Radical Cyclopropanol Ring Opening Initiated Tandem Cyclizations for Efficient Synthesis of Phenanthridines and Oxindoles

Abstract

β-Keto radicals can be readily generated from single-electron oxidation and ring opening of cyclopropanols. Herein, we report new ways of trapping β-keto radicals derived from Mn(III)-mediated oxidative cyclopropanol ring opening with biaryl isonitriles and N-aryl acrylamides derived from anilines. Through tandem radical cyclization processes, substituted phenanthridines and oxindoles can be synthesized in one step and good to excellent yield. These new synthetic methods feature broad substrate scope and mild reaction conditions, efficiently form two carbon-carbon bonds, and use cheap and commercially available manganese salts as oxidants. Concomitant installation of ketone functionality in the final products provides a handle for further functionalization of these important and biologically relevant scaffolds.

Graphical Abstract

Our recent interest¹ in harnessing the inherent ring-strain and unique reactivity of cyclopropanols² for efficient carbon-carbon and carbon-heteroatom bond forming reactions prompted us to develop new ways of trapping the β-keto alkyl radicals derived from oxidative cyclopropanol ring opening reactions to synthesize medicinally useful chemical scaffolds. Cyclopropanols are readily available from the corresponding esters or lactones with the Kulinkovich or Simmons-Smith protocols. Under various oxidative conditions, they can be converted to highly reactive β-carbonyl radicals, which often undergo reaction pathways such as oxidations, dimerizations, and additions to unsaturated systems.^3–6 We envisioned the possibility of trapping the β-keto alkyl radicals derived from cyclopropanols with biaryl isonitriles⁷ and N-aryl acrylamides⁸ (Scheme 1), both of which are effective radical acceptors. After the initial radical reaction with the β-keto alkyl radicals, the newly generated radicals B/D are expected to cyclize with the intramolecularly tethered aromatic ring to lead to 6-ketoalkylated phenanthridines 3 and 3-ketoalkylated 2-oxindoles 5 after further oxidation and aromatization. Substituted phenanthridines⁹ and 2-oxindoles¹⁰ are both important motifs in bioactive alkaloid natural products and drug molecules.

Scheme 1.

Reaction design.

We began our studies by investigating the reaction of cyclopropanol 1a with 2-isocyanobiphenyl 2a under oxidative conditions. After addition of 1.7 equivalents of Mn(acac)₃ to a stirred solution of 1a and 2a in MeOH, we observed rapid consumption of the cyclopropanol (<5 min) but low conversion of 2a. Gratifyingly, however, the corresponding phenanthridine derivative 3a was observed and isolated in 19% yield (entry 1). Reasoning that the reactive β-keto alkyl radical intermediate may have competitive self-coupling side reactions, we decided to use a 2-fold excess of 1a added slowly to the mixture of 2a and Mn(acac)₃ and improved the yield to 56% (entry 2). After a brief optimization study summarized in table 1, we found that the cyclization could be most efficiently carried out using 2.2 equivalents of Mn(acac)₃ and tert-butyl alcohol as solvent. The only side product observed in the reaction mixture was phenanthridine 6.¹¹ Using either the cyclopropanol 1a or aryl isonitrile 2a as the excess reagent did not greatly affect the yield (entries 6 and 7), but around 50% of the aryl isonitrile 2a can be recovered when it is used in excess. Notably, we also found that Mn(acac)₃ could be used in catalytic amounts in the presence of tert-butyl hydroperoxide (TBHP) as co-oxidant to give the product in 67% yield (entry 9). Since TBHP is an exceptionally dangerous chemical and more expensive than Mn(acac)₃, we decided not to further optimize this catalytic condition. Interestingly, when oxygen was used as oxidant, no desired product was formed. Instead, a significant amount of cyclic peroxide 7 was formed (64% yield), presumably from trapping the β-keto alkyl radical derived from 1a by oxygen followed by cyclization on the newly generated ketone. A similar process has been reported by Kulinkovich et al.¹²

Table 1.

Phenanthridine synthesis optimization.^a

entry	1a/2a	X	solvent (conc.)	additive (equiv.)	yieldb
1c	1/1.1	1.7	MeOH (0.01 M)	--	19%
2c	2/1	2.2	MeOH (0.01 M)	--	56%
3	1/2	1.5	MeOH (0.01 M)	--	57%
4	1/2	2.2	MeOH (0.01 M)	--	70%
5	1/2	2.2	iPrOH (0.01 M)	--	67%
6	1/2	2.2	tBuOH (0.01 M)	--	83%
7	2/1	2.2	tBuOH (0.01 M)	--	86%
8	2/1	2.2	tBuOH (0.1 M)	--	65%
9	2/1	0.1	tBuOH (0.01 M)	TBHP (2.2)	67%
10	2/1	0.1	tBuOH (0.01 M)	O2 (balloon)	0%

^aReactions conducted using 0.125 mmol of the limiting reagent (1a or 2a), with a solution of 1a added slowly to the solution of 2a and oxidant over 2 h under argon atmosphere at room temperature (RT).

^bIsolated yields following flash chromatography.

^cOxidant added in one portion to mixture of 1a and 2a.

In order to probe the scope and generality of this new phenanthridine synthesis method, a collection of cyclopropanols and biaryl isonitriles were prepared and subjected to the optimized conditions (Figure 1). In general, variously substituted aryl and alkyl cyclopropanols underwent the reaction smoothly to obtain the products in moderate to excellent yields. Halogens including fluorine and bromine were tolerated, as well as methyl and silyl ethers (3aa-3ac, 3ja). Alkenes were also tolerated, with alkenes distal to the formed radical centers leading to significantly higher yields than substrates containing proximal alkenes (cf. 3ga vs 3ha). Aryl isonitriles with both electron-donating tert-butyl and electron-withdrawing trifluoromethyl groups on the 4’-position reacted well under these conditions. Napthyl-derived isonitrile reacted with high regioselectivity to form 3ed and 3gd (7:1 and 11:1 regiomeric ratio respectively). A larger scale reaction using 3.3 mmol of cyclopropanol 2e and 6.6 mmol of isonitrile 1a successfully gave compound 3ea in 62% yield, demonstrating the scalability of this process.

Having demonstrated the utility of trapping the β-keto alkyl radicals derived from cyclopropanols by aryl isonitriles in the synthesis of substituted phenanthridines, we reasoned that a similar process could take place if N-aryl acrylamides derived from anilines were used as the radical acceptors, which would provide efficient access to ketoalkylated 2-oxindole derivatives. 2-Oxindoles are privileged structural motifs found in many alkaloid natural products with medicinal importance as well as lifesaving pharmaceutical compounds.¹⁰

Starting from the reaction conditions established for the phenanthridine synthesis, we were able to quickly identify optimized conditions to unite readily available cyclopropanols and aniline-derived N-aryl acrylamides to 3,3-disubstituted 2-oxindoles (Table 3). Similarly to the phenanthridine synthesis, various cyclopropanols containing halogen, alkene, methyl ether and silyl ether functionalities were well tolerated in the reaction. Variation of N-substitution on the amide gave good yields in the case of N-methyl and N-benzyl amides (5ba and 5bb). Substitution on the aniline ring was found to have little effect on the reaction, with methyl (5bc) chloro (5bf), trifluoromethyl (5bd), and methoxy (5be, 5bg) substituents all giving good to excellent yields of the corresponding 2-oxindole products.

Table 3.

Mn(III)-mediated oxindole formation substrate scope.

Mechanistically, the formation of both the phenanthridine and 2-oxindole derivatives is proposed to start with hydrogen atom abstraction and single electron oxidation of cyclopropanol 1 by Mn(acac)₃ to produce an oxy-radical, which subsequently rearranges to β-keto alkyl radical A (Scheme 1). The β-keto radical then adds intermolecularly to either the aryl isonitrile 2 or the α,β-unsaturated amide 4 to produce an imidoyl radical B or an α-amido radical D. Subsequent homolytic aromatic substitution leads to the cyclohexadienyl radicals C and E. Oxidation and rearomatization of these cyclohexadienyl radicals with the second equivalent of Mn(acac)₃ then leads to formation of the phenanthridine (3) or 2-oxindole (5) products. The fact that oxygen inhibits the conversion of 1 to 3 and the formation of peroxide 7 support the proposed radical process.

In summary, we have developed two novel applications for β-keto radicals derived from readily available cyclopropanols towards the synthesis of phenanthridine¹³ and 2-oxindole derivatives.¹⁴ These reactions showcase the applicability of cyclopropanols as a source of easily-generated alkyl radicals that can be integrated into heterocyclic scaffolds. The reactions are fast, efficient and take place under mild oxidative conditions to generate two carbon-carbon bonds in a radical cascade sequence. The resulting ketone functionality in the products can serve as a point of further diversification for complex molecule synthesis.

Table 2.

Mn(III)-mediated phenanthridine formation.