Benzo-Fused 1,4-Heterocycles via Dialkyl Carbonate Chemistry

Article abstract of DOI:10.1055/s-0037-1611710

A novel halogen-free synthesis of benzo-fused six-membered 1,4-heterocycles through the chemistry of dialkyl carbonates is reported. Commercially available catechol, 2-aminophenol, and 2-aminothiophenol were reacted first with ethylene carbonate in an autoclave to give O -hydroxyethyl, N -hydroxyethyl, and S -hydroxyethyl derivatives respectively, through a B _Al 2 mechanism. Then 2-(2-hydroxyethoxy)phenol and 2-(2-hydroxyethylamino)phenol were cyclized in excellent yields by reaction with dimethyl carbonate (DMC) and DABCO as a bicyclic organic base to give the corresponding benzodioxine and benzoxazine derivative, respectively. Moreover, 2-(2-aminophenylthio)ethanol afforded the benzothiazine derivative in good yield by reaction with DMC with an excess of a strong base such as NaH. The investigation on the cyclization reaction has highlighted that several equilibria are involved leading to the formation of carbonate and carbamate intermediates through B _Ac 2 mechanisms. Depending on the reaction conditions employed, these intermediates may undergo either kinetic-controlled ring closure by a B _Al 2 mechanism or by-product formation.

Full text of DOI:10.1055/s-0037-1611710

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
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M. Musolino et al.
Feature
Synthesis
Benzo-Fused 1,4-Heterocycles via Dialkyl Carbonate Chemistry
Manuele Musolino
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Fabio Aricò*
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Department of Environmental Sciences, Informatics and
Statistics, Ca’ Foscari University, Via Torino 155, 30172
Venezia Mestre, Italy
O
Y
X
NCO2CH3
O
O
1.
, cat., base
Fabio.arico@unive.it
85%
O
O
X = OH; Y = OH
X = OH; Y = NH2
X = NH2; Y = SH
H3CO OCH
3 , base, 90 °C
2.
NCO2CH3
71%
S
Received: 17.10.2018
Accepted after revision: 10.12.2018
Published online: 18.02.2019
Six-membered bicyclic fused 1,4-heterocycles contain-
ing nitrogen neighboring an aromatic ring, such as 3,4-di-
hydro-2H-1,4-benzoxazines (benzomorpholines) and 3,4-
dihydro-2H-1,4-benzothiazines have also received consid-
erable attention due to their wide range of biological and
therapeutic properties.3–6
DOI: 10.1055/s-0037-1611710; Art ID: ss-2018-z0704-fa
Abstract A novel halogen-free synthesis of benzo-fused six-mem-
bered 1,4-heterocycles through the chemistry of dialkyl carbonates is
reported. Commercially available catechol, 2-aminophenol, and 2-amino-
thiophenol were reacted first with ethylene carbonate in an autoclave
to give O-hydroxyethyl, N-hydroxyethyl, and S-hydroxyethyl derivatives
respectively, through a BAl2 mechanism. Then 2-(2-hydroxyethoxy)phe-
nol and 2-(2-hydroxyethylamino)phenol were cyclized in excellent
yields by reaction with dimethyl carbonate (DMC) and DABCO as a bi-
cyclic organic base to give the corresponding benzodioxine and benzox-
azine derivative, respectively. Moreover, 2-(2-aminophenylthio)ethanol
afforded the benzothiazine derivative in good yield by reaction with
DMC with an excess of a strong base such as NaH. The investigation on
the cyclization reaction has highlighted that several equilibria are in-
volved leading to the formation of carbonate and carbamate intermedi-
ates through BAc2 mechanisms. Depending on the reaction conditions
employed, these intermediates may undergo either kinetic-controlled
ring closure by a BAl2 mechanism or by-product formation.
Benzomorpholines are important building blocks in
many drugs, bioactive molecules, and herbicides. Several
1,4-benzoxazine derivatives exhibit pharmaceutical prop-
erties such as potassium channel openers (PCOs), inhibitor
of nitric oxide synthase (Figure 1), central nervous system
depressants, antipsychotic agents, calcium antagonists, and
antibacterial agents. Specific derivatives are potential drugs
for treating neurodegenerative, inflammatory, auto-
immune, cardiovascular, and diabetic disorders.3 Numerous
examples of benzomorpholines drugs, such as levofloxacin
(Figure 1), ciprofloxacin, norfloxacin, and efavirenz incor-
porate in the core structure a fluorine atom that has been
demonstrated to enhance solubility, lipophilicity, metabolic
stability, and binding selectivity.4 Recently, chiral 1,4-ben-
zoxazines have attracted increasing attention not only as a
result of their biological activities, but also as interesting
catalysts for the asymmetric transfer hydrogenation of α,β-
unsaturated aldehydes.5
Key words heteroycles, cyclization reaction, green chemistry, alkyla-
tion, chemoselectivity
1 Introduction
Six-membered bicyclic 1,4-heterocycles containing oxy-
gen, nitrogen, and sulfur atoms neighboring an aromatic
ring, 1,4-benzodioxane, 3,4-dihydro-2H-1,4-benzoxazine,
and 3,4-dihydro-2H-1,4-benzothiazine are incorporated in
numerous natural products and biologically active pharma-
ceuticals.1 Piperoxan (Figure 1), fluparoxan, and americanol
A are few examples of well-known pharmaceuticals incor-
porating a 1,4-benzodioxane backbone.2 This structural
unit is also present in sweetening agent isovanillyl and in
many natural products, such as silybin, isosilybin, haedoxan
A, eusiderin, etc.
3,4-Dihydro-2H-1,4-benzothiazine derivatives are also
very interesting heterocycles that display diverse biological
activities and pharmaceutical properties (Figure 1) as anti-
bacterial, antidiabetic, antiarrhythmic, antitumor, and neu-
rodegenerative diseases.6
Considering their remarkable biological relevance, sev-
eral methodologies have been developed for the synthesis
of this type of benzo-fused 1,4-heterocycles. The most com-
mon procedures include direct cyclization using a metal
catalyst, such as palladium,7 copper-catalyzed intramolecu-
lar direct ring closure,3d,8 and several other methods based
on chlorine or halogen chemistry.9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
M. Musolino et al.
Feature
Synthesis
CH3
F
N
N
O
OH
O
O
O
O
O
O
N
OH
HO
N
Isovanillyl
Piperoxan
Levofloxacin
S
S
N
O
N
CH3
NH2
O
N
H
N
F3C
N
H
N
O
N
N
H3C
H3C
Inhibitor of Nitric Oxide Synthase
(NOS)
Ion Channel
Antagonistic Activity
Histamine H1
Receptor
Figure 1 Examples of pharmaceutically and biologically active 1,4-benzodioxines, 3,4-dihydro-2H-1,4-benzoxazines, and 3,4-dihydro-2H-1,4-benzo-
thiazines
Some of these synthetic approaches have limitations,
that is, availability of the starting materials or reagents,
high costs of the catalysts, and lack generality of the proce-
dure; thus, exploiting new, routinely applicable and greener
methodologies to construct these heterocycles is highly
desirable.3d,7–9
Short-chain dialkyl carbonates (DACs), and in particular
dimethyl carbonate (DMC), are achieving increasing impor-
tance as green reagents and solvents in laboratory scale re-
actions, as well as, in the chemical industry processes.10
This is mainly due to the versatility of DACs as reagents and
solvents, and to their non-toxicity for the human health
and the environment.11
Recently, DMC has been used in the synthesis of several
five-membered N- and O-heterocycles. In these reactions
DMC acts as a sacrificial molecule, since it is not present in
the final products, but only in the reaction intermediates as
a halogen-free leaving group.12 DMC-based synthesis of
heterocycles takes place via a BAc2 followed by a BAl2 mech-
anism resulting in general application, as it is effective for
Biographical Sketches
Prof. Fabio Aricò obtained his
master degree in Chemistry
from the University of Messina
in 1999. He then moved to UK
where he was awarded a Ph.D.
at Reading University; work was
focusing on macrocycle-poly-
mer interconversion. He then
spent two years as post-doctoral
fellow in Sir Fraser Stoddart
group at the UCLA (USA) work-
ing on supramolecular systems.
In 2005, he moved back to Italy
where he joined the Interuniver-
sity Consortium of Chemistry
for the Environment collaborat-
ing with the University Ca’
Foscari. Since 2016 he is an as-
sociate Professor at Ca’ Foscari
University (Venezia); main re-
search interests are green
chemistry, chlorine-free chem-
istry, dialkyl carbonates, and
new synthetic pathways.
After the graduation in organic
chemistry at the University of
Milan in 2006, Dr. Manuele
Musolino has worked as medic-
inal chemist for both academia
(University of Milan) and indus-
try (Sanofi-Aventis Spa) cover-
ing the role of research
assistant. In 2012, he was
awarded a Scottish Universities
Life Sciences Alliance (SULSA)
four-year Ph.D. fellowship in
Medical Sciences, which was
successfully carried out at the
University of Aberdeen, Scot-
land. Since March 2017 he has
been working as a Research Fel-
low at Ca’ Foscari University of
Venice, deeply involved in the
development and uses of dialkyl
carbonate (DAC) chemistry as a
valid and prospective alterna-
tive to the halogen chemistry.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
M. Musolino et al.
Feature
Synthesis
aliphatic and aromatic 1,4-diols, incorporating several
functionalities. It is noteworthy that DMC or other small
DACs are also efficient reagents in the preparation of
heterocycles via transposition reaction in the one-pot
three-component synthesis of six-membered cyclic carba-
mates and in a base-free synthesis of large macrocycles.13
In this work, we have undertaken a study to synthesize
via DAC chemistry, different six-membered benzo-fused
1,4-heterocycles, 1,4-benzodioxines, 1,4-benzoxazines, and
1,4-benzothiazines starting from commercially available
reagents (catechol, 1,2-aminophenol, and 1,2-aminothiol,
respectively). The cyclization reactions have been achieved
in two steps having in common the use of an organic car-
bonate as the key reagent. Reaction conditions, chemoselec-
tivity, and general application of this novel synthetic
approach have been addressed.
nium salt as a catalyst; however, rather harsh reaction con-
ditions were necessary to collect the product in moderate
to good yield.16
In this case study, the alkylation reaction was investigat-
ed both in batch and autoclave conditions, by reacting cate-
chol (1) with EC in acetonitrile and testing the efficiency of
weak bases such as NaHCO3, K2CO3, and Cs2CO3; and strong
bases, NaH, bicyclic amines such as 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2]octane
(DABCO), and a heterogeneous catalyst NaY faujasite (see
Supporting Information for details).
Best found reaction conditions involved the reaction of
catechol and EC in the presence of DBU (1 mol equiv) as
base in acetonitrile at 150 °C for 14 hours. The alkylation
proceeded with a conversion of 84% and a selectivity of 90%
toward intermediate 2 (calculated by NMR analysis). Purifi-
cation through chromatography on silica gel afforded pure
compound 2 in 72% yield. The bis-alkylated derivative rep-
resented the only reaction by-product.
2 Results and Discussion
2,3-Dihydro-1,4-benzodioxine (3) was then obtained
straightforwardly by reaction of compound 2 with DMC at
reflux using DABCO as a base.12c The filtration of the reac-
tion mixture through a silica pad followed by the solvent
concentration under vacuum afforded the cyclic compound
3 in a quantitative yield (Scheme 2).
The herein proposed synthetic approach to benzo-fused
1,4-heterocycles encompasses two steps as depicted in
Scheme 1.
O
Y
X
cat.
cat.
Y
Y
base
OH base
+
O
O
DMC
O
X
X
O
OH
OH
O
DBU
OH
DABCO
DMC
3 X = O; Y = O
6 X = O; Y = NCO2CH3
9 X = NCO2CH3; Y = S
1 X = OH; Y = OH EC
4 X = OH; Y = NH2
7 X = NH2; Y = SH
2 X = OH; Y = O
5 X = OH; Y = NH
8 X = NH2; Y = S
+
O
O
O
OH
3 97%
1
EC
2 72%
Step 1
Step 2
Scheme 2 Synthesis of 1,4-benzodioxane 3
Scheme 1 Synthesis of benzo-fused 1,4-heterocycles via DAC chemistry
Synthesis of 1,4-Benzoxazine
1. Synthesis of the cyclic precursors 2, 5, and 8 by reac-
tion of a bis-functionalized benzene (catechol, 2-amino-
phenol, 2-aminothiophenol) with the cyclic carbonate, eth-
ylene carbonate (EC);
2. Cyclization of the precursors employing DMC as a re-
agent and solvent in the presence of a base or a catalyst to
achieve the desired six-membered heterocycles 3, 6, and 9.
Scheme 3 reports in detail the two-step synthetic ap-
proach set up for the preparation of benzomorpholine 6.
Similar to the procedure used for 1,4-benzodioxane DAC ap-
proach, in the first step 2-aminophenol was reacted with
EC. For the purpose of this work, the preparation of 1,4-
benzomorpholine, it would make no difference if the
alkylation reaction led to 2-(2-aminophenoxy)ethanol or to
2-(2-hydroxyethylamino)phenol (5). Both substrates can
undergo cyclization, although previous investigations
Synthesis of 1,4-Benzodioxane
In order to investigate the feasibility of the proposed
synthetic approach, we first attempted the preparation of
the 1,4-benzodioxane moiety that we have previously pre-
pared starting from the commercially available 2-(2-
hydroxyethoxy)phenol (2).12c However, this substrate is
quite expensive when compared to 1,2-dihydroxybenzene,
namely catechol.
The most common synthetic procedures for the cyclic
precursor 2 include reaction of catechol with ethylene
oxide14 or with 2-haloethanol.15 In few examples, EC has
been used as reagent in the presence of a tetrabutylammo-
H
N
O
NCO2CH3
O
NH2
NaY
OH
DABCO
DMC
+
O
O
OH
OH
4
EC
5 88%
6 85%
Intermediates of the cyclization reaction
OCO2CH3
O
O
H
N
N
N
O
O
OCO2CH3
OH
OH
10
11
12
Scheme 3 Synthesis of 1,4-benzoxazine 6
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
M. Musolino et al.
Feature
Synthesis
outlined that intramolecular reaction between phenol and
an aliphatic alcohol is favored compared to the one involv-
ing an aniline and an alcohol.12
In this view, it has been previously reported that, in the
presence of NaY faujasite as the catalyst, the reaction of bi-
functional anilines such as aminophenols with an excess of
DMC (used as solvent and reagent) proceeds with a very
high mono-N-methyl chemoselectivity.17
It should be also mentioned that few synthetic ap-
proaches to 2-(2-hydroxyethylamino)phenol (5) have been
reported in the literature mainly involving the use of chlo-
rine chemistry or ring opening of epoxides.18
terized. It should be mentioned that the reaction inter-
mediate 12 is also an interesting heterocycle, because many
drugs containing a benzoxazolinone core have been studied
for their hypnotic and pharmacological properties, such as
anticonvulsant, antipyretic, analgesic, cardiotonic, and anti-
bacterial effect20 and have been found effective as in-
doleamine 2,3-dioxygenase 1 (IDO1) inhibitors.21
Table 1 Synthesis of the N-Methoxycarbonylbenzomorpholine 6a
Entry
Base
Mol equiv
Time (h)
Selectivity (%)b
10
12
6
In our first attempt, a solution of 2-aminophenol and EC
in acetonitrile was heated at reflux (90 °C) in the presence
of NaY. In this case study, ethylene carbonate was used in
stoichiometric amount as an aqueous workup would be
necessary to separate the excess of unreacted EC from the
product. Analyses of the reaction mixture showed that, de-
spite the low yield achieved (ca. 5%), the only product
formed was the 2-(2-hydroxyethylamino)phenol (5). When
the same reaction was performed in an autoclave at 150 °C
the alkylated product 5 was isolated in 88% yield confirm-
ing the high chemoselectivity of the N-alkylation reaction
due to the presence of the faujasite. The product was recov-
ered as light-yellow crystals after an easy purification by
crystallization in dichloromethane. Besides, the faujasite
employed for the alkylation, can be re-used several times
without losing its efficiency.
The isolated 2-(2-hydroxyethylamino)phenol (5) was
then subjected to the cyclization reaction (Table 1). To the
best of our knowledge, the synthesis of the N-methoxycar-
bonylbenzomorpholine (6) has been previously reported in
the literature exclusively via chlorine-based chemistry (74%
yield).19
In the herein proposed procedure, several bases have
been tested: weak base K2CO3 and Et3N (Table 1, entries 1,
2); nitrogen bicyclic Lewis bases, DABCO, DBU, and triazab-
icyclodecene (TBD) (entries 3–5); and strong bases sodium
methoxide and potassium tert-butoxide (entries 6, 7). All
the experiments have been conducted in the presence of a
stoichiometric amount of base at the refluxing temperature
of DMC (90 °C) used as both reagent and solvent.
DABCO and superbase TBD were the only bases capable
of promoting the cyclization reaction in quantitative yield
(Table 1, entries 3 and 5). N-Methoxycarbonylbenzo-
morpholine (6) was easily recovered from the reaction mix-
ture by simple filtration on a silica gel pad followed by
evaporation of the residual solvent (85% isolated yield). It
should be mentioned that DABCO was a more efficient base
than TBD as the cyclization reaction reached completion al-
ready after six hours (entry 8).
All the other bases (Table 1, entries 1, 2, 4, 6, and 7) pro-
moted the quantitative conversion of 2-(2-hydroxyethyl-
amino)phenol (5) into the five-membered cyclic carbamate
12 that was isolated as a pure compound and fully charac-
1
2
K2CO3
Et3N
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.50
0.25
0.25
0.10
0.10
24
24
24
24
24
24
24
6
–
–
100
100
–
–
–
100
–
3
DABCO
DBU
–
4
–
100
–
5
TBD
–
100
–
6
NaOMe
t-BuOK
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
–
100
73
–
7
–
27
100
100
25
100
–
8
–
9
6
–
–
10
11
12
13
6
–
75
–
24
6
–
68
–
32
100
24
–
a Reaction conditions: 2-(2-hydroxyethylamino)phenol 5 (1 equiv), DMC
(50 equiv), 90 °C. Conversion of the starting reagent 5 was quantitative in
all experiments.
b Selectivity was calculated by 1H NMR spectroscopy.
The Lewis acid, boron trifluoride diethyl etherate,
strongly acidic cation exchanger Amberlyst-15, and ampho-
teric catalyst hydrotalcite KW2000 have also been tested
for the cyclization reaction (1:1 w/w with the substrate);
however, analysis of the reaction mixture showed only the
presence of the unreacted starting reagent.
In a second set of experiment, the effect of the amount
of DABCO on the formation of the benzomorpholine 6 was
investigated. Data reported in Table 1 showed that this bi-
cyclic base can be used in substoichiometric amounts (Table
1, entries 9–13), from 0.10 to 0.50 equivalent although the
cyclization rate was slower (24 h). When the reaction was
performed with 10% mol of DABCO for six hours the me-
thoxycarbonylated intermediate 10 was the major product
observed.
In order to elucidate a possible reaction mechanism, the
cyclization reaction was performed employing 25% mol of
DABCO (Table 1, entry 11). Samples were taken at time in-
tervals, and intermediates and product formation were an-
alyzed by 1H NMR spectroscopy. The results are depicted in
Scheme 4 (stacked spectra are included in the Supporting
Information).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
M. Musolino et al.
Feature
Synthesis
of the reaction mixture were taken at time intervals and
their 1HNMR spectra showed the quantitative conversion of
the substrate 12 into the benzomorpholine 6. This result
confirms the proposed mechanism involving most likely
the ring opening of the cyclic carbamate 12 to the bismeth-
yl carbonate intermediate 13 followed by the formation of
the heterocycle 6 via BAl2 mechanism.
O
a)
O
H
H
N
BAc2
N
N
BAc2
OCO2CH3
OH
OH
10
OH
5
OH
11
BAc
2
OCO2CH3
CO2CH3
N
CO2CH3
N
N
O
BAc2
BAl2
OCO2CH3
Synthesis of 1,4-Benzothiazine
O
2-Aminothiophenol was selected as the starting reagent
to prepare 1,4-benzothiazine 9 (Scheme 5). The synthesis of
the acyclic intermediate 2-(2-aminophenylthio)ethanol (8)
was straightforward, as a result of the higher nucleophilici-
ty of the thiol group compared to the amino one. The
alkylation reaction of 2-aminothiophenol was carried out
in an autoclave at 150 °C in the presence of K2CO3 resulting
in the formation of 2-(2-aminophenylthio)ethanol (8) in a
quantitative yield. Attempts to perform the reaction in the
presence of faujasite led to lower yield, due to the formation
of a considerable amount of a 2-aminothiophenol dimer via
disulfide bond.22 The synthesis of compound 8 (in 84%
yield) was previously reported in the literature, although
the procedure was based upon chlorine chemistry.23
OH
O
12
13
6
b)
O
S
SH
S
K2CO3
OH NaH
Scheme 4 a ) Plausible reaction mechanism for the formation of the
N-methoxycarbonylmorpholine 6; b) Cyclization reaction over time
according to the experiment in Table 1, entry11. Samples taken at time
intervals (20 min, 40 min, 1 h, 2 h, 3 h, 6 h, 8 h, and 24 h). Intermedi-
ates and product formation were analyzed via 1H NMR spectroscopy.
+
O
O
DMC
N
NH2
NH2
CO2CH3
7
EC
8 95%
9 71%
Intermediate and by-product
S
S
N
OCO2CH3
According to the data collected, the starting 2-(2-
NH2
14
hydroxyethylamino)phenol (5) first undergoes
a car-
CO2CH3
15
boxymethylation of the aliphatic hydroxyl group forming
the intermediate 10. At this point the amino group is most
probably methoxycarbonylated by DMC forming a very re-
active bismethyl carbonate 13 that was not isolated. The
latter compound is the key intermediate, as it can be con-
verted into either the five-membered cyclic carbamate 12
or the desired benzomorpholine 6.
It is interesting to note that the cyclic carbamate 12 is
indeed a reaction intermediate as, once formed, it is slowly
converted into the cyclic product 6. A rather small amount
of cyclic carbamate 11 is also formed from the intermediate
10 through an intramolecular BAc2 mechanism. It should be
noted that all the reactions of the proposed mechanism are
thermodynamically controlled except for the formation of
the final product 6 that takes place via a kinetically con-
trolled and irreversible BAl2 mechanism (Scheme 4).
As proof of concept, an experiment was carried out em-
ploying a pure sample of the five-membered cyclic carba-
mate 12 isolated by column chromatography. This com-
pound was dissolved into DMC (50 equiv) in the presence of
DABCO (1 equiv) and heated at 90 °C according to the reac-
tion conditions previously used for the cyclization of 2-(2-
hydroxyethylamino)phenol (5) (Table 1, entry 8). Samples
Scheme 5 Synthesis of N-methoxycarbonyl-1,4-benzothiazine 9
Conversion of compound 8 to the desired N-methoxy-
carbonyl-3,4-dihydro-2H-1,4-benzothiazine (9), was inves-
tigated by employing a variety of bases in different reaction
conditions, as depicted in Table 2. The obtained results
show that the reaction course strictly depends on the type
of base used to activate the NH2 group toward a six-mem-
bered ring closure by an irreversible BAl2 mechanism.
In a first set of experiments, the reaction was conducted
at the reflux temperature of DMC (60 equiv) in the presence
of stoichiometric amount of a base. In these conditions, the
use of potassium carbonate or DBU led to the formation of
the methoxycarbonylated intermediate 14 as the major
product (Table 2, entries 1, 2). DABCO or TBD, which provid-
ed the best outcomes in the synthesis of the morpholine
derivative 6, was inefficient to promote the formation of
the benzothiazine derivative 9. Both experiments gave by-
product 15 as the major reaction product (entries 3, 4). A
stoichiometric amount of strong base t-BuOK and NaOMe
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

F
M. Musolino et al.
Feature
Synthesis
Table 2 Synthesis of the N-Methoxycarbonyl-3,4-dihydro-2H-1,4-
benzothiazine (9)a
5). Then, the compound 14 may undergo either elimination
reaction to afford the N-methyl carbamate by-product 15 or
N-carboxymethylation followed by cyclization reaction to
give the desired compound 9 (Scheme 6).
Entry
Base
Mol equiv Time (h)
Selectivity (%)b
14 15
9
S
S
S
OCO2CH3
OCO2CH3
c
1
2
K2CO3
DBU
1
1
1
1
1
1
1
3
3
3
3
3
3
24
24
24
24
24
24
24
3
100
93
14
–
–
–
NH2
14
NCO2CH3
H
7
78
100
–
–
8
N
CO2CH3
9
3
DABCO
TBD
By-product formation
4
–
5
NaOMe
t-BuOKd
NaH
100
100
75
–
–
S
S
S
6
–
–
NH2
NCO2CH3
H
N
CO2CH3
7
0
25
79
14
–
15
8
NaOMee
NaH
21
45
59
34
25
67
Scheme 6 Possible reaction mechanism for the formation of the
N-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazine (9)
9
3
41
41
–
10
11
12
13
DABCO
NaOMef
NaHf
24
3
66
75g
8
In conclusion, we have developed and optimized a novel
two-step synthetic strategy to achieve in good to excellent
yields three different benzo-fused 1,4-heterocycles, by ex-
ploiting the versatility of DACs as carboxymethylating and
methylating agents and solvents. This general procedure
consisted in the selective monoalkylation of starting com-
pounds, catechol, 2-aminophenol, and 2-aminothiophenol
by reaction with EC in an autoclave followed by cyclization
at 90 °C by using DMC as both solvent and reagent. In order
to maximize the process yields, different conditions have
been tested for both alkylation and cyclization steps by tak-
ing into account the nucleophilicity of the heteroatom
directly involved in the reaction. Benzodioxine 3 and ben-
zomorpholine derivative 6 were prepared quickly and in
quantitative yield from 2-(2-hydroxyethoxy)phenol and 2-
(2-hydroxyethylamino) phenol, respectively, employing
DABCO as a base.
The benzothiazine derivative 9 was instead prepared in
good yield from 2-(2-hydroxyethylthio)phenol by using an
excess of strong base, NaH and NaOMe, respectively. Even-
tually, for each synthesis the main reaction intermediates
and by-products were identified, isolated, and character-
ized via NMR spectroscopy and MS spectrometry and
cyclization mechanisms have been proposed.
It should also be mentioned that the simplicity of this
synthetic approach can lead to the preparation of a range of
differently substituted benzo-fused 1,4-heterocycles. In
particular, the use of commercially available 4-chloro-1,3-
dioxolan-2-ones (chloroethylene carbonate) or 4-vinyl-1,3-
dioxolan-2-one (vinyl ethylene carbonate) instead of EC
may allow the introduction of a chlorine or vinyl moiety
into heterocycles leading to further modification. This could
be used to achieve structures such as piperoxan and isovan-
illin. Glycerol carbonate can be also employed as building
block although its hydroxyl moiety would have to be pro-
tected to avoid formation of by-products in the cyclization
steps.
3
–
DABCOf
24
25
a Reaction conditions: 2-(2-aminophenylthio)ethanol 8 (1 equiv), DMC
(60 equiv), 90 °C. Conversion of the starting reagent 5 was quantitative in
all experiments, unless otherwise specified.
b Selectivity was calculated via 1H NMR spectroscopy.
c 90% conversion.
d 81% conversion.
e 9 was isolated in 63% yield.
f With 180 equiv DMC.
g 71% isolated yield.
led to the formation of the O-methoxycarbonylated inter-
mediate 14 as the major product (entries 5 and 6). Sodium
hydride was the only base – used in stoichiometric amount –
that promoted the cyclization reaction to 1,4-benzothiazine
9 although in moderate yield (entry 7).
Better results were achieved using an excess of bases
(Table 2, entries 8–10). Freshly prepared NaOMe employed
in three equivalents promoted the formation of the benzo-
thiazine 9 in high yield (79%); the reaction was complete
after only three hours at reflux temperature (entry 8). An
excess of NaH and DABCO did not favor the cyclization even
when the reaction was carried out for 24 hours (entries 9,
10). However, it should be mentioned that higher amount
of base causes inhomogeneous stirring and the reaction
workup to isolate benzothiazine 9 was more difficult, espe-
cially in the case of sodium methoxide (entry 8). In this
view, further experiments were conducted in more diluted
conditions (180 mol equiv of DMC). As a result, the cycliza-
tion reaction was efficiently promoted both by NaOMe and
NaH in three hours (entries 11, 12). Pure 1,4-benzothiazine
9 was isolated in 71% yield by chromatography on silica gel.
Among the bases tested, only DABCO was ineffective in
these reaction conditions (entry 13).
According to the results reported in Table 2, the reaction
mechanism for the formation of benzothiazine 9 involves
most probably, first the reaction of compound 8 with DMC
to give the methoxycarbonylated intermediate 14 (Scheme
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
M. Musolino et al.
Feature
Synthesis
Acidic hydrolysis or palladium-catalyzed hydrogenoly-
sis of N-methoxycarbonylbenzomorpholine and N-
1,4-Benzodioxane
6
2-(2-Hydroxyethoxy)phenol (2)14–16
methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazine (9) in
mild conditions would lead to the related benzomorpholine
and 3,4-dihydro-2H-1,4-benzothiazine with a free amino
group that could be also easily subject to further modifica-
tion. In the specific case of 1,4-benzothiazine, this could be
used to prepare compounds with ion channel antagonistic
activity.6
Regarding the possibility to introduce substituents on
the aromatic moiety of benzo-fused 1,4-heterocycles, sev-
eral commercially available 2-aminophenol, such as 2-ami-
no-4-chlorophenol, 2-amino-3-nitrophenol, and 4-amino-
3-hydroxybenzoic acid are available and can be investigated
as substrates.
Finally, numerous synthetic approaches are reported in
the literature, which allow the introduction of reactive
groups such bromine, nitro and acyl moieties, in the aro-
matic ring of 1,4-benzodioxane.24 Modifications of the
herein discussed benzo-fused 1,4-heterocycles will be the
subject of further investigations.
In an autoclave, to a solution of catechol (1; 1.00 g, 9.08 mmol) and EC
(0.80 g, 9.08 mmol) in MeCN (30 mL) was added DBU (1.34 mL, 9.08
mmol) and the mixture was heated to 150 °C for 24 h under stirring.
Then, the mixture was cooled to r.t., filtered through a silica gel pad,
and concentrated under vacuum to give a brown oil. Purification by
flash chromatography (FC) on silica gel eluting with hexane/EtOAc
(4:1, Rf = 0.42) gave the compound 2 as a grey solid; mp 99–101 °C;
yield: 1.01 g (72%).
1H NMR (CDCl3, 400 MHz): δ = 7.01–6.81 (m, 4 H), 6.23 (br, 1 H), 4.22–
4.15 (m, 2 H), 4.07–3.96 (m, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 146.5, 145.9, 122.5, 120.2, 115.6,
113.4, 70.6, 61.4.
2,3-Dihydro-1,4-benzodioxine (3)12c
To a solution of 2 (1.00 g, 6.49 mmol) in DMC (30 mL, 350.00 mmol)
was added DABCO (0.73 g, 6.49 mmol) and the mixture was refluxed
under stirring for 3 h. Then, the mixture was filtered through a silica
gel pad and the solvent was concentrated under vacuum to give com-
pound 3 as a yellow oil; yield: 0.86 g (97%).
1H NMR (CDCl3, 400 MHz): δ = 6.76–6.64 (m, 3 H), 6.58–6.53 (m, 1 H),
3.77 (t, J = 6.1 Hz, 2 H), 6.24 (t, J = 6.1 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 143.6 (2 C), 121.4 (2 C), 117.3 (2 C),
64.4 (2 C).
All reagents were purchased from Sigma Aldrich and used without
any further purification. NaOMe (Table 2, entries 5, 8, 9) was freshly
prepared at 0 °C and under N2 flow by adding portionwise Na to an-
hyd MeOH. After the complete dissolution of Na, the solvent was con-
centrated under vacuum to give NaOMe as a white solid.
1H NMR spectra were recorded at 400 MHz on a Bruker Ascend TM
400 spectrometer. The chemical shifts are reported in ppm from the
solvent resonance as the internal standard (CDCl3: 7.26 ppm; CD3OD:
3.33 ppm) as well as TMS. Data are reported as follows: chemical
shift, integration multiplicity (standard abbreviations) and coupling
constants (Hz). 13C NMR spectra were recorded at 100 MHz on a
Bruker AscendTM 400 spectrometer. Chemical shifts are reported in
ppm from the solvent resonance as internal standard (CDCl3: 77 ppm;
CD3OD: 49 ppm).
1,4-Benzoxazine
2-[(2-Hydroxyethyl)amino]phenol (5)19
In an autoclave, to a solution of 2-aminophenol (4.00 g, 36.65 mmol)
and EC (3.23 g, 36.65 mmol) in ACN (100 mL) was added NaY faujasite
(4.00 g, 100% wt.) and the mixture was heated to 150 °C for 5 h under
stirring. Then, the mixture was cooled to r.t., filtered through a silica
gel pad and concentrated under vacuum to give a dense orange oil.
Crystallization from CH2Cl2 afforded 5 as a brownish solid; mp 87–
89 °C; yield: 4.94 g (88%).
1H NMR (CD3OD, 400 MHz): δ = 6.76–6.64 (m, 3 H), 6.58–6.53 (m, 1
H), 3.77 (t, J = 6.1 Hz, 2 H), 6.24 (t, J = 6.1 Hz, 2 H).
13C NMR (CD3OD, 100 MHz): δ = 144.9, 137.6, 119.8, 117.6, 113.5,
DIP-EI-MS spectra of compounds 9, 10, 11, 14, and 15 were record-
ed on a large-scale tandem mass spectrometer (Waters AutoSpec
6F – Organic Synthesis and Mass Spectrometry Lab – University of
Mons, Belgium) combining six sectors of E1B1c1E2c2E3B2c3E4 con-
figuration (E stands for electric sector, B for magnetic sector and c for
collision cell). General conditions were, 8 kV accelerating voltage, 70
eV ionizing electron energy and 200 °C ion source temperature. The
PEI samples (1 mg), introduced in small Pyrex capillaries, were direct-
ly introduced into the ion source without any external heating. The
ions were obtained under electron ionization in positive ion mode
(200 μA trap current). The full scan mass spectra were recorded by
scanning the field of the first magnetic sector and collecting the ions
with an off-axis photomultiplier detector. Accurate mass measure-
ments were acquired using perfluorokerosene (PFK) as the internal
standard.
111.3, 60.4, 45.8.
HRMS: m/z [M – H]– calcd for C8H10NO2: 152.0717; found: 152.0720.
2-[(2-Hydroxyphenyl)amino]ethyl Methyl Carbonate (10)
The cyclization intermediate 10 was synthesized by the reaction of 5
(0.20 g, 1.31 mmol) in DMC (6.00 mL, 65.50 mmol) by adding DABCO
(0.04 g, 0.33 mmol) to the reaction mixture and heating to reflux un-
der stirring. After 40 min, the mixture was cooled to r.t., filtered
through a silica gel pad and the solvent was concentrated under vacu-
um to give a crude brown oil. Purification by FC on silica gel by eluting
with hexane/EtOAc (9:1; Rf = 0.23) gave 10 as a brown oil; yield: 0.12
g (43%).
1H NMR (CDCl3, 400 MHz): δ = 6.91–6.84 (m, 1 H), 6.79–6.63 (m, 1 H),
4.37 (t, J = 5.5 Hz, 2 H), 3.82 (s, 3 H), 3.47 (t, J = 5.5 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 155.9, 144.2, 136.1, 121.5, 118.6,
HRMS spectra of compounds 5, 6, 8, and 12 were recorded on a Ther-
mo Scientific LTQ Orbitrap XL mass spectrometer, via a full scan mode
and with a mass resolution R = 100000.
114.6, 112.8, 66.6, 55.0, 43.3.
HRMS: m/z [M]+ calcd for C10H13NO4: 211.0845; found: 211.0848.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
M. Musolino et al.
Feature
Synthesis
3-(2-Hydroxyphenyl)oxazolidin-2-one (11)
2-[(2-Aminophenyl)thio]ethyl Methyl Carbonate (14)
The cyclization intermediate 11 was synthesized by dissolving com-
pound 10 (0.10 g, 0.47 mmol) in aq 2 M NaOH (5 mL). After 10 min
under stirring, the solution was neutralized with aq 2 M HCl (5 mL)
and extracted with Et2O (3 × 5 mL). Then the organic phase was dried
(anhyd Na2SO4) and concentrated under vacuum to give 11 as a
brown wax; yield: 0.08 g (97%).
The cyclization intermediate 14 was synthesized by the reaction of 8
(1.00 g, 5.91 mmol) with DMC (29.90 mL, 354.60 mmol) by adding K2-
CO3 (0.82 g, 5.91 mmol) to the reaction mixture and heating to reflux
under stirring. After 24 h, the mixture was cooled to r.t., salts were
filtered off, and the solvent was concentrated under vacuum to give
14 as a yellow oil; yield: 1.23 g (99%).
1H NMR (CDCl3, 400 MHz): δ = 7.90 (br, 1 H), 7.24–7.16 (m, 1 H), 7.11–
7.04 (m, 2 H), 7.00–6.94 (m, 1 H), 4.68–4.59 (m, 2 H), 4.21–4.13 (m,
2 H).
1H NMR (CDCl3, 400 MHz): δ = 7.42 (dd, J1 = 7.7 Hz, J2 = 1.5 Hz, 1 H),
7.20–7.10 (m, 1 H), 6.77–6.65 (m, 2 H), 4.27 (br, 2 H), 4.23 (t, J = 6.7
Hz, 2 H), 3.78 (s, 3 H), 3.00 (t, J = 6.7 Hz, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 157.6, 149.7, 127.8, 125.7, 121.4,
13C NMR (CDCl3, 100 MHz): δ = 145.5, 148.7, 136.6, 130.4, 118.6,
121.1, 120.7, 63.6, 47.0.
116.1, 115.1, 66.2, 54.9, 33.1.
HRMS: m/z [M]+ calcd for C9H9NO3: 179.0582; found: 179.0585.
HRMS: m/z [M]+ calcd for C10H15NO3S: 227.0616; found: 227.0618.
Methyl [2-(2-Oxobenzo[d]oxazol-3(2H)-yl)ethyl] Carbonate (12)
Methyl Methyl[2-(vinylthio)phenyl]carbamate (15)
The cyclization intermediate 12 was synthesized by reaction of 5
(1.00 g, 6.53 mmol) in DMC (27.50 mL, 326.50 mmol) by adding
NaOMe (0.35 g, 6.53 mmol) to the reaction mixture and heating to re-
flux under stirring. After 24 h, the mixture was cooled to r.t., filtered
53975-2193811 through a silica gel pad and the mixture was concen-
trated under vacuum to give 12 as a yellow oil; yield: 1.10 g (71%).
1H NMR (CDCl3, 400 MHz): δ = 7.25–7.18 (m, 2 H), 7.16–7.11 (m, 1 H),
7.09–7.05 (m, 1 H), 4.48 (t, J = 6.0 Hz, 2 H), 4.14 (t, J = 6.0 Hz, 2 H), 3.75
(s, 3 H).
The cyclization by-product 15 was synthesized by reaction of 8 (0.20
g, 1.19 mmol) with DMC (6.4 mL, 59.5 mmol) by adding TBD (0.17 g,
1.19 mmol) to the reaction mixture and heating to reflux under stir-
ring. After 48 h, the mixture was cooled to r.t., filtered through a silica
gel pad and the solvent was concentrated under vacuum to give a
crude brown oil. Purification by FC on silica gel eluting with hex-
ane/EtOAc (9:1, Rf = 0.18) gave 15 as a bright yellow oil; yield: 0.19 g
(72%).
1H NMR (CDCl3, 400 MHz): δ = 7.46–7.40 (m, 1 H), 7.33–7.17 (m, 3 H),
6.48 (dd, J1 = 15.7 Hz, J2 = 9.7 Hz, 1 H), 5.51–5.40 (m, 2 H) 3.73 (br s, 3
H, OCH3 rotamers), 3.22 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 155.3, 154.4, 142.7, 131.1, 123.9,
122.7, 110.1, 108.5, 64.8, 55.1, 41.3.
HRMS: m/z [M + H]+ calcd for C11H12NO5: 238.0710; found: 238.0719.
13C NMR (CDCl3, 100 MHz): δ = 156.1, 142.1, 134.1 131.0, 130.4, 128.4,
128.2, 128.0, 117.3, 53.0, 37.3.
HRMS: m/z [M]+ calcd for C11H13NO2S: 223.0667; found: 223.0669.
Methyl 2,3-Dihydro-4H-1,4-benzoxazine-4-carboxylate (6)19
A solution of 10 (0.50 g, 3.27 mmol) and DABCO (0.36 mL, 3.27 mmol)
in DMC (13.76 mL, 163.50 mmol) was heated to reflux for 4 h under
stirring. Then the mixture was filtered through a silica gel pad and con-
centrated under vacuum to give 6 as a yellow wax; yield: 0.54 g (85%).
1H NMR (CDCl3, 400 MHz): δ = 7.35–7.31 (m, 1 H), 7.30–7.33 (m, 1 H),
6.99–6.92 (m, 2 H), 4.46–4.39 (m, 2 H), 3.98–3.91 (m, 2 H), 3.83 (s, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 157.5, 155.0, 128.9, 128.3, 126.1,
120.9, 112.1, 62.5, 55.6, 47.0.
HRMS: m/z [M + Na]+ calcd for C10H11NO3 + Na+: 216.0631; found:
216.0633
Methyl 2,3-Dihydro-4H-1,4-benzothiazine-4-carboxylate (9)
To a solution of compound 8 (0.50 g, 2.95 mmol) in DMC (45 mL,
534.52 mmol) was added NaH (60% dispersion in mineral oil, 0.35 g,
8.85 mmol) and the mixture was heated to reflux for 24 h under stir-
ring. Then, the mixture was filtered through a silica gel pad and the
solvent concentrated under vacuum to give a brown oil. Purification
by FC on silica gel eluting with hexane/Et2O (97:3, Rf = 0.19) gave 9 as
a reddish oil; yield: 0.44 g (71%).
1H NMR (CDCl3, 400 MHz): δ = 7.47 (br, 1 H), 7.19–7.14 (m, 1 H), 7.12–
7.02 (m, 2 H), 3.98–3.92 (m, 2 H), 3.81 (s, 3 H), 3.25–3.19 (m, 2 H).
13C NMR (CDCl3, 100 MHz): δ = 154.9, 136.4 127.0, 126.7, 126.6, 125.4,
124.0, 53.2, 42.9, 28.3.
1,4-Benzothiazine
HRMS: m/z [M]+ calcd for C10H11NO2S: 209.0510; found: 209.0507.
2-[(2-Aminophenyl)thio]ethan-1-ol (8)23
In an autoclave, to a solution of 2-aminothiophenol (7; 4.00 g, 31.95
mmol) and EC (2.81 g, 31.95 mmol) in MeCN (100 mL) was added
K2CO3 (4.42 g, 31.95 mmol) and the mixture was heated to 150 °C for
5 h under stirring. Then the mixture was filtered through a silica gel
pad and concentrated under vacuum to obtain a crude oil, which was
dissolved in Et2O (20 mL), washed with H2O (3 × 20 mL) and dried (an-
hyd Na2SO4). The compound 8 was obtained as a dense brown oil by
solvent evaporation under vacuum; yield: 5.14 g (95%).
1H NMR (CDCl3, 400 MHz): δ = 7.42 (dd, J1 = 7.7 Hz, J2 = 1.5 Hz, 1 H),
7.20–7.14 (m, 1 H), 6.79–6.72 (m, 1 H), 3.75 (br s, 2 H), 3.66 (t, J = 5.8
Hz, 2 H), 2.91 (t, J = 5.8 Hz, 2 H).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611710.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

I
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I