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. 2020 Nov 23;12(4):1479-1485.
doi: 10.1039/d0sc05725h.

Regiodivergent synthesis of pyrazino-indolines vs. triazocines via α-imino carbenes addition to imidazolidines

Alejandro Guarnieri-Ibáñez  1 , Adiran de Aguirre  1 , Céline Besnard  2 , Amalia I Poblador-Bahamonde  1 , Jérôme Lacour  1
Affiliations

Regiodivergent synthesis of pyrazino-indolines vs. triazocines via α-imino carbenes addition to imidazolidines

Alejandro Guarnieri-Ibáñez et al. Chem Sci. .

Abstract

Hexahydropyrazinoindoles were prepared in a single step from N-sulfonyl triazoles and imidazolidines. Under dirhodium catalysis, α-imino carbenes were generated and formed nitrogen ylide intermediates that, after subsequent aminal opening, afforded the pyrazinoindoles predominantly via formal [1,2]-Stevens and tandem Friedel-Crafts cyclizations. Of mechanistic importance, a regiodivergent reactivity was engineered through the use of a specific unsymmetrically substituted imidazolidine that promoted the exclusive formation of 8-membered ring 1,3,6-triazocines. Based on DFT calculations, an original Curtin-Hammett-like situation was demonstrated for the mechanism. Further derivatizations led to functionalized tetrahydropyrazinoindoles in high yields.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Reactivity of N-sulfonyl triazoles with aminals.
Fig. 1
Fig. 1. Selected biologically active pyrazino[1,2-a]indoles.
Scheme 2
Scheme 2. Hexahydropyrazino[1,2-a]indoles 3. aFrom 3aA′: Na, naphthalene, THF, 17 h, −78 °C to 25 °C. bStick view of the crystal structure of 3aA′ (major diastereoisomer). cInseparable mixture of diastereoisomers. d3 equiv. of N-sulfonyl-1,2,3-triazole were used.
Scheme 3
Scheme 3. Access to substituted hexahydro-1,3,6-triazocines 4. aStick view of the crystal structure of 4aE. Hydrogen atoms are omitted for clarity and the MeO group presents a local disorder.
Fig. 2
Fig. 2. Computed Gibbs energy profile for the formation of the iminium intermediate C. Donor–donor energies (Ar1, Ar2 EDGs) in black and donor–acceptor (Ar1 EDG, Ar2 EWG) in magenta, all in kcal mol−1.
Fig. 3
Fig. 3. Computed Gibbs energy profile for the 8-membered (left, N-cyclization) or 6-membered (right, C-cyclization) ring formation from the iminium intermediate C. Donor–donor (Ar1, Ar2 EDGs) energies in black and donor–acceptor (Ar1 EDG, Ar2 EWG) in magenta, all in kcal mol−1.
Scheme 4
Scheme 4. Global mechanistic rationale.
Scheme 5
Scheme 5. One-step access to tetrahydropyrazino[1,2-a]indoles 5. aStick view of the crystal structure of 5aA. Hydrogen atoms are omitted for clarity.
Scheme 6
Scheme 6. Late stage functionalization of 5aAvia oxidative C–C bond formation: (a) (i) CuCl2 (1 equiv.), THF/MeNO2 (1 : 1), 25 °C, 3 h; (ii) iPr2EtN (1.1 equiv.), 25 °C, 2 h. (b) (i) CuCl2 (1 equiv.), THF, 25 °C, 16 h; (ii) 1-(tert-butyldimethylsilyloxy)-1-methoxyethene (2 + 1 equiv.), 25 °C, 6 h. (c) CuCl2 (1 equiv.), THF, 25 °C, 16 h; (ii) NaCN (1.5 + 1.5 equiv.), MeOH, 25 °C, 6 h. Insert: stick view of the crystal structure of 6. Hydrogen atoms are omitted for clarity and the CH2NO2 chain presents a local disorder.
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