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. 2024 May 23;14(24):16784-16800.
doi: 10.1039/d3ra08974f. eCollection 2024 May 22.

C(sp3)-H cyclizations of 2-(2-vinyl)phenoxy- tert-anilines

Petra Dunkel  1 , Dóra Bogdán  1 , Ruth Deme  1 , Ádám Zimber  1 , Veronika Ballayová  1   2 , Eszter Csizmadia  1 , Bence Kontra  1   3 , Eszter Kalydi  1 , Attila Bényei  4 , Péter Mátyus  1   5 , Zoltán Mucsi  3   6   7
Affiliations

C(sp3)-H cyclizations of 2-(2-vinyl)phenoxy- tert-anilines

Petra Dunkel et al. RSC Adv. .

Abstract

1,5-hydride transfer-triggered cyclization reactions offering a robust method for C(sp3)-C(sp3) coupling and the synthesis of e.g. tetrahydroquinolines have been thoroughly investigated in the literature. Catalysts allowing milder reaction conditions or the development of enantioselective processes were important recent contributions to the field, as well as the studies on subtrates with oxygen or sulfur heteroatoms (besides the originally described nitrogen heterocycles). In a series of studies, we focused on expanded, higher order H-transfers/cyclizations by positioning the interacting substituents on distanced rings. Cyclizations of appropriately functionalized biaryl and fused bicyclic systems led to 7-9 membered rings. In the frame of this research, we set out to study the feasibility of the cyclization and the factors affecting it by in silico methods. The conclusions drawn from computational studies were complemented by cyclization screens on 2-(2-vinyl)phenoxy-tert-anilines and their CH2-expanded analogues, the results of which are presented here. Besides isolating the expected oxazonine products in several cases, we also observed a unique dimer formation, leading to an interesting 5-6-5 ring system.

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Conflict of interest statement

There are no conflicts of interest to declare.

Figures

Scheme 1
Scheme 1. Typical [1,5]-H transfer/cyclization of 2-vinyl-N,N-dialkylanilines (1; “tert-amino effect”) and its potential variants.
Scheme 2
Scheme 2. Examples for enantioselective and sequential [1,5] hydride transfer/cyclization processes.
Scheme 3
Scheme 3. Higher order H-transfer/cyclization processes (ring-VII–X), resulting in larger ring sizes.
Scheme 4
Scheme 4. Preparation and cyclization of 2-(2-vinyl)phenoxy-tert-anilines (14a–i) to oxazonine products (15a–i). Reaction conditions: 14a–c: CH2(CN)2, EtOH, rt; 14d–f: CNCH2CO2Et, EtOH, rt; 14g–i: CH2(CO2Et)2, toluene, reflux; 14a (71%); 14b (65%); 14c (35%); 14d (73%); 14e (86%); 14f (80%); 14g (60%); 14h (65%); 14i (48%); 15a (27%); 15b (21%); 15d (28%); 15c,e–i (n.d).
Fig. 1
Fig. 1. X-ray structure of 14c and 15a.
Fig. 2
Fig. 2. 1H NMR monitoring of the cyclization (5 mg 14b in 0.5 mL DMSO-d6, 100 °C, NMR spectra taken at the indicated time points, the 30 min spectrum showing full conversion).
Scheme 5
Scheme 5. (A) Products 15b and 23 formed upon heating a more concentrated (1 g/10 mL) DMSO solution of 14b (MW, 100 °C, 15 min). (B) Dimer product obtained from 14h.
Scheme 6
Scheme 6. Reaction mechanism proposed for the formation of the octahydro-dipyrroloquinoline derivative 23 (orange) in comparison with the formation of 15b (blue) and the calculated enthalpies for the possible reaction pathways (14b → 15b or 14b → 23). The related enthalpy values can be seen in Fig. S10.
Scheme 7
Scheme 7. Natural products containing an octahydro-dipyrroloquinoline scaffold.
Scheme 8
Scheme 8. Preparation and cyclization of halo-substutited 2-(2-vinyl)phenoxy-tert-anilines (31a–f) to oxazonine products (32a–f). Reaction conditions: 31a,c,e: CH2(CN)2, EtOH, rt; 31b,d,f: CNCH2CO2Et, EtOH, rt; 31a (48%); 31b (46%); 31c (67%); 31d (60%); 31e (72%); 31f (65%); 32a (35%); 32b (n.d.); 32c (25%); 32d (30%); 32e (62%) 32f (21%).
Scheme 9
Scheme 9. The synthesis of –CH2–O-bridged vinyl derivatives.
Scheme 10
Scheme 10. Comparison of sigmatropic rearrangement and ionic reactions.
Fig. 3
Fig. 3. Calculated solvent dependence of the TSs and the formation of intermediate 43 in various solvents as a function of (ε − 1)/(2ε + 1) at B3LYP/6-31G(d,p)//PCM(solvent) level of theory.
Fig. 4
Fig. 4. Simplified reaction mechanism of the cyclization of compounds 1a–e. Calculated enthalpies of TS(1a–e), the formation of intermediate 43a–e, and products 2a–e at B3LYP/6-31G(d,p)//PCM(DMSO) level of theory.
Fig. 5
Fig. 5. Calculated enthalpies of TS(1a) and TS(1f–q), the formation of intermediate 43a and 43f–q as well as 1a and 1f–q at B3LYP/6-31G(d,p)//PCM(DMSO) level of theory. The effect of the EWG group on the cyclization [B3LYP/6-31G(d,p)//PCM(DMSO)]. The colour code of the cells illustrates the potential of the reactions. Dark green and green cells are feasible, white cells are in the edge of the feasibility, while light red and red cells refer to the forbidden reactions.
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