Enantiocontrolled Connective Synthesis of Allenes by Carbenoid Eliminative Cross-Coupling between α-(Methylthio)vinylcuprate Species and α-(Carbamoyloxy)alkylboronates

Abstract

A convenient enantiocontrolled synthesis of allenes (R¹R²C=C=CHR³, R¹ = aryl/alkyl, R², R³ = alkyl) is described based on carbenoid eliminative cross-coupling (CEX_C) between geometrically pure higher-order α-(methylthio)vinylcuprates, generated in situ by carbocupration of thioalkynes (then activation by addition of n-BuLi), and enantioenriched α-(carbamoyloxy)alkylboronates (15 examples, 30–78% yield, 15–95% ee). The stereochemical fidelity of this CEX_C process is substrate dependent, a phenomenon tentatively attributed to a putative organocopper-mediated allene racemization pathway.

Key words

allene - ate complex - carbenoid - double bond - elimination - 1,2-metalate rearrangement

Publikationsverlauf

Eingereicht: 14. Februar 2023

Angenommen nach Revision: 12. April 2023

Accepted Manuscript online:
12. April 2023

Artikel online veröffentlicht:
06. Juni 2023

• References and Notes

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For reviews on allene synthesis, see:
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The most common indirect approaches for stereocontrolled allene synthesis involve stereospecific and/or enantioselective reactions from propargyl (and other alkynyl) systems, e.g.:
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Ketene olefination has been a viable strategy for allene synthesis for over a century and it offers options for enantiocontrol. For the inaugural report and a more recent stereocontrolled example, see:
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• 10 Four pathways are potentially available to lead from the carbenoid substrates to the product C=C system in CEX_C (only one pathway is shown in Scheme 1 for the sake of simplicity). This is because, in principle at least, either M or M′ could act as the site of ate-complex formation, and either X or X′ could act as the nucleofugal leaving group in the rearrangement step. In the welcome scenario that the stereospecificity of each process is the same regardless of M vs. M′ or X vs. X′, all four pathways converge on the same stereoisomer of the product and so which pathway is followed is inconsequential. If this is not the case, however (e.g., vicinal M and X eliminate in a syn fashion but perhaps M and X′ eliminate in an anti fashion), then promiscuity between competing pathways will result in an erosion in stereochemical fidelity. See ref. 9 for further details.
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Numerous ingenious CEX_C-based allene syntheses using α-chlorovinylmagnesiums generated in situ by sulfoxide–metal exchange have been introduced by the Satoh group. For selected examples, see:
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Reviews:
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• 21 Representative Procedure for the Synthesis of (M)-5-(4-Methoxyphenyl)-1-phenyl-3,4-nonadiene (24d, Table [2], Entry 4) A solution of thioester 20d (62.0 mg, 0.348 mmol)²⁰ and CuI (62 mg, 0.325 mmol) in dry Et₂O (6 mL) at rt under Ar was treated with n-BuLi (0.25 mL, 2.30 M in hexanes, 0.575 mmol) and stirred for 10 min. The reaction mixture was cooled to –78 °C, and n-BuLi (0.30 mL, 2.30 M in hexanes, 0.69 mmol) was added. The resulting solution of putative higher-order vinylcuprate (E)-22d was stirred for 3 h at –78 °C. Boronate (R)-23a (156 mg, 0.416 mmol)^11a in dry PhMe (4.5 mL) was added, and the reaction mixture was stirred for 1 h at –78 °C, allowed to warm to rt, and then heated at 75 °C (bath temperature) for 30 min. The reaction mixture was cooled to rt, sat. aq. NH₄Cl (3 mL) was added, and the layers separated. The aqueous phase was extracted with Et₂O (3 × 5 mL), and the combined organic phases were washed with brine (5 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, eluting with 0–10% CH₂Cl₂ in hexanes) to afford allene (M)-24d (66.8 mg, 0.218 mmol, 63%, 95% ee) as a colorless oil: [α]_D ²⁰ –92.0 (c 0.40, CHCl₃). IR (neat): 2956, 2870, 1947, 1604, 1510, 1250, 1173, 832, 699 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.30–7.18 (7 H, m), 6.82 (2 H, d, J = 8.1 Hz), 5.49 (1 H, tt, J = 6.7, 2.7 Hz), 3.80 (3 H, s), 2.79 (2 H, tm, J = 7.2 Hz), 2.46–2.40 (2 H, m), 2.36–2.30 (2 H, m), 1.51–1.32 (4 H, m), 0.92 (3 H, t, J = 7.2 Hz) ppm. ¹³C NMR (175 MHz, CDCl₃): δ = 203.5 (0), 158.4 (0), 142.0 (0), 129.8 (0), 128.8 (2 C, 1), 128.5 (2 C, 1), 127.1 (2 C, 1), 126.0 (1), 113.9 (2 C, 1), 105.6 (0), 93.7 (1), 55.5 (3), 35.8 (2), 31.3 (2), 30.3 (2), 30.0 (2), 22.7 (2), 14.2 (3) ppm. See the Supporting Information for a more detailed experimental procedure and a description of the CSP HPLC analysis method used to determine ee.

Organocopper species are known to racemize allenes, but the process is generally slow, and it does not necessarily preclude enantiocontrolled allene formation using copper reagents and catalysts (e.g., ref. 5f), see:
• 22a Claesson A, Olsson L.-I. J. Chem. Soc., Chem. Commun. 1979; 524
• 22b Alexakis A, Marek I, Mangeney P, Normant JF. J. Am. Chem. Soc. 1990; 112: 8042