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Synthesis of 1‑Azaanthraquinone: Sequential C−N Bond Formation/ Lewis Acid Catalyzed Intramolecular Cyclization Strategy Ashwini Borah,†,‡ Abhilash Sharma,†,‡,§ Hemanta Hazarika,†,‡,§ Kumud Sharma,†,‡ and Pranjal Gogoi*,†,‡ †
Applied Organic Chemistry Group, Chemical Science and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, India ‡ Academy of Scientific and Innovative Research, CSIR, New Delhi, Delhi 110020, India S Supporting Information *
ABSTRACT: A synthetic strategy has been developed for the synthesis of 1-azaanthraquinones. This synthetic protocol consists of sequential Pd-catalyzed carbon−nitrogen bond formation followed by Lewis acid catalyzed intramolecular cyclization. The Pdcatalyzed aminated intermediate was isolated and characterized. This sequential reactions strategy provides a wide range of 1azaanthraquinones with good yields.
A
radical,11 lithiation of 2-(2-chloro-4-pyridyl)-4,4-dimethyl-4,5dihydro-oxazole and subsequent condensation with aromatic aldehydes,12 and reaction of 2-acylated 3-phenoxymethyl-l,4naphthoquinones with aqueous ammonium hydroxide.13 Although there are several methods for the synthesis of azaanthraquinones, a few methods are reported for the synthesis of 1-azaanthraquinones.2e Radical couplings using 2amino-1,4-naphthoquinones14 and chlorocyclization of Npropargylaminoquinone are notable examples for the synthesis of 1-azaanthraquinones.15 Recently, Wang et al. reported a Pdcatalyzed cascade method for the synthesis of 1-azaanthraquinones.16 However; in all cases, limited substrate scope and side product formations are the limitations of those reported methods. Therefore, development of methods for the synthesis of 1-azaanthraquinones are important and highly desirable. Recent reports from our laboratories have described the design of reactive substrates for metal-catalyzed carbon−carbon bond formation followed by condensation/cyclization of reactive intermediates. This strategy has been demonstrated for a variety of processes such as the synthesis of pyrimidines,17a polyaromatic hydrocarbons,17b phenanthridines, and fused quinolines.17c In the context of heterocycle synthesis, these synthetic strategies provide valuable heterocycles from acyclic precursors. In continuation of our research, we report here a synthetic methodology for the synthesis of 1azaanthraquinones via a sequential palladium-catalyzed aryl
nthraquinones are important class of polyaromatic compounds that have been used as critical component for many dyes, drugs, and organic materials.1 Its derivative azaanthraquinones are found in a considerable number of natural product antibiotics and drug candidates.2 Azaanthraquinone alkaloids are present in Annonaceous plants, and an ethanolic extract of the roots of G. grif fithii was found to be significantly cytotoxic against a number of human cancer cell lines.3 Scorazanone was isolated from the roots of Goniothalamus scortechinii and identified as 2,3-dimethoxy-4hydroxybenzo[g]quinoline-9,10-dione.4 Pixantrone is an experimental antineoplastic drug with fewer toxic effects on cardiac tissue and is now in phase III clinical trials for the treatment of aggressive non-Hodgkin’s lymphoma.5 Pyridoacridine alkaloids6 such as cleistopholine, amphimedine, meridine, and ascididemin are a similar type of azaanthraquinone and also possess prominent cytotoxic properties (Figure 1). On the other hand, theoretical investigations of azaanthraquinone analogues for intercalation reveals that they would be very effective intercalants and potential antitumor agents of considerable interest.7 Therefore, there is significant interest in the synthesis of this privileged structural unit. Several azaanthraquinones have been described in the literature,8 and their synthetic routes have usually involved the classical Friedel−Crafts approach,8g introduction of the 9,10-carbonyl functions by oxidation of the corresponding hydrocarbon,8h cycloaddition using azadienes and azadienophiles,9 intramolecular Michael-type addition of azadienes to 1,4-naphthoquinones,10 6-exo-trig radical cyclization of imine © 2017 American Chemical Society
Received: June 9, 2017 Published: July 5, 2017 8309
DOI: 10.1021/acs.joc.7b01427 J. Org. Chem. 2017, 82, 8309−8316
Note
The Journal of Organic Chemistry
Figure 1. Representative bioactive azaanthraquinone derivatives.
Scheme 1. Synthesis of 1-Azaanthraquinones from 2-Benzoyl-3-halonaphthalene-1,4-dione and Aniline
Table 1. Optimization Studies for the Synthesis of Azaanthraquinonea
entry
reaction conditions
yieldf of 3a/4a (%)
1 2 3 4 5 6 7 8 9 10 11b 12c 13c,e 14c,e 15c,d 16c,e 17c,e 18c,e 19c,e 20c,e 21c,e 22c,e
Pd(OAc)2 (2 mol %), BINAP (4 mol %), Cs2CO3, toluene Pd(OAc)2 (2 mol %), Ph3P (8 mol %), Cs2CO3, toluene Pd(OAc)2 (2 mol %), tBu3P (8 mol %), Cs2CO3, toluene Pd(OAc)2 (2 mol %), Cy3P (8 mol %), Cs2CO3, toluene Pd2(dba)3 (2 mol %), BINAP (4 mol %), Cs2CO3, toluene Pd(PPh3)4 (2 mol %), Cs2CO3, toluene Pd(OAc)2 (5 mol %), BINAP(10 mol %), Na2CO3, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K3PO4, toluene K2CO3, DMF Pd(OAc)2 (5 mol %), BINAP (10 mol %), In(OTf)3, K2CO3, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; In(OTf)3, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; I2, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; AlCl3, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; In(OTf)3, DCM Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; In(OTf)3, xylene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; Sc(OTf)3, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; Cu(OTf)2, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; Ag(OTf), toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; BF3OEt2, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; TsOH, toluene Pd(OAc)2 (5 mol %), BINAP (10 mol %), K2CO3, toluene; workup; TFA, toluene
53/trace 47/trace 43/trace 49/trace 59/trace 50/trace 89/trace 91/trace 87/trace 39/trace 63/trace −/71 −/35 −/47 −/39 −/70 −/50 −/30 −/25 −/70 −/65 −/trace
Reaction conditions: 1a (1.0 mmol), aniline 2a (1.2 mmol), catalyst, ligand, base (2 mmol), in solvent(3 mL), at 90 °C for 12 h. bIn(OTf)3 (10 mol %). cWorkup followed by In(OTf)3 (10 mol %), in representative solvent (3 mL) at 100 °C for 36 h. d40 °C for 48 h;trace: less than 10% yield. e Lewis acid/Bronsted acid (10 mol %). fIsolated yield. a
from β-halo-α,β-unsaturated aldehydes [2 mol % of Pd(OAc)2 and 4 mol % of BINAP, Cs2CO3, toluene, 90 °C]17a provided the desired 1-azaanthraquinone 4a, albeit in only
