New L-serine derivative ligands were prepared and tested as cocatalyst in the Diels-Alder reactions between cyclopentadiene (CPD) and methyl acrylate, in the presence of several Lewis acids. The catalytic potential of the
The synthesis of bicyclic compounds has large significance due to their use as synthetic intermediates in the preparation of a vast variety of compounds of chemical, biological, and pharmaceutical interest [
The acid catalyzed Diels-Alder reactions, namely, between cyclopentadiene (CPD) and acrylates, is well documented [
In this work, we studied the use of moderate strength Lewis acids as catalysts for Diels-Alder reaction between CPD (
Lewis acid catalyzed Diels-Alder reaction between CPD (
The work started with the study of several Lewis acids tested as catalysts in the Diels-Alder reaction between CPD (
Results of the Diels-alder reaction between
Entry | Catalyst | Reaction time/h |
|
|
---|---|---|---|---|
1 | — | 4 | — | — |
2 | AlCl3 | 87 | 95/5 | |
3 | AlMe3 | 70 | 93/7 | |
4 | FeCl3 | 75 | 95/5 | |
5 | TiCl4 | 80 | 94/6 | |
6 | SnCl4 | 67 | 94/6 | |
7 | Cu(OTf)2 | 35 | 98/2 | |
8 | ZnI2 | 11 | 94/6 | |
9 |
|
20 | 38 | 85/15 |
10 |
|
16 | 92/8 | |
11 |
|
2 | 32 | 94/6 |
12 | AlCl3 | 20 | 53 | 91/9 |
The reactions were performed with 10% of catalyst, at 0°C in dichloromethane, except in the mentioned cases.
As expected, in the absence of catalyst, the reaction did not take place (entry 1). For the catalyzed reactions, it is noteworthy the correlation observed between the Lewis acid strength and the yield of the reaction: the best results were achieved when the stronger Lewis acids AlCl3, FeCl3, and TiCl4 were employed (entries 2, 4 and 5, resp.). In comparison with AlCl3, a slight decrease in the reaction yield was observed when AlMe3 was used (entry 3). SnCl4 originated a lower yield than the previous mentioned strong Lewis acids (entry 6). For Cu(OTf)2 and ZnI2, which are moderate Lewis acids, the yields were quite low (entries 7, 8); nevertheless, their poor solubility in the solvent used (dichloromethane) may also explain these results. The increase of the reaction time (entries 9, 10) and of the amount of catalyst employed (entry 11) did not significantly change the results in terms of yield. In fact, similar results were observed in a previous work comprising the catalytic cycloaddition reaction between CPD and methyl glyoxylate oxime [
Considering this, we synthesized new L-serine derivative ligands as inexpensive ligands for application on the Diels-Alder reactions. Serine has two major advantages for this purpose: being cheap and readily available and having three functional groups that may be easily functionalized, thus allowing chemical and structural design. In fact, serine was earlier used for other purposes as evaluation as ligand for complex formation with Cd(II), complexation with Cu(II) for antibacterial studies, and used as recyclable catalyst for asymmetric aldol reactions [
The chemical structures of the prepared L-serine derivative ligands
L-serine derivative ligands used in the Diels-Alder reaction between
The Diels-Alder reaction represented in Scheme
Results of the Diels-alder reaction between
Entry | Catalyst | Ligand | Reaction time/h |
|
|
e.e./%3 |
---|---|---|---|---|---|---|
1 | AlCl3 |
|
4 | traces | — | — |
2 | FeCl3 |
|
4 | <5 | — | — |
3 |
|
|
20 | — | — | — |
4 |
|
|
20 | <5 | — | — |
5 |
|
|
20 | 31 | 90/10 | <1 |
6 |
|
|
20 | 59 | 82/18 | <1 |
7 | ZnI2 |
|
4 | 23 | 87/13 | <1 |
8 |
|
|
20 | 58 | 87/13 | <1 |
9 |
|
|
20 | 21 | 86/14 | 12 ( |
10 |
|
|
20 | 30 | 83/17 | 24 ( |
11 |
|
|
20 | 57 | 82/18 | 8 ( |
12 |
|
|
20 | 56 | 88/12 | 10 ( |
13 |
|
|
20 | 51 | 83/17 | 8 ( |
The reactions were performed with 10% of both catalyst and ligand, at 0°C in dichloromethane, except in the mentioned cases.
It is noteworthy that ligand
The bidentate serine derivative ligands
Finally, the use of metal to ligand molar ratio of 1 : 2 led to similar results to the usual 1 : 1 molar ratio, suggesting that each metal ion coordinates to only one serine derivative ligand, contrary to what occurs with
L-serine based ligands showed good potential to be applied in Diels-Alder reactions, particularly if coordinated to moderate-strength Lewis acids such as Cu(OTf)2 and ZnI2. This is an alternative to the usage of strong Lewis acids such as AlCl3 or FeCl3, as serine derivative ligands proved to allow good yields at mild conditions are cheap and easy to prepare.
The results also anticipate that the change of the serine carboxylic residue by a chiral amide group may influence the stereochemistry of the Diels-Alder reaction, with this subject being currently under study and developed in our laboratory.
All solvents were distilled and dried using standard methods. CPD was freshly bidistilled prior to use. All starting material and reagents were from commercial suppliers (Aldrich, Fluka, Bachem) and used without purification. Serine
Flash column chromatography was performed on silica gel (60 Å, 230, 240 mesh) and analytical thin-layer chromatography (TLC) on precoated silica gel 60 F254 plates using iodine vapor and/or UV light (254 nm) for visualization. Melting points were determined on an electrothermal melting point apparatus and are uncorrected. Optical rotations were measured on a conventional thermostated polarimeter using a sodium lamp.
To a suspension of catalyst (0.10 eq) in anhydrous dichloromethane (10 mL) at the conditions referred in Table
For Diels-Alder reaction catalyzed by a serine-metal complex to a suspension of catalyst (0.10 eq) in anhydrous dichloromethane (10 mL) at the conditions referred to as in Table
(±)
(±)
The authors thank to the Fundação para a Ciência e a Tecnologia (FCT) for financial support and COMPETE through Grant no. PEst-C/EQB/LA0006/2011 and through project ref. PTDC/QUI-QUI/105304/2008. C. A. D. Sousa thanks the Grant SFRH/BPD/80100/2011.