Promotion of 1,3-dipolar cycloaddition between azides and β-enaminones by deep eutectic solvents

Article abstract of DOI:10.1039/c5nj03654b

A simple procedure to obtain 4-acyl-1-substituted-1,2,3-triazoles, using a deep eutectic solvent (DES), ChCl and ethylene glycol at a 1:2 ratio, as the reaction medium is described. The products were obtained in high selectivity and good yields (70-84%).

Full text of DOI:10.1039/c5nj03654b

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Deep Eutectic Solvents Promoting 1,3-Dipolar Cycloaddition
Between Azide and β-enaminones
Received 00th January 20xx,
Accepted 00th January 20xx
Marcos Antonio Pinto Martins*a , Guilherme Caneppele Paveglioa, Leticia Valvassori Rodriguesa,
Clarissa Piccinin Frizzoa, Nilo Zanattaa, and Helio Gauze Bonacorsoa
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple procedure to obtain 4-acyl-1-substituted-1,2,3-triazoles, eutectic solvents (DES) has been reported a few times in the
using a deep eutectic solvent (DES) — ChCl and ethylene glycol at literature, and DES have become an environmentally friendly
a 1:2 ratio — as reaction media is described. The products were alternative to hazardous (organic) solvents due to their low
obtained at high selectivity and good yields (70–84%). The vapour pressure (reduced air pollution), non-flammability
advantages of the method include: easy work-up, metal-free (process safety), and nontoxicity.13,14 Despite the current DES
conditions, its inexpensiveness, and the ability to be used four being used in organic reactions, there are only three articles
times without a loss in yield.
that have used DES to promote the 1,3-dipolar cycloaddition.
In 2015, Ramón et al. used the DES ChCl:Urea (1:2) as reaction
The reaction of alkynes and azides is the most commonly media for the synthesis of 3,5-disubstituted isoxazoles and
described 1,3-dipolar cycloaddition, and it is also the most related isoxazolines, employing aldehydes, hydroxylamine
used synthetic route for 1,2,3-triazoles.1a-c The importance of hydrochloride, NCS, and phenylacetylene in
a one-pot
this synthetic route increased when Sharpless and Meldal reaction.14 The other works involved the 1,3-dipolar
introduced copper as the catalyst in this reaction, which made cycloaddition between phenylacetylene and alkyl azide.15,16 In
it possible to obtain 1,4-dissubstituted 1,2,3-triazoles with high 2009, Konig et al.15 employed a mixture of D-sorbitol and urea
regioselectivity.1d Heterocycles containing a triazole skeleton and NH4Cl (type IV DES) at a ratio of 7:2:1, with CuI as catalyst.
have become important pharmacophores for the development and this led to the product being isolated at high selectivity.
of drugs, mainly because they are stable compounds that can Recently, García-Álvarez et al.16 evaluated the effect of type III
mimic peptide bonds.2 In particular, 4-acyl-1-substituted-1,2,3- DES, using CuI as catalyst in the same reaction. Product was
triazoles have shown bactericidal3 and anti-histamine activity,4 obtained with high selectivity, and the best results were
and they are also potassium channel activators5 and obtained when glycerol was used.
tuberculosis and protein inhibitors.6,7 The 4-acyl-1-benzyl- The 1,3-Dipolar cycloaddition reaction of α,β-unsaturated
1,2,3-triazoles have been synthesized from ynones8–10 or ketones such as 1,1,1-trihalomethyl-4-alcoxy-3-alken-2-ones
17
propargylic alcohol11 by 1,3-dipolar cycloaddition with alkyl and β-enaminones is limited. Recently, Bonacorso et al.
azides.
Often,
4-acyl-1-substituted-1,2,3-triazoles
are were successful in the synthesis of rufinamide analogues from
synthesized from substrates which contain triple bonds and the 1,3-dipolar cycloaddition of 1,1,1-trihalomethyl-4-alcoxy-3-
need copper or other additives, which, in some cases, is not alken-2-ones and alkyl azides. However, the reaction involved
sufficient for a highly selective reaction.5 Additionally, these long times, difficult work-up, and low selectivity.
protocols employ toxic and expensive solvents and catalysts, Considering our previous experience with catalysed ionic liquid
which are difficult to dispose,12,10 thus making numerous reactions,18,19 as well as the fact that DES are promising in
difficult work-up stages necessary (e.g., evaporation of solvent, organic syntheses13-16,20-23, we envision that DES could improve
distillation, column chromatography, etc.). Other routes have the reactivity of α,β-unsaturated ketones [CCC block] in 1,3-
many reaction steps,8,9 low yields,2,9,12 and use reagents that dipolar cycloaddition reactions.
are difficult to access and handle.8,10 The 1,3-dipolar Thus, the aim of this work was to evaluate the use of type III
cycloaddition of phenylacetylene and alkyl azide in deep DES in a reaction between β-enaminones and organic azide for
the synthesis of 4-acyl- 1-substituted-1,2,3-triazoles by 1,3-
dipolar cycloaddition. We propose an alternative synthetic
route without solvents, which involves high boiling points,
difficult disposal10 (Toluene, DMSO, and DMF), easy work-up,
a.
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química,
Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil.
and is metal-free and highly selective.
E-mail: mmartins@base.ufsm.br
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Table 1. Optimization of 1,3-dipolar cycloaddition of
enaminone 1a and benzyl azide
Table 2. 1,3-dipolar cycloaddition of enaminones 1a-h and
benzyl azide 2, using DES (ChCl:ethylene glycol at 1:2).
2.
O
O
N
+
NMe2
N3
N
N
1a
2
6a
Entry Time
(h)
T
Catalyst
Conversion Yield
i: ChCl:ethylene glycol (1:2), 24 h, 130 °C
(°C)
80
(%) a
(%) b
Product
6a
R
Ph
R1
Ph
Yield (%) a
1
15
18
24
24
24
24
24
24
24
24
24
24
ChCl:Urea (1:2)
17:83 c
59:41c
88:12d
>99 d
-
81
84
83
82
83
77
83
84
70
83
2
120 ChCl:Urea(1:2)
120 ChCl:Urea(1:2)
130 ChCl:Urea(1:2)
-
3
-
6b
4-MeC6H4
4-OMeC6H4
4-BrC6H4
4-IC6H4
4-O2NC6H4
Naft-2-yl
4,4’-Biphenyl
Ph
Ph
4
84 e
6c
Ph
5
130
-
83:17d
17:83 d
88:12d
99:1 d
-
6d
Ph
6
118 Toluenef
-
6e
Ph
7
130 ChCl:Glycerol(1:1)
130 ChCl:Glycerol(1:2)
130 ChCl:Ethyleneglycol(1:1) 99:1 d
130 ChCl:Ethyleneglycol(1:2) >99 d
-
6f
Ph
8
78
79
81
-
9
6g
Ph
10
11
12
6h
Ph
130 1 Equiv. ChCl
91:9 d
7a
Octyl
130 2 equiv. Ethyleneglycol
92
75
aPercentage for 6a:1a obtained by NMR; bYields of purified product; c
Reaction conditions: Enaminone 1a (1.0 eq): azide 2 (1.0 eq):DES (1.0
eq); d Reaction conditions: Enaminone 1a (1.0 eq): azide 2 (1.5 eq): DES
(1.0 eq). e Product not purified. f 5 mL.
8a
Ph
4-OMeC6H4
4-ClC6H4
9a
Ph
77
a Yields of purified products.
We started our study from the reaction of β-enaminone 1a
and azide , by evaluating DES performance in order to
and urea mixture (ratio of 1:2). The reaction in ChCl and
ethylene glycol (ratio of 1:2) resulted in the -enaminone 1a
2
β
determine the best condition for the synthesis of 4-acyl-1-
substituted-1,2,3-triazoles, as shown in Table 1. Firstly, we
being fully converted into product (Table 1, entry 10). The
reaction in the presence of choline chloride was not effective
(Table 1, entry 11). Finally, the reaction with 2 equiv. of the
ethylene glycol resulted in good conversion, but unsatisfactory
yield. Despite the ChCl and urea mixture (ratio of 1:2) having
the best yield, it could be seen that the isolated product
contained impurities (observed in 1H NMR spectrum).
Simeonov and Afonso24 showed that during synthesis of the
ChCl and urea mixture, urea can be decomposed to form
ammonia. Ammonia formation could be responsible for
impurities observed in the NMR spectra of product 3a. The
TGA analysis of the ChCl and urea mixture showed that the
decomposition of ChCl started at 179 °C. Thus, in order to
avoid the ammonia effect in the reaction, the ChCl and
ethylene glycol mixture (ratio of 1:2) was chosen as the best
medium.
examined a 1a:2:DES molar mixture (starting with a ratio of
1:1:1), stirred and heated at 80 °C for 15 h (Table 1, entry 1).
However, it was not sufficient for complete conversion. The
increase in the time to 18 h and 24 h, and temperature to
120°C, did not result in complete conversion either (Table 1,
entries 2 and 3, respectively). Satisfactory conversion was
achieved only when the reaction was conducted at 130 °C for
24 h (Table 1, entry 4). Furthermore, the reaction without DES
did not produce good results (Table 1, entry 5). In the next
step, toluene was evaluated; however, low conversions were
obtained compared to DES (Table 1, entry 6). A ChCl and
glycerol mixture (ratio of 1:1) was the least efficient reaction
medium among the DES studied (Table 1, entry 7). ChCl and
glycerol (ratio of 1:2) and ChCl and ethylene glycol (ratio of
1:1) did not achieve full conversion (Table 1, entries 8 and 9,
respectively), but they showed very similar results to the ChCl
The product obtained with the ChCl and ethylene glycol
Figure 2. Recyclability of the ChCl and ethylene glycol mixture
2 | J. Name., 2012, 00, 1-3
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(ratio of 1:2) in the 1,3-dipolar cycloaddition of enaminone 1a
Figure 1. Possible pathway of the proposed mechanism.
and azide 2. Yield of isolated products.
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mixture (ratio of 1:2) was isolated without impurities. Simply recycled DES was used for up to four runs without significant loss in
washing with hexane was sufficient to remove excess benzyl conversion and yields (Figure 2).
azide and also furnish the triazoles in a pure form. In order to In conclusion, we have established an efficient synthesis of a
gain insight into the generality of this 1,3-dipolar cycloaddition series of 4-acyl-1-substituted-1,2,3-triazoles using the DES ChCl
reaction, azide
using the established reaction conditions. Furthermore, the first time that the DES ChCl and ethylene glycol (ratio of
different organic azides 3,4,5 were reacted with -enaminone 1:2) has provided the best result in an organic reaction. The
2 was reacted with other β-enaminones (1a–h), and ethylene glycol (at a ratio of 1:2) as reaction media. This is
β
1a. All products were obtained at good yields (77–84%), as results presented in this paper demonstrate that a ChCl and
shown in Table 2. The reactions were accompanied by 1H NMR ethylene glycol mixture (at a ratio of 1:2) is able to promote
spectroscopic data, in which one can see the disappearance of the synthesis of these compounds via an alternative synthetic
a doublet signal of α-carbonyl hydrogen in the β−enaminones route without using solvents that are difficult to separate of
(~5.75 ppm) and the appearance of the singlet signal at ~8.2 the products.
ppm associated with the aromatic hydrogen of the 4-acyl-1- Furthermore, the use of it as reaction media made a highly
substituted-1,2,3-triazole (product). Compounds 6a-h were selective synthesis possible in metal-free conditions, with an
fully characterized by H and 13C NMR. Compounds 6b
1
,
6d
,
6e,
easy work-up. Additionally, a ChCl and ethylene glycol mixture
and 6g and 9a are described here for the first time (see data in (ratio of 1:2) is cheap, biodegradable, and allows recycling and
the Electronic Supplementary Information). The chemical shifts reuse without a significant loss of yield.
corroborate with the literature and confirm the well-defined
9,11
regiochemistry of compounds 6a-h
.
Experimental
Results showed that the synthesis of 4-acyl-1-substituted-
1,2,3-triazoles by the 1,3-dipolar cycloaddition reaction of Preparation of DES: The DES were prepared by combining ChCl
organic azide 2 and β-enaminones (1a–h) in a mixture of ChCl with different HBDs, in accordance with the procedures in the
and ethylene glycol (ratio of 1:2) was not influenced by the literature.26
presence of electron-withdrawing groups (EWG) or electron- General procedure for DES catalysed synthesis of 4-acyl-1-
releasing groups (ERG) in the aromatic ring of the
β
-
substituted-1,2,3-triazoles: The β-enaminone (1.0 eq), DES (1.0 eq),
enaminones (1a-h) — see Table 2.
and organic azide (1.5eq) were mixed together in a 10 mL round-
Interestingly, the ChCl and ethylene glycol mixture (ratio of bottomed flask. The reaction was stirred at 130 °C for 24 h.
1:2) has been used as an electrochemical solvent.25 However, Chloroform (10 mL) was added, and the resulting product (6a-h,7-9)
to the best of our knowledge; it has not been successfully used was extracted from the DES (3 x 2 mL H2O). The chloroform was
in organic reactions. The success of the ChCl and ethylene dried over anhydrous Na2SO4 and evaporated until dry, thus leaving
glycol mixture (ratio of 1:2) in comparison with the ChCl and the desired triazoles. Product 6e was separated using column
urea mixture (ratio of 1:2) in this reaction is evidenced by the chromatography for purification (Hexane and EtOAc at a 3:1 ratio).
non-formation of byproducts, which ensures further product The other products were purified by washing with hexane. The
1
purification steps are avoided. The ChCl and urea mixture structures of compounds (6a-h,7-9) were confirmed by H/13C NMR
(ratio of 1:2) has more basic sites (for forming hydrogen spectroscopy. This information is available in the Supplementary
bonds) than the ChCl and ethylene glycol mixture (ratio of 1:2), material.
and probably allows the formation of byproducts. A possible
hypothetic mechanism for the interaction of the ChCl and
Acknowledgements
The authors are grateful for the financial support from: the National
ethylene glycol mixture (ratio of 1:2) with azide and β-
enaminones is depicted in Figure 1. It was based on the
Council for Scientific and Technological Development (CNPq) —
mechanism proposed by Pérez and Ramón14 for a ChCl and
Universal/Proc. 475556/2012-7; the Rio Grande do Sul Foundation
urea mixture (ratio of 1:2) in the synthesis of 3,5-disubstituted
for Research Support (FAPERGS) — Proc. 2262-2551/14; and the
isoxazoles/isoxazolines. In the proposed mechanism (Figure 1),
Coordination for Improvement of Higher Education Personnel
one equivalent of the ethylene glycol interacts with the azide,
(CAPES/PROEX). The fellowships from CNPq (M.A.P.M, H.G.B., and
whereas the other equivalent interacts with the carbonyl of
N.Z.) and CAPES (L.V.R. and G.C.P.) are also acknowledged. We wish
the β-enaminone via hydrogen bonds. Additionally, the choline
to thank Professor P. Machado (PUC-RS/Brazil) for providing
hydroxyl group can complex with the double bond of β-
HRMAS samples analysis.
enaminone. These interactions probably decrease the energy
gap of the frontier orbitals involved in the reaction, thus
Notes and references
favouring the reaction.
Finally, investigation of the recovery and reuse of DES was
1.
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azide 2. After the extraction, hexane was added to the aqueous
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DES was obtained in a pure form, without further purification. The
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Metal-free, high selectivity and efficient synthesis of 4-acyl triazoles in DES (ChCl:ethylene
glycol)