Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Brønsted Base-Catalyzed Reductive Cyclization of Alkynyl α‑Iminoesters through Auto-Tandem Catalysis Azusa Kondoh‡ and Masahiro Terada*,† †
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
‡
Org. Lett. Downloaded from pubs.acs.org by AUSTRALIAN NATL UNIV on 08/15/18. For personal use only.
S Supporting Information *
ABSTRACT: A novel reductive cyclization of alkynyl α-iminoesters was developed through auto-tandem catalysis with a Brønsted base as the catalyst. The reaction system involves two mechanistically different elementary processes, both of which are efficiently catalyzed by an organosuperbase P2-tBu: the unprecedented reduction of α-iminoesters with 1-dodecanethiol as the reductant to provide α-aminoesters and the following intramolecular addition of ester enolates to an alkyne. The operationally simple reaction under mild conditions provides new efficient access to N-H indoline derivatives, demonstrating the high potential of auto-tandem catalysis with a Brønsted base as a methodology for organic synthesis.
B
Scheme 1. Brønsted Base-Catalyzed Reductive Cyclization of Alkynyl α-Iminoesters 1 through Auto-Tandem Catalysis (This Work)
rønsted base catalysis is fundamental and reliable catalysis in organic chemistry, which enables the transformation of small molecules as intended in a catalytic fashion.1 Transformations based on Brønsted base catalysis are generally initiated by the deprotonation of a substrate by a Brønsted base catalyst to generate an anionic species. The resulting anionic species then participates in an elementary process, such as nucleophilic addition to an electrophile, rearrangement, or isomerization, to form a different anionic intermediate that is subsequently protonated by a conjugated acid of the Brønsted base or the substrate to provide a product along with the regeneration of the Brønsted base catalyst or the starting anionic species. These conventional catalytic cycles have been adopted in a tremendous amount of applications so far. One efficient application to construct structurally complex molecules is a multistep reaction through auto-tandem catalysis. Auto-tandem catalysis is a process in which one catalyst promotes more than two mechanistically distinct processes in a single reactor.2 Whereas auto-tandem catalysis using a Brønsted base as the catalyst is particularly attractive due to its operational simplicity and the mildness of the reaction conditions, most of the reactions reported to date consist of two or more independent nucleophilic addition reactions that limit the substrate design and thus the accessible structural motifs.3 Therefore, the development of reactions involving auto-tandem catalysis with a new combination of elementary processes would provide new facile access to a range of structurally complex molecules. In this context, we report herein a novel reductive cyclization of alkynyl α-iminoesters to construct a heterocyclic framework containing nitrogen under auto-tandem catalysis with the Brønsted base as a catalyst (Scheme 1). The first catalytic cycle involves an unprecedented © XXXX American Chemical Society
chemoselective reduction of the imine moiety of N-(2alkynylaryl)-α-iminoester 1 with 1-dodecanethiol (2a) as the reductant under the influence of a Brønsted base catalyst to provide α-aminoester 3. Then α-aminoester 3 undergoes intramolecular cyclization in the second catalytic cycle, which involves the formation of enolate A through deprotonation by the Brønsted base catalyst and the following intramolecular addition of the enolate to an alkyne moiety, providing N-H indoline 5.4 The key feature of our strategy is a distinctive elementary process under Brønsted base catalysis, that is, the catalytic reduction. During the course of our study on the development Received: July 17, 2018
A
DOI: 10.1021/acs.orglett.8b02236 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters of a new methodology involving Brønsted base catalysis,5 we serendipitously found that a Brønsted base catalyzed the reduction of α-iminocarbonyl compounds (Scheme 2).
alkyne moiety on the substituent on the nitrogen atom was chosen as the initial substrate. First, 1a and 2.0 equiv of 2a were treated with 10 mol % P2-tBu (pKBH+ = 21.5 in DMSO)8 in DMF at room temperature. As a result, 1a was fully consumed, and desired indoline 5a was obtained in 73% NMR yield as the product along with disulfide 4a (Table 1, entry 1).
Scheme 2. Catalytic Reduction of α-Iminocarbonyl Compounds 6a and 8a with 1-Dodecanethiol (2a)a
Table 1. Screening of Reaction Conditionsa
a
Yields and amounts of products were determined by 1H NMR analysis of crude mixture.
Treatment of α-iminoester 6a with 1.1 equiv of 1dodecanethiol (2a) in the presence of 10 mol % of P2-tBu in DMF provided α-aminoester 7a in 43% yield along with the formation of didodecyl disulfide (4a). The use of 2.1 equiv of thiol 2a increased the yield of 7a to 85%, and accordingly, the production of 4a was also increased, clearly suggesting that thiol 2a serves as the reductant in the reaction. The reduction of α-iminoketone 8a also proceeded under identical reaction conditions in a highly chemoselective manner; only the imine moiety of 8a was reduced, and the corresponding αaminoketone 9a was obtained in 93% yield. Most importantly, to the best of our knowledge, such reduction of imines under Brønsted base catalysis has not been reported so far, indicating that our finding should expand the repertoire of elementary processes under Brønsted base catalysis. In addition, as a distinctive feature of the process, the anionic species generated by the deprotonation, that is, thiolate, is not introduced into the product molecule, which is uncommon in the reactions under Brønsted base catalysis. Therefore, 1-dodecanethiol (2a), which is known as an odorless thiol,6 is potentially recyclable by the reduction of disulfide 4a7 and thus would be regarded as an environmentally benign reductant. Motivated by this finding, we envisioned utilizing the newly found reduction as an elementary process in a multistep reaction under auto-tandem catalysis with a Brønsted base. The reduction of α-iminoesters would generate an acidic proton at the position α to the ester moiety, which would be further transformable through a conventional elementary process, such as nucleophilic addition to an electrophile, initiated by the deprotonation by a Brønsted base catalyst. Thus, as an immediate goal to provide proof of concept, we designed a reductive cyclization of N-(2-alkynylaryl)-α-iminoester 1 (Scheme 1). Generally, a fundamental difficulty of autotandem catalysis emerges from the likelihood that the optimal conditions differ for the two catalytic processes. We successfully managed to resolve this issue by using an organosuperbase and describe herein a new efficient synthesis to N-H indoline derivatives, which demonstrates the high potential of auto-tandem catalysis with a Brønsted base as a methodology for organic synthesis. We began our investigation by evaluating the viability of the designed reaction system. α-Iminoester 1a having a terminal
entry
base
solvent
5ab (%)
3ab (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15e
P2-tBu P4-tBu P1-tBu TBD DBU iPr2NEt tBuOK KHMDS P2-tBu P2-tBu P2-tBu P2-tBu P2-tBu P2-tBu P2-tBu
DMF DMF DMF DMF DMF DMF DMF DMF THF Et2O toluene CH2Cl2 DMSO CH3CN DMF
73 76
