Nine-Membered Benzofuran-Fused Heterocycles: Enantioselective

Communication Cite This: J. Am. Chem. Soc. 2017, 139, 15304-15307

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Nine-Membered Benzofuran-Fused Heterocycles: Enantioselective Synthesis by Pd-Catalysis and Rearrangement via Transannular Bond Formation Zi-Qiang Rong,§,† Li-Cheng Yang,§,† Song Liu,‡ Zhaoyuan Yu,‡ Ya-Nong Wang,† Zher Yin Tan,† Rui-Zhi Huang,† Yu Lan,*,‡ and Yu Zhao*,† †

Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543 Republic of Singapore School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, People’s Republic of China

‡

S Supporting Information *

Scheme 1. Asymmetric Nine-Membered Ring Formation

ABSTRACT: The first enantioselective formal [5+4] cycloaddition is realized under palladium catalysis to deliver benzofuran-fused nine-membered rings. These medium-sized heterocycles and derivatives undergo unique rearrangements induced by transannular bond formation, resulting in the production of two classes of densely substituted polycyclic heterocycles in excellent efficiency and stereoselectivity.

M

edium-sized rings, and nine-membered ones in particular, represent a special group of chemical space distributed in many natural products and bioactive compounds.1 Due to their unique conformation, these mediumsized rings (and their macrocyclic analogs) are also known to undergo unconventional, stereoselective transformations based on a peripheral attack.2 More general exploration of the reaction profiles of this class of compounds, however, is rare in the literature, largely due to the lack of efficient access to them. Catalytic methods to deliver nine-membered rings in an enantioenriched form are especially under-developed; great progress has only been achieved for certain [4,1,3] bicyclic structures through a formal [6+3] cycloaddition (Scheme 1a).3 Very recently, an intriguing Ir-catalyzed allylic-substitutionretro-Mannich sequence was also reported for the synthesis of indole-fused nine-membered amines (Scheme 1b).4 The development of efficient and flexible synthesis of ninemembered rings through intermolecular cycloaddition is still highly desired and may allow the discovery of new reactivities of these intriguing cyclic compounds. We report herein the first example of enantioselective formal [5+4] cycloaddition between azadienes and vinylethylene carbonates (VECs) via palladium catalysis. The benzofuran-fused nine-membered heterocycles prepared in this way can undergo intriguing rearrangement induced by transannular bond formation to deliver two classes of novel polycyclic heterocycles bearing multiple stereogenic centers in high efficiency and stereoselectivity (Scheme 1c). Recent efforts from our laboratory have identified azadiene 15 as an effective four-atom synthon in cycloaddition reactions to produce benzofuran-fused heterocyclic compounds that represent an important structural motif in biologically active entities.6 The reaction of 1 with substituted VEC 27 under Pd© 2017 American Chemical Society

catalyzed conditions led to the efficient synthesis of ninemembered heterocycles 3.5b In an attempt to develop an enantioselective variant of this reaction, we examined various chiral ligands with Pd2(dba)3 for the model reaction of 1a and 2a (Scheme 2). We anticipated that stereoselectivity for this process would be challenging to achieve, as the discrimination of the pro-chiral faces of substrate 1 had to be realized by the chiral palladium catalyst associated with the other partner of this reaction (as illustrated by the proposed TS I, Scheme 2). Early efforts were focused on the screening of chiral ligands with an extended or congested environment. Unfortunately, such attempts led to significantly reduced reactivity. After much experimentation, good reactivity and promising selectivity were finally achieved with some classical bis- or monophosphine ligands that lack substitution on their backbones. In the presence of L6, in particular, a promising 79% ee was obtained for 3a with an excellent yield of 95%. Various reaction conditions were examined at this stage, and decreasing the reaction temperature Received: August 28, 2017 Published: October 17, 2017 15304

DOI: 10.1021/jacs.7b09161 J. Am. Chem. Soc. 2017, 139, 15304−15307

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Journal of the American Chemical Society Scheme 2. Optimization of Formal [5+4] Cycloadditiona

substrates to deliver 3m−3w in good enantioselectivity. Due to the relatively low reactivity of these substrates, these reactions had to be carried out at ambient temperature for high conversion. In the case of 3u, a single recrystallization boosted the ee to >99%, the absolute configuration of which was unambiguously assigned by X-ray analysis. Diastereoselective epoxidation of the olefin moiety of the enantioenriched nine-membered heterocycles through peripheral attack2 was also carried out to deliver the epoxyheterocycles 4 in high dr. The major diastereomers of these compounds were all isolated in good yield with >98% retention of enantiopurity (Scheme 4). Scheme 4. Diastereoselective Peripheral Epoxidationa

a

The reaction was carried out by using 2 equiv of 2a (vs 1a) and 5 mol % catalyst in toluene.

proved to be beneficial. When the reaction was carried out at 0 °C, the enantioselectivity of 3a could be increased to 88% ee. With the optimal reaction conditions in hand, we set out to explore the generality of this catalytic enantioselective synthesis of nine-membered heterocycles. As shown in Scheme 3, various Scheme 3. Scope of Formal [5+4] Cycloadditiona a

See Scheme 2 and the SI for details. All yields are isolated yields for the pure major diastereomer. bConfiguration confirmed by X-ray (SI).

With the epoxy-containing medium-sized heterocycles in hand, we turned our attention to the exploration of selective transformation of these compounds. Preliminary attempts on the substitution of the epoxide moiety with external nucleophiles were not successful, probably due to the blocking sterics from attacking across the interior of the cyclic structure. To our excitement, when compound 4a was simply treated with the common Lewis acid BF3, a clean conversion of the epoxynine-membered ring to a skeletally distinct benzofuran-fused [6,6] polycyclic compound 5a was observed with highly efficiency and excellent diastereoselectivity (Scheme 5). This transformation proceeded smoothly with a range of 4 bearing substituents at different positions and in all cases a single diastereomer of 5a−5e was formed with >98% chirality transfer from the substrate. The relative and absolute configuration of Scheme 5. Rearrangement of the Epoxy-Heterocycle 4

a

See Scheme 2 and the SI for details.

para-, meta- or ortho-substituents of both electron-rich and electron-poor characters at the aryl group on the substituted VECs could be well-tolerated to deliver 3a−3i in excellent yield and 86−92% ee. A furan-containing VEC could also undergo efficient cycloaddition to produce 3j in excellent yield and good ee. VECs bearing alkyl substituents also engaged in the cycloaddition to deliver 3k and 3l in high efficiency and good ee, demonstrating the wide scope for this catalytic asymmetric transformation. Various azadiene partners also engaged in efficient cycloaddition regardless of the electronic properties on the 15305

DOI: 10.1021/jacs.7b09161 J. Am. Chem. Soc. 2017, 139, 15304−15307

Communication

Journal of the American Chemical Society

excited to observe a clean conversion of 3a to a mixture of diastereomers 6a and epi-6a in a good 6:1 dr (Scheme 7). The

this series of products were unambiguously assigned by single crystal X-ray analysis of 5e. It is noteworthy that this intriguing transformation involves the cleavage and formation of multiple C−C and C−O bonds. In particular, the electron-rich amino-substituted benzofuran moiety likely serves as the nucleophile to attack the activated epoxide through a transannular C−C bond formation to initiate the rearrangement process.8 Through this one-pot procedure, highly functionalized polycyclic ketals bearing three stereogenic centers are accessed as a single diastereomer in an enantioenriched form. Clearly, the specific conformation and electronic properties of the nine-membered ring should account for this unusual transformation. To elucidate the detailed mechanism, density functional theory (DFT) method MN12-L was employed to study the mechanism of the BF3promoted rearrangement of epoxy-heterocycles 4.9 As shown in Scheme 6, the BF3-activated epoxide moiety in A undergoes a facile bond cleavage via TS-1 to yield the

Scheme 7. Ring Contraction and Ts Migration of 3

Scheme 6. DFT Calculation on 5 Formation

structures of both isomers were assigned by single crystal X-ray analysis unambiguously. It is intriguing that the transannular C−C bond formation even took place between the benzofuran and the unactivated alkene moiety in 3, with a concomitant migration of the tosyl functionality from the nitrogen to the alkene carbon. This reaction worked well for different analogous substrates to produce the highly rigid polycyclic compounds 6 bearing four continuous stereogenic centers (with two quaternary ones). It is also interesting to note that the three new stereocenters are formed in the same relative configuration (6a and epi-6a). This complexity-building process again demonstrated the unique reactivity of these medium-sized heterocycles. Regarding the mechanism of this unusual transformation, it is noteworthy that the simple deprotection of N-tosyl group is believed to proceed through a radical mechanism.10a The rearrangement of tosyl protected enamines to the corresponding α-tosyl imines was also reported in recent years.10b,c In our system, the addition of TEMPO and BHT were found to suppress the reaction, and the conversion of 3a to 6a could also be realized under UV irradiation. These results provided a strong support for a radical pathway. Instead of undergoing a rearrangement simply on the amino-benzofuran moiety,10b we propose that the tendency of the nine-membered heterocycle to undergo transannular C−C bond formation induced the C− S bond formation on the alkene moiety to yield 6 in high efficiency. DFT calculation was also employed to study the energetic profile of the rearrangement of 3 (Scheme 8). The C−S bond cleavage in 3a can take place via a minimum energy crossing point MECP-111 with a relative energy of 55.4 kcal/mol to generate nitrogen radical intermediate F and sulfur Ts radical. Such a high activation energy reveals that refluxing or photoactivation is required for this initiation step. When the Ts radical is generated, it could react with styrene moiety to generate a benzyl radical G via a radical addition transition TS5 with a barrier of only 15.4 kcal/mol. The subsequent transannular C−C bond formation proceeds through MECP-2 to generate product 6. Overall, the formation of product 6a is exergonic by 10.5 kcal/mol from 3a. More calculations on alternative pathway (e.g., transannular C−C bond formation

zwitterionic B. An interesting conformational change takes place in this step due to the significant stabilization by a cation−π interaction in B. In this specific conformation of the nine-membered ring, it is noteworthy that the transannular C− C bond formation takes place through a remarkably low activation barrier of 1.4 kcal/mol (TS-2) and produces iminium C in an exergonic fashion. The energetics of these two steps provide a true statement of the unique property and reactivity of these benzofuran-fused nine-membered heterocycles. In the following rate-determining step of this reaction, the C−C bond cleavage by oxonium formation results in rearomatization in D via TS-3 (11 kcal/mol). Diastereoselective ketal formation delivers E, release of product 5 from which then regenerates BF3 to close the cycle. In addition to rearrangement of epoxide 4, a completely unexpected transformation of 3 was also discovered by noticing some change in the NMR spectra of 3a upon prolonged storage. By simply heating a solution of 3a in toluene, we were 15306

DOI: 10.1021/jacs.7b09161 J. Am. Chem. Soc. 2017, 139, 15304−15307

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Scheme 8. DFT Calculation on 6 Formation

before C−S bond formation) is also included in the SI, which proceeds with a higher activation energy. In summary, we represent here enantioselective synthesis and unique transformations of benzofuran-fused nine-membered heterocycles. The exploration of other medium-sized ring’s synthesis and reactivity are currently underway.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b09161. Experimental procedures and characterization data (PDF) Data for C36H28ClNO4S (CIF) Data for C36H28ClNO5S (CIF) Data for C36H28ClNO5S (CIF) Data for C68H64N2O9S2 (CIF) Data for C32H27NO4S (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Zhaoyuan Yu: 0000-0002-9570-3512 Yu Lan: 0000-0002-2328-0020 Yu Zhao: 0000-0002-2944-1315 Author Contributions §

Z.-Q. Rong and L.-C. Yang contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the Ministry of Education of Singapore (R-143-000-613-112) and GSK-EDB (R-143-000-564-592).

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REFERENCES

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DOI: 10.1021/jacs.7b09161 J. Am. Chem. Soc. 2017, 139, 15304−15307