A green metal-free "one-pot" microwave assisted synthesis of 1,4-dihydrochromene triazoles

Article abstract of DOI:10.1039/d1ra01169c

The synthesis of several 4-aryl-1,4-dihydrochromene-triazoles was achieved via a metal-free "one-pot"procedure using PEG400 as the sole solvent in an eco-friendly process. Using microwave irradiation, the triazole derivatives were obtained in good yields and short reaction times starting from readily accessible building blocks.

Full text of DOI:10.1039/d1ra01169c

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A green metal-free “one-pot” microwave assisted
synthesis of 1,4-dihydrochromene triazoles†
Cite this: RSC Adv., 2021, 11, 10336
*
Tania M. F. Alves, Guilherme A. M. Jardim
ˆ
and Marco A. B. Ferreira
Received 12th February 2021
Accepted 24th February 2021
The synthesis of several 4-aryl-1,4-dihydrochromene-triazoles was achieved via a metal-free “one-pot”
procedure using PEG400 as the sole solvent in an eco-friendly process. Using microwave irradiation, the
triazole derivatives were obtained in good yields and short reaction times starting from readily accessible
building blocks.
DOI: 10.1039/d1ra01169c
rsc.li/rsc-advances
Novel green technologies play a pivotal role in modern society
The use of water as a benign solvent in organic reactions is
economics and way of life, and are being considered an always appreciated as it is one of the most abundant, cheapest,
important engine of transformation by directly affecting and greener solvents.13 As another important green alternative,
people's daily lives.1 In this sense, the “Click Chemistry” polyethylene glycol 400 (PEG400) has been used to enhance the
philosophy encompasses several features within the “Twelve solubility of organic compounds. An important feature of PEG400
Principles of Green Chemistry”, including mild reaction is its ability to act as a crown ether,14 enhancing the solubility of
conditions, simple operation, simple product isolation proce- metal-based salts such as sodium azide (Scheme 1A).
dures, solvent-free conditions, readily available starting mate-
rials and reagents, high yields and selectivity.2
Kumar and Varma demonstrated that aqueous PEG400 is an
excellent solvent for Cu(I)-catalysed Huisgen cycloadditions
Among the “Click” reaction arsenal, the formation of 1,2,3- (Scheme 1A).15 In the same year, Yao et al. reported the synthesis
triazoles emerged as a reliable approach for the synthesis of of 4-aryl-1,4-dihydrochromene-triazoles from 3-nitrochromens
novel compounds, being present in several elds of science, in DMSO (Scheme 1B).16 In recent years, nitroolens have been
particularly in biomedical chemistry and drug design.3 1,2,3- efficiently explored, allowing the direct obtention of 1H-1,2,3-
Triazoles are useful building blocks in organic chemistry owing triazoles using sodium azides with concomitant aromatiza-
to their stablily to moisture, oxidation, and metabolism in tion,10–14,16 and HNO2 release, which assists in the decomposi-
organisms.4 Moreover, these moieties are powerful pharmaco- tion of residual NaN3.10f Aiming for a more sustainable process,
phores, playing an important role in bio-media.5 Mainly repre- based on microwave irradiation and sequential metal-free “one-
sented by the Cu(I) catalyzed Huisgen cycloaddition over the last pot” reactions, we developed a methodology starting from
years, the majority of reports englobes the use of sodium/ simple building blocks such as substituted benzaldehydes and
organic azides and alkynes.6
nitromethane, avoiding the manipulation of potentially toxic
Green and sustainable triazole synthesis approaches have nitroalkenes, and using PEG400 as the sole solvent for the
gained the attention of chemists more recently, with highlights synthesis of aryl-1,4-dihydrochromene 1H-1,2,3-triazoles
to metal-free conditions,7 heterogeneous reactions employing
an immobilized catalyst8 and microwave irradiation.9 Regarding
green protocols that use nitroolens as dipolarophiles,10 the
metal-free acid-catalyzed approach by Guan et al.11 as well as the
use of palladium- and copper-supported mesoporous poly-
aromatic hydrocarbons by Banerjee et al.12 represent important
advances in this eld. However, due the lack of solubility of
azides, DMSO and DMF are the solvents of choice for those
transformations.
Centre for Excellence for Research in Sustainable Chemistry (CERSusChem),
˜
Department of Chemistry, Federal University of Sao Carlos – UFSCar, Rodovia
´
˜
˜
Washington Luıs, Km 235, SP-310, Sao Carlos, Sao Paulo, 13565-905, Brazil.
E-mail: marco.ferreira@ufscar.br
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra01169c
Scheme 1 Previously reported procedures and novel microwave
assisted “one-pot” metal-free reaction.
10336 | RSC Adv., 2021, 11, 10336–10339
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(Scheme 1C). We believe that this novel procedure can open new withdrawing groups (derivatives 2b–d). The reaction proceeded
possibilities for the synthesis of such an important scaffold in smoothly for substrates bearing a methyl group in the olen
medicinal chemistry.
terminal carbon (derivatives 2e–g), with unexpected lower yields.
Our study began with the optimization of a reaction model
Inspired by the previous results, new experiments were plan-
consisting of 1a, sodium azide and PEG400 as the solvent under ned to expand the methodology for the obtention of
microwave irradiation conditions (300 W) (Table 1-entry 1). With dihydrochromene-triazole moieties in a “one-pot” microwave
a reaction time of 10 min at 120 ꢀC, a complex mixture of prod- procedure, which initially explored the individual elementary
ucts was obtained. In the second attempt, temperature was steps. For this endeavour, the synthesis of nitrochromene 3a was
maintained at 80 ꢀC for 20 min, and 2a was obtained in 37% yield conducted using parameters obtained in the optimization steps
(entry 2). Based on previous reports,11 catalytic amounts of acids (Scheme 3A). The reaction of 1a with salicylaldehyde at 80 ꢀC in
were employed, aiming at reducing the formation of 1,3,5-tri- 35 min using acid Al2O3 gave 3a in 56% yield (entry 1). Best
phenylbenzene. The addition of p-toluene sulfonic acid (PTSA) results were found using benzoic acid/pyrrolidine (pyrro.) (81%,
resulted in a slightest yield improvement, while the use of entry 2) and PTSA as additives (83%, entry 3). As shown in entry 5,
camphor sulfonic acid (CSA) led to a decrease in yield (entries 3– reaction carried out under conventional heating over 2.5 h
4). Although an increase in the yield was not observed by resulted in minor yield improvements. Next, 3a was submitted to
increasing the concentration of the reaction medium (entry 5), the reaction with sodium azide using different amounts of ben-
a better result was observed when catalytic amounts of several zoic acid and PTSA to nd the optimized quantity of the additives
acids were used under the same conditions (entry 6–9), and the (Scheme 3B). For our delight, the reaction with 50 mol% of both
best result was found for benzoic acid (62%, entry 9), with acids afforded 4a in 80% and 78%, respectively aer ne tuning
a minor increase in the reaction time. Previous results showed the reaction temperature and time (10 min at 110 ꢀC) (entries 8–
similar performance for acetic acid as the solvent.10f Next, an 9). Similar yields were obtained by performing the reaction under
increase in the amount of benzoic acid led to a decrease in the conventional heating over 2.5 h (entry 12). Starting from 1a, the
yield (entries 10–11) and attempts of using mixtures of solvents “one pot” synthesis of 4a was accomplished in 80% yield over two
resulted in the reaction inhibition (entries 12–13). Furthermore, steps, as exemplied in Scheme 3C.
doubling the reaction concentration, decreasing the reaction
temperature and raising the reaction time led to unsatisfactory
results (entries 14–15).
To demonstrate the effectiveness of the optimized reaction,
model substrates 1b–g were previously synthesized and applied as
starting materials, and resulted in derivatives 2b–g in yields lower
than obtained by that the model substrate 1a (Scheme 2).
Apparently, no differences were observed for para-substituted
benzo nitroolens with electron-donating and electron-
Scheme 2 Initial results for reaction scope.
Table 1 Selected optimization results
Entry
Solvent
Temp.
Time
1a (M)
Additive (mol%)
Yielda (%)
1
2
3
4
5
6
7
8
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400
PEG400/EtOH (8 : 2)
PEG400/H2O (8 : 2)
PEG400
120
80
80
80
80
80
80
80
80
80
80
80
80
80
60
10
20
20
20
20
20
20
20
25
25
25
35
35
20
35
0.2
0.2
0.2
0.2
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.8
0.4
—
—
Mixture
37%
40%
30%
35%
48%
54%
30%
62%
58%
48%
Trace
Trace
34%
Trace
PTSA (10)
CSA (10)
—
PTSA (10)
CSA (10)
TFA (10)
PhCO2H (10)
PhCO2H (20)
PhCO2H (30)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
PhCO2H (10)
9
10
11
12
13
14
15
PEG400
a
All yields were isolated.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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Scheme 5 Three step “one-pot” microwave assisted synthesis of 4a,
4d and 4i.
Scheme 3 Optimization and fine tuning for the “one-pot” synthesis of
4a. aReaction conducted using conventional heating (oil bath).
5A). Derivatives 4a, 4d and 4i were obtained in good yields per
reaction step, showing that a three-step “one-pot” procedure is
feasible for the synthesis of these triazole moieties.
The methodology was scaled to provide information about the
robustness of microwave irradiation. As shown in Scheme 6A,
scaling up to 0.2, 0.5 and 1 mmol (2.5ꢁ and 5ꢁ folder) provided
4a with almost no variation in the yield for the two-step process,
although a decrease in the yield was observed for the three-step
reaction. Scaling up to 2 mmol (10ꢁ folder) in the two-step
reaction resulted in almost 20% less yield, and the decrease in
yield was observed for larger amounts (3 mmol–15ꢁ folder, 5
mmol–25ꢁ folder and 10 mmol–50ꢁ folder). For the three-step
procedure, no product was observed aer scaling up to 3 mmol.
Next, two green chemistry metrics (E-factor and atom
economy) were calculated for the conventional multistep
procedure, and the three-step microwave irradiation method
(see ESI†).17 As shown in Scheme 6B, E-factor was determined
for the two procedures by comparing parameters regarding the
extraction and purication in both cases. It is notable that the
three-step microwave irradiation procedure shows the E-factor
value closer to the ideality mostly because it “skips” two clas-
sical extraction and purication steps. When calculation was
performed in the absence of these two parameters, the method
presents an E-factor ¼ 72, which is mostly due to the decrease in
the amount of the solvent used in the reaction steps. In both
Next, the sequential procedure was used to synthesize
a series of novel derivatives bearing different structural features
(Scheme 4). Starting from phenyl-substituted nitroolens 1a–k,
the novel sequential “one-pot” reaction was executed, which
afforded derivatives 4a–k in average to high yields in a two-step
procedure. The reaction proceeded smoothly with electron-
withdrawing groups at the para position, as showed for deriv-
atives 4d and 4g, as well as derivative 4j, which bears a nitro
group at the meta position. A slight decrease in the yield was
observed for derivatives bearing electron-donating groups at the
para position (4b–c, 4e–f), meta and ortho positions (4i and 4k),
and same behaviour was observed for derivative 4h, which bears
a methoxy group at both meta and para positions. Different
salicylaldehyde derivatives were also employed, which afforded
derivatives 4l–o in good yields. Slight reduction in the yield was
observed for both electron-withdrawing and electron-donating
groups, with major decrease for brominated derivative 4n
(55%) and yields ranging from 55% to 64% (Scheme 4).
To expand the functionality of the methodology, the synthesis
of substituted nitroolens was conducted via microwave irradi-
ation to verify the orthogonality of the reactants needed in the
next steps. To our delight, substituted 2-nitrovinyl benzenes were
detected via the TLC analysis, and further steps were carried out
for the synthesis of aryl-1,4-dihydrochromeno-triazoles (Scheme
Scheme 4 Scope for sequential “one-pot” procedure.
10338 | RSC Adv., 2021, 11, 10336–10339
Scheme 6 Scaling effect and green chemistry metrics for 4a.
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cases, the atom economy is the same, since this green chemistry
metric does not consider the other reagents, solvents and
catalysts used in the purication and extraction steps.
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In summary, a three step “one-pot” procedure was successfully
developed for the synthesis of important biological motifs using
PEG400 as the sole solvent in the process. All reaction steps
were carefully investigated to determine the best reaction
parameters encompassing the “one-pot” methodology.
Considered an eco-friendly solvent, the use of PEG400, allied
with microwave irradiation, provided a fast, efficient, and green
reaction for obtaining dihydrochromene-triazole hybrids in
good overall yields. Scaling experiments were conducted,
showing the limit in which the reaction maintains its robust-
ness. A quantitative comparison based on Green Chemistry
metrics between the multistep conventional heating and “one-
pot” microwave irradiation procedure showed that the second
method presents advantages in terms of sustainability.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
The authors gratefully acknowledge FAPESP (grants 2014/
50249-8; 2020/10246-0; and 2020/01255-6), GlaxoSmithKline,
CAPES (Finance Code 001), PNPD/CAPES and CNPq for funding
and fellowships.
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RSC Adv., 2021, 11, 10336–10339 | 10339