Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

Article abstract of DOI:10.3762/bjoc.14.246

A new metal-free one-pot three-component procedure towards fully substituted triazolochromenes has been developed, starting from commercially available materials. Salicylaldehydes and nitroalkenes were reacted under solvent-free conditions, followed by a

Full text of DOI:10.3762/bjoc.14.246

Assembly of fully substituted triazolochromenes via a novel
multicomponent reaction or mechanochemical synthesis
Robby Vroemans1, Yenthel Verhaegen1, My Tran Thi Dieu1,2 and Wim Dehaen*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2689–2697.
1Molecular Design and Synthesis, Department of Chemistry, KU
Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium and 2The
University of Danang, University of Science and Education, 459 Ton
Duc Thang, Lien Chieu, Danang, Vietnam
doi:10.3762/bjoc.14.246
Received: 24 July 2018
Accepted: 08 October 2018
Published: 22 October 2018
Email:
Wim Dehaen* - wim.dehaen@chem.kuleuven.be
Associate Editor: T. J. J. Müller
* Corresponding author
© 2018 Vroemans et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
ball milling; multicomponent reaction; 3-nitro-2H-chromene; one-pot
synthesis; 1,2,3-triazole
Abstract
A new metal-free one-pot three-component procedure towards fully substituted triazolochromenes has been developed, starting
from commercially available materials. Salicylaldehydes and nitroalkenes were reacted under solvent-free conditions, followed by a
1,3-dipolar cycloaddition of the intermediate 3-nitro-2H-chromenes with organic azides in a one-pot two-step sequence. The tria-
zolochromenes were formed with complete regioselectivity and new biologically relevant structures were synthesized via extension
of the developed procedure and via postfunctionalization. The mechanochemical synthesis was carried out for several salicylalde-
hydes and gave a clear improvement in the yield of the corresponding triazolochromenes and consequently showed to be a viable
alternative for solid salicylaldehydes.
Introduction
Chromenes are important structural motifs and are omnipresent tives and are highly reactive due to the presence of the
in nature and drugs for medicinal applications [1-4]. Vitamin E nitroalkene moiety, which enables them to undergo a high
[5-8], arahypin-5 [9,10], THC and other cannabinoids [11-14] variety of reactions and functionalizations [15].
are only a few examples of biologically relevant chromenes.
Hence, the search for new methodologies towards the rapid Combining the chromene core with the 1,2,3-triazole structural
assembly of chromene analogs is of utmost importance for motif has led to some interesting new molecules [16-31]. Very
many researchers. In this regard, 3-nitrochromenes are easily recently, spiro-fused triazolochromenes were found to be active
available building blocks for chromene and chromane deriva- as antitubercular agents [32], indicating that the development of
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new triazolochromenes in a straightforward manner is still of zolochromenes, without the isolation of the intermediate
major interest. Previously, NH-triazolochromenes were synthe- 3-nitrochromenes, have not been reported until now.
sized starting from 3-nitrochromenes with sodium azide
[16-22], via intramolecular cyclization of a diazomethane group Results and Discussion
and a nitrile [23], or via our recently reported NH-triazole syn- To prove the plausibility of the one-pot three-component reac-
thesis starting from 6-methoxyflavanone [24]. Furthermore, tion, we commenced our trials with the synthesis and isolation
1,4,5-trisubstituted 1,2,3-triazole annulated chromenes have of 3-nitro-2H-chromene (3) as reported in the literature [15],
been reported via an intramolecular arylation reaction of 1,2,3- followed by the 1,3-dipolar cycloaddition of the nitroalkene
triazoles [25-31]. Yet, the developed methodologies for trisub- moiety with organic azides. We based the 1,3-dipolar cycload-
stituted triazolochromenes generally lack a substituent on the dition reaction on the synthesis of NH-triazoles by Guan et al.
2-position, except for a sporadic methyl group which drastical- using p-toluenesulfonic acid as the catalyst in DMF [19], but
ly lowers the yield and often the use of transition metals is with benzyl azide (4a) instead of sodium azide (Scheme 1). Our
needed [28]. The additional substituents on the chromene core initial test gave a promising result, since after a reaction time of
and 1,2,3-triazole offer a lot of possibilities for further derivati- five days for the cycloaddition step the desired product 5a was
zation and optimization towards biologically relevant structures obtained in 67% yield, together with an oxidized ring opened
such as flavonoid structures.
side product 6 in 20% yield. The overall yield of 5a after two
steps was 48%, considering that the 3-nitro-2H-chromene (3)
Our group developed a Knoevenagel-assisted three-component was obtained in a yield of 71%.
reaction of (protected) salicylaldehyde, ethyl nitroacetate and
organic azides, in which the synthesis of both triazolocoumarin We continued our studies by verifying the obtained regiochem-
regioisomers was accomplished [33]. Interestingly, the ex- istry, in which we synthesized the different regioisomers 5a, 10
pected regioisomer was not observed in the case of the in situ and 11 via different pathways (Scheme 2). The regiospecific
formed 3-nitrocoumarins. Hence, in our continued exploration syntheses [36] of compounds 5a and 11 were accomplished
towards novel multicomponent reactions for the assembly of tri- by triazolization of the corresponding flavanone 7 and
azole-fused (hetero)cycles [24,33-42], we opted to develop a 2-phenylchroman-3-one (8), respectively. As anticipated, these
new one-pot two-step three-component reaction starting from methods furnished both regioisomers in poor yields since the
salicylaldehydes, nitroalkenes and organic azides, without isola- chromanones 7 and 8 are known to be unstable under the tria-
tion of the intermediate 3-nitrochromenes, in a regioselective zolization conditions [36]. Hence, no further attempts were
manner and without the use of metals. Salicylaldehydes with a made to improve these yields. Additionally, NH-triazole 9 could
high melting point or low solubility proved difficult to convert be alkylated using benzyl bromide and potassium carbonate in
to the intermediate 3-nitrochromene derivatives [15]. In this acetone providing a mixture of alkylated triazolochromenes 5a,
regard, applying mechanochemistry has been proven previ- 10 and 11. The polarity of the 2-alkylated triazolochromene 10
ously to be a viable alternative [43]. To the best of our know- is significantly different than the other two which were ob-
ledge, both the development of a metal-free sequential one-pot tained as an inseparable mixture of both regioisomers 5a and 11
three-component reaction and the mechanochemically assisted in a 1:3 ratio. Comparing the 1H NMR spectra (see Supporting
3-nitrochromene synthesis towards fully substituted tria- Information File 1, Figure S1 for NMR comparison), we can
Scheme 1: Two-step reaction towards triazolochromene 5a and obtained oxidized side product 6.
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Scheme 2: Reaction pathways leading to the different regioisomers.
make unambiguous conclusions about the regiochemistry of the study). The optimized conditions for the one-pot three-compo-
synthesized compounds 5a, 10 and 11 (Scheme 2). As the prod- nent reaction were determined to be 1 equivalent nitroalkene,
uct contains a stereocenter, there is a possibility to see dia- 1.2 equivalents of salicylaldehyde and 0.1 equivalents of
stereotopic splitting of the benzylic protons. In the spectrum of DABCO as catalyst in the first step at 40 °C, and 2 equivalents
the obtained product 5a starting from 3-nitro-2H-chromene and of benzyl azide, 2 equivalents of acetic acid, 0.3 equivalents of
flavanone, this splitting is not observed (A2 pattern). The BHT as antioxidant, 4 Å MS and DMF under argon atmosphere
benzylic peak of the 2-alkylated product 10 shows an AB split- at 120 °C in the second step. Crude NMR analysis of the reac-
ting pattern and the third regioisomer 11 shows a substantial tion mixture under optimized conditions showed solely regio-
AX splitting pattern. This striking difference can be rational- isomer 5a, which was obtained in 54% yield after chromato-
ized in function of the proximity of the stereocenter to the dia- graphic purification. Additionally, the optimized conditions
stereotopic protons. Further proof was provided by characteriza- gave improved yields compared to the two-step synthesis and
tion of side product 6 [44], which is formed during the reaction circumvented the formation of oxidized side product 6. As vari-
by oxidation and ring-opening of triazolochromene 5a ation of the substituents on the three different starting materials
(Scheme 1). All these observations confirm the expected regio- is necessary to obtain a diverse library, there is one main limita-
selectivity in the formation of triazolochromene 5a via 3-nitro- tion to overcome. The first step of the reaction relies on the
2H-chromene (3).
fluidity of salicylaldehyde (1a) to liquefy the reaction mixture.
Salicylaldehyde analogs 1c–f are solids at 40 °C and hence, to
Next, the two-step synthesis was converted into a one-pot two- overcome this problem, some slight modifications from the op-
step synthesis, circumventing the need for isolating the interme- timized conditions were done (see Supporting Information
diate 3-nitro-2H-chromene (3), which would greatly facilitate File 1, pages S6 and S7 for more detailed description of the per-
the purification of the overall reaction since the 3-nitro-2H- formed experiments for compound 5a). Eventually, the use of
chromenes and their starting materials show similar retention two equivalents of triethylamine was needed but the overall
factors. Since the triazolochromenes 5 are showing much lower yield of 5a was still lower as it only reached 38%.
retention factors, the one-pot synthesis would display a great
improvement in the labor intensiveness both for the purifica- With the obtained optimized conditions and proof of regioselec-
tion steps and reaction set-up. The reaction was further opti- tivity in hand, further investigation towards the generality of
mized using salicylaldehyde (1a), β-nitrostyrene (2a) and this three-component reaction was carried out by varying
benzyl azide (3a) as model substrates (see Supporting Informa- the substrate scope (Figure 1). We first studied a range of
tion File 1, pages S4–S8 for full description of the optimization salicylaldehydes 1a–f, from which 5a and 5b were obtained in
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Figure 1: Scope with respect to various salicylaldehydes 1a–f, nitroalkenes 2a–d and organic azides 4a–g. aReaction conditions for two-step one-pot
procedure: 1. 1 (1.2 equiv), 2 (1 equiv), DABCO (0.1 equiv), 1.5 h, 40 °C; 2. 4 (2 equiv), acetic acid (2 equiv), BHT (0.3 equiv), 4 Å MS (50 mg), DMF
(0.1 mL), 24 h, 120 °C. bReaction conditions for two-step one-pot procedure with solid salicylaldehydes: 1. 1 (1.2 equiv), 2 (1 equiv), triethylamine
(2 equiv), 1.5 h, 40 °C; 2. Same as for a. cReaction time for the second step: 27 h. dReaction time for the first step: 24 h; second step: 29 h. eReaction
time for the first step: 2 h. fReaction time for the first step: 3 h. gReaction time for the first step: 38 h. hReaction time for the second step: 30 h.
iReaction time for the second step: 45 h.
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the best yields since salicylaldehydes 1a and 1b are liquids. As vent-free, we opted to try our own optimized solvent-free condi-
mentioned earlier, the altered conditions for solid salicylalde- tions for the in situ syntheses of 3-nitro-2H-chromenes, fol-
hydes result in general in a decrease in yield. Yet, we were able lowed by the 1,3-dipolar cycloaddition in a reaction vial.
to diversify towards electron-rich triazolochromenes 5b and 5c, Despite being a two-pot procedure, purification of the interme-
resulting in a drastic loss in yield for the more sterically diate 3-nitro-2H-chromene is still circumvented. Hence, our
hindered compound 5c. Furthermore, electron-deficient and initial trials were performed by using solid salicylaldehydes
halogenated analogs 5d–f were successfully synthesized. In a 1c–f (Figure 2), resulting in a significant increase in yield for
next series, we examined the substitution pattern on the triazolochromenes 5c–f compared to the one-pot procedure de-
nitroalkene part. Electron-rich substituents 3,4,5-trimethoxy- veloped as described above (Figure 1). To compare the two
phenyl and piperonyl were tolerated and furnished products 5g methodologies, the two highest yielding liquid salicylaldehydes
and 5h, respectively. 2,2-Dimethyl-substituted derivative 5i was in the one-pot protocol, i.e., 1a and 1b, were reacted in the two-
prepared from 2-methyl-1-nitroprop-1-ene (2d) and interest- step mechanochemically assisted reaction, giving rise to slightly
ingly, 1,4-bis((E)-2-nitrovinyl)benzene (2e) furnished bis- lowered yields for compounds 5a and 5b. Hence, the use of the
chromenotriazole 5p in 26% yield (Scheme 3). Finally, the ball milling procedure is advantageous when solid salicylalde-
scope with respect to organic azides was investigated by per- hydes are used. Complementary to this the one-pot three-com-
forming reactions with alkyl and aryl azides 4a–g. Electron-rich ponent reaction gave better results for liquid salicylaldehydes.
aliphatic azides produced products 5j–l in moderate yields. Ad-
ditionally, electron-rich and electron-deficient aromatic azides In order to show the utility of the developed methodologies
were explored, resulting in slightly lower yields and elongated towards possible drug discovery, the scalability of the reactions
reaction times in the cycloaddition step compared to aliphatic was explored (Scheme 4). Both developed methodologies easily
azides. Unfortunately, this reaction has encountered some limi- led to gram scale syntheses without significant loss in yield, i.e.,
tations towards certain substrates (not shown). In the case of a 50% and 40% for the one-pot three-component reaction and
strongly electron-withdrawing substituent on the nitroalkene mechanochemical procedure, respectively.
part for (E)-1-nitro-4-(2-nitrovinyl)benzene and sterically
hindered 2-hydroxy-1-naphthaldehyde, only the oxidized prod- Finally, the versatility of these novel methodologies was
uct analogous to 6 was observed. 2-Hydroxy-4-nitrobenzalde- demonstrated by performing postfunctionalization strategies
hyde and 2,6-dihydroxybenzaldehyde were unreactive in the towards well-known biologically active analogs (Scheme 5) [3].
cycloaddition reaction.
Pd-catalyzed reactions were effected on bromotriazolo-
chromene 5e. The piperazin-1-ylchromenes have been identi-
As previously mentioned, solid salicylaldehydes furnish tria- fied to be potent inhibitors at the 5-HT1A receptor and at the
zolochromenes in diminished yields in the one-pot three-com- 5-HT transporter [45,46]. Thus, Buchwald–Hartwig amination
ponent reaction (Figure 1, compounds 5c–f). Hence, a of 1-phenylpiperazine and 5e furnishes piperazin-1-ylchromene
mechanochemical two-step protocol was developed, since a 12 in 64% yield. Furthermore, as highly methylated flavonoid
report by Jia and Zhang et al. [43] previously showed that derivatives [47] and 6-(3,5-dimethoxyphenyl)chromenes
ball milling could be a convenient manner to produce [48,49] have been demonstrated to be potent anti-seizure drugs
3-nitrochromenes. Because our first step is best performed sol- and anticancer agents, respectively, a Suzuki–Miyaura reaction
Scheme 3: Synthesis of bis-chromenotriazole 5p.
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Figure 2: Generality of products obtained via the two-pot mechanochemical procedure, varying the salicylaldehydes 1a–f. aReaction conditions for
ball milling procedure, followed by 1,3-dipolar cycloaddition in a reaction vial: 1. 1 (1.2 equiv), 2a (1 equiv), DABCO (0.1 equiv), 15 min, 30 Hz;
2. 4a (2 equiv), acetic acid (2 equiv), BHT (0.3 equiv), 4 Å MS (50 mg), DMF (2 mL), 24 h, 120 °C. bReaction time for the first step: 2 h. The overall
isolated yields are given for 2 steps.
Scheme 4: Scale-up of the one-pot three-component reaction and two-step ball milling procedure.
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Scheme 5: Postfunctional transformations of triazolochromenes.
was performed yielding 13 in 51% yield. Since aldehydes are Conclusion
interesting and versatile functional moieties for further derivati- We developed a sequential one-pot three-component reaction to
zation, e.g., used in the synthesis of heterocyclic scaffolds access a variety of novel triazolochromenes avoiding the purifi-
[33,34,50], several multicomponent reactions [40,51-53], etc., cation of intermediate 3-nitro-2H-chromenes. The regiochem-
we wished to convert dimethyl acetal 5j into aldehyde appended istry of the reaction was determined and proven, followed by a
triazolochromene 14 and at the same time examine the stability scope study using various salicylaldehydes, nitroalkenes and
under strong acidic conditions. Aldehyde appended tria- organic azides. Solid salicylaldehydes gave diminished yields in
zolochromene 14 was synthesized in 85% yield, providing the the one-pot three-component protocol, hence a two-step
proof for their relative stability under acidic conditions. Finally, mechanochemical approach was developed offering higher
triazolium salt 15 was prepared from 5a in 60% yield and yields and resulting in a complementary route for solid salicyl-
renders a polar triazolium annulated chromene.
aldehydes. The applicability of the newly developed protocols
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Supporting Information File 1
Experimental part.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-246-S1.pdf]
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Acknowledgements
19.Quan, X.-J.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2014, 16,
5728–5731. doi:10.1021/ol5027975
We thank the KU Leuven for financial support. RV thanks the
Fonds Wetenschappelijk Onderzoek – Vlaanderen (FWO) for a
Ph.D. fellowship (1S13516N). Prof. Dr. Koen Binnemans is
thanked for granting the permission to use the ball milling appa-
ratus, Gerrit Van Haele and Karel Duerinckx are acknowledged
for technical assistance of the used equipment. Mass spectrome-
try was made possible by the support of the Hercules Founda-
tion of the Flemish Government (grant 20100225-7).
20.Schwendt, G.; Glasnov, T. Monatsh. Chem. 2017, 148, 69–75.
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ORCID® iDs
Robby Vroemans - https://orcid.org/0000-0001-8641-6901
Yenthel Verhaegen - https://orcid.org/0000-0003-2937-5642
Wim Dehaen - https://orcid.org/0000-0002-9597-0629
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