A new and efficient one-pot synthesis of 2-hydroxy-1,4-dihydrobenzoxazines via a three-component Petasis reaction

Article abstract of DOI:10.1016/j.tetlet.2014.07.093

The secondary amines synthesized by the reaction between 2-aminophenols and aromatic aldehydes, via the reduction of the corresponding imines, were employed in the synthesis of new 2-hydroxy-2H-1,4-benzoxazine derivatives through a one-pot Petasis multico

Full text of DOI:10.1016/j.tetlet.2014.07.093

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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A new and efficient one-pot synthesis of 2-hydroxy-1,
4-dihydrobenzoxazines via a three-component Petasis reaction
Louisa Chouguiat a, Raouf Boulcina a, Bertrand Carboni b, Albert Demonceau c, Abdelmadjid Debache a,
⇑
a Laboratoire de Synthèse des Molécules d’intérêts Biologiques, Université Constantine 1, 25000 Constantine, Algeria
b Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite´ Rennes 1, Campus de Beaulieu, 35042 Rennes CEDEX, France
c Laboratoire de Chimie Macromoléculaire et de Catalyse Organique, Université de Liège, 4000 Liège, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The secondary amines synthesized by the reaction between 2-aminophenols and aromatic aldehydes, via
the reduction of the corresponding imines, were employed in the synthesis of new 2-hydroxy-2H-1,
4-benzoxazine derivatives through a one-pot Petasis multicomponent reaction in good to excellent
yields.
Received 7 March 2014
Revised 3 June 2014
Accepted 23 July 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2-Hydroxy-2H-1,4-benzoxazine
Petasis reaction
Secondary amines
Multicomponent reaction
Multicomponent reactions are highly efficient and atom
-economic transformations in synthetic organic chemistry.1 They
can be used for constructing an array of compound libraries in
the medicinal chemistry field.
solvents, usually CH2Cl2, toluene, alcohols such as methanol or
hexafluoroisopropanol, and also in water.6f
Additionally, the 1,4-benzoxazine7 moiety is an integral part of
several naturally occurring substances. For example, various glyco-
sides of the 2-hydroxy-2H-1,4-benzoxazine skeleton have been
found to occur in graminaceous plants such as maize, wheat, rye,
and rice, and have been suggested to act as plant resistance factors
against microbial diseases and insects.8 The 1,4-benzoxazine moi-
ety was also found in various antibiotics such as C-1027.9
Generally, 1,4-benzoxazine compounds were usually synthe-
sized via a multistep process, such as the cyclocondensation of
o-aminophenols with suitable dihalo derivatives,10 cyclocondensa-
The Petasis reaction (the application of a boronic acid nucleo-
phile in the Mannich reaction) has received increasing attention
due to its utility as a powerful and convenient method for the syn-
thesis of functionalized amine derivatives,2 such as
a-amino car-
boxylic acids and derivatives,3 b-amino alcohols,4 allyl amines,5
and various heterocyclic compounds,6 while new applications con-
tinue to be developed.7
This one-step, three-component reaction involves coupling of an
amine, an organoboronic acid, and a carbonyl compound function-
alized at the a-position to give the corresponding amine derivative
in a short and experimentally simple process. Along with the acces-
sibility of reagents and mild reaction conditions, this approach is an
attractive alternative to other methodologies.
A large variety of alkenyl, aryl, and heteroaryl boronic acids,
various primary and secondary amine derivatives (e.g., diamines,
N-hydroxylamines, N-sulfinyl amines, hydrazines), and functional-
tion of o-aminophenols with
carbonyl group reduction with BH3,11 and alkylation of o-nitrophe-
nol with an
-haloaldehyde followed by reductive cyclization.12
a-halo-acyl bromides followed by
a
Alternatively, these 1,4-benzoxazine moieties can be prepared via
ring-opening of an epoxide with o-halosulfonamides followed by
cyclization,13 or by ring-opening of an epoxide with o-aminophe-
nols followed by cyclocondensation.14
As part of our ongoing research on multicomponent reactions,15
we have developed, a new alternative route to the conventional
multistep synthesis of 2-hydroxy-1,4-benzoxazines via a Petasis
multicomponent reaction (Scheme 1).
ized carbonyl compounds (e.g.,
a-keto acids and a-hydroxy alde-
hydes) have been shown to participate in this reaction with
success.2 The reaction can be carried out in many different
The proposed strategy involves the use of 2-(benzylamino)
phenols 4 as reactants. They were prepared in high yields by con-
densation of substituted 2-aminophenols 1 and benzaldehydes 2
followed by reduction in a one-pot process. These key intermediates
⇑
Corresponding author. Tel./fax: +213 31 81 88 62.
E-mail address: a_debache@yahoo.fr (A. Debache).
http://dx.doi.org/10.1016/j.tetlet.2014.07.093
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chouguiat, L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.093

2
L. Chouguiat et al. / Tetrahedron Letters xxx (2014) xxx–xxx
R3
desired secondary amine 4a in very high yield. This process was
R2
H
R4
generalized to synthesize various substituted amines as shown in
Table 1. Most of the reactions were found to proceed cleanly to give
60–90% yields of the products. The time taken for the completion
of the reactions varied between 18 and 24 h (Scheme 2).
Our investigations on the Petasis process identified dichloro-
methane at room temperature as the optimum medium for the
reaction of 2-(4-methoxybenzylamino)-4-methylphenol (4b) with
phenylboronic acid (5a) and glyoxal (6). These conditions provided
useful yields and reasonable reaction times. Further, we observed
improved results by employing methanol as the solvent, resulting
in a yield of 89% of the desired 1,4-benzoxazine 7b (Table 2, entry
2). Despite the relatively long reaction times proving to be a limi-
tation of room temperature processes, high yields of the desired
product were achieved (Scheme 3).
On the basis of these results, we have explored the substrate
scope and limitations. A series of diverse 1,4-benzoxazines bearing
different substitution patterns 7a–i were prepared in moderate to
excellent yields by reactions of aryl boronic acids 5 with 2-(arylm-
ethylamino)phenols 4a–f and glyoxal (6), and the results are listed
in Table 2.16 It was observed that the reactions of phenylboronic
acid furnished the products in higher yields than those with 4-
methylphenylboronic acid.
O
R3
R4
R1
R2
N
OH
B
two steps
R5
R1
NH2
OH
OH
+
R5
H
O
OH
O
H
major
O
Scheme 1.
subsequently reacted with aryl boronic acids 5 and glyoxal 6 in
methanol at ambient temperature to afford the target compounds
7 in good yields.
We began our research by preparing secondary amines 4.
Indeed, 2-(4-methoxybenzylamino)phenol (4a) was obtained from
the condensation of 2-aminophenol (1a) (1 equiv) with benzalde-
hyde (2a) (1 equiv) in dry methanol or dichloromethane at room
temperature. The reaction proceeded smoothly and provided, after
24 h, an excellent yield of the corresponding imine (3a). The
addition of an excess of NaBH3CN and stirring the mixture for
24 h at ambient temperature resulted in the formation of the
The scope of the reaction with regard to the secondary amines
was also explored. Electron-donating substituents underwent the
Table 1
Synthesis of 2-(arylmethylamino)phenols 4a
Entry
R1
R2
R3
H
R4
2-(Arylmethylamino)phenol
Yieldb (%)
M.p. (°C)
OCH3
H
N
1
H
H
OCH3
83
104-106
OH
4a
OCH3
H
H3C
N
2
3
4
5
CH3
H
H
H
H
H
OCH3
OCH3
Br
84
60
90
75
136-138
148-150
86-90
OH
4b
OCH3
H
N
Cl
Cl
H
OH
4c
Br
H
N
H3C
CH3
H
OH
4d
O2N
H
N
H
NO2
H
90-92
OH
4e
NO2
H
N
H3C
6
CH3
H
NO2
H
95
120-122
OH
4f
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), MeOH (5 ml), rt, 24 h, then NaBH3CN (3 mmol) was added and stirring was continued for 24 h.
Isolated yields.
b
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L. Chouguiat et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
R3
R3
R3
R2
R4
R2
R4
R2
H
R4
R1
NH2
OH
H
N
MeOH, r. t.
24 h
R1
R1
N
NaBH3CN
+
O
MeOH, r. t.
24 h
OH
OH
1
4
2
3
Scheme 2.
Table 2
The Petasis reaction of secondary amines 4, aryl boronic acids 5, and glyoxal (6)a
Entry
Secondary amine
R5
1,4-Benzoxazine
Mp (°C)
Yieldb (%)
drc
H3CO
CH3
N
1
4a
CH3
Oil
76
95:5
O
OH
OH
7a
H3CO
H3C
N
O
2
3
4b
4c
H
H
Oil
Oil
89
70
86:14
88:12
7b
7c
H3CO
Cl
N
O
OH
Br
H3C
N
O
4
5
4d
4d
H
131–132
132–134
72
86
90:10
97:3
OH
7d
Br
CH3
CH3
H3C
N
O
OH
7e
NO2
N
O
6
7
4e
4e
H
170–171
141–143
56
46
83:17
90:10
OH
7f
NO2
CH3
N
CH3
O
OH
7g
NO2
8
9
4f
4f
H
125–127
160–162
64
38
85:15
95:5
H3C
H3C
N
O
OH
OH
7h
NO2
CH3
CH3
N
O
7i
a
b
c
Reactions conditions: 4 (1 mmol), 5 (1 mmol), (6) (1 mmol), MeOH (5 ml), rt, 24 h.
Isolated yields.
Determined by 1H NMR spectroscopy.
Please cite this article in press as: Chouguiat, L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.093

4
L. Chouguiat et al. / Tetrahedron Letters xxx (2014) xxx–xxx
R3
R3
R2
R4
R4
R2
Ha
OH
B
H
N
R1
Hb
3
R5
OH
MeOH, r.t.
24 h
+
R5
R1
N
O
OH
O
5
major
H
4
OH
2
H
O
7
6
Scheme 3.
transfer of the aryl group to generate the cis 2-hydroxy-1,4-benzox-
azines 7. Equilibration of the hemiacetal after this intramolecular
delivery affords the trans isomer.
In summary, we have developed a new and general approach
for the library synthesis of 1,4-benzoxazine derivatives via Petasis
reactions of easily available 2-(arylmethylamino)phenols with gly-
oxal and various boronic acids without any catalyst. Our method
allows access to a wide range of 2-hydroxy-1,4-benzoxazines,
which may be useful compounds for medicinal and materials
chemistry. Simple substrates and operational simplicity are signif-
icant advantages of this procedure. Further investigations regard-
ing the exact mechanism of this Petasis condensation and the
further transformations of these heterocycles are currently in
progress.
Acknowledgments
Figure 1. X-ray crystal structure (ORTEP) of compound 7f (CCDC 1012140). Crystal
data:C21H18N2O4, Mr = 362.37; orthorhombic, Pna21; Hall symbol:
P 2c–2n;
a = 12.7332 (14) Å; b = 14.2777 (14) Å; c = 19.003 (2) Å; V = 3454.8 (6) Å3, Z = 8.
The authors gratefully acknowledge le Ministère de l’Enseigne-
ment Supérieur et de la Recherché Scientifique (Algeria) for the
financial support of this research program.
reaction to give the highest yields (Table 2, entries 1–3). The pres-
ence of an electron-withdrawing bromine group led to slightly
higher yields (entries 4 and 5), however, the yields were lower
when a nitro group was present (entries 6–9). As outlined in
Table 2, all these compounds were obtained as mixtures of diaste-
reoisomers with the ratio depending on substituents at different
positions of the 1,4-benzoxazine core. The assignment of a relative
trans configuration for the major isomer was secured by X-ray
crystallographic analysis of 7f, the hydroxyl group being in an axial
position in the solid state (Fig. 1).17
Considering previous studies on the borono-Mannich reaction
with glyoxal,6d,18 a plausible pathway for the formation of compound
7 is proposed in Scheme 4. This involves an initial condensation of
2-(arylmethylamino)phenols 4 with glyoxal (6) to give a cyclic imin-
ium intermediate 8. The coordination between the hydroxyl function
of this species and the boron atom of 5 leads to the formation of a tet-
racoordinate boron intermediate 9 that undergoes an irreversible
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.07.
093.
References and notes
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N
H
Ar
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R1
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B
+
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OH
OH
OH
H
O
O
H
9
8
O
6
Ar
Ar
R1
N
O
Ar'
OH
R1
N
Ar'
OH
O
7
Scheme 4.
Please cite this article in press as: Chouguiat, L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.093

L. Chouguiat et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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complete, the mixture was poured into ice water. The resulting precipitate was
filtered, washed with H2O, and dried. The resulting amine was obtained in very
high purity and in excellent yield.
2-(4-Methoxybenzylamino)phenol (4a): IR (KBr): 3333; 1601 cmÀ1 1H NMR
.
8. Niemeyer, H. M. Phytochemistry 1988, 27, 3349.
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(250 MHz, DMSO-d6) d: 9.34 (s,1H, NH); 7.27 (d, 2H, J = 7.9 Hz, CH arom.); 6.87
(d, 2H, J = 7.9 Hz, CH arom.); 6.67 (d, 1H, J = 7.1 Hz, CH arom.); 6.56 (t, 1H,
J = 7.1 Hz, CH arom.); 6.40 (d, 2H, J = 7.1 Hz, CH arom.); 5.17 (s, 1H, OH); 4.20 (s,
2H, CH2); 3.71 (s, 3H, OCH3). 13C NMR (63 MHz, DMSO-d6) d: 158.4; 144.5;
137.6; 132.7; 128.8; 120.0; 116.2; 114.1; 113.7; 110.6; 55.4; 46.4.
Typical experimental procedure for the synthesis of 1,4-benzoxazine derivatives 7: A
mixture of 2-(arylmethylamino)phenol 4 (1 mmol), boronic acid 5 (1 mmol),
and glyoxal (6) (1 mmol) in MeOH (5 mL) was stirred at room temperature for
24 h. The solvent was removed in vacuo to give crude product 7, which was
purified by flash chromatography (silica gel, CH2Cl2). Spectroscopic data for the
major isomer of 4-(2-nitrobenzyl)-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]
12. Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.; Yoden, T.; Uchida, W.;
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16. Typical experimental procedure for the synthesis of 2-(arylamino)phenols 4: A
mixture of 2-aminophenol derivative (1) (3 mmol) and aromatic aldehyde (2)
(3 mmol) in MeOH (10 ml) was stirred at room temperature for 24 h (monitored
by TLC). After formation of the imine 3, NaBH3CN (9 mmol) and HCl (a few
drops) were added and stirring was continued for 24 h. After the reaction was
oxazin-2-ol (7f): IR (KBr): 3429, 2920, 1608, 1512, 1250, 1036 cmÀ1 1H NMR
.
(250 MHz, CDCl3) d: 8.09 (d, 1H, J = 7.5 Hz, CH arom); 7.91 (d, 1H, J = 7.5 Hz, CH
arom.); 7.56 (t, 1H, J = 7.5 Hz, CH arom.); 7.42 (t, 1H, J = 7.5 Hz, CH arom); 7.33–
7.30 (m, 3H, CH arom.); 7.21–7.18 (m, 2H, CH arom.); 6.92–6.83 (m, 2H, H
arom.); 6.74–6.67 (m, 1H, CH arom.); 6.45 (d, 1H, J = 7.5 Hz, CH arom.); 5.60 (br
s, 1H, H2); 5.06 (d, 1H, J = 18.5 Hz, Hb); 4.62 (d, 1H, J = 18.5 Hz, Ha); 4.51 (br s, 1H,
H3); 3.26 (s, 1H, OH). 13C NMR (62.9 MHz, CDCl3) d: 148.1; 141.1; 139.7; 138.3;
134.1; 134.0; 133.7; 129.0; 130.0; 128.3; 128.0; 126.9; 125.3; 122.9; 117.9;
117.5; 110.6; 92.7; 64.3; 50.2. HRMS: (M+H)+, found 363.1352, C21H19N2O4
requires 363.1346.
17. Chouguiat, L.; Boulcina, R.; Bouacida, S.; Merazig, H.; Debache, A. Acta
Crystallogr. Sect. E 2014, 70, 0863.
18. Schlienger, N.; Bryce, M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023.
Please cite this article in press as: Chouguiat, L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.093