Dihydroquinazolinones as adaptative C(sp3) handles in arylations and alkylations via dual catalytic C-C bond-functionalization

Abstract

C-C bond forming cross-couplings are convenient technologies for the construction of functional molecules. Consequently, there is continual interest in approaches that can render traditionally inert functionality as cross-coupling partners, included in this are ketones which are widely-available commodity chemicals and easy to install synthetic handles. Herein, we describe a dual catalytic strategy that utilizes dihydroquinazolinones derived from ketone congeners as adaptative one-electron handles for forging C(sp³) architectures via α C-C cleavage with aryl and alkyl bromides. Our approach is achieved by combining the flexibility and modularity of nickel catalysis with the propensity of photoredox events for generating open-shell reaction intermediates. This method is distinguished by its wide scope and broad application profile--including chemical diversification of advanced intermediates--, providing a catalytic technique complementary to existing C(sp³) cross-coupling reactions that operates within the C-C bond-functionalization arena.

Fig. 1. C–C bond activation of ketone derivatives.

a Reactivity of ketones. b Traditional methods for ketone C–C cleavage. c Strategies for catalytic C–C bond activation of ketones. d Metallaphotoredox approach for using ketones as cross-coupling synthons.

Fig. 2. Dihydroquinazolinones as sp³ handles via a C–C cleavage.

As Table 1 (entry 1), using aryl bromide (0.20 mmol). Isolated yields, average of at least two independent runs. Unless stated otherwise, R¹ = Me in the ketone derivative. ^aR¹ = Et in the ketone derivative. ^bUsing NiCl₂·DME as Ni source in NMP (0.2 M). ^cUsing 5-CzBN (2 mol%) as photocatalyst, LiBr (1.2 eq.) as additive. ^{d 1}H NMR yield using CH₂Br₂ as standard. ^eR¹ = Ph in the ketone derivative. ^fR¹ = 4-methoxyphenyl in the ketone derivative. ^gR¹ = benzo[d][1,3]dioxol-5-yl in the ketone derivative. ^hAryl bromide (0.20 mmol), ketone derivative (0.30 mmol), 4-CzIPN (2 mol%), NiBr₂·diglyme (10 mol%), L1 (15 mol%), LiHMDS (1.5 eq.), in dioxane (0.1 M).

Fig. 3. Telescoping the formation of dihydroquinazolinones from ketone congeners.

Using ketone (0.63 mmol) and 2- aminobenzamide (0.6 mmol) to form dihydroquinazolinone, then as Table 1 entry 7 using aryl bromide (0.20 mmol). Yields denote isolated material.

Fig. 4. Scope of sp³ alkylation.

Alkyl bromide (0.20 mmol), dihydroquinazolinone (0.30 mmol), NiBr₂·diglyme (10 mol%), L6 (15 mol%), NaBr (1.5 eq.), NaHCO₃ (1.0 eq.) in DMF (0.1 M) at 40 °C for 24 h. Isolated yields, average of two independent runs. Unless stated otherwise, R² = Me in the ketone derivative. ^aDMF (0.2 M). ^bR² = Ph in the ketone derivative.

Fig. 5. Preliminary mechanistic experiments.

a TEMPO radical trapping studies. b Radical clock experiments. c Mechanistic experiments with well-defined nickel species.

Fig. 6. Radical cyclization as a function of catalyst loading.

2 u (0.12 mmol), 4d (0.10 mmol), Ni(OAc)₂·4H₂O (10 mol%), L4 (15 mol%), 4-CzIPN (2 mol%), NaBr (1.2 eq.), Na₂CO₃ (1.0 eq.) in NMP (0.10 M) at 40 °C, for 24 h.

Fig. 7. Proposed mechanism.

Proposed reaction pathway involves a reductive quenching photoredox cycle for the generation of alkyl radical from dihydroquinazolinone, which is captured by Ni(II) oxidative addition complexes to form Ni(III) species for subsequent cross-coupling by reductive elimination. The photoredox and nickel catalytic cycles are simultaneously closed by electron transfer from reduced photocatalyst to Ni(I) species generated post-reductive elimination.