Chapter 1
Various Synthetic Methods
of Benzoxazine Monomers
S. Ohashi and H. Ishida1
Case Western Reserve University, Cleveland, OH, United States
1
Corresponding author: e-mail: hxi3@cwru.edu
Chapter Outline
1 Introduction
2 Various Synthetic Methods Used for Benzoxazine
Synthesis
2.1 Mannich-Condensation Based Benzoxazine
Synthesis
2.2 Benzoxazine Synthesis via Cycloaddition
1 INTRODUCTION
Ever since Holly and Cope presented the first paper on the
synthesis of a heterocyclic compound termed benzoxazine
in 1944 [1], many papers on this class of compounds have
been published. Although there are several benzoxazine
isomers (depending on the position of the oxygen and
nitrogen in the oxazine ring) the discussion in this chapter
will be restricted to the 1,3-benzoxazines because these
are the compounds exclusively used for polymerization.
2 VARIOUS SYNTHETIC METHODS USED
FOR BENZOXAZINE SYNTHESIS
2.1 Mannich-Condensation Based
Benzoxazine Synthesis
For the first synthesis of a benzoxazine monomer, Holly and
Cope reported the benzoxazine resulting from the reaction
of ortho-hydrorybenzylamine with formaldehyde or other
aldehydes in water/benzene solvent (Scheme 1). It was the
first benzoxazine synthesis that utilized the Mannich con-
densation reaction of amine and aldehyde [1]. Mannich con-
densation involves an amino alkylation of an acidic proton
(eg, a proton at a-carbon of aldehyde and ketone, a proton
of phenols, heterocyclic compounds, and acetylenes etc.)
by formaldehyde and an amine having active protons.
Advanced and Emerging Polybenzoxazine Science and Technology. http://dx.doi.org/10.1016/B978-0-12-804170-3.00001-9
Copyright © 2017 Elsevier Inc. All rights reserved.
3 2.3 Other Reactions for Benzoxazine Synthesis 6
2.4 Benzoxazine Synthesis With Alternative Energy
3 Sources 6
2.5 Synthesis of Naphthoxazine, Benzoxazine
3 Analogue 7
6 3 Conclusion 7
2.1.1 One-pot Benzoxazine Synthesis
In 1949, Burke suggested a new and simple preparation
method for benzoxazine synthesis, which was a one-pot
reaction of three main components, phenol, amine, and
formaldehyde in 1:1:2 molar ratio as shown in Scheme 2
[2]. This method has been generalized as polybenzoxazine
and has been universally studied during the last 20 years
because of its simplicity and diversity of substituents on
both phenol and amine. For example, alkenyl [3], halogenic
[4,5], nitro [5], aldehyde [5,6], cyano [7], carboxyl [8], mal-
eimide [9] groups etc. can be adopted onto benzene of ben-
zoxazine by using functional phenols. Both alkyl and aryl
amine also produce a large variety of functional benzoxa-
zines. Furthermore, in the use of bisphenol and/or diamine
compounds, bifunctional or main-chain polymeric benzox-
azines can be obtained, from which polymers with typically
higher thermal and mechanical properties than polymerized
monofunctional benzoxazines can be derived [10]. As
another advantage of this method, solvent-less synthesis
can be utilized in the melt state [11]. It avoids the solvent
residue that may cause serious defects during processing,
saves the solvent and its recovery cost, and there is no
concern about the solubility of raw materials in organic
solvent.
As advanced processes of one-pot synthesis, there are
several examples that utilized the reactive precursors
instead of simply using primary amines and formaldehyde.
3
4 PART I Synthesis and Properties of Benzoxazine Resins

NH2 O NH

OH R R⬘ O R
R⬘

R, R⬘ : H, Me, n-Pr, n-Bu, n-Hex, Ph

SCHEME 1 First synthesis of benzoxazine with o-hydroxybenzylamine.

H2N O N
OH H H O
SCHEME 2 First one-pot Mannich condensation synthesis of benzoxazine.

In 1961, Burke et al. introduced hydroquinone-based bifunc-
tional benzoxazine synthesis with 1,3,5-hexahydrotriazine
formed by formaldehyde and benzylamine (Scheme 3;
[12]). Afterwards, Ishida et al. generalized this method with
the proposed mechanism as shown in Scheme 3 as the active
intermediate [13].
Additionally, another precursor was reported for ben-
zoxazine synthesis around the same time as the proposed
one-pot, three-component synthesis by Burke et al. via
1,3,5-hexahydrotriazine. Bis(alkoxymethyl)alkylamine,
which can be synthesized with alkyl amine, alcohol, and
formaldehyde, was first used for benzoxazine synthesis in
1962 as shown in Scheme 4 [14].
These methods cannot be used in the presence of a
primary amine, and differ from the simple, one-pot Mannich
condensation synthesis of benzoxazine. Thus, these methods
were adapted in cases where reactive phenolic compounds,
such as hydroxybenzaldehyde and hydroxybenzoic acid,
are used with a primary amine, allowing for the expansion
of the applicability of a one-pot benzoxazine synthesis to a
broader selection of compounds.
2.1.2 Benzoxazine Synthesis via
Ortho-Hydroxybenzylamine Structure
As shown in Scheme 5, the difunctional benzoxazine was
prepared with bis(ortho-hydrorybenzylamino)ethane and
formaldehyde by Billman and Dorman in 1963 [15]. This
N-substituted ortho-hydroxybenzylamine has been widely
used as a precursor to synthesize benzoxazine although it
includes multiple reaction processes. Generally, this ortho-
hydroxybenzylamine has been obtained with high yield by
the reduction of a Schiff base made of ortho-hydroxy benz-
aldehyde (salicylaldehyde) and primary amine [16,17]. The
notable advantage of this synthesis is the flexible substitution
of functional groups on the oxazine ring. For example, a

O
N
OH N
O
N O
N N H H

OH O O

N N

SCHEME 3 Benzoxazine synthesis with 1,3,5-hexahydrotriazine.

O
N
i-C4H9 OH N
O
O
N
O
i-C4H9
OH O O

N N

SCHEME 4 Benzoxazine synthesis with bis(alkoxymethyl)alkylamine.

 Various Synthetic Methods of Benzoxazine Monomers Chapter 1 5

OH O
H O
N N
N N
H H H
HO O
SCHEME 5 N-substituted benzoxazine synthesis via ortho-hydroxybenzylamine.

O
O P O O O
H P H H P
O O
N
N N
OH H
OH O
SCHEME 6 DOPO-containing benzoxazine synthesis via ortho-hydroxybenzylamine.

O By simply adding substituents on ortho-hydroxyben-

R R
N R⬘ H N
H tures can be made, as is the case with one-pot Mannich
OH O R⬘
R: Me, t-Bu, Ar
R⬘: Me, Ar
SCHEME 7 Oxazine ring closure with aldehyde compounds.
nucleophilic attack of DOPO (9,10-dihydro-9-oxa-10-
phosphenanthrene-10-oxide) to imino carbon can lead to
DOPO-containing ortho-hydroxybenzylamine, which was
reported as a precursor of flame retardant benzoxazines
(Scheme 6; [18]). The Betti reaction with phenol, primary
amine and benzaldehyde is also available to synthesize
ortho-hydroxybenzylamine, which is a precursor for phenyl
group substituted benzoxazine [19]. As shown in
Scheme 7, another substitution on the oxazine ring can be
achieved by the ring closure of ortho-hydroxybenzaldehyde
with various aldehyde compounds instead of formaldehyde
and regardless of the aldehyde being aliphatic or aromatic
[20]. Additionally, the oxazine ring can be closed by the
reaction of ortho-hydroxybenzaldehyde with not only alde-
hydes but with methylene bromide also [21].
zaldehyde and amine, a huge variety of benzoxazine struc-
condensation synthesis. Furthermore, this method enhances
the availability of benzoxazine synthesis because its intra-
molecular cyclization allows the reaction condition to mod-
erate, which minimizes side reactions caused by high
temperature. The one-pot Mannich condensation method
sometimes requires relatively high temperature to close
the oxazine ring.
2.1.3 Polycyclic Benzoxazine Synthesis via N,
O-Acetal Forming Reaction
Polycyclic benzoxazine is one of the unique benzoxazine
structures and was reported as an intriguing compound for
pharmaceutical usage. Differing in the starting materials
for normal Mannich condensation benzoxazine synthesis,
the reaction of cyclic secondary amines and salicylaldehyde
or its derivatives resulted in a fused-ring benzoxazine through
N,O-acetal intermediate (Scheme 8; [22]). The uniqueness of
the structure and its synthetic method expand a variety of
benzoxazine compounds, which are expected to possess
remarkable properties in a monomer and/or its polymer form.

H HN N

OH O
SCHEME 8 Polycyclic benzoxazine synthesis with salicylaldehyde and 1,2,3,4-tetrahydroisoquinoline.

Ts
N EtO2C CO2Et
CO2Et
TsHN
Brønsted acid NH
EtO2C N
O Ar
Ar
O
SCHEME 9 [3 + 3] Cycloaddition of azomthine ylide with quinone monoimine.
6 PART I Synthesis and Properties of Benzoxazine Resins

N N

O O
SCHEME 10 Diels-Alder reaction of ortho-quinone methide with benzylmethyleneamine.

OH
OH O N t-Bu
O N
t-Bu (CH2)6N4 t-Bu
t-Bu

t-Bu
t-Bu t-Bu
t-Bu
SCHEME 11 Benzoxazine synthesis via a Duff reaction with hexamethylenetetramine.

2.2 Benzoxazine Synthesis via
Cycloaddition
Benzoxazine structure can also be comprised of cycload-
dition. In the presence of Brønsted acid at room temperature,
benzoxazine structure was produced by the [3 + 3] cycload-
dition of quinone monoimine and azomethine ylide in high
yield (Scheme 9; [23]). Another benzoxazine synthesis via
cycloaddition is [4 + 2] Diels-Alder reaction of a short-lived
intermediate, ortho-quinone methide, with benzylmethyle-
neamine (Scheme 10; [24]). While this cycloaddition method
is less common than other synthetic methods, due to the com-
plexity of the reactants compatibility, nonetheless, it con-
tributes to the diversity of the benzoxazine structure.
2.3 Other Reactions for Benzoxazine
Synthesis
Other synthetic methods for benzoxazines have also been
exploited as benzoxazine chemistry and its application is
becoming more popular in the pharmaceutical, biological,
H room temperature as opposed to the normal condition for
OH N N K2CO3
OH N O
X
X: Cl or Br
SCHEME 12 Benzoxazine synthesis with halogenated triazole.
and polymer chemistry fields. For example, a Duff reaction
with phenol and hexamethylenetetramine (Scheme 11;
[25]), the reaction of halogenated triazole with salicylal-
cohol (Scheme 12; [26]), and the cyclization of methyl-
ortho-tolyl ether with a primary amine (Scheme 13; [27])
are utilized for benzoxazine synthesis, though they are not
generally used.
2.4 Benzoxazine Synthesis With Alternative
Energy Sources
In benzoxazine synthesis, alternative methods of heating are
used and are reported to be more efficient than the conven-
tional heating method. Those alternative energy application
methods include ultrasound and microwave irradiation, and
mechanical grinding. The most serious concern of original
benzoxazine synthesis is the side reaction during heating at
elevated temperature. However, these alternative methods
can prevent the side reaction by reacting in ambient condi-
tions or by shortening the reaction time. For example, as
shown in Scheme 14, linear aliphatic ether linked benzox-
azine can be synthesized under ultrasound irradiation at
N N
conventional heating was 65°C for 5 h [28]. Microwave
N irradiation can dramatically shorten the reaction time. An
example reported for the reaction shown in Scheme 15
allowed for the shortening of the reaction from a range of

R
Br N
R NH2
O Cl O

R : i-Pr, t-Bu, Cyclohexyl

SCHEME 13 Benzoxazine synthesis with halogenated methyl-ortho-tolyl ether.

OH O O O O
O Ultrasound n
n
H2N NH2 H H RT, 2.5 h N N

O O
SCHEME 14 Ultrasound assisted benzoxazine synthesis.
 Various Synthetic Methods of Benzoxazine Monomers Chapter 1 7

OH
O Microwave O
H2N NH2 N N
H H 4 min O

SCHEME 15 Microwave assisted benzoxazine synthesis.

SCHEME 16 Synthesis of oxazine ring-substituted benzoxazines via mechanical grinding.

R1
R2 N R2
OH O
R1 NH2 2 O
R2 H

R1: H, alkyl, aryl

R2: H, alkyl, aryl
SCHEME 17 Synthesis of naphthoxazine.

several hours to a few days by heating alone, to several
minutes through microwave synthesis [29].
Although mechanical grinding was not applied to 1,3-
benzoxazine synthesis, it was successfully applied to 3,1-
benzoxazine synthesis at room temperature using acetic
acid as a catalyst as shown in Scheme 16 [30]. This method
resulted in remarkably high yield in short reaction times at
room temperature. Thus, there is high likelihood that this
approach is also applicable for 1,3-benzoxazine synthesis.
of naphthoxazine can be minimized during the reaction.
Actually, the economically beneficial synthesis, such as
room temperature synthesis and the reaction in aqueous
solvents, have been introduced [39,40]. Hence, naphthox-
azine is not only a benzoxazine analogue that simply
shows similar properties, but it is able to be synthesized
with a wider range of reaction conditions than benzoxa-
zines, resulting in a large variety of aromatic ring fused
oxazines that can offer characteristic properties.

2.5 Synthesis of Naphthoxazine, 3 CONCLUSION

Benzoxazine Analogue
Since benzoxazines have shown attractive properties for
pharmaceutical and polymeric applications, analogous
compounds such as naphthoxazine have also been studied.
Naphthoxazine has condensed polynuclear aromatic stru-
cture and its polymer is expected to have high thermal sta-
bility. Many naphthoxazines have been prepared in the
same way as the benzoxazines since Burke et al. repor-
ted the first naphthoxazine synthesized with 2-naphthol,
methyl amine and formaldehyde in 1952 (Scheme 17;
[31–38]). Due to the high reactivity of naphthol, the reac-
tion condition for naphthoxazine synthesis is moderate
and the byproducts caused by thermal oligomerization
In this chapter, various methods of benzoxazine (and its ana-
logue, naphthoxazine) synthesis have been introduced. As
the vast number of phenolic derivatives and amine deriva-
tives are commercially available as either synthetic com-
pounds or as natural and renewable resources, each class
of synthetic method results in an extremely large number
of benzoxazines. With the development methods that are
more advanced than the more generally used Mannich con-
densation methods, the ability to synthesize more benzoxa-
zines dramatically increases. This rich molecular design
flexibility makes benzoxazines, and the polymers derived
therefrom, the best choice for materials that allow for a tai-
loring of desired properties.
8 PART I Synthesis and Properties of Benzoxazine Resins
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