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. 2022 Jan 6;13(10):2900-2908.
doi: 10.1039/d1sc05899a. eCollection 2022 Mar 9.

Overcoming peri- and ortho-selectivity in C-H methylation of 1-naphthaldehydes by a tunable transient ligand strategy

Yujian Mao  1 , Jing Jiang  1 , Dandan Yuan  1 , Xiuzhen Chen  1 , Yanan Wang  1 , Lihong Hu  1 , Yinan Zhang  1
Affiliations

Overcoming peri- and ortho-selectivity in C-H methylation of 1-naphthaldehydes by a tunable transient ligand strategy

Yujian Mao et al. Chem Sci. .

Abstract

Methyl groups widely exist in bioactive molecules, and site-specific methylation has become a valuable strategy for their structural functionalization. Aiming to introduce this smallest alkyl handle, a highly regioselective peri- and ortho-C-H methylation of 1-naphthaldehyde by using a transient ligand strategy has been developed. A series of methyl-substituted naphthalene frameworks have been prepared in moderate to excellent yields. Mechanistic studies demonstrate that peri-methylation is controlled by the higher electronic density of the peri-position of 1-naphthaldehyde as well as the formation of intermediary 5,6-fused bicyclic palladacycles, whereas experimental studies and theoretical calculations inferred that a 5-membered iridacycle at the ortho-position of 1-naphthaldehyde leads to energetically favorable ortho-methylation via an interconversion between the peri-iridacycle and ortho-iridacycle. Importantly, to demonstrate the synthetic utility of this method, we show that this strategy can serve as a platform for the synthesis of multi-substituted naphthalene-based bioactive molecules and natural products.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (A) Methyl groups in natural products and bioactive molecules. (B) Selectivity from benzene to naphthalene. (C) Peri- and ortho-C–H functionalizations of naphthalene. (D) Regioselective C–H methylation of 1-naphthaldehydes with tunable TDGs.
Scheme 1
Scheme 1. Synthesis of diverse naphthaldehydes via sequential C–H functionalizationsa. aReaction conditions: (a) 1a or 3a, CH3BF3K (3.5 eq.), Pd(OAc)2 (10 mol%), TDG (60 mol%), Cu(TFA)2-xH2O (2 eq.), CsOAc (2 eq.), HFIP : AcOH = 7 : 1, H2O (10 eq.), 90 °C, sealed tube, 36 h. (b) 1a, CH3BF3K (2 eq.), [Cp*IrCl2]2 (5 mol%), TDG (20 mol%), AgNTf2 (20 mol%), AgOAc (2.5 eq.), AcOH, 90 °C, N2, sealed tube, 4 h. (c) 2a, [Ru(p-cymene)Cl2]2 (5 mol%), AgSbF6 (20 mol%), 2-methyl-3-(trifluoromethyl)aniline (20 mol%), 4-chlorobenzoic acid (0.5 eq.), 1-ethyl-1H-pyrrole-2,5-dione (1.5 eq.), DCE : HFIP = 5 : 1, 60 °C, N2, sealed tube, 36 h. (d) 2a, Pd(OAc)2 (10 mol%), methyl 4-iodobenzoate (2 eq.), 2-amino-2-methylpropanoic acid (40 mol%), AgTFA (1 eq.), HFIP : TFA = 9 : 1, 110 °C, sealed tube, 24 h. (e) 2a, [CpIrCl2]2 (4 mol%), 3-trifluoromethylaniline (40 mol%), 4-methylbenzenesulfonyl azide (2 eq.), AgPF6 (24 mol%), DCE, 100 °C, N2, sealed tube, 36 h. (f) 2a or 3a, NCS (1.3 or 1.5 eq.), Pd(OAc)2 (10 mol%), anthranilic acid (30 mol%), AgTFA (10 mol%), TFA (10 eq.), DCE, 60 °C, sealed tube, 24 h. (g) 3a, Pd(OAc)2 (10 mol%), K2S2O8 (2 eq.), MeOH (20 eq.), 3-(trifluoromethyl)aniline (40 mol%), CH2Cl2, 60 °C, sealed tube, 36 h. (h) 3a, NBS (1.5 eq.), Pd(OAc)2 (10 mol%), 2-amino-4-nitrobenzoic acid (50 mol%), AgTFA (10 mol%), TfOH (50 mol%), DCE, 90 °C, sealed tube, 24 h.
Scheme 2
Scheme 2. Synthetic transformation of regioselective peri- and ortho-C–H methylation.
Scheme 3
Scheme 3. Mechanistic studies.
Fig. 2
Fig. 2. (A) The calculated reaction energy profile of palladacycle complex formation steps. (B) IBO analysis of the palladium-assisted peri-C–H activation of TS2.
Fig. 3
Fig. 3. (A) The calculated reaction energy profile of the formation of intermediate 24. (B) IBO analysis of the iridium-assisted ortho-C–H activation of TS3. (C) The calculated reaction energy profile of the formation of product 23.
Scheme 4
Scheme 4. Possible mechanistic pathway.
See this image and copyright information in PMC

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