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H Bond Activation-Based Catalytic Approach to Tetrasubstituted Chiral Allenes

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H Bond Activation-Based Catalytic Approach to Tetrasubstituted Chiral Allenes ARTICLE Received 7 May 2015 | Accepted 25 Jun 2015 | Published 6 Aug 2015 DOI: 10.1038/ncomms8946 OPEN A C–H bond activation-based catalytic approach to tetrasubstituted chiral allenes Shangze Wu1, Xin Huang1, Wangteng Wu1, Pengbin Li1, Chunling Fu1 & Shengming Ma1 Enantioselective synthesis of fully substituted allenes has been a challenge due to the non-rigid nature of the axial chirality, which spreads over three carbon atoms. Here we show the commercially available simple Rh complex may catalyse the CMD (concerted metalation/deprotonation)-based reaction of the readily available arenes with sterically congested tertiary propargylic carbonates at ambient temperature affording fully substituted allenes. It is confirmed that the excellent designed regioselectivity for the C–C triple bond insertion is induced by the coordination of the carbonyl group in the directing carbonate group as well as the steric effect of the tertiary O-linked carbon atom. When an optically active carbonate was used, surprisingly high efficiency of chirality transfer was realized, affording fully substituted allenes in excellent enantiomeric excess (ee). 1 Laboratory of Molecular Recognition and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang 310027, China. Correspondence and requests for materials should be addressed to S.M. (email: [email protected]). NATURE COMMUNICATIONS | 6:7946 | DOI: 10.1038/ncomms8946 | www.nature.com/naturecommunications 1 & 2015 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8946 llenes have been becoming more and more important due Results to their presence in nature and the recent demonstration Identification of the leaving group. With the purpose of Aof their great potentials in modern organic chemistry synthesizing the most challenging tetra-subtituted allenes, we first with very nice reactivities, which led to their versatile applications tried to identify a proper leaving group for the tertiary in the efficient total syntheses of some natural products propargylic alcohol (Fig. 2): When N-methoxybenzamide 1a was 1–4 and drugs . Thus, the highly selective synthesis of allenes reacted with tertiary propargylic methyl ether 2a1 in a mixed is of great importance5–10. On the basis of recent advance- solvent of MeOH and water (20/1) under the catalysis of ments, the enantioselective synthesis of 1,3-disubstituted or [Cp*RhCl2]2 at room temperature, no allene was formed with 1a 1,1,3-trisubstituted allenes has been at least partially solved6, being recovered; when we introduced a phosphate as leaving however, enantioselective synthesis of tetrasubstituted is still a group (2a2), interestingly the expected tetrasubstituted allene 3aa 6–10 18 challenge . Here we propose that the well-established CMD was afforded in 8% NMR yield! When propargylic acetate 2a3 (concerted metalation/deprotonation) process of arenes11–16 was used, the yield was improved to 46%; with these results in would generate organometallic intermediates in situ, which hand, we envisioned to have a methoxy group to replace the would, in principle, react with 2-alkynylic derivatives with an methyl group in the acetyl unit to increase the electron density of appropriate leaving group to afford allenes via regioselectivity- the carbonyl oxygen, that is, carbonate: to our delight, the reversed insertion and thermodynamically non-favoured carbonate 2a was indeed the best and the yield was further b-elimination (Fig. 1b). However, the challenge is the improved to 76%. After further optimization of the parameters of regioselectivity of the carbometalation of the C–C triple bond the reaction, the reaction of 1.2 equiv. 1a and 2a in a mixed with the in situ generated aryl metallic species17–22 since the solvent of MeOH and water (20/1) under the catalysis of reported insertion reaction with the C–C triple bond in [Cp*RhCl2]2 with 30 mol% NaOAc as base was chosen as the propargylic alcohols affording the [4 þ 2]-products with the optimized reaction conditions for further study (for details of undesired regioselectivity18. To achieve our goal, we proposed to optimization, see Supplementary Table 1). reverse the regioselectivity by installing a directing entity in the propargylic leaving group, thus avoiding the formation of Substrate scope. The reaction proceeded well on a gram scale, undesired B-type insertion intermediate18. In addition, it affording 3aa in 82% yield (Fig. 3). Having the optimized reaction should be noted that stereospecific b-elimination of the targeted conditions in hand, the generality of the reaction was then intermediate A providing highly optically active allenes is investigated. Electron-donating groups such as t-butyl and challenging as the Rh-catalysed reaction of stoichiometric methoxy as well as electron-withdrawing groups such as CF and amount each of aryl boronic acids and optically active 3 F in the aryl unit were all tolerated in the amides giving the propargylic acetates with forming allenes in an extremely low corresponding fully substituted allenes in good to excellent yields efficiency of chirality transfer due to the mixed syn- and anti- (Fig. 3; 3aa, 3ba, 3ca, 3da, 3ea, 3bf and 3cf). It was noteworthy non-stereospecific b-elimination23–25. In such a well-designed that when a meta-substituted 1d was used, the less hindered C–H process, the oxidation state of the metal in the catalyst would bond was exclusively functionalized and an o-fluorine atom did remain the same, thus, making it catalytic in [M] and free of any not hamper the reaction affording 3ea in 79% yield (Fig. 3, 3da oxidants for the regeneration of catalyst in many of C–H and 3ea). The R1,R2, and R3 groups in the 2-alkynylic carbonate functionalization reactions11–16. could be alkyl or aryl groups (Fig. 3; 3ac, 3ad, 3ae, 3af, 3ag, 3ah, Herein, we wish to report the realization of such a concept for 3bf and 3cf). Substrates with sterically hindered i-Bu or o-tolyl the synthesis of tetrasubstituted allenes via the commercially groups also worked (Fig. 3, 3ac and 3ag). available [Cp*RhCl2]2 catalysed coupling between readily avail- able essential chemicals, that is, arenes and 2-alkynylic carbonates with a surprisingly high efficiency for point-to-axial chirality Compatibility of functional groups. To show the robustness of transfer. After careful studies, it is believed that the directing our newly developed catalytic allene synthesis strategy, substrates group and the steric effect of the tertiary 2-alkynylic carbonates with synthetically useful yet sensitive functional groups were are responsible for the reversed regioselectivity for the insertion of explored without any protection: to our delight, Cl, Br, CO2Me, the C–C triple bond. CN and even unprotected free alcohol were all well tolerated, a CMD process of arenes and the subsequent reaction with a C–C triple bond 2 1 2 1 2 Cat. [M] R1 R R R R R R–H R–[M] + R M M R b This work: R–M formation via CMD-regiospecific insertion affording A-stereospecific β-elimination R2 R1 R3 1 2 X Y R R Cat. [M] DG R–H R–[M] 2 3 R 3 R R R R2 R3 R1 R1 X catalytic in [M] X DG DG RM MR A B Figure 1 | Carbometallations of alkynes. (a) CMD-based reaction of R–H with alkynes. (b) This work: new concept and challenge for allene synthesis. 2 NATURE COMMUNICATIONS | 6:7946 | DOI: 10.1038/ncomms8946 | www.nature.com/naturecommunications & 2015 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8946 ARTICLE O O 2 mol% [Cp*RhCl2]2 OMe OMe N N 30 mol% NaOAc H H + Bu Bu MeOH/H O = 20/1, LG 2 room temperature 1a 2 3aa Bu Bu Bu Bu OMe O O O O P OEt O O OEt OMe 2a1 2a1 2a3 2a no reaction 8% 46% 76% 1 Yields were determined by H NMR using CH2Br2 as internal standard. Figure 2 | The effect of leaving groups. A carbonate was found to be the most efficient. O O 2 mol% [Cp*RhCl2]2a OMe OMe R2 N N 30 mol% NaOAc R H 1 3 R H + R R R1 MeOH/H2O = 20/1, 0 °C OCO2Me 12 R2 R3 3 O O OMe 1 2 b OMe 3ac, R = Bu, R = i-Bu, 68% N 3aa, R = H, 80% (82%) N 1 2 d,e,f R H 3ad, R = n-C H , R = Ph, 56% 3ba, R = 4-t-Bu, 73% H 5 11 Bu R1 3ae, R1= Ph, R2 = Me, 80%g 3ca, R = 4-OMe, 74%c 3af, R1= Ph, R2 = Et, 79%g 3da, R = 3-CF3, 83% 1 2 g 3ag, R = o-MeC6H4, R = Me, 77% 3ea, R = 2-F, 79% R2 O O O OMe OMe OMe N N N H H H Bu t-Bu Ph MeO Ph Et Et Et Et 3ah, 77% 3bf, 73%h 3cf, 74%i Figure 3 | Substrate scope. Electron-withdrawing and electron-donating as well as bulky groups were all tolerated. aThe reaction was conducted b with 1 (1.2 mmol), 2 (1 mmol), [Cp*RhCl2]2 (0.02 mmol), NaOAc (0.3 mmol), MeOH (6 ml), and H2O (0.3 ml) and monitored by TLC. Reaction was conducted on 7 mmol scale. cReaction was conducted at À 10 °C, 1a (1.3 mmol) and NaOAc (1 mmol) was used. dReaction was conducted at room e f g temperature. 1a (2 mmol), [Cp*RhCl2]2 (0.05 mmol) was used. The acetate was used instead because of the unstability of the carbonate. 1a (1.5 mmol), h i [Cp*RhCl2]2 (0.04 mmol) was used. 1b (1.5 mmol), [Cp*RhCl2]2 (0.04 mmol) was used. 1c (1.5 mmol), [Cp*RhCl2]2 (0.04 mmol) was used. showing the broad synthetically attractive functional group exclusively functionalized giving 3ka in 81% yield (Fig.
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