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Additive-Driven Rhodium-Catalyzed [4+1]/[4+2] Annulations of N-Arylphthalazine-1,4-dione with #-Diazo Carbonyl Compounds Pidiyara Karishma, Chikkagundagal K. Mahesha, Devesh S Agarwal, Sanjay K. Mandal, and Rajeev Sakhuja J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01630 • Publication Date (Web): 05 Sep 2018 Downloaded from http://pubs.acs.org on September 7, 2018
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The Journal of Organic Chemistry
Additive-Driven Rhodium-Catalyzed [4+1]/[4+2] Annulations of NArylphthalazine-1,4-dione with α-Diazo Carbonyl Compounds Pidiyara Karishma,a Chikkagundagal K. Mahesha,a Devesh S. Agarwal,a Sanjay K. Mandalb and Rajeev Sakhuja*a a
Department of Chemistry, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India
Email:
[email protected] b
Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Sector 81, S.A.S. Nagar, Manuali P.O., Punjab 140306, India
Abstract: A Rh(III)-catalyzed strategy involving the [4+1] annulation of 2-arylphthalazine1,4-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 good functional group tolerance and high atom-efficiency. Keywords: C-H Activation; Annulation; Transition-metal catalysis; Phthalazine; Carbene 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, much effort has been devoted to the construction of fused and functionalized phthalazines in the past, mainly through conventional acid/base-mediated strategies20 or multicomponent
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reactions.20 Despite much effort, efficient and atom-economic methods have not been developed to access fused-phthalazines via modern organic chemistry.
Figure 1. Selected examples of biologically active fused and functionalized phthalazines 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 chemist’s toolbox in the past decade.21,22 Among these reactions, transitionmetal-catalyzed C−H functionalization via C–H activation is a central process and thus has received substantial limelight.23 Specifically, transition-metal-catalyzed 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 this strategy, transition-metal-catalyzed annulation protocols on 2-arylphthalazine-1,4-dione using different coupling partners have attracted much 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 2-phenylphthalazie-1,4-diones in the presence of Cu(OAc)2 as the external oxidant (Scheme 1i).31 Similarly, Perumal and co-workers reported Rhcatalyzed dehydrogenative C–H/N–H functionalization to prepare phthalazino[2,3a]cinnolines from internal alkynes (Scheme 1ii).32 Very recently, Ji and co-workers disclosed a RhIII-catalyzed oxidant-free [4+1] annulation approach for the synthesis of quaternary-center-bearing
divergent
heterocycles,
b]phthalazines from propargyl alcohols (Scheme 1iii).
including 33
indazolo[1,2-
Similarly, Gogoi 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
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The Journal of Organic Chemistry
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 α-diazo carbonyl compounds have served as versatile electrophilic intermediates for various [m+n] annulations.35-46 However, carbene insertion strategy on 2-arylphthalazine-1,4-dione has not been developed to date. We envisioned the possible formation of phthalazine-fused heterocycles via 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 hydroxy-dihydroindazolo[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). Previous Work
OH R
O N N R1
O
1
CH3COOH, 110 oC, 8 h
R2 N
R1 Gogoi et. al. Org. Lett. 2018, 20, 2297 Present Work (v) O
O
N NH
R2
R
O
R1
(iv) (iii)
t-AmOH, 100 oC, 8 h
[Cp*RhCl2]2 (5 mol %) NaOAc (1 equiv)
N N
o
PhCl, 90 C, 12 h O
O R2
R1
Ji et. al. J. Org. Chem. 2018, 83, 4650 O R4
R3
O
N2 3
N N
OH
O
O R2 N N
R1
O
R2 R1 [RuCl 2(p-cymene)] 2 (5 mol %) DPPP (10 mol %) Cu(OAc)2.H2O (1 equiv) K2CO3 (1 equiv)
O
R1 O R2 Perumal et. al. Org. Biomol. Chem., 2016, 14, 1958
(i)
Gandhi et. al. Chem. Commun., 2016, 52, 2509
N
R2 R1 [Cp*RhCl2]2 (2.5 mol %) AgSbF 6 (10 mol %) (ii) Cu(OAc)2.H2O (1 equiv) t-AmOH, 100 oC, 6 h
[RuCl2(p-cymene)] 2 (5 mol %) KPF6 (30 mol %) Cu(OAc)2 (2 equiv)
COOR4 [Cp*RhCl 2]2 (2.5 mol %) AgSbF 6 (10 mol %) DCE, 110 oC, 14-16 h, N2
R
R N NH
1
O
2
R4
R3 N2
[Cp*RhCl 2]2 (2.5 mol %) CsOAc (50 mol %) DCE, r.t., 16-18 h, Air
O R
R2 N N
1
O
OH
R4
Scheme 1. Previous and present approaches for the annulation of N-arylphthalazine-1,4dione with different coupling partners via C-H activation Results and Discussion Our investigation began by optimizing the reaction conditions for coupling 2-phenyl-2,3dihydrophthalazine-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 air atmosphere (Table 1, entry 3). Careful analysis of 1H and 13C
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NMR, COSY, HMBC, and HSQC of the 3aa confirmed the formation of an unprecedented hydroxy-dihydroindazolo-fused phthalazine, possibly resulting via the [4+1] annulation of 1a and 2a. An increase in the yield of 3aa to 38% and 49% was observed by replacing NaOAc with KOAc and CsOAc, respectively (Table 1 entries 4 and 5). Further screening study on the additive loading revealed that 50 mol% is the optimum CsOAc concentration required to furnish 86% of 3aa (Table 1, entries 6 and 7). No further increase in the yield of 3aa was observed by either increasing the catalyst to 5 mol% or additive loading to 100 mol% (Table 1, entries 8 and 9). Solvent switching to xylene or toluene produced no product; the use of ACN, THF, MeOH, or DMF was found to be detrimental, producing 3aa in moderate-to-low yields (Table 1, entries 10–15). Interestingly, only a small amount of 3aa was observed (along with other overlapping intermediate(s) spots on TLC) when the reaction was performed under the optimized conditions in nitrogen atmosphere, indicating that aerobic conditions are essential for the desired [4+1] annulation (Table 1, entry 16). Finally, the reaction between 1a and 2a was performed using [Cp*RhCl2]2/CsOAc under oxygen atmosphere, and 3aa was isolated in 88%) yield (Table 1, entry 17). Table 1. Selected optimizationa of reaction conditions for synthesis of 3aa
Entry No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.c 17.d
Catalyst (mol %) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (5.0) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5) [Cp*RhCl2]2 (2.5)
Additive (mol %) 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)
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Solvent DCE DCE DCE DCE DCE DCE DCE DCE DCE Xylene Toluene ACN THF MeOH DMF DCE DCE
Temp. ( °C) r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t.
Yields (3aa)b 32 38 49 56 86 87 86 60 68 40 20
