 5 °C, instead of at room temperature.)
Experimental Section
General Methods: Solvents were purified by standard procedures
and distilled before use. Reagents and starting materials from com-
mercial suppliers were used without further purification IR spectra
were recorded as neat films, and the frequencies are given in cm–1.
1
The reaction progress was monitored by H NMR analysis of ali-
quots from the reaction mixture. Upon completion, the crude mix-
ture was poured over water at 0 °C, and the yellow solid product
that precipitated was filtered and used in the next reaction step
without further purification.
Melting points are reported in °C. The 1H and NMR spectro-
13
scopic data were recorded with a 200 MHz spectrometer. For 1H
NMR, the chemical shifts are reported in ppm with tetramethylsil-
ane (TMS) as the internal standard, and the data are reported as
chemical shift (in ppm), multiplicity [s (singlet), d (doublet), t (trip-
let), q (quartet), m (multiplet), br. (broad), coupling constant (in
Hz), and number of hydrogen atoms. The splitting patterns that
could not be clearly distinguished are designated as multiplets (m).
For 13C NMR, the chemical shifts are reported in ppm, and the
number of attached hydrogen atoms is provided. High resolution
mass spectrometry was performed using ESI ionization and a qua-
drupole TOF (QTOF) mass analyzer. Flash chromatography was
performed with 70–200 mesh silica gel. The starting salicylalde-
hydes were either commercially available or synthesized according
to published methods.[13]
(E)-2-[1-(2-Hydroxybenzylideneamino)-2-nitroethyl]phenol (5a): Fol-
lowing the general procedure and using salicylaldehyde (610 mg,
5 mmol) and nitromethane (1.8 mL, 25 mmol) for a reaction time
of 8 h gave imine 5a (586 mg, 82% yield); m.p. 135–138 °C
(CH2Cl2/MeOH). 1H NMR (200 MHz, CDCl3, 25 °C): δ = 4.89–
4.93 (m, 2 H), 5.46 (dd, J = 4, 8 Hz, 1 H), 6.80–6.96 (m, 4 H),
7.25–7.31 (m, 4 H), 8.44 (s, 1 H) ppm. 13C NMR (50 MHz, CDCl3,
25 °C): δ = 66.0 (CH), 79.0 (CH2), 115.9 (CH), 117.2 (CH), 118.6
(C), 119.3 (CH), 120.5 (CH), 123.5 (C), 128.3 (CH), 129.8 (CH),
132.4 (CH), 133.3 (CH), 154.2 (C), 160.9 (C), 162.7 (CH) ppm. IR
(Nujol): ν = 762, 1158, 1554, 1638 cm–1. HRMS (ESI-QTOF):
˜
calcd. for C15H14N2O4Na [M + Na]+ 309.0846; found 309.0853.
General Procedure for the Preparation of 2-Hydroxynitrostyrenes:
The corresponding aldehyde (1.0 mmol), nitromethane (2.4 g,
5.0 mmol), and acetic acid (1.7 mL, 3.4 mmol) were added drop-
wise into a two-necked round-bottomed flask that was equipped
with a thermometer and cooled with an ice bath. The resulting
mixture was stirred at 0 °C, and then pyrrolidine (0.6 mL,
2.9 mmol) was added dropwise by an addition funnel. The progress
(E)-Dimethyl 2-[(2-Hydroxybenzylideneamino)(2-hydroxyphenyl)-
methyl]malonate (5f): Following the general procedure and using
salicylaldehyde (610 mg, 5 mmol) and dimethyl malonate (3.3 g,
25 mmol) for a reaction time of 1.5 h gave compound 5f (714 mg,
80% yield); m.p. 182–185 °C (CH2Cl2/MeOH). 1H NMR
(200 MHz, CD3OD, 25 °C): δ = 3.61 (s, 3 H), 3.73 (s, 3 H), 4.48
(d, J = 10 Hz, 1 H), 5.36 (d, J = 10 Hz, 1 H), 6.75–6.99 (m, 5 H),
7.09–7.40 (m, 3 H), 8.41 (s, 1 H) ppm. 13C NMR (50 MHz,
CD3OD, 25 °C): δ = 52.8 (CH3), 53.1 (CH3), 57.4 (CH), 67.0 (CH),
117.4 (CH), 117.8 (CH), 118.5 (CH), 118.7 (CH), 121.1 (CH), 125.5
(C), 129.3 (CH), 129.8 (CH), 132.4 (CH), 133.5 (CH), 154.1 (C),
1
of the reaction was monitored by H NMR analysis of aliquots of
the reaction mixture. Upon completion, the crude mixture was
poured over water, and the solid product that precipitated was fil-
tered and then purified by recrystallization (methanol/diethyl ether
mixture). The physical and spectroscopic data of all the 2-hydroxy-
nitrostyrenes were identical to those reported.[6,13]
162.5 (C), 167.2 (CH), 168.3 (C), 168.4 (C) ppm. IR (Nujol): ν =
˜
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1612, 1729 cm–1. HRMS (ESI-QTOF): calcd. for C19H20NO6 [M +
CH2), 115.9 (C), 116.7 (CH), 118.2 (C), 118.7 (CH), 122.9 (CH),
125.9 (CH), 128.8 (CH), 129.2 (CH), 130.3 (CH), 132.8 (CH), 148.7
H]+ 358.1285; found 358.1285.
(C), 149.6 (C), 153.7 (C) ppm. IR (Nujol): ν = 749, 982, 1209, 1463,
˜
(E)-2-[(2-Hydroxybenzylideneamino)(2-hydroxyphenyl)methyl]-1,3-
diphenylpropane-1,3-dione (5g): Following the general procedure
but reducing the molar ratio of nucleophile/aldehyde from 5:1 to
2:1 and using salicylaldehyde (610 mg, 5 mmol) and dibenzoyl
methane (2.2 g, 10 mmol) for a reaction time of 3 h gave imine 5g
(842 mg, 75% yield); m.p. 145–147 °C (diethyl ether/MeOH). 1H
NMR (200 MHz, [D6]DMSO, 25 °C): δ = 5.75 (d, J = 10 Hz, 1 H),
6.58–7.11 (m, 6 H), 7.11–7.66 (m, 9 H), 7.94 (d, J = 8 Hz, 2 H),
8.07 (d, J = 8 Hz, 2 H), 8.52 (s, 1 H), 9.88 (s, 1 H), 12.97 (s, 1
H) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 59.4 (CH),
69.0 (CH), 116.3 (CH), 117.0 (CH), 119.2 (2 CH), 119.7 (CH),
126.3 (CH), 129.0 (2 CH), 129.4 (3 CH), 129.5 (2 CH), 129.6 (2
CH), 129.9 (CH), 132.6 (CH), 133.2 (CH), 134.4 (CH), 134.5 (CH),
136.7 (C), 137.3 (C), 155.6 (C), 160.8 (C), 166.4 (CH), 193.7 (C),
1560, 1741 cm–1. HRMS (ESI-QTOF): calcd. for C16H13N2O5 [M
+ H]+ 313.0819; found 313.0819.
Dimethyl 2-(6-Oxo-8,13a-dihydro-6H-benzo[e]benzo[5,6][1,3]oxaz-
ino[4,3-b][1,3]oxazin-8-yl)malonate (10f): Following the general pro-
cedure and using imine 5f (410 mg, 1.1 mmol) for a reaction time
of 2.5 h gave benzoxazine 10f (352 mg, 80% yield): m.p. 130–132 °C
(CHCl3/diethyl ether). 1H NMR (200 MHz, CDCl3, 25 °C): δ =
3.69 (s, 3 H), 3.74 (s, 3 H), 4.19 (d, J = 8 Hz, 1 H), 6.27 (d, J =
8 Hz, 1 H), 6.56 (s, 1 H), 6.87–7.04 (m, 2 H), 7.08–7.33 (m, 4 H),
7.41–7.57 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ =
52.1 (CH), 53.2 (CH3), 53.3 (CH3), 57.9 (CH), 78.7 (CH), 115.3
(C), 116.6 (CH), 118.0 (CH), 120.3 (C), 122.5 (CH), 125.2 (CH),
127.3 (CH), 128.2 (CH), 129.7 (CH), 131.9 (CH), 148.4 (C), 149.2
195.6 (C) ppm. IR (Nujol): ν = 762, 1015, 1638, 1690 cm–1. HRMS
˜
(C), 152.8 (C), 167.1 (C), 167.3 (C) ppm. IR (Nujol): ν = 755, 970,
˜
(ESI-QTOF): calcd. for C29H24NO4 [M + H]+ 450.1700; found
450.1704.
1216, 1599, 1748 cm–1. HRMS (ESI-QTOF): calcd. for C20H18NO7
[M + H]+ 384.1078; found 384.1075.
2-[Amino(2-hydroxyphenyl)methyl]malononitrile (8): Following the
general procedure but reducing the molar ratio of the nucleophile/
aldehyde from 5:1 to 2:1 and using salicylaldehyde (610 mg,
5 mmol) and malononitrile (660 mg, 10 mmol) for a reaction time
of 2 h gave compound 8 (768 mg, 82% yield) as a pale brown solid;
2-(6-Oxo-8,13a-dihydro-6H-benzo[e]benzo[5,6][1,3]oxazino[4,3-b]-
[1,3]oxazin-8-yl)-1,3-diphenylpropane-1,3-dione (10g): Following the
general procedure and using imine 5g (400 mg, 0.9 mmol) for a
reaction time of 2 h gave benzoxazine 10g (322 mg, 76% yield);
m.p. 120–122 °C (CHCl3/EtOH). 1H NMR (200 MHz, CDCl3,
25 °C): δ = 6.05 (d, J = 8 Hz, 1 H), 6.52 (s, 1 H), 6.80–7.05 (m, 4
H), 7.13–7.25 (m, 3 H), 7.29–7.62 (m, 8 H), 7.92–8.06 (t, J = 8 Hz,
4 H) ppm. 13C NMR (50 MHz, CDCl3, 25 °C): δ = 52.6 (CH), 64.7
(CH), 79.1 (CH), 115.2 (C), 116.5 (CH), 118.0 (CH), 122.6 (C),
125.0 (CH), 127.5 (CH), 128.0 (CH), 129.0 (5 CH), 129.1 (2 CH),
129.2 (2 CH), 129.4 (CH), 131.7 (CH), 134.2 (CH), 134.3 (CH),
136.1 (C), 136.8 (C), 148.5 (C), 149.2 (C), 152.6 (C), 193.4 (C),
1
m.p. 147–150 °C (CH2Cl2/MeOH). H NMR (200 MHz, CD3OD,
25 °C): δ = 4.13 (d, J = 4 Hz, 1 H), 4.25 (d, J = 4 Hz, 1 H), 7.07
(d, J = 8 Hz, 1 H), 7.20 (t, J = 8 Hz, 1 H), 7.34 (d, J = 8 Hz, 1 H),
7.39 (t, J = 8 Hz, 1 H) ppm. 13C NMR (50 MHz, CD3OD, 25 °C):
δ = 38.4 (2 CH), 116.7 (CH), 117.7 (C), 119.3 (C), 125.2 (CH),
128.7 (CH), 130.2 (CH), 150.4 (C), 164.4 (C) ppm. IR (Nujol): ν =
˜
1268, 1366, 1456, 2196, 3345 3442 cm–1. HRMS (ESI-QTOF):
calcd. for C10H6N2O [M – 17]+ 171.0553; found 171.0555.
193.7 (C) ppm. IR (Nujol): ν = 756, 996, 1216, 1599, 1723 cm–1.
˜
HRMS (ESI-QTOF): calcd. for C30H21NO5Na [M
498.1312; found 498.1315.
+
Na]+
2-Oxo-2H-chromene-3-carboxylic Acid (9): Following the general
procedure but reducing the molar ratio of the nucleophile/aldehyde
from 5:1 to 2:1 and using salicylaldehyde (610 mg, 5 mmol) and
Meldrum’s acid (1.4 g, 10 mmol) for a reaction time of 2 h gave
compound 9 (840 mg, 89% yield) as a brown solid. Its physical and
spectroscopic properties were identical to those described in the
literature.[15]
Supporting Information (see footnote on the first page of this arti-
cle): 1H NMR spectra of compounds 4a–4d, 5a, 5f, 5g, 7g (mixture
with 5g), 8, 9, 10a, 10f, and 10g; 13C NMR, IR, and MS spectra
of compounds 5a, 5f, 5g, 8, 10a, 10f, and 10g; Cartesian coordi-
nates of the optimized structures; and details regarding how the
temperature affects the appearance of product 4.
General Procedure for the Preparation of Benzoxazines: Caution!
Because the toxic gas phosgene is employed in this preparation, the
reaction should be performed in an efficient hood. The glassware
may be coated with a solution of phosgene and should, therefore,
be washed with ethanol containing ammonia before removing from
the hood. The corresponding imine (1.0 mmol) was dissolved in
anhydrous THF (5.0 mL) in a two-necked round-bottomed flask
that was equipped with a thermometer, and the solution was cooled
to –80 °C. Phosgene [20% solution in toluene, 2.1 mL, 4.0 mmol]
was then added, and the reaction mixture was warmed to room
temperature. The progress of the reaction was monitored by 1H
NMR analysis of aliquots of the reaction mixture. Upon comple-
tion, the solvent was removed under reduced pressure, and the
crude product was purified by crystallization.
Acknowledgments
Financial support of this work from the Junta de Castilla y León
(SA223A11-2) and the University of Salamanca is gratefully ac-
knowledged. The authors thank the mass spectrometry service and
X-ray diffraction service of the NUCLEUS Platform of the Univer-
sity of Salamanca. The authors also thank the Ministry of Educa-
tion of Spain for the grant to A. L. F. A., Dr. César Raposo is
thanked for the mass spectra and useful advice, and Dr. Victoria
Alcázar is thanked for her kind help.
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6
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Job/Unit: O42016
/KAP1
Date: 21-03-14 10:31:46
Pages: 8
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Received: January 15, 2014
Published Online: ᭿
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7

Job/Unit: O42016
/KAP1
Date: 21-03-14 10:31:46
Pages: 8
L. Simón, J. R. Morán et al.
FULL PAPER
Heterocyclic Chemistry
V. Tena Pérez, Á. L. Fuentes de Arriba,
L. M. Monleón, L. Simón,* O. H. Rubio,
F. Sanz, J. R. Morán* ....................... 1–8
A High Yield Procedure for the Prepara-
tion of 2-Hydroxynitrostyrenes: Synthesis
of Imines and Tetracyclic 1,3-Benzoxazines
Keywords: Synthetic methods / Hetero-
cycles / Schiff bases / Nucleophilic ad-
dition / Elimination
The reaction of salicylaldehyde, nitrometh-
ane, and ammonium acetate yields a sur-
prisingly stable imine, which hinders the
synthesis of 2-hydroxynitrostyrene. Herein,
we present a procedure to overcome this
drawback and report the reaction of this
stable imine with phosgene to afford
benzoxazines in good yields.
8
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