Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 11661−11673
Additive-Driven Rhodium-Catalyzed [4+1]/[4+2] Annulations of N‑Arylphthalazine-1,4-dione with α‑Diazo Carbonyl Compounds Pidiyara Karishma,† Chikkagundagal K. Mahesha,† Devesh S. Agarwal,† Sanjay K. Mandal,‡ and Rajeev Sakhuja*,† †
Department of Chemistry, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Sector 81, SAS Nagar, Manuali P.O. Mohali, Punjab 140306, India
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S Supporting Information *
ABSTRACT: A Rh(III)-catalyzed strategy involving the [4+1] annulation of 2-arylphthalazine-1,4-diones with α-diazo carbonyl compounds was developed, accessing a series of unprecedented hydroxy-dihydroindazolo-fused phthalazines in good to excellent yields. By varying the additive, phthalazino-fused cinnolines were synthesized under Rh-catalyzed conditions via [4+2] annulation between the same starting materials. Notably, such two strategies showed a good functional group tolerance and high atom efficiency.
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INTRODUCTION Phthalazine is an interesting ubiquitous diazaheterocyclic motif found in numerous marketed drugs1 and functional materials.2 Though rarely observed as natural products,3 phthalazines exhibit diverse biological activities such as antitumor,4−6 anticonvulsant,7−9 antihypertensive,10 anti-inflammatory,11−13 cardiotonic,14 antimicrobial,15−17 and analgesic18,19 activities (Figure 1). Thus, great effort has been devoted to the construction of fused and functionalized phthalazines in the past, mainly through conventional acid/base-mediated strategies20 or multicomponent reactions.20 Despite much effort, efficient and atom-economic methods have not been developed to access fused phthalazines via modern organic chemistry. In the present perspective, carbon−carbon (C−C) and carbon−heteroatom (C−X; X = N, O, etc.) bond-forming reactions are the most exemplified transformations that have flooded the chemist’s toolbox in the past decade.21,22 Among these reactions, transition-metal-catalyzed C−H functionalization via C−H activation is a central process and thus has received substantial limelight.23 Specifically, transition-metalcatalyzed oxidative annulation via C−H activation involving directing groups is among the most acclaimed approach for sequential C−C/C−N bond formations.24−30 By embracing © 2018 American Chemical Society
this strategy, transition-metal-catalyzed annulation protocols on 2-arylphthalazine-1,4-dione using different coupling partners have attracted great interest in recent years. For example, in 2016, Gandhi and co-workers reported a Ru-catalyzed deoxygenation-oxidative annulation approach for the synthesis of phthalazino[2,3-a]cinnolines from propargyl alcohols and 2phenylphthalazine-1,4-diones in the presence of Cu(OAc)2 as the external oxidant (Scheme 1i).31 Similarly, Perumal and coworkers reported Rh-catalyzed dehydrogenative C−H/N−H functionalization to prepare phthalazino[2,3-a]cinnolines from internal alkynes (Scheme 1ii).32 Very recently, Ji and coworkers disclosed a Rh III-catalyzed oxidant-free [4+1] annulation approach for the synthesis of quaternary-centerbearing divergent heterocycles, including indazolo[1,2-b]phthalazines from propargyl alcohols (Scheme 1iii).33 Similarly, Gogoi’s group synthesized substituted quinazolines by unprecedented RuII-catalyzed C−H activation and annulation reaction between 2-phenylphthalazine-1,4-diones and alkynes in the presence of a bidentate ligand, 1,3-bis(diphenylphosphino)propane (Scheme 1iv).34 Received: June 29, 2018 Published: September 5, 2018 11661
DOI: 10.1021/acs.joc.8b01630 J. Org. Chem. 2018, 83, 11661−11673
Article
The Journal of Organic Chemistry
Figure 1. Selected examples of biologically active fused and functionalized phthalazines
Scheme 1. Previous and Present Approaches for the Annulation of N-Arylphthalazine-1,4-dione with Different Coupling Partners via C−H Activation
α-Diazo carbonyl compounds are valuable two-carbon synthons for carbenoid generation because of their relative “green” character and ease of preparation. Transition-metal carbenoids generated through the decomposition of such αdiazo carbonyl compounds have served as versatile electrophilic intermediates for various [m+n] annulations.35−46 However, the carbene insertion strategy on 2-arylphthalazine1,4-dione has not been developed to date. We envisioned the possible formation of phthalazine-fused heterocycles via the Rh-catalyzed C−H carbenoid functionalization approach using α-diazo carbonyl compounds. In continuation of our efforts on C−H functionalization,47−52 herein we report additive-driven Rh-catalyzed tandem strategies for the synthesis of hydroxydihydroindazolo[1,2-b]phthalazines and phthalazino[2,3-a]cinnolines from 2-arylphthalazine-1,4-diones and α-diazo
carbonyl compounds via [4+1] and [4+2] annulation, respectively (Scheme 1v).
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RESULTS AND DISCUSSION Our investigation began by optimizing the reaction conditions for coupling 2-phenyl-2,3-dihydrophthalazine-1,4-dione (1a) and ethyl 2-diazo-3-oxobutanoate (2a) using [Cp*RhCl2]2 (2.5 mol %) as the catalyst (Table 1). No product formation was observed in the absence of any additive or in the presence of Cu(OAc)2 (20 mol %) at room temperature for 18 h (Table 1, entries 1 and 2) To our delight, an annulated product 3aa was obtained in 32% yield when NaOAc (20 mol %) was used in combination with [Cp*RhCl2]2 (2.5 mol %) in DCE at room temperature for 18 h under an air atmosphere (Table 1, entry 3). Careful analysis of 1H and 13C NMR, COSY, HMBC, 11662
DOI: 10.1021/acs.joc.8b01630 J. Org. Chem. 2018, 83, 11661−11673
Article
The Journal of Organic Chemistry Table 1. Selected Optimizationa of Reaction Conditions for the Synthesis of 3aa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c 17d
catalyst (mol %) [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2 [Cp*RhCl2]2
(2.5) (2.5) (2.5) (2.5) (2.5) (2.5) (2.5) (2.5) (5.0) (2.5) (2.5) (2.5) (2.5) (2.5) (2.5) (2.5) (2.5)
additive (mol %)
solvent
temp (°C)
yields (3aa)b
Cu(OAc)2 (20) NaOAc (20) KOAc (20) CsOAc (20) CsOAc (30) CsOAc (50) CsOAc (100) CsOAc (50) CsOAc (50) CsOAc (50) CsOAc (50) CsOAc (50) CsOAc (50) CsOAc (50) CsOAc (50) CsOAc (50)
DCE DCE DCE DCE DCE DCE DCE DCE DCE xylene toluene ACN THF MeOH DMF DCE DCE
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt
0 0 32 38 49 56 86 87 86 0 0 60 68 40 20
