Enantioselective synthesis of 3-substituted isoindolinones via chiral phase transfer catalyzed intramolecular aza-Michael reactions

Optically active isoindolinones are synthesized by asymmetric intramolecular azaMichael reactions using cinchoninium phase-transfer organocatalysts. The resulting compounds are useful intermediates for the synthesis and development of benzazepine-receptor antagonists.


Introduction
2,3-Dihydro-1H-isoindol-1-ones (Isoindolinones) also called phthalimidines represent a class of bicyclic lactams which have attracted much attention from the scientific community due to the broad scope of their biological activities.[1] In particular, enantiopure compounds bearing a polysubstituted acetamido group at C-3 (Figure 1) have been extensively studied and play an important role as key targets for the pharmaceutical industry.Indeed, highly functionalized models, such as JM-1232 (1) [2] and DN-2327 (pazinaclone, 2) [3] have been reported as benzodiazepinereceptor agonists for the treatment of anxiety.From these studies, the importance of the absolute configuration of the stereocenter on the pharmacological activity became clear.[2c]Consequently, the development of short, versatile and efficient procedures for the stereocontrolled preparation of these highly functionalized 3 substituted isoindolinones constitutes an area of current interest, and alternative methods are currently the object of intense synthetic endeavor.Organic chemists have at their disposal a variety of synthetic strategies for the racemic synthesis of 3-(N,N-disubstituted)acetamido isoindolinones mainly based upon metal-catalyzed tandem reactions.[4] To the best of our knowledge, in these bicyclic lactams, control of the stereogenic center α to the nitrogen has only been achieved through catalytic asymmetric reduction of a 3-alkoxycarbonylmethylene isoindolinone followed by a twostep ester-amide interconversion sequence.[5] The aza-Michael reaction involving the reaction of activated alkenes and amines was mainly applied in organic synthesis through the use of various metal or organic catalysts, [6] phase-transfer catalysis has been less studied for aza-Michael reactions.[7,8] Herein, we wish to disclose an alternative, efficient and new synthetic route to enantioenriched 3-(N,N-disubstituted)acetamido isoindolinones.

Our alternative strategie
Considering that most isoindolinones have been synthesized directly from orthohalogenated benzamides through fast palladium-catalyzed tandem Heck and aza-Michael reactions, [4a-j] we concluded that the stereoselectivity of such a synthetic pathway would be difficult to control and the isolation of key reaction intermediates would be challenging.[4h,i]Hence, we envisioned a retrosynthetic strategy depicted in Scheme 1. Isoindolinones 3 may be available from an asymmetric intramolecular aza-Michael reaction of benzamides 4 by the construction of the lactam ring system and the concomitant control of the stereogenic center at C3.The stereoselectivity of the intramolecular aza-Michael reaction should be controlled by the catalyst chirality.The required benzamides 4 should be easily obtained from the corresponding unsaturated benzoic acids 5 by coupling with an array of primary amines.The acid 5 should, in turn, be readily prepared through a two-step sequence involving a cross-coupling Heck type reaction between 2bromoester 7 and acrylamides 8 followed by deprotection of the tert-butyl esters 6.

Elaboration of parent unsaturated amides 4a-d
The new synthetic route required the preliminary elaboration of the unsaturated tert-butyl benzoic acid esters 6a-c, which were readily prepared through a palladium-catalyzed Heck crosscoupling between aryl bromide 7 and various acrylamides 8a-c (Scheme 2).
Scheme 2. Synthesis of 3-substituted isoindolinone precursors Removal of the tert-butyl protecting group was then achieved by treatment with trifluoroacetic acid to furnish benzoic acids 5a-c, which were then engaged in the next step without further purification.Coupling of these highly conjugated carboxylic acids with aniline 9 and 2aminopyridine 10 finally delivered the required parent amides 4a-d.It was worth noting that this coupling reaction led directly to the corresponding cyclized products 3 when acrylamide fragments were replaced by conjugated esters.

Asymmetric intramolecular aza-Michael reaction of amides 4a-d. Access to enantioenriched 3-substituted isoindolinones 3a-d.
The asymmetric intramolecular aza-Michael reactions of substrates 4a-d (scheme 4) was studied by screening various phase transfer catalysts (Scheme 3) and reaction conditions (Table 1).Because some aza-Michael reactions have been shown to proceed without the use of any catalyst or additional reagent, [6e,9] we first performed a number of control experiments.Conducting the reaction with reagent 4a led to product 3a by using a base such as Cs 2 CO 3 , in toluene (entry 1).Using the same reaction conditions, Maruoka catalyst (S)-11 and cinchoninium salt 13a were shown to afford 3a in high conversions with 20 and 21% enantiomeric excess (ee), respectively (entries 2 and 5), whereas poor asymmetric induction was achieved by the use of cinchonidinium salt 12a or 12b (entries 3 and 4).The use of cinchoninium salt 13a in combination with other bases (entries 6-8) or solvents (entries 9 and 10) did not improve the initially obtained ee value (entry 5).The bromide couteranion of 13a was shown to be preferred to the chloride of 13b (entries 5 and 11); other anions like iodide and tetrafluoroborate were tried by ion exchange in situ but no improvement in the ee value arose from these attempts (entries 12 and 13).Finally, the use of catalyst 13a at 0 °C resulted in complete loss of enantiomeric excess in the product 3a (entry 14).The effect of substitution of the benzyl fragment of cinchoninium 13a on the reaction was then studied.Whereas an ortho-fluoro substituent led to loss of asymmetric induction (entry 15), a para-positioned tert-butyl fragment had no effect on the selectivity of the reaction (entry 16).The change from a benzyl to an anthracenyl group resulted in complete loss of enantioselection (entry 17).Disappointing results were also obtained from the functionalization of the alcohol fragment from cinchoninium 13a (entries 18-20).Whereas an allyl function did not change the course of the reaction, provided Cs 2 CO 3 was used as a base, a methyl substituent led to complete loss of asymmetric induction.Because we were unable to improve catalyst 13a by scaffold modification, we decided to investigate oligomeric cinchoninium salts [7b,10] based on 13a.Whereas, dimeric catalysts 14a and 14c afforded 3a in lower ee than 13a (entries 5, 21 and 23), meta-substituted cinchoninium salt 14b led to product 3a in a 45% ee (entry 22).Encouraged by this result, we prepared trimeric cinchoninium catalyst 15 and allowed it to react with 4a.We were glad to obtain isoindolinone 3a in 95% conversion (78% isolated yield) and 76% ee (entry 24).Whereas the use of K 2 CO 3 did not allow any reaction (entry 25), changing the temperature (entry 26) or solvent (entry 27) led to a decrease of 3a enantioselectivity using catalyst 15.Reagent 4b, bearing a 2pyridyl substituent, led to product 3b in 72% yield but no enantioselectivity was observed (entry 28).Asymmetric aza-Michael reactions of benzamide substrates 4c-d worked well using catalyst 15, although enantioselectivities of 3c-d were lower, with ee values around 60% (entries 29 and 30). a Reaction time : 24h.b Isolated yield after purification by flash chromatography.c measured by HPLC (Daicel Chiralpak AD CSP, Hexane-iPrOH, 7:3; 20 °C, 0.5 ml/min, 275 nm.d no reaction after 6 h.e with 10 mol% NaI.f with 10 mol% NaBF4.g same result using Toluene/CHCl3 (7/3).h same result using KOH 50% aq.as base.
Table 1 Phase transfer-Catalyzed intramolecular Aza-Michael reaction of 4a-d a

Conclusion
In summary, we have developed a new synthetic route to optically active isoindolinones, which are useful intermediates for the synthesis and development of benzodiazepine-receptor agonists.To access such isoindolinones, asymmetric intramolecular aza Michael reactions proved to be a valuable synthetic route provided selected oligomeric cinchoninium salts were used as phase-transfer catalysts.Further results and improvements related to this project will be reported in due course.