Rh-catalysed asymmetric conjugate addition of boronic acids to nitroalkenes employing a P-chiral P,π-hybrid ligand

Abstract

A Rh-catalysed asymmetric conjugate addition of aryl boronic acids to β-substituted nitroalkenes was developed employing a P-chiral P-alkene hybrid bidentate ligand with enantioselectivities of up to 94 : 6 er. DFT modelling of the transition state for the addition reaction was consistent with our previous model for stereocontrol employing this family of chiral ligands. Application of the β-chiral nitroalkanes was demonstrated in the intramolecular Buchwald–Hartwig amination and aminocarbonylation to provide 5- and 6-membered chiral heterocycles.

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Introduction

The metal catalysed asymmetric conjugate addition of carbon-based nucleophiles to nitroalkenes is an important reaction for the asymmetric synthesis of β-chiral amines and α-chiral carbonyl compounds.¹ In particular, the asymmetric conjugate addition of aryl boronic acids to nitrostyrenes² allows access to β-chiral benzhydryl amines (3) that can be applied to the synthesis of important biologically relevant compounds³ (Scheme 1). After the pioneering work of Hayashi and Miyaura⁴ who demonstrated the Rh-catalysed conjugate addition of aryl boronic acids to α,β-unsaturated carbonyl electrophiles enabled by Rh-boron exchange,⁵ significant research efforts by many groups in this area have expanded the scope of this reaction to include imines⁶ and α-ketoesters⁷ as competent electrophiles. Notably, Hayashi⁸ and Carreira⁹ first demonstrated that bidentate alkene-based ligands lead to more reactive catalysts for the Rh-catalysed conjugate addition of aryl boronic acids. Since that time, olefin-containing bidentate ligands including dienes, sulphur–alkene, and phosphorous–alkene bidentate ligands have been developed and applied to this class of transformation.¹⁰

Scheme 1 Synthetic utility of nitroalkene conjugate addition reactions.

Recently, we have expanded the scope of the P-chiral dihydrobenzooxaphosphole-based phosphine ligand series developed within Boehringer Ingelheim (Scheme 2) for a wide array of catalytic asymmetric transformations¹¹ to include a new series of P-chiral P-alkene hybrid ligands (JoshPhos)¹² that are applicable to the asymmetric Rh-catalysed conjugate addition of aryl boronic acid nucleophiles to enones and imines with high enantioselectivities. Therefore, we reasoned that this system may also be useful in the conjugate addition of arylboronic acids to nitroalkene electrophiles. Herein, we disclose the application of our JoshPhos-based ligands to the asymmetric Rh-catalysed conjugate addition of aryl boronic acids to nitroalkenes.

Scheme 2 P-Chiral dihydrobenzooxaphosphole-based ligands.

Results and discussion

Initial reaction optimization studies were performed using nitrostyrene (1a) and p-methoxyphenyl boronic acid (Table 1). Use of aqueous KOH to prepare the Rh–OH catalyst in situ at variable reaction temperatures gave poor to modest yields despite the fact that complete consumption of 1a was observed in all cases (entries 1–3). The only impurity that could be isolated and identified was tentatively assigned as 11 that presumably formed from the conjugate addition of the product 10a onto 1a. Although HRMS and ¹HNMR spectroscopic analysis was consistent with the proposed assignment, 11 was isolated as an inseparable mixture of what appeared to be four diastereomers, and therefore, conclusive structural assignment was not possible. We next examined KHF₂ as an additive given its demonstrated utility in the Rh-catalysed addition of boronic acids to nitroalkenes (entries 4–11).^2b,e Use of KHF₂ eliminated the formation of 11 resulting in an improved yield, but incomplete conversion was observed (entry 4). Incomplete conversion was partly due to the fact that 60 °C was required for good reaction rates, and protodeboronation of the boronic acid became an issue (i.e. no boronic acid remained after ∼3 h by HPLC analysis). Tuning of the electronics of the JoshPhos ligand did not lead to improved conversions (entries 5 and 6). A solvent screen (entries 7–11) identified THF as the optimal solvent leading to full conversion and good yield with minimal formation of 11. Cyclopentyl methyl ether (CPME) was also identified as a good solvent. Finally, use of the ArBF₃K salt in place of boronic acid 9a could also be employed; however, the reaction was significantly slower under these conditions (entries 12 and 13).

Table 1 Optimization of the Rh-catalysed conjugate addition employing 1a^a

Entry	Ligand	Additive	Solvent (T °C)	% Yield^b	er^c
a Conditions: 0.335 mmol 1a and 3 equiv. 9a (1.01 mmol). b Isolated yield. c Determined by chiral HPLC. d 50 mol% 1.5 M KOH (0.11 mL). e 300 mol% 3 M aqueous KHF2 (0.33 mL). f 10 h reaction time. g ArBF3K used instead of ArB(OH)2. h 5 mol% 0.1 M KOH (0.17 mL). i 15 h reaction time.
1	L1	KOH^d	PhMe (22)	27	92 : 8
2	L1	KOH^d	PhMe (40)	45	91 : 9
3	L1	KOH^d	PhMe (60)	53	89 : 11
4	L1	KHF2 ^e	PhMe (60)	71	90 : 10
5	L2	KHF2 ^e	PhMe (60)	33	92 : 8
6	L3	KHF2 ^e	PhMe (60)	72	85 : 15
7	L1	KHF2 ^e	CPME (60)	80	91 : 9
8	L1	KHF2 ^e	Dioxane (60)	63	88 : 12
9	L1	KHF2 ^e	DCE (60)	66	88 : 12
10	L1	KHF2 ^e	THF (60)	85	91 : 9
11^f	L1	KHF2 ^e	THF (40)	68	92 : 8
12^g	L1	KOH^h	PhMe (60)	48	90 : 10
13^g^,^i	L1	KOH^h	THF (60)	86	91 : 9

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The substrate scope was next analysed (Scheme 3). In general, electron-rich boronic acids gave the best yields in the conjugate addition reaction (10a–10c, 10h–10j, 10l). Notably, a thioether (10c) and a free phenol (10i) were tolerated well in the chemistry to afford the requisite enantioenriched chiral precursors to cherylline (4)^3a and McN-5652-Z (6).^3b Halogen containing aryl boronic acids were somewhat problematic due to competitive protodeboronation of the aryl boronic acid (10e, ent-10j). However, this limitation can be circumvented by reversing the polarity of the coupling by incorporating the halogen substitution on the nitroalkene with use of an electron-rich boronic acid as nucleophile (10j). However, in this case, improved yields were realized when CPME was employed, as use of THF led to the formation of significant amount of the impurity analogous to 11. This solvent switch inhibited impurity formation and enabled an excellent yield of 10j which maps onto the core of the anti-depressant diclofensine (5). ortho-Substitution was not tolerated on the arylboronic acid nucleophile, however, ortho-substitution was tolerated on the nitroalkene partner (10g, 10h). Heterocycles could also be employed on the nitroalkene fragment (10k, 10l), as could alkyl substitution (10m, 10n). Lastly, an α,β-disubstituted nitroalkene was tested (1-nitrocyclohexene)^2a but was found to be unreactive using the current system.

Scheme 3 Rh-catalysed conjugate addition of aryl boronic acids to nitroalkenes. Reaction conditions: 0.5 mmol nitroalkene, boronic acid (1.5 mmol), [(η₂-CH₂CH₂)₂RhCl]₂ (2.9 mg, 0.0075 mmol), L1 (6.2 mg, 0.020 mmol), 0.5 mL 3 M KHF₂, 1.9 mL THF. ^a Reaction performed using 5 equiv. ArB(OH)₂. ^b Reaction performed on 1.0 g scale. ^c Reaction performed using CPME as solvent.

The proposed mechanism for the present conjugate addition is given in Scheme 4. Based on our previous work employing aryl boronic acids as nucleophiles with our (JoshPhos) RhOH catalyst¹² and the work of others,² the active catalyst is likely the (L1) Rh–OH complex 12. Transmetalation likely occurs through either the boronic acid 9 or a mixed species such as 13 rather than from 14 because when 14 is used directly in place of boronic acid 9 the rate of the reaction was significantly reduced (Table 1, entries 12 & 13 vs. 4 & 10).

Scheme 4 Proposed catalytic cycle and stereochemical model for the Rh-catalysed conjugate addition of boronic acids to nitroalkenes employing ligand L1. S = solvent.

Binding of the nitroalkene electrophile is proposed to prefer coordination through 16 rather than 17 to avoid a steric interaction between the nitro-group and the phenyl group on the alkene of the P,olefin-ligand backbone. Subsequent insertion from complex 16 generates 18 that upon protonation releases the product with the observed absolute stereochemistry and regenerates 12. DFT modelling^13,14 of the reaction identified transition structure TS-1 that was fully consistent with this proposal. The formation of impurity 11 is possible from 18 through coordination of additional nitroalkene followed by insertion and protonation to regenerate catalyst 12. If protonation of 18 is difficult, then significant amounts of impurity 11 would be expected. This scenario would be likely under more neutral to basic reaction conditions. Thus, the role of the KHF₂ in minimizing the formation of 11 may be due to the increased acidity of the reaction medium with this additive. In support of this conjecture is the fact that the pH of 3 M KHF₂ was measured to be ∼2–3, and the aqueous layer present at the end of the nitroalkene conjugate addition reaction had a pH of ∼6.

The synthetic utility of the conjugate addition products is illustrated in Scheme 5. Nitrocompound 10g was chemoselectively reduced to amine 19 using heterogeneous catalysed hydrogenation. Amine 19 was then converted to useful pharmacophores¹⁵ using Pd-catalysed transformations. Intramolecular aminocarbonylation¹⁶ led to the synthesis of 6-membered ring lactam 20, and Cu-catalysed intramolecular Buchwald–Hartwig¹⁷ amination gave access to the chiral 5-membered ring indoline 21.

Scheme 5 Application of the Rh-catalysed conjugate addition products in Pd-catalysed ring-formation reactions to access 5- and 6-membered chiral heterocycles.

Conclusions

In summary, a Rh-catalysed asymmetric conjugate addition of aryl boronic acids to nitroalkenes was developed employing our P-chiral P,π-hybrid JoshPhos ligands based off of the dihydrobenzooxaphosphole core. The reaction proceeds in moderate to excellent yields with moderate to good enantioselectivities. A mechanistic rational was presented that accounts for the observed stereochemical outcome in the reaction and describes the beneficial effect of KHF₂ at minimizing double addition to the nitroalkene electrophile by providing a more acidic reaction mixture to facilitate product protonation from the catalyst. Finally, the synthetic utility of the conjugate addition reaction was demonstrated in the Pd-catalysed synthesis of 5- and 6-membered chiral heterocycles.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00311g

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