Chiral Organocatalyzed Intermolecular Rauhut–Currier Reaction of Nitroalkenes with Ethyl Allenoate

Abstract

An enantioselective intermolecular Rauhut–Currier (RC) reaction of nitroalkenes with ethyl allenoate has been established with quinidine-derived β-isocupreidine. The present RC reaction afforded α-functionalized allenoates 3 in up to 94% yield with 59% enantiomeric excess (ee).

The Rauhut–Currier (RC) reaction^1,2) is a Lewis base-catalyzed carbon–carbon bond-forming reaction between two different α,β-unsaturated carbonyl compounds, wherein one compound acts as a latent enolate, providing α-substituted enones. In contrast to the related Morita–Baylis–Hillman (MBH) and aza-MBH reactions,^2–5) wherein the latent enolate reacts with another aldehyde or imine, the RC reaction lacks reactivity and selectivity; using two distinct α,β-unsaturated carbonyl compounds leads to a mixture of homo- and heterocouplings.

Nitroalkenes are widely used as electron-deficient alkenes; they are employed in diverse organic reactions and act as Michael acceptors, dienophiles, and 1,3-dipoles.⁶⁾ Despite the fact that nitroalkenes are excellent Michael acceptors, nitroalkenes mostly work as nucleophiles in the RC reaction because the Lewis base catalyst initially reacts at the β-position of the nitroalkene, resulting in the corresponding α-nucleophilic carbanion.⁷⁾ In 2007, Henry and Kwon presented an achiral phosphine-catalyzed intramolecular RC reaction of a nitroalkene (Michael acceptor) and an allenoate (nucleophile) as a solitary example; in their system, sequential bond-formation took place after the intramolecular RC reaction, leading to a formation of the tricyclic product⁸⁾ (Chart 1a). Controlling chemoselectivity and imparting asymmetric induction to the product in the RC reaction of nitroalkenes and allenoates remain a challenging task.

Chart 1. Rauhut–Currier Reaction of Nitroalkenes with Allenoates

Herein we report the first chemo-, regio-, and enantioselective intermolecular RC reaction of allenoates 2 with nitroalkenes 1. Quinidine-derived β-isocupreidine (β-ICD)⁹⁾ was the optimal tested catalyst for the RC reaction, affording α-functionalized allenoates 3¹⁰⁾ with excellent yields under mild reaction conditions in a single operation (Chart 1b).

As part of our efforts to explore enantioselective bifunctional catalysis,¹¹⁾ we were interested in facile accesses to chiral α-substituted allenoates, which are useful platforms for the rapid asymmetric construction of complex molecules.¹²⁾ We initiated our investigation by employing (2-nitrovinyl)benzene (1a) with ethyl allenoate (2a) as substrates and examined their potential modes of reaction with various Lewis base catalysts (Table 1). One of our tested achiral catalysts, 1,4-diazabicyclo[2.2.2]octane (DABCO) promoted the reaction to give product 3a in 28% yield, along with self-condensation of 2a (entry 1). Triphenylphosphine (PPh₃), methyldiphenylphospine (MePPh₂), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and N,N-dimethyl-4-aminopyridine (DMAP) are inactive in this transformation (entries 2 and 3).¹³⁾ Therefore, chiral azabicyclo[2.2.2]-type catalysts were tested for the enantioselective version of this reaction. Quinine-derived α-isocupreine (α-ICPN)¹⁴⁾ and β-ICD afforded the desired RC product 3a in moderate-to-good yields (entries 4 and 5). The RC reaction rate ordinarily increases in Brϕnsted acid.²⁾ Although 2-naphthol (20 mol %) was added to the reaction mixture, the reaction rate decreased and the racemic form of 3a was obtained in less than 10% yield (entry 6). We also examined the catalytic effects of other cinchona alkaloid derivatives, however, no reaction was observed in any of the cases (entries 7 and 8). Neither [n+2] annulation⁸⁾ nor RC γ-adduct¹⁵⁾ 4a was obtained from β-ICD.

Table 1. Screening of Reaction Conditions

Entry	Organocatalyst (20 mol %)	Yield (%)	ee (%)a,b)
1	DABCO	28	Racemic
2	PPh3, MePPh2 or DBU	Complex mixture	–
3	DMAP	Trace	–
4	α-ICPN	41	29 (−)
5	β-ICD	77	42 (+)
6	β-ICD +2-naphtholc)	10>	Racemic
7	Quinidine or Quinine	Trace	—
8	Cat. A or Cat. B	Trace	—

a) Determined by using HPLC (Daicel Chiralpak IE). b) Parentheses indicate the sign of optical rotation. c) Twenty molar % of 2-naphthol was added.

Encouraged by these results, we went on to study the effects of solvent on the reaction of 1a with 2a (Table 2). Ethereal solvents such as Et₂O, 1,2-dimethoxyethane (DME), 1,4-dioxane, and cyclopentyl methyl ether (CPME) (entry 2), along with toluene and MeCN (entry 3) did not show any improvement. Among the solvents we tested, halogenated solvents (CH₂Cl₂ or CHCl₃) led to α-functionalized allenoate 3a in 94% yields, respectively (entries 4 and 5). In terms of enantioselectivity, the reaction in CHCl₃ afforded the better outcomes (44% enantiomeric excess (ee), entry 5). These outcomes suggested that delicate steric interactions and/or hydrogen bonding between the substrates and β-ICD are critical to efficiently promote the RC reaction.¹⁶⁾

Table 2. Effect of Solvent on RC Reaction

Entry	Solvent	Yield (%)	ee (%)a)
1	THF	77	42 (+)
2	Et2O, DME, 1,4-Dioxane, or CPME	No reaction	—
3	Toluene or MeCN	Trace	—
4	CH2Cl2	94	40 (+)
5	CHCl3	94	44 (+)

a) Determined by using HPLC (Daicel Chiralpak IE).

Next, we investigated the substrate scope of this catalyst system under the optimized reaction conditions (Chart 2). Regardless of whether the aromatic substituent of 1 is electron-withdrawing or electron-donating, β-ICD and 2 promoted the reaction. We used 2-(2-nitrovinyl)furan (1i) as a substrate, which afforded RC α-adduct 3i in 90% yield with 44% ee. The reaction of 1-methyl-2-(2-nitrovinyl)benzene (1j) and 1-nitrooct-1-ene (1k) allowed to produce 3j and 3k, however with low enantioselectivity or low chemical yield. The RC reaction of γ-methyl allenoate 2b as a substrate did not give the desired product 3l.

Chart 2. Substrate Scope^a)

a) ee values of products 3 were determined by using HPLC (Daicel Chiralpak IE for 3a–b; Daicel Chiralpak IB for 3c, 3g–h, and 3j; Daicel Chiralpak IF for 3d–f; Daicel Chiralpak IC for 3i, 3k). b) For 24 h. c) No reaction.

The α-substituted allenoates obtained via enantioselective intermolecular RC reactions are useful substrates for the furanone oxime synthesis.¹⁰⁾ Therefore, we investigated the one-pot synthesis of five-membered cyclic N-hydroxyimidic acid ester 5a. After mixing 1a and 2a in the presence of β-ICD and stirring for 1 h, MePPh₂ was added to the reaction mixture (Chart 3). As expected, N-hydroxyimidic acid ester 5a was obtained in 62% overall yield with 47% ee in two steps.¹⁷⁾

Chart 3. One-Pot Synthesis of Five-Membered Cyclic N-Hydroxyimidic Acid Ester 5a

In summary, we developed an atom-economic and stereoselective approach for the synthesis of chiral α-functionalized allenoates, via a catalytic, asymmetric RC reaction of nitroalkenes and allenoates. Our efforts are currently underway to determine absolute configuration of product 3, to improve the catalytic efficiency, and to apply this method to the synthesis of natural product.

Acknowledgments

This work was supported by the Japan Society for the Promotion for Science (JSPS) KAKENHI Grant Numbers JP16K08163 (C), JP16H01152 (Middle Molecular Strategy), and JP17H05373 (Coordination Asymmetry), the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, JSPS, and JST Advance Catalytic Transformation Program for Carbon Utilization (ACT-C) Grant Number JPMJCR12YK, JSPS Core-to-Core Program, A. Advanced Research Networks, and Sakura Program. K. K. thanks the Grant-in-Aid for JSPS Research Fellow. We acknowledge the technical staff of the Comprehensive Analysis Center of ISIR, Osaka University (Japan).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

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