Next Article in Journal
A New Method of Synthesis of Epalrestat
Previous Article in Journal / Special Issue
Efficient Synthesis of Eight-Membered Cyclic Diaryl Sulfides via an Aryne Reaction with 2-Methylenebenzothiophene-3-Ones
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Reactions
Volume 6
Issue 2
10.3390/reactions6020036
reactions-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Solvent-Free 1,3-Dipolar Cycloadditions of Nitrones for a More Sustainable Synthesis of Glycomimetics

by
Debora Pratesi
*,
Alessio Morano
,
Andrea Goti
,
Francesca Cardona
and
Camilla Matassini
*
Dipartimento di Chimica “Ugo Schiff” (DICUS), Università di Firenze, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, FI, Italy
*
Authors to whom correspondence should be addressed.
Reactions 2025, 6(2), 36; https://doi.org/10.3390/reactions6020036
Submission received: 18 April 2025 / Revised: 23 May 2025 / Accepted: 30 May 2025 / Published: 5 June 2025
(This article belongs to the Special Issue Cycloaddition Reactions at the Beginning of the Third Millennium)
Browse Figures
Versions Notes

Abstract

1,3-Dipolar cycloadditions on nitrone dipoles are key reactions to access five-membered heterocycles, which are useful intermediates in the synthesis of biologically relevant glycomimetics. The good atomic balance and high stereoselectivity characteristic of such reactions make them good candidates for the development of green protocols. In the present work, these features were maximized by avoiding the use of organic solvents and considering starting materials derived from biomass. Reactions involving (acyclic and cyclic) carbohydrate-derived nitrones as dipoles and levoglucosenone as dipolarophile were considered. Performing selected 1,3-dipolar cycloadditions in neat conditions showed reduced reaction times, maintaining similar selectivity and yields with respect to the classical protocols. The use of microwave irradiation and orbital shaking were also exploited to increase the sustainability of the synthetic protocols. The collected results highlight the potential of solvent-free 1,3-dipolar cycloadditions in the design of efficient synthetic routes according to green chemistry principles, such as prevention, atom economy, safer solvents and auxiliaries, and use of renewable feedstocks.

Graphical Abstract

1. Introduction

1,3-Dipolar cycloadditions provide one of the most useful methods to access five-membered ring heterocycles [1,2], as attested by the vast research conducted in this field in the past 50 years (see selected Reviews [3,4,5,6,7,8,9]) and the widespread use of this type of reaction in nearly all chemistry areas, ranging from materials chemistry [10] to drug discovery [11].
A general 1,3-dipolar cycloaddition (1,3-DC) involves a 1,3-dipole compound (4π system) which reacts with a dipolarophile (2π system) in a [4π + 2π] cycloaddition thermally allowed by the Woodward–Hoffmann rules [12]. 1,3-Dipoles are usually classified into two classes: allyl type, in which the central atom can be nitrogen (e.g., azomethine ylides, azomethine imines, nitrones, etc.) or oxygen (carbonyl ylides, carbonyl imines, carbonyl oxides, etc.), and propargyl-allenyl type (e.g., nitrile ylides, nitrile oxides, azides, etc.) [13]. The structural variety of dipolarophiles, which can, in principle, be any compound containing a double or triple bond, isolated or conjugated, is responsible for the high versatility of 1,3-dipolar cycloadditions [14].
Although the mechanism of the 1,3-DC was widely debated in the 1960s, the idea of a concerted but asynchronous process for the formation of the new σ-bonds has been broadly accepted to date. Nevertheless, cycloadditions are commonly represented using a transition state involving the 4π-electron component of the 1,3-dipole that interacts with the 2π-electron component of the dipolarophile [3]. One of the main advantages of 1,3-dipolar cycloadditions is represented by the high regio- and stereoselectivity of the reactions. The regioselectivity of a 1,3-DC can be predicted on the basis of the frontier orbitals theory because the nature of the substituents on both the 1,3-dipole and the dipolarophile (i.e., the presence of electron-donating or electron-withdrawing groups) affects the frontier molecular orbital (FMO) energies determining the dominant HOMO-LUMO interaction(s) of the transition state, as well as the orbital coefficient values at the connecting atoms determining the preferred orientation of reagents [15]. On the other hand, the high stereoselectivity of 1,3-DC reactions for alkene dipolarophiles and ally-type dipoles is strongly related to the concerted nature of the reaction mechanism, which results in the retention of the relative configuration of the original dipolarophile in the final adduct. In addition, since the cycloaddition is usually faster than the eventual 1,3-dipole isomerization and exo/endo selectivity is often high, the reaction is stereoselective also respect to the 1,3-dipole.
A key role in the vast scenario of 1,3-dipolar cycloadditions is played by 1,3-DC of nitrones 1 with alkenes 2 to access isoxazolidines 3 (Figure 1) [16], bearing up to three new contiguous stereocentres, which depend both on the stereochemistry of the dipolarophile and on the exo/endo approach of the two partners of the cycloaddition. The isoxazolidines 3 can then be easily converted into attractive compounds such as γ-amino alcohols, valuable building blocks in the total synthesis of natural products [17], and glycomimetics, an important family of biologically active compounds including polyhydroxylated and aminopolyhydroxylated carbocycles, azasugars, amino sugars, and polyhydroxylated alkaloids with pyrrolidine, indolizidine, and pyrrolizidine structure [18], also called iminosugars [19].
There is no class of glycomimetics that has not been efficiently prepared through the essential mediation of acyclic [20] or cyclic [21] nitrones. A general method for the straightforward synthesis of indolizidine and pyrrolizidine iminosugars was developed by Brandi, Goti, and co-workers, by means of highly stereoselective 1,3-DC of cyclic nitrones (namely polyhydroxylated pyrroline N-oxides) followed by simple transformations of isoxazolidine adducts [22]. In particular, carbohydrate-derived nitrones have proven to be useful tools for a stereoselective approach towards stereochemically complex carbocycles and heterocycles, not only due to the presence of several contiguous stereogenic centers with a well-defined configuration, but also due to the possibility of temporarily adding a variety of moieties to the hydroxyl groups of carbohydrates (for examples, see: [23,24,25,26]). Moreover, the increasing attention of the scientific community towards the use of renewable sources makes carbohydrates, readily obtained from biomass, ideal candidates as sustainable starting materials [27]. This aspect, combined with the intrinsic high atom economy and selectivity of 1,3-DC reactions, prompted us to revise the conditions usually employed for the obtainment of isoxazolidine intermediates in order to maximize the sustainability of the synthetic processes exploited to access glycomimetics. Since cycloaddition reactions are characterized by a negative volume of activation, previous studies conducted in our group demonstrated that the use of high pressure strongly accelerates and improves the yield of 1,3-DC reactions, as reported for the cycloaddition of enantiopure hydroxylated nitrones to glycals to access pseudo aza-C-disaccharides [28]. Conversely, no attention had been paid previously to the type of solvents used in such reactions, which are usually volatile organic solvents. Many efforts have been recently devoted to replacing organic solvents with non-flammable, non-volatile, non-toxic, and inexpensive green solvents, thus performing 1,3-DC reactions in ionic liquid, fluorinated solvents and water [29]. However, due to the early transition states characteristic of concerted cycloaddition reactions, it is reported that the choice of solvent has very little influence on the rate of the 1,3-DC [1]. Therefore, performing the reactions in neat conditions represents the ideal choice from the green chemistry perspective, since it avoids the use of conventional volatile solvents and can minimize the overall waste production, even though scarcely explored until now [30,31,32,33,34].
Herein, we report our attempts to optimize 1-3-DC reactions using carbohydrate-derived dipolarophiles or carbohydrate-derived nitrones (cyclic or acyclic), as well as a combination of both, in neat conditions.

2. Results

With the aim of probing the efficacy of solvent-free conditions in 1,3-dipolar cycloadditions of biomass-derived compounds, cycloadditions with a single reagent (1,3-dipole or dipolarophile) derived from biomass or cycloadditions that involve a 1,3-dipole and a dipolarophile both derived from biomass were explored in our experiments. In particular, levoglucosenone (4, Scheme 1) and N,N-dimethylacrylamide were chosen as dipolarophiles, while different acyclic and cyclic nitrones (derived from sugars or tartaric acid) were employed as 1,3-dipoles.
Levoglucosenone (4) is a highly functionalized chiral synthon that can be produced by pyrolysis of cellulose-containing industrial residual materials such as waste paper [35], and it is a promising 1,6-anhydrosugar for obtaining highly added-value chemicals in various applications including pharmaceutics [36,37,38] and material chemistry [39,40,41]. Although the interest in this valuable compound has grown a lot in recent years, some of its functionalities have not yet been deeply explored. In the literature, there are few examples in which levoglucosenone is used as a dipolarophile in 1,3-dipolar cycloadditions with nitrones, but no example of solvent-free cycloadditions has been reported, to the best of our knowledge. For this reason, we decided to fill this gap by reproducing already reported 1,3-dipolar cycloadditions with levoglucosenone in neat conditions. First of all, cycloadditions of levoglucosenone with the diversely substituted acyclic nitrones 5–10 to form the corresponding isoxazolidine adducts 11–16 were studied, as shown in Scheme 1.
As the model reaction, we considered the 1,3-DC reaction of levoglucosenone (4) and N-benzyl-C-phenylnitrone 5, described by Paton and collaborators [42]. The authors reported that the reaction proceeded completely regio- and stereoselectively with the obtainment of cycloadduct 11 as the sole product in 87% yield by refluxing in dry toluene for 48 h (Table 1, Entry 1). The complete regioselectivity observed for 11 is in agreement with a qualitative FMO analysis for a 1,3-dipole of type II. In the cycloaddition with a 1,2-disubstituted alkene with an electron-donating (alkyl) and an electron-withdrawing (ketone) substituent, [13] as in levoglucosenone, both LUMOdipole-HOMOdipolarophile and HOMOdipole-LUMOdipolarophile interactions are to be considered. In both the interactions the coefficients of the orbitals at C and O of the nitrone and those at sp2-C of alkene converge to place the EDG group at C-5 and the EWG at C-4 of isoxazolidine. Regarding the steroselectivity, the cycloadduct 11 derived from an endo approach of nitrone 5 to levoglucosenone and anti with respect to the 1,6-anhydro bridge.
N-benzyl-C-phenylnitrone 5 was synthesized as described in the literature [43], and several solvent-free attempts were carried out using a slight excess of dipolarophile (1.2 equivalents) at different temperatures. While at room temperature no desired product could be observed even after more than 7 days, more encouraging results were obtained by heating the reaction mixture in an oven (Table 1, Entry 2–4). In fact, it was possible to obtain the cycloadduct 11 in 57–58% yield, both at 40 °C and at 60 °C, with reaction times strongly decreased (17 h vs. 96 h), by increasing the temperature (Table 1, Entry 3 vs. Entry 2). By carrying out the cycloaddition reaction at the temperature reported in the literature (110 °C), it was possible to obtain the desired cycloadduct 11 in only 3 h with satisfactory yield (63%, Table 1, Entry 4). Given the promising results, we envisaged that heating via microwave irradiation could further reduce reaction times (Table 1, Entry 5–6). The best results were obtained by heating in microwave at 110 °C with a power of 300 W, accessing cycloadduct 11 in 68% yield in only 1 h (Table 1, Entry 6).
Another interesting example of 1,3-dipolar cycloadditions involving levoglucosenone for synthesis of potential enzymatic inhibitors is that reported by Peri and coworkers [44]. In particular, they explored the cycloaddition with three differently substituted nitrones (6–8) in dry dichloromethane at room temperature for 8 h in the presence of zinc chloride as Lewis acid promoter. In all cases, two different cycloadducts, resulting from the endo-anti (3S) and the exo-anti (3R) approaches (separable by column chromatography) were obtained in different ratios, with total yields between 69–84% (Table 1, Entry 7,10,13). As shown in Table 1, it was possible to reduce the reaction times found in the literature (8 h) and increase yields by replicating the different cycloadditions under neat conditions by heating at 80 °C. At lower temperatures, the reaction times did not decrease considerably. N-Phenyl-C-4-bromophenylnitrone 6 [45], N-phenyl-C-3-bromophenylnitrone 7 [46], and N-4-bromophenyl-C-phenylnitrone 8 [47] were synthesized as described in the literature and reacted with a slight excess of levoglucosenone. Under solvent-free conditions, by heating at 80 °C, the cycloaddition of levoglucosenone to nitrone 6 led to the two desired cycloadducts 12a and 12b in 3S:3R 1:1.2 ratio after 2.5 h and in 81% total yield (compared to the 3S:3R 1:1 ratio and 77% yield reported in the literature, Table 1, Entry 8 vs. Entry 7). By using microwave heating, the reaction completed in only 45 min with a total yield of 79% (Table 1, Entry 9). Applying solvent-free conditions and conventional heating at 80 °C to N-phenyl-C-3-bromophenylnitrone 7, the corresponding cycloadducts 13a and 13b were obtained in 3S:3R 1:2.2 ratio after 3 h in 69% total yield (compared to the 3S:3R 1:3.5 ratio and 69% yield reported in the literature, Table 1, Entry 11 vs. Entry 10). The yield was slightly increased (72%) by using microwave irradiation at 80 °C, which also allowed the reaction time to be decreased to only 45 min (Table 1, Entry 12). With N-4-bromophenyl-C-phenylnitrone 8, the use of neat conditions allowed the reaction times to be reduced, but did not increase the reaction yield. Heating at 80 °C provided cycloadducts 14a and 14b in a 3S:3R 1:1 ratio and 75% total yield (compared to the 3S:3R 1:1.5 and 84% yield reported in the literature, Table 1, Entry 14 vs. Entry 13). Even in this case, the yield was slightly increased (81%) by using microwave irradiation at 80 °C, decreasing the reaction time to only 45 min as well (Table 1, Entry 15).
Table 1. 1,3-DC reactions of acyclic nitrones 5–10 and levoglucosenone (4) (1.2 equivalents).
Table 1. 1,3-DC reactions of acyclic nitrones 5–10 and levoglucosenone (4) (1.2 equivalents).
EntryNitroneRR′Reaction ConditionsHeatingTemperatureTimeProduct
(Yield) a
1 b5-benzyl-phenyldry toluenestandard110 °C48 h11 (87%)
25-benzyl-phenylsolvent-freestandard40 °C96 h11 (57%)
35-benzyl-phenylsolvent-freestandard60 °C17 h11 (58%)
45-benzyl-phenylsolvent freestandard110 °C3 h11 (63%)
55-benzyl-phenylsolvent-freemicrowaves (150 W)110 °C1.5 h11 (63%)
65-benzyl-phenylsolvent-freemicrowaves (300 W)110 °C1 h11 (68%)
7 c6-phenyl-4-bromophenyldry CH2Cl2ZnCl2 · Et2O-r.t.8 h12 (77%)
86-phenyl-4-bromophenylsolvent-freestandard80 °C2.5 h12 (81%)
96-phenyl-4-bromophenylsolvent-freemicrowaves (150 W)80 °C45 min12 (79%)
10 c7-phenyl-3-bromophenyldry CH2Cl2ZnCl2 · Et2O-r.t.8 h13 (69%)
117-phenyl-3-bromophenylsolvent-freestandard80 °C3 h13 (69%)
127-phenyl-3-bromophenylsolvent-freemicrowaves (150 W)80 °C45 min13 (72%)
13 c8-4-Br-phenyl-phenyldry CH2Cl2ZnCl2 · Et2O-r.t.8 h14 (84%)
148-4-Br-phenyl-phenylsolvent-freestandard80 °C3 h14 (75%)
158-4-Br-phenyl-phenylsolvent-freemicrowaves (150 W)80 °C45 min14 (81%)
16 d9-benzylReactions 06 00036 i001dry toluenestandard60 °C24 h15 (78%)
17 e9-benzylReactions 06 00036 i002solvent-freestandard60 °C6 h15 (61%)
18 e9-benzylReactions 06 00036 i003solvent-freemicrowaves (150 W)60 °C4 h15 (62%)
1910-benzylReactions 06 00036 i004dry toluenestandard60 °C18 h16 (60%)
2010-benzylReactions 06 00036 i005solvent-freestandard60 °C6 h16 (62%)
21AG-benzylReactions 06 00036 i006solvent-freemicrowaves (150 W)60 °C3 h16 (57%)
a Isolated yield after flash column chromatography. b Reference [42]. c Reference [44]. d Reference [38]. e Reactions performed using 2.0 equivalents of levoglucosenone.
In 2020, exploring the functions of levoglucosenone to obtain new glycomimetics as carbonic anhydrase inhibitors [38], we investigated the 1,3-DC reaction of levoglucosenone with nitrone 9, which can be obtained from d-mannose in five steps [48,49,50]. We were delighted to observe that the reaction occurred in a completely regio- and stereoselective manner, leading to the endo-anti cycloadduct 15 as the sole product in 78% yield, by heating at 60 °C in dry toluene for 24 h (Table 1, Entry 16). To obtain the desired product in a reasonable time, it was necessary to carry out the reaction at high concentration (2M), thus minimizing the solvent amount. For this reason, we thought that it would be of great interest to also try this reaction in solvent-free conditions. We initially heated nitrone 9 with the usual slight excess of levoglucosenone (1.2 equivalents) at 60 °C (same temperature as in the literature) in neat conditions, and cycloadduct 15 was obtained in a time frame comparable with classical conditions (18 h vs. 24 h). Using a larger amount of levoglucosenone (2 equivalents), the cycloadduct 15 was obtained in good yield (61%) in 6 h (Table 1, Entry 17). Performing the reaction in the same conditions by replacing conventional heating with microwave irradiation led to adduct 15 in 62% yield in only 4 h (Table 1, Entry 18).
Considering the interest in studying cycloadditions that involve both the dipole and the dipolarophile derived from biomass, a new 1,3-dipolar cycloaddition between levoglucosenone and nitrone 10 obtained from d-glucose [51] was studied. The first attempt was carried out by heating in dry toluene at 60 °C, and cycloadduct 16 was obtained as the sole product in 18 h and 60% yield (Table 1, Entry 19). Through NOESY and 1H NMR experiments, it was possible to unequivocally determine the absolute configuration of the newly formed stereogenic centres of the adduct, which derived from an endo-anti approach (Scheme 2, and Supplementary Materials for 1H NMR and NOESY spectra). Indeed, the NOESY coupling between proton H-7 and proton H-8a confirmed the anti approach of the nitrone 10 to the 1,6-bridge of levoglucosenone. On the other hand, the small value of the coupling constant between H-3 and H-3a (J = 3.7 Hz) confirmed the endo approach of nitrone 10. Under solvent-free conditions, the cycloadduct 16 was obtained with complete regio- and stereoselectivity in 62% yield by heating at 60 °C (same temperature as in dry toluene) for 6 h (Table 1, Entry 20). The reaction time was also halved in this case (only 3 h) by heating to 60 °C via microwave irradiation, obtaining the new cycloadduct 16 in a similar 57% yield. (Table 1, Entry 21).
To investigate the influence of neat conditions on 1,3-DC reactions with enantiopure cyclic nitrones, key intermediates for the synthesis of pyrrolizidine iminosugars [22], we initially replaced levoglucosenone 4 with the commercially available dipolarophile N,N-dimethylacrylamide.
Nitrone 17, easily obtained from d-arabinose [52,53], was successfully employed in 1,3-DC reactions with suitable dipolarophiles, providing bicyclic isoxazolidines with an excellent selectivity which can be ascribed to the peculiar “all-trans” disposition of the benzyloxy groups in nitrone 17 (Scheme 3). Indeed, the substituents at C-3 and C-5 allow exclusively anti cycloadducts to be obtained, and the steric bulk of substituent at C-4 ensures an excellent exo selectivity [52,54].
In particular, nitrone 17 reacted with N,N-dimethylacrylamide to obtain the exo-anti cycloadduct 18 in a totally regio- and stereoselective manner; cycloadduct 18 is the precursor of 7-deoxycasuarine, a potent inhibitor of glycosidases [53]. In this case, the regioselectivity of the cycloaddition may be dominated by the higher differentiation of the carbon and oxygen coefficients in the LUMO orbital of the nitrone, while the low orbital coefficients difference in its HOMO [21] makes the preferred HOMOdipole-LUMOdipolarophile orbital interaction unable to exert any regioselectivity. Thus, the regioselectivity, especially with moderately electron-deficient substituted alkenes such as esters and amides, is shown to be controlled by the higher energy LUMOdipole-HOMOdipolarophile interaction, which favors the formation of 5-substituted isoxazolidines. Steric effects may also play a relevant role in determining the observed selectivity. The cycloaddition was performed in dichloromethane at room temperature and provided 18 in 72 h and 85% yield (Table 2, Entry 1). The attempts in solvent-free conditions gave the desired adduct 18 both at room temperature (54 h, 60% yield, Table 2, Entry 2), and by heating at 40 °C (18 h, 59% yield, Table 2, Entry 4). Interestingly, the use of an orbital shaker to perform the reaction allowed 18 to be obtained at a higher 71% yield at room temperature in 15 h (Table 2, Entry 3).
Encouraged by these results, we explored the unprecedented cycloaddition of nitrone 17 to levoglucosenone. Unfortunately, a complex mixture of cycloadducts, which were impossible separate and characterize, were obtained in dry toluene by heating at 60 °C for 96 h (Table 2, Entry 5). This result was partially predictable since a ‘mismatched’ double asymmetric induction occurs in this case. Therefore, no trials in solvent-free conditions were carried out.
However, as a final attempt, we turned to another enantiopure cyclic nitrone (19, Scheme 3) which was previously employed by some of us in 1,3-DC reaction with levoglucosenone [55]. Nitrone 19, obtained from L-tartaric acid [56], was initially reacted with N,N-dimethylacrylamide in toluene at room temperature (Table 2, Entry 6). After 2.5 h, three different cycloadducts, 20a, 20b, and 20c, were obtained in a 1:0.4:0.1 molar ratio, as attested by the ¹H NMR analysis of the crude reaction mixture. Purification by flash column chromatography allowed pure 20a to be isolated, with compounds 20b and 20c as an inseparable mixture, in 65% overall yield. The complete regioselectivity of the reaction was confirmed by bidimensional NMR experiments performed on the purified cycloadducts. As previously mentioned for nitrone 17, in this case the regioselectivity of the cycloaddition is dictated by the less energetically favorable LUMOdipole–HOMOdipolarophile interaction, leading to the formation of the 5-isoxazolidine with the electron-poor alkene [21]. NOESY and 1H NMR experiments performed on isolated compound 20a allowed the stereochemistry of the adduct to be determined; it derived from an exo-anti approach (Scheme 4a, see Supplementary Materials for NOESY spectra). Indeed, the NOESY coupling of the proton H-3a with the proton H-5 confirmed the anti approach of the dipolarophile relative to the hindering group (-OtBu) on C-3 of the nitrone 19, and the NOESY correlation between H-2 and H-4 confirmed the exo approach. Although compounds 20b and 20c were obtained as an inseparable mixture, all signals in the ¹H and ¹³C NMR spectra were successfully assigned. This enabled the execution of NOESY experiments to elucidate the structures of the cycloadducts: the presence of NOESY correlation between H-5 and H-2 along with the absence of correlation between H-3a and H-5, confirmed an exo-syn approach of the dipolarophile (Scheme 4b) for the major cycloadduct of the two-component mixture 20b, while the endo-syn diastereoselectivity for the minor cycloadduct 20c was confirmed by selective irradiation of H-3a, which showed a NOESY correlation with H-2 but not with H-5 (Scheme 4c).
Performing the 1,3-DC without solvent at room temperature with the orbital shaker, cycloadduct 20a and a mixture of 20b and 20c were obtained with the same selectivity and a slightly higher and shorted reaction time (70% yield, 1 h vs. 65% 2.5 h, Table 2, Entry 7 vs. Entry 6).
These results prompted us to apply the solvent-free conditions to the 1,3-dipolar cycloaddition of nitrone 19 with levoglucosenone, previously reported in dry toluene [55]. In this case, thanks to the high facial selectivity of levoglucosenone, a single exo-anti cycloadduct 21 was obtained at room temperature in 2 h with 88% yield (Table 2, Entry 8). Neat conditions at room temperature did not provide the desired product even after 7 days. Conversely, by heating at 80 °C, the sole cycloadduct 21 was obtained with similar reaction times and yields to that of the reaction in toluene reported in the literature (2 h, 80% yield, Table 2, Entry 9). At temperatures lower than 80 °C, the reaction times did not significantly decrease with respect to the literature. Using microwaves irradiation at 80 °C, the reaction time decreased to only 45 min, and similar 76% yield was obtained (Table 2, Entry 10).

3. Discussion

In this work, a more sustainable version of 1,3-dipolar cycloadditions of nitrones for the synthesis of glycomimetics was investigated. Considering that cycloadditions are favored by a volume contraction, we envisaged that solvent-free conditions could decrease the reaction times. In order to develop greener protocols, we also focused on the use of starting materials obtainable from biomass, such as carbohydrate-derived nitrones as dipoles and levoglucosenone, derived from cellulose-containing waste material, as dipolarophile.
First, 1,3-dipolar cycloadditions previously reported in the literature between levoglucosenone and acyclic nitrones were replicated in neat conditions (Table 1). From the first experiments with N-benzyl-C-phenylnitrone 5, it was clear that heating in neat conditions could achieve the desired cycloadduct 11 faster than under solvent conditions. In addition, using microwave heating made it possible to further reduce the reaction time, selectively obtaining the desired product in only 1 h (vs. 48 h in solvent), with a good 68% yield.
Given the first promising results, other 1,3-dipolar cycloadditions were replicated between levoglucosenone and the differently substituted N-phenyl-C-phenylnitrones 6–8. With N-4-bromophenyl-C-phenylnitrone 6, no reaction occurred without solvent at room temperature. Conversely, the couple of cycloadducts 12a and 12b was obtained in solvent-free conditions in 2.5 h by heating in an oven at 80 °C, or in 45 min (vs. 8 h) by microwave irradiation at 80 °C, with slightly higher yields compared to the literature. Also, with N-phenyl-C-3-bromophenylnitrone 7, it was possible to reduce the reaction time (3 h with standard heating or 45 min with microwave irradiation) for the synthesis of the cycloadducts 13a and 13b, obtained with slightly higher yields with respect to the reaction performed in classical conditions. Considering that the literature procedure involved the use of a zinc complex to improve the diastereoisomeric ratio (vide supra), in most cases, our reaction conditions led to similar results in terms of selectivity and yields, avoiding the use of metals and with reduced reaction times, thus providing a more sustainable protocol.
Moreover, the replication under solvent-free conditions of cycloadditions of levoglucosenone with the nitrone 9 derived from d-mannose led to the formation of the desired adduct 15 in shorter time (4 h vs. 24 h) and comparable yields. During this work, a 1,3-dipolar cycloaddition between levoglucosenone and the nitrone 10 derived from d-glucose was explored that had not been previously reported. When performed in dry toluene (18 h), the reaction led to the formation of a single cycloadduct 16 whose stereochemistry was interpreted thanks to NOESY and 1H NMR studies. Under solvent-free conditions the cycloadduct was obtained with the same yield and shorter reaction time (3 h vs. 18 h).
To complete the work, attempts of cycloaddition with enantiopure cyclic nitrones were also repeated (Table 2). Nitrone 17 derived from d-arabinose and N,N-dimethylacrylamide efficiently reacted in solvent-free conditions, affording cycloadduct 18 stereoselectively at room temperature with a very good 71% yield when an orbital shaker was employed. Additional experiments were conducted between nitrone 19 derived from L-tartaric acid and N,N-dimethylacrylamide, leading to the formation of novel cycloadducts 20a, 20b, and 20c (the latter two obtained as an inseparable mixture). When performed in toluene (2.5 h), the reaction yielded three cycloadducts whose stereochemistry was assigned on the basis of NOESY and 1H NMR studies. Under neat conditions and orbital shaking, the cycloadducts were obtained with the same stereoselectivity with higher yield and shorter reaction time (1 h vs. 2.5 h), even at room temperature.
Finally, 1,3-DC of nitrone 19 with levoglucosenone led to cycloadduct 21 as the sole product, heating at 80 °C, with reaction times and yield comparable to the previous literature (dry toluene). The reaction time was lowered by using microwave heating (45 min vs. 2 h).
The collected results shed light on a new procedure for performing 1,3-dipolar cycloadditions as solvent-free and catalyst-free reactions, thus aligning with some of the 12 principles of green chemistry (prevention, atom economy, safer solvents and auxiliaries, use of renewable feedstocks) [57]. We have also further explored the great potential of levoglucosenone, a biomass-derived highly functionalized compound that can be involved in more sustainable procedures to synthesize new glycomimetics. In general, it has been observed that, under solvent-free conditions, the reaction times of cycloadditions are shorter than in solvent. Further studies are required to broaden the range of reactions replicated under neat conditions.

4. Materials and Methods

4.1. General Details

Commercial reagents were used as received. All reactions were monitored by TLC on 0.25 mm silica gel plates (Merck F254, Merk Life Science S.r.l., Merck KGaA, Darmstadt, Germany). Column chromatographies were carried out on Silica Gel 60 (32–63 μm) or on silica gel (230–400 mesh, Merck). Yields refer to spectroscopically and analytically pure compounds unless otherwise stated. Melting points were obtained with a Stuart Scientific melting point apparatus and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Varian Gemini 200 MHz, a Varian Mercury 400 MHz, or a Varian INOVA 400 MHz instrument at 25 °C. Chemical shifts are reported relative to CDCl3 (13C: δ = 77.0 ppm). Integrals are in accordance with assignments, and coupling constants are given in Hz. For detailed peak assignments, 2D spectra were carried out (COSY, HSQC, NOESY, and NOE as necessary). Small scale microwave-assisted syntheses were carried out in a microwave apparatus for synthesis (CEM Discover, CEM Corporation, Matthews, NC, USA) with a septum-sealed reaction vessel, and the reaction mixture temperature was monitored by an infrared temperature sensor. IR spectra were recorded with a BX FTIR Perkin-Elmer system spectrophotometer and an IRAffinity-1S Shimadzu spectrophotometer. ESI-MS spectra were recorded with a Thermo Scientific™ (Thermo Fisher Scientific, Waltham, MA, USA) LCQ fleet ion trap mass spectrometer. Optical rotation measurements were performed on a JASCO DIP-370 polarimeter.

4.2. General Procedure for Solvent-Free 1,3-Dipolar Cycloaddition of Nitrones and Dipolarophiles

Nitrone 5–10, 17, and 19 (1 equiv) were added to levoglucosenone 4 (1.2 or 2 equiv) or N,N-dimethylacrylamide (1.2 equiv). The reaction was left, or shaken at room temperature, or heated in an oven, or heated via microwave irradiation (see Table 1 and Table 2 for temperature and reaction time). The end of the reaction was confirmed by TLC, and the crude was purified by flash column chromatography purification on silica gel, obtaining the compounds 11–16, 18, 20a–c, and 21 with yields between 57–81%.
For all the obtained products that are known compounds reported in the literature (11–15, 18, 21), 1H NMR spectral data and m.p. when solid are reported in the Supplementary Materials and are in agreement with the literature.

4.3. Synthesis of Cycloadduct 16

Nitrone 10 [51] (50.4 mg, 0.131 mmol) was added to a solution of levoglucosenone (4) (16.6 mg, 0.131 mmol) in dry toluene (0.150 mL) under nitrogen atmosphere. The reaction was heated at 60 °C for 18 h. The end of the reaction was confirmed by TLC (eluent hexane:AcOEt 2:1). The reaction crude was purified by flash column chromatography purification on silica gel (eluent hexane:AcOEt 7:3) obtaining the compound 16 (39.4 mg, 0.077 mmol) as colourless oil with 60% yield.
According to the General Procedure, compound 16 (33.8 mg, 0.066 mmol, 62%) was obtained as colourless oil from the reaction of nitrone 10 [51] (41 mg, 0.107 mmol) and levoglucosenone (4) (16.2 mg, 0.128 mmol) at 60 °C in an oven for 6 h, followed by flash column chromatography purification on silica gel (eluent hexane:AcOEt 7:3, Rf: 0.2).
According to the General Procedure, compound 16 (35.2 mg, 0.069 mmol, 57%) was obtained as colourless oil from the reaction of nitrone 10 [51] (46.6 mg, 0.121 mmol) and levoglucosenone (4) (18.4 mg, 0.146 mmol) at 60 °C for 3 h under microwave irradiation (150 W), followed by flash column chromatography purification on silica gel (eluent hexane:AcOEt 7:3, Rf: 0.2). [α]20D = −124.4 (c 0.8, CHCl3). IR (CHCl3): 3020, 2916, 2849, 1756, 1456, 1379, 1163, 1115, 1076, 941 cm−1. C28H31NO8: MS-ESI (m/z, %) = 1040.8 (100, [2M+Na]+), 532.1 (85, [M+Na]+). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.28 (m, 10H, Ar), 5.97 (d, J = 3.9 Hz, 1H, H-2′), 5.18 (s, 1H, H-5), 4.70–4.66 (m, 3H, H-3′, H-8, -OCH2), 4.50 (d, J = 11.1 Hz, 1H, -OCH2), 4.21 (d, J = 6.7 Hz, 1H, H-8a), 4.06–4.00 (m, 4H, H-4′, H-5′, -NCH2), 3.93 (dd, J = 3.7, 6.1 Hz, 1H, H-3), 3.75 (dd, J = 5.6, 7.7 Hz, 1H, Ha-7), 3.47 (d, J = 7.7 Hz, 1H, Hb-7), 3.32 (dd, J = 3.7, 6.7 Hz, 1H, H-3a), 1.41 (s, 3H, -CH3), 1.32 (s, 3H, -CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.8 (s, 1C, CO), 137.1 (s, 1C, Ar), 137.0 (s, 1C, Ar), 130.4, 129.2, 128.9, 128.5, 128.4, 128.4, 128.2, 128.0, 127.9, 127.3 (d, 10C, Ar), 111.9 (s, 1C, O-C-O), 105.0 (d, 1C, C-2′), 100.6 (d, 1C, C-5), 82.5 (d, 1C, C-4′), 81.8 (d, 1C, C-8), 80.1 (d, 1C, C-5′), 78.8 (d, 1C, C-8a), 72.8 (d, 1C, C-3′), 71.6 (t, 1C, -OCH2), 65.5 (d, 1C, C-3), 65.6 (t, 1C, C-7), 62.8 (t, 1C, -NCH2), 52.1 (d, 1C, C-3a), 26.8 (q, 1C, -CH3), 26.4 (q, 1C, -CH3) ppm.

4.4. Synthesis of Cycloadducts 20a, 20b and 20c

Compounds 20a (brown oil) and a mixture of 20b and 20c 1:0.7 (pale yellow oil) were obtained in a ratio of 1:0.4:0.1 with 65% of total yield from the reaction of nitrone 19 [56] (40.0 mg, 0.174 mmol) and N,N-dimethylacrylamide (0.209 mmol, 22 µL) in toluene (0.087 mL) at room temperature for 2.5 h, followed by flash column chromatography purification on silica gel (eluent AcOEt, 20a Rf: 0.2 and 20b + 20c Rf: 0.1).
According to the General Procedure, compounds 20a (brown oil) and a mixture of 20b and 20c 1:0.7 (pale yellow oil) were obtained in a ratio of 1:0.4:0.1 with 70% of total yield from the reaction of nitrone 19 [56] (40.0 mg, 0.174 mmol) and N,N-dimethylacrylamide (0.209 mmol, 22 µL) in an orbital shaker at room temperature for 1 h, followed by flash column chromatography purification on silica gel (eluent AcOEt, 20a Rf: 0.2 and 20b + 20c Rf: 0.1).
20a: [α]20D = 84.1 (c 1.0, CHCl3). IR (neat) ν = 2972, 2936, 2872, 1651, 1393, 1192, 1061 cm−1. C17H32N2O4: MS-ESI (m/z, %) = 351.08 (100, [M+Na]+), 678.92 (83, [2M+Na]+), 329.08 (75, [M+H]+). 1H NMR (400 MHz, CDCl3): δ = 4.90 (t, J = 7.0 Hz, 1H, H-2), 3.92–3.88 (m, 1H, H-5), 3.76 (t, J = 3.8 Hz, 1H H-4), 3.56 (ddd, J = 9.0, 5.6, 3.4 Hz, 1H, H-3a), 3.45 (dd, J = 10.9, 5.9 Hz, 1H, Ha-6), 3.08 (s, 3H, Me), 3.00 (ddd, J = 12.6, 9.0, 7.0 Hz, 1H, Ha-3), 2.92 (s, 3H, Me), 2.87 (dd, J = 10.9, 7.3, Hz, 1H, Hb-6), 2.25 (m, 1H, Hb-3), 1.16 (s, 9H, -OtBu), 1.16 (s, 9H, -OtBu) ppm. 13C NMR (100 MHz, CDCl3): δ = 168.6 (s, 1C, C=O), 82.1 (d, 1C, C-4), 77.1 (d, 1C, H-5), 74.7 (d, 1C, H-2), 74.1 (s, 2C, Cq), 71.0 (d, 1C, C-3a), 60.7 (t, 1C, C-6), 37.2 (q, 1C, Me), 36.5 (t, 1C, C-6), 35.98 (q, 1C, Me), 28.75 (q, 3C, -OtBu), 28.6 (q, 3C-OtBu) ppm.
20b + 20c: IR (neat) ν = 2972, 2934, 1649, 1366, 1111 cm−1. C17H32N2O4: MS-ESI (m/z, %) = 329.18 (100, [M+H]+), 351.15 (44, [M+Na]+), 679.09 (69, [2M+Na]+). 1H NMR (400 MHz, CDCl3): δ = 4.71 (dd, J = 7.4, 4.5 Hz, 1H, H-2, 20b), 4.60 (dd, J = 7.4, 4.5 Hz, 1H, H-2, 20c), 4.13 (q, J = 7.4 Hz, 1H, H-5, 20c), 4.04 (dd, J = 8.0, 6.4 Hz, 1H, H-5, 20b), 3.96 (t, J = 7.4 Hz, 1H, H-4, 20c), 3.92–3.89 (m, 1H, H-4, 20b), 3.87–3.84 (m, 1H, H-3a, 20b), 3.82–3.78 (m, 1H, H-3a, 20c), 3.37 (dd, J = 13.5, 7.4 Hz, 1H, Ha-6, 20c), 3.31 (dd, J = 13.7, 6.4 Hz, 1H, Ha-6, 20b), 3.10 (s, 3H, Me, 20b), 3.09 (s, 3H, Me, 20c), 2.96 (s, 3H, Me, 20c), 2.94 (s, 3H, Me, 20b), 2.92–2.87 (m, 3H, Hb-6, 20b, Ha-3, Hb-6, 20c), 2.74 (ddd, J = 12.8, 8.7, 4.5 Hz, 1H, Ha-3, 20b), 2.54 (ddd, J = 12.8, 7.4, 4.7 Hz, 1H, Hb-3, 20b), 2.19 (ddd, J = 12.9, 8.4, 7.4 Hz, 1H, Hb-3, 20c), 1.18 (s, 9H, -OtBu, 20b), 1.16 (s, 18H, -OtBu, 20b and 20c), 1.14 (s, 9H, -OtBu, 20c) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8 (s, 1C, C=O, 20b), 168.5 (s, 1C, C=O, 20c), 77.6 (d, 1C, C-4, 20b), 77.4 (d, 1C, C-4, 20c), 76.8 (d, 1C, C-2, 20c), 75.9 (d, 1C, C-2, 20b), 75.8 (d, 1C, C-5, 20b), 74.3 (d, 1C, C-5, 20c), 74.2 (s, 1C, Cq, 20b), 73.9 (s, 1C, Cq, 20c), 73.8 (s, 1C, Cq, 20c), 73.7 (s, 1C, Cq, 20b), 66.6 (d, 1C, C-3a, 20c), 65.8 (d, 1C, C-3a, 20b), 59.8 (t, 1C, C-6, 20c), 59.7 (t, 1C, C-6, 20b), 37.4 (q, 1C, Me, 20b), 37.2 (q, 1C, Me, 20c), 36.2 (q, 1C, Me, 20b), 36.0 (q, 1C, Me, 20c), 33.9 (t, 1C, C-3, 20c), 33.1 (t, 1C, C-3, 20b), 28.7 (q, 6C, -OtBu, 20b and 20c), 28.6 (q, 6C, -OtBu, 20b and 20c) ppm.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions6020036/s1, Figure S1: 1H NMR of compound 16 (400 MHz, CDCl3); Figure S2: 13C NMR of compound 16 (100 MHz, CDCl3); Figure S3: 1D NOESY of compound 16 (irradiation of H-8a at 4.21 ppm, 400 MHz, CDCl3); Figure S4: 1D NOESY of compound 16 (irradiation of Hb-7 at 3.47 ppm, 400 MHz, CDCl3); Figure S5: 1H NMR spectrum of 20a (400 MHz, CDCl3); Figure S6: 13C NMR spectrum of 20a (400 MHz, CDCl3); Figure S7: 1D NOESY spectrum of 20a (irradiation of H-2 at 4.90 ppm, 400 MHz, CDCl3); Figure S8: 1D NOESY spectrum of 20a (irradiation of H-4 at 3.76 ppm, 400 MHz, CDCl3); Figure S9: 1D NOESY spectrum of 20a (irradiation of H-3a at 3.56 ppm, 400 MHz, CDCl3); Figure S10: 1D NOESY spectrum of 20a (irradiation of H-5 at 3.92–3.88 ppm, 400 MHz, CDCl3); Figure S11: 1H NMR spectrum of 20b + 20c (400 MHz, CDCl3); Figure S12: 13C NMR spectrum of 20b + 20c (400 MHz, CDCl3); Figure S13: 1D NOESY spectrum of 20b + 20c (irradiation of H-2 of 20b at 4.71 ppm, 400 MHz, CDCl3); Figure S14: 1D NOESY spectrum of 20b + 20c (irradiation of H-5 of 20b at 4.04 ppm, 400 MHz, CDCl3); Figure S15: 1D NOESY spectrum of 20b + 20c (irradiation of H-3a of 20c at 3.82–3.78 ppm, 400 MHz, CDCl3); Figure S16: 1D NOESY spectrum of 20b + 20c (irradiation of H-2 of 20c at 4.60 ppm, 400 MHz, CDCl3). For all the obtained products that are known compounds reported in the literature (11–15, 18, 21) 1H NMR spectral data and m.p. when solid are reported in the Supplementary Materials and are in agreement with the literature. For all obtained new compounds (16 and 20a–c) 1H NMR, 13C NMR, 1D NOESY spectra are reported in the Supplementary Materials. Refs. [38,42,43,44,45,46,47,48,49,50,52,53,55,56] are mentioned in the Supplementary Materials.

Author Contributions

Conceptualization, D.P., C.M., A.G. and F.C.; methodology, D.P. and A.M.; formal analysis, D.P., A.M. and A.G.; writing—original draft preparation, D.P. and C.M.; writing—review and editing, all authors; supervision, C.M.; funding acquisition, D.P. and C.M. All authors have read and agreed to the published version of the manuscript.

Funding

Funded by the European Union—Next Generation EU. National Recovery and Resilience Plan (NRRP)—M4C2 Investment 1.3—Research Program PE00000004 “Made in Italy Circolare e Sostenibile—MICS”—CUP B83C22004890007.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Acknowledgments

The financial support provided by the MUR—Dipartimenti di Eccellenza 2023–2027 (DICUS 2.0, CUP: B97G22000740001) to the Department of Chemistry “Ugo Schiff” of the University of Florence is acknowledged.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Padwa, A.; Pearson, W.H. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Wiley: New York, NY, USA, 2002. [Google Scholar]
  2. Huisgen, R. Adventures with heterocycles. Chem. Pharm. Bull. 2000, 48, 757–765. [Google Scholar] [CrossRef] [PubMed]
  3. Kissane, M.; Maguire, A.R. Asymmetric 1,3-dipolar cycloadditions of acrylamides. Chem. Soc. Rev. 2010, 39, 845–883. [Google Scholar] [CrossRef] [PubMed]
  4. Pellissier, H. Asymmetric 1,3-dipolar cycloadditions. Tetrahedron 2007, 63, 3235–3285. [Google Scholar] [CrossRef]
  5. Gothelf, K.V.; Jorgensen, K.A. Asymmetric 1,3-Dipolar Cycloaddition Reactions. Chem. Rev. 1998, 98, 863–909. [Google Scholar] [CrossRef]
  6. Frühauf, H.W. Metal-Assisted Cycloaddition Reactions in Organotransition Metal Chemistry. Chem. Rev. 1997, 97, 523–596. [Google Scholar] [CrossRef]
  7. Broggini, G.; Molteni, G.; Terraneo, A.; Zecchi, G. Transition metal complexation in 1,3-dipolar cycloadditions. Heterocycles 2003, 59, 823–858. [Google Scholar] [CrossRef]
  8. Karlsson, S.; Högberg, H.E. Asymmetric 1,3-dipolar cycloadditions for the construction of enantiomerically pure heterocycles. A review. Org. Prep. Proced. Int. 2001, 33, 103–172. [Google Scholar] [CrossRef]
  9. Osborn, H.M.I.; Gemmell, N.; Harwood, L.M. 1,3-Dipolar cycloaddition reactions of carbohydrate derived nitrones and oximes. J. Chem. Soc. Perkin Trans. 2002, 1, 2419–2438. [Google Scholar] [CrossRef]
  10. Zhu, J.; Lines, B.M.; Ganton, M.D.; Kerr, M.A.; Workentin, M.S. Efficient Synthesis of Isoxazolidine-Tethered Monolayer Protected Gold Nanoparticles (MPGNs) via 1,3-Dipolar Cycloadditions under High-Pressure Conditions. J. Org. Chem. 2008, 73, 1099–1105. [Google Scholar] [CrossRef]
  11. Krasinski, A.; Radic, Z.; Manetsch, R.; Raushel, J.; Taylor, P.; Sharpless, K.B.; Kolb, H.C. In Situ Selection of Lead Compounds by Click Chemistry: Target-Guided Optimization of Acetylcholinesterase Inhibitors. J. Am. Chem. Soc. 2005, 127, 6686–6692. [Google Scholar] [CrossRef]
  12. Hoffmann, R.; Woodward, R.B. Selection rules for concerted cycloaddition reactions. J. Am. Chem. Soc. 1965, 87, 2046–2048. [Google Scholar] [CrossRef]
  13. Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley: New York, NY, USA, 1984. [Google Scholar]
  14. Breugst, M.; Reissig, H.U. The Huisgen reaction: Milestones of the 1,3-dipolar cycloaddition. Angew. Chem. Int. Ed. 2020, 59, 12293–12307. [Google Scholar] [CrossRef]
  15. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; Wiley-Interscience: London, UK, 1976. [Google Scholar]
  16. Frederickson, M. Optically active isoxazolidines via asymmetric cycloaddition reactions of nitrones with alkenes: Applications in organic synthesis. Tetrahedron 1997, 53, 403–425. [Google Scholar] [CrossRef]
  17. Lait, S.M.; Rankic, D.A.; Keay, B.A. 1,3-Aminoalcohols and Their Derivatives in Asymmetric Organic Synthesis. Chem. Rev. 2007, 107, 767–796. [Google Scholar] [CrossRef] [PubMed]
  18. Koumbis, A.E.; Gallos, J.K. 1,3-Dipolar Cycloadditions in the Synthesis of Carbohydrate Mimics. Part 2: Nitrones and Oximes. Curr. Org. Chem. 2003, 7, 585–628. [Google Scholar] [CrossRef]
  19. Compain, P.; Martin, O.R. Iminosugars: From Synthesis to Therapeutic Applications; Wiley VCH: New York, NY, USA, 2007. [Google Scholar]
  20. Confalone, P.N.; Huie, E.M. The [3 + 2] Nitrone–Olefin Cycloaddition Reaction. Org. React. 1988, 36, 1. [Google Scholar]
  21. Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F.M.; Goti, A. [3 + 2] Dipolar cycloadditions of cyclic nitrones with alkenes. Org. React. 2017, 94, 1. [Google Scholar]
  22. Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F.M.; Goti, A. Stereocontrolled Cyclic Nitrone Cycloaddition Strategy for the Synthesis of Pyrrolizidine and Indolizidine Alkaloids. Chem. Eur. J. 2009, 15, 7808–7821. [Google Scholar] [CrossRef]
  23. Cycloaddition Reactions in Carbohydrate Chemistry; Giuliano, R.M., Ed.; ACS Symposium Series 494; American Chemical Society: Washington, DC, USA, 1992. [Google Scholar]
  24. Herczegh, P.; Kovács, I.; Erdösi, G.; Varga, T.; Agócs, A.; Szilágyi, L.; Sztaricskai, F.; Berecibar, A.; Lukacs, G.; Olesker, A. Stereoselective cycloaddition reactions of carbohydrate derivatives. Pure Appl. Chem. 1997, 69, 519–524. [Google Scholar] [CrossRef]
  25. Kanemasa, S.; Tsuge, O. Recent advances in synthetic applications of nitrile oxide cycloaddition. Heterocycles 1990, 30, 719–736. [Google Scholar] [CrossRef]
  26. Broggini, G.; Zecchi, G. Pyrrolizidine and indolizidine syntheses involving 1,3-Dipolar cycloadditions. Synthesis 1999, 6, 905–917. [Google Scholar] [CrossRef]
  27. Sheldon, R.A. Green and sustainable manufacture of chemicals from biomass: State of the art. Green Chem. 2014, 16, 950–963. [Google Scholar] [CrossRef]
  28. Cardona, F.; Salanski, P.; Chmielewski, M.; Valenza, S.; Goti, A.; Brandi, A. Remarkable High-pressure Enhancement of Enantiopure Nitrone Cycloadditions to Glycals: General Access to (1 → 2)-Linked Pseudo Aza-C-disaccharides. Synlett 1998, 12, 1444–1446. [Google Scholar] [CrossRef]
  29. Martina, K.; Tagliapietra, S.; Veselov, V.V.; Cravotto, G. Green Protocols in Heterocycle Syntheses via 1,3-Dipolar Cycloadditions. Chem. Front. 2019, 7, 95. [Google Scholar] [CrossRef]
  30. Mabrour, M.; Bougrin, K.; Benhida, R.; Loupy, A.; Soufiaoui, M. An efficient one-step regiospecific synthesis of novel isoxazolines and isoxazoles of N-substituted saccharin derivatives through solvent-free microwave-assisted [3+2] cycloaddition. Tetrahedron Lett. 2007, 48, 443–447. [Google Scholar] [CrossRef]
  31. Pospíšil, J.; Potáček, M. Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: Scope and limitations. Tetrahedron 2007, 63, 337–346. [Google Scholar] [CrossRef]
  32. Nguyen, T.B.; Martel, A.; Dhal, R.; Dujardin, G. 1,3-Dipolar Cycloaddition of N-Substituted Dipolarophiles and Nitrones: Highly Efficient Solvent-Free Reaction. J. Org. Chem. 2008, 73, 2621–2632. [Google Scholar] [CrossRef]
  33. Almansour, A.I.; Suresh Kumar, R.; Arumugam, N.; Sriram, D. A solvent free, four-component synthesis and 1,3-dipolar cycloaddition of 4(H)-pyrans with nitrile oxides: Synthesis and discovery of antimycobacterial activity of enantiomerically pure 1,2,4-oxadiazoles. Eur. J. Med. Chem. 2012, 53, 416–423. [Google Scholar] [CrossRef]
  34. Chakraborty, B. Solvent-free synthesis and 1,3-dipolar cycloaddition reactions of N-methyl-C-(2-furyl) nitrone in a ball mill and anticancer activities of the new cycloadducts. J. Heterocycl. Chem. 2020, 57, 477–485. [Google Scholar] [CrossRef]
  35. Comba, M.B.; Tsai, Y.H.; Sarotti, A.M.; Mangione, M.I.; Suárez, A.G.; Spanevello, R.A. Levoglucosenone and its new applications: Valorization of cellulose residues. Eur. J. Org. Chem. 2018, 2018, 590–604. [Google Scholar] [CrossRef]
  36. Camp, J.E.; Greatrex, B.W. Levoglucosenone: Bio-based platform for drug discovery. Front. Chem. 2022, 10, 902239. [Google Scholar] [CrossRef]
  37. Liu, X.; Carr, P.; Gardiner, M.G.; Banwell, M.G.; Elbanna, A.H.; Khalil, Z.G.; Capon, R.J. Levoglucosenone and Its Pseudoenantiomer iso-Levoglucosenone as Scaffolds for Drug Discovery and Development. ACS Omega 2020, 5, 13926–13939. [Google Scholar] [CrossRef] [PubMed]
  38. Pratesi, D.; Matassini, C.; Goti, A.; Angeli, A.; Carta, F.; Supuran, C.T.; Spanevello, R.; Cardona, F. Glycomimetic Based Approach toward Selective Carbonic Anhydrase Inhibitors. ACS Med. Chem. Lett. 2020, 11, 727–731. [Google Scholar] [CrossRef]
  39. Banwell, M.G.; Liu, X.; Connal, L.A.; Gardiner, M.G. Synthesis of Functionally and Stereochemically Diverse Polymers via Ring-Opening Metathesis Polymerization of Derivatives of the Biomass-Derived Platform Molecule Levoglucosenone Produced at Industrial Scale. Macromolecules 2020, 53, 5308–5314. [Google Scholar] [CrossRef]
  40. Stanfield, M.K.; Terry, R.S.; Smith, J.A.; Thickett, S.C. Levoglucosan and levoglucosenone as bio-based platforms for polymer synthesis. Polym. Chem. 2023, 14, 4949–4956. [Google Scholar] [CrossRef]
  41. Flourat, A.L.; Pezzana, L.; Belgacem, S.; Dosso, A.; Sangermano, M.; Fadlallah, S.; Allais, F. Levoglucosenone to 3D-printed green materials: Synthesizing sustainable and tunable monomers for eco-friendly photo-curing. Green Chem. 2023, 25, 7571–7581. [Google Scholar] [CrossRef]
  42. Blake, A.J.; Cook, T.A.; Forsyth, A.C.; Gould, R.O.; Paton, R.M. l,3-Dipolar Cycloaddition Reactions of Levoglucosenone. Tetrahedron 1992, 48, 8053–8064. [Google Scholar] [CrossRef]
  43. Coşkun, N.; Parlar, A. One-Pot Synthesis and Hydroxylaminolysis of Asymmetrical Acyclic Nitrones. Synth. Commun. 2005, 35, 2445–2451. [Google Scholar] [CrossRef]
  44. Muller, C.; Gomez-Zurita Frau, M.A.; Ballinari, D.; Colombo, S.; Bitto, A.; Martegani, E.; Airoldi, C.; van Neuren, A.S.; Stein, M.; Weiser, J.; et al. Design, Synthesis, and Biological Evaluation of Levoglucosenone-Derived Ras Activation Inhibitors. Chem. Med. Chem. 2009, 4, 524–528. [Google Scholar] [CrossRef]
  45. Wang, C.; Wang, D.; Yan, H.; Wang, H.; Pan, B.; Xin, X.; Li, X.; Wu, F.; Wan, B. Rhodium-Catalyzed Cyclization of Diynes with Nitrones: A Formal [2+2+5] Approach to Bridged Eight-Membered Heterocycles. Angew. Chem. Int. Ed. 2014, 53, 11940–11943. [Google Scholar] [CrossRef]
  46. Wang, X.; Li, J.; Du, H.; Liang, W.; Lou, C.; Wu, Y.; Liu, B. Synthesis of 1,4-epoxy-2-aryltetrahydro-1-benzazepines via rhodium(III)-catalyzed C–H allylation/intramolecular 1,3-dipolar cycloaddition. Chem. Commun. 2024, 60, 2401–2404. [Google Scholar] [CrossRef] [PubMed]
  47. Djahieche, M.; Boufenaya, H.; Boukhari, A. Regio-and stereoselectivity of [3+2] cycloaddition reaction of methacrolein with diarylnitrones catalyzed by chiral rhodium complex. Rev. Roum. Chim. 2019, 64, 973–980. [Google Scholar] [CrossRef]
  48. Parmeggiani, C.; Matassini, C.; Cardona, F.; Goti, A. On the Oxidation of Hydroxylamines with o-Iodoxybenzoic Acid (IBX). Synthesis 2017, 49, 2890–2900. [Google Scholar]
  49. Matassini, C.; Mirabella, S.; Goti, A.; Cardona, F. Double Reductive Amination and Selective Strecker Reaction of a d-Lyxaric Aldehyde: Synthesis of Diversely Functionalized 3,4,5-Trihydroxypiperidines. Eur. J. Org. Chem. 2012, 2012, 3920–3924. [Google Scholar] [CrossRef]
  50. Chen, F.-E.; Zhao, J.-F.; Xiong, F.-J.; Xie, B.; Zhang, P. An improved synthesis of a key intermediate for (+)-biotin from d-mannose. Carbohydr. Res. 2007, 342, 2461–2464. [Google Scholar] [CrossRef] [PubMed]
  51. Dondoni, A.; Franco, S.; Junquera, F.; Merchán, F.L.; Merino, P.; Tejero, T. Synthesis of N-Benzyl Nitrones. Synth. Commun. 1994, 24, 2537–2550. [Google Scholar] [CrossRef]
  52. Cardona, F.; Faggi, E.; Liguori, M.; Cacciarini, M.; Goti, A. Total syntheses of hyacinthacine A2 and 7-deoxycasuarine by cycloaddition to a carbohydrate derived nitron. Tetrahedron Lett. 2003, 44, 2315–2318. [Google Scholar] [CrossRef]
  53. Martella, D.; D’Adamio, G.; Parmeggiani, C.; Cardona, F.; Moreno-Clavijo, E.; Robina, I.; Goti, A. Cycloadditions of Sugar-Derived Nitrones Targeting Polyhydroxylated Indolizidines. Eur. J. Org. Chem. 2016, 2016, 1588–1598. [Google Scholar] [CrossRef]
  54. Revuelta, J.; Cicchi, S.; Goti, A.; Brandi, A. Enantiopure Cyclic Nitrones: A Useful Class of Building Blocks for Asymmetric Syntheses. Synthesis 2007, 4, 485–504. [Google Scholar] [CrossRef]
  55. Cardona, F.; Lalli, D.; Faggi, C.; Goti, A.; Brandi, A. Quasienantiomeric levoglucosenone and isolevoglucosenone allow the parallel kinetic resolution of a racemic nitrone. J. Org. Chem. 2008, 73, 1999–2002. [Google Scholar] [CrossRef]
  56. Cicchi, S.; Höld, I.; Brandi, A. New synthesis of five-membered cyclic nitrones from tartaric acid. J. Org. Chem. 1993, 58, 5274–5275. [Google Scholar] [CrossRef]
  57. Li, M.-Y.; Gua, A.; Li, J.; Liu, Y. Advanced green synthesis: Solvent-free and catalyst-free reaction. Green Synth. Catal. 2025, 6, 36–66. [Google Scholar] [CrossRef]
Reactions 06 00036 g001
Figure 1. General scheme of 1,3-DC of nitrones with alkenes to form isoxazolidines, valuable intermediates for the synthesis of biological relevant compounds such as γ-aminoalcohols and glycomimetics (a pyrrolizidine iminosugar is reported as general example). * Denotes a stereogenic carbon atom.
Figure 1. General scheme of 1,3-DC of nitrones with alkenes to form isoxazolidines, valuable intermediates for the synthesis of biological relevant compounds such as γ-aminoalcohols and glycomimetics (a pyrrolizidine iminosugar is reported as general example). * Denotes a stereogenic carbon atom.
Reactions 06 00036 g001
Reactions 06 00036 sch001
Scheme 1. Compounds 11–16 obtained from 1,3-dipolar cycloaddition of acyclic nitrones 5–10 and levoglucosenone (4).
Scheme 1. Compounds 11–16 obtained from 1,3-dipolar cycloaddition of acyclic nitrones 5–10 and levoglucosenone (4).
Reactions 06 00036 sch001
Reactions 06 00036 sch002
Scheme 2. Endo-anti approach of 1,3-dipolar cycloaddition of nitrone 10 and levoglucosenone to obtain the cycloadduct 16. ‡ Indicates a transition state.
Scheme 2. Endo-anti approach of 1,3-dipolar cycloaddition of nitrone 10 and levoglucosenone to obtain the cycloadduct 16. ‡ Indicates a transition state.
Reactions 06 00036 sch002
Reactions 06 00036 sch003
Scheme 3. Synthesis of cycloadduct 18 obtained from nitrone 17 and N,N-dimethylacrylamide and cycloadducts 20 and 21 starting from cyclic nitrone 19 with N,N-dimethylacrylamide and levoglucosenone 4. * Denotes a stereogenic carbon atom.
Scheme 3. Synthesis of cycloadduct 18 obtained from nitrone 17 and N,N-dimethylacrylamide and cycloadducts 20 and 21 starting from cyclic nitrone 19 with N,N-dimethylacrylamide and levoglucosenone 4. * Denotes a stereogenic carbon atom.
Reactions 06 00036 sch003
Reactions 06 00036 sch004
Scheme 4. Different approaches of 1,3-dipolar cycloaddition of nitrone 19 and N,N-dimethylacrylamide to obtain: (a) cycloadduct 20a; (b) cycloadduct 20b; (c) cycloadduct 20c. ‡ Indicates a transition state.
Scheme 4. Different approaches of 1,3-dipolar cycloaddition of nitrone 19 and N,N-dimethylacrylamide to obtain: (a) cycloadduct 20a; (b) cycloadduct 20b; (c) cycloadduct 20c. ‡ Indicates a transition state.
Reactions 06 00036 sch004
Table 2. 1,3-DC reactions of cyclic nitrones 17 and 19 with N,N-dimethylacrylamide and levoglucosenone (4).
Table 2. 1,3-DC reactions of cyclic nitrones 17 and 19 with N,N-dimethylacrylamide and levoglucosenone (4).
EntryNitronesDipolarophileReaction ConditionsHeatingTemperatureTimeProduct
(Yield)
1 a17N,N-dimethylacrylamideCH2Cl2-r.t.72 h18 (85%)
217N,N-dimethylacrylamidesolvent-free-r.t.54 h18 (60%)
317N,N-dimethylacrylamidesolvent-free-
(orbital shaker)		r.t.15 h18 (71%)
417N,N-dimethylacrylamidesolvent-freestandard40 °C18 h18 (59%)
517levoglucosenondry toluenestandard60 °C96 h-
619N,N-dimethylacrylamidetoluene-r. t.2.5 h20 (65%)
719N,N-dimethylacrylamidesolvent-free-
(orbital shaker)		r.t.1 h20 (70%)
8 b19levoglucosenonedry toluene-r.t.2 h21 (88%)
919levoglucosenonesolvent-freestandard80 °C2 h21 (80%)
1019levoglucosenonesolvent-freemicrowaves (150 W)80 °C45 min21 (76%)
a Reference [53]. b Reference [55].
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Pratesi, D.; Morano, A.; Goti, A.; Cardona, F.; Matassini, C. Solvent-Free 1,3-Dipolar Cycloadditions of Nitrones for a More Sustainable Synthesis of Glycomimetics. Reactions 2025, 6, 36. https://doi.org/10.3390/reactions6020036

AMA Style

Pratesi D, Morano A, Goti A, Cardona F, Matassini C. Solvent-Free 1,3-Dipolar Cycloadditions of Nitrones for a More Sustainable Synthesis of Glycomimetics. Reactions. 2025; 6(2):36. https://doi.org/10.3390/reactions6020036

Chicago/Turabian Style

Pratesi, Debora, Alessio Morano, Andrea Goti, Francesca Cardona, and Camilla Matassini. 2025. "Solvent-Free 1,3-Dipolar Cycloadditions of Nitrones for a More Sustainable Synthesis of Glycomimetics" Reactions 6, no. 2: 36. https://doi.org/10.3390/reactions6020036

APA Style

Pratesi, D., Morano, A., Goti, A., Cardona, F., & Matassini, C. (2025). Solvent-Free 1,3-Dipolar Cycloadditions of Nitrones for a More Sustainable Synthesis of Glycomimetics. Reactions, 6(2), 36. https://doi.org/10.3390/reactions6020036

Article Metrics

Back to TopTop