A Enamide-based diastereoselective synthesis of isoindolo[2,1-a ]quinolin-11(5 H )-ones with three contiguous stereogenic centers

Supporting information for this article is given via a link at the end of the document.


Introduction
Nitrogen heterocycles are ubiquitous structural motifs in natural products and active pharmaceutical ingredients. [1]Therefore, the development of novel methods for the efficient construction of nitrogencontaining heterocycles remains a highly active field of research. [2]In this context, the synthetic accessibility of so far uncommon fused heterocycles, leading to expanded scaffold diversity, is of great interest. [3]In the last 20 years, aliphatic heterocycles have gained increasing popularity. [4]Their defined three-dimensional structures offer intriguing opportunities to improve the pharmacokinetic profile of potential drug candidates. [5]Hence, there is an growing demand for novel approaches towards the synthesis of three-dimensional heterocyclic scaffolds.
In the last years we have described several methods for the rapid assembly of aliphatic heterocycles containing multiple stereogenic centers utilizing enamides as common building block (Scheme 1a). [6]amides and enecarbamates are highly versatile building blocks in organic synthesis [7] .Their intricate reactivity has been utilized for the construction of various heterocycles, in particular in cycloaddition reactions [6] .Among these, the Povarov synthesis of tetrahydroisoquinolines [8] , an inverse electron demand aza-Diels-Alder reaction between N-arylimines and enamides as electron-rich dienophiles, has been studied extensively. [7,9]An interesting example of such a reaction is the aza-Diels-Alder reaction between N-acyliminium cations, derived from N-aryl-3-hydroxyisoindolinones 7, with tertiary enamides 8, affording dihydroisoindolo[2,1-a]quinolin-11(5H)-ones 9 (Scheme 1b) [10] .This method leads to an intriguing fused heterocyclic scaffold with two stereocenters in good yields and high stereoselectivities.However, only reactions with vinyl lactams 8 were investigated so far.We envisioned, that this process should be also amendable to secondary enamides 4 bearing an additional substituent at the beta-position.Thereby, it would enable the synthesis of dihydroisoindolo[2,1a]quinolin-11(5H)-one scaffold 11 with up to three contiguous stereocenters and different amide residues (Scheme 1c).
Scheme 1: Cyclization reactions using enamides and enecarbamates as building blocks.

Results and Discussion
We commenced our studies by investigating the reaction between N-aryl-3-hydroxyisoindolinone 10a and (E)-enamide E-4a (Fehler!Verweisquelle konnte nicht gefunden werden.).To our delight treatment of both starting materials with BF3•OEt2 as Lewis acid in CH2Cl2 afforded the desired product 11.Best yields were obtained with 1.1 equivalents BF3•OEt2 at 0°C and a slow addition of the enamide E-4a to a mixture of the acyliminium precursor 10a and BF3•OEt2 (entry 1).Using this optimized procedure, the fused heterocycle 11 could be isolated in 88% overall yield and a diastereomeric ratio of 77:23.Only the two shown diastereomers syn-11a (1,2-syn-2,3-anti) and anti-11a (1,2-anti-2,3-syn) could be detected in the crude reaction mixture. [11]Lower reaction temperatures (e.g.-50 °C) led to a slower reaction rate, necessitating a higher loading of BF3•OEt2, and decreased yields (entry 2).Slow addition of 4a to the reaction mixture avoids competing decomposition of the enamide.Yet, direct addition of BF3•OEt2 to a mixture of both starting materials furnished the desired product 11 in acceptable yield (entry 3).Reduction of the amount of BF3•OEt2 led to decreased yields (entry 4).
Reactions in other solvents, such as CHCl3, toluene or THF did not furnish the desired product.
Decomposition of the starting materials was observed in these solvents (entry 5).Only in acetonitrile formation of the product took place, albeit in a lower yield of 46 % (entry 6).Efforts to replace BF3•OEt2 with catalytic amounts of different Lewis acids, such as Bi(OTf)3, Cu(OTf)2 or Fe(OTf)3, were not successful.Only small amounts of the desired product (< 10%) could be detected after prolonged reaction times (entry 7).

Table 1. Optimization of the formation of the dihydroisoindolo[2,1-a]quinolin-11(5-H)-one 11.
entry Deviations from optimized conditions [a] yield [b] (%) d.r.Next, we studied the influence of the enamide configuration on the outcome of the reaction.
Interestingly, reaction of both the (E)-and the (Z)-enamide 4a afforded dihydroisoindolo[2,1a]quinolin-11(5H)-one 11a in comparable yields and diastereoselectivities (Fehler!Verweisquelle konnte nicht gefunden werden.).Indeed, even a 1:1 mixture of E-4a and Z-4a furnished the desired product 11a in 80% yield and a diastereomeric ratio of 72:28.These results indicate a stepwise reaction pathway.Furthermore, these observations greatly facilitated our further research efforts.Our preferred method for the preparation of the starting enamides, a nickel-catalyzed isomerization of the corresponding allylamides, [12] usually delivers a mixture of the (E)-and (Z)-isomer.Instead of separating the two isomers of the corresponding enamide 4 by column chromatography, the formed E/Z-mixture could be used directly in all subsequent studies. [13]heme For acylimine precursors 10x and 10z a competing acid-mediated elimination to the corresponding 3methyleneisoindolin-1-ones 12a and 12b was observed (Scheme 5).This type of acid-mediated elimination has been described recently by Topolovcan and Gredičak.[14] Scheme 5: .Acid-mediated elimination to cyclic enamides 12.
The obtained results, in particular the same stereochemical outcome for the (E)-and (Z)-enamide, A Schlenk tube, equipped with a septum and a magnetic stirrer, is charged with N-acyliminiumionprecursor 10 (0.50 mmol, 1.00 eq. ) and dichloromethane (2.50 mL).The solution is cooled to 0 °C and BF3•OEt2 (0.55 mmol, 1.10 eq., 70 µL) is added.Over the course of 30 min enamide 4 (0.75 mmol, 1.50 eq.) in dichloromethane (2.5 mL) is added dropwise.The reaction is stirred for 2 h at 0 °C.After TLC showed complete consumption of the N-acyliminiumion-precursor, the reaction is stopped by the addition of saturated aqueous NaHCO3 (5 mL).The organic layer is separated, and the aqueous phase is extracted with dichloromethane (3x 10 mL).The combined organic layers are dried over Na2SO4, filtered off and the solvent is evaporated under reduced pressure.The crude product is purified and the two diastereomers separated by column chromatography (n-hexane:CHCl3 + 3% acetone = 8:2→2:8).

Scheme 3 :
Scheme 2: Influence of the enamide configuration.Yields refer to overall isolated yield of both diastereomers after column chromatography; d.r. in parentheses determined by 1H-NMR of crude mixture; Bz = benzoyl.