Ligand Controlled Ir-Catalyzed Regiodivergent Oxyamination of Unactivated Alkenes

Abstract

An intramolecular Ir(III)-catalyzed regiodivergent oxyamination of unactivated alkenes provides valuable γ-lactams, γ-lactones and δ-lactams. The regioselectivity is controlled by the electronically tunable cyclopentadienyl Ir(III)-complexes enabling oxyamination via either 5-exo or 6-endo pathways. With respect to the mechanism, we propose a highly reactive [3.1.0] bicycle intermediate derived from Ir(V) nitrene-mediated aziridination to be a key intermediate toward the synthesis of γ-lactams.

Graphical Abstract

Regio- and stereoselective alkene oxyamination is attractive as a strategic synthetic disconnect¹ because of the abundance of vicinal N, O motifs in biologically active natural products and pharmaceuticals and the wide availability of alkene precursors. Inspired by Sharpless’ pioneering asymmetric amino-hydroxylation reaction,² extensive effort has been made using transition-metal catalysis involving Os,³ Cu,⁴ Pd,⁵ Rh,⁶ Fe⁷ Au⁸ and Mn,⁹ among other strategies.¹⁰ In cases where the alkene is not electronically biased, regioselective oxyamination remains challenging. Intramolecular oxyamination wherein the alkene is tethered with a N- or O-containing group has been developed to overcome this limitation, providing access to 5-exo and 6-endo products selectively (Scheme 1a). For example, Donohoe^3b has shown the utility of Os-catalyzed 5-exo aminohydroxylation of alkene tethered carbamates for the synthesis of all syn amino-diol motifs. Sorensen^5b and Liu^5e have reported intramolecular 5-exo/6-exo oxyaminations of alkenes via combination of a Pd(II)-catalyst with PhI(OAc)₂ or H₂O₂ as the oxidant and oxygen source. More recently, the 5-exo cyclization was realized through Fe(IV)-nitrene mediated amino-benzoxylation reported by Xu.^7c In contrast, 6-endo oxyamination is relatively less explored, and the Thorpe-Ingold effect is usually required to increase 6-endo selectivity. For example, Liu^5g reported asymmetric 6-endo aminoacetoxylation of unactivated alkenes by Pd(II/IV) catalysis, with high regioselectivities only accomplished when a significant Thorpe–Ingold effect was used. A general catalytic system which can enable oxyamination with either regioselectivity (5-exo and 6-endo) as well as with reversed sense of oxyamination remains unknown.

Scheme 1.

Alkene Oxyamination

Our group has recently described a regiodivergent diamination of terminal alkenes,¹¹ wherein the regioselectivity is controlled by the reaction solvent. With relatively acidic HFIP as the reaction medium, γ-lactams are obtained selectively, while the selectivity could be switched by employing basic TFE/2M KHCO₃ cosolvent system leading to δ-lactams selectively. However, expanding this transformation for substrates tethered with internal alkenes or weaker nucleophiles like carboxylic acids proved problematic. Based on our continuing interest in investigation of Cp ligand effects for Rh- and Ir-catalysis,¹² we speculated that ligand manipulation could potentially provide a more general solution. Herein, we report a regiodivergent oxyamination of unactivated alkenes controlled by the Cp ligand on Ir with more electron-deficient systems leading to 6-endo selectivity compared to high 5-exo selectivity for Cp* (Scheme 1b). The use of exogenous nitrenoid precursor on alkenyl acid substrates leads to inverted regioselectivity. Finally, stereoselective trans-addition of N, O-motifs to the 1,2-dialkyl alkene enables access to either syn or anti isomers by simply switching the alkene geometry (Z/E). In contrast, the E styrenyl alkene delivers syn-addition product in good yield.

We commenced our study by coupling the alkene tethered N-pivaloylhydroxamate 1a with propionic acid 2a as the nucleophile (Table 1). Unlike previous studies where the O-motif is mostly from either an external oxidant (eg. PhIOAc₂)^5b,5c,5g or an internal oxidant (eg. RNH-OBz)^4a,7c, our method incorporates readily available carboxylic acids. Using [Cp*IrCl₂]₂ in combination with CsOPiv in HFIP, we were pleased to find that the desired oxyamination product 3aa was formed in 47% yield and 6.7:1 regioselectivity favoring γ-lactam (5-exo). The competitive coupling with pivalate was detected in negligible yield (<5%), but the coupling with chloride was observed with 10% yield from 2.5 mol% of [Cp*IrCl₂]₂. Therefore, the employment of preformed cationic iridium catalyst was utilized to avoid amino-chlorination byproduct formation, improving the yield to 68% (entry 2). K₂CO₃ was chosen as the optimal base for 5-exo-selectivity, as it was found to be more general during substrate scope study. In order to obtain δ-lactams (6-endo selectivity), the use of our previous conditions (TFE/2M KHCO₃) led to trace amount of oxyamination product (entry 4). We speculated that the failure arose from the weaker nucleophilicity of carboxylates compared to secondary amines. Thus, a more electron-deficient Cp ligand may be able to increase π-acidity of the Ir-catalyst and therefore promote the nucleophilic attack by carboxylates.

Table 1.

Reaction Optimization^a

entry	catalyst	solvent	yield (%)b	rr (γ:δ)c
1d	[Cp*IrCl2]2	HFIP	47	6.7:1
2	[Cp*Ir(CH3CN)3](SbF6)2	HFIP	68	8.5:1
3e	[Cp*Ir(CH3CN)3](SbF6)2	HFIP	71(68)f	8.2:1
4	[Cp*IrCl2]2	TFE/2M KHCO3	trace	--
5	[CpTMIrCl2]2	HFIP	trace	--
6	[Cp*PhIrCl2]2	HFIP	28	1.1:1
7	[Cp*sdPhIrCl2]2	HFIP	27	1:3.9
8	[Cp*pCF3IrCl2]2	HFIP	65	1:9.3
9	[Cp*sdpCF3IrCl2]2	HFIP	61	<1:20
10	[Cp*pCF3Ir(CH3CN)3](SbF6)2	HFIP	75	1:11
11g	[Cp*pCF3Ir(CH3CN)3](SbF6)2	HFIP	75(70)f	<1:20

^aReactions were conducted on a 0.06 mmol scale using 1a (1.0 equiv), 2a (2.5 equiv), [Cp^x-Ir] (5.0 mol% Ir-monomer), CsOPiv (20 mol%).

^bYield of major isomer as determined by ¹H NMR.

^cDetermined by analysis of ¹H NMR of the unpurified reaction mixture.

^d1.0 equiv CsOPiv.

^e20 mol% K₂CO₃ instead of CsOPiv.

^fIsolated yield of major isomer.

^g24 °C instead of 30 °C.

In the event, we found a significant improvement in reactivity and selectivity towards δ-lactam 4aa by applying more electron-deficient Cp ligands (entry 5–9). Although Cp*^sdpCF3 delivers the best regioselectivity for δ-lactams, Cp*^pCF3 was selected as optimal for further development due to its higher reactivity and ease of preparation. The corresponding cationic iridium complex was also successfully used to increase reactivity (entry 10), while selectivity was further improved when the reaction was conducted at ambient temperature (entry 11).

With optimized reaction conditions in hand, we turned to evaluate the scope of γ-lactam formation (5-exo). The reaction tolerates both aliphatic and aromatic acids (3aa-3af, Scheme 2). When benzoic acids are used, stoichiometric amount of base is required for good yield (3af). The influence of substituents at the α- and β-position of the alkenyl hydroxamate was explored. Substituents at the α-position caused significant Lossen rearrangement, whereas substrates containing β-substitution participated smoothly, even when containing a more sterically hindered β di-methyl moiety (3bb, 3cb). More importantly, in addition to terminal olefins, substrates bearing an internal alkene are also compatible, with complementary diastereomers formed from cis and trans 1,2-dialkyl alkenes reflective of a stereoselective anti-addition of N- and O-groups to the double bond (3dg, 3eg, 3fg).¹³ The relative stereochemistry of 3dg was confirmed by X-ray crystallography of the corresponding alcohol.

Scheme 2. γ-Lactam Scope^a.

^aConditions: 1 (0.1 mmol, 1.0 equiv), 2 or ZnX₂ (2.5 equiv), [Cp*Ir(CH₃CN)₃]₂(SbF₆)₂ (5 mol%), K₂CO₃ (20 mol%), HFIP (0.3 M), 30 °C for 16 h. ^b1.0 equiv K₂CO₃. ^c40 °C. ^dFrom E-olefin; ^eFrom Z-olefin; ^f4°C.

To further extend this method, chloride and bromide were also tested as an external nucleophile (3ai, 3aj). Zinc halides were found to be the optimal halide source, providing amino-chlorination and -bromination products in good yields. Gratifyingly sterically hindered 1,1-disubstituted alkene was successfully transformed to the desired γ-lactam containing a quaternary carbon center (3ij). Internal alkenes are also suitable substrates; cis-alkene delivers 3ej with excellent diastereoselectivity and good yield. In contrast to oxyamination, however, the E olefin delivers the same diastereoisomer as the major product (3ej), albeit with lower diastereoselectivity (1.8:1 dr).

Interestingly, styrenyl systems participate well but deliver products with different selectivity. Substrate 1g provides syn-addition product with excellent selectivity (eq 1). On the other hand, diastereomeric 1h provides a mixture of syn and anti addition product in poor selectivity (eq 2). The former is consistent with a recent report by Chang¹⁴ implicating a [3+2]-type mechanism. We view the latter result as evidence that in some cases, the two mechanisms are competitive.

(1)

(2)

Given that it would be enabling to deliver the amino alcohols with reversed regioselectivity about the alkene, we wondered whether alkenoic acids^4h,4i,4n could be engaged with exogenous hydroxamate ester by a presumably mechanistically related manifold. Thus, we decided to test this transformation by simply switching the positions of carboxylic acids and pivaloylhydroxamate tethering the acid nucleophile to the alkene. We were delighted to find the reaction proceeds smoothly with electron-deficient [Cp*^pCF3IrCl₂]₂ producing desired amino lactones in almost quantitative yield (7a-7c, Scheme 3). Additionally, 4,4-disubstituted alkenes are successfully applied, leading to amino lactones bearing a congested quaternary center (7d, 7e). More importantly, a 6-exo cyclization process can also be realized in high yield promoted by a more electron-deficient Cp*^sdpCF3Ir(III)-catalyst.¹⁵

Scheme 3. Amino Lactone Scope^a.

^aConditions: 1 (0.1 mmol, 1.0 equiv), BocNHOPiv (1.5 equiv), [Cp*^pCF3IrCl₂]₂ (2.5 mol%), NaOPiv (1.0 equiv), HFIP (0.3 M), 40 °C for 16 h. ^b5 mol% of [Cp*^pCF3IrCl₂]₂. ^c5 mol% of [Cp*^sdpCF3IrCl₂]₂.

Next, we sought to investigate the scope of δ-lactams (6-exo selectivity). This reaction was found to be compatible with various aliphatic and aromatic acids (4aa-4ao, Scheme 4). Different substitutions such as β-halides or α-hetero-atoms are well tolerated. Additionally, unlike the synthesis of γ-lactams, α-substituted substrates are converted to δ-lactams with excellent diastereoselectivity (4jb, 4kb). ¹⁶ This is most likely attributed to the electron-deficient Cp*^pCF3Ir-catalyst suppressing Ir-nitrene formation and concomitantly initiating the other reaction pathway via its π-Lewis acidity.

Scheme 4. δ-Lactam Scope^a.

^aConditions: 1 (0.1 mmol, 1.0 equiv), 2 (2.5 equiv), [Cp*^pCF3Ir(CH₃CN)₃]₂(SbF₆)₂ (5 mol%), CsOPiv (20 mol%), HFIP (0.3 M), 30 °C for 16 h. ^b24 °C. ^c2.5 mol% [Cp*^sdpCF3Ircl₂]₂ used. ^d1.0 equiv CsOPiv used. ^e40 °C. ^fThe relative stereochemistry was determined via NOESY analysis.

In the course of these studies, we made a serendipitous observation that we believe sheds light on the mechanism of oxyamination. We isolated aziridine containing intermediate 11 when conducting the reaction in the presence of 10 (Scheme 5). We hypothesize that this reaction proceeds via the strained azabicyclo[3.1.0] intermediate 8, formed via an Ir(V)-nitrene-mediated aziridination, which is intercepted by the solvent (hexafluoro-2-propanol) through cleavage of the strained amide bond instead of opening the aziridine ring. ¹⁷ To further support the proposed mechanism, aminal 11 was isolated and subjected to propionic acid or methylaniline in HFIP. The corresponding oxyamination (3aa) and diamination (12) products are formed in good yields, which is likely through retro-Michael addition/cyclization to reform the key intermediate 8 and subsequent irreversible quenching by the external nucleophile.

Scheme 5.

Mechanistic Studies

These findings lead us to propose the following mechanisms to account for each product. The observed strong ligand effect is consistent with our previous proposed reaction pathways.¹¹ Accordingly, the divergent syntheses of γ- and δ-lactams are dependent on the electronic nature of the Cp ligand. When applying an electron-rich Cp*, γ-lactams are formed via an Ir(V)-nitrene intermediate. In contrast, when electron-deficient Cp*^pCF3 is subjected to the reaction conditions, δ-lactams are synthesized via a proposed nucleophilic attack on the activated alkene prior to Ir nitrene formation (D in Scheme 5). Last, regiocomplementary products result from carboxylate trapping of an activated Ir-nitrene alkene complex leading to aminolactone product (F in Scheme 5).¹⁸

In conclusion, we have successfully developed a regiodivergent and stereoselective oxyamination of unactivated alkenes. The regioselectivity is controlled by tuning the electronics of the Cp ligands. Value-added structures such as γ-lactams, γ-lactones and δ-lactams can be rapidly assembled from readily available starting materials. Importantly, the experimental evidence strongly suggests the existence of a highly electrophilic azabicyclo[3.1.0] intermediate, which unveils the mechanistic details of stereoselective γ-lactam formation.