Synthesis of azapolycyclic systems via the intramolecular [4 + 2] cycloaddition chemistry of 2-(alkylthio)-5-amidofurans

Albert Padwa, John D. Ginn, Scott K. Bur, Cheryl K. Eidell, Stephen M. Lynch

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with β-alkoxy-γ-dithiane amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G* model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.

Original languageEnglish (US)
Pages (from-to)3412-3424
Number of pages13
JournalJournal of Organic Chemistry
Volume67
Issue number10
DOIs
StatePublished - May 17 2002
Externally publishedYes

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Cycloaddition
Furans
Amides
Azepines
Lactams
Thermolysis
Electron transitions
Electron energy levels
Ground state
Activation energy
Temperature
furan

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis of azapolycyclic systems via the intramolecular [4 + 2] cycloaddition chemistry of 2-(alkylthio)-5-amidofurans. / Padwa, Albert; Ginn, John D.; Bur, Scott K.; Eidell, Cheryl K.; Lynch, Stephen M.

In: Journal of Organic Chemistry, Vol. 67, No. 10, 17.05.2002, p. 3412-3424.

Research output: Contribution to journalArticle

Padwa, Albert ; Ginn, John D. ; Bur, Scott K. ; Eidell, Cheryl K. ; Lynch, Stephen M. / Synthesis of azapolycyclic systems via the intramolecular [4 + 2] cycloaddition chemistry of 2-(alkylthio)-5-amidofurans. In: Journal of Organic Chemistry. 2002 ; Vol. 67, No. 10. pp. 3412-3424.
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abstract = "A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with β-alkoxy-γ-dithiane amides 13-16 and 27-32 in 40-70{\%} yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100{\%} yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G* model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.",
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AB - A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with β-alkoxy-γ-dithiane amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G* model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.

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