(4+3) Annulation of Donor-Acceptor Cyclopropanes and Azadienes: Highly Stereoselective Synthesis of Azepanones

Abstract

Azepanes are important seven-membered heterocycles, which are present in numerous natural and synthetic compounds. However, the development of convergent synthetic methods to access them remains challenging. Herein, we report the Lewis acid catalyzed (4+3) annulative addition of aryl and amino donor-acceptor cyclopropanes with 2-aza-1,3-dienes. Densely substituted azepane derivatives were obtained in good to excellent yields and with high diastereoselectivity. The reaction occurred under mild conditions with ytterbium triflate as the catalyst. The use of copper triflate with a trisoxazoline (Tox) ligand led to an enantioselective transformation. The obtained cycloadducts were convenient substrates for a series of further modifications, showing the synthetic utility of these compounds.

Keywords: Azadienes; Azepanones; Cycloadditions; Cyclopropanes; Tox-Ligands.

Scheme 1

(4+3) Annulations for the synthesis of: A) benzoazepines; B) Seven‐membered carbocycles; C) Saturated azepanes scaffolds (This work).

Scheme 2

Preliminary investigation of the (4+3) annulation using azadiene 1.

Scheme 3

Scope of the reaction. A) Product 5 a.a, obtained from model substrate 2 a and azadiene 4 a; X‐Ray diffraction of 5 a.a. B) Products obtained from diverse (hetero)aryl and alkenyl DACs 2. C) Products obtained from diverse azadienes 4. D) Products obtained from cyclopropanes containing a phthalimide (4 l) or a thymine (4 m) substituent. General conditions: 0.20 mmol (1.0 equiv) cyclopropane 2, 0.30 mmol (1.5 equiv) azadiene 4, 20 mol % Yb(OTf)₃, 140–150 mg 3 Å MS, DCM (0.1 M), RT, overnight. [a] Performed on 0.10 mmol scale. [b] Average yield over two reiterations. [c] With 0.50 mmol (2.5 equiv) azadiene 4 a.

Scheme 4

Scope of the enantioselective version of the (4+3) annulation. General conditions: 0.10 mmol (1.0 equiv) cyclopropane 2, 0.15 mmol (1.5 equiv) azadiene 4, 20 mol % Cu(OTf)₂, 22 mol % (S)‐CyTox (L5), 60–70 mg 3 Å MS, Toluene (0.6 mL)/DCM (0.4 mL), RT, overnight. [a] Performed on 0.6 mmol scale. [b] 10 mol % Cu(OTf)₂, 11 mol % (S)‐CyTox (L5).

Scheme 5

Modification of products 5. Reaction conditions: a) 1. H₂, Pd/C (10 mol %), MeOH/EtOAc (1/1); 2. Cu₂O, MeCN, 80 °C. b) 4‐CzIBn (5 mol %), Ph‐EBX (1.5 equiv), Cs₂CO₃ (1.5 equiv), DCM, 25 °C, Kessil lamp (440 nm). c) 1. 2‐Mercaptopyridine N‐oxide (1.25 equiv), EDCI⋅HCl (2.0 equiv), DMAP (20 mol %), DCM, 0–25 °C; 2. ⁿBu₃SnH (3.0 equiv), AIBN (10 mol %), toluene, 80 °C. Yield provided over 2 steps. d) LiAlH₄ (2.5 equiv), THF, 75–50 °C. e) 1. NaH (1.2 equiv), MeI (3.0 equiv), DMF/THF, 0 to 25 °C; 2. Me₃OBF₄ (3.0 equiv), 2,6‐di‐tertBu‐Py (3.3 equiv), DCM, 25 °C then NaBH₄ (10 equiv) and MeOH, 0 °C. f) Ethylenediamine (5.0 equiv), DCM/MeOH, 38 °C.