Copper(II)-Catalyzed Enantioselective Intramolecular Carboamination of Alkenes

The transition-metal mediated intramolecular carboamination of alkenes is a direct method for complex nitrogen heterocycle synthesis. A number of research groups have investigated this transformation in recent years.¹ The catalytic asymmetric carboamination of alkenes is an obvious challenge for these reactions, and has been realized rarely.^1d Herein is described a novel copper(II)-catalyzed asymmetric carboamination reaction that involves intramolecular addition of arylsulfonamides across terminal alkenes to provide chiral sultams. Sultams and sulfonamides are common components of biologically active small molecules.²

The copper-facilitated synthesis of heterocycles via addition of heteroatoms to alkenes and alkynes is an important area in organic synthesis.³ We have recently reported the first copper(II)-facilitated intramolecular carboamination of alkenes, a net oxidative cyclization process (Scheme 1).^1c,f In depth mechanistic studies led us to conclude that the stereochemistry determining C-N bond forming step occurred via syn aminocupration of the alkene (cf. 3 → 5 via 4, Scheme 1).^1f If the copper salt is involved in the stereochemistry-determining step, chiral ligands on copper could allow for a stereocontrolled synthesis of the product. In the proposed C-N bond-forming transition state 4, the substrate occupies two coordination sites on a tetracoordinate copper(II),⁴ leaving two coordination sites available for a bidentate ligand (Scheme 1). Inspired by this analysis, we initiated a search for an appropriate oxidant for copper turnover and ligand for asymmetric induction. Herein is reported the first catalytic as well as catalytic asymmetric variant of this copper(II)-facilitated carboamination reaction.

Scheme 1.

Copper(II)-Promoted Carboamination and Mechanism

In the search for conditions catalytic in copper, we screened a number of oxidants [O₂, PhI(OAc)₂, oxone, Me₃NO, MnO₂],with and without ligands in different solvents for the conversion of 1a to 2a with a catalytic amount (0.2 equiv) of copper(II) ethylhexanoate. The highest conversions were obtained with MnO₂ (3 equiv) as oxidant in trifluorotoluene in the presence of ligands (Table 1). Under the optimized conditions but in the absence of copper(II), no reaction occurs. In toluene, a mixture of carboamination and hydroamination products 2a and 7 was observed (Table 1, entries 3 and 4). We hypothesized the hydroamination product 7 is formed via carbon radical (e.g. 6) capture of a hydrogen atom from solvent. Gratifyingly, changing the solvent to trifluorotoluene substantially decreased formation of the hydroamination adduct (Table 1, entries 5, 6 and 8). The carboamination reactions stoichiometric in copper(II) (cf. Scheme 1) start out blue [due to copper(II)] and terminate as orange-brown heterogeneous mixtures, indicating formation of copper(0), possibly from disproportionation of copper(I) to copper(II) and copper(0). Reoxidation of copper(0) under the mildly basic reaction conditions used in these reactions is challenging. We hypothesized that ligands would stabilize copper(I) and copper(II) in preference to copper(0).³ Addition of diethylsalicylamide 8 (0.2 and 0.8 equiv) increased the reaction yields, likely due to improved copper turnover (Table 1, compare entries 1 and 2 with 3–6).⁵ We changed the copper(II) source to Cu(OTf)₂ to achieve better ligand chelation (entries 6–8). The bipyridine ligand 9 (0.2 equiv) gave more efficient conversion when Cu(OTf)₂ was used (compare entry 6 to 8).

Table 1.

Dependence on Solvent and Ligand^a

entry	R	solvent	ligand (equiv)	yield (%) 2	yield (%) 7
1	EH	PhCH3	--	<5	trace
2	EH	PhCF3	--	7	trace
3	EH	PhCH3	8 (0.2)	41	7
4	EH	PhCH3	8 (0.8)	63	17
5	EH	PhCF3	8 (0.8)	75	<5
6	OTf	PhCF3	8 (0.8)	29	<5
7	OTf	PhCH3	9 (0.2)	59	12
8	OTf	PhCF3	9 (0.2)	60	<5

^aReaction conditions: Substrate 1a was dissolved in solvent (0.1 M) and treated with K₂CO₃ (1 equiv), MnO₂ (3 equiv), CuR₂ (0.2 equiv) and the specified amount of ligand and stirred in a sealed tube at 120 °C for 24 h.

^bYields refer to amount of compound isolated after chromatography on SiO₂. Remainder of material was always unreacted starting 1a. EH = 2-ethylhexanoate.

We screened chiral ligands 10–13 by precomplexing Cu(OTf)₂ (0.2 equiv) with ligand (0.2 equiv) followed by addition of substrate 1a, K₂CO₃ (1 equiv) and MnO₂ (3 equiv) and heating in a sealed tube for 24 h in PhCF₃ (Table 2).

Table 2.

Chiral Ligand Screening^a

entry	equiv Cu(OTf)2	ligand (equiv)	yield (%)	%eec	ERc
1	0.2	(R,R)-10a (0.2)	54	24	62:38
2	0.2	(S,S)-10b (0.2)	53	14	43:57
3	0.2	(S,S)-10c (0.2)	73	28	36:64
4	0.2	(S,S)-11a (0.2)	75	86	7:93
5	0.2	(R,R)-11a (0.2)	85	92	96:4
6	0.2	(S,S)-11b (0.2)	50	24	38:62
7	0.2	(R,R)-11c (0.2)	55	82	91:9
8	0.2	(R,S)-12 (0.2)	<5	--	--
9	0.2	(R,R)-13 (0.2)	18	4	48:52
10	0.15	(R,R)-11a (0.15)	64	92	96:4
11	0.05	(R,R)-11a (0.05)	34	--	--
12d	0.2	(R,R)-11a (0.2)	72	94	97:3

^aReaction conditions: Cu(OTf)₂ and ligand were combined, dissolved in PhCF₃ (0.1 M w/r to 1a) and heated at 50 °C for 1 h. Substrate 1a, MnO₂ (3 equiv) and K₂CO₃ (1 equiv) were added and the reaction tube sealed and heated at 120 °C for 24 h unless otherwise noted.

^bYield refers to amount of isolated 2a after purification by flash chromatography on SiO2.

^cEnantiomeric excess and ratios were determined by chiral HPLC analysis (chiralcel OD-H).

^dReaction was run at 110 °C.

We quickly found that 2,2-bis[(4R)-4-phenyl-2-oxazolin-2-yl]propane (11a) gave the highest asymmetric induction, providing carboamination adduct 2a in 85% isolated yield, 92% enantiomeric excess (Table 2, entry 5). We were unable to reduce the catalyst loading below 0.2 equiv without adversely affecting the product yield (Table 2, entries 10 and 11). Lowering the reaction temperature to 110 °C provided the product in slightly lower yield (72%) and 94% enantiomeric excess (Table 2, entry 12). Ligands 12 and 13 rendered the copper(II) complex less reactive (entries 8 and 9).

The generality of the reaction was examined as shown in Table 3. γ-Alkenyl arylsulfonamides 1 cyclized in 45–85% yield and 80–94% ee.⁶ The 2-sulfamido thiophene substrate 1 4 reacted very sluggishly but with good enantioselectivity. N-Tosyl-2-allylaniline 16 reacted efficiently but with low (46%) enantioselectivity and N-tosyl-2-allylbenzylamine 18 reacted sluggishly and in moderate yield and enantioselectivity to provide tetrahydroisoquinoline 19 (entry 12).

Table 3.

Scope of Enantioselective Carboamination with (R,R)-11a^a

entry	substrate	product	yield (%)b	ee (%)c	ERc
1	1a, R1 = Me, R2 = Me	2a	85	92	96:4
2	1b, R1= Me, R2 = H	2b	73	92	96:4
3	1c, R1= Me, R2 = Cl	2c	45	92	96:4
4	1d, R1= Me, R2 = OMe	2d	75	94	97:3
5	1e, R1= Ph, R2 = Me	2e	78	94	97:3
6	1f, R1 = -CH2(CH2)2CH2-, R2= Me	2f	83	92	96:4
7	1g, R1= -CH2(CH2)3CH2-, R2 = Me	2g	68	92	96:4
8	1h, R1= H, R2 = Me	2h	68	80	90:10
9	1i, R1 = H, R2= H	2i	77	82	91:9
10d	14	15	30	86	93:7
11	16	17	75	46	73:27
12d	18	19	63	72	86:14

^aReaction conditions: Cu(OTf)₂ (0.2 equiv) and (R,R)-11a (0.2 equiv) were combined and treated with PhCF₃ (0.1 M w/r to substrate) and heated at 50 °C for 1h. Substrate (1 equiv), MnO₂ (3 equiv) and K₂CO₃ (1 equiv) were added and the reaction tube was sealed and heated at 120 °C for 24 h unless otherwise noted. All reactions were run at least two times to ensure reproducibility.

^bYields refer to amount isolated after purification by flash chromatography on SiO₂.

^cEnantiomeric excess and ratios were determined by chiral HPLC anlaysis (chiralcel OD-H or AD-RH).

^dReactions were run for 96 h.

X-Ray crystal structures of sultams 2g and 15 indicate the (S)-configuration. The other carboamination adducts in Table 3 are assigned the S stereochemistry by analogy. Sultam 2i was converted to the known 2(S)-benzylpyrrolidine 20,⁷ an intermediate used in the synthesis of a potent calcium-sensing receptor antagonist,⁸ by reductive removal of SO₂ (Scheme 2). Pyrrolidine (S)-20 is thus available by this method in three steps from commercially available starting materials (see Supporting Information for complete details).

Scheme 2.

Transition State Model and Removal of SO₂

The observed stereochemistry is consistant with transition state A (Scheme 2), where the substrate’s N-substituent is on the face opposite of the oxazoline phenyl substituent it is cis to about the distorted square planar copper center.⁴

The method reported herein provides access to enantiomerically enriched nitrogen heterocycles. Applications of this reaction toward the synthesis of bioactive compounds are underway. This method will also inspire the development of other copper(II)-catalyzed enantioselective amination reactions.

Supplementary Material

1si20070816_09. Supporting Information Available.

Experimental procedures, compound characterization data, X-ray structures with determination of absolute configuration and HPLC traces with determination of enantiomeric excess. This material is available free of charge via the Internet at http://pubs.acs.org.