Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis

A straightforward methodology for the enantioselective synthesis of 1,2-dihydrophthalazines via dearomatization of phthalazines by anion-binding catalysis has been developed. The process involves the Mannich-type addition of silyl ketene acetals to in situ generated N-acylphthalazinium chlorides using a tert-leucine derived thiourea as a H-bond donor catalyst. Ensuing selective and high-yielding transformations provide appealing dihydro- and tetrahydro-phthalazines, phthalazones, and piperazic acid homologues, en route to biologically relevant molecules.

B enzodiazines are important bioactive heterocycles with a wide range of applications in the pharmaceutical and agrochemical fields. 1 Among them, phthalazine (2,3-diazanaphthalene) and dihydrophthalazine derivatives are probably the most privileged pharmacophores (Figure 1). 2 For example, azelastine (a phthalazone) is an efficient histamine antagonist approved for the treatment of allergic rhinitis 3 and dihydrophthalazine SYM2206 is an AMPA receptor modulator with anticonvulsant activity. 4Chiral racemic dihydrophthalazines BAL0030543 5 and (S)-RAB1 and their analogues 6 are potent dihydrofolate reductase inhibitors that have demonstrated activity against antibiotic-resistant strains of Staphylococcus aureus, among other Gram-positive bacteria.On the other hand, monocyclic derivatives have also shown interesting bioactivities.Selected examples are cilazapril, a marketed saturated pyridazine (piperazic acid derivative) drug for the treatment of hypertension, 7 and matlystatins, a group of potent metalloproteinase inhibitors. 8However, their potential as therapeutic weapons contrasts with the scarcity of methodologies for accessing these chiral molecules in an enantioselective fashion.In this regard, a straightforward approach consists of the stereoselective dearomatization of phthalazin-2-ium salts derived from readily available phthalazines.
Several examples demonstrate the use of phthalazinium dicyanomethanides as stable azomethine ylides in [3 + 3] and [3 + 2] cycloaddition reactions.These reactions are enabled by Cu(I) and iminium catalysis, respectively (Scheme 1A). 9 Furthermore, an N-alkyl phthalazinium iodide was subjected to enamine catalysis for a nucleophilic dearomatization reaction in an intramolecular version.However, only a single example was reported (Scheme 1B). 10 Herein, we report the asymmetric synthesis of 1,2-dihydrophthalazines through dearomatization of phthalazines via anion-binding catalysis using H-bond donor organocatalysts (Scheme 1C).The process involves the nucleophilic addition of silyl ketene acetals to in situ generated N-acyl-phthalazinium halides.
Pioneered by Jacobsen, 11 anion-binding catalysis 12 has enabled a wide range of nucleophilic dearomatizations of mono aza-heterocycles, such as isoquinolines, quinolines, and pyridines. 13However, attempts to implement these methodologies in diaza-heterocycles remain challenging due to the increased complexity associated with the presence of two nitrogens prone to be acylated, resulting in multiple reactive positions and thereby lower yields and side reactions.Moreover, enantioselectivities have been often compromised.To the best of our knowledge, only quinazolines (1,3diazanaphthalenes) have been efficiently dearomatized with high enantioselectivities by asymmetric anion-binding catalysis.Employing chiral triazoles (CH-bond donors), Garcı á Manchenõ and co-workers successfully developed the dearomatization of quinazoline through a nucleophilic C2-addition of silyl ketene acetals (up to 92% ee), while phthalazine and pyridazine underwent dearomatization reactions with moderate enantioselectivities. 14 It is worth mentioning that alternative metal-catalyzed dearomatization of pyridazine also remains virtually unknown.
According to an anion-binding activation mode, the nature of the halide anion modified the reaction outcome.Hence, product 8aa was isolated in lower enantioselectivity from reactions performed using benzoyl bromide or fluoride as the acylating reagent (73% and 30% ee, respectively).With the optimal conditions in hand, the catalyst loading could be reduced to 5 mol % without compromising yield or enantioselectivity.Next, the reactions of 1a and 2a, employing BzCl as the acylating reagent, were investigated in more detail.A comparison of noncatalyzed vs catalyzed reaction kinetics revealed maximum differentiation at the beginning of the process (from −78 °C to −30 °C), affording 8aa in 75% NMR-yield after 6 h (vs <5% in the background) (Figure 2).Moreover, it was observed that the enantioselectivity was slightly lower at the early stages (from −78 to −60 °C; 79% and 82% ee after 2 and 4 h, respectively), reaching a maximum value of 88% ee after 6 h, which remained constant until the end of the reaction.Therefore, a slow temperature gradient (from −78 °C to rt) was employed as optimal methodology for further studies (Scheme 3).Different nucleophiles were initially tested.
Additionally, 4-chloro substituted 8ha was subjected to Sonogashira coupling to yield product (S)-18 (77%).To illustrate the synthetic potential of dihydrophthalazines 8 as cyclic β-hydrazino acid precursors, hydrolysis of both the i Prester and Bz-amide was performed under basic conditions [NaOH (3M), 37 °C].Subsequent chemoselective Oalkylation through S N 2 of 2-bromoacetophenone yielded 19 without compromising the stereochemical integrity of the starting material (8aa).Additionally, milder basic conditions [NaOH (1M), from 0 °C to rt] allowed selective saponification of the i Pr-ester.Peptide-type coupling of the corresponding carboxylic acid with enantiopure L-phenyl- alanine ethyl ester, promoted by HBTU, afforded (S,S)-20 in good overall yield (67%, 2 steps) and without a loss of enantiomeric purity (98% of diastereomeric excess).Crystals of (S,S)-20 suitable for X-ray diffraction analysis served to determine the absolute S configuration of the newly created stereogenic center in (S)-8la.Within the Troc-protected series, the absolute S configuration of dihydrophthalazine 3aa and dihydropyridazine 15aa was assigned by a chemical correlation.Assuming a uniform stereochemical pathway, the absolute configurations of all other products were assigned by analogy.In summary, anion-binding catalysis has enabled a threecomponent enantioselective dearomatization reaction of phthalazines, employing benzoyl chloride as the optimal acylating reagent and silyl ketene acetals as nucleophiles.This general methodology afforded 1,2-dihydrophthalazines in moderate-to-good yields and high enantioselectivities in most cases.Subsequent derivatizations provide direct access to key building blocks for the synthesis of dihydro-and tetrahydrophthalazines, phthalazones, and piperazic acid homologues.

Figure 2 .
Figure 2. Noncatalyzed vs catalyzed reaction kinetics.Reactions were performed in MTBE with 5 mol % of catalyst from −78 to 10 °C.