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Chiral Gold Phosphate-Catalyzed Tandem Hydroamination/Asymmetric Transfer Hydrogenation Enables Access to Chiral Tetrahydroquinolines Yu-Liu Du, Yue Hu, Yi-Fan Zhu, Xi-Feng Tu, Zhi-Yong Han, and Liu-Zhu Gong J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00153 • Publication Date (Web): 07 Apr 2015 Downloaded from http://pubs.acs.org on April 9, 2015
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The Journal of Organic Chemistry
Chiral
Gold
Phosphate-Catalyzed
Hydroamination/Asymmetric
Transfer
Tandem
Hydrogenation
Enables Access to Chiral Tetrahydroquinolines
Yu-Liu Du, Yue Hu, Yi-Fan Zhu, Xi-Feng Tu, Zhi-Yong Han* and Liu-Zhu Gong
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Table of Contents
Abstract A
highly
efficient
chiral
gold
phosphate-catalyzed
tandem
hydroamination/asymmetric transfer hydrogenation reaction is described. A series of chiral tetrahydroquinolines were obtained in excellent yields and enantioselectivities. In this reaction, the gold catalyst enables both the hydroamination step as a π-Lewis acid and the asymmetric hydrogen-transfer process as an effective chiral Lewis acid.
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Chiral 1,2,3,4-tetrahydroquinoline not only represents a prevalent skeleton in numerous naturally occurring alkaloids and artificial bio-related molecules, but also emerges as a privileged building block in drug discovery, which has stimulated a great demand and consequent development of asymmetric synthetic methods for it.1 Generally, catalytic asymmetric hydrogenation of prepared quinolines provides the most widely-used access to chiral tetrahydroquinolines (Scheme 1, eq 1).2 Various group VIII transition metals, such as iridium3, ruthenium4, rhodium5 and palladium6, incorporated with chiral ligands, deliver high efficiency for the enantioselective reduction of quinolines. Rueping and co-workers developed the first organocatalytic asymmetric transfer hydrogenation of quinolines.7 Recently, we found that chiral gold phosphate is able to catalyze the asymmetric transfer hydrogenation of quinolones very efficiently. Scheme 1 Strategy for enantioselective synthesis of chiral
1,2,3,4-tetrahydroquinolines
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Despite
these
achievements,
asymmetric
hydrogenation
of quinolines
inevitable suffers from harsh conditions and low overall step efficiency brought by preceding quinoline synthesis. To overcome this, we and other groups7 have been involved in step-economical tetrahydroquinoline syntheses with readily available materials. From o-aminobenzaldehyde and β-keto esters, we developed
a
tandem
Friedländer
condensation/asymmetric
transfer
hydrogenation reaction via Mg(OTf)2/chiral phosphoric acid relay catalysis.8 Through the combination gold catalysis and chiral Brønsted acid catalysis, alkynyl amines were directly transformed into chiral tetrahydroquinolines (eq 2).9 However, this Au/organo relay catalytic process demands 5 mol % gold catalyst and 15 mol % chiral phosphoric acid10, thus lowering the practical
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applicability of this metholodgy. Previously, we have found that chiral gold phosphate could serve as a highly efficient catalyst for the asymmetric transfer hydrogenation of quinolines11, with the stereoselectivity controlled by the chiral counter anion12,13. We envisioned that, with an efficient gold catalyst, the tandem process might be realized through solely gold catalysis.14 Herein, we disclose
a
high
yielding
and
enantioselective
cascade
hydroamination/asymmetric transfer hydrogenation reaction, catalyzed by as low as 0.2 mol % single chiral gold phosphates (eq 3)11,15. Our initial investigation included the reaction of 2-(3-phenyl-2-propyl) aniline (1a) with Hantzsch ester (2a) at 90 oC using a chiral gold phosphates generated in situ from 1 mol % of IMesAuMe and 1 mol % BINOL-based phosphoric acid (4). Among the chiral phosphoric acids we investigated (entries 1-5), 4e was identified to be ideal for this process, which improved the stereochemical outcome to 98% ee with 80% yield. Then, several gold ligands were examined (entries 5-7). Carbene-type ligand IMes provided the best result in yield and enantioselectivity (entry 5) while PPh3 gave the product with excellent stereoselectivity but only 5% yield (entry 7) and IPr ligand led to moderate yield and poor enantioselectivity (entry 6). With the results above, an examination of different Hantzsch esters (entries 8-10) revealed that 2a was the best hydride source. Moreover, a brief screening of solvents (entries 11-13) resulted that toluene is optimal for this reaction regarding both yield and enantioselectivity. With the optimized condition in hand, we tried to lower the
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The Journal of Organic Chemistry
catalyst loading (entries 14-16). To our delight, 0.2 mol % of catalyst still furnished the reaction without any drop of yield and enantioselectivity. Further decreasing gold loading to 0.1 mol % led to the retention of stereoselectivity and, however, a notable reduction of target product yield.
Table 1 Evaluation of Catalysts and Optimization of Reaction Conditions a
entry
B*-H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
4a 4b 4c 4d 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e 4e
[Au] mol % 1 1 1 1 1 1 1 1 1 1 1 1 1 0.5 0.2 0.1
5
Solvent
yield (%)
ee b
5a 5a 5a 5a 5a 5b 5c 5c 5c 5c 5a 5a 5a 5a 5a 5a
Tol Tol Tol Tol Tol Tol Tol Tol Tol Tol CH2C lg2f THF p-Xylene Tol Tol Tol
47 57 68 54 80 55 5 74 68 60
