| Author: | Lam, Long Yin |
| Title: | Sodium arylsulfinates as a versatile sulfur surrogate for the synthesis of diaryl thioethers and n-aryl sulfonamides |
| Advisors: | Ma, Cong (ABCT) |
| Degree: | Ph.D. |
| Year: | 2023 |
| Subject: | Sulfur compounds -- Synthesis Sulfur drugs Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Applied Biology and Chemical Technology |
| Pages: | xiv, 287 pages : color illustrations |
| Language: | English |
| Abstract: | The construction of sulfur-containing scaffolds represents one of the critical research areas in synthetic chemistry owning to the predominant role of sulfur in pharmaceuticals for the broad bioactivity against diverse diseases. Among various sulfur functionalities, thioether and sulfonamide have contributed to a significant portion of sulfur-containing drugs. However, the current synthetic methods for thioether and sulfonamide were often limited by harsh conditions, low safety profile or expensive catalytic system. This thesis demonstrated our research progress in developing synthetic protocols for thioether and sulfonamide synthesis using commodity chemicals. Thioether was commonly prepared from thiols and derivatives, which are usually volatile and give a pungent odor. Chronic exposure to thiols would lead to organ toxicity and even death. To avoid the use of thiols, we explored the feasibility of using sodium arylsulfinate as an odorless and solid thiol surrogate in thioether synthesis. At first, aryl iodide was used as a coupling partner with sodium arylsulfinate in sulfenylation. After the optimization, thioethers could be obtained with yields up to 92% using DABCO as the base and inexpensive CuO / d-glucose as the catalytic system. The mechanistic study suggested a radical deoxygenation mechanism mediated by DABCO via the formation of the DABCO N-oxide radical cation. The success of S-arylation between aryl iodide and sodium arylsulfinate has initiated our further study in exploring other potential coupling partners for sulfenylation. Later, we developed a Chan-Lam type C-S coupling between aryl boron compounds and sodium arylsulfinate. By reacting arylboronic acid with sodium arylsulfinate, K2SO3 using Cu(TFA)2 / 1,10-Phen as the catalytic system, diaryl thioethers could be obtained in up to 92% yield with more than 50 examples. Other organoboron groups, like boronic acid pinacol ester, potassium trifluoroborate and boroxine, were all well tolerated in this reaction. The efficacy of the reaction was inhibited upon the addition of TEMPO, suggesting a radical mechanism. Also, the radical trapping experiment and HRMS analysis on the reaction mixture suggested a K2SO3-mediated selfÂ-deoxygenation mechanism of sodium arylsulfinate to generate the thiyl radical as the sulfenylating species. We later turned our focus to the synthesis of alkynyl sulfide with sodium arylsulfinate. By reacting alkyne and sodium arylsulfinate with CuI, ascorbic acid, DABCO and Na2SO3, the alkynyl sulfide could be obtained in 34% yield, despite the conditions were not fully optimized. The preliminary mechanistic study showed that the generation of the thiolate anion instead of the thiyl radical is the key to afford alkynyl sulfide instead of vinyl sulfide. The traditional method to prepare sulfonamide often involved the nucleophilic substitution between sulfonyl chloride and amine, which cannot fulfill the increasing requirement of green chemistry. Meanwhile, the limited scope to alkylamines as the coupling partner in the current synthetic methods encouraged us to explore the direct sulfonamidation between arylamine and sodium arylsulfinate as sulfonyl chloride surrogate. The preliminary screening on the catalytic system showed insignificant improvement to the reaction yield. On the contrary, by applying K2S2O8 as an aniline activator, sulfonamides could be obtained in high yields after the optimization study. The reaction demonstrated a high chemoselectivity to amines, as hydroxyl, boronic acid pinacol ester, benzamide and sulfonamide substituted aniline were compatible in this reaction. The result of the control experiment suggested a radical coupling mechanism between the anilinium radical and the sulfonyl radical. To expand the substrate scope of sulfonamide synthesis from aniline to heteroaniline, the rapid growth of photocatalytic chemistry has elicited our awareness in developing a photocatalytic sulfonamidation protocol. The ongoing optimization study showed that 2-nitropyridine could react with sodium arylsulfinate to afford the sulfonamide in 50% yield via in-situ reduction under the CuBr2 / Ru(bpy)3Cl2 co-catalytic system. Interestingly, the current conditions work only with N-hetero nitroarenes. In the preliminary mechanistic study, we found that nitrobenzene could not be reduced by Na2S2O4 in the control experiment. In summary, we developed a series of mild, inexpensive and safe methods for synthesizing thioethers and sulfonamides using solid sodium arylsulfinate. These methods could bypass the associated drawbacks using thiols for thioether synthesis, and directly afford N-arylsulfonamides, which was barely described in literature. The utility of sodium arylsulfinate as an appropriate sulfur surrogate for generation of reactive and stable thiyl and sulfonyl radicals were demonstrated. |
| Rights: | All rights reserved |
| Access: | open access |
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