Synthesis and Photophysical Properties of 1,4-Dihydro-2 H,5H-chromeno[4,3-D][1,3]oxazin-5-ones, and Derivatives Containing Tethered 1,2,3-Triazoles, from 4-Aminocoumarins

Article abstract of DOI:10.1055/s-0037-1612428

A facile protocol for the unprecedented one-pot H ₂ SO ₄ -mediated hydroxymethylation/cyclative N, O -acetalization of 4-aminocoumarins to 1,4-dihydro-2 H,5 H -chromeno[4,3- d ][1,3]oxazin-5-ones, in moderate to good yields, was deve

Full text of DOI:10.1055/s-0037-1612428

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
A
en
M. C. Dilelio et al.
Paper
Synthesis
Synthesis and Photophysical Properties of 1,4-Dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-ones, and Derivatives Containing
Tethered 1,2,3-Triazoles, from 4-Aminocoumarins
Marina C. Dilelioa
Nathan P. Britesa
Larissa A. Vieiraa
Bernardo A. Iglesiasa
Teodoro S. Kaufman*b
R2
O
R1
H
R1
H2SO4,
H2O
N
R2
H
N
O
R3
R1 = alkyl, Ar
2 = H, Me
R2
N
N
R
O
O
R
N
0
0
0
0-0
0
0
3-3
1
7
3-2
1
7
8
R
O
O
Claudio C. Silveira*a
0
0
0
0-0
0
0
2-1
9
1
8-0
0
0
0
# up to 90% yield
# 18 examples
# Visible light
R2 = H
3 = alkyl, aryl
N
O
O
Br
R
R3N3
a Departamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria, RS, Brazil
emission
# Stokes shift up
to 12 × 103 cm–1
Photophysical characterization
silveira@quimica.ufsm.br
R
O
b Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad
de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional
de Rosario, Suipacha 531, 2000 Rosario, Argentina
Received: 28.01.2019
Accepted after revision: 15.03.2019
Published online: 10.04.2019
Several natural products are 1,3-oxazine derivatives
(Figure 1). Representative structures are terresoxazine
(A),5a maltoxazine (B)5b,c and brevioxime (C).5d,e Many 1,3-
DOI: 10.1055/s-0037-1612428; Art ID: ss-2019-m0056-op
Abstract A facile protocol for the unprecedented one-pot H2SO4-me-
diated hydroxymethylation/cyclative N,O-acetalization of 4-aminocou-
marins to 1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-ones, in
moderate to good yields, was developed and optimized. The scope and
limitations of the transformation, which takes place in water or wa-
ter/THF mixtures, were also studied. The nitrogen atom of the resulting
tricycles was used to tether alkyl, aryl and 1,2,3-triazolylmethyl moi-
eties, employing a two-step click chemistry approach for the latter. The
photophysical properties of the heterocycles, as well as of their 1,2,3-
triazole derivatives, were also examined. The N-aryl derivatives exhibit-
ed high quantum yields of fluorescence (up to Φf = 0.69) and very large
Stokes shifts (up to 201 nm).
HO
O
O
Me
O
N
Me
N
N
O
O
O
N
OH
C, Brevioxime
A, Terresoxazine
B, Maltoxazine
H
N
CO2Me
Me
Me
MeO2C
H
N
O
O
N
O
H
N
Me
N
N
N
Me
N
Key words 4-aminocoumarins, tethered triazoles, 1,3-oxazines, cy-
clization reaction, photophysical properties
H
OMe
N
D, Elbasvir
Bn
N
Me
The coumarin core is a privileged scaffold. Decoration of
this heterocycle proved to be an effective strategy toward
the development of new bioactive compounds1 and techno-
logically relevant materials. The interest in the latter is re-
lated to their photophysical properties, especially strong
fluorescence, which are at the heart of various applications,
such as optical chromophores, sensitive fluorescent probes2
and laser dyes,3 among others.
Ph
N
O
N
O
O
O
O
O
N
O
Me
O
CO2Et
Me
O
O
N
F
G
H
H
Me
E, PD-102,807
O
O
On the other hand, oxazines are six-membered hetero-
cycles which contain one atom each of nitrogen and oxygen.
There are several isomeric oxazines, and their dihydro and
tetrahydro forms are also known. The different approaches
toward their synthesis have been recently reviewed.4
N
N
O
O
N
O
N
O
N
N
I
Me
Me
Figure 1 Selected examples of relevant heterocycles, natural products
and pharmacologically active compounds, displaying the coumarin,
1,3-oxazine and 1,2,3-triazole motifs
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

B
M. C. Dilelio et al.
Paper
Synthesis
oxazines are interestingly bioactive,6,7 and the heterocyclic
motif is present in various active pharmaceutical ingredi-
ents, such as the antiviral agent elbasvir (D)8 and PD-
102,807 (E), a selective antagonist for the muscarinic ace-
tylcholine receptor M4.9a,b In addition, this scaffold has re-
cently gained interest due to the photophysical properties
of some of its derivatives.9c,d
Table 1 Synthesis of the Starting 4-Aminocoumarins 2a–l
R3
H
N
4
OH
5
R2
R2
6
NH4OAc (R3 = H) or R3NH2
130 °C, 4–6 h
3
2
7
O
O
O
O
8
1
R1
R1
4
2
Coumarins fused to 1,3-oxazines have been reported.
Essentially all of them have been synthesized by sequential
aminomethylation of 7-hydroxy- (F),6a,10 4-hydroxy- (G)11
and 3-hydroxy- (H)12a coumarins, followed by N,O-acetal-
ization. 1,3-Oxazines resulting from other hydroxycouma-
rins have also been described.12b–d
Triazoles are five-membered heterocycles with three ni-
trogen atoms, being found in antifungals (ravuconazole,
fluconazole),13a antibiotics (tazobactam, cefatrizine)13b and
antiepileptics (rufinamide),13c among others. The 1,2,3-re-
gioisomer has gained biological significance,14 coumarins
with an attached triazole motif have been tested as antican-
cer, antibacterial and antitubercular (I) agents.15 1,2,3-Tri-
azoles have also elicited interest for the photophysical
properties of their derivatives.16
Recently, we have focused our attention on the synthe-
sis and evaluation of polysubstituted coumarins.17 In pur-
suit of such an interest, herein we report the synthesis of
the unprecedented 1,4-dihydro-2H,5H-chromeno[4,3-
d][1,3]oxazin-5-ones 1 from 4-aminocoumarins 2, through
a convenient one-pot hydroxymethylation/N,O-acetaliza-
tion sequence in aqueous medium, as well as their N-func-
tionalization with alkyl, aryl and tethered 1,2,3-triazolyl-
methyl (3) moieties (Scheme 1). Considering the scarcity of
information on the photophysical properties of 4-amino-
coumarin derivatives,18 photophysical characteristics of the
synthetic heterocycles are also discussed.
Entry
Coumarin R1
R2
R3
Product Yield (%)
1
2
4a
4b
4c
4a
4b
4c
4a
4a
4a
4a
4a
4a
H
H
H
2a
2b
2c
2d
2e
2f
62
75
82
79
80
78
57
77
80
69
70
73
Me
H
H
Cl
H
H
Cl
H
H
H
H
H
H
H
3
H
4
H
Ph
5
Me
H
Ph
6
Ph
7
H
4-MeC6H4
4-FC6H4
4-ClC6H4
Bn
2g
2h
2i
8
H
9
H
10
11
12
H
2j
H
PhCH2CH2
n-Bu
2k
2l
H
Next, the installation of the 1,3-oxazine moiety was un-
dertaken. We reasoned that the proposed framework
should be accessible if we could manage to control the un-
precedented 3-hydroxymethylation of the starting 4-ami-
nocoumarins,19b and couple this transformation with an
N,O-acetalization of the resulting -amino alcohols. Since
formaldehyde is the most suitable reagent for both reac-
tions, it was hoped that ideally both transformations could
be performed as a one-pot process.
Surprisingly, however, we found out that only a handful
of scattered articles report the access to 1,3-oxazines from
enamino derivatives of 1,3-dicarbonyl compounds.20 Fur-
ther, it was apparent that the transformation has not been
carried out previously with enamines resulting from 3-keto
lactones. In addition, due to the reactivity of the resulting
product, the 3-hydroxymethylation of coumarins is also a
highly uncommon transformation, which may result in
over-reaction.21
With this background in mind, we initially undertook
optimization of the synthesis of oxazine derivative 1a, by
reaction between 4-aminocoumarin (2a) and formalde-
hyde. First, the reaction was studied under Lewis acid pro-
motion (Table 2) and consumption of the starting material
was monitored by TLC, where the product was luminescent
when irradiated with UV light. However, in dioxane, only
traces of product were detected when the reaction was
driven by 1 equivalent of BF3·OEt2 (entry 1). Changing the
promoter to SnCl4 gave a 42% yield of 1a after 3 hours at
60 °C (entry 2), which increased to 71% upon using THF as
solvent over 1.5 hours (entry 3). On the other hand,
R2
R1
H
R1
O
N
O
N
O
O
O
R2
H
R2
R3
R2 = H, Me
R1 = H, alkyl, Ar
N
N
R
O
R
N
2
1
Br
N
O
O
R3N3
R1 = R2 = H
R
O
3
Scheme 1 Proposed synthetic approach toward 1,4-dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-ones 1 and 1,2,3-triazolylmethyl-substi-
tuted derivatives 3
The starting 4-aminocoumarins 2a–l were conveniently
and uneventfully synthesized in 57–82% yield (Table 1), as
reported by Saha and co-workers,19a from the readily avail-
able 4-hydroxycoumarins 4a–c, by heating for 4–6 hours
with NH4OAc and different primary amines.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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M. C. Dilelio et al.
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Synthesis
FeCl3·6H2O resulted in a 76% yield of 1a when THF was em-
ployed as solvent (entry 4), but a meagre performance was
attained (34% yield) when the reaction was executed in wa-
ter (entry 5).
mance was attained in water with 12 equivalents of the ac-
id, after warming the reaction at 60 °C for 0.5 hours (77%
yield, entry 14). Although the transformation exhibited a
result similar to that of entry 4, the shorter reaction time
combined with the use of a convenient mineral acid in wa-
ter were considered highly convenient conditions and the
best choice. Diminishing the amount of H2SO4 led to re-
duced yields, even after longer reaction times. In addition,
carrying out the reaction at room temperature was also less
efficient.
After establishing the optimal reaction conditions to ac-
cess the dihydro-1,3-oxazine system, the substrate scope
for the synthesis of heterocycles 1 was investigated, extend-
ing the study to the starting aminocoumarins 2b–l. Intro-
duction of an additional point of variation through the in-
stallation of an additional substituent on the nitrogen atom
(2d–l) proved to be important, since it ultimately afforded
more stable heterocycles.
In general, the optimized protocol proved to be effective
(Table 3) with formaldehyde at 60 °C (entries 1–11), fur-
nishing moderate to good yields of product (34–85%) in re-
action times ranging from 0.5 to 18 hours. Not unexpected-
ly, the reactions of the primary amines 2a–c were compara-
tively speedier (entries 1–3), whereas among the secondary
amines, in general, those bearing alkyl or benzyl substitu-
ents (entries 10–17) reacted faster than their aromatic
counterparts (entries 4–9). Interestingly, while the use of
TFA as promoter (Table 2, entries 8 and 9) proved to offer
suboptimal results during the optimization stage, it was su-
perior to H2SO4 in the case of coumarins 2e and 2f (Table 3,
entries 5 and 6).
In addition, it was found that, under the standard condi-
tions, benzylamine 2j gave only a 16% yield of 1j after 5
hours (entry 10); however, the yield increased to 44–49%
(0.5–1 h) when THF was added as cosolvent (entries 11 and
12). The transformation was also successful at room tem-
perature (entry 13), proceeding in 3.5 hours and 47% yield.
Analogously, compound 1k was obtained in 56% yield after
4 hours (entry 14).
A similar observation was made with 4-aminocoumarin
2l (entries 15–17), which gave only a 13% yield of 1l when
the reaction was executed in water. In this case, addition of
THF improved the performance to 25% yield, while running
the reaction at room temperature resulted in a 39% yield of
1l.
When the reaction protocol was applied to other alde-
hydes (entries 18–20), the most reactive acetaldehyde (en-
try 18) furnished the expected heterocycle 1m (90% yield
after 1 h), whereas the less reactive benzaldehyde and bu-
tanal gave no reaction at all (entries 19 and 20).
Although the intimate details of the constructive mech-
anism for the dihydro-1,3-oxazine ring system of the 1,3-
oxazino[5,4-c]coumarins remain unclear, a mechanistic
picture for the reaction can be advanced, based on litera-
ture proposals for similar transformations.22
Table 2 Optimization of the Synthesis of 1,4-Dihydro-2H,5H-chrome-
no[4,3-d][1,3]oxazin-5-one (1a)a
H
NH2
O
N
O
O
O
H2C=O, conditions
O
2a
1a
Entry
Promoter (equiv) Solvent
Temp (°C)Time (h) Yield (%)b
1
2
BF3·OEt2 (1)
SnCl4 (1)
dioxane
dioxane
THF
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
r.t.
60
3
traces
42
3
3
SnCl4 (1)
1.5
4
71
4
FeCl3·6H2O (1)
FeCl3·6H2O (1)
H3BO3 (1)
TsOH (1)
TFA (1)
THF
76
5
H2O
2
34
6
dioxane
dioxane
dioxane
THF
4
–
7
16
traces
61
8
2
9
TFA (1)
2
56
10
11
12
13
14
15
16
17
18
19
HCl (12)
dioxane
THF
1.5
3
21
HCl (12)
35
HCl (12)
H2O
2
44
HCl (12)
H2O
3.5
0.5
3.5
2
70
H2SO4 (12)
H2SO4 (12)
H2SO4 (4)
H2SO4 (8)
H2SO4 (12)
H2SO4 (1)
H2O
77
THF
47
H2O
61
H2O
3.5
0.5
0.5
47
H2O
63
H2O
60c
a Reaction conditions, unless otherwise stated: 2a (0.5 mmol), 37% formal-
dehyde solution (2 mL), promoter (1 equiv), open system.
b After purification by column chromatography.
c 37% formaldehyde solution (1 mL).
With the aim of still improving the yield, the perfor-
mance of protic acids was tested. However, essentially no
product was observed when H3BO3 or TsOH in dioxane was
used (entries 6 and 7). Interestingly, however, yields of 61%
and 56% were achieved with TFA when the solvents were
dioxane and THF (entries 8 and 9), respectively. The use of
3 M HCl in different media (entries 10–13) revealed that the
best performance (70% yield) was reached in water (60 °C,
3.5 h), at the expense of using 12 equivalents of the pro-
moter.
On the other hand, tests with 3 M H2SO4 were also car-
ried out (entries 14–19) to assess the most suitable
amounts of acid and formaldehyde required, as well as the
ideal temperature for the synthesis. Here, the best perfor-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

D
M. C. Dilelio et al.
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Synthesis
Table 3 Scope of the Synthesis of 1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-ones 1
R4
R3
H
R3
2
N
O
N
O 3
1
10
7
R2
R2
9
R4CHO, H2SO4, H2O, 60 °C
R4
4
5
8
O
O
O
6
R1
R1
2
1
Entry
Coumarin
R1
R2
R3
R4
Time (h)
Product
Yield (%)a
1
2
2a
2b
2c
2d
2e
2f
H
H
H
Cl
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.5
0.5
0.5
16
16
16
1.5
16
18
5
1a
1b
1c
1d
1e
1f
77 (61)b
85
Me
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3
H
41
4
Ph
Ph
Ph
79
5
34 (78)b
38 (76)b
6
c
7
2g
2h
2i
4-MeC6H4
H
1g
1h
1i
–
8
4-FC6H4
H
82
40
16
49d
44e
47d,f
56
13
25e
39e,f
90
–
9
4-ClC6H4
H
10
11
12
13
14
15
16
17
18
19
20
2j
Bn
H
1j
2j
Bn
H
0.5
1
1j
2j
Bn
H
1j
2j
Bn
H
3.5
4
1j
2k
2l
PhCH2CH2
H
1k
1l
n-Bu
n-Bu
n-Bu
H
H
3
2l
H
1
1l
2l
H
1
1l
2a
2a
2a
Me
Ph
n-Pr
1
1m
1n
1o
H
24
24
H
–
a Isolated yield after column chromatography.
b TFA used as acid catalyst.
c The product was detected by EI-MS, but extensive decomposition took place during the chromatographic purification.
d THF added.
e THF added after 30 min of reaction.
f Reaction carried out at room temperature.
In the first stage, a hydroxymethylation of 2a can be
suggested (Scheme 2), where the double bond of coumarin
2a may perform a nucleophilic attack at the electrophilic
center of the aldehyde, to give iminium intermediate A, un-
der assistance by the lone electron pair of the nitrogen. Sub-
sequent removal of the proton attached to C-3 would re-
generate the coumarin unsaturation (B) and the acid medi-
um.
In the next step, hydroxymethyl enamine intermediate
B may undergo an acid-catalyzed N,O-acetalization. Thus,
the electrophilic center of the aldehyde would be attacked
again, by the free electron pair of the amine, resulting in
bis-hydroxymethyl intermediate C. A prototropic rear-
rangement would then take place, to afford protonated in-
termediate D which, in the next step, could undergo dehy-
dration to furnish Mannich base E. Then, the thus-formed
iminium ion could be attacked by the neighboring alcohol
in a fashion reminiscent of the Prins reaction, to give pro-
tonated intermediate F. Final deprotonation of the latter
should result in dihydro-1,3-oxazine derivative 1a.
A quite similar mechanism could account for analogous
transformations, such as the gold-catalyzed mechanochem-
ical synthesis of tetrahydropyrimidines and octahydro-
quinazolines from enaminone derivatives of 1,3-dicarbonyl
precursors.23
The photophysical properties of the synthesized hetero-
cycles were next examined, commencing with an analysis
of their UV spectra (Figure 2), measured between 250 and
400 nm, on 10–4 M DMSO solutions. The coumarin ring oxy-
gen atom has an sp2 hybridization, being part of the -sys-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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M. C. Dilelio et al.
Paper
Synthesis
Table 4 Photophysical Data of 1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-ones 1
a
d
Entry
Compound
max, nm (, mol–1·cm–1
)
em, nm (Φf)b
E
0-0 (eV)c
Stokes shift (nm, 103 cm–1
)
1
2
1a
1b
1c
1d
1e
1f
279 (2529), 314 (3693)
279 (2521), 316 (3696)
306 (6019), 324 (6347)
280 (2428), 314 (3590)
287 (4151), 315 (4521)
268 (sh),e 322 (4507)
280 (6578), 313 (8530)
281 (3575), 314 (4940)
265 (3836), 303 (5022)
257 (3878), 306 (4737)
260 (4607), 305 (5546)
296 (3448), 315 (3664)
380 (0.48)
379 (0.30)
395 (0.42)
502 (0.32)
495 (0.37)
523 (0.69)
501 (0.47)
492 (0.68)
416 (0.59)
428 (0.66)
426 (0.52)
377 (0.25)
3.594
3.583
3.492
2.870
2.837
2.883
2.871
2.890
3.492
3.483
3.454
3.647
66, 5.5
63, 5.3
3
71, 5.5
4
188, 11.9
180, 11.5
201, 11.9
188, 12.0
178, 11.5
113, 9.0
122, 9.3
121, 9.3
62, 5.2
5
6
7
1h
1i
8
9
1j
10
11
12
1k
1l
1m
a In DMSO solution at a concentration of 10–4 M; the position of the first maximum (~255 nm) is not listed.
b In DMSO solution at a concentration of 10–6 M, employing 9,10-diphenylanthracene (DPA) as standard (Φf = 0.65) in CHCl3.
c E0-0 = 1240/.
~
d Δ = em – max, in nm, or Δ = 107 · (1/max – 1/em), in cm–1
.
e sh = shoulder.
+
Most probably, any n→* transition which also takes place
( <100) is submerged under the comparatively stronger
→* transitions ( >2400). The band around 255 nm may
be caused by →* transitions in the isocyclic ring; the re-
maining bands seem to correspond to characteristic transi-
tions between molecular orbitals of the whole coumarin
ring system.24a The lower-energy band has been assigned to
the HOMO→LUMO transition, whereas it has been pro-
posed that the 285 nm band corresponds to the HOMO-
1→LUMO transition.24b
OH
:
NH2
NH2
H
H
O+
H
H
O
O
O
O
2a
A
– H+
H
H
+
O+
OH2
:OH
N+
H
H
..
N
H
OH
OH
NH2 OH
H
In the less-functionalized compounds 1a,b, the first
maximum was hardly visible (Table 4, entries 1 and 2), be-
ing more evident in 1c and 1m (entries 3 and 12). Com-
pounds 1j–l, bearing nitrogen substituents unable to conju-
gate with the nitrogen (n-Bu, Bn, PhCH2CH2), displayed
broad maxima (entries 9–11) around 268 nm, whereas 9-
chloro derivatives 1c and 1f showed the most hypsochro-
mic peaks of the series, at 324 and 322 nm, respectively
(entries 3 and 6). Bathochromic and hyperchromic effects
were detected on the second and third maxima of the N-
aryl-substituted derivatives 1e, 1f, 1h and 1i, related to the
substituent electron-withdrawing ability (entries 5–8). No-
tably, fluorinated derivative 1h (entry 7) exhibited a mark-
edly higher absorption in the studied range, with  = 8530
(max = 313 nm). However, all compounds displayed very
low absorption at 375 nm and were essentially transparent
in the visible region.
O
O
O
O
O
O
D
C
B
– H2O
H
..
OH
H
+
O
H
H
+N
N
O
O
O
N
– H+
O
O
O
O
E
F
1a
Scheme 2 Plausible mechanism of the H2SO4-promoted cyclization of
4-aminocoumarin (2a) with formaldehyde to afford 1,4-dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-one (1a)
tem of the molecule, and the UV spectra of the heterocycles
may show →* and n→* transitions, where one of the lat-
ter relates to the C=O chromophore. It was observed (Figure
2A) that the compounds exhibit spectra with a similar gen-
eral shape, and 2–3 distinguishable maxima, around 255
nm, at approximately 285 ± 20 nm and at 315 ± 10 nm.24
The fluorescence measurements were made on 10–6
M
DMSO solutions, where other coumarin derivatives have af-
forded higher fluorescence intensity than in other sol-
vents.18a It was detected that the emission maxima (em
)
and fluorescence quantum yields (Φf) depend on the cou-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

F
M. C. Dilelio et al.
Paper
Synthesis
ty, its 9-chloro congener 1f displayed the most-red-shifted
emission (em = 523 nm) and the highest quantum efficien-
cy (Φf = 0.69), comparable with that of 1i (entry 8).
Some multicolor imaging microscopy methods require
fluorophores with large Stokes shifts, to reduce the number
of detection channels and simplify the experimental imag-
ing scheme. These fluorophores, among them coumarins,
are still rare.25 The N-aryl-substituted 1,4-dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-one motif is a compact fluo-
rophore with a large Stokes shift and many potential diver-
sification points. It may be considered as a starting scaffold,
suitable for further modification toward enlarging the list
of chemical probes for microscopy and similar fields.
Next, further functionalization of the rather unstable
tricyclic compounds was conveniently achieved in two
steps by means of a click reaction,26 affording more stable
heterocycles. Thus, compound 1a was first submitted to an
N-alkylation with propargyl bromide in DMF for 5 hours,
using KOH as base,27 to obtain 5 in 66% yield (Table 5). Then,
the latter was subjected to catalytic azide–alkyne cyclo-
addition with different alkyl and aryl azides in the presence
of sodium ascorbate and CuSO4 as the catalyst system26c for
3–5 hours, which afforded the expected 1,4-disubstituted
1,2,3-triazoles 3a–e in good to excellent overall yields. The
azides required for the click cycloaddition reaction were
Figure 2 (A) Excitation spectra of 1,4-dihydro-2H,5H-chromeno[4,3-
d][1,3]oxazin-5-ones 1a–f,h–m in DMSO at a concentration of 10–4 M.
(B) Emission spectra of the heterocycles, in DMSO at a concentration of
10–6 M.
Table 5 Triazolization of 1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]ox-
azin-5-one (1a)
marin substituents. Excitation of the lowest-energy absorp-
tion band at its maximum resulted in em around 385 ± 10
nm (Figure 2B) in the case of the N-unsubstituted com-
pounds 1a–c and 1m (Table 4, entries 1–3 and 12), where a
comparatively small Stokes shift (62–71 nm; equivalent to
5.2–5.5 × 103 cm–1) was observed. This parameter indicates
the extent of the red shift of the fluorescence maximum
(em) compared to the corresponding absorption peak
(max). Their Φf values were in the range 0.25–0.48, being
lower among the compounds bearing methyl substituents
on the homocyclic (1b) and oxazine (1m) rings.
H
N
O
O
O
N
O
O
O
Br
R
N
N
KOH, DMF,
r.t., 5 h (66%)
N
1a
5
RN3, Na ascorbate (5 mol%),
CuSO4·5H2O (5 mol%),
urea (5 mol%), MeOH, r.t.
N
O
O
O
3a–e
Installation of a nitrogen substituent caused a notice-
able red shift in the emission maxima. The heterocycles 1j–
Entry
R
Time (h) Product
Yield (%)a
l (entries 9–11) bearing non-conjugating substituents (em
=
1
2
3
4
Bn
Ph
4
4
3
5
3a
3b
3c
3d
96
68
69
65
422 ± 6 nm), displayed a small shift (~35 nm) and a slight
increase in their Stokes shift (117 ± 4 nm; equivalent to 9.0–
9.3 × 103 cm–1). These compounds also displayed higher Φf
values (0.52–0.66) than their N-unsubstituted congeners
(entries 1–3 and 12). On the other hand, the N-aryl-substi-
tuted compounds 1d–f,h,i (entries 4–8) possessed emission
maxima around 500 nm and larger Stokes shifts (180–200
nm). This results in lower E0-0 values (2.83–2.89 eV), mean-
ing that their normalized excitation and emission spectra
cross each other at longer wavelengths. While the N-phe-
nyl-substituted derivative 1d exhibited the highest intensi-
4-MeC6H4
4-ClC6H4
5
5
3e
84
MeO
O
O
a Isolated yield after column chromatography.
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G
M. C. Dilelio et al.
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Synthesis
conveniently obtained by diazotization–azidation of the
corresponding anilines in the case of the aromatic com-
pounds, while nucleophilic substitution of the correspond-
ing alkyl halides with azide ion was used to access the re-
maining counterparts.28
The excitation spectra of alkyne precursor 5 and the re-
sulting 1,2,3-triazole derivatives 3a–e (Figure 3) were ac-
quired in DMSO solutions, as done before. In general, the
spectra were reminiscent of that of the structurally similar
compound 1j (Figure 3A). The heterocycles displayed a
sharp peak at 263 ± 5 nm (Table 6) and a twin peak around
302 and 314 nm (entries 1–5), except for the coumarin de-
rivative 3e (entry 6). All of these compounds were essen-
tially UV transparent beyond 350 nm.
values, in the range 0.41–0.66, and the Stokes shifts (89–
112 nm; equivalent to 6.7–8.4 × 103 cm–1) were also similar
to those exhibited by 1j.
All products were characterized by NMR spectroscopy
and high-resolution mass spectrometry. In the 1H NMR
spectra, H-2 was observed as a singlet in the  4.55 ppm re-
gion, whereas H-4 appeared as broad doublet around  4.85
ppm. The latter experienced a small deshielding (~0.2 ppm)
and became a singlet in the N-aryl derivatives (1d–f,h,i),
and suffered a similar shielding effect in the case of the
non-conjugating alkyl (1k, 1l), benzyl (1j) and 1,2,3-tetra-
zole (3a–e) derivatives.
On the other hand, in the 13C NMR spectra, the diagnos-
tic C-2 resonance was observed at ~92 ppm in the N-unsub-
stituted tricycles (1a–c), being more shielded (~82 ppm) in
the N-aryl derivatives (1d–f,h,i) and even slightly more
shielded (~78 ppm) in the heterocycles bearing non-conju-
gating substituents (1j–l and 3a–e). A characteristic and
highly deshielded singlet ( 8.35–9.0 ppm) confirmed the
presence of the 1,2,3-tetrazole moiety in 3a–e.
In summary, we have developed and optimized a facile
and convenient H2SO4-mediated one-pot approach to the
synthesis of fused coumarin and 1,3-oxazine heterocycles.
The reaction takes place in moderate to good yields, from 4-
aminocoumarins in water or water/THF mixtures, provid-
ing a direct and useful entry to the virtually unexplored
1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-ones.
The use of amines for the preparation of the 4-aminocou-
marin precursors yields N-substituted tricycles. On the oth-
er hand, N-alkylation of the oxazine moiety with a propar-
gyl halide, followed by copper-catalyzed azide–alkyne cyc-
loaddition, enabled the installation of a tethered 1,2,3-
triazole moiety.
The photophysical characteristics of the heterocycles
were studied, with the observation that N-alkylation of the
oxazine moiety (alkyl, benzyl, 1,2,3-triazolylmethyl) caused
a small red shift (~35 nm) of the fluorescence spectra,
which displayed emission peaks around 419 ± 10 nm,
whereas the N-phenyl derivatives exhibited fluorescence
peaks in the green region (~500 nm) and Stokes shifts up to
Figure 3 (A) Excitation spectra of alkyne 5 and 1,2,3-triazole deriva-
tives 3a–e of 1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one in
DMSO, in the range 250–450 nm. (B) Emission spectra of the com-
pounds in DMSO, in the range 350–580 nm.
On the other hand, the emission spectra of 3a–e (Figure
3B) were similar in shape, also resembling the emission
spectrum of 1j and displaying a single maximum at 413 ± 2
nm except for compound 3c (lambda em= 426 nm). Their Φf
Table 6 Photophysical Data of Compound 5 and the 1,2,3-Triazole Derivatives 3a–e of 1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
a
d
Entry
Compound
max, nm (, mol–1·cm–1
)
em, nm (Φf)b
E
0-0 (eV)c
Stokes shift (nm, 103 cm–1
)
1
2
3
4
5
6
5
266 (5151), 301 (6417), 314 (6045)
268 (1940), 302 (2519), 314 (2368)
260 (6803), 302 (4942), 314 (4551)
258 (5135), 301 (3111), 314 (2793)
262 (7181), 301 (4406), 314 (3951)
<250, 324 (7987)
411 (0.63)
415 (0.64)
413 (0.41)
426 (0.61)
411 (0.66)
413 (0.50)
3.483
3.594
3.604
3.604
3.615
3.406
97, 7.5
101, 7.8
99, 7.6
112, 8.4
97, 7.5
89, 6.7
3a
3b
3c
3d
3e
a In DMSO solution at a concentration of 10–4 M.
b In DMSO solution at a concentration of 10–6 M, employing DPA as standard (Φf = 0.65) in CHCl3.
c E0-0 = 1240/.
~
d Δ = em – max, in nm, or Δ = 107 · (1/max – 1/em), in cm–1
.
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H
M. C. Dilelio et al.
Paper
Synthesis
200 nm (equivalent, in wavenumber units, to 1d: 11.9/1h:
12 × 103 cm–1). The large Stokes shifts (up to 12 × 103 cm–1),
coupled with Φf values in the range 0.25–0.69, with most
compounds being over 0.5, turn these compounds into po-
tential scaffolds toward the design of organic dyes useful for
biological imaging.
with brine (10 mL), dried over MgSO4 and concentrated under re-
duced pressure, and the residue was purified by silica gel column
chromatography.
1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one (1a)
Yellowish solid; yield: 77% (78 mg); mp 211–213 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.29 (s, 1 H), 7.85 (dd, J = 7.9, 1.3
Hz, 1 H), 7.62–7.56 (m, 1 H), 7.38–7.30 (m, 2 H), 4.85 (d, J = 3.4 Hz, 2
H), 4.52 (s, 2 H).
The reagents for synthesis were obtained commercially. Solvents
were purified and dried according to usual procedures.29 All other re-
agents were used as received, without further purification. The prog-
ress of reactions was monitored by TLC on silica gel plates. For detec-
tion of the spots, the plates were exposed to UV light (254 and 365
nm), I2 or H2SO4/vanillin solution. Chromatographic purifications
were performed by column chromatography employing silica gel
(230–400 mesh, 40–63 m), and eluting with hexane–EtOAc mix-
tures of increasing polarity. Melting points were taken on an MQAPF-
13C NMR (100 MHz, DMSO-d6):  = 158.9, 152.4, 147.7, 131.7, 123.7,
122.0, 116.9, 113.7, 92.0, 72.9, 63.2.
EI-MS: m/z (%) = 203 (M+, 50), 174 (100), 146 (58), 118 (47), 91 (94),
63 (95).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C11H10NO3: 204.0661;
found: 204.0670.
7-Methyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
(1b)
301 melting point apparatus and are reported uncorrected. 1H and 13
C
NMR spectra were recorded on Bruker 400 and 600 (for compound
1m) MHz NMR spectrometers, with the samples dissolved in DMSO-
d6. Chemical shifts are given in ppm downfield from the signal of
TMS, used as internal standard, and coupling constants (J) are ex-
pressed in hertz (Hz). Electron-impact low-resolution mass spectra
(EI-MS) were obtained on a Shimadzu QP2010 gas chromatograph
coupled to a mass spectrometer. The relative intensity of the signals is
given. High-resolution mass spectral data were obtained on an LTQ
Orbitrap Discovery mass spectrometer (Thermo Fisher Scientific), us-
ing sodium formate as reference. UV–vis absorption spectra were ac-
quired on a Shimadzu UV-2600 spectrophotometer and fluorescence
spectra were obtained with a Varian Cary 50 fluorescence spectro-
photometer. The emission slit was set at 2.0 mm.
Brownish solid; yield: 85% (92.3 mg); mp 204–206 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.24 (s, 1 H), 7.70–7.65 (m, 1 H),
7.48–7.43 (m, 1 H), 7.23 (t, J = 8.1 Hz, 1 H), 4.83 (d, J = 3.5 Hz, 2 H),
4.52 (s, 2 H), 2.36 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 158.5, 150.5, 147.7, 132.3, 125.4,
122.8, 119.3, 113.3, 91.9, 72.8, 62.9, 14.9.
EI-MS: m/z (%) = 217 (M+, 64), 188 (100), 160 (30), 132 (31), 104 (29),
77 (50).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C12H12NO3: 218.0812;
found: 218.0812.
9-Chloro-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
(1c)
Photophysical Determinations
Yellowish solid; yield: 41% (48.4 mg); mp 255–257 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.45 (s, 1 H), 8.03–8.00 (m, 1 H),
7.63–7.59 (m, 1 H), 7.38–7.34 (m, 1 H), 4.84 (s, 2 H), 4.51 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 158.5, 151.0, 146.7, 131.4, 127.9,
121.7, 119.0, 115.1, 92.7, 72.9, 63.1.
EI-MS: m/z (%) = 239 ([M + 2]+, 17), 237 (M+, 50), 210 (33), 208 (100),
153 (29), 125 (33), 89 (26), 63 (39).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C11H9ClNO3: 238.0271;
UV–vis absorption spectra were measured at 1.0 nm intervals, with
the samples dissolved in DMSO at a concentration of 10–4 M, in a 10
mm optical path length quartz cuvette. Fluorescence spectra and flu-
orescence quantum yields were measured on 10–6 M DMSO solutions
of the compounds, in a 10 mm optical path length quartz cuvette. Ex-
citation was performed at the lowest-energy electronic transition of
each derivative and the spectra were corrected according to the man-
ufacturer’s instructions. The fluorescence quantum yields (Φf) were
measured by comparison with the corrected fluorescence spectrum
of 9,10-diphenylanthracene (DPA) in CHCl3 (Φf = 0.65, ex = 366
nm),17a,30 using the standard equation:
found: 238.0277.
Φfspl = Φfref · Ifspl · Aref · ηspl/(Ifref · Aspl · ηref
)
1-Phenyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
(1d)
where Φf, If, A, and η are the fluorescence quantum yield, integrated
fluorescence intensity under the emission band of the fluorophore,
optical density at the excitation wavelength, and refractive index of
the studied solvents, respectively, for the sample (spl) and the refer-
ence (ref).
White solid; yield: 79% (110 mg); mp 200–201 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.51–7.46 (m, 1 H), 7.42–7.33 (m, 3
H), 7.25–7.15 (m, 3 H), 7.09–7.03 (m, 1 H), 6.98–6.94 (m, 1 H), 5.04 (s,
2 H), 4.66 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 159.0, 152.5, 149.0, 146.7, 131.0,
129.5 (2 C), 125.4, 124.7, 124.4 (2 C), 123.4, 117.0, 115.5, 109.9, 82.8,
63.5.
EI-MS: m/z (%) = 279 (M+, 32), 248 (100), 220 (19), 204 (36), 167 (21),
77 (57).
1,4-Dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-ones 1; General
Procedure
A stirred solution of 37% formaldehyde in water (2 mL, 24.67 mmol)
was successively treated with 3 M H2SO4 (2 mL) and a 4-aminocouma-
rin 2 (0.5 mmol). The reaction was heated at 60°C and further stirred
until judged complete by TLC, when the mixture was treated with sat-
urated NaHCO3 solution to neutralize the acid and EtOAc (4 × 15 mL)
to extract the product. The combined organic extracts were washed
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C17H14NO3: 280.0974;
found: 280.0989.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

I
M. C. Dilelio et al.
Paper
Synthesis
7-Methyl-1-phenyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxaz-
1-Benzyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
in-5-one (1e)
(1j)
White solid; yield: 34% (50.4 mg); mp 198–199 °C.
White solid; yield: 49% (71.8 mg); mp 136–137 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.38–7.32 (m, 3 H), 7.23–7.19 (m, 1
H), 7.18–7.14 (m, 2 H), 6.98–6.93 (m, 1 H), 6.84–6.80 (m, 1 H), 5.04 (s,
2 H), 4.66 (s, 2 H), 2.38 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 159.0, 150.8, 149.5, 147.0, 132.0,
129.5 (2 C), 125.8, 125.3, 124.4 (2 C), 123.0, 122.4, 115.3, 109.9, 82.9,
63.4, 15.3.
EI-MS: m/z (%) = 293 (M+, 42), 263 (58), 262 (100), 218 (32), 180 (23),
77 (63).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C18H16NO3: 294.1125;
1H NMR (400 MHz, DMSO-d6):  = 7.63–7.56 (m, 2 H), 7.51–7.40 (m, 5
H), 7.38–7.27 (m, 2 H), 4.59 (s, 2 H), 4.57 (s, 2 H), 4.55 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 158.9, 153.1, 152.4, 137.2, 131.5,
128.8 (2 C), 127.5, 127.1 (2 C), 124.2, 122.9, 117.3, 115.8, 108.5, 78.7,
63.1, 55.6.
EI-MS: m/z (%) = 293 (M+, 13), 202 (15), 91 (100), 65 (12).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C18H16NO3: 294.1125;
found: 294.1126.
found: 294.1133.
1-Phenethyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-
one (1k)
9-Chloro-1-phenyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxaz-
in-5-one (1f)
Yellowish solid; yield: 56% (86 mg); mp 119–120 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.56–7.45 (m, 1 H), 7.46 (dd, J = 8,
1.4 Hz, 1 H), 7.36 (dd, J = 8.3, 1.0 Hz, 1 H), 7.28–7.20 (m, 6 H), 4.74 (s, 2
H), 4.50 (s, 2 H), 3.54 (t, J = 7.3 Hz, 2 H), 3.06 (t, J = 7.3 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 158.9, 153.1, 152.3, 138.7, 131.2,
128.9 (2 C), 128.2 (2 C), 126.3, 123.9, 123.5, 117.0, 115.8, 108.5, 78.3,
63.0, 54.0, 34.7.
Yellow solid; yield: 38% (59.4 mg); mp 195–197 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.56–7.52 (m, 1 H), 7.45–7.37 (m, 3
H), 7.30–7.24 (m, 1 H), 7.23–7.19 (m, 2 H), 6.87–6.86 (m, 1 H), 5.03 (s,
2 H), 4.67 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 158.4, 151.0, 147.7, 146.0, 130.5,
129.5 (2 C), 127.2, 125.6, 124.4 (2 C), 123.7, 118.9, 116.8, 110.5, 82.6,
63.3.
HRMS (ESI-Orbitrap): m/z [M + Na]+ calcd for C19H17NNaO3:
330.1101; found: 330.1098.
EI-MS: m/z (%) = 313 (M+, 39), 283 (59), 282 (100), 238 (17), 77 (78).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C17H13ClNO3: 314.0578;
1-n-Butyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
(1l)
found: 314.0578.
White solid; yield: 39% (51.1 mg); mp 68–70 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.70–7.65 (m, 1 H), 7.63–7.56 (m, 1
H), 7.43–7.36 (m, 2 H), 4.64 (s, 2 H), 4.50 (s, 2 H), 3.34–3.26 (m, 2 H),
1.79–1.69 (m, 2 H), 1.37–1.25 (m, 2 H), 0.90 (t, J = 7.4 Hz, 3 H).
1-(4-Fluorophenyl)-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]ox-
azin-5-one (1h)
Yellowish solid; yield: 82% (121.5 mg); mp 185–186 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.53–7.46 (m, 1 H), 7.43–7.38 (m, 1
H), 7.27–7.16 (m, 4 H), 7.12–7.07 (m, 1 H), 6.96 (dd, J = 8.1, 1.5 Hz, 1
H), 5.00 (s, 2 H), 4.65 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 159.0, 153.4, 152.4, 131.3, 124.2,
123.5, 117.2, 115.9, 108.0, 78.4, 63.1, 52.5, 30.8, 19.6, 13.7.
EI-MS: m/z (%) = 259 (M+, 37), 242 (20), 186 (100), 174 (16), 115 (39),
13C NMR (100 MHz, DMSO-d6):  = 160.2 (JC–F = 142.7 Hz), 158.5,
152.5, 149.0, 143.2 (JC–F = 2.9 Hz), 143.1, 131.1, 126.6 (2 C, JC–F = 5.1
Hz), 126.5, 124.5, 123.6, 117.1, 116.7 (2 C, JC–F = 22.7 Hz), 116.2, 115.4,
110.1, 83.0, 63.4.
77 (13).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C15H18NO3: 260.1287;
found: 260.1299.
EI-MS: m/z (%) = 297 (M+, 41), 267 (64), 266 (100), 246 (27), 222 (44),
185 (29), 75 (21).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C17H13FNO3: 298.0874;
2,4-Dimethyl-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-
one (1m)
White solid; mixture of 1,3-cis- and 1,3-trans-isomers (~2.2:1); yield:
found: 298.0873.
90% (104 mg); mp 248–250 °C.
1H NMR (600 MHz, DMSO-d6):  (major) = 8.17 (br s, 1 H, NH), 8.01
(dd, J = 7.8, 1.2 Hz, 1 H, H-8), 7.61–7.55 (m, 1 H, H-9), 7.37–7.29 (m, 2
H, H-7 and H-10), 5.03 (q, J = 7.4 Hz, 1 H, H-2), 4.71 (q, J = 7.4 Hz, 1 H,
H-4), 1.45 (d, J = 7.4 Hz, 3 H, Me-2), 1.41 (d, J = 7.4 Hz, 3 H, Me-4); 
(minor) = 8.09 (br s, 1 H, NH), 7.99 (dd, J = 7.8, 1.2 Hz, 1 H, H-8), 7.61–
7.55 (m, 1 H, H-9), 7.37–7.29 (m, 2 H, H-7 and H-10), 4.84 (q, J = 7.4
Hz, 1 H, H-2), 4.82 (q, J = 7.4 Hz, 1 H, H-4), 1.47 (d, J = 7.4 Hz, 3 H, Me-
2), 1.45 (d, J = 7.4 Hz, 6 H, Me-4).
1-(4-Chlorophenyl)-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]ox-
azin-5-one (1i)
Yellowish solid; yield: 40% (62 mg); mp 216–218 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.53–7.47 (m, 1 H), 7.43–7.37 (m, 3
H), 7.24–7.18 (m, 2 H), 7.14–7.08 (m, 1 H), 6.96 (dd, J = 8.1, 1.5 Hz, 1
H), 5.03 (s, 2 H), 4.65 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 158.8, 152.4, 148.5, 145.4, 130.9,
129.5, 129.2 (2 C), 126.0 (2 C), 124.3, 123.5, 116.9, 115.2, 110.4, 82.6,
63.3.
EI-MS: m/z (%) = 313 (M+, 39%), 283 (36), 248 (100), 207 (38), 204
(56), 111 (31), 75 (32).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C17H13ClNO3: 314.0584;
found: 314.0603.
13C NMR (100 MHz, DMSO-d6):  (major) = 159.6, 152.9, 147.5, 132.0,
123.8, 123.7, 117.2, 114.4, 96.5, 72.9, 67.8, 20.6, 20.5;

(minor) = 159.1, 152.4, 149.1, 132.4, 123.8, 123.0, 117.0, 114.1, 97.6,
78.8, 70.6, 20.3, 19.8.
EI-MS: m/z (%) = 231 (M+, 30), 216 (100), 198 (54), 186 (387), 130
(23), 91 (18), 77 (12).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C13H14NO3: 232.0974;
found: 232.0984.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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M. C. Dilelio et al.
Paper
Synthesis
1-(Prop-2-yn-1-yl)-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxaz-
in-5-one (5)
1-((1-Phenyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-one (3b)
A solution of 1a (1.015 g, 5 mmol) in DMF (15 mL) was treated with
KOH (0.396 g, 6.6 mmol). After stirring for 15 min, propargyl bromide
(0.5 mL, 6.6 mmol) was added and the mixture was further stirred at
r.t. for 5 h. Then, H2O (20 mL) was added and the product was extract-
ed with EtOAc (4 × 20 mL). The combined organic extracts were
washed with brine (10 mL), dried over MgSO4 and concentrated under
reduced pressure, and the residue was purified by silica gel column
chromatography to afford 5 as a white solid; yield: 792 mg (66%); mp
124–125 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.78–7.73 (m, 1 H), 7.64–7.58 (m, 1
H), 7.44–7.38 (m, 2 H), 4.72 (s, 2 H), 4.53 (s, 2 H), 4.16 (d, J = 2.5 Hz, 2
H), 3.33 (t, J = 2.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6):  = 158.6, 152.2, 151.8, 131.3, 124.0,
123.0, 116.9, 115.6, 109.5, 79.5, 79.0, 75.5, 62.7, 42.0.
White solid; yield: 68% (245 mg); mp 159–161 °C.
1H NMR (400 MHz, DMSO-d6):  = 9.00 (s, 1 H), 8.22–8.17 (m, 1 H),
7.96–7.91 (m, 2 H), 7.66–7.57 (m, 3 H), 7.53–7.47 (m, 1 H), 7.47–7.40
(m, 2 H), 4.66 (s, 2 H), 4.57 (s, 2 H), 4.55 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 159.0, 152.7, 152.5, 144.4, 136.6,
131.4, 129.8 (2 C), 128.6, 124.3, 123.7, 122.3, 120.0 (2 C), 117.0, 115.9,
109.5, 78.0, 63.0, 46.9.
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C20H17N4O3: 361.1295;
found: 361.1300.
1-((1-(p-Tolyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4-dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-one (3c)
White solid; yield: 69% (257 mg); mp 221–222 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.88 (s, 1 H), 8.21–8.15 (m, 1 H),
7.83–7.78 (m, 2 H), 7.67–7.61 (m, 1 H), 7.48–7.38 (m, 4 H), 4.69 (s, 2
H), 4.60 (s, 2 H), 4.56 (s, 2 H), 2.40 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 158.7, 152.6, 152.4, 144.0, 138.0,
134.2, 131.2, 129.9 (2 C), 124.0, 123.6, 122.0, 119.8 (2 C), 116.9, 115.8,
109.2, 78.0, 62.9, 46.8, 20.3.
EI-MS: m/z (%) = 241 (M+, 80), 212 (42), 202 (100), 128 (53), 102 (39),
77 (24).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C14H12NO3: 242.0817;
found: 242.0830.
Aryl Azides; General Procedure
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C21H19N4O3: 375.1452;
found: 375.1457.
The corresponding aniline (5 mmol) was added to a stirred solution of
6 N HCl, maintained at 0 °C in an ice bath. The solution was first treat-
ed with NaNO2 (0.414 g, 6 mmol) and, 10 min later, with NaN3 (0.390
g, 6 mmol). The reaction mixture was stirred in the ice bath for 30
min, when H2O (20 mL) was added and the organic product was ex-
tracted with EtOAc. The product was used directly in the next step.
1-((1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-1,4-dihy-
dro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one (3d)
White solid; yield: 65% (254 mg); mp 237 °C (dec).
1H NMR (400 MHz, DMSO-d6):  = 8.98 (s, 1 H), 8.19–8.14 (m, 1 H),
8.01–7.95 (m, 2 H), 7.71–7.61 (m, 3 H), 7.48–7.42 (m, 2 H), 4.67 (s, 2
H), 4.60 (s, 2 H), 4.55 (s, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 158.7, 152.5, 152.4, 144.4, 132.8,
131.2, 129.6 (2 C), 124.0, 123.5, 122.2, 121.6 (2 C), 116.9, 115.7, 109.2,
78.0, 62.8, 46.8.
Alkyl Azides; General Procedure
A stirred solution of the corresponding halide (5 mmol) in DMSO (10
mL) was treated with NaN3 (390 mg, 6 mmol) and the reaction mix-
ture was stirred overnight at r.t. Then, H2O (20 mL) was added and the
organic product was extracted with EtOAc. The product was used di-
rectly in the next step.
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C20H16ClN4O3: 395.0905;
found: 395.0909.
1,4-Disubstituted 1,2,3-Triazoles 6a–e; General Procedure
A stirred solution of alkyne 5 (0.241 g, 1 mmol) in MeOH (5 mL) was
successively treated with sodium ascorbate (10 mg, 5 mol%), urea (3
mg, 5 mol%) and CuSO4·5H2O (12 mg, 5 mol%). The reaction mixture
was stirred for 15 min at r.t. when the azide (1.2 mmol of alkyl azide;
2 mmol of aryl azide) was added. After the reaction was judged com-
plete by TLC, H2O (20 mL) was added and the product was extracted
with EtOAc (4 × 15 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgSO4 and concentrated under re-
duced pressure. The residue was purified by silica gel column chro-
matography.
1-((1-((7-Methoxycoumarin-4-yl)methyl)-1H-1,2,3-triazol-4-
yl)methyl)-1,4-dihydro-2H,5H-chromeno[4,3-d][1,3]oxazin-5-one
(6e)
Golden solid; yield: 84% (395 mg); mp 194–196 °C.
1H NMR (400 MHz, DMSO-d6):  = 8.39 (s, 1 H), 8.08 (dd, J = 8.0, 1.4
Hz, 1 H), 7.78 (d, J = 8.7 Hz, 1 H), 7.65–7.58 (m, 1 H), 7.44–7.36 (m, 2
H), 7.03–6.97 (m, 2 H), 5.95 (d, J = 1.1 Hz, 2 H), 5.76 (s, 1 H), 4.66 (s, 2
H), 4.62 (s, 2 H), 4.51 (s, 2 H), 3.89 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 162.6, 159.5, 158.7, 154.9, 152.4,
152.3, 149.9, 143.7, 131.2, 125.6, 124.9, 123.9, 123.6, 116.9, 115.7,
112.1, 110.4, 110.3, 109.1, 101.0, 78.3, 62.7, 55.8, 49.1, 47.1.
1-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-1,4-dihydro-2H,5H-
chromeno[4,3-d][1,3]oxazin-5-one (3a)
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C25H21N4O6: 473.1456;
White solid; yield: 96% (358 mg); mp 155–157 °C.
found: 473.1464.
1H NMR (400 MHz, DMSO-d6):  = 8.35 (s, 1 H), 8.13 (dd, J = 8, 1.3 Hz,
1 H), 7.65–7.59 (m, 1 H), 7.46–7.27 (m, 7 H), 5.63 (s, 2 H), 4.61 (s, 2 H),
4.53 (s, 2 H), 4.51 (s, 2 H).
Funding Information
13C NMR (100 MHz, DMSO-d6):  = 159.0, 152.8, 152.5, 143.6, 136.0,
131.5, 128.7 (2 C), 128.0, 127.7 (2 C), 124.3, 124.2, 123.8, 117.1, 115.9,
109.3, 78.2, 63.0, 52.9, 47.1.
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C21H19N4O3: 375.1452;
found: 375.1457.
The authors are thankful to Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq, Grant 429158/2018-1), Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conse-
jo Nacional de Investigaciones Científicas y Técnicas (CONICET, PUE
IQUIR 2016).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–L

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M. C. Dilelio et al.
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Synthesis
Acknowledgment
Chem 2013, 8, 1930. (b) Yayla, H. G.; Peng, F.; Mangion, I. K.;
McLaughlin, M.; Campeau, L.-C.; Davies, I. W.; DiRocco, D. A.;
Knowles, R. R. Chem. Sci. 2016, 7, 2066.
M.C.D. thanks CAPES for her fellowship.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612428.
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