Phosphine-Promoted [3 + 3] Annulations of Aziridines With Allenoates: Facile Entry Into Highly Functionalized Tetrahydropyridines

Abstract

The phosphine-mediated [3 + 3] annulations of aziridines and allenes are experimentally simple reactions, run under very mild conditions, for the preparation of highly functionalized tetrahydropyridines in yields of up to 98% and trans/cis ratios of up to 97:3. In addition to steps that are typical of nucleophilic phosphine-catalyzed reactions of allenoates, the mechanism of this new reaction features apparent nucleophilic aromatic substitution and concomitant desulfonylation, hitherto unknown processes during phosphine-promoted cycloaddition reactions. Notably, these reactions are the first reported examples of aziridines as reaction partners in nucleophilic phosphine-catalyzed transformations.

Intermolecular cycloadditions are powerful reactions for synthesizing carbo- and heterocycles from simpler starting materials.¹ The development of many transition metal- and organomolecule-promoted cycloadditions has expanded the scope of starting materials that can be engaged in such transformations.² Nucleophilic phosphine catalysis is now established as a reliable platform for cycloadditions employing activated allenes as one of the reaction partners.³ In phosphine-promoted processes, allenes typically react as three- and four-carbon synthons in [3 + 2] and [4 + 2] additions, respectively, with alkenes or imines.⁴ Based on this behavior, we pondered the possibility of employing aziridines as a three-atom components in [4 + 3] and [3 + 3] annulations with allenoates (Eq 1).

(1)

While [4 + 2] and [3 + 2] cycloadditions are used widely in organic synthesis, only a limited number of [3 + 3] additions have been reported to date.⁵ Aziridines contain one of the most valuable three-membered ring systems in modern synthetic chemistry; they are extremely versatile synthetic building blocks.⁶ Although formal [3 + 3] cycloadditions of aziridines with Pdtrimethylenemethane (TMM) species have been used to furnish piperidines,^5b the phosphonium enolate zwitterionic intermediate⁷ has not been employed previously for coupling with aziridines. Herein, we describe the development of a new phosphine-promoted [3 + 3] annulation of aziridines with allenoates to afford highly functionalized tetrahydropyridines under simple and mild conditions (Eq 2).

(2)

Initially, we examined the reaction of N-nosylaziridine 1a and diethyl 2-vinylidenesuccinate (2) with PBu₃ (20 mol%) at room temperature (Table 1, entry 1).⁸ Although the aziridine was consumed completely within 24 h, we obtained no product from its coupling with the allenoate. Given that the aziridine ring can be opened directly through nucleophilic attack,⁹ we employed the weaker nucleophile PPh₃ to take advantage of its more discerning reactivity.¹⁰ To our delight, we isolated the [3 + 3] adduct 3a in modest yield and excellent diastereoselectivity (trans/cis, 10:1; entry 2).¹¹ Surprisingly, the three carbon atoms constituting the tetrahydropyridine 3a were the α, β, and β´ carbon atoms of the starting allenoate rather than the α, β, and γ carbon atoms encountered in well-established phosphine-mediated [3 + 2] annulations.⁴ Moreover, the p-nitrobenzene ring was attached to the γ carbon atom of the starting allenoate, with an apparent loss of SO₂ (vide infra). The reaction yield improved significantly, without erosion of the diastereoselectivity, after increasing the amount of PPh₃ (entry 3). Although NMR spectroscopy revealed that some free phosphine remained after the reaction, we added 1 equiv of phosphine to expedite the reaction (entry 4); more than 1 equiv of PPh₃ did not improve the reaction efficiency (entry 5). The reaction was best run in CH₂Cl₂ (entry 6) and at room temperature; the product decomposed at elevated temperatures (entry 7). Other tertiary phosphines did not facilitate the reaction as well as PPh₃ did (entries 8–11).

Table 1.

Phosphine-Mediated [3 + 3] Aziridine/Allene Annulation^a

entry	PR3	mol%	yield (%)b	dr (trans/cis)c
1	PBu3	20	0	N/A
2	PPh3	20	15	10:1
3	PPh3	50	37	9:1
4	PPh3	100	73	9:1
5	PPh3	200	61	9:1
6d	PPh3	100	63	9:1
7e	PPh3	100	48	9:1
8	EtPPh2	100	2	–
9	Et2PPh	100	0	N/A
10	P(NMe2)3	100	0	N/A
11	P(OEt)3	100	0	N/A

^aAll reactions were performed using 0. 1 mmol of 1a and 4.8 equiv of 2 in CH₂Cl₂ at rt for 72 h, unless otherwise specified.

^bIsolated yield after chromatographic purification.

^cDiastereoisomeric ratio determined through HPLC (internal standard: 2-bromopyridine).

^d1,2-Dichloroethane as solvent; other common organic solvents provided isolated product yields of less than 10%.

^e40 °C, 48 h.

We examined a range of aziridine derivatives for their [3 + 3] annulations under the optimized reaction conditions (Table 2). Aryl-substituted aziridines underwent the reaction in good to excellent yield with good 1,2-trans-diastereoselectivity; phenyl groups featuring electron-withdrawing or -donating substituents at the ortho, meta, and para positions worked well (entries 1–11), as did a naphthyl group (entry 12). Interestingly, the alkyl-substituted aziridine 1n provided a different regioisomeric tetrahydropyridine with diminished diastereoselectivity, favoring the formation of the 1,3-cis-product 3n (entry 13).¹¹ Whereas aryl-substituted C–N bonds of aziridines are polarized for nucleophilic fission, alkyl-substituted carbon atoms block direct nucleophilic attack. The unsubstituted aziridine substrate provided a poorer yield (entry 14), presumably because it is more susceptible to phosphine-mediated direct ring opening, leading to undesired side products.⁹

Table 2.

Syntheses of Tetrahydropyridines^a

entry	R1	R2	product	yield (%)b	dr (trans/cis)c
1	H (1b)	2-MeC6H4	3b	88	90:10
2	H (1c)	3-MeC6H4	3c	82	86:14
3	H (1d)	4-MeC6H4	3d	64	89:11
4	H (1e)	2,4-Me2C6H3	3e	82	81:19
5	H (1f)	2,5-Me2C6H3	3f	98	92:8
6	H (1g)	4-FC6H4	3g	76	88:12
7	H (1h)	2-ClC6H4	3h	46	97:3
8	H (1i)	3-ClC6H4	3i	86	83:17
9	H (1j)	4-ClC6H4	3j	84	90:10
10	H (1k)	3-BrC6H4	3k	58	85:15
11	H (1l)	4-BrC6H4	3l	75	88:12
12	H (1m)	2-naphthyl	3m	58	85:15
13	Me (1n)	H	3n	66	41:59
14	H (1o)	H	3o	37	N/A

^aAll reactions were performed using 0.1 mmol of the aziridine and 4.8 equiv of the allenoate.

^bIsolated yields.

^cDiastereoisomeric ratio determined using HPLC (internal standard: 2-bromopyridine).

To better understand the mechanisms of these intriguing processes, we subjected the deuterium-labeled allenoate 2D (92% D) to [3 + 3] annulations with the aziridines 1a and 1b (Scheme 1). We obtained the tetrahydropyridines 3p and 3q in yields comparable with those of the non-deuterated allenoate 2, but with 19 and 25% deuterium at the γ carbon atoms of 3p and 3q, respectively, and 27% deuterium at their β´ carbon atoms. The loss of deuterium content at the γ carbon atom and its incorporation at the β´ carbon atom suggests the formation of intermediates featuring carbanions located at both carbon atom centers. The decrease in the overall deuterium content was due to the presence of adventitious water, which facilitated the intermolecular proton transfer processes.¹²

Scheme 1.

Deuterium Labeling Experiments

Based on these observations, Scheme 2 presents our suggested reaction mechanism. Addition of PPh₃ to the allenoate forms the intermediate 4, which undergoes proton transfer to give the vinylogous ylide 5.^4k Aziridine ring opening occurs at the β´ carbon atom to furnish the intermediate 6.¹³ Sulfonamide/dienolate equilibrium⁴ⁱ provides the intermediate 7, which undergoes intramolecular¹⁴ nucleophilic aromatic substitution and concomitant desulfonylation.¹⁵ Subsequent conjugate addition and β-elimination of PPh₃ generates the tetrahydropyridine product 3.¹⁶

Scheme 2.

Suggested Mechanism for the Formation of Tetrahydropyridine 3

In summary, we have developed a phosphine-mediated [3 + 3] cycloaddition annulation manifold for allenes, incorporating, for the first time, aziridine derivatives as reaction partners. The reaction is operationally simple and produces highly functionalized tetrahydropyridines in good to excellent yield with high levels of diastereoselectivity. The allenoate provides its α, β, and β´ carbon atoms in the [3 + 3] cycloaddition—a new mode of reactivity for this versatile class of molecules. The mechanism includes apparent intramolecular nucleophilic aromatic substitution and extrusion of SO₂; this unprecedented behavior expands the reaction repertoire of nucleophilic phosphine catalysis. We are currently exploring the further applications of azidirines in nucleophilic phosphine catalysis.

Supplementary Material

1_si_001. Supporting Information Available.

Representative experimental procedures and spectral data for all new compounds (PDF). Crystallographic data for 3a and 3n (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.