ABSTRACT
Transition‐metal‐catalyzed cycloisomerization of vinyl‐allenes has attracted enormous attention over the past decades, and multitudinous efficient synthetic strategies have been discovered based on this methodology. However, the generation of metal carbenes in these reactions is mostly limited to the noble‐metal catalysts (Au and Pt). Here we show that non‐noble‐metal catalyst (Cu) enable the catalytic cycloisomerization/oxidation of vinyl‐allenes by generating α‐alkyl alkenylcopper carbenes. This protocol leads to the practical and controllable construction of various valuable cyclopentenones in mostly good to excellent yields.
Keywords: Allenes, copper, Cycloisomerization, Donor/Donor Carbenes, Oxidation
Transition‐metal‐catalyzed cycloisomerization of vinyl‐allenes for the generation of metal carbenes has attracted enormous attention. However, this method is mostly limited to the noble‐metal catalysts. Here we show that non‐noble‐metal‐catalyzed cycloisomerization/oxidation of vinyl‐allenes by generating α‐alkyl alkenylcopper carbenes, thus leading to the practical and controllable construction of various valuable cyclopentenones
.
1. Introduction
Cyclopentenones are important constituents of numerous bioactive molecules as well as natural products featuring interesting biological activities such as cis‐jasmone [1], natural product ktedonoketone [2], trichodenone B [3], didemnenones D [4], prostaglandin A1 [5], combretastatin A‐4 [6], sesquiterpenes from Acorus calamus rhizomes (Figure 1) [7]. Their enone structure allows a broad diversity of chemical transformations at all five positions on the ring structure, including carbonyl reactivities, enone reactivities, olefin reactivities, and reactivities at allylic position [8, 9, 10]. As such, the synthesis of these substituted cyclopentenones has received extensive attention, including aldol reaction [11], ring‐closing metathesis [12], Nazarov cyclization [13, 14, 15], Pauson−Khand reaction [16, 17], Piancatelli rearrangement [18, 19], and ring‐expansion reactions [20]. Despite these achievements, the development of new strategies is still urgently needed.
FIGURE 1.
Selected examples bearing the cyclopentenone core structure.
Allenes have proven to be powerful synthons in organic chemistry due to the broad diversity of functionalizations at all three positions on the allene structure [21, 22, 23, 24, 25, 26, 27]. Recently, catalytic generation of metal carbenes from easily available allenes represent an important progress in metal carbene chemistry, as they circumvented the employment of potentially explosive and not easily accessible diazo compounds as starting materials [28, 29]. For example, a gold(I)‐catalyzed cycloisomerization of cyclohexenyl‐allenes for the synthesis of cyclopentadienes via a presumable gold carbenes has been discovered by Toste et al. (Scheme 1a) [30]. In addition, Liu and co‐workers showed that gold carbenes generated from the cycloisomerization of vinyl‐allenes could be used for the construction of
SCHEME 1.
Generation of metal carbenes from allenes.
Various heterocycles (Scheme 1b) [31, 32]. In spite of these significant achievements, these reactions have been mostly limited to noble‐metal catalysts. Thus, the development of non‐noble metal‐catalyzed cycloisomerization of vinyl‐allenes for the generation of metal carbenes is highly desirable. With our continuous interest in allene chemistry [33, 34, 35]. we herein describe an efficient copper‐catalyzed cycloisomerization/oxidation of vinyl‐allenes via the donor/donor copper carbenes, thus leading to highly site‐selective synthesis of a range of cyclopentenones (Scheme 1c).
2. Results and Discussion
At the outset, vinylallene 1a was chosen as model substrate (see the Supporting Information for details) and a range of experiments were executed by using TBHP 2a as the oxidant (Table 1). Optimized conditions involved the employment of Cu(CH3CN)4PF6 as the catalyst using MeCN as the solvent and TBHP 2a as oxidant, at 60°C, affording the cyclopentenone 3a in 75% yield (entry 1). Other copper catalysts, such as Cu(CH3CN)4BF4, Cu(CH3CN)4OTf, CuOTf, CuI or Cu(OAc)2, were inefficient (entries 2−6). Decreasing the reaction temperature to 40°C and elevating the reaction temperature to 80 °C, were inefficient (entries 7−8). The selection of solvent is essential and MeCN was the most suitable, and acetone, DCE, and PhCl were mediocre (entries 9−11). Control experiments suggested the indispensable role of the copper catalyst and oxidant, and this cycloisomerization/oxidation reaction failed to produce even a trace of 3a in the absence of the catalyst or oxidant (entries 12−13).
TABLE 1.
Optimization of reaction conditions. a
|
| Entry | Variations | Yield (%) 3a b |
|---|---|---|
| 1 | None | 75 |
| 2 | Cu(CH3CN)4BF4 instead of Cu(CH3CN)4PF6 | 51 |
| 3 | Cu(CH3CN)4OTf instead of Cu(CH3CN)4PF6 | 32 |
| 4 | CuOTf instead of Cu(CH3CN)4PF6 | 53 |
| 5 | CuI instead of Cu(CH3CN)4PF6 | 57 |
| 6 | Cu(OAc)2 instead of Cu(CH3CN)4PF6 | 56 |
| 7 | 40°C instead of 60°C | 43 |
| 8 | 80°C instead of 60°C | 64 |
| 9 | acetone instead of MeCN | 26 |
| 10 | DCE instead of MeCN | 35 |
| 11 | PhCl instead of MeCN | 24 |
| 12 | no Cu(CH3CN)4PF6 | <1 |
| 13 | no TBHP | <1 |
The reaction was performed with 1a (0.1 mmol), 2a (0.3 mmol), and catalyst (10 mol %) in MeCN (4 mL) at 40 to 80 °C in vials.
Measured by 1H NMR analysis using diethyl phthalate as the internal standard.
With the optimized reaction conditions in hand, we then set out to assess the scope of the reaction by varying the vinylallenes (Table 2). Allenes with either electron‐withdrawing or ‐donating substituents, such as F, Cl, Br, Me, OMe, and even I, on the aromatic ring, were suitable substrates and were transformed into the expected cyclopentenones 3b–g in 61%–90% yields. The molecular structure of 3e was further confirmed by X‐ray diffraction (see the Supporting Information for details) [36]. Substitutions at different positions on R1 were easily tolerated, leading to the cyclopentenones 3h–o in yields ranging from 64% to 95%. In particular, this tandem reaction proceeded smoothly with allenes bearing sterically hindered ortho substituents. Moreover, it was found that the naphthalene‐linked allene 3p also worked well. This catalytic reaction also proceeded smoothly with allenes by changing R3 group from Me to more steric hindered n‐butyl and changing R2 group from Me to more sterically demanding groups such as Et and Ph, leading to the formation of the corresponding cyclopentenones 3q–v in yields ranging from 57% to 88%. Changing R1 from phenyl to furan, thiophene, cyclopropyl, cyclopentyl, ethyl slightly impacted the yields, affording the resulting cyclopentenones 3w–aa in 51%−69% yields.
TABLE 2.
Reaction scope for the formation of cyclopentenones 3. a
|
1 = 0.05 M; isolated yields are reported.
8.0 mmol scale.
The synthetic utility of the functionalized cyclopentenones were examined (Scheme 2). First, 3a was prepared on a gram scale in 70% yield under the optimized reaction condition (see the Supporting Information for details). Subsequently, 3a could be selectively reduced by i Bu2AlH into cyclopentenol 4 in almost quantitative yield. Additionally, 3a could be readily converted into the compound 5 in 52% yield by relevant oxidative chlorination at adjacent position to the carbonyl group (see the Supporting Information for details).
SCHEME 2.
Synthetic transformations.
A possible mechanism for the formation of 3a was presented (Scheme 3). First, the copper‐catalyzed cycloisomerization/oxidation began with exergonic η 2‐coordination to the olefinic unit of 1a, forming reactant Cu‐activated allene complex A, followed by intramolecular nucleophilic attack by the vinyl group to form allylic cation intermediate B. Then, regiospecific vinyl‐allene cyclization occurred to provide the donor/donor type carbene of α‐alkyl alkenylcopper carbene C. This result was consistent with our previous work [33], in which α‐alkyl alkenylcopper carbene was presumably involved through cyclization of divinylallene. The formation of copper carbene was also strongly supported by theoretical calculations in our previous work. Finally, α‐alkyl alkenylcopper carbene C could be oxidized by 2a [33], yielding the functionalized cyclopentenone 3a. In particular, the undesired 1,2‐H shift could be completely suppressed in such an oxidative copper catalysis.
SCHEME 3.
Plausible reaction mechanism for the formation of 3a.
3. Conclusion
In conclusion, we have discovered an efficient copper‐catalyzed cycloisomerization/oxidation of vinyl‐allenes via intramolecular cyclization‐initiated carbene oxidation, enabling the practical and controllable synthesis of a range of valuable functionalized cyclopentenones. Compared to the related gold catalysis, copper catalysis may be advantageous in catalytic asymmetric reactions over gold catalysis due to the linear coordination favored by gold. The development of copper‐catalyzed asymmetric cascade cyclization of vinyl‐allenes and mechanistic explorations are the themes of continuing study in our laboratory.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Detailed experimental procedures and complete characterization data (including 1H, and 13C NMR spectra) for all new compounds are provided in the Supporting Information.Supporting File 1: asia70816‐sup‐0001‐SuppMat.pdf.
Supporting File 2: asia70816‐sup‐0002‐Data.rar.
Acknowledgments
We are grateful for financial support from the Sponsored by Natural Science Foundation of Henan (252300420245), the financial support from the Postgraduate Education Reform and Quality Improvement Project of Henan Province (YJS2026XSJC23), the National Natural Science Foundation of China (22001059).
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Detailed experimental procedures and complete characterization data (including 1H, and 13C NMR spectra) for all new compounds are provided in the Supporting Information.Supporting File 1: asia70816‐sup‐0001‐SuppMat.pdf.
Supporting File 2: asia70816‐sup‐0002‐Data.rar.
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.