Fifth International Electronic Conference on Synthetic Organic Chemistry (ECSOC-5), http://www.mdpi.org/ecsoc-5.htm, 1-30 September 2001
[E0023]

Synthesis of Substituted Furans And Substituted Benzenes Via Microwave Enhanced Diels-Alder Reactions

Yousef M. Hijji*, Joseph Wanene, Emmanuel Obot and Jenora Fuller

Chemistry Department, Morgan State University, Baltimore MD 21251, USA. Tel. 443-885-1661 Fax 410-319-3778 E-mail http://www.mdpi.net/ecsoc-5/e0023/[email protected]

Received: 15 August 2001 / Uploaded 22 August 2001

Abstract: Microwave enhanced Diels-Alder reaction of furan and substituted furan with acetylenic dienophiles to give 3,4- and multisubstituted furans in high yields within minutes. Substituted benzenes were obtained from 1,3-cyclohexadienes. The 4+2 Cycloadduct underwent retro Diels-Alder Reaction to eliminate acetylene or ethylene and provides the mentioned products. The reactions were slow in refluxing toluene. Cerium (III) chloride in combination with microwave irradiation increased the reaction rate and improved the yields for the low yielding reactions.
Key Word: Microwave, Diels-Alder reaction, retro Diels-Alder, substituted furans, substituted benzene, cerium chloride.
Introduction: Microwave enhancement of organic reactions has interested chemist recently1. Microwave heating is very useful in organic synthesis as the reactions can be performed efficiently, solventless2, with high reaction rates3, low byproducts high yields and ease of experimental manipulations. Due to all these factors more focus is been paid nowadays to microwave enhanced chemical reactions.

Diels-Alder reaction is a powerful construction protocol in organic synthesis and a crucial key step in a wide variety of natural products skeleton construction. Since this reaction is a thermal reaction, the influence of microwave irradiation should be significant. Efforts have been paid to promote the reaction by Lewis acid catalysis4, and high pressure5. Microwave effect on Diels-Alder reaction has not been investigated thoroughly. The effect of microwave enhancement of the cycloaddition of furan with acetylenic dienophile was significant in providing the Cycloadductin high yield in 10 minutes.6

Furan and substituted benzenes can be found in many naturally occurring compounds.7 Polysubstituted furans are present as a key structural unit in many natural products, and pharmaceuticals. 8 Substituted furans are important intermediates and building blocks in organic synthesis.Reviews concerning the synthesis of polysubstituted furans have appeared in the literature 9,10. Due to their importance, interest in the synthesis of these units is in demand to have efficient methods of their creation. 3-, and 3,4- substituted furans are the most difficult to synthesize. One of the strategies to synthesize 3-, and 3,4 –substituted furans involved Diels-alder, retro Diels-alder reaction of 4-substituted oxazole 11and substituted acetylenic dienophiles to obtain the substituted furans in moderate yields. The reaction are performed in sealed tube and heated to 300 C for days. Upon our investigation of the reaction of furan and acetylenic dienophiles under microwave in a capped vial diethyl 3.4-furandicarboxylate was obtained as the sole product in 20 minutes. Investigation of the reaction product at earlier time showed the presence of the adduct in addition to the final product. This stimulated our interest in investigating this reaction to develop it as a strategy for the synthesis of furan moieties. The results of the investigation of the reaction of the furans with acetylenic dienophiles were general producing polysubstituted furan in 20 minutes or less. Analogous reactions were observed with substituted oxazoles and 1,3-cyclohexadienes.

In this paper we wish to present the results of the reactions of 1,3-cyclohexadienes, furans, and 2,4,5-trimethyloxazole with acetylenic dienophiles under microwave irradiation conditions.

 Scheme 1: Diels-Alder reaction of 1,3-cyclohexadiene and acetylenic dienophiles under microwave irradiation:

Table 1: Diels-Alder reaction of cyclohexadienes with acetylenic Dienophiles:
 
Entry Diene Dienophile Conditions Product %Yield
1 1a 2a mW 20 min 4a  96
2 1a 2a 2 h (reflux) 4a 95
3 1a 2b 20 min 4ab  93
4 1a 2b 15 h ,reflux   NR
5 1b 2a mW 20 min 4ba  88
6 1b 1a 1 h reflux 4ba 95
8 1b 2b mW, 20 min 4bb(ortho), and 4bb (meta)  65 (5:1) isomers
9 1b 2b 9.5 h reflux Mixed isomers 88
10 1c 2a mW, 20 min 4ca 20
11 1c 2b mW, 20 min 4cb1, 4cb2 20 both isomers
12 1c 2a 10 h reflux 4ca 8
13 1c 2b 10 h reflux   NR
14 1c 2a mw, 20 min, CeCl3 4ca 66
15 1c 2b mw, 20 min, CeCl3 4cb 50

 

The reactions of 1,3-cyclohexadienes 1a with diethylacetylene dicarboxylate (DEAD) 2a and ethyl propiolate 2b proceeded within 20 minutes to provide products 4a and 4b in excellent yields. If the reactions are checked after few minutes, a mixture of 3 and 4 is observed. Compounds 3 undergo elimination of ethylene to give 4 as the sole product at the end of reaction. Similar results are obtained with 1b, as both diene are reactive, while a-terpinene 1c reacted more sluggishly due to steric factors to provide the corresponding 4 in a lower yield. In cases where regioisomers are obtained they were not separated, but identified by GC- MS. Cerium chloride hepta hydrate was used as a catalyst with these reactions in combination with microwave irradiation. For the reactive dienes 1a and 1b in high yield were obtained in shorter time 5 minutes. The yields of the reactions of 1c with 2a and 2b increased to 66% and 50% in the presence of cerium (III) chloride. The reactions between dienes 1 and dienophiles 2 were done in toluene under reflux conventional heating. 1a gave 95% of 4a in 2 hours while no product was obtained with 1b after 15 hours. 1b reacted with 2a in one hour and with 2b in to give the corresponding products in 95 % and 88 % respectively. This indicates that the reaction proceeds under conventional heating similarly but at a lower rate with reactive dienes and dienophiles. Trace amounts of products are observed when 1c is heated with 2a and 2b under reflux in toluene for 10 hours. Cerium (III) chloride increased the yield in the microwave reactions of 1c with 2a and 2b to 66 and 50% respectively.

Scheme2: Diels-Alder reaction of furans with acetylenic Dienophile under microwave heating.

Table 2: Diels- Alder Reaction of Heterocyclic Dienes with Acetylenic Dienophiles:
 
Entry Diene Dienophile Product Yield
1 5a 2a 7aa 88
2 5a 2b 7ab 80
3 5b 2a 7ba 76
4 5b 2b 7bb1 +7bb2 50 (4:1 mixture) isomers
5 5c 2a 7ca 63
6 5c 2b   NR
7 5d 2a 7da 85
8 5d 2b 7da 82
9 2,4,5-Trimethyloxazole (8) 2a 7da 35
10 (8) 2b 7db 32

Furans underwent analogous reactions, but eliminated acetylene to produce substituted furans. Furan 5a reacted with 2a and 2b to give furan carboxylic esters 7a and 7b in high yield as shown in table 2. 2-, and 2-5- substituted furans gave analogous product but with a lower yield, due to steric hindrance. 2-dimethylphenylsilylfuran 5c reacted with 2a to give trisubstitued furan 7ca in 63 % yield. 7ca was converted to 7a by treatment with tetrabutyl ammonium fluoride in THF, for structural confirmation.

We also investigated the reaction of 2,4,5-trimethyloxazole with 2a and 2b. The reaction provided tetrasubstituted and trisubstituted furans by cycloaddition and the elimination of acetonitrile. The yields were moderate but we are optimizing the conditions to obtain higher yields. The addition of cerium chloride tends to catalyze the reaction and yields up to 70 % were obtained. This process is general in the synthesis of furans with various substitutions.

No significant reaction was observed with the furans and oxazole used under reflux with conventional heating.

We have investigated the microwave enhanced Diels-Alder reactions of the dienes mentioned with a number of olefinic dienophiles, maleic anhydride, maleimides, benzoquinones, maleate, fumarate, a,b-unsaturated carbonyl dienophiles, excellent yields of the cycloadducts were obtained. The results will be reported in due course.

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