Divergent synthesis of N-heterocycles via controllable cyclization of azido-diynes catalyzed by copper and gold

Abstract

Gold-catalyzed intermolecular alkyne oxidation by an N-O bond oxidant has proven to be a powerful method in organic synthesis during the past decade, because this approach would enable readily available alkynes as precursors in generating α-oxo gold carbenes. Among those, gold-catalyzed oxidative cyclization of dialkynes has received particular attention as this chemistry offers great potential to build structurally complex cyclic molecules. However, these alkyne oxidations have been mostly limited to noble metal catalysts, and, to our knowledge, non-noble metal-catalyzed reactions such as diyne oxidations have not been reported. Herein, we disclose a copper-catalyzed oxidative diyne cyclization, allowing the facile synthesis of a wide range of valuable pyrrolo[3,4-c]quinolin-1-ones. Interestingly, by employing the same starting materials, the gold-catalyzed cascade cyclization leads to the divergent formation of synthetically useful pyrrolo[2,3-b]indoles. Furthermore, the proposed mechanistic rationale for these cascade reactions is strongly supported by both control experiments and theoretical calculations.

Fig. 1

Selected examples bearing the pyrrolo[3,4-c]quinolin-1-one and pyrrolo[2,3-b]indole core structure. Some of these molecules are synthesized in the next section

Fig. 2

Transition-metal-catalyzed oxidative diyne cyclization. a Au-catalyzed oxidative diyne cyclization (Hashmi). b Rh-catalyzed oxidative diyne cyclization (Tang). c Cu-catalyzed oxidative diyne cyclization and Au-catalyzed cascade cyclization (this work)

Fig. 3

Reaction scope for the formation of pyrrolo[3,4-c]quinolin-1-ones 2. Reaction conditions: [1] = 0.05 M; yields are those for the isolated products

Fig. 4

Copper-catalyzed oxidative cyclization of chiral N-propargyl (azido)ynamides 1. Substrate scope of chiral N-propargyl ynamides 1

Fig. 5

Reaction scope for the formation of pyrrolo[2,3-b]indoles 3. Reaction conditions: [1] = 0.05 M; yields are those for the isolated products

Fig. 6

Synthetic applications. a Synthesis of bioactive molecules 5b and 5c. b Synthesis of caspase-3 inhibitor 5d. c Transformation of 3a into 6a and 6b

Fig. 7

Control experiments with ¹⁸O labeling study. a Reactions were run in the presence of 20 equiv of H₂ ¹⁸O. b Reactions were run in the presence of ¹⁸O₂ atmosphere (1 atm)

Fig. 8

Trapping of the presumable vinyl copper carbene intermediate. Substrate scope of alkyl-substituted N-propargyl ynamide 1v

Fig. 9

Plausible mechanism accounting for the divergent Cu^I/Au^I-catalyzed formation of 2a/3a. Relative free energies of key intermediates and transition states were computed at the SMD-M06/DZP level of theory in solvent (DCE for Cu^I catalysis and CH₃NO₂ for Au^I catalysis) at 298 K. Data for Au^I catalysis were given in parentheses