Jie
Wang‡
a,
Wei-Feng
Zheng‡
a,
Yuling
Li
b,
Yin-Long
Guo
*b,
Hui
Qian
*a and
Shengming
Ma
ab
aResearch Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433, P. R. China. E-mail: qian_hui@fudan.edu.cn
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, P. R. China. E-mail: ylguo@sioc.ac.cn
First published on 1st March 2024
We report here an asymmetric carboxylation reaction based on kinetic resolution of tertiary propargylic alcohols by identifying Pd((R)-DTBM-SEGphos)Cl2 as the pre-catalyst. A variety of optically active tertiary propargylic alcohols and tetrasubstituted 2,3-allenoic acids were obtained in good yields with excellent enantioselectivities. The salient features of this report include the use of readily available substrates, a readily available precatalyst, mild reaction conditions, remarkable functional group tolerance, gram-scale synthesis, and versatile synthetic transformations. Mass spectrometry experiments trapped some key intermediates, which revealed the mechanism.
Entry | x | T (°C) | t (h) | (S)-2a | (S)-1a | (E)-2a′ | 1a′ |
---|---|---|---|---|---|---|---|
Yield,b eec (%) | Recovery,b eec (%) | Yieldb (%) | Yieldb (%) | ||||
a Reaction conditions: rac-1a (0.2 mmol), Pd((R)-DTBM-SEGphos)Cl2 (2 mol%), (PhO)2POOH (x mol%), and H2O (20 equiv.) in toluene (1 mL) at T °C with a CO balloon unless otherwise noted. b Determined by 1H NMR analysis using dibromomethane as the internal standard. c Determined by HPLC analysis. d 20 mol% PPh3 was added. | |||||||
1d | 20 | −5 | 18 | 0, — | 100, — | — | — |
2d | 2 | 25 | 18 | 23, 90 | 78, 30 | — | — |
3 | 20 | 15 | 18 | 17, 93 | 78, 16 | — | 5 |
4 | 20 | 15 | 36 | 20, 94 | 65, 19 | — | 13 |
5 | 20 | 20 | 18 | 51, 85 | 44, 90 | 2 | 4 |
6 | 15 | 20 | 18 | 51, 84 | 41, 93 | 2 | 4 |
7 | 10 | 20 | 18 | 51, 82 | 46, 98 | 2 | 2 |
8 | 10 | 20 | 12 | 45, 91 | 54, 70 | — | — |
9 | 5 | 20 | 18 | 55, 82 | 45, 96 | — | — |
10 | 2.5 | 20 | 18 | 51, 85 | 51, 91 | — | — |
Next, we turned our attention to the substrate scope for the formation of chiral 2,3-allenoic acids (Scheme 3). No obvious steric effect was observed since the substrates containing the methyl group at the 2-, 3- or 4-position of the phenyl group provided the targeted products (S)-2b, (S)-2c and (S)-2w in good yields (37%–41%) with high ee (91%–92%). The substrates bearing the functional groups OMe, Cl, Br, and CO2Me on the phenyl ring also underwent the carboxylation reaction efficiently, affording the corresponding products (S)-2d–(S)-2g in good yields with more than 90% ee. 2-Naphthyl substituted and 3-thienyl substituted propargylic alcohols were also well tolerated (1h and 1x). Notably, the alkyl substituted substrates at R3 could also be converted to the desired products (S)-2i and (S)-2j smoothly. R1 with different carbon chains bearing a variety of different functional groups (halide, cyano, allyl) afforded the desired products (S)-2k–(S)-2s and (S)-2u in good yields with no less than 90% ee. Furthermore, when R2 was an ethyl group, the reaction also formed the chiral 2,3-allenoic acids (S)-2t and (S)-2v with high enantioselectivities. However, when R2 was Bn, the reaction was slow, affording 15% of (S)-2y with 71% ee after 72 hours.
Combining the 1H NMR monitoring experiment (for details see ESI Table 1†) and mass spectrometric studies, a catalytic cycle was proposed as shown in Scheme 6. First, Pd((R)-DTBM-SEGphos)Cl2I would be reduced in situ to form the catalytically active species Pd(0)((R)-DTBM-SEGphos) II. Then II would react with the configuration-matched H+-activated propargylic alcohol (R)-1′ to afford the allenylpalladium intermediate (Sa)-MS-Int. IIvia stereo-defined anti-SN2′-type oxidative addition. The subsequent reaction of (Sa)-MS-Int. II with CO and H2O delivered the carboxylation intermediate (Sa)-MS-Int. III and/or (Sa)-MS-Int. III′, which generated the product 2,3-allenoic acid (S)-2avia reductive elimination. Moreover, the slowly reacting propargylic alcohol (S)-1a could be recovered in excellent ee.
Footnotes |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo00082j |
‡ These authors contributed equally. |
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