WWW.DISSERTATION.XLIBX.INFO
FREE ELECTRONIC LIBRARY - Dissertations, online materials
 
<< HOME
CONTACTS



Pages:   || 2 | 3 | 4 | 5 |

«Signature: _ Stephen Wilson Date Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative Redox Dehydration By ...»

-- [ Page 1 ] --

Distribution Agreement

In presenting this thesis or dissertation as a partial fulfillment of the requirements for an

advanced degree from Emory University, I hereby grant to Emory University and its agents the

non-exclusive license to archive, make accessible, and display my thesis or dissertation in whole

or in part in all forms of media, now or hereafter known, including display on the world wide

web. I understand that I may select some access restrictions as part of the online submission of this thesis or dissertation. I retain all ownership rights to the copyright of the thesis or dissertation. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation.

Signature:

_____________________________ ______________

Stephen Wilson Date Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative Redox Dehydration By Stephen Wilson Master of Science Chemistry _________________________________________

Lanny S. Liebeskind, Ph.D.

Advisor _________________________________________

Huw M.L. Davies, Ph.D.

Committee Member _________________________________________

Christopher C. Scarborough, Ph.D.

Committee Member

Accepted:

_________________________________________

Lisa A. Tedesco, Ph.D.

Dean of the James T. Laney School of Graduate Studies ___________________

Date Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative Redox Dehydration By Stephen Wilson B.S., University of Richmond, 2012 Advisor: Lanny S. Liebeskind, Ph.D.

An

Abstract

of A thesis submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Master of Science in Chemistry 2015 Abstract Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative

–  –  –

Benzo-1,3,2-dithiazole-1,1-dioxides (BDTs) are novel 5-membered heterocycles bearing an internal sulfur-nitrogen bond and are structurally similar to benzoisothiazolones (BiTs). A new method for the synthesis of these molecules was developed and a series of BDTs were made and studied as potential BiT alternatives in organocatalytic redox-coupled, metal catalyzed dehydrative bond constructions. The BDTs could be synthesized via generation of a sulfenyl chloride from o-benzylthiobenzene sulfonamide followed by condensation with the adjacent nitrogen. The BDTs could react with carboxylic acids in a redox dehydration with triphenylphosphine or triethyl phosphite to generate BDT-derived thioesters. This reaction worked well with aliphatic acids and to a lesser extent with aromatic acids. These thioesters could then undergo coupling with boronic acids to give S-arylated products, but the reaction between BDT-derived thioester and amine gave only hydrolysis of the thioester with no desired amide formation. Finally, the reduced form of BDT, the o-mercaptobenzene sulfonamide, could be oxidized back to the BDT at temperatures above 100 oC in the presence of a variety of oxidants. Future work will be de done to assess the utility of BDTs as organocatalysts in redox dehydration reactions as well as explore other alternative applications.

Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative

–  –  –

First and foremost, I would like to thank my advisor, Dr. Lanny Liebeskind, for all of the help, support and guidance he has given me during my graduate school career. With his help and encouragement, I have experienced significant growth as a chemist, a scientist, and most importantly a person. He has been very supportive in all of my decisions and I will always have a deep gratitude for his mentorship and look back on these years fondly.

I would also like to thank my committee members, Dr. Huw Davies and Dr. Chris Scarborough for their advice and support. Their criticisms helped me focus my research and, eventually, got me to the point where I had a nice story to tell about my work. My gratitude also goes out to Dr. Dennis Liotta, Dr. Simon Blakey and Dr. Frank McDonald for their efforts in the classroom to help me further my education.

Next, I would like to thank all of the Liebeskind lab members that I had the privilege to work alongside over the past 2 and a half years. Your advice was invaluable and I attribute much of what I have learned in lab to the support of my coworkers. I truly would not have been able to get to this point without your help.

I would like to thank my family for their unwavering love support as well as their genuine interest in trying to learn about my work. Finally, I would like to thank my girlfriend Emily Ryan for constantly standing next to me, helping me make important decisions, and

–  –  –

Benzo-1.3,2-dithiazole-1,1-dioxide Synthesis 8 Phosphine Mediated Thioesterification of BDT 13 Phosphite Mediated Thioesterification of BDT 16

–  –  –

Scheme 1. Formation of thioesters as described by Mukaiyama and Srogl Scheme 2.

Mechanism for thioesterification of BiTs Scheme 3. Aerobic coupling of thioesters and boronic acids Scheme 4. Aerobic ketonization with recycle of BiT Scheme 5. Condensation of 2-(chlorosulfonyl)phenyl hypochlorothioite with amine Scheme 6. Pummerer rearrangement product from t-butyl thiol Scheme 7. Thermal cyclization of t-butyl sulfoxide to disulfide 1a Scheme 8. Cu-catalyzed oxidation of o-mercapto benzenesulfonamide to disulfide Scheme 9. Synthesis of BDT 2a from benzylthioether and sulfuryl chloride Scheme 10. Synthesis of BDTs 2a-2c Scheme 11. Synthesis of BDTs 2d-2f Scheme 12. Synthesis of thioester 4 from triphenylphosphine Scheme 13. Synthesis of thioester 6a from 5 and triphenylphosphine Scheme 14. Reaction between 1a and triethylphospite Scheme 15. Cu-catalyzed coupling of thioester 6a and boronic acid 7 Scheme 16. Cu-catalyzed coupling of thioester 6a and boronic acid 7 with N-methylimidazole Scheme 17. Coupling of thioester 6a and boronic acid 7 with stoichiometric copper Scheme 18. Reaction of thioester 6a with amine Scheme 19. Reaction of thioester 6a with amine under copper catalyzed conditions Scheme 20. Catalytic amidation with BDT 1a

–  –  –





Figure 1. Previous methods for synthesis of benzoisothiazolones Figure 2.

BiT catalyzed redox condensation Figure 3. Structure of BDT Figure 4. Proposed methods for synthesis of benzo-1,3,2-benzodithiazole-1,1-dioxides Figure 5. Benzo-1,3,2-dithiazole-1,1-dioxide library 31 Figure 6. P NMR from thioesterification of 1a

–  –  –

Table 1. Thioester 4 from 2a and p-toluic acid with varying temperature and solvent Table 2.

Thioester synthesis with BDT, N-Boc-phenylalanine and triphenylphosphine Table 3. Thiosterification of 2a with p-toluic acid and triethylphosphite Table 4. Thioester synthesis with BDT, N-Boc-phenylalanine and triethyl phosphite Table 5. Mo-catalyzed oxidation of disulfide 1a to BDT at varied temperature

–  –  –

Introduction Benzoisothiazolones (BiTs) are well known 5-membered heterocycles containing an internal sulfur-nitrogen bond and are widely used in pharmaceutical and agricultural industries.

In particular, it has been shown that specific BiT derivatives exhibit antifungal and antimicrobial activities,1,2 can selectively inhibit phosphatase enzymes,3,4 and possess anti-HIV and anti-cancer properties.5,6 Because of their biological importance, the synthesis of activity of BiTs has been extensively studied.

As illustrated in Figure 1, a number of methods to construct benzoisothiazolones have been reported. These methods include: (a) condensation of 2-(chlorocarbonyl)phenyl hypochlorothioite and amine,7 (b) treatment of 2-(t-butylthio)-5-nitrobenzamide with trimethylsilyl chloride,8 (c) cyclization of t-butyl sulfoxides9 and (d) copper-catalyzed

–  –  –

and some wasted reagent, benzoisothiazolones can be obtained in high yields and with a wide variety of structural variation. Further, BiTs are synthetically useful molecules that can react with reducing agents to give o-mercaptobenzamides,11 thiols to give unsymmetrical disulfides,12,13 as well as a variety of phosphorus, carbon and sulfur nucleophiles to give other products.11 Another interesting transformation of BiTs has been described by Villalbos8 and then Srogl.14 In 2008, she reported the conversion of BiTs into thioesters via redox dehydration of carboxylic acids using an organophosphine reductant. This reaction is analogous to the thioesterification of disulfides previously described by Mukaiyama.15 A direct comparison of these two reactions is given in Scheme 1. Both are redox reactions in which sulfur is reduced to a thiol which goes on to generate thioester by reacting with an acyloxyphosphonium intermediate and resulting in oxidation of a phosphine to phosphine oxide (Scheme 2). The major disadvantage in Mukaiyama’s procedure is the loss of half of the disulfide as thiol. The BiT reaction does not suffer from this drawback, and as we will see, the BiT-derived thioesters are

–  –  –

One interesting application in which BiT-derived thioesters are important is the copper catalyzed aerobic ketone synthesis from thioesters and boronic acids as described by Liebeskind.16 In this reaction, ortho mercaptobenzamides are involved in a coupling reaction with boronic acids to synthesize a variety of peptidyl-based and other synthetically useful ketones (Scheme 3).17 A major limitation of this procedure is the need for a sacrificial equivalent of boronic acid in order to trap (as a thioether) any thiolate generated under the reaction conditions. This drives the reaction forward by facilitating the release of the copper catalyst that was previously tied up as a stable copper thiolate. As a result, a full equivalent of the S-arylated ortho mercaptobenzoic acid amide is obtained as an undesired side product. In an effort to overcome this limitation, the Liebeskind group became interested in the oxidative recycle of ortho mercaptobenzoic acid amides to BiTs as a way to “internally” trap thiolate without the need for wasted reagents or the production of side products. In recent results from Matthew Lindale18 this goal was achieved via the use of N-methylimidazole (NMI) as a ligand on

–  –  –

The Liebeskind group now envisioned a fully catalytic protocol for dehydrative bond construction by linking thioesterification and the coupling of BiT-derived thioesters, shown in Schemes 2 and 4, through an oxidative recycle of the BiT. This reaction can also be generalized to reaction partners beyond boronic acids and the full catalytic cycle is described in Figure 2.

This catalytic cycle takes advantage of BiTs as redox organocatalysts for the construction of amides, esters and ketones. The cycle begins with the generation of a BiT-derived thioester in a Mukaiyama-like dehydration as described above. Results from the Liebeskind lab have also significantly improved this protocol by replacing organophosphine reductants with triethyl phosphite. The use of triethylphosphite both eliminates the need for more reactive organophosphines and dramatically simplifies the reaction workup since P(OEt)3 is converted to water soluble OP(OEt)3 during the reaction. The synthesis of a variety of thioesters synthesized by this method has been described by Leighann Lam.20 The next step consists of a reaction between the thioester and a nucleophilic reaction partner to generate the acylated product, an

–  –  –

reaction partner determines the product outcome (i.e. amine, alcohols and boronic acids will give rise to amides, esters and ketones respectively), making the catalytic cycle generalizable to a wide range of substrates beyond the scope described thus far. The final step of the cycle is copper catalyzed aerobic regeneration of the BiT. To date, a variety of amides have been synthesized using this procedure, and work is underway to extend the utility of this catalytic reaction into making esters and ketones.

Another class of molecules bearing an internal sulfur-nitrogen bond is benzo-1,3,2dithiazole-1,1-dioxides, here referred to as BDTs. The structure of the BDT (Figure 3) is

–  –  –

Further, since sulfonamides are stronger electron withdrawing groups, we can predict that the sulfenamide functional group (S-N bond) on the BDT is more electrophilic than that of BiTs and as a result should react more rapidly with nucleophiles. If this is true, then BDTs may be useful redox organocatalysts.

Despite their structural similarities to BiTs, a widely used and versatile molecule, surprisingly little work can be found in the literature on BDTs, and the only known information is described in two patents.7,21 The first patent discusses the synthesis of 5-nitro-1,3,2-dithiazoledioxides, a molecule with the same internal sulfur-nitrogen-sulfur bonds. The second describes the synthesis of N-aryl BDTs from a condensation reaction between 2chlorosulfonyl)phenyl hypochlorothioite and amines as shown in Scheme 5. The patent also describes BDTs as potential medicaments but does not give any specific details beyond the synthesis of a small sample of molecules. With relatively little known about BDTs, there is a lot of potential for the discovery of new and interesting chemistry. Here we describe a study of BDTs as potential alternatives to BiTs in some known catalytic systems.

A general synthetic route to BDTs was explored, and the BDTs were then studied as redox organocatalysts in place of BiTs. The study took place in three parts: (1) thioesterification of carboxylic acids with BDTs and both phosphine and phosphite reducing agents, (2) reaction of amines and boronic acids with BDT-derived thioesters and (3) oxidative regeneration of the

–  –  –

done to examine the use of BDTs as redox organocatalysts for the synthesis of interesting and useful organic molecules such as amides, ketones and esters.

Results / Discussion There are a variety of methods we could envision for the successful synthesis of BDTs.

–  –  –



Pages:   || 2 | 3 | 4 | 5 |


Similar works:

«RULES AND REGULATIONS FOR SWEDISH TROTTING 2015 Svensk Travsport Hästsportens Hus 161 89 Stockholm Sweden 0046-8-627 21 20 www.travsport.se kundtjanst@travsport.se This text is an extract from paragraphs in the Rules and Regulations for Swedish trotting 2015 and is valid during the current year.TABLE OF CONTENTS Rules and Regulations for Swedish Trotting 4 Entry Application 4 Pre-competition 4 Equipment 5 – Horse 5 – Driver 6 – Rider 6 Pre-race 6 Starting Procedures 8 – Auto start 8...»

«The Wave: A Teaching Tool for Minimising Resistance Author Christine Herzog, Auckland Workers' Educational Association The Wave can be applied to a range of educational settings and subjects. It is particularly effective when the subject matter is controversial and requires learners to consider various viewpoints or contexts different to their own. What is The Wave? The tool provides a reliable, easy-to-deliver, easyto-understand, easy-to-remember learning experience that highlights two main...»

«SWEET SIXTEEN AND NEVER BEEN DRUNK? ADOLESCENT ALCOHOL USE, PREDICTORS AND CONSEQUENCES Joris J. van Hoof 3 Thesis, University of Twente ISBN: 978-90-365-3092-7 Van Hoof, J. J. (2010). Sweet Sixteen and Never Been Drunk? Adolescent Alcohol Use, Predictors and Consequences. Enschede, The Netherlands: University of Twente. Cover design: Marleen Mulder-Wieske Printed by: Gildeprint B.V., Enschede 4 SWEET SIXTEEN AND NEVER BEEN DRUNK? ADOLESCENT ALCOHOL USE, PREDICTORS AND CONSEQUENCES PROEFSCHRIFT...»

«MA Dissertation’ Mr MD Nin [2011] University of Central Lancashire Faculty of Arts, Humanities & Social Sciences Northern School of Design Postgraduate Project/Dissertation DE4115 2010/11 Project/Dissertation „The Great Divide‟ Is there a useful connection between science and art? Matthew D Nin (MA Ceramics) www.mattninceramics.wordpress.com | www.hands-onclay.co.uk 1 MA Dissertation’ Mr MD Nin [2011] 1. Introduction Throughout my practice over the years within Art & Design, when given...»

«How you talk about God. ! Welcome, ! Third week of our Ten Commandment Series. 3rd commandment “Do not take God’s name in Vain.” ! Have you thought about what that means? I think for many they equate it to any foul language. ! Illus: 3rd grade Jumping on Trampoline with Tyson, and he shares with me all the Four Letter words he learned, Mom listening through window and I got a front row seat to his mouth being washed out with soap! What many Mom’s think—is that there’s a list of good...»

«2011 Orthodontics PRAGUE November 24–26, 2011, Kaiserstejnsky palace www.orthodontics-ios.eu Dentofacial Orthopedics Improved Contemporary Approaches Listen to the world’s most famous speakers, in fabulous Prague, every year during the first Advent u ng s p ild Total number of credit hours: 18 un b Fo r t k te Fortbildungspunkte: 12 + 6 12+6 Sponsored by: DENTAURUM, DTI Institute 9th International Orthodontic Symposium www.orthodontics-ios.eu Invitation Dear Colleagues, The International...»

«ORGANISME INTER-ÉTATIQUE UNIVERSITÉ DE YAOUNDÉ II-SOA INSTITUT DE FORMATION ET DE RECHERCHE DEMOGRAPHIQUES FACTEURS ASSOCIES AUX ATTITUDES DE STIGMATISATION A L’EGARD DES PERSONNES VIVANT AVEC LE VIH/SIDA AU CAMEROUN Mémoire présenté et soutenu en vue de l'obtention du Diplôme de MASTER PROFESSIONNEL EN DÉMOGRAPHIE Par Aminatou NZIE Comité d’Encadrement Directeur : Dr. Didier NGANAWARA Lecteur : Dr. Samuel KELODJOUE Yaoundé, Novembre 2010 Nzie Aminatou 2009-2010 ENGAGEMENT Les...»

«SECTION 05520 HANDRAILS AND RAILINGS PART 1 GENERAL 1.1 SECTION INCLUDES A. Aluminum component railing systems. 1.2 RELATED SECTIONS A. Section 03300 CastInPlace Concrete;7 coordination with substrate. B. Section 06100 Rough Carpentry: Blocking requirements and installation. C. Section 06410 Interior Architectural Woodwork: Wood rail cap installed on railing system. 1.3 REFERENCES A. American Architectural Manufacturers Association (AAMA) 2604 Voluntary Specification, Performance Requirements...»

«Ain Shams University Women’s college Curricula and Methods of teaching Department The Effectiveness of a TaskBased Instruction program in Developing the English Language Speaking Skills of Secondary Stage Students A thesis Submitted for the Ph.D. degree in Education (Curricula and Methods of Teaching English as a Foreign Langauge) By Shiamaa Abd EL Fattah Torky Assistant Researcher at the Curricula Development Department The National Center for Educational Research and Development Supervised...»

«When do high stock returns trigger equity issues?∗ Aydo˘an Altı g University of Texas at Austin aydogan.alti@mccombs.utexas.edu Johan Sulaeman University of Texas at Austin johan.sulaeman@phd.mccombs.utexas.edu November 2007 ∗ Preliminary. Any comments and suggestions are welcome. When do high stock returns trigger equity issues? Abstract One of the most prominent stylized facts in corporate finance is that equity issues tend to follow periods of high stock returns. We document that...»

«Instrument Inversion in Zulu Jochen Zeller University of KwaZulu-Natal, Durban, South Africa 1. Introduction ∗ A prominent feature of Bantu languages is the existence of so-called inversion constructions in which the logical subject (an agent or theme NP) appears post-verbally, while the pre-verbal grammatical subject position is occupied by an argument ranked lower on the thematic hierarchy. A well-known example is locative inversion, illustrated by the Chicheŵa sentence in (1b) (see e.g....»

«City Clerk Department 2180 Milvia Street, Berkeley, CA 94704 Tel: (510) 981-6908 ● TDD: (510) 981-6903 ● Fax: (510) 981-6901 E-mail: clerk@cityofberkeley.info ● Website: http://www.cityofberkeley.info/clerk FORMS AND INSTRUCTIONS FOR PERSONS SUBMITTING PRIMARY ARGUMENTS AND REBUTTAL ARGUMENTS FOR BALLOT MEASURES ON THE NOVEMBER 8, 2016 GENERAL MUNICIPAL BALLOT PRIMARY ARGUMENT PERIOD OPENS: 8:00 a.m., Monday, August 15, 2016 DEADLINE FOR FILING ARGUMENTS: 12:00 p.m., Friday, August 19,...»





 
<<  HOME   |    CONTACTS
2016 www.dissertation.xlibx.info - Dissertations, online materials

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.