Enantio- and Regioselective CuH-Catalyzed Hydroamination of Alkenes

Abstract

A highly enantio- and regioselective copper-catalyzed hydroamination reaction of alkenes has been developed using diethoxy(methyl)silane (DEMS) and esters of hydroxylamines. The process tolerates a wide variety of substituted styrenes, including trans-, cis-, and β,β-disubstituted styrenes to yield α–branched amines. In addition, aliphatic alkenes coupled to generate exclusively the anti-Markovnikov hydroamination products.

Hydroamination, the direct formation of a C-N bond by the formal addition of an amine to an alkene, is a powerful synthetic procedure with the potential to gain access to amine products which are widely featured in pharmaceutically active compounds.¹ Although great progress has been made in the field of late transition metal-catalyzed hydroamination,² several challenges still exist. For example, the intermolecular process requires activated alkenes such as vinyl arenes.^2a,i,h or acrylic acid derivatives,^2c while asymmetric variants are limited to the addition of aryl amines to simple β-unsubstituted styrene derivatives and achieve only moderate levels of enantiomeric excess.^2a,3 In addition, there are limited methods available to obtain the anti-Markovnikov product in hydroamination reactions of aliphatic amines.⁴ Thus, there remains a need for the development of asymmetric hydroamination reactions that tolerate a wide variety of substitution patterns on the alkene component and proceed with high regio- and enantioselectivity.

Over the last decade, our laboratory has reported several examples of asymmetric reactions involving copper-hydride (CuH) intermediates.^5a.e We postulated that this CuH strategy could serve as a platform for the hydroamination of alkenes (Eq. 1). In our approach for asymmetric intermolecular hydroamination, we propose that insertion of an alkene (1, 4) into a chiral ligand-bound LCu(I)H species (I) would form an alkyl-copper complex (II) (Figure 1).⁶ Sub-sequent oxidative addition of an electrophilic amine source, such as a hydroxylamine 2,⁷ followed by reductive elimination, would form the C-N bond enantioselectively. The copper (I) species generated would then undergo transmetalation with an external hydride-transfer reagent to reform I.¹⁰ This mechanism (Figure 1) comes in a straightforward manner from a combination of our previous work in two are-as.^5a,11 Herein, we report a mild copper-catalyzed hydroamination strategy using a chiral copper catalyst with a broad substrate scope. We note that toward the end of our work, a paper describing a method similar to the first portion (asymmetric) of this chemistry by Hirano and Miura was reported. ^2a

Figure 1.

Proposed catalytic cycle for CuH catalyzed hydroamination of alkenes

We began our investigation by attempting the hydroamination of styrene (1a) using readily available Cu(OAc)₂ and easily accessible O-benzoylhydroxylamine 2a (Table 1). Various ligands and hydride-transfer reagents were tested. We were able to achieve the desired cross-coupled products in up to 74% ee using polymethylhydrosiloxane (PMHS) or diethoxymethylsilane (DEMS) in conjunction with the commercially available ligand BINAP (L1) (entries 2-3). DEMS generated the desired product in the highest yield (entry 3), and thus was chosen as the hydride transfer reagent of choice in the examination of other chiral ligands (entries 4-8). We were able to realize up to 97% ee when using (R)-DTBM-SEGPHOS (L5) as the ligand (entry 7). Further optimization revealed that the reaction proceeds with low catalyst loading (2 mol%) at 40 °C (entry 8), without diminishing the yield or enantioselectivity. The reaction exclusively generated an α-branched amine, which is consistent with the proposed catalytic cycle (Figure 1) because the hydride migration from the copper catalyst to the alkene would generate the more stable α-bond Cu species.¹²

Table 1. Reaction Optimization.

Entry	Cu(OAc)2	Hydride Reagent	L	Yield 4aa	ee
1	10 mol%	HBpin	L1	2%	ndb
2	10 mol%	PMHS	L1	40%	741%
3	10 mol%	DEMS	L1	64%	73%
4	10 mol%	DEMS	L2	83%	65>%
5	10 mol%	DEMS	L3	99%	95>%
6	10 mol%	DEMS	L4	99%	79%
7	10 mol%	DEMS	L5	99%	97%
8c	2 mol%	DEMS	L5	97%	97%

^aGC yields with dodecane as the internal standard.

^bNot determined.

^cReaction was carried out at 40 °C.

With an optimized protocol in hand, we then explored the substrate scope with respect to the styrene component (Table 2). This hydroamination tolerates a variety of substituents on the aryl ring of styrene (3b-g). The reaction also works efficiently with both trans- and cis-β-substituted styrenes (3h-o). Even hindered β,β-disubstituted styrenes undergo hydroamination in high yield and ee in this reaction (3p-q). Notably, the hydroamination of β,β-disubstituted styrene 1q gave the product 3q as a single diastereomer.

Table 2. Scope of Different Styrene Derivatives ^a.

^alsolated yields (average of two runs). 2 (1 mmol), O-benzoyl-N,N-dibenzylhydroxylamine (1.2 mmol), Cu(OAc)₂ (2 mol %), (R-DTBM-SEGPHOS (2.2 mol %), DEMS (2 mmol), THF (0.5 M), 40 °C, up to 36 h.

^bCu(OAc)₂ (4 mol %), (R-DTBM-SEGPHOS (4.4 mol %).

^CTHF (1 M).

We next explored the use of other amine electrophiles in this reaction. We found that this reaction is applicable to several alkyl- and dialkyl-N-OBz amines (Table 3). N-(OBz)azepane and other heterocyclic-N-OBz amines also furnished the respective hydroamination products in high yields and enantioselectivities.

Table 3. Scope of Amine Electrophiles with Styrene ^a.

^alsolated yields (average of two runs). 2 (1 mmol), hydroxyla-mine (1.2 mmol), Cu(OAc)₂ (2 mol %), (R-DTBM-SEGPHOS (2.2 mol %), DEMS (2 mmol), THF (1 M), 40 °C, up to 36 h.

^bTHF (0.5 M).

Since hydroamination of unactivated alkenes remains a challenge, we examined whether the developed protocol would be applicable with aliphatic alkenes.^4b We found that terminal aliphatic alkenes could be effectively hydroaminated under the same conditions (Tables 4 and 5). In every case, the reaction exclusively produces the anti-Markovnikov products. Like the reaction with styrene, this protocol tolerated alkenes containing a primary alkyl bromide (5c), an epoxide (5g), and was compatible with alkenes containing a tosylamine (5d), an amide (5e), a pyridine (5f), a tert-butyldimethylsilyl ether (5i), and ones with geminal substituents (5h-i). Additionally, a number of amine electrophiles, including the sterically hindered tetramethylpiperidine N-OBz (5m), cross-coupled efficiently. Our hypothesis for the observed selectivity for the anti-Markovnikov products is that the hydride migration from the copper catalyst proceeds to form the less sterically crowded terminal copper intermediate (Scheme 1); here there is no electronic advantage as for styrenes to form the 2°-alkyl-Cu intermediate. Oxidative addition of the hydroxylamine and subsequent reductive elimination would generate the un-branched tertiary amines.

Table 4. Hydroamination of Terminal Aliphatic Al-kenes^a.

^aIsolated yields (average of two runs). 2 (1 mmol), O-benzoyl-N,N-dibenzylhydroxylamine (1.2 mmol), Cu(OAc)₂ (2 mol %), (±)-DTBM-SEGPHOS (2.2 mol %), DEMS (2 mmol), THF (0.5 M), 40 °C, up to 36 h.

^bTHF (1 M).

Table 5. Scope of Amine Electrophiles with 4-Phenyl-1-butene^a.

^aIsolated yields (average of two runs). 2 (1 mmol), hydroxyla-mine (1.2 mmol), Cu(OAc)₂ (2 mol %), (±)-DTBM-SEGPHOS (2.2 mol %), DEMS (2 mmol), THF (0.5 M), 40 °C, up to 36 h.

^bCu(OAc)₂ (4 mol %), (±)-DTBM-SEGPHOS (4.4 mol %) were used.

As a demonstration of the robustness and practicality of this method, it was carried out at 10 mmol scale (Scheme 2) using the β-substituted styrene ((E)-(3-methoxyprop-1-en-1-yl)benzene) as β-substituted styrenes are known to be difficult substrates in asymmetric hydroamination reactions.³ We were able to lower the catalyst loading to 1 mol% with no decrease in the yield or enantioselectivity.

Scheme 1.

Anti-Markovnikov Hydroamination of Aliphatic Alkene

In summary, we have reported a mild method for synthesizing chiral tertiary amines by employing an asymmetric copper-catalyzed hydroamination. Substitution occurs in a regioselective manner to generate a C-N bond at the α-position of styrene derivatives. This method has been shown to be compatible with various substituted styrene derivatives, and styrenes with β–substitution. Additionally, this method allows the development of copper-catalyzed anti-Markovnikov hydroaminations of terminal aliphatic alkenes. We are currently investigating the asymmetric version of internal aliphatic alkene hydroamination, which will be reported in due course.

Scheme 2.

Large-scale Hydroamination Reaction of β-substituted Styrene