Easy installation of 1,2,3-triazoles or iodo-1,2,3-triazoles onto indole-fused oxazinones via CuAAC-based MCR in the presence of 18-crown-6

Article abstract of DOI:10.1080/00397911.2019.1611857

An efficient protocol was developed to prepare indole-fused oxazinones using silver nitrate. The latter substrates were subjected to multicomponent reactions in the presence of 18-crown-6, which afforded diverse new heterocycles based on an indole-fused oxazinone-1,2,3-triazole scaffold.

Full text of DOI:10.1080/00397911.2019.1611857

Synthetic Communications
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Easy installation of 1,2,3-triazoles or iodo-1,2,3-
triazoles onto indole-fused oxazinones via CuAAC-
based MCR in the presence of 18-crown-6
A. Mayooufi, M. Romdhani-Younes, Y. Carcenac & J. Thibonnet
To cite this article: A. Mayooufi, M. Romdhani-Younes, Y. Carcenac & J. Thibonnet (2019):
Easy installation of 1,2,3-triazoles or iodo-1,2,3-triazoles onto indole-fused oxazinones
via CuAAC-based MCR in the presence of 18-crown-6, Synthetic Communications, DOI:
10.1080/00397911.2019.1611857
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https://doi.org/10.1080/00397911.2019.1611857
Easy installation of 1,2,3-triazoles or iodo-1,2,3-triazoles
onto indole-fused oxazinones via CuAAC-based MCR in the
presence of 18-crown-6
A. Mayooufia,b, M. Romdhani-Younesb, Y. Carcenaca, and J. Thibonneta
a
ꢀ
ꢁ
ꢁ
Laboratoire Synthese et Isolement de Molecules BioActives (SIMBA), Faculte des Sciences et
b
ꢁ
Techniques, Universite de Tours, Tours, France; Laboratoire de Chimie Organique Structurale et
Macromoleculaire, Departement de Chimie, Faculte des Sciences de Tunis, Campus Universitaire
El-Manar, Tunis, Tunisie
ꢁ
ꢁ
ꢁ
ABSTRACT
ARTICLE HISTORY
Received 20 February 2019
An efficient protocol was developed to prepare indole-fused oxazi-
nones using silver nitrate. The latter substrates were subjected to
multicomponent reactions in the presence of 18-crown-6, which
afforded diverse new heterocycles based on an indole-fused oxazi-
none-1,2,3-triazole scaffold.
KEYWORDS
Azides; click chemistry;
iodolactonization; iodo-
triazoles; multicompo-
nent reactions
GRAPHICAL ABSTRACT
Introduction
Polycyclic indole scaffolds constitute the structural core of numerous important classes
of molecules that display an extensive range of biological and pharmacological proper-
ties.[1] For example HKI 0231A and HKI 0231B have shown the ability to inhibit 3a-
hydroxysteroid dehydrogenase, which is a key enzyme in the inflammatory process.[2]
More complex polycyclic indole alkaloids, such as vincristine and vinblastine (antitumor
agents),[3] have been widely investigated.[4] Triazole-bearing indoles (Fig. 1) have also
shown wide-ranging biological activities, such as compound A (anti-adipogenic and
anti-dyslipidemic activity),[5] molecule B (selective inhibitors and inducers of bacterial
biofilms),[6] compound C (antimicrobial activity),[7] and compound D (antifungal
agent).[8] In addition, indole-fused oxazinone derivatives are present in a large number
ꢀ ꢁ
Laboratoire Synthese et Isolement de Molecules
BioActives (SIMBA), EA7502, Universite de Tours, Faculte des Sciences et Techniques, Parc de Grandmont, 32 av. Monge,
37200, Tours, France.
CONTACT J. Thibonnet
jerome.thibonnet@univ-tours.fr
ꢁ
ꢁ
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
A. MAYOOUFI ET AL.
Figure 1. Selected biologically active indole-fused oxazinones and indoles incorporating the 1,2,3-tri-
azole moiety.
of bioactive compounds and some representative members of this family are also
depicted in Fig. 1. For example, compound E,[9] compound F,[10] and compound G,[11]
show anticancer properties. Etodolac H is used for the treatment of arthritis,[12] and
oxazinoindolones I showed anti-inflammatory activity.[13] The aforementioned findings
(Fig. 1) gained our attention because of their great importance in biological sciences,
and because these structures have rarely been described in the literature.
We envisioned that combining a triazole moiety with the indole fused oxazinones
scaffold may lead to potentially bioactive molecules. In the present work, we describe an
easy way to install 1,2,3-triazole and iodo-triazole moieties onto indole-fused oxazinones
through an efficient CuAAC-based multicomponent reaction in the presence of 18-
crown-6 (Fig. 2).
Results and discussion
To achieve our goals, the appropriate cyclization precursors 3a–b were obtained in two
steps starting from ester indoles 1a–b (Scheme 1). After N-alkylation of the latter with
allyl bromide, the resulting indole was saponified to 3a–b in good yields (see SI).

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3
Figure 2. Retrosynthetic strategy for the sequential synthesis of indole-fused oxazinones incorporating
the 1,2,3-triazole moiety.
Scheme 1. Preparation of acids 3a–b.
Table 1. Optimization of Iodolactonization.
Entry
Electrophile (equiv)
Temp (ꢀC)
Base (equiv)
Solvent (ratio)
Additif (equiv)
Yielda (%)
1
2
3
4
5
6
7
8
I2 (3)
70
ꢁ20
70
70
70
70
70
25
25
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (3)
NaHCO3 (3)
K2CO3 (3)
Na2CO3 (3)
KOH (3)
NaH (2)
NaH (2)
NaH (2)
NaH (2)
CHCl3/H2O (1/3)
CH2Cl2
CH2Cl2
–
84
81
54
NIS (2.3)
ICl (3)
NBS (3)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
I2 (3)
2,6-lutidine
–
–
–
–
–
b
CH2Cl2
–
CHCl3/H2O (1/3)
CHCl3/H2O (1/3)
CHCl3/H2O (1/3)
CH2Cl2
CH2Cl2
CH2Cl2
80
80
80
88
99
96c
96
–
9
10
11
AgNO3 (0.5)
AgNO3 (1)
AgNO3 (1.5)
25
25
CH2Cl2
aIsolated yields after column chromatography.
bStarting material, no bromolactonization was observed.
c30 min time of reaction.
For the iodocyclization reaction, other workers[14] reported that the use of I2 and
NaHCO3 at 70 ꢀC afforded the products 4a in 84% yield while using NIS and lutidine
gave the desired compound 4a in 81% yield (Table 1, entries 1 and 2). For our part, we
wished to reexamine this iodocyclization reaction. Firstly, we tested the efficacy of dif-
ferent sources of electrophilic iodine, such as ICl and NIS instead of I2 without chang-
ing other factors (Table 1, entries 3 and 4), but we observed a decrease in the
yield of the desired product 4a. We then evaluated the effect of different bases on the

4
A. MAYOOUFI ET AL.
Scheme 2. Synthetic routes towards triazole-bearing oxazinoindolones.
iodine-mediated electrophilic cyclization of 3a (Table 1, entries 5–8). The results showed
that sodium hydride was the most effective base at room temperature (Table 1, entry 8).
To optimize the reaction conditions, we tested the addition of AgNO3, and this effect-
ively improved the conversion to reach 99% of the desired product (Table 1, entry 9).
An increase in the quantity of the latter additive from 0.5 to 1 equiv reduced the reac-
tion time from 2 h to 30 min, but the yield was not improved (Table 1, entries 10 and
11). Compound 4b was also obtained in good yield (95%) under the same conditions.
This protocol displayed higher yields and lower reaction times than that previously
reported by Joseph and coworkers.[14]
Next, we examined the reactivity of the di-iodinated indole 4a via CuAAC-based
MCR in order to obtain the desired triazole compound 6a. Various one-pot multicom-
ponent syntheses of 1,2,3-triazoles starting from organic halides have been reported in
the literature. We first examined the reaction of di-iodinated indole 4a according to a
literature procedure for an analogous transformation.[15] In our case, the starting di-
iodinated indole 4a was reacted with sodium azide and phenyl acetylene at 50 ꢀC in
EtOH/H2O for 15 h, in the presence of copper iodide. Under these conditions, no
desired product 6a was formed. Although we tested various conditions by changing the
solvents, copper catalysts, base and temperature used for this one-pot two-step
sequence, no successful combination was found.
To access the desired compound 6a, a two-step strategy for the click reaction was
adopted (Scheme 2). Di-iodinated precursor 4a was subjected to nucleophilic substitu-
tion to introduce the azide group under conditions similar to those already employed
for related substrates.[16] Preliminary experiments were carried out using sodium azide
in MeOH/H2O at room temperature. Only a complex mixture of products was obtained,
so different reaction conditions were tested. Initially, we screened the solvent used for
the substitution of 4a to form the azide 5a, and found that the use of aprotic solvents
DMF, acetone and MeCN gave the desired product in only low yield (30%). An increase
in the quantity of NaN3 from 3 to 6 equivalents did not improve the yield of the reac-
tion, and in all cases the isolated yield of the desired product 5a did not exceed 40%.
We also found that increasing the temperature from 25 ꢀC to 55 ꢀC gave only a mixture

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Scheme 3. Optimization of the reaction between indole-fused oxazinones 4a–b and sodium azide.
of products and no desired product 5a was isolated. However, the use of phase transfer
agents proved to be crucial to improve the outcome of the reaction (Scheme 3).[17] We
found that the best phase transfer agent was 18-crown-6 rather than TBAI or TBAF.
Further investigation showed that increasing the amount of additive reduced the reac-
tion time but did not give better yields. Significantly, the protocol was also tolerant of
the di-iodinated precursor 3b to furnish the product 4b in 88% yield.
This success in the synthesis of 5a–b led us to investigate cycloaddition (CuAAC)
reactions of the azide for building systems bearing a 1,2,3-triazole moiety. Traditional
approaches for the synthesis of 1,2,3-triazoles starting from an azide precursor have
been reported in the literature.[18] A first attempt with CuSO4ꢂ5H2O (10 mol%), sodium
ascorbate (20 mol%) and phenylacetylene (1.5 equiv) in toluene:H2O (3:1) at room tem-
perature provided the corresponding product with a moderate yield (53%). After testing
different solvents, we found that by using chlorinated solvents, such as CH2Cl2 or
CHCl3, the products 6a–b could be obtained in higher yields (89% and 82% respect-
ively) (Scheme 4).
In keeping with our efforts to examine the reactivity of 5a, we attempted to synthe-
size 5-iodotriazole 7 through a simple one-pot cycloaddition/iodination reaction.
Initially, we tested this reaction under conditions previously defined by our group
(Table 2, entry 1).[19] This protocol gave the desired product 7 in 55% yield and with a
27/73 ratio of 6a/7, respectively. To increase the selectivity of the reaction, we examined
a range of solvents, catalysts, and reaction times. The use of I2 or NBS as an electro-
philic trapping reagent did not give better results than ICl (Table 2, entries 2 and 3).
Next, we screened other organic solvents (Table 2, entry 4 and 5). The use of chlori-
nated solvents, such as CH2Cl2 or CHCl3, improved the yield of this one pot reaction
but always gave a mixture of 7 and the mono-iodinated compound 6a (85:15). The add-
ition of catalysts, such as NaI or LiI was unsuccessfully tested (Table 2, entries 6 and 7).
We therefore turned our attention to the reaction duration, and it appeared that
extended reaction times increased the yield of the side product 6a (Table 2, entries
8–11). The best result in terms of yield and selectivity was obtained when the reaction
time was limited to 48–50 h (Table 2, entries 8 and 9).
Multicomponent reactions are chemical processes which represent an economically
useful way to synthesize a large number of potentially bioactive molecules by combining
several reaction steps in a single operation. For example, various MCR syntheses of
1,2,3-triazoles have been published in the past decade starting from organic halides,
sodium azide, and terminal alkynes. Our preliminary results showed that 1,2,3-triazoles
could be obtained in very good yields only in the presence of 18-crown-6 starting from

6
A. MAYOOUFI ET AL.
Scheme 4. 1,3-Dipolar cycloaddition between 5a–b and phenylacetylene.
Table 2. Optimization of one-pot cycloaddition/iodation reaction.
Entry
Electrophile (equiv)
Solvent
Time0 (h)
Ratio (7/6a)a
Yield of 7 (%)b
55
1
2
3
4
5
6
7
8
9
ICl (1.2)
NBS (1.2)
I2 (1.2)
THF
THF
THF
60
60
60
60
60
60
60
50
48
40
72
(73/27)
–
c
–
46
74
(71/29)
(85/15)
(88/12)
(88/12)
(88/12)
(90/10)
(93/7)
(95/5)
(66/34)
ICl (1.2)
ICl (1.2)
ICl (1.2))
ICl (1.2)
ICl (1.2)
ICl (1.2)
ICl (1.2)
ICl (1.2)
CHCl3
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
70
72d
74e
77
76
60
53
10
11
aRatios were measured via 1H NMR.
bIsolated yields.
cDegradation.
dAddition of 20 mol% of LiI.
eAddition of 20 mol% of NaI.
the corresponding 4a through the classical two-step route.[20] With this knowledge in
hand, we re-attempted the one-pot process for the two previously defined steps to
prepare the substrate 6a–b from the organic halides 4a–b. Pleasingly, this time the mul-
ticomponent reaction worked well in the presence of 18-crown-6, and the desired 1,2,3-
triazoles 6a–b were obtained in 90 and 88% yield, respectively. Using the optimized

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Scheme 5. Synthesis of triazole-bearing oxazinoindolones through a CuAAC one-pot procedure.
conditions, we then focused on exploring the scope of this reaction with various alkynes
and sodium azide. The corresponding indole-fused oxazinone-1, 2, 3-triazole scaffolds
6a–l were isolated in good to excellent yields (see SI). As shown in Scheme 5, both elec-
tron-withdrawing and electron-donating groups can be successfully incorporated in the
alkyne component, without substantially altering the one-pot process’ efficiency.

8
A. MAYOOUFI ET AL.
Scheme 6. One-pot azidation/cycloaddition/iodation reaction.
We have also shown that iodo-triazole 7 could efficiently be obtained via a simple one-
pot cycloaddition/iodination reaction starting from azido-indole-fused oxazinones. We sup-
posed that indole-fused oxazinone 4a could be converted into iodotriazole 7 in the presence
of 18-crown-6 via a MCR process (Scheme 6). In this context, indole-fused oxazinone 4a,
phenylacetylene, sodium azide and ICl reacted in the presence of copper iodide, 18-crown-6
and Et3N as base. Under these conditions, the desired iodo-triazole 7 was obtained in 76%
yield as a major product but mixed with 5% of 6a. It was found that 18-crown-6 is indis-
pensable for this multicomponent click reaction. This one-pot reaction led to the isolation of
the desired iodo-triazole 7 with a better yield than in the two-step sequence (70%).
Conclusions
In summary, we have developed a new protocol to prepare indole-fused oxazinones. We
have also demonstrated that these gave access to a novel series of heterocyclic deriva-
tives based on triazole and indole-fused oxazinones, prepared using CuAAC based mul-
ticomponent reactions. Further investigations concerning the resulting products 6a–i
are ongoing in our laboratory, and an evaluation of their biological activity is underway
at the Lilly platform.
Experimental
General procedure for the synthesis of ethyl 1-Allyl-5-bromo-1H-indole-2-
carboylate (2b)
In a two-necked round bottom flask, NaH 60% (44 mg, 1.1 mmol, 1.1 equiv.) was dissolved
in DMF (6 mL). Compound 1b (1 mmol, 1 equiv.) in DMF (3 mL) was added dropwise at
0 ꢀC under argon. The mixture was stirred for 30 min at room temperature. A solution of
allyl bromide (145.2 mg, 1.2 mmol, 1.2 equiv.) in DMF (3 mL) was added dropwise at 0 ꢀC.
After 4 h of stirring at room temperature, the mixture was hydrolyzed by aqueous NH4Cl
(20 mL), extracted by diethyl ether (6 ꢃ 10 mL), and the organic phases were washed with
brine (3 ꢃ 10 mL), dried over MgSO4 and concentrated under vacuum.
General procedure for the synthesis of indole-2-carboxylic acids 3
In a round bottom flask, NaOH 12% (240 mg, 6 mmol, 3 equiv.) was slowly added to a
solution of indole ester 2a–b (2 mmol, 1 equiv.) in ethanol (6 mL). The mixture was

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9
stirred at 45 ꢀC for 3 h, cooled to 0 ꢀC and acidified with HCl (1 M) to obtain pH ¼ 1.
The resulting precipitate was filtered and washed with hexane.
General procedure for the synthesis of iodoindole-fused oxazinones 4
In a round bottom flask containing carboxylic acid 3 (1.11 mmol) and 25 mL of
CH2Cl2, we added sodium hydride (88 mg, 2.22 mmol), iodine (845 mg, 3.33 mmol) and
silver nitrate (94 mg, 0.55 mmol). The mixture was stirred overnight at room tempera-
ture. The medium was hydrolyzed by saturated solution of Na2S2O3 (30 mL) then
extracted by dichloromethane (3 ꢃ 25 mL). The organic phase was washed with NaCl
(3 ꢃ 10 mL), dried over MgSO4 and concentrated under vacuum to give the products
4a–b. Spectroscopic data of known compound 4a are identical to those reported
previously.[14]
General procedure for the synthesis of azides 5
A mixture of the appropriate 4a–b (0.76 mmol), sodium azide (148 mg, 2.28 mmol), 18-
crown-6 (100 mg, 0.38 mmol) and acetone (20 mL) was stirred at room temperature
until completion of the reaction (TLC). The solvents were evaporated under reduced
pressure, and the mixture was then poured into water, extracted with CH2Cl2
(3 ꢃ 40 mL), dried (MgSO4), and concentrated in vacuum. The crude product was puri-
fied by silica gel chromatography using PE/EtOAc (1:4) mixture as eluent.
General procedure for the synthesis of triazoles 6
Starting from azide 5
Finely powdered CuSO4, 5 H2O (10 mol%) and sodium ascorbate (20 mol%) were slowly
added to a stirred solution of 5 (0.8 mmol) and appropriate terminal alkyne (1.2 mmol)
in H2O/CHCl3 (3:1 ¼ 22.5 mL/7.5 mL) at 0–10 ꢀC. The mixture was then warmed to
room temperature and stirred until completion (TLC). The mixture was filtered, con-
centrated and diluted with water (30 mL). The aqueous layer was extracted with CHCl3
(3 ꢃ 20 mL). The combined organic layers were washed with H2O and then with brine,
dried over MgSO4 and concentrated in vacuum. The crude products were purified by
flash chromatography on silica gel (EtOAc:PE ¼ 4:1) to afford the pure triazoles 6a
and 6c–l.
Starting from bis-iodine 4
Sodium azide (148 mg, 2.28 mmol) and 18-crown-6 (100 mg, 0.38 mmol) were added to
a solution of compound 4 (0.76 mmol) in H2O:CHCl3 (3:1 ¼ 22.5 mL/7.5 mL), and the
suspension was stirred for 30 min. The mixture was then degassed at 0 ꢀC and terminal
alkyne (4.0 mmol), sodium ascorbate (641 mg, 4.0 mmol) and CuSO4ꢂ5 H2O (76 mg,
0.4 mmol) were successively added. The mixture was stirred overnight. The reaction was
quenched by the addition of an aqueous saturated NH4Cl solution. After being stirred
for further 15 min, the mixture was filtered through a Celite pad. The aqueous phase

10
A. MAYOOUFI ET AL.
was extracted with EtOAc (3 ꢃ 20 mL) and the combined organic layers were washed
with brine, dried over MgSO4 and concentrated under reduced pressure. The crude
material was then purified by flash chromatography on silica gel (EtOAc:PE ¼ 4:1) giv-
ing compounds 6a and 6b.
General procedure for the synthesis of triazole 7
Starting from azide 5
A mixture of azide 5a (1 mmol), terminal alkyne (1.3 mmol), Et3N (1.2 mmol), CHCl3
(100 mL), ICl (195 mg, 1.2 mmol), and CuI (190 mg, 1 mmol) was stirred at room tem-
perature under an argon atmosphere for 48 h. The solvent was removed by distillation
under reduced pressure and the crude residue was purified by flash chromatography
over silica gel (CHCl3:MeOH ¼ 88:12) to afford the pure desired triazole product 7.
Starting from bis-iodine 4
Compound 4a–b (0.76 mmol) was dissolved in CHCl3 (20 mL). Sodium azide (148 mg,
2.28 mmol) and 18-crown-6 (100 mg, 0.38 mmol) were then added to the solution and
the suspension was stirred for 30 min. The mixture was then degassed at 0 ꢀC and ter-
minal alkyne (4.0 mmol), Et3N (125 lL, 0.92 mmol), CuI (145 mg, 0.76 mmol) and ICl
(148 mg, 0.91 mmol) were successively added. The mixture was stirred at room tempera-
ture under an argon atmosphere for 60 h. The reaction mixture was quenched by the
addition of an aqueous saturated NH4Cl solution and stirred for further 15 min. The
mixture was filtered through a pad of Celite. The aqueous phase was extracted with
EtOAc (3 ꢃ 20 mL) and the combined organic layers were washed with brine, dried over
Na2SO4 and concentrated under reduced pressure. The crude product was then purified
by flash chromatography on silica gel (EtOAc:PE ¼ 4:1).
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
J. Thibonnet
http://orcid.org/0000-0003-3817-210X
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