Niobium ( V ) Chloride as Catalyst in Diels-Alder Reaction of Furan Ring

De acordo com a literatura, a reação de Diels-Alder de furano sem uso de catalisador pode durar várias semanas e apresenta baixo rendimento devido à baixa reatividade do dieno. O uso de catalisadores ácidos de Lewis ou de altas pressões são descritos como métodos eficazes para melhorar o rendimento da reação. Este trabalho descreve nosso estudo recente sobre a utilização de pentacloreto de nióbio, como catalisador em reações de Diels-Alder entre furano e alguns dienófilos reativos, entre os quais o acrilato de metila apresentou bons rendimentos, especialmente sob temperaturas mais baixas. Outros dienófilos apresentaram rendimentos mais baixos devido a problemas, tais como a formação de produtos secundários e de elevado caráter de reversibilidade da reação.


Introduction
The Diels-Alder reaction of furan ring (1) with a reactive dienophile (2) provides 7-oxabicyclo[2.2.1] hept-5ene (3), an important intermediate in the synthesis of several natural products such as terpenes (4), prostaglandins (5), shikimic acid (6), and its analogues (Scheme 1). 1,2everal researchers have described methods for synthesizing these cyclic intermediates.The Diels-Alder reaction using a furan ring is the simplest because it requires a single reaction stage.However, furan has low reactivity as a diene and requires the use of Lewis acid catalysts, high pressures, or highly reactive dienophiles.Another problem concerning this cycloaddition is how easily it undergoes a reverse reaction -retro-Diels-Alder -due to the stability of the diene.Therefore, high reaction temperatures are often avoided. 2ecent studies have shown the potential gains of using niobium compounds as Lewis acids in organic synthesis compared to other inorganic compounds of known acidity. 3The activity of niobium pentachloride as a catalyst has been described in several reactions such as epoxide opening, [4][5][6] the Diels-Alder reaction, 7,8 synthesis of pyranoquinoline derivatives, 9 Mannich reactions, 10 syntheses of α-aminonitriles, 11 arylation of aromatic compounds, 12 and cyanosilylation of carbonyl compounds, 13 among others. 14,15Most of the time, NbCl 5 provided higher yields and selectivity compared to the Lewis acids usually used in these reactions.
This study used niobium pentachloride as the Lewis acid in synthesizing 7-oxabicyclo[2.2.1]hept-5-ene (3) derivatives through the Diels-Alder reaction between furan (1) and reactive dienophiles (2a-d) (Scheme 2) to evaluate the catalyst activity in the reaction yields and the selectivity of the products.

Experimental
The starting materials are commercially available and were used without purification, except for furan, which was treated and distilled according to the literature. 16nfrared (IR) spectra were recorded on a FTLA2000-102-ABB BOMEM FT-IR spectrophotometer using Pike Technologies MIRacle Single Reflection ATR accessory, 45°, ZnSe, using atmosphere as blank. 1 H and 13 C nuclear magnetic resonance (NMR) spectra were recorded using a Varian 400 (400 MHz) spectrometer with tetramethylsilane (TMS) as the internal standard.

General experimental methods
The reactions were carried out in anhydrous medium, because NbCl 5 is easily hydrolyzed.Ten millimoles of dienophile (2a-d) were added to a sealed round bottom flask with NbCl 5 (0.05, 0.25, and 1.0 mmol).The mixture was stirred until a yellowish solution was achieved.Then, 11 mmol of diene (1) were slowly added, with the system kept under constant agitation all along the reaction length.The mixture obtained was diluted at the end of the reaction with 75 mL of ethyl acetate.This solution was washed with 100 mL of diluted sodium bicarbonate.The solvent was evaporated, and the products obtained were analyzed through IR spectroscopy and nuclear magnetic resonance of ¹H (400 MHz) and ¹³C (100 MHz).The reactions yields were calculated in terms of wt.%.8][19] Ratios of the endo and exo adducts were determined through the relation of the integral of the ¹H NMR signals from the corresponding double bond hydrogens of the endo and exo adducts.
The reactions were carried out without solvents, initially because the diene and dienophiles were liquid and to contribute to the application of environmentally friendly methodologies in organic synthesis, implying minimum residue generation, whereas the Diels-Alder reaction does not generate side products, and during the extraction of the adduct, the NbCl 5 is hydrolyzed, providing Nb 2 O 5 .nH 2 O, which has low toxicity.
First, the optimum conditions for the reaction between furan (1) and methyl acrylate (2a) were studied (Table 1).Then, the ideal catalyst ratio was determined: 0.5 and 2.5 mol% of NbCl 5 showed some activity in 24 reaction hours at different temperatures, whereas with 10 mol% of the catalyst, for the same reaction length, the yields were good (42-77%), especially at lower temperatures.
The Diels-Alder reaction is reversible, and due to the easy way in which cycloadditions with 1 undergo a reverse reaction, we started a study on the ideal reaction length using 10 mol% of the catalyst.Shorter times increased the yields, and temperature was again an important factor in the conversion rates; the lower the temperature, the higher the yields.In general, product selectivity was higher for the endo adduct in all reaction conditions.
Comparing the best result achieved for the reaction between furan (1) and methyl acrylate (2a) catalyzed by NbCl 5 to what has been reported in the literature (Table 2), higher product yields were achieved under shorter reaction Scheme 2. The Diels-Alder reaction between furan (1) and several reactive dienophiles (2a-d).
time and without using solvent.Most methods reported show higher selectivity for the endo adduct compared to our results.
When acrylonitrile (2b) was used as the dienophile (Table 3), low yields were achieved even with 10 mol% of NbCl 5 and at low temperatures.A problem observed during this reaction was the formation of byproducts mainly at -20 °C, possibly resulting from polymerization of acrylonitrile.Reaction times shorter than those used in the reaction between 1 and 2a were tested to try to decrease the byproduct formation; however, our attempts were unsuccessful.Adduct selectivity was in general lower than that observed for product 3a.
Reaction times longer than those we used are required to achieve higher yields for product 3b as shown in Table 4.
Although the dienophilicity of dimethyl maleate (2c) is increased due to the β-carboalkoxy group, reactions using 2c as the dienophile did not show any conversion even in the presence of up to 10 mol% of NbCl 5 in 24 h, at room temperature or 0 °C.Tests using the solvent (CH 2 Cl 2 ) were unsuccessful.At these temperatures, retro-Diels-Alder must be favored, Hayashi et al. 24 observed higher yields and selectivity in reactions carried out at -20 and -50 °C using HfCl 4 as the Lewis acid catalyst.Thus, experiments at lower temperatures were performed to try to improve the results.
For reactions between furan (1) and 2-chloroacrylonitrile (2d) (Table 5), we adopted conditions that had provided good conversion rates for other adducts.Since 2d is a more reactive dienophile, two catalyst ratios were tested (2.5 and 10 mol%) for 2 hours of reaction.In general, the yields were low.At 0 °C and -20 °C the yields were higher with 10 mol% of catalyst.At room temperature, however, the yields were lower with higher amounts of catalyst (entry 2, Table 5).To explain this behavior, the reaction was carried out for 1 and 4 h, and the yields achieved were 12 and 6%, respectively.Thus, a reverse reaction is favored by time under this temperature, which can also justify the higher ratio of the exo adduct.The yields obtained for 3d were lower than those achieved using other Lewis acids (Table 6).However, higher selectivity for the exo adduct was observed when NbCl 5 was used.

Conclusions
NbCl 5 has been shown to be an active catalyst for the Diels-Alder reaction between furan (1) and methyl acrylate (2a), with good yields and reasonable selectivity for the endo adduct.When the dienophile was dimethyl maleate (2c), NbCl 5 had no activity.In the reactions that used acrylonitrile (2b) as the dienophile, lower yields and selectivity were achieved, and byproducts formed.With 2-chloro-acrylonitrile (2d), the yields were also low; however, higher selectivity for the exo adduct was observed.

Table 2 .
Comparison of methodologies for synthesizing 3a described in the literature with the best result achieved when NbCl 5 is used a Pressure of 15 kbar; b not informed by the author.r.t.: room temperature.

Table 4 .
Comparison of methodologies for synthesizing 3b described in the literature with the best result achieved when NbCl 5 is used

Table 3 .
Yields and the endo:exo ratio for reactions between furan (1) and acrylonitrile (2b) a Only byproducts were observed in the ¹H NMR spectrum.r.t.: room temperature.