Molecular Diversity 7: 175–180. KLUWER/ESCOM © 2003 Kluwer Academic Publishers. Printed in the Netherlands.
175
Short communication
Enhancing stereochemical diversity by means of microwave irradiation in the absence of solvent: Synthesis of highly substituted nitroproline esters via 1,3-dipolar reactions Angel D´ıaz-Ortiz1∗ , Antonio de la Hoz1 , M. Antonia Herrero1 , Pilar Prieto1 , Ana S´anchezMigall´on1, Fernando P. Coss´ıo2∗ , Ana Arrieta2 , Silvia Vivanco2 & Concepci´on Foces-Foces3 ´ Area de Qu´ımica Org´anica, Facultad de Qu´ımica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain; 2 Departamento de Qu´ımica Org´anica I, Facultad de Qu´ımica, Universidad del Pa´ıs Vasco, Apto. 1072, 20080 Donostia, San Sebastian, Spain; 3 Departamento de Cristalograf´ıa, Instituto de Qu´ımica-F´ısica ‘Rocasolano’, CSIC, Serrano 119, E-28006 Madrid, Spain (∗ Author for correspondence, E-mail:
[email protected], Fax: +34 926295318) 1
Received 27 May 2003; Accepted 20 June 2003
Key words: azomethine ylide, 1,3-dipolar cycloaddition, microwaves, proline esters, solventless
Summary Microwave irradiation induces the 1,3-dipolar cycloaddition of imines derived from α-aminoesters with βnitrostyrenes in the absence of solvent within 10–15 min. The reaction proceeds to give yields in the range 81–86% and three isomeric pyrrolidines are obtained in the cycloaddition. Consequently, the use of three imines and two βnitrostyrenes gives rise to a library of 18 nitroproline esters. The use of classical heating with longer reaction times (24 h) gives lower yields of products (below 50%) and only two stereoisomers can be detected in each reaction.
Introduction Combinatorial chemistry allows the synthesis of a large number of molecules by varying combinations of modular components. The application of this technique in the preparation of new compounds for drug discovery is well documented [1–5]. Microwave-assisted organic synthesis is a highspeed methodology with clear benefits: significant rate-enhancements and higher products yields are usually observed [6–10]. In several cases, the stereoand/or regiochemical outcome of microwave-assisted reactions has been found to be different to that observed under classical heating [11, 12]. The combination of the microwave heating methodology and combinatorial chemistry provides an increase in speed and effectiveness in the synthesis of organic compounds – changes that cannot be achieved by conventional heating methods. In recent years, a considerable number of publications have described the preparation of di-
verse libraries using a combination of microwave and combinatorial chemistry methodologies [13–15]. Imines derived from α-aminoesters can be thermally isomerized to azomethine ylides [16, 17] that undergo 1,3-dipolar cycloadditions with dipolarophiles to afford pyrrolidine derivatives [18–20]. These nitrogen heterocycles are the basis of a large number of biologically active alkaloids [21] that are of great interest in medicinal chemistry, e.g. as glycosidase inhibitors [22–24]. This cycloaddition reaction, which allows the preparation of highly-substituted five-membered heterocycles, has been employed in the synthesis of several libraries of functionalized pyrrolidines [25–31]. As a continuation of our current research [32, 33], we report here the 1,3-dipolar cycloaddition between imines derived from α-aminoesters and nitroalkenes under focused microwaves in the absence of solvent.
176
Scheme 1.
Results and discussion
Microwave irradiation induces the thermal isomerization of imines 1–3 to the corresponding azomethine ylides, which then undergo 1,3-dipolar cycloaddition with substituted β-nitrostyrenes 4, 5 within 10– 15 min to afford the pyrrolidines 6–10 in 81–86% yield (Scheme 1). Reactions were performed in open vessels at atmospheric pressure in a modified Prolabo MX350 microwave reactor with total control of power and temperature by an infrared sensor. Reaction conditions, yields and stereoisomer ratios are summarized in Table 1 [34]. Three stereoisomers were obtained in each of the cycloadditions. Therefore, by using a combination of two imines and three β-nitrostyrenes, a library of 18 racemic highly-substituted nitroproline esters can be obtained.
On using classical heating with an oil bath (toluene reflux, 24 h), these cycloadditions afforded yields below 50% and only stereoisomers a and b were obtained [35] (c.a., 50:50). Consequently, only 12 racemic nitroproline esters can be obtained with a combination of two imines and three β-nitrostyrenes. On the basis of these results, microwave irradiation has numerous benefits in comparison with classical heating methods: reaction times are shortened, product yields increased and a new stereoisomer can be obtained. These advantages are ideal for applications in combinatorial chemistry. The stereochemistry of cycloadducts a and b was easily deduced by comparison with the products obtained by classical heating and corresponds to the expected endo and exo approach, respectively. The stereochemistry of adducts c was inferred by X-ray crystallography of the N-acetyl derivative 11 [36] (Scheme 2 and Figure 1).
177 Table 1. 1,3-Cycloaddition reactions between imines 1–3 and β-nitrostyrenes 4–5 under microwave irradiation in the absence of solvent Reagents
R1
Reaction conditions
R2
Yield
Stereoisomer ratiosb
(%)a
a
Power
Temperature
Time
1+4
210 W
120 ◦ C
10 min
Me
OMe
86
33
2+4
210 W
110 ◦ C
10 min
Cl
OMe
84
31
3+4 1+5 2+5
270 W 240 W 270 W
120 ◦ C 120 ◦ C 120 ◦ C
15 min 13 min 10 min
OH Me Cl
OMe Cl Cl
84 82 81
39 31 37
a Isolated product. b Ratios observed under classical heating in boiling toluene (Ref. 35) are given in parentheses.
Scheme 2.
Figure 1. Molecular structure of compound 11.
b 44 (50/50) 45 (44/56) 41 49 42
c 23 24 20 20 21
178
Scheme 3.
The new stereoisomers c, which was not obtained by classical heating, could be formed by: (i) epimerization of the endo or exo adducts during the course of the reaction or (ii) thermal isomerization of the imine (Scheme 3). The first process can be excluded on the basis that a mixture of adducts 6a and 6b (obtained by classical heating) was stable when exposed to microwave irradiation under the appropiate reaction conditions for 15 min. We therefore propose a thermal isomerization of the imine by rotation in the carboxylic part of the ylide. In both conformers a hydrogen bond should stabilize the structure. The endo approach of the β-nitrostyrene to the second conformation of the ylide would explain the formation of stereoisomers c (Scheme 3). This process is observed exclusively under microwave irradiation – it may be that under these conditions it is possible to break the hydrogen bond in the first conformation (1 –3 ) and allow the subsequent rotation of this part of the ylide. Formation of the second dipole (1 –3 ) exclusively under microwave irradiation should be related to a higher polarity, hardness and a lower polarizability than the first dipole as we have previously showed in cycloaddition reactions to C70 [12]. Computational studies on model reactions are underway.
Table 2. Microwave irradiation (240 W/120 ◦ C/10 min) Reagents
Overall yield (%)
Products (ratio)
1 (0.5 equiv) + 2 (0.5 equiv) + 5 (1 equiv)
88
6a (12) + 6b (18) + 6c (13) + 9a (15) + 9b (32) + 9c (10)
1 (1 equiv) + 4 (0.5 equiv) + 5 (0.5 equiv)
90
9a (10) + 9b (19) + 9c (7) + 10a (16) + 10b (27) + 10c (21)
We also studied the cycloaddition of a mixture of imines 1 (0.5 equiv) and 2 (0.5 equiv) with the β-nitrostyrene 5 (1 equiv) as well as a mixture of β-nitrostyrenes 4 (0.5 equiv) and 5 (0.5 equiv) with the imine 1 (1 equiv). The results are summarized in Table 2. These results indicate that, in spite of the lower electrophilicity of β-nitrostyrene 4 with respect to 5, and the different nucleophilicity of azomethine ylides derived from imines 1 and 2, in both experiments the overall molecular diversities achieved are similar. This fact shows the potential and the wide scope of this methodology to generate large libraries of nitroproline esters using a very simple experimental device.
179 Conclusions In conclusion, imines derived from α-aminoesters can be thermally isomerized to azomethine ylides, which subsequently undergo 1,3-dipolar cycloadditions with β-nitrostyrenes. The use of microwave irradiation leads to dramatically reduced reaction times, improved product yields and a new stereoisomer that is not formed during classical heating. These important benefits can be advantageously applied in combinatorial chemistry to obtain large nitroproline ester libraries.
Acknowledgements Financial support from the Spanish DGESIC (Projects BQU2001-1095, BQU2001-0904 and BQU20000868), Gobierno Vasco/Eusko Jaurlaritza, Universidad del País Vasco/Euskal Herriko Unibertsitatea (Project 9/ UPV00170.215-13548/2001) and Junta de Comunidades de Castilla-La Mancha (Project PAI-02-019) is gratefully acknowledged.
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