Enantioselective Iridium-Catalyzed Allylation of Nitroalkanes: Entry to β-Stereogenic α-Quaternary Primary Amines

Abstract

The first systematic study of simple nitronate nucleophiles in iridium-catalyzed allylic alkylation are described. Using a tol-BINAP-modified π-allyliridium C,O-benzoate catalyst, α,α-disubstituted nitronates substitute racemic branched alkyl-substituted allylic acetates, thus providing entry to β-stereogenic α-quaternary primary amines. DFT calculations reveal early transition states that render the reaction less sensitive to steric effects and distinct trans-effects of diastereomeric chiral-at-iridium π-allyl complexes that facilitate formation of congested tertiary-quaternary C-C bonds.

Graphical Abstract

Chiral amines are prevalent among FDA approved drugs,¹ as are protocols for their synthesis.² The vast majority of catalytic enantioselective methods for the construction of chiral amines deliver N-substituted carbon stereocenters.² Catalytic enantioselective methods applicable to the formation of acyclic chiral β-stereogenic amines are far less common and encompass asymmetric hydrogenation of enamines,³ allylic amines/amides⁴ or nitrolefins,⁵ 1,4-reductions and 1,4-additions to nitroolefins,^6,7 and dynamic kinetic resolutions via aldehyde reductive amination.⁸ These methods do not deliver chiral β-stereogenic α-quaternary primary amines. Catalytic enantioselective Tsuji–Trost nitronate allylic alkylation-reduction potentially provides access to acyclic chiral β-stereogenic amines, but such methods are underdeveloped.^9–12 Palladium-catalyzed allylic alkylations typically display linear regioselectivity, and consequently focus on reactions that proceed via symmetric π-allylpalladium intermediates⁹ or prochiral nucleophiles (α-nitroesters).¹² Beyond vinyl epoxides,^10a only a single system for catalytic asymmetric allylic alkylation of unactivated nitronates with mono-substituted π-allyl precursors that displays branched regioselectivity has been described.^10b,c Only two examples of corresponding iridium-catalyzed nitronate allylic alkylations are reported.¹¹ Both the palladium- and iridium-based catalyst systems rely on linear aryl-substituted π-allyl precursors and display incomplete diastereo- and regioselectivity (Figure 1).

Figure 1.

Unactivated nitronates in catalytic enantioselective allylic alkylations of mono-substituted π-allyl precursors.

In connection with studies of π-allyliridium C,O-benzoate-catalyzed nucleophilic allylations of carbonyl compounds,¹³ we recently found these same complexes are competent catalysts for electrophilic allylation, as demonstrated in regio- and enantioselective aminations of racemic branched alkyl-substituted allylic acetates to form acyclic chiral α-stereogenic amines.¹⁴ Aspiring to access corresponding chiral β-stereogenic amines, a study of nitronate nucleophiles was undertaken. Here, we demonstrate that α,α-disubstituted nitroalkanes participate in highly enantioselective allylic alkylation with racemic branched alkyl-substituted allylic acetates. Despite forming congested contiguous quaternary-tertiary C-C bonds, complete branched regioselectivities are observed. DFT calculations reveal early transition states that render the reaction less sensitive to steric effects and distinct trans-effects of diastereomeric chiral-at-iridium π-allyl complexes that facilitate formation of congested tertiary-quaternary C-C bonds.

In initial experiments, allylic acetate 1a (100 mol%) was exposed to 2-nitropropane 2a (1125 mol%) as solvent (1.0 M) in the presence of Cs₂CO₃ (500 mol%) and the π-allyliridium C,O-benzoate complex modified by (S)-tol-BINAP, Ir-I, at 100 °C. The homoallylic nitroalkane 3a was formed in 51% yield and 95% ee (Table 1, entry 1). Lower loading of 2-nitropropane 2a (450 mol%) with DMF (0.5 M) as solvent improved yield and enantioselectivity (Table 1, entry 2), but further reduction in the loading of 2a led to a small decrease in yield (Table 1, entry 3). A slight decrease in temperature (80 °C) improved the yield of 3a without diminishing enantioselectivity (Table 1, entry 4). Lower loading of Cs₂CO₃ decreased the yield of 3a (Table 1, entry 5) and water (100 mol%) dramatically decreased conversion of 1a (Table 1, entry 6). Other π-allyliridium C,O-benzoates were evaluated but did not improve the yield of 3a (Table 1, entries 7–10).

Table 1.

Selected optimization experiments in the enantioselective iridium-catalyzed allylic alkylation of racemic branched alkyl-substituted allylic acetate 1awith nitronate 2a.^a

	Entry	2a (mol%)	catalyst	Cs2C03 (mol%)	T°C	Yield (%)	ee (%)
	1b	1125	lr-I	500 mol%	100	51	95
	2	450	lr-I	500 mol%	100	67	99
	3	240	Ir-I	500 mol%	100	35	99
	4	450	lr-I	500 mol%	80	71	99
	5	450	lr-I	300 mol%	80	56	99
	6C	450	lr-I	500 mol%	80	<10	-
	7	450	lr-II	500 mol%	80	51	99
	8	450	lr-III	500 mol%	80	53	99
	9	450	Ir-IV	500 mol%	80	43	99
	10	450	Ir-V	500 mol%	80	50	99

^aYields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR of crude reaction mixtures. Enantioselectivities were determined by HPLC analysis.

^b2a = solvent (1.0 M).

^cH₂O (100 mol%). See Supporting Information for experimental details.

To evaluate reaction scope, optimal conditions for the formation of 3a (Table 1, entry 4) were applied to the allylic alkylation of α,α-disubstituted nitroalkanes 2a-2j with racemic branched alkyl substituted allylic acetates 1a-1n (Scheme 1). As illustrated by the conversion of 2-nitropropane 2a to adducts 3a-3h, diverse (hetero)aromatic groups (3a-3e), (thio)ethers (3f, 3g), cyclopropyl groups (3h) are tolerated. As demonstrated by the formation of adducts 3i-3x, cyclic nitroalkanes 2b-2h are also competent partners for allylic alkylation. This includes nitrocyclobutane (2b), nitrocyclopentane (2c), N-Cbz- and N-Boc-4-nitropiperidines (2d and 2g, respectively), as well as 1,1-disubstituted 4-nitrocyclohexanes (2e, 2f), nitrocycloheptane (2h) and the spirocyclic nitroalkanes (2i, 2j). In all cases, good to excellent yields of adducts 3a-3x were obtained with high levels of enantiomeric enrichment (87–99% ee) and complete branched regioselectivity. The nonsymmetric nitroalkane (1-nitroethyl)benzene provided high yields of allylic alkylation product, but low diastereomeric ratios were observed. Low conversions were observed using allylic acetates bearing α- or β-branched alkyl moieties. As revealed by the conversion of 3f, 3k, 3l, 3s and 3v to amines 4f, 4k, 4l, 4s and 4v, respectively, zinc-mediated reduction of the allylation products provides entry to chiral β-stereogenic α-quaternary primary amines (Scheme 2).

Scheme 1.

Iridium-catalyzed allylation nitroalkanes 2a-2j using allylic acetates 1a-1n to form homoallylic nitroalkanes 3a-3x.^a

^aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis. ^bNMP was used as the reaction solvent. ^c(S)-Ir-tol-BINAP, X= OMe. ^dIr-catalyst (10 mol%). See Supporting Information for experimental details.

Scheme 2.

Zinc-mediated reduction of 3f, 3k, 3l, 3s and 3v to form β-stereogenic α-quaternary primary amines 4f, 4k, 4l, 4s and 4v.

^aYields are of material isolated after filtration through celite. See Supporting Information for experimental details

Density functional theory (DFT) calculations were carried out to investigate the origin of regio- and enantioselectivity of the Ir-catalyzed allylic alkylation.^15,16 As numerous diastereomeric π-allyliridium C,O-benzoate complexes may exist in equilibration prior to the allylation, the relative stabilities, reactivities and regioselectivities of all 16 possible stereoisomers of the π-crotyliridium(III) complex were computed (Figure 2). These include diastereomers A, B, C, and D, where the C,O-benzoate resides in different coordination sites of the octahedral Ir complex,¹⁷ with four different coordination modes of the π-crotyl ligand for each diastereomer. Here, the suffix exo or endo describes whether the allyl C2−H points away or towards the C,O-benzoate ligand, and distal or proximal describes if the C3−methyl points away or towards the C,O-benzoate (see Figure S2 for the relative stabilities of all 16 isomers). Computed activation barriers for the addition of ⁻CMe₂NO₂ anion to each π-crotyliridium(III) isomer leading to branched and linear products are shown in Figure 2B. The 16 π-crotyliridium(III) isomers exhibited very different reactivity and regioselectivity. The most reactive isomer, D_exo_proximal, strongly favors the branched product (ΔΔG^‡(B-L) = −8.5 kcal/mol), while some less reactive isomers, such as A_endo_proximal and B_endo_proximal, prefer the linear product. These results suggest stereogenicity at iridium not only affects reactivity but also regioselectivity. To assess the origin of these effects, computational analysis on the electronic and structural properties of the diastereomeric π-crotyliridium(III) complexes were performed.

Figure 2.

Computed activation free energies of the addition of ⁻CMe₂NO₂ to different π-crotyliridium(III) isomers. All activation barriers (ΔG^‡) are with respect to A_endo_distal.

The computed transition state structures of the outer sphere addition of the nitronate nucleophile all involve long forming C–C distances (usually >2.4 Å in branch-selective TSs and >2.2 Å in linear-selective TSs. See Figure 3 and Figure S3 in the SI). These early transition states suggest that the addition is not sensitive to steric effects, and thus, the regioselectivity is mainly controlled by the electronic properties of the π-allyl complexes. The computed ground state properties of the π-crotyliridium(III) isomers and the distortion/interaction model analysis of the allylation transition states revealed enormously different electronic properties and their influences on the regioselectivity. In branch-selective isomers, such as D_exo_proximal (Figure 3A), the Ir−C3 distance is much longer than Ir−C1. This geometry leads to weaker d→π* backbonding at C3 and more positive charge on C3 compared to C1 (Figure 3A),¹⁸ making the more substituted C3 terminus more electrophilic.¹⁹ In addition, the transition state of nitronate addition to C3 (TS-1) is promoted by the smaller distortion energy of the π-crotyliridium complex (ΔE_dist-Ir) as the ground state Ir−C3 bond of D_exo_proximal is predistorted to a longer distance (2.50 Å) that is closer to that in TS-1 (2.87 Å). In contrast, electronic effects strongly disfavor branch-selective addition with A_endo_proximal (Figure 2B), because the more substituted terminus C3 is less electrophilic than C1, as evidenced by the negative charge on C3. In addition, the Ir−C3 bond becomes shorter than Ir−C1, leading to greater distortion energy (ΔE_dist-Ir) to elongate the Ir−C3 bond in the branch-selective transition state (TS-3).

Figure 3.

Origin of regioselectivity. Bisphosphine ligand and some H-atoms are omitted for clarity. All Gibbs free energies are in kcal/mol with respect to A_endo_distal. ΔE_dist-Ir: distortion energy of the π-crotyliridium complex to reach its geometry in the TS for nucleophilic addition.

The same analyses on all 16 isomers of the π-crotyliridium complex revealed good correlations between the computed regioselectivity for each isomer and the C3/C1 difference in NPA charge and Ir−C3 bond distance, i.e. diastereomers with more positive charge on C3 and a longer Ir−C3 bond give higher branch-selectivity (Figure 4).²⁰ These results are consistent with our findings that regioselectivity is controlled by electronic effects, including the allyl electrophilicity and the distortion of the π-allyl complex. The electronic properties of the diastereomeric π-crotyl complexes also are affected by the trans effect²¹ of the bisphosphine and the chelating C,O-benzoate ligands on the stereogenic Ir center. In diastereomers A and B, due to the stronger trans effect of the aryl vs phosphine groups, addition occurs at sites trans to the aryl group, leading to branched products in “distal” isomers and linear products in “proximal” isomers. In disastereomers C and D, “proximal” isomers, in which C3 is trans to a phosphorus atom, give higher branched regioselectivity. This is consistent with the stronger trans effects of phosphine vs carboxylate ligands. These branch-selective “proximal” isomers of C and D are also among the most reactive in all 16 stereoisomers (Figure 2B), as the π-acceptor ability of the phosphine ligand promotes addition at sites trans to phosphorus.²²

Figure 4.

Electronic effects on allylation regioselecitivy of different stereoisomers of the π-crotyliridium complex.

Stereogenicity at iridium is also a critical determinant of enantioselectivity. Due to trans effects (vide supra), the “proximal” isomers of C and D are the most reactive among all 16 stereoisomers. The four most favorable pathways involve D_exo_proximal (TS-1) and C_endo_proximal (TS-7), which give (S)-product, and D_endo_proximal (TS-6) and C_exo_proximal (TS-5), which give (R)-product. Optimized structures of these branch-selective transition states are shown in Figure 5. The two transition states leading to the (R)-product, TS-5 and TS-6, are destabilized because the allyl C2−H moiety in TS-5 and the C3−methyl in TS-6 clash with a P-tolyl group of (S)-tol-BINAP. Thus, TS-5 and TS-6 are 1.6 and 1.8 kcal/mol less stable than the lowest-energy transition state, TS-1 that gives the (S)-product. In TS-1, the steric repulsions between tol-BINAP and the allyl group are absent. Our calculations are consistent with the experimentally observed enantioselectivity for the (S)-product.

Figure 5.

Optimized structures for additions of ⁻CMe₂NO₂ anion giving branched product. Gibbs free energies are with respect to A_endo_distal.

In summary, we report iridium-catalyzed allylic alkylations of nitronate nucleophiles. This method, which employs an air and water stable π-allyliridium C,O-benzoate catalyst modified by tol-BINAP, enables highly regio- and enantioselective substitution of racemic branched alkyl-substituted allylic acetates by α,α-disubstituted nitronates and, hence, entry to β-stereogenic α-quaternary primary amines. As revealed by DFT calculations, early transition states that render the reaction less sensitive to steric effects and distinct trans-effects of diastereomeric chiral-at-iridium π-allyl complexes facilitate formation of congested tertiary-quaternary C-C bonds. Related asymmetric allylic alkylations of nonstabilized carbanions are currently underway.²³