Fe(III)-Catalyzed Bicyclization of Yne-Allenones With Indoles for the Atom-Economic Synthesis of 3-Indolyl Cyclobutarenes

A new Fe(III)-catalyzed bicyclization reaction of yne-allenones with indoles has been established, enabling the direct construction of cyclobuta[a]naphthalen-4-ols with an all-carbon quaternary center in good to excellent yields. This reaction was performed by using low-cost FeCl3 as the catalyst and EtOH as the environmentally benign solvent, providing a green protocol for constructing the cyclobutarene framework with a high degree of atom economy and functional group compatibility. The reaction mechanism was proposed to proceed through a [2 + 2] cycloaddition/1,6-conjugate addition cascade.


INTRODUCTION
Development of practical and sustainable synthetic methods for the rapid construction of valuable cyclic target molecules, along with minimum environmental impacts, represents an endeavor of utmost importance in both academia, and industry (Anastas and Warner, 1998;Bruckmann et al., 2008;Martins et al., 2009;Jiang et al., 2010;Huang et al., 2018a). In this context, chemical transformations following the principles of atom-economy are generally believed to be green since such reactions enable different molecular fragments into integrated cyclic frameworks by recombining chemical bonds with maximum atom utilization and minimum generation of the chemical waste (Trost, 1995(Trost, , 2002Trost et al., 2003;Banert and Plefka, 2011;Kotha et al., 2013).
The key to realize this goal is to implement reaction cascades, which allow the direct formation of multiple chemical bonds in a one-pot operation and can lead to a remarkable increase in resource efficiency for the overall process (Barluenga et al., 2009;Fuerstner, 2009;Tietze et al., 2009;Jones et al., 2010;Wang et al., 2015;Sugimoto and Matsuya, 2017;Zhang et al., 2017). Specifically, bicyclization cascades have emerged as an important platform for the synthesis of bioactive small-molecule libraries for their SAR studies (Dömling et al., 2012;Brauch et al., 2013;Vlaar et al., 2013;Koopmanschap et al., 2014;Rotstein et al., 2014;Huang et al., 2018b). Due to their annulation efficiency, economic and environmental aspects, and ease of operation as well as diminished waste disposals Su et al., 2014;Tian et al., 2015;Chen et al., 2017;Huang et al., 2017;Liu et al., 2017b,c;Wang L. et al., 2017). In view of the environmental awareness of the chemical community, the combination of the presented bicyclization strategy and the use of environmentally benign solvents will furnish the transformations under avoidance of potential pollutants (Bihani et al., 2013;Wang J.-Y. et al., 2017;Sha et al., 2018a). Nevertheless, the design and development of environmentally compatible bicyclization cascades without generation of toxic waste and by-products holds considerable challenges.

RESULTS AND DISCUSSION
At the beginning of our studies, yne-allenone 1a and Nmethylindole (2a) were chosen as the model substrates to explore the feasibility of double [2 + 2] cycloaddition relay reaction with our previous conditions ( Table 1, entry 1). Instead of the expected naphtho[1,2-a]carbazol-5-ol 4a, 3-indolyl substituted cyclobuta[a]naphthalen-4-ol 3a was obtained in 60% yield. The following screening of solvents, such as N,N-dimethylformamide (DMF), 1,4-dioxane, tetrahydrofuran (THF), MeOH, and EtOH, showed that use of DMF and 1,4-dioxane as reaction media completely suppressed the reaction process (entries 2-3) whereas the latter three all made the transformations work more efficiently (entries 4-6). Among these, EtOH proved to be the best choice, providing the product 3a with the highest yield of 76% (entry 6). Increasing the component ratio to 1:2 is not beneficial for this transformation as a lower conversion was observed (63%, entry 7). In contrast, fine-tuning the component ratio to 1:1.2 could improve the reaction efficiency, resulting in a higher yield of 3a (81%, entry 8). As the next optimization step, we conducted the screening of a variety of Lewis acid catalysts, such as ZnCl 2 , Y(OTf) 3 and FeCl 3 that are often employed in the catalytic transformations, for this cyclization-addition cascade by using EtOH as the reaction media. The former two led to remarkably lower conversions (entries 9-10). Delightingly, the latter one showed the best catalytic performance in this transformation, delivering higher yield of 3a as compared with BF 3 •Et 2 O (85%, entry 11 vs. 8). It is found that the reaction efficiency was proven to display an important dependence on the loading of the Fecatalyst. An increase in the FeCl 3 loading had a detrimental impact on the reaction yield (entry 12) whereas reducing the catalytic amount of FeCl 3 to 10 mol% could accelerate the conversion into 3a in an increased the yield to 88%. When the reaction temperature was elevated to 70 • C, the reaction process was inhibited in some extent (entry 14). On the contrary, decreasing the reaction temperature to 30 • C facilitated SCHEME 1 | Profiles for [2 + 2] cycloaddition of yne-allenones. the current transformation and gave a higher yield of 90% (entry 15).
Next, the scope with respect to indoles components was evaluated. As anticipated, the different substituents including methoxy (2b), chloro (1c and 1d), bromo (1e), methyl (1f and 1g), located at different positions of the indole ring would be accommodated, confirming the reaction efficiency, as the cyclobuta[a]naphthalen-4-ol products 3w-3bb were offered in 76-92% yields. Finally, the free indole turned out to be a suitable reaction partner, leading to the formation of products 3cc and 3dd in 78 and 81% yields, respectively. Products 3 were fully characterized by their NMR and HR-MS spectral analysis. In the case of product 3a, its structure was further confirmed by X-ray crystallography (Figure 1). MECHANISM Based on the above experimental observations and literature reports (Haibach et al., 2011;Li et al., 2015Li et al., , 2018aLiu et al., 2016Liu et al., , 2017aOzaki et al., 2017;Sha et al., 2018b), a feasible mechanism for forming products 3 was proposed in Scheme 3. Initially, the intramolecular [2 + 2] cycloaddition of yne-allenones 1 rapidly occurs to yield cyclobutene intermediate A.
In the presence of Fe-catalyst, 1,6-addition of indoles into intermediate B gives intermediate C, which converts into the final products 3 through proton transfer (PT), together with the regeneration of Fecatalyst.

CONCLUSION
In summary, starting from readily available yne-allenones and indoles, we have established a new Fe-catalyzed [2 + 2] cycloaddition/1,6-conjugate addition cascade for the high-efficient and benign synthesis of a variety of 3-indolyl cyclobuta[a]naphthalen-4-ols with good to excellent yields. The current green protocol has the advantages of broad scope of substrates, good tolerance of functional group and high atom utilization as well as mild reaction conditions. Further application of the resulting cyclobutarenes is underway in our laboratory.

General
All melting points are uncorrected. The NMR spectra were recorded in CDCl 3 or DMSO-d 6 on a 400 MHz instrument with TMS as internal standard. Chemical shifts (δ) were reported in ppm with respect to TMS. Data are represented as follows: chemical shift, mutiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constant (J, Hz) and integration. HRMS analyses were carried out using a TOF-MS instrument with an ESI source. X-Ray crystallographic analysis was performed with a SMART CCD and a P4 diffractometer (the copies of NMR see Supplementary Material). All yne-allenones 1 are known compounds and their preparation followed the previously reported procedures (Wei et al., 2009;Liu et al., 2017a;Li et al., 2018b).

AUTHOR CONTRIBUTIONS
HL, BJ, and GL designed the project. HL performed the experiments. HL, W-JH, and S-JT analyzed the data. HL, BJ, and GL wrote the manuscript.

FUNDING
We are grateful for financial support from the NSFC (Nos. 21332005, 21472071 and 21871112), the Outstanding Youth Fund of JSNU (YQ2015003) and Robert A. Welch Foundation (D-1361, USA).