Manipulations of phenylnorbornyl palladium species for multicomponent construction of a bridged polycyclic privileged scaffold

Abstract

Hexahydromethanocarbazole is a privileged scaffold in the discovery of new drugs and photoactive organic materials due to its good balance between structural complexity and minimized entropy penalty upon receptor binding. To address the difficulty of synthesizing this highly desirable bridged polycyclic scaffold, we designed a convenient multicomponent reaction cascade as intercepted Heck addition/C-H activation/C-palladacycle formation/electrophilic attack of ANP/N-palladacycle formation/Buchwald amination. A distinguishing feature of this sophisticated strategy is the successive generation of two key phenylnorbornyl palladium species to control the reaction flow towards desired products. DFT calculations further reveal the crucial roles of Cs₂CO₃ and 5,6-diester substitutions on the norbornene reactant in preventing multiple side-reactions. This innovative method exhibits a broad scope with good yields, and therefore will enable the construction of natural-product-like compound libraries based on hexahydromethanocarbazole.

Fig. 1. Presence of Hexahydromethanocarbazole.

Hexahydromethanocarbazole moieties present in natural products, materials, solar cells, and potential therapeutic compounds.

Fig. 2. Strategies and methods in synthesizing hexahydro-1,4-methanocarbazole ring.

Traditional methods involved palladium-catalyzed direct condensation, or electrophilic insertion by external amine surrogates. In contrast, “detour” strategy in this work employed successive generation of two key phenylnorbornyl palladium species to construct the hexahydro-1,4-methanocarbazole core and introduce 5-substitution in tandem. Ligands to Pd^II, and electrophile-Pd^IV complexes were omitted when illustrating for the sake of clarity.

Fig. 3. Initial investigations on NBE analogs capable of ortho C(sp²)-H activation to synthesize the 5-substituted hexahydro-1H-1,4-methanocarbazoles.

Reaction conditions: 2-iodo-N-methylaniline (1.0 eq.), NBE analog (1.0 eq.), morpholino benzoate (1.3 eq.), Pd(OAc)₂ (5% eq.), PPh₃ (10% eq.), NaOtBu (2.5 eq.), acetonitrile, 100 ^oC, 12 h.

Fig. 4. Influences of NBE substitutions in synthesizing the corresponding 5-substituted hexahydro-1H-1,4-methanocarbazoles.

Reaction conditions: 2-iodo-N-methylaniline (1.0 eq.), NBE analog (1.0 eq.), morpholino benzoate (1.3 eq.), Pd(OAc)₂ (5% eq.), TFP (10% eq.), Cs₂CO₃ (2.5 eq.), toluene, 100 ^oC, 12 h.

Fig. 5. Generation of 5-substituted hexahydro-1H-1,4-methanocarbazoles with various electrophiles.

Reaction conditions: ^[a]2-iodo-N-methylaniline (1.0 eq.), NBE-5,6-diCOOiPr (1.0 eq.), N-benzoyloxyamine (1.3 eq.), Pd(OAc)₂ (5% eq.), TFP (10% eq.), Cs₂CO₃ (2.5 eq.), toluene, 100 ^oC, 12 h; ^[b]arylbromide (1.3 eq.), and DMF were used instead; ^[c]n-pentylbromide (1.3 eq.), PPh₃ (10% eq.), and DMF were used instead; ^[d] benzoic anhydride (1.3 eq.), PdCl₂ (5% eq.), and DME were used instead.

Fig. 6. Compatibility of substituents on 2-iodo-N-methylaniline.

Reaction conditions: substituted 2-iodo-N-methylaniline (1.0 eq.), NBE-5,6-diCOOiPr (1.0 eq.), morpholino benzoate (1.3 eq.), Pd(OAc)₂ (5% eq.), TFP (10% eq.), Cs₂CO₃ (2.5 eq.), toluene, 100 ^oC, 12 h.

Fig. 7. Influence of N-substituents on the production of 5-substituted hexahydro-1H-1,4-methanocarbazoles.

Reaction conditions: N-substituted 2-iodoaniline (1.0 eq.), NBE-5,6-diCOOiPr (1.0 eq.), morpholino benzoate (1.3 eq.), Pd(OAc)₂ (5% eq.), TFP (10% eq.), Cs₂CO₃ (2.5 eq.), toluene, 100 ^oC, 12 h.

Fig. 8. Computed free energy profile of Int_V → V → by-product 1a and 1b.

Intermediates and transit states with 5,6-diCOOiPr were illustrated in dark red, while unsubstituted ones were illustrated in black. The energies are given in kcal/mol.

Fig. 9. Computed free energy profile of Int_I → TS1 → II.

Intermediates and transit states with 5,6-diCOOiPr were illustrated in dark red, while unsubstituted ones were illustrated in black. The energies are given in kcal/mol.

Fig. 10. Transition state structures TS1 and TS1(a).

Transition state structures of the Cs₂CO₃-induced C-H activation through a concerted metalation–deprotonation process to result in II and II(a). A With 5,6-diCOOiPr NBE (barrier height 20.5 kcal/mol), where a coordination between Cs and carbonyl O was observed, and B With the unsubstituted NBE (barrier height 22.6 kcal/mol). Different orientations of TFP were noted.