Expeditious Diastereoselective Synthesis of Elaborated Ketones via Remote Csp 3 –H Functionalization

The quest for selective C–H functionalization reactions, able to provide new strategic opportunities for the rapid assembly of molecular complexity, represents a major focus of the chemical community. Examples of non-directed, remote Csp3–H activation to forge complex carbon frameworks remain scarce due to the kinetic stability and thus intrinsic challenge associated to the chemo-, regio- and stereoselective functionalization of aliphatic C–H bonds. Here we describe a radical-mediated, directing-group-free regioselective 1,5-hydrogen transfer of unactivated Csp3–H bonds followed by a second Csp2–H functionalization to produce, with exquisite stereoselectivity, a variety of elaborated fused ketones. This study demonstrates that aliphatic acids can be strategically harnessed as 1,2-diradical synthons and that secondary aliphatic C–H bonds can be engaged in stereoselective C–C bond-forming reactions, highlighting the potential of this protocol for target-oriented natural product and pharmaceutical synthesis.

The oxidative 1,2-difunctionalization of alkenes with carbon nucleophiles represents a great challenge in synthetic organic chemistry and the development of metal-free reactions cap able of efficiently producing complex and functionalized molecules istheobject of significantresearch efforts worldwide.
The group of Professor Morifumi Fujita from the University of Hyogo (Japan) has recently been working on this problem. "In this type of functionalization, the alkene is initially oxidized and then receives nucleophilic attacks," said Professor Fujita. He continued: "Oxidation of the carbon nucleophile needs to be avoided; however, more reactive carbon nucleophiles are more easily oxidized. Thus, the reactivity of both alkene and carbon nucleophile must be tuned. To enhance the reactivity of the alkene towards oxidation, we focused our attention on achieving nucleophilic assistance in the oxidation." "Our extensive screening of reaction substrates and condi-tionsallowedustofindthat6-phenyl-1-silyloxy-hex-3-ene1 was the most suitable alkene substrate for the oxidative carbon-carbon bond formation (Scheme 1)," explained Professor Fujita, continuing: "It is remarkable that the silyloxy group does not act as a protection group; however, it preferentially promotes the nucleophilic oxycyclization to yield 2. The nucleophilic assistance of the silyloxy group was also observed in the dioxycyclization of ortho-(4-silyloxybut-1-enyl)benzoate with a hypervalent iodine reagent. 1

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The oxidative arylation first proceeds through enantioface-differentiating electrophilic addition of lactate-based chiral hypervalent iodine reagent 3 to the alkene (Scheme 1). The following oxycyclization may be accelerated owing to induc tive electron-donation of the silyl group. Nucleophilic attack of the phenyl group completes the double cyclization yielding 2.
Professor Fujita said: "The lactate-based chiral hypervalent iodine reagent has been used for several types of highly enantioselectiveoxidationssinceourresearchgroupfirstreported it in 2007. 2 Electrospray ionization mass spectrometry measurements indicate interaction of the lactate moiety with theelectron-deficientiodineatomof3. 3 We postulate that the interaction may induce pseudo chirality at the iodine center leading to high enantioselectivity." Thanks to the concise preparation of 3 and easy derivatization of the lactate side chain, the reagent design allowed the authors to achieve further development of the enantioselective oxidation with hypervalent iodine.
As shown in Scheme 2, a wide range of both electron-rich and electron-deficient arenes were found to participate in theoxidativearylation."Althoughtheelectron-deficientaryl group has lower reactivity as a carbon nucleophile, even the CF 3 substrate yielded the oxidative arylation product 2f," said Professor Fujita. "Desymmetrization in the oxidative arylation was also achieved to yield 2h as the single diastereomer. Aminoarylation also proceeded to yield methanesulfonyl Mio Shimogaki was born in Hyogo (Japan) in 1989. She completed her B.Sc. at the University of Hyogo (Japan) in 2012. Since April 2012 she has been carrying out her graduate studies on the development of novel oxidation reactions with hypervalent iodine and application to asymmetric syntheses of bioactive natural products at the same university. In March 2017 she will complete her doctoral thesis on oxidative cyclization of alkene using chiral hypervalent iodine(III). Her research interest focuses on the development of new strategies for oxidation with hypervalent iodine.

Prof. T. Noël
The Noël group is interested in the develop ment of new enabling tools which assist chemists in their daily job and allow them to carry out hazardous manipula tions without compromising personal and environmental safety. Key in our strategy is the use of continuous-flow tech nology. Continuous-flow reactors have been increasingly used in synthetic organic chemistry to facilitate chemistries which are otherwise difficult to carry out. This includes gas-liquid reactions, photochemical transformations, chemistry utiliz ing hazardous compounds, extreme reaction conditions and multi step reaction sequences. Underlying all these advances are chemical engineering principles that enable chemical pro cesses to be carried out under perfectly controlled reaction conditions.
Taking advantage of these tools, our ambition is to devel op new catalytic strategies for chemical synthesis that engage novel reactivity concepts which facilitate the rapid generation of biologically active molecules. By combining these tools and new reactivity concepts, we strive in the long run to develop an automated and chemo-catalytic equivalent to Nature's bio synthetic machinery that will build essentially any molecule on demand.
Our approach is unique in the sense that we position ourselves at the interface of organic synthetic chemistry and chemical engineering. I have an M.Sc. in chemical engineering and I obtained my Ph.D. in organic synthetic chemistry. My group consists of both synthetic chemists and chemical en gineers. Consequently, we are able to rapidly recognize those synthetic problems which would benefit from microreactor technology and to tackle the problem from a different angle than was done traditionally.

Prof. T. Noël
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A63 SYNFORM When did you get interested in synthesis?
Prof. T. Noël I got interested in organic synthesis in high school. In my final year, we got a basic introduction to organic chemistry and I immediately realized that this was a topic that seemed natural to me. After the examinations, the teacher came to me and said that I had talent for organic chem istry and that I should do something with it. I never forgot those encouraging remarks and every time I needed to make a decision about my career, I chose the more synthetic career path.
Next, I started my academic education and I enrolled in a chemical engineering program. The reason I chose chemical engineering is because of the large breadth of different to pics it provides. It not only offers chemistry subjects but also courses on mathematics, mechanics, automation, electricity, etc. Also, we got some basic organic chemistry courses and again I was deeply interested in the subject. Immediately, I realized that all the pieces fell into place and I deeply enjoyed the project. This was the ideal subject for me as knowledge about both organic synthesis and chemical en gineering was required to come to a satisfactory result.

SYNFORM What do you think about the modern role and prospects of organic synthesis?
Prof. T. Noël Organic synthesis is an indispensable part of many related disciplines, for example chemical biology, mate rials science, medicinal chemistry, nanotechnology, molecu lar motors, etc. Without organic synthesis, these disciplines would simply not be possible. It is therefore crucial that we keep training future student generations in this important discipline.
I believe personally that more and more synthetic process es will be automated in the future. If you read the recent re ports on this subject, then you will learn that a combination of smart programming and flow reactors allows computers to optimize chemical reactions. This type of work remains a timeconsuming undertaking for the chemist but can now be done overnight with great success. Moreover, it also avoids ex posure to hazardous chemicals and is therefore perfectly suit able for carrying out those optimizations which pose a high risk to the practitioner (e.g. working with oxygen gas under high pressure, working with HCN, or other toxic substances). This does not mean that chemists will be entirely replaced.
Chemists will still be required to monitor the processes, to provide input and to make a final selection in what is worth pursuing and what is not. Nevertheless, there is still a lot of work on the plate to really make these automated optimiza tion robots widely applicable and failproof.
Another important role for organic synthesis is the devel opment of milder transformations which are driven by sustain able activation modes, for example photoredox catal ysis, electrochemistry, and other roomtemperature catalysis modes. Currently, thermochemical activation is one of the mostused ways to drive chemical reactions forward. Striking ly, industrial process heating operations account for 70% of the total energy use. The development of new synthetic methods and processes driven by renewable energy sources, for ex ample solar and wind energy, would be a tremendous impro vement. Here as well, continuous-flow chemistry can help to maximize the energy efficiency of these transformations, for example by overcoming the Bouguer-Lambert-Beer limita tion of photochemistry.

SYNFORM Your research group is active in the area of photoredox catalysis and C-H activation. Could you tell us more about your research and its aims?
Prof. T. Noël Since the start of my independent academic career in 2012, my group has been intrigued by visible light photoredox catalysis. Photoredox catalysis provides neat so lutions for previously elusive organic transformations (broad scope, high functional group tolerance, mild reaction condi tions). We have developed a number of different photocatalytic transformations over the years, including the Stadler-Ziegler reaction, trifluoromethylation reactions, oxidation chemistry and disulfide formation. Typically, we select those transformations which have a gaseous reagent. Such gasliquid reaction mixtures can be handled in flow very well and mass transfer limitations are minimized. However, one of the biggest hurdles of photoredox chemistry was its scalability and we have worked on continuous-flow microreactor solu tions to overcome these challenges. We have also studied the engineering aspects concerned with photocatalytic gas-liquid reactions in flow. This includes the potential (i) to extract kinetics efficiently, (ii) to increase the energy efficiency of the photomicroreactor and (iii) to scale the chemistry up with a numberingup strategy.

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Similarly, we have selected C-H activation chemistry as a notable field where continuous-flow processing can make a difference. Again, we try to select reactions with a gaseous reagent, for example oxygen. These transformations are very hard to carry out in standard batch labware. Due to improved gas-liquid characteristics and excellent heat transfer, we were able to reduce the reaction times from hours to the minute range.

SYNFORM What is your most important scientific achievement to date and why?
Prof. T. Noël This is a hard question as I like each publi cation we have published. However, our recent discovery on Luminescent Solar Concentrator based photomicroreactors is definitely something special (D. Cambié, F. Zhao, V. Hessel, M.

G. Debije, T. Noël 'A leafinspired luminescent solar concen trator for energy-efficient continuous-flow photochemistry'
Angew. Chem Int. Ed. 2017, 56, 1050). Previously, solar pho tochemistry was done by placing the reaction flask outside in the sun. Reaction times were typically in the range of several hours to days depending on the amount of light. So, almost nobody uses solar energy to power their reactions due to the low solar intensity at higher latitudes. However, our novel leaf-inspired photomicroreactor (see Figure 1) allows efficient harvesting of solar energy by using a luminescent solar con centrator. The reactor is fabricated from PDMS polymer which contains fluorescent dyes that can capture solar light and, due to internal reflection, the re-emitted light is guided towards the reaction channels. Moreover, the emission profile of the embedded dye was matched with the absorption spectrum of the photocatalyst which flows in the reaction channels. Due to this spectral overlap, the reaction mixture flowing in the channels experiences an amplified photon flux that is wave lengthconcentrated to an energy window where the reaction occurs optimally. Interestingly, our device works particularly well in those regions where sunlight is not abundant. The de vice can capture diffuse light and still direct this light effici ently to the reaction channels. The ability to concentrate ener gy aids in enhancing the chemical reactivity in the reaction channels and makes solar energy a viable activation mode in organic synthesis.

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Arylboronates are widely used in organic chemistry, and methods that could produce arylboronates from easily avail able starting materials in a transitionmetalfree manner are in high demand. Although there are several precedents in the literature, problems such as the expense of the boron source, low reactivity, and operational inconvenience remain to be solved.
The group of Professor Lei Jiao at Tsinghua University (Beijing, P. R. of China) studied the mechanism of carbonhalogen bond activation of haloarenes by small organic molecules, which is a key step in basepromoted homolytic aromatic substitution (BHAS) reactions (J. Am. Chem. Soc. 2016, 138, 7151; Chem. Eur. J. 2017, 23, 65). Professor Jiao said: "As a consequence, we were interested in utilizing the aryl radical generated in this process to synthesize more useful molecules, rather than merely producing biaryl compounds. Therefore, we hoped to synthesize arylboronates from halo arenes using this carbon-halogen bond activation strategy." With this idea in mind, the group first tried to capture the aryl radical directly by using bis(pinacolato)diboron (B 2 pin 2 ). "We simply added B 2 pin 2 to a BHAS reaction system (ArI/ DMEDA/tBuOK in benzene)," said Professor Jiao. "However, only the biaryl product (ArPh) was found and no borylation product could be observed. It seemed that the aryl radical reacted with B 2 pin 2 in a low efficiency, as shown in several literature reports." Professor Jiao's group stopped attempting this reaction for months, until Li Zhang -a PhD studentfound a new publication that reported the formation of pyrid inestabilized boryl radical by the reaction between 4cyano pyridine and B 2 pin 2 (Angew. Chem. Int. Ed. 2016, 55, 5985). "An idea soon came to his mind that the pyridinestabilized boryl radical might trap the aryl radical more easily than B 2 pin 2

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itself to generate arylboronate, thanks to the persistent radical effect," said Professor Jiao. "We discussed this new idea and agreed that it was worth trying." He continued: "Indeed when we added a catalytic amount of 4cyanopyridine to the reaction system, the arylboronate product was observed. After optimization of the reaction con ditions, the designed borylation reaction for aryl iodides was realized in good yields. However, aryl bromides were found to be less suitable substrates using the conditions above. We therefore sought to boost their reactivity by tuning the elec tronic nature of the pyridine catalyst, but failed. Fortunately, we finally solved the problem by replacing the paracyano group in the pyridine catalyst by a paraphenyl group, which was thought to further stabilize the boryl radical." The optimized conditions of the borylation reaction were at that point very simple: just mixing each reaction compo nent and the solvent in a vessel and heating in an oil bath was sufficient. "The reaction is best performed under inert atmo sphere, but it is not very sensitive to air -reaction un der air produced the desired borylation product with slight ly de creased yield," explained Professor Jiao. "The reaction is scalable if performed in a flask, producing arylboronates on >1 g scale in one batch. The scope of the borylation reaction is broad, including aryl iodides, aryl bromides, activated aryl chlorides, and alkenyl iodides (Scheme 1)." These features make this method rather attractive for diverse synthetic ap plications. In particular, for the borylation of aryl iodides, inexpensive pyridine could be used as the catalyst instead of 4-phenylpyridine, making the synthesis more cost-effective. "We believe that this reaction could serve as a good comple ment to the present synthetic methods for producing arylbro nates," said Professor Jiao.
The mechanism of the reaction is also intriguing. Al though experimental results supported the intermediacy of the aryl radical in the borylation process, another question still remain ed: whether the aryl radical reacts with the py ridinestabilized boryl radical (the designed radical coupling pathway) or with the ate complex formed by B 2 pin 2 and MeOK (the S RN 1 pathway). "To solve this problem, we designed a series of competition experiments and found that the prefe rence for borylation compared with a hydrogen atom transfer probe was favored by increasing the amount of the pyridine catalyst," said Professor Jiao. He concluded: "This piece of evi dence strongly supported the C-B bond formation through the interaction between an aryl radical and a pyridinerelated boryl species, rather than the ate complex or B 2 pin 2 ."

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Selective C-H functionalization reactions offer new strategic opportunities for the rapid assembly of molecular complexity. However, and despite substantial efforts particularly in the field of transition-metal catalysis, examples of non-directed, remote Csp 3 -H activation to forge complex carbon frameworks remain scarce due to the kinetic stability and thus intrinsic challenge associated with the chemo-, regio-and stereoselective functionalization of aliphatic C-H bonds. Professor Cristina Nevado at the University of Zurich (Switzerland) is interested in exploring new research avenues in the area of selective C-H bond activation. She said: "Radical-centered C-H functionalizations represent a distinct option to activate isolated, aliphatic C-H bonds via an H-atom abstraction mechanism as seminally exemplified by the Hofmann-Löffler-Freytag (HLF) reaction. Typically, Csp 3 -H functionalizations using 1,n-H-transfer rely on pre-formed radical precursors such as Csp 2 -halide bonds, azides, amidines, etc. Due to the highly reactive nature of the free-radical species involved, reaction control in terms of stereo-and site-selectivity remains challenging and thus only a few applications in complex settings have been reported thus far." On the other hand, alkyl carboxylic acids are ubiquitous in nature and can be readily found in both natural products as well as in commercial chemical supplier catalogues. "The carboxylic group is typically stable and eminently diversifiable owing to the field of combinatorial chemistry, in which carboxylic acids are the 'workhorse' building block," said Professor Nevado. She continued: "Recently, our group has describ ed a radical-mediat-ed, directing-group-free regioselective 1,5-hydrogen transfer of unactivated Csp 3 -H bonds followed by a second Csp 2 -H functionalization utilizing alkyl carboxylic acids and vinyl azides as starting materials to produce a variety of elabor ated fused ketones with exquisite stereoselectivity (Scheme 1). This study demonstrates that aliphatic acids can be strategically harnessed as 1,2-diradical synthons and that secondary aliphatic C-H bonds can be engaged in stereoselective C-C bond-forming reactions, highlighting the potential of this protocol for target-oriented natural product and pharmaceutical synthesis." "The presence of electron-withdrawing groups (ester, fluoro, chloro or bromo) in the para-position of the aryl vinyl azide moiety proved to be amenable to the standard reaction conditions," said Professor Nevado. She added: "Synthetically useful yields were also obtained with substrates bearing electrondonating groups at the para position. 2-Fluorobenzene vinyl azide could be efficiently engaged in this reaction. 3-Fluoro-, 3,4-difluoro-, 3-methyl-and 3-methoxy-substituted substrates produced 3,4-dihydronaphthalen-1(2H)-ones in good yields with moderate ortho-regioselectivities. In con trast, 3-trifluoromethyl-and 3-tert-butyl-substituted sub strates favored the para-cyclized adducts in 6:1 and >20:1 ratio, respectively. These results clearly indicate that the regio selectivity is dictated by both the steric and electronic nature of the meta-substituents in the starting material. He teroaromatics could also be selectively incorporated as demonstrated by the successful reaction of a quinoline deriva tive. It is important

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to point out that only syn-diastereoisomers are observed in these transformations (Figure 1)." Different aliphatic acids were also studied ( Figure 2). "Five-and seven-membered tertiary carboxylic acids could be easily incorporated in this reaction, representing a straightforward route to the core structure of the hamigerans A and B, secondary metabolites with promising cytotoxic as well as potent antiviral activities," explained Professor Nevado. She continued: "Acyclic substrates were also highly efficient partners in these transformations so that fully aliphatic as well as homobenzylic carboxylic acids bearing both electron-donating and electron-withdrawing groups could be efficiently coupled under the reported conditions. Secondary carboxylic acids were also evaluated. A 2-tetrahydronaphthyl derivative produced the desired hexahydrochrysene-based ketone in synthetically useful yield whereas β,γ-disubstituted 3,4-dihydronaphthalen-1(2H)-ones could be isolated in moderate to good yields as single diastereoisomers. The reaction protocol is also compatible with amino acids so that phenylalanine derivatives could be used in this reaction. Both benzofuran and quinoline derivatives proved to be amenable to the standard reaction conditions in the presence of 2,2-dimethyl-3-phenylpropanoic acid, delivering tricyclic adducts, respectively. Xray diffraction analysis confirmed the structural assignment