Asymmetric Dearomatization of Phthalazines by Anion-BindingCatalysis

Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis Marta Velázquez, Rosario Fernández,*JoséM. Lassaletta,*and David Monge* Cite This: Org. Lett. 2023, 25, 8797−8802 Read Online ACCESS Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: 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. Benzodiazines are important bioactive heterocycles with a wide range of applications in the pharmaceutical and agrochemical fields. 1 Among them, phthalazine (2,3-diaza- naphthalene) 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. 4 Chiral 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. Received: October 10, 2023 Revised: November 12, 2023 Accepted: November 29, 2023 Published: December 1, 2023 Figure 1. Selective bioactive diazaheterocycles. Scheme 1. Catalytic Asymmetric Dearomatization of Phthalazines Letterpubs.acs.org/OrgLett © 2023 The Authors. Published by American Chemical Society 8797 https://doi.org/10.1021/acs.orglett.3c03325 Org. Lett. 2023, 25, 8797−8802 This article is licensed under CC-BY 4.0 Downloaded via UNIV DE SEVILLA on May 14, 2024 at 08:43:34 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. 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. 8 However, 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. 13 However, 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 (1,3- diazanaphthalenes) have been efficiently dearomatized with high enantioselectivities by asymmetric anion-binding catalysis. Employing chiral triazoles (CH-bond donors), Garcıa Mancheno 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. Preliminary experiments were conducted employing phthalazine (1a) as a model substrate, 2,2,2-trichloroethyl chloroformate (TrocCl) as acylating reagent, and isopropyl TBS-ketene acetal 2a as the nucleophile. The model reaction was initially studied in methyl tert-butyl ether (MTBE) employing a temperature gradient (from −78 °C to room temperature over 18 h). Although a quite insoluble phthalazinium salt was generated, a significant background reaction took place in the absence of any catalyst (entry 1, Table 1). From the initial screening of hydrogen-bond donor (HBD) organocatalysts (see Supporting Information), tertleucine derived thiourea Iemerged as the most promising Table 1. Screening of Organocatalysts and Optimization of the Reaction Parameters a a Reactions performed at 0.1 mmol scale. b Determined by 1H NMR using mesitylene as internal standard. c Determined by HPLC. d (R)- enantiomer. Scheme 2. Optimization of Acylating Reagents a a (a) Reactions performed at 0.2 mmol scale. Yields given for isolated products after chromatography. ee’s were determined by HPLC on chiral stationary phases. (b) Reaction performed with 5 mol % of catalyst loading. Figure 2. Noncatalyzed vs catalyzed reaction kinetics. Reactions were performed in MTBE with 5 mol % of catalyst from −78 to 10 °C. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c03325 Org. Lett. 2023, 25, 8797−8802 8798 candidate, affording (S)-3aa in 57% NMR-yield and 81% ee (entry 2). Organocatalyst II, featuring a combination of tertleucine and (1R,2R)-1,2-diaminocyclohexane scaffolds similar to the optimal catalyst originally reported for the dearomatization of isoquinolines, 11 displayed almost no stereocontrol (entry 3). Next, HBDs III-VII, bearing the more rigid 2- substituted pyrrolidino amide motifs, were evaluated (entries 4−8). In general, these catalysts exhibited good catalytic activities, achieving a maximum yield of 75% with thiourea IV. In accordance with a better conformational control exerted by the 2-methyl-2-phenylpyrrolidine scaffold, 15 (S)-3aa was obtained in 89% ee employing either thiourea IV or urea V (entries 5 and 6). Remarkably, catalyst VII, featuring a more extended πmoiety, afforded 3aa as a racemic mixture (entry 8). Other ethereal solvents (Et2O or THF) and toluene were tolerated (entries 9−12). However, none of them overcame the results obtained with MTBE. The influence of the acylating reagent on the reactivity and selectivity was further investigated (Scheme 2). In the chlorinated series, 2-chloroethoxycarbonyl- protected adduct 4aa was obtained in lower enantioselectivity (66% ee), while only traces of product were formed with 1,1,1- trichloromethoxycabonyl chloride 5aa. Phthalazines 6aa and 7aa, bearing Cbz and Ac protecting groups, were isolated in 75 and 98% yields, albeit with lower enantioselectivities (55 and 64%, respectively). To our delight, Bz-protected adduct 8aa was obtained with essentially the same enantioselectivity than Troc-3aa (88% ee) and a better yield (87%). Other substitution patterns in the phenyl ring [9aa (o-Cl), 10aa (p- Cl), 11aa (p-NO2), and 12aa (p-Me)] did not improve the enantioselectivity of the process (up to 86% ee for 10aa). 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 Scheme 3. Substrate Scope a a (a) Reactions performed at 0.2 mmol scale. (b) Reaction performed at 1 mmol scale. (c) 2.5 equiv of 2a. (d) 10 mol % of catalyst loading. Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c03325 Org. Lett. 2023, 25, 8797−8802 8799 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. Silyl ketene acetals bearing isopropyl, methyl, ethyl, and benzyl ester moieties (2a−d) performed efficiently, affording dihydrophthalazines (S)-8aa−8ad in generally good yields (79−89%) and enantioselectivities (84−90% ee). However, the use of tert-butyl ketene acetal 2e led to a moderate yield (49%) and lower enantioselectivity (78% ee). Silyl enol ethers derived from acetone and cyclohexanone were not reactive in this transformation, while acetophenonederived 2f afforded 8af in quantitative yield, albeit in low enantioselectivity (8% ee). Finally, vinylogous reagent 2g was also tolerated, affording 8ag in good yield (87%) with moderate enantioselectivity (55% ee). Next we carried out the dearomatization reaction of different phthalazines using 2a as a representative nucleophile. Within the symmetric series, the product (S)-8ba, bearing an additional fused aromatic ring, was obtained in 93% ee. 6,7-Disubstitution was further evaluated: 6,7-dimethyl phthalazine (1d) proved to be also a suitable substrate, affording the corresponding product (S)-8da in excellent yield (91%) and enantioselectivity (92%). On the other hand, the introduction of chloro or alkoxy groups at these positions afforded products in poorer yields and enantioselectivities [(S)-8ca, 54%, 46% ee; (S)-8ea, 77%, 40% ee]. The introduction of oxygenated substituents near the reactive center had a negative impact in the enantioselectivity. Thus, the dearomatization of 5,8-dimethoxyphthalazine (1f) afforded (S)-8fa in 70% yield and 14% ee. Benzo[f]phthalazine 1g afforded an inseparable mixture of regioisomers 8ga/8ga′ (1:2) in good yield (88%) and moderate to excellent ee values (59 and 90% ee, respectively). More interestingly, C4- monosubstituted phthalazines afforded adducts (S)-8ha−8pa in moderate-to-good yields (50−80%) and excellent enantioselectivities (89−98% ee), regardless of the nature of the substituents: chloro, cyano, alkoxy groups, with various substitution patterns, heteroaryls (exemplified by R = pyrrole), and a saturated heterocycle (R = morpholine). Finally, the challenging substrate 1q, bearing both phthalazine and isoquinoline scaffolds, was evaluated. Remarkably, a double dearomatization process involving the corresponding dibenzoyl bis-chloride allowed the generation of two stereogenic centers in (S,S)-8qa with excellent stereocontrol [19:1 dr, 98% ee (major)] and 71% yield. Finally, the methodology was extended to the dearomatization of pyridazine 13a. Under the optimized conditions, dihydropyridazines (S)-14aa and (S)-14ae were obtained in high yields and moderate-to-good ee values of 52 and 85% ee, respectively. It′s worth noting that Bz-pyridazinium chloride was more soluble in MTBE than the corresponding Bz-phthalazinium salt, thereby favoring the competing background reaction (82% NMR-yield in absence of catalyst). Additionally, other solvents and fixed temperatures (−78 °C) were unsuccessfully tested (see Supporting Information). On the contrary, Troc-pyridazinium chloride was less soluble than Bz-protected one and (S)-15aa, (S)- 15ad, and (S)-15ae were synthesized with superior enantioselectivities (85−95% ee), albeit in moderate yields (46%, 55%, and 31%, respectively) even when using 10 mol % of catalyst loadings. Remarkably, the best enantioselectivity in this case was obtained when combined with tert-butyl ketene acetal 2e, in contrast with the trend observed in the dearomatization of 1a. Finally, the synthetic usefulness of dihydrophthalazines 8 was demonstrated by accessing several selected targets (Scheme 4). Under standard hydrogenation conditions [Pd(C)/ 1 atm (H2)], 8aa underwent a chemoselective hydrogenation of the C�N double bond to afford cyclic hydrazino ester (S)-16. Under the same conditions, (S)-8ka was efficiently transformed into the phthalazone derivative (S)- 17 in high yields and without noticeable racemization. Additionally, 4-chloro substituted 8ha was subjected to Sonogashira coupling to yield product (S)-18 (77%). To illustrate the synthetic potential of dihydrophthalazines 8as cyclic β-hydrazino acid precursors, hydrolysis of both the iPrester and Bz-amide was performed under basic conditions [NaOH (3M), 37 °C]. Subsequent chemoselective O- alkylation through SN2 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 iPr-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 Sconfiguration of the newly created stereogenic center in (S)-8la. Within the Troc-protected series, the absolute Sconfiguration of dihydrophthalazine 3aa and dihydropyridazine 15aa was assigned by a chemical correlation. Scheme 4. Transformations of Dihydrophthalazines 8 Organic Letters pubs.acs.org/OrgLett Letter https://doi.org/10.1021/acs.orglett.3c03325 Org. Lett. 2023, 25, 8797−8802 8800 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. ■ASSOCIATED CONTENT Data Availability Statement The data underlying this study are available in the published article and its Supporting Information. * sı Supporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c03325. Experimental details, optimizations, spectroscopic and analytical data for new compounds, HPLC traces, crystallographic data of (S,S)-20 (PDF) Accession Codes CCDC 2300394 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. ■AUTHOR INFORMATION Corresponding Authors David Monge −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), 41012 Sevilla, Spain; orcid.org/0000-0001-8007-4111; Email: [email protected] Rosario Fernández −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), 41012 Sevilla, Spain; orcid.org/0000-0002-1755-1525; Email: [email protected] José M. Lassaletta −Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), 41092 Sevilla, Spain; orcid.org/ 0000-0003-1772-2723; Email: [email protected] Author Marta Velázquez −Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), 41012 Sevilla, Spain; orcid.org/0000-0002-4350-4968 Complete contact information is available at: https://pubs.acs.org/10.1021/acs.orglett.3c03325 Author Contributions The manuscript was written through contributions of all authors. Notes The authors declare no competing financial interest. ■ACKNOWLEDGMENTS We thank the Spanish MICINN (grants PID2019-106358GB- C21, PID2019-106358GB-C22, and PID2022-137888NB- I00), European FEDER funds, and the Junta de Andalucía (grants P18-FR-3531, P18-FR-644, and US-1262867) for financial support. 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