Photoinduced Olefin Diamination with Alkylamines

Abstract Vicinal diamines are ubiquitous materials in organic and medicinal chemistry. The direct coupling of olefins and amines would be an ideal approach to construct these motifs. However, alkene diamination remains a long‐standing challenge in organic synthesis, especially when using two different amine components. We report a general strategy for the direct and selective assembly of vicinal 1,2‐diamines using readily available olefin and amine building blocks. This mild and straightforward approach involves in situ formation and photoinduced activation of N‐chloroamines to give aminium radicals that enable efficient alkene aminochlorination. Owing to the ambiphilic nature of the β‐chloroamines produced, conversion into tetra‐alkyl aziridinium ions was possible, thus enabling diamination by regioselective ring‐opening with primary or secondary amines. This strategy streamlines the preparation of vicinal diamines from multistep sequences to a single chemical transformation.

Piperidine 1 (12 L, 0.12 mmol, 1.2 equiv.) and the solvent (0.5 mL, 0.2 M, dry and degassed by bubbling through with N2 for 20 min) were added and the mixture was stirred in the dark for 1 h at room temperature. 4-Phenyl-1-butene 10 was added along with an additional 0.5 mL of the same solvent, followed by the acid. The blue LEDs were immediately switched on and the mixture was stirred under irradiation for 1 h.
KOH (1.0 M, 3 mL) and EtOAc (3 mL) were added and the mixture was shaken vigorously. 1,3,5-Trimethoxybenzene (17 mg, 0.1 mmol, 1.0 equiv.) was added and the layers were separated. The aqueous layer was extracted with EOAc (x3), the combined organic layers were dried (MgSO4), filtered and evaporated. CDCl3 (0.4 mL) was added and the mixture was analysed by 1 H NMR spectroscopy to determine the NMR yield.

Protonation of N-Chloropiperidine
A solution on N-chloropiperidine (12 mg, 0.1 mmol, 1.0 equiv.) in CD2Cl2 in a dry NMR tube was treated with the acid (0.6 mmol, 6.0 equiv.) and the sample was immediately analysed by 1 H NMR spectroscopy.
This study demonstrated that AcOH is not able to protonate N-chloropiperidine.

Quantum Yield Determination
The quantum yield was determined using the method reported by Yoon [11] at three different times. Since the reaction is fully complete after 10 s, this indicates  > 200 in CH2Cl2 and supports a radical chain mechanism. All yields were determined by 1 H NMR spectroscopy with 1,3,5-trimethoxybenzene as the internal standard.

Aziridinium Formation
A stock solution of 11 (126 mg, 0.5 mmol, 1.0 equiv.) and 1,3-dinitrobenzene (84 mg, 0.5 mmol, 1.0 equiv.) as the internal standard in CD3CN (2.5 mL) was prepared and was added to five NMR tubes (3 x 500 L): A. Tube 1: nothing else added.   The putative -iodoamine intermediate S13 involved in the formation of 59 was detected by positive ESI MS analysis of the mixture in the NMR tube in the presence of 1% HCOOH (Figure 3).

Aziridinium Ring-Opening
A CD3CN solution of 59 was treated with Et2NH (5.0 equiv.) and an 1 H NMR spectrum was recorded after 5 minutes showing complete conversion into the diamine 60 ( Figure   4).

General Procedure for the Olefin Diamination Using Free Amines -GP3
A dry tube equipped with a stirring bar was charged with NCS (

General Procedure for the Diamination of Styrenes -GP5
A tube equipped with a stirring bar was charged with NCS (1.0 equiv.) and Ru ( h at 0 ºC. The second amine (3.0 equiv.) was added, followed by Na2CO3 (5.0 equiv.).
The mixture was stirred for 1 h at room temperature, then H2O (2 mL) was added and the mixture was shaken vigorously. The layers were separated and the aqueous layer was extracted with CH2Cl2 (x 2). The combined organic layers were dried (MgSO4), filtered and evaporated. Purification by preparative TLC chromatography on silica gave the products.
The blue LEDs were immediately switched on and the mixture was stirred under irradiation at 0 ºC for 1 h. NaOH (1.0 M in MeOH) was added and the mixture was stirred for 1 h at 60 ºC. The mixture was allowed to cool to room temperature, diluted with H2O (10 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. Purification by flash column chromatography or preparative TLC chromatography on silica gel gave the products.

General Experimental Details
The flow process was performed with the set-up shown in (Figure ) on a Masterflex L/R model 77200-60 pump connected with a photochemical 450 nm LED reactor (PennOC photoreactor M1, Figure ) containing Aldtech FT tubing (1.6 mm internal diameter). The calculated volume of solvent in the reactor was 6.66 mL. SI-67

General Flow Procedure
To a 250 mL flask charged with a stirring bar, was added NCS (9.310 g, 70 mmol, 1.0 equiv.), Ru(bpy)3Cl2•6H2O (26.2 mg, 0.35 mmol 0.05 mol%) and CH2Cl2 (120 mL, 0.58 M). The heterogeneous solution was sonicated for 5 minutes until complete solubilisation of NCS, then cooled to 0 °C. 1 (7 mL, 70 mmol, 1.0 equiv.) was then added dropwise over 10 minutes under vigorous stirring. The solution was then allowed to warm to room temperature stirring for 1 h. TFA (32 mL, 420 mmol, 6.0 equiv.) was then added giving a homogeneous bright orange solution which was divided in three fractions. Each fraction was poured in a 100 mL flask (approx. 53 mL of crude in each flask). Prior to the pumping of the reaction, the reactor was fully liquid filled with CH2Cl2 from the solvent reservoir. 10 (31.5 mL, 70 mmol, 1.0 equiv.) was divided in three portions (10.5 mL, 23.33 mmol, 0.33 equiv. each) and added sequentially in each of the three flasks under vigorous stirring, pumping the solution into the system at the end of every addition. Once the entire content of the three flasks was pumped through the reactor (approx. 3-4 minutes into the system), CH2Cl2 was allowed to flush from the solvent reservoir, until all the reaction solution had been collected (approx. 2 minutes). The reaction solution was pumped at 46 mL/min resulting in a theoretical residence time of 8.7 s within the photochemical reactor. The collected homogeneous orange solution was added dropwise over 30 min to a 0 °C solution of 3.5 M sodium hydroxide (200 mL, 10 equiv.). The organic phase was collected, and the aqueous phase extracted with CH2Cl2 (50 mL x 3). The combined organic phases were dried (MgSO4), filtered, and evaporated to give an oil. The crude was then purified by column chromatography on silica gel eluting cyclohexane:EtOAc (9:1) to give 11 as an oil (8.44 g, 48%). Low yield was the result of the partial evaporation of the product under the high vacuum used. The reaction was repeated on the same scale adding 1,3,5trimethoxybenzene as internal standard. The yield in this case was 87% (17 mmol min -1 ).