Expedient access to saturated nitrogen heterocycles by photoredox cyclization of imino-tethered dihydropyridines

This work describes an expedient access to sp3-rich nitrogen heterocycles via mild photoredox cleavage of 4-alkyl-1,4-dihydropyridines followed by cyclization of the resultant carbon-centered radicals with tethered imines.


General Procedure B: Morpholine-Forming Amino-DHP Reagents (Step 2)
Sodium hydride (60% in mineral oils, pre-washed with pentane, 2.0 equiv.) was placed in an oven-dried two-necked flask, evacuated and placed under a nitrogen atmosphere. Anhydrous THF (0.3 M) was then added, and the solution was cooled down to 0 °C. Next, dibenzyl-protected amino-alcohol 1 in anhydrous THF was added dropwise, and the resultant solution was warmed up to room temperature and stirred for 3 h. The reaction mixture was cooled down to 0 °C, and DMAP (0.02 equiv.), tetrabutylammonium iodide (0.1 equiv.), and 2- To a cooled (0 °C) solution of dibenzyl-protected acetal 2 (1.0 equiv.) in THF (0.3 M) was added aqueous 6 N HCl (10 equiv.). The reaction mixture was warmed up to room temperature and stirred for 7 h. Upon completion, the reaction was quenched with saturated aqueous NaHCO 3 at 0 °C, and methylene chloride was added. The aqueous layer was extracted with methylene chloride, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure, yielding dibenzyl-protected aldehyde product 3. The crude product was used in the next step as such, without further purification.

Hantzsch esters
A mixture of aldehyde 3 (1.0 equiv.), ethyl acetoacetate or 3-oxobutanenitrile (1.0 equiv.), ethyl 3aminocrotonate or 3-aminocrotononitrile (1.0 equiv.), and trifluoroacetic acid (1.1 equiv.) in diglyme (0.3 M) was heated to 95 °C and stirred overnight. Upon completion, the reaction was cooled down to room temperature, quenched with aqueous NaHCO 3 , and ethyl acetate was added. Next, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was then purified by silica gel flash chromatography (eluent: n-heptane/EtOAc 4:1 v/v). Pure fractions were combined and concentrated under reduced pressure, yielding dibenzyl-protected DHP product 4.
Next, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was then purified by silica gel flash chromatography (eluent: n-heptane/EtOAc 4:1 v/v). Pure fractions were combined and concentrated under reduced pressure, yielding dibenzyl-protected DHP product 4.

General Procedure F: Morpholine-Forming Amino-DHP Reagents (Step 5)
A suspension composed of dibenzyl-protected amino-DHP 4 (1.0 equiv.) and Pd/C (0.1 equiv.) in absolute ethanol (0.1 M) was evacuated and backfilled with hydrogen gas. The reaction mixture was then pressurized at 3 bar, and stirred at room temperature for 4-6 h. Upon completion, the mixture was filtered through a Celite plug, and the filtrate was concentrated under reduced pressure. Next, the crude product was purified by reverse-phase flash chromatography (C18, eluent: water/MeCN 3:2 v/v with 0.1% NH 4 OH as modifier). Pure fractions were combined and evaporated under reduced pressure. Lyophilization yielded pure, dry amino-DHP reagent 5.

General Procedure G: Thiomorpholine-and Piperazine-Forming Amino-DHP Reagents (Step 1)
To a two-necked round-bottomed flask with a Dean-Stark apparatus attached were added: primary amine 6 (1.0 equiv.), Et 3 N (3.5 equiv.), phthalic anhydride (1.0 equiv.), and anhydrous toluene (0.1 M). The reaction mixture was then refluxed for 2 days. Upon completion, the solution was cooled down to room temperature, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (eluent: To a cooled (0 °C) solution of Boc-protected pyrrolidino amine 8 (1.0 equiv.) in anhydrous CH 2 Cl 2 (0.25 M) was added trifluoroacetic acid (50 equiv.) dropwise over 10 min. After an additional 15 min of stirring at 0 °C, the reaction mixture was warmed up to room temperature and stirred for 6 h. The mixture was then concentrated under reduced pressure and then lyophilized, yielding the trifluoroacetate salt of free pyrrolidine 9.

General Procedure I: Thiomorpholine-Forming Amino-DHP Reagents (Step 2)
To a solution composed of phthalimide-protected thiol 7 (1.0 equiv.), tetrabutylammonium iodide (0.1 equiv.), and potassium carbonate (2.05 equiv.) in anhydrous MeCN (0.5 M) was added 2-bromo-1,1dimethoxyethane (2.05 equiv.). The reaction mixture was heated to reflux for 18-20 h, and then concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (eluent: n-heptane/EtOAc 4:1 v/v). Pure fractions were combined and concentrated under reduced pressure, yielding phthalimide-protected thioether acetal 10.

S13
chloride. The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (eluent: n-heptane/EtOAc 4:1 v/v first to remove the bis-alkylation byproduct, followed by CH 2 Cl 2 /MeOH 95:5 v/v to elute the desired mono-alkylation product). Pure fractions were combined and concentrated under reduced pressure, yielding phthalimide protected amino-acetal 11.

General Procedure K: Piperazine-Forming Amino-DHP Reagents (Step 3): p-Tosyl Piperazines
A solution of phthalimide protected amino-acetal 11 (1.0 equiv.) and Et 3 N (1.3 equiv.) in anhydrous CH 2 Cl 2 (0.3 M) was cooled down to 0 °C. Next, p-toluenesulfonyl chloride (1.3 equiv.) was added in one portion, and the resultant mixture was stirred at 0 °C for 15 min. The reaction mixture was then brought to room temperature and stirred for 14 h. The crude mixture was loaded directly onto silica gel and purified by silica gel flash chromatography (eluent: n-heptane/EtOAc 4:1 v/v). Pure fractions were combined and concentrated under reduced pressure, yielding p-tosyl protected amino-acetal 12.
Pure fractions were combined and concentrated under reduced pressure, yielding Cbz protected amino-acetal 13.

General Procedure M: Thiomorpholine-and Piperazine-Forming Amino-DHP Reagents (Step 4)
To a cooled (0 °C) solution of phthalimide-protected acetal 10, 12, or 13 (1.0 equiv.) in THF (0.3 M) was added aqueous 6 N HCl (10 equiv.). The reaction mixture was warmed up to room temperature and stirred for 7 h. Upon completion, the reaction was quenched with saturated aqueous NaHCO 3 at 0 °C, and methylene chloride was added. The aqueous layer was extracted with methylene chloride, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure, yielding phthalimide-protected aldehyde product 14, 15, or 16. The crude product was used in the next step as such, without further purification.

General Procedure O: Thiomorpholine-and Piperazine-Forming Amino-DHP Reagents (Step 6)
To a solution of phthalimide-protected DHP 17, 18, or 19 (1.0 equiv.) in absolute methanol (0.3 M) was added hydrazine (50% w/w aqueous solution, 10 equiv.). The reaction mixture was heated to 50 °C and stirred for 9-12 h. The mixture was then filtered through a Celite plug, and the filtrate was concentrated under reduced pressure. Next, the crude product was purified by reverse-phase flash chromatography (C18, eluent: water/MeCN 3:2 v/v with 0.1% NH 4 OH as modifier). Pure fractions were combined and evaporated under reduced pressure. Lyophilization yielded pure, dry amino-DHP reagent 20, 21, or 22.

General Procedure P: Metal Phosphate Salts
An oven-dried scintillation vial was charged with either dibutyl phosphate 23 or diphenyl phosphate 24 (1.0 equiv.) and absolute ethanol (0.5 M) under a nitrogen atmosphere. Next, either LiOEt (1.0 M solution in ethanol, 1.0 equiv.), Ca(OMe) 2 (1.0 equiv.), or Mg(Ot-Bu) 2 (1.0 equiv.) was added in one portion. The reaction mixture was then heated to 50 °C and stirred for 6 h. After cooling down to room temperature, the solution was concentrated under reduced pressure, yielding the various metal phosphate salts as off-white solids.

Characterization of Starting Materials Complete List of Synthesized Amino-DHP Reagents
Scheme S2. List of synthesized amino-DHP reagents.