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. 2022 Apr 15;87(8):5279-5286.
doi: 10.1021/acs.joc.2c00065. Epub 2022 Mar 24.

Highly Selective Synthesis of Seven-Membered Azaspiro Compounds by a Rh(I)-Catalyzed Cycloisomerization/Diels-Alder Cascade of 1,5-Bisallenes

Jordi Vila  1 , Miquel Solà  1 , Anna Pla-Quintana  1 , Anna Roglans  1
Affiliations

Highly Selective Synthesis of Seven-Membered Azaspiro Compounds by a Rh(I)-Catalyzed Cycloisomerization/Diels-Alder Cascade of 1,5-Bisallenes

Jordi Vila et al. J Org Chem. .

Abstract

The synthesis of spiro compounds featuring seven- and six-membered rings in the spirobicyclic motif is successfully achieved through a cascade process encompassing a rhodium(I)-catalyzed cycloisomerization followed by a highly selective Diels-Alder homodimerization. The scope of the reaction is analyzed based on a series of synthetic substrates, and control experiments and DFT calculations led us to justify the exquisite degree of selectivity observed.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Bioactive molecules that contain seven-membered azaspiro scaffolds.
Scheme 1
Scheme 1. Synthesis of Spiro Derivatives through Diels–Alder Reactions
Figure 2
Figure 2
Possible cycloadducts that can be formed in the homo-Diels–Alder of cycloheptatriene cHT.
Figure 3
Figure 3
COSY and HMBC crosspeaks and NOE contacts observed in 2a confirming the formation of regioisomer 2A and selected 1H and 13C (in italics) NMR shifts of 2a.
Figure 4
Figure 4
Scope of the cascade process. Byproducts 3a–3f (5–13% yields) and 3g (20% yield) were observed in the 1H NMR of the reaction crude.
Figure 5
Figure 5
(a) Gibbs energy profile in kcal·mol–1 for the transformation of cHT (from 1g) into 2g. (b) Molecular structures of TScs(2Aendo) and TScs(2Aexo). (c) Values of the condensed Fukui functions f– and f+ (units are electrons) on the HOMO and LUMO orbitals.
Scheme 2
Scheme 2. Species Detected by ESI(+)-MS when the Reaction Is Run in the Presence of TEMPO
See this image and copyright information in PMC

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