Post-Ugi gold-catalyzed diastereoselective domino cyclization for the synthesis of diversely substituted spiroindolines

Summary An Ugi four-component reaction of propargylamine with 3-formylindole and various acids and isonitriles produces adducts which are subjected to a cationic gold-catalyzed diastereoselective domino cyclization to furnish diversely substituted spiroindolines. All the reactions run via an exo-dig attack in the hydroarylation step followed by an intramolecular diastereoselective trapping of the imminium ion. The whole sequence is atom economic and the application of a multicomponent reaction assures diversity.


Introduction
The importance of nitrogen containing heterocyclic molecules in chemical biology is undisputed. The synthesis of such biologically interesting heterocycles is generally target-oriented, inspired by nature or randomly directed. In all these cases the design of a synthetic sequence to produce a library of diversely substituted molecules is the first and most important step. The basic concept of diversity-oriented synthesis (DOS) involves short reaction sequences, a strong focus on bond construction, and functional group compatibility [1][2][3]. Reactions that involve multiple bond formation, such as multicomponent reactions [4][5][6][7][8][9] and tandem reactions [10][11][12][13][14][15][16], are very useful in this context.

Results and Discussion
The use of benzoic acid as an acid component in the Ugi-4CR did not produce the Ugi-adduct in good yield even after a prolonged reaction time. Therefore, we switched to phenylacetic acid. The Ugi-4CR of indole-3-carboxaldehyde (1a), propargylamine (2a), phenylacetic acid (3a) and tert-butylisonitrile (4a) in methanol at 50 °C gave the Ugi-adduct 5a with an excellent yield of 94%. With compound 5a in hand we were keen to apply the previously developed conditions for intramolecular hydroarylation [44]. Reaction of 5a with 5 mol % of Au(PPh 3 )SbF 6 in chloroform at room temperature produced the desired spiroindoline 6a in a moderate yield of 55% along with some unidentified byproducts ( Table 1, entry 1). The use of a protic acid with a gold catalyst is known in the literature [61][62][63][64]. To our delight, when the above reaction was carried out  Having the optimized conditions in hand (Table 1, entry 2), various Ugi-adducts 5b-q were synthesized and subjected to this hydroarylation domino cyclization sequence (Table 2). Different substituents are well-tolerated and the sprioindolines were obtained in good to excellent yields. A methyl substituent on the indole nitrogen did not hamper the domino cyclization (Table 2, entries 4, 6,11,12,14,15). Substituents like tertbutyl, cyclohexyl and n-butyl on the isonitrile are well-tolerated for the domino cyclization on the second position of the indole ( Table 2, entries 1-16). Regarding the substituents coming from the acid part, tert-butyl gave a decreased yield probably due to steric hindrance ( Table 2, entry 5). It is noteworthy that the gold-catalyzed intramolecular hydroarylation exclusively gives the exo-dig product in all cases and with complete diastereoselectivity.
A plausible mechanism [30,44] is shown in Scheme 2 with only the R-isomer of the Ugi-adduct 5a to simplify the discussion. The cationic gold coordinates with the terminal alkyne which becomes activated for a nucleophilic attack. This can occur from both sides of the indole core. When the attack occurs from the back side of the indole core, spiro intermediate B

Conclusion
In conclusion we have developed a diversity-oriented post-Ugi gold-catalyzed intramolecular hydroarylation domino cyclization sequence for the diastereoselective synthesis of spiroindolines. The mild reaction conditions and short synthetic sequence are the merits of this method. The flexibility given by the multicomponent reaction assures the generation of diversity.

Experimental
General procedure for the synthesis of spiroindolines 6a-q To a screw capped vial Au(PPh 3 )Cl (5 mol %) and AgSbF 6 (5 mol %) were loaded along with chloroform (2 mL). Ugi product 5 (0.2 mmol) was added followed by TFA (1 equiv), and the reaction mixture was stirred at rt. After completion, the reaction mixture was partitioned between EtOAc (100 mL) and 2 N K 2 CO 3 solution (2 × 50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (10% diethyl ether in dichloromethane) to afford compound 6a-q.

Supporting Information
Supporting Information File 1 Experimental section.