BORANES AS SOURCES OFHYDROGEN RADICALS

byJackie Zi Wei Luk

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OF

BACHELOR OF SCIENCE

inThe Faculty of Science(Honours Chemistry)

THE UNIVERSITY OF BRITISH COLUMBIA(Vancouver)

April 2011

Jackie Zi Wei Luk, 2011Abstract

We have explored several substituted benzotriazole boranes and showed that these complexes are a suitable source of hydrogen radical for the Barton-McCombie deoxygenation reaction. Screening studies have demonstrated that 1-methylbenzotriazole boranes showed the highest reactivity as a hydrogen atom donor and optimization studies were performed. We have shown that initiators with higher half-lives tend to improve yields and propose a mechanism to support this hypothesis. Studies were performed to determine whether the required amount of ligand is catalytic; however, these studies were inconclusive. Control tests have confirmed the necessity of all reagents presented in our work. Future work can be performed to elucidate the results from the catalytic studies as well as possible applications.

Table of ContentsAbstractiiTable of ContentsiiiList of SchemesivList of FiguresvList of TablesviList of AbbreviationsviiAcknowledgmentsviiiChapter 1INTRODUCTION11.1.Objectives11.2.Radical Reactions11.3.Deoxygenation Reactions21.4.The Barton-McCombie Deoxygenation51.5.Substitutes for Tributyltin Hydride7Chapter 2BENZOTRIAZOLE-BORANE COMPLEX STUDIES102.1.Introduction102.2.Synthesis of 1-Methylbenzotriazole Borane112.3.Hydrogen-Radical Donor Screening112.4.Optimization122.5.Sub-Stoichiometric Amount of 1-Methylbenzotriazole142.6.Radical Pathway Study182.7.Control Tests192.8.Other Activated Xanthates20Chapter 3APPLICATION AND FUTURE STUDIES21Appendix IEXPERIMENTALS23Appendix II 1H and 13C NMR spectra30References43

List of SchemesScheme 1: Hydrobromination and Radical Hydrobromination2Scheme 2: Synthesis of intermediate for (+)-makassaric acid3Scheme 3: Deoxygenation of Primary and Tertiary Alcohols not Involving Radicals4Scheme 4: Limitation of the Wolff-Kishner Reduction with Hindered Carbons4Scheme 5: First Example of Barton-McCombie Deoxygenation5Scheme 6: Preparation of Thiocarbonyl Derivatives6Scheme 7: The Barton-McCombie Mechanism7Scheme 8: NHC-Boranes in the Barton McCombie Reaction9Scheme 9: Synthesis of 1-methylbenzotriazole borane11Scheme 10: Barton-McCombie with Benzotriazole-Borane Substitutes12Scheme 11: Initiator Screening13Scheme 12: Equilibrium Between Free and Bound Borane15Scheme 13: Proposed Mechanism Xanthate 25 as Substrate15Scheme 14: Sub-stoichiometric Amounts of Ligand-Borane Complex17Scheme 15: Sub-Stoichiometric Amounts of Benzotriazole Ligand17Scheme 16: Radical Pathway Test With Cyclopropane Ring Opening18Scheme 17: Testing Other Common Nitrogen Ligands19Scheme 18: Control Tests20Scheme 19: Deoxygenation of Activated Xanthate20Scheme 20: Selective Deoxygenation of Benzylic Position21

List of FiguresFigure 1: Nitrogen Heterocyclic carbene boranes9Figure 2: Nitrogen Heteroaryl Boranes9Figure 3: Substituted Benzotriazole Boranes10

List of TablesTable 1: Product to Reactant Ratios from Screening Benzotriazole-Boranes12Table 2: NMR Yields of Reactions Using Different Initiators14Table 3: Catalytic Loading of 1-Methylbenzotriazole Ligand17

List of AbbreviationsAIBNAzobisisobutyronitrileABCNAzobiscyclohexanenitrileBDEBond Dissociation EnthalpyBuButylCDCl3DeuterochloroformDCMDichloromethaneDMAP4-(dimethylamino)pyridineDMSDimethylsulfideE1Unimolecular EliminationIRInfraredMeMethylMOMMethoxymethyl NHCNitrogen-Heterocyclic CarbeneNMON-Methylmorpholine-N-Oxide NMRNuclear Magnetic ResonancePhPhenylSN2Bimolecular Nucleophilic SubstitutionTCDIThiocarbonyldiimidazoleTHFTetrahydrofuranTHPTetrahydropyranTLCThin Layer ChromatographyTPAPTetrapropylammonium perruthenate

AcknowledgmentsI am deeply grateful to the people who made this thesis possible. I would like to express my deepest gratitude towards my supervisor, Dr. Glenn Sammis, for his insight, advice, assistance, and the opportunity to work on this project. Throughout this project, he has provided invaluable support and ideas.

Thank you to all the graduate students in the Sammis Lab for countless tips and suggestions inside the lab and outside the lab. Special thanks to Maria Zlotorzynska for the demonstration of using laboratory equipment. Without her knowledge and support, this work would not have been successful. I am very grateful to the NMR staff for the training provided using the NMR facilities and providing support when needed.I would like to thank the Chemistry 449 class for support during the Chem 449 symposium, especially Kanghee Park, Elaine Wong, Kye Seo Hwang, and Henry Tang for their camaraderie, entertainment, and support.

Most importantly, I would like to thank my family for their infinite support, care, and love. I dedicate this thesis to my mother, Wendy Luk, and late father, Wai Luk.

viii

Chapter 1INTRODUCTION

Objectives

The purpose of this project was to find a suitable borane-ligand complex as a hydrogen radical donor in Barton-McCombie deoxygenation reactions. Chapter 1 provides the background information of previous replacements for organotin reagents. Chapter 2 gives detail on the work involved with the new hydrogen radical donor. In chapter 3, the possible applications and recommendations for future studies are presented.

Radical Reactions

Radical reactions are reactions involving single electron processes. These reactions are interesting and synthetically useful because they display complementary reactivity to their ionic, non-radical counterparts.1 For example, hydrobromination of alkenes lead to the Markovnikov product 2. This results from the initial protonation of the alkene, leading to carbocation 1, which then reacts with the bromide ion to form the alkyl halide 2 (Scheme 1).1 If a radical initiator, such as a peroxide, is introduced to the system, we observe the anti-Markovnikov product.1 As the radical initiator abstracts a hydrogen atom from HBr, the bromine radical formed reacts with the alkene to forms radical 3. This then abstracts a hydrogen atom from HBr to form the alkyl halide 4 and regenerates the bromine radical. Another advantage of radical reactions as highlighted in this example is that they are self-propagating.1 Once the radical is initially formed, propagation steps continue to maintain radical species throughout the reaction until completion or termination.1

Scheme 1: Hydrobromination and Radical Hydrobromination

Deoxygenation Reactions

Deoxygenation reactions are invaluable synthetically. Incorporation of oxygen functionality in molecules is commonly done to reach intermediates and products of a synthesis.2,3 Examples include carbon-carbon bond forming modifications such as a carbonyl addition, alkylation of the alpha position to a carbonyl, and aldol condensations. In a recent synthesis of (+)-makassaric acid, a protein kinase inhibitor, the first step of the retrosynthetic analysis involved the linkage of two carbons via the 1,2-addition of aldehyde 5 by organolithium 6 (Scheme 2).4 The reaction between aldehyde 5 and organolithium 6 yields the alcohol product 7. In order to obtain product 8, further reactions are required, including a deoxygenation reaction (scheme 2).3

Scheme 2: Synthesis of intermediate for (+)-makassaric acid

There are many deoxygenation methods, but few good methods for secondary hydroxyl deoxygenation. Tosylation of alcohol 9 and then reducing the intermediate 10 with a hydride source, such as sodium cyanoborohydride, to obtain deoxygenated product 11 is effective for primary alcohols but not for more hindered alcohols as SN2 reactions at hindered carbons are unfavorable.5 Tertiary alcohol 12 can undergo different reactivity, namely E1 reaction, to form the deoxygenated alkene 13. Since the tertiary carbocation is stabilized by hyperconjugation, the elimination step is favorable. Hydrogenation of alkene 13 can then give the desired deoxygenation alkyl product 14 (Scheme 3).5 However, secondary alcohols do not form carbocations of nearly the same stability as tertiary alcohols, and thus secondary alcohols do not go through E1 readily.5 Moreover, the hydrogenation step may have regioselectivity issues and thus limit the utility of this transformation.

Scheme 3: Deoxygenation of Primary and Tertiary Alcohols not Involving Radicals

The most commonly used method for removing secondary alcohols are Barton-McCombie deoxygenation reactions. These reactions are done in mild conditions and often high yielding.6 In the synthesis of (+)-makassaric acid, as other methods including the Wolff-Kishner reduction have failed to yield product 8, Basabe et al. utilized the Barton-McCombie deoxygenation conditions to remove the secondary hydroxyl group with 67% yield. (Scheme 4).4

Scheme 4: Limitation of the Wolff-Kishner Reduction with Hindered CarbonsThe Barton-McCombie Deoxygenation

In the mid-1970s Barton and McCombie sought to develop new methods for deoxygenating alcohols. They primarily focused on secondary alcohols since effective methods for deoxygenating primary and tertiary alcohols were known. Their interest in secondary alcohols also stemmed from the fact that carbohydrates, important pre-cursors to polyhydroxylated antibiotics, contain mainly secondary hydroxyl-groups.6 While working with cholesterol derivatives and carbohydrates, Barton and McCombie discovered a new way to deoxygenate alcohol-containing compounds (Scheme 5).6One of the carbohydrate derivatives Barton and McCombie deoxygenated was alcohol 15. It was transformed into xanthate 16, and then finally the deoxygenated product 17. Not only does this method work well with secondary alcohols, tertiary alcohols are readily deoxygenated using this method.7,8

Scheme 5: First Example of Barton-McCombie Deoxygenation

Unlike the previously discussed deoxygenation, the proposed mechanism involves radical intermediates.6 Since the driving force of the deoxygenation is the formation of a tin-sulfur bond and a carbon-oxygen -bond, the first step is to transform the alcohol into a thiocarbonyl derivative. There are two methods typically used to modify the alcohol to its corresponding thiocarbonyl derivative (Scheme 6). These reactions are fairly easy to perform and yield the xanthate derivative and the thiocarbonylimidazole derivative.9,10 The thiocarbonyl derivative is then reacted with a hydrogen radical source, typically tributyltin hydride, and a radical initiator, typically azobisisobutyronitile (AIBN).

Scheme 6: Preparation of Thiocarbonyl Derivatives

The first step of the mechanism is the fragmentation of AIBN by light (or heat). The product of this dissociation yields the isobutyronitrile radical which then abstracts a hydrogen atom from tributyltin hydride. The tin radical then reacts with the thiocarbonyl, forming a strong tin-sulfur bond which drives the reaction forward, leaving the alkyl radical as an intermediate. It is because of this intermediate that secondary and tertiary alcohols deoxygenate preferentially due to radical stability at these more substituted carbons. The final step of the mechanism is for the alkyl radical to abstract a hydrogen atom from tributyltin hydride, yielding the deoxygenated product and regenerating the tin radical for further reaction (Scheme 7).6

Scheme 7: The Barton-McCombie Mechanism

Substitutes for Tributyltin Hydride

The most common source of hydrogen radical widely used is organotin compounds. Many organotin derivatives, including tributyltin hydride, are notorious for being extremely toxic neurologically. They are also known for being difficult to separate from the reaction mixture after the desired reaction.11,12 Therefore, it has been a task for radical chemists to search for other sources of hydrogen radical sources, suitable for replacing organotin compounds in deoxygenation reactions.12

Borane compounds have been investigated as substitutes for organotin. They tend to have lower toxicity than organotin and borane complexes have been known to exhibit radical reactivity.13,14 For borane complexes to effectively replace organotin in the Barton-McCombie reaction, there are two considerations: the borane compound must have a weak B-H bond for the initiation and propagation step, and the resulting borane-sulfur complex must have a strong B-S bond. Tributyltin hydride is successful as a hydrogen atom source in the Barton-McCombie reaction because of its weak Sn-H bond (78 kcal/mol) as well as the tendency to form strong Sn-S bonds. The weak Sn-H bond allows homolytic cleavage, forming the tributyltin radical, subsequently used in the propagation of the Barton-McCombie reaction. Rablen and Hartwig have calculated that uncoordinated boranes have B-H BDE typically around 105-106 kcal/mol.15 Computation studies have also shown that Lewis base coordinated boranes have reduced B-H BDEs.15 For example, a simple ammonia-borane complex lowers the BDE of the B-H bond to 102 kcal/mol while a phosphine-borane complex lowers the BDE to 92 kcal/mol.15 However, even with complexation, the B-H bond is still much stronger in comparison to the Sn-H bond.14,15Curran et al., in 2009, explored other coordinated boranes as possible replacements for organotin compounds in the Barton-McCombie reaction. They examined ligands in the nitrogen-heterocyclic carbene (NHC) family and studied the effects NHC coordination had on B-H reactivity (Figure 1).14 They utilized two NHC-boranes, 18a and 18b, in xanthate reductions (similar to the Barton-McCombie) and performed kinetic studies on their results (Scheme 8).14 The studies done on the rates of reactions showed that the B-H BDE of these NHC-boranes were approximately 80-88 kcal/mol.14 They were able to isolated the borane-xanthate compounds, supporting the strengths of B-S bonds.14

Figure 1: Nitrogen Heterocyclic carbene boranes

Scheme 8: NHC-Boranes in the Barton McCombie Reaction

Following the work of Curran, Laleve studied other ligand-borane complexes involving nitrogen-heteroaryl ligands, 21a, 21b, and 21c (Figure 2).16 Kinetic information collected in this experiment showed that the B-H BDE of these molecules were 81-82 kcal/mol.16 It is suggested by studies done by Laleve that the reason for this decrease in B-H BDE is due to the delocalization of spin density from the borane to the ligand; a similar explanation by Curran was given to explain the lowering of B-H BDE in NHC-boranes.14,16 Laleve has reported using these boranes to perform other radical reactions. However, he has not reported using these in the Barton-McCombie reaction.16

Figure 2: Nitrogen Heteroaryl BoranesChapter 2BENZOTRIAZOLE-BORANE COMPLEX STUDIES

1. 1. 1. Introduction

In 2009, Shi, from West Virginia University, first used benzotriazole-borane complexes in reductive amination reactivity with aldehydes and ketones.17 The Shi group has provided us computational data showing that benzotriazole coordinated boranes have a significantly lower B-H BDE than other borane complexes.17,18 He showed that substituted benzotriazoles, 22a, 22b, 22c, and 22d, had approximately B-H BDE of 67-72 kcal/mol. Moreover, toxicity studies have shown that benzotriazole ligands are more bio-compatible, less toxic and less of a health hazard to humans in comparison with organotin compounds.18,19 These properties make benzotriazole-borane complexes promising replacements for organotin in Barton-McCombie reactions.

Figure 3: Substituted Benzotriazole Boranes

Synthesis of 1-Methylbenzotriazole Borane

We tested benzotriazole-boranes for their B-H reactivity by using these ligand-borane complexes as a substitute for tributyltin hydride in the Barton-McCombie. A representative synthesis of benzotriazole borane 22a is shown below (Scheme 9). To obtain borane 22a, we started with methylating benzotriazole 23 to obtain benzotriazole 24[endnoteRef:1]. Having added tetrahydrofuran-borane complex, the borane and benzotriazole 24 coordinated to form borane 22a. [1: Compound 24 was prepared by Maria Zlotorzynska.]

Scheme 9: Synthesis of 1-methylbenzotriazole borane

Hydrogen-Radical Donor Screening

Initial studies were done to determine which of 22a-d had the most promising hydrogen-radical donating capability. We substituted each of the benzotriazole-borane complex for tributyltin hydride in the reaction with xanthate 25. 25 was prepared from the corresponding alcohol using the method listed in Scheme 6. Upon reacting all four different benzotriazoles, using AIBN and UV light (350 nm) for 8 hours with the xanthate 25, we decided to work with the methylated benzotriazole borane as this gave us the highest product (26) to reactant ratio[endnoteRef:2] (Scheme 10, Table 1). [2: Products to reactant ratios were obtained using NMR integrations of corresponding product and reactant signals (described in Appendix I)]

Scheme 10: Barton-McCombie with Benzotriazole-Borane Substitutes

Table 1: Product to Reactant Ratios from Screening Benzotriazole-BoranesBenzotriazole-Borane UsedProduct:Reactant

22a1:3.7

22b1:7

22c1:7.3

22d0

Optimization

Having chosen the benzotriazole borane to work with, conditions of the reaction (with 22a) needed to be adjusted to maximize overall yield. Increasing reaction time to 18 hours allowed the reaction to go to 100% conversion (absence of substrate). Thus, further optimizations were done using 18-hour reaction time. We began our optimization by investigating different initiators. The half-lives of thermal initiators are well-known and tabulated by the Sigma-Aldrich company.20 We suspected that the yield depended on the decomposition rates of the initiator and therefore, tried slower releasing initiators. At first, we substituted AIBN with two different initiators: lauroyl peroxide and azobiscyclohexanenitrile (ABCN), a commonly used substitute for AIBN. Using AIBN, we obtained a 55% yield. The substitution with lauroyl peroxide increased the yield to 72%, while with ABCN, yield improved to 78%[endnoteRef:3] (Table 2). The 10-hour half-lives of the initiators in increasing order is AIBN, lauroyl peroxide, ABCN, di-tbutyl peroxide ((tBuO)2), and tbutyl hydroperoxide (tBuOOH) (Table 2). Because the half-life and decomposition rate are inversely proportional, the optimization experiment confirmed that the slow release of initiator improved yields. As an addition experiment to verify this, instead of adding 0.15 equivalence of ABCN all at once, we partitioned it into three 0.05 equivalence portions and added it 2.5 hours apart. We ran these two reactions for 8 hours total as opposed to running at 18 hours to determine the conversion since we know at 18 hours, no starting material remained. The results from this experiment were that the incremental addition of initiator increased the conversion from 3:1 to 11.2:1 product to reactant ratio. This experiment supported the fact that the slower release of initiator increased the yield. To avoid having to add initiator every several hours, we replaced the initiator used with one of the slowest decomposing initiators: tBuOOH and (tBuO)2 (Scheme 6).20 Reactions (18 hours) with these peroxides increased the yield to 80% (di-tbutyl peroxide) and 83% (tbutyl hydroperoxide), which further supports that the slower release of initiator improves the yields (Table 2). [3: Yields were obtained by measuring the amount of reactant before the experiment and amount of product after the reaction using the internal standard 1,3,5-trimethoxybenzene (described in Appendix I)]

Scheme 11: Initiator ScreeningTable 2: NMR Yields of Reactions Using Different InitiatorsRadical Initiator10 hr. Half-life oCNMR Yield %[endnoteRef:4] [4: These NMR Yields are averages]

AIBN6555

Lauroyl peroxide6572

ABCN8878

(tBuO)212580

tBuOOH17083

Sub-Stoichiometric Amount of 1-Methylbenzotriazole

A possible explanation as to why a slower releasing radical initiator improves yield is the equilibrium between free and bound borane. It has been reported that boranes in solution tend to be in both the coordinated and free state.21 An experiment was also performed[endnoteRef:5] to confirm the presence of free BH3 upon adding benzotriazole borane by observing the reduction of an aldehyde. A slower dissociating initiator would allow time for the equilibrium to re-establish as the bound-state boranes are being consumed. It is important for the system to equilibrate as the free boranes have too high of a B-H BDE to allow hydrogen radical donating capability (Scheme 12). [5: This experiment was performed by Maria Zlotorzynska]

Scheme 12: Equilibrium Between Free and Bound Borane

Scheme 13: Proposed Mechanism Xanthate 25 as SubstrateWe propose this mechanism (Scheme 13) to show the cycle the ligand goes through during this deoxygenation reaction. Starting with 22a, the benzotriazole-borane, we first have a hydrogen abstraction by radical initiator (or deoxygenated radical alkyl) to form 27. This radical borane reacts with the xanthate 25 to form the intermediate, 28. The intermediate then collapses and expels the deoxygenated radical alkyl group, which then abstracts a hydrogen atom from another borane complex to yield 26, the deoxygenated product. The borane intermediate transforms into 29 which in the subsequent step, dissociates into the 1-methylbenzotriazole ligand, 24, and S-boryl S-methyl dithiocarbonate, 30. The benzotriazole ligand can then recombine with borane, 31, (from another source, such as DMS-borane) to reproduce 22a. Because the benzotriazole ligand is not consumed in this Barton-McCombie reaction, we hypothesize that the amount of benzotriazole ligand required may be catalytic. We tested this possibility by replacing the full equivalence of the ligand-borane complex with half equivalence of the complex and half equivalence of another borane source, DMS-borane (Scheme 14). Using these new conditions, we obtained an NMR yield of 54%. The yield is lower compared to the initial experiments with 1.2 equivalence of the ligand-borane complex, which is not surprising as we have lower amounts of the complex. The results from this experiment suggests that it is not catalytic since a 50% loading of the borane gave approximately 50% yield. To further our studies, we performed an experiment where the borane and ligand was added separately. We used a sub-stoichiometric loading of the ligand and a full equivalence of borane (DMS-borane) to determine whether a catalytic amount of the ligand would be sufficient to maximize yield (Scheme 15). The results of these experiments are tabulated (Table 3). However, what is interesting is that the yields of these catalytic studies are lower than the experiment with 1.2 equivalents of ligand-borane complex. It is unclear which step of the ligand cycle is rate determining and causes this trend.

Scheme 14: Sub-stoichiometric Amounts of Ligand-Borane Complex

Scheme 15: Sub-Stoichiometric Amounts of Benzotriazole Ligand

Table 3: Catalytic Loading of 1-Methylbenzotriazole LigandEquivalents of 24 % NMR Yield

0.346

0.450

0.548

0.648

Radical Pathway Study

The earlier proposed mechanism is based on the radical Barton-McCombie pathway and an experiment was performed to support this. This was achieved by acknowledging the rates of opening of cyclopropane. It is known that the rate of opening of a cyclopropane ring alpha to a carbon radical is ~108 s-1.22 This rate is faster than most other radical reactions and thus by having this group alpha to the oxygen, we can determine whether this deoxygenation goes through a radical mechanism by observing the presence or absence of the cyclopropane ring and alkene product (Scheme 16). We reacted thiocarbonyl derivative 32 under the optimized conditions (full equivalence of borane-ligand complex, di-tbutyl peroxide), and confirm the presence of a radical mechanism. A radical-free pathway would lead to the cyclopropane product while a radical pathway (Scheme 16) would lead to alkene 33. Although a mixture of products was observed, the presence of alkene 33 supports the radical mechanistic pathway.

Scheme 16: Radical Pathway Test With Cyclopropane Ring Opening

Control TestsOther nitrogen ligands were tested as possible substitutes, including pyridine and Hunigs base (N,N-diisopropylethylamine) (Scheme 17). Reactions were set-up using DMS-borane as the borane source and three different ligands, 24, 34, and 35 to test the reductive deoxygenation capability of these ligands with tBuOOH. As expected, the deoxygenated product 26 was obtained using ligand 24 but no deoxygenated product was found when using 34 or 35. Control tests were performed in order to confirm the necessity of all reagents (Scheme 18). The four experiments conducted contained all the reagents for control except one reagent, the variable. The absence of either 350nm UV light, borane, ligand, or borane-ligand complex leads to no deoxygenated product. The results from these tests confirm the requirement of all the reagents used in our previous experiments.

Scheme 17: Testing Other Common Nitrogen Ligands

Scheme 18: Control Tests

Other Activated Xanthates

In addition to xanthate 25, we have applied this deoxygenation method with substrate 36[endnoteRef:6] using the optimized conditions for substrate 25. The deoxygenation was a success, giving product 37, with a 71% NMR yield (Scheme 19). [6: Substrate 36 was prepared by Maria Zlotorzynska]

Scheme 19: Deoxygenation of Activated XanthateChapter 3APPLICATION AND FUTURE STUDIESDeoxygenation of xanthate 25 to yield 26 was shown to be successful in this project. Using the same optimized conditions, the deoxygenated product was not observed with xanthate 38. (Scheme 20).

Scheme 20: Selective Deoxygenation of Benzylic Position

An application for this selectivity in literature is the synthesis of sidechain of zaragozic acid.23 Robichaud, Berger, and Evans synthesized a side chain of zaragozic acid in 1993 that could benefit from our deoxygenation methods (Scheme 21). One step that the authors were having trouble was to selectively deoxygenate the benzylic alcohol. The first method employed by them used lithium metal in liquid ammonia and that gave yields of 40%.23 Using the chemistry that we have devised, the yields of the reaction could be improved and/or the step counts can be reduced.

Scheme 21: Deoxygenation Step of the Synthesis to a Sidechain of Zaragozic Acid

As we have successful deoxygenated xanthate 36, future studies could improve on the number of substrates and possibly optimizing further the conditions for each substrate. As organotin compounds are used in many different radical reactions, other than the Barton-McCombie, we could test the suitability of 1-methylbenzotriazole borane as a substitute for organotin in those reactions.

Finally, as mentioned before, the mechanistic studies involving catalytic amounts of ligand were not entirely conclusive. Future work on the rates of the dissociation and association of borane onto the ligand could elucidate the reasons behind the yields that do not depend on ligand concentration, but are lower when adding ligand and borane separately compared to adding the ligand-borane complex.

Appendix IEXPERIMENTALS

2. General MethodsAll reactions were performed under nitrogen in oven-dried glassware. All non-deuterated solvents used were purified by MBRAUN MB-SPS solvent purification system. All deuterated solvents were from commercial sources and used without further purification. All chemicals used were purchased from commercial sources as well and used without further purification. Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates. Chromatographic separations were effected over Fluka 60 silica gel.

InstrumentationInfrared (IR) spectra were obtained using a Thermo Nicolet 4700 FT-IR spectrometer. Proton nuclear magnetic resonance (1H NMR) spectra were recorded using a Bruker AV-300 or AV-400 spectrometer. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded using a Bruker AV-400 spectrometer. Chemical shifts reported in parts per million (ppm) are referenced to centerline of deuterochloroform (7.27 ppm 1H NMR; 77.0 ppm 13C NMR) or deuterobenzene (7.16 ppm 1H NMR). Mass spectra were recorded with Waters LC-MS spectrometer.

General Methods for NMR YieldsReported product-to-reactant ratios were obtained using 1H NMR spectra. The peaks corresponding to products and reactants were integrated and then divided by the hydrogen atoms expected to produce a ratio. NMR yields were obtained using 1,3,5-trimethoxybenzene as the internal standard. A 1H NMR spectrum was taken before and after the reaction. The product and reactant peaks were then integrated to obtain a yield.

General Method for DeoxygenationThiocarbonyl derivative (xanthate or thiocarbonyl imidazole) (0.05 mmol) was dissolved in deuterobenzene (1 mL) in an NMR tube. Substituted benzotriazole borane (0.06 mmol) and radical initiator (0.0075 mmol) is added to this solution. 1,3,5-trimethoxybenzene (0.015 mmol) is added as an internal standard. The NMR tube is then placed in the photoreactor (350 nm UV light) for 18 hours.

Synthesis of 22a

1-methylbenzotriazole borane: 1-methylbenzotriazole 24 (0.6657 g, 5 mmol) was dissolved in dry THF (5 mL) at room temperature. To this solution, BH3-THF (5.5 mL, 1.0 M in THF) was added dropwise by a syringe. The solution was stirred and checked by TLC. After completion (30 minutes), 0.3809 g of 22a (52%) was obtained by vacuum filtration as a white solid. 1H NMR (400 MHz, CDCl3) 8.21 (m, 1H), 7.61-7.71 (m, 3H), 4.39 (s, 3H) 2.34-3.01 (br m, 3H) ppm; 13C NMR (400 MHz, CDCl3) 139.79, 134.08, 129.32, 127.30, 118.15, 110.06, 35.67 ppm.

1H and 13C NMR spectra match literature values:Liao, W. Chen, Y. Liu, Y., Duan, H., Petersen, J. L., Shi, X. Chem. Commun. 2009, 6436-6438Synthesis of 25

O-benzyl S-methyl dithiocarbonate: A solution of S1 (2.07 mL, 20 mmol) was prepared in THF (50 mL). The solution was cooled to 0oC and sodium hydride (0.9599g, 60% in oil, 24 mmol) was added portionwise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0oC, carbon disulfide (2.40 mL, 40 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (1.49 mL, 24 mmol) was then added to the solution at 0oC and the solution was re-warmed to room temperature. This solution was stirred overnight (18 hours). The reaction mixture was quenched with ammonium chloride and then extracted with diethyl ether three times. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a yellow oil. Purification by flash chromatography (3:1 hexanes:ethyl acetate) gave 3.96 g of 11 (99%) as a yellow oil. IR (neat) 3089-2848, 1197, 1057 cm-1; 1H NMR (400 MHz, CDCl3) 7.35-7.44 (m, 5H), 5.56 (s, 2H) 2.59 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3) 215.70, 134.71, 128.62, 128.53, 75.13, 19.09 ppm.

1H and IR spectra match literature values:Chaturvedi, D., Ray, S. Monatshefte fr Chemie. 2006, 137, 1219-1223

Synthesis of 32

Cyclopropylphenylmethanol: A solution of S1 (2.193 g, 15 mmol) was prepared in methanol (75 mL). To this solution, sodium borohydride (0.5675 g, 15 mmol) was added portionwise. The reaction was stirred for one hour. The solution was then worked up with ammonium chloride, and then extracted with diethyl ether. The combined organic layers were washed with brine. The resulting solution was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to provide 2.054 g of S3 (92%). 1H NMR (400 MHz, CDCl3) 7.28-7.45 (m, 5H), 4.01 (d, 1H), 2.19 (s, 1H), 1.19-1.27 (m, 1H), 0.63-0.68 (m, 1H), 0.53-0.62 (m, 1H), 0.46-0.51 (m, 1H), 0.46-0.41 (m, 1H) ppm; 13C NMR (400 MHz, CDCl3) 143.47, 127.98, 127.14, 125.65, 78.16, 18.80, 3.23, 2.44 ppm.

1H and 13C NMR spectra match literature values:Holland, H. L., Chernishenko, M. J., Conn, M., Munoz, A., Manoharan, T. S., Zawadski, M. A. Can. J. Chem. 1990, 68, 696-700

O-(cyclopropyl(phenyl)methyl) 1H-imidazole-1-carbothioate: To a solution of (0.4446 g, 3 mmol) S3 in DCM (15 mL), 1,1-thiocarbonyldiimidazole (0.8019 g, 4.5 mmol) and 4-(dimethylamino)pyridine (0.0366 g, 0.3 mmol) were added. The solution was stirred for 24 hours, and then concentrated by rotary evaporation. Purification by column chromatography (2:3 hexanes:ethyl acetate) afforded 0.6580 g of 32 (85%) as a yellow oil. IR (neat) 3123-3004, 1690, 1469, 1364, 1270, 1215, 1135, 1098, 885, 745, 697 cm-1; 1H NMR (400 MHz, CDCl3) 8.16 (s, 1H), 7.28-7.46 (m, 6H), 7.07 (m, 1H) 4.26 (d, 1H), 1.45-1.51 (m, 1H), 0.71-0.80 (m, 2H), 0.45-0.51 (m, 1H), 0.54-0.61 (m, 1H) ppm; 13C NMR (400 MHz, CDCl3) 211.53, 165.45, 140.50, 135.42, 130.79, 127.81 127.64, 115.84, 55.61, 16.80, 6.73, 6.14 ppm.[endnoteRef:7] [7: Mass spectroscopy was attempted but was not successful]

Synthesis of 38

O-Phenylethyl S-methyl xanthate: A solution of S4 (0.36 mL, 3 mmol) was prepared in THF (15 mL). The solution was cooled to 0oC and sodium hydride (0.1440g, 60% in oil, 3.6 mmol) was added portionwise. The resulting solution was then warmed to room temperature and stirred for one hour. After cooling the solution to 0oC, carbon disulfide (0.36 mL, 6 mmol) was added dropwise and the resulting solution was stirred for one hour at room temperature. Methyl iodide (0.22 mL, 3.6 mmol) was then added to the solution at 0oC and the solution was re-warmed to room temperature. This solution was stirred overnight (18 hours). The reaction mixture was quenched with ammonium chloride and then extracted with diethyl ether three times. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated by rotary evaporation to give a brownish-yellow oil. Purification by flash chromatography (3:1 hexanes:ethyl acetate) gave 0.5698 g of 38 (89%) as a brownish-yellow oil. 1H NMR (400 MHz, CDCl3) 7.24-7.35 (m, 5H), 4.80-4.83 (t, 2H) 3.11-315 (t, 2H), 2.54 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3) 215.87, 129.12, 128.78, 126.91, 100.13, 74.17, 34.83, 19.06 ppm.

1H and 13C NMR spectra match literature values:Park, H. S., Lee, H. Y., Kim, Y. H. Org. Lett. 2005, 7 (15), 3187-3190

Appendix II 1H and 13C NMR spectraCompound 22

1H NMR (400 MHz, CDCl3) 8.21 (m, 1H), 7.61-7.71 (m, 3H), 4.39 (s, 3H) 2.34-3.01 (br m, 3H) ppm

13C NMR (400 MHz, CDCl3) 139.79, 134.08, 129.32, 127.30, 118.15, 110.06, 35.67 ppm

Compound 25

1H NMR (400 MHz, CDCl3) 7.35-7.44 (m, 5H), 5.56 (s, 2H) 2.59 (s, 3H) ppm

13C NMR (400 MHz, CDCl3) 215.70, 134.71, 128.62, 128.53, 75.13, 19.09 ppm

.

Compound S31H NMR (400 MHz, CDCl3) 7.28-7.45 (m, 5H), 4.01 (d, 1H), 2.19 (s, 1H), 1.19-1.27 (m, 1H), 0.63-0.68 (m, 1H), 0.53-0.62 (m, 1H), 0.46-0.51 (m, 1H), 0.46-0.41 (m, 1H) ppm

13C NMR (400 MHz, CDCl3) 143.47, 127.98, 127.14, 125.65, 78.16, 18.80, 3.23, 2.44 ppmCompound 32

1H NMR (400 MHz, CDCl3) 8.16 (s, 1H), 7.28-7.46 (m, 6H), 7.07 (m, 1H) 4.26 (d, 1H), 1.45-1.51 (m, 1H), 0.71-0.80 (m, 2H), 0.45-0.51 (m, 1H), 0.54-0.61 (m, 1H) ppm

13C NMR (400 MHz, CDCl3) 211.53, 165.45, 140.50, 135.42, 130.79, 127.81 127.64, 115.84, 55.61, 16.80, 6.73, 6.14 ppm Compound 38

1H NMR (400 MHz, CDCl3) 7.24-7.35 (m, 5H), 4.80-4.83 (t, 2H) 3.11-315 (t, 2H), 2.54 (s, 3H) ppm

13C NMR (400 MHz, CDCl3) 215.87, 129.12, 128.78, 126.91, 100.13, 74.17, 34.83, 19.06 ppm

1H NMR of Reactions Listed in Table 122a

22b

22c

22dThe substrate peak used (Ph-CH2-OS2CH3) has a chemical shift of 5.41 ppm. The product peak used (Ph-CH3) has a chemical shift of 2.11 ppm.

1H NMR of Reactions Listed in Table 2Using AIBN

Using Lauroyl Peroxide

Using ABCN

Using di-tbutyl peroxide

Using tbutyl hydroperoxide

The internal standard peak used has a chemical shift of 6.25 ppm. The product peak used (Ph-CH3) has a chemical shift of 2.11 ppm.

1H NMR of Reactions Listed in Table 30.3 equivalents of 24

0.4 equivalents of 24

0.5 equivalents of 240.6 equivalents of 24

The internal standard peak used has a chemical shift of 6.25 ppm. The product peak used (Ph-CH3) has a chemical shift of 2.11 ppm.1H NMR of Deoxygenation of 36

The internal standard peak used has a chemical shift of 6.25 ppm. The product peak used (Ph-CH2OC(=O)CH3) has a chemical shift of 1.63 ppm.

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