The First General Electron Transfer Reductions of Carboxylic Acid Derivatives Using Samarium Diiodide

A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy In the faculty of Engineering and Physical Sciences

2014

Malcolm Peter Spain

School of Chemistry

Malcolm Spain PhD Thesis Contents

Abstract ...... 5

Declaration...... 6

Acknowledgements ...... 9

Abbreviations ...... 10

Chapter 1. Introduction ...... 13

1.1 Introduction to samarium diiodide ...... 13

1.2 Reduction of ketones and aldehydes ...... 15

1.3 Reduction of carboxylic acid derivatives ...... 23

Chapter 2. Investigations of the SmI2–H2O system ...... 27

2.0 Preliminary studies of the SmI2–H2O system ...... 27

2.1 Directing group effects ...... 31

2.1.1 Optimisation ...... 32

2.1.2 Rates of directed reductions...... 34

2.1.3 Substrate scope ...... 36

2.1.4 Mechanistic studies ...... 38

2.2 Mechanistic studies of lactone reduction ...... 42

2.2.1 Dependence of lactone reduction on water concentration ...... 43

2.2.2 Dependence of radical stability upon water concentration ...... 48

2.3 Aromatic reductions ...... 58

2.3.1 Determination of the effective redox potential of SmI2–H2O systems ...... 59

2.3.2 Optimisation of hydrocarbon reductions ...... 61

Malcolm Spain PhD Thesis 2.3.3 Mechanism of hydrocarbon reductions ...... 63

2.3.2 Substrate scope ...... 68

2.4 - Reductions of barbituric acids ...... 70

2.4.1 Optimisation ...... 71

2.4.3 Mechanistic studies ...... 73

Chapter 3. Investigations of the SmI2–amine–H2O system ...... 78

3.1 Ester Reduction ...... 78

3.1.1 Ester reduction optimisation studies ...... 79

3.1.2 Substrate scope of the ester reduction ...... 82

3.1.3 Mechanism of ester reduction ...... 86

3.2 Acid Reduction ...... 96

3.2.1 Acid reduction optimisation studies ...... 96

3.2.2 Substrate scope of the acid reduction ...... 97

3.2.3 Mechanism of acid reduction...... 100

Chapter 4. New divalent lanthanide complexes ...... 107

4.1 Effective redox potential of TmI2–MeOH ...... 107

4.2 The role of proton donors ...... 108

4.3 TmI2-mediated reduction of carboxylic acid derivatives ...... 110

Chapter 5. Synthesis of samarium diiodide ...... 116

5.1 Investigation of commercially available samarium(II) iodide solutions ...... 117

5.2 Preparation of samarium diiodide solutions ...... 120

5.2.1 Methods of preparation ...... 120

5.2.2 The influence of water ...... 121

Malcolm Spain PhD Thesis 5.2.3 The influence of oxygen ...... 122

5.2.4 The influence of peroxides ...... 123

5.2.5 Preparation procedure ...... 124

5.2.6 Imamoto’s procedure ...... 125

5.2.7 Effect of the quality of samarium metal on the preparation of samarium(II)

iodide ...... 126

5.2.8 Activation of samarium metal ...... 127

5.2.9 Stability of solutions of samarium(II) iodide ...... 130

5.3 Reduction of Meldrum’s acids (practical protocol for the use of SmI2–H2O

Solutions) ...... 132

Chapter 6. Conclusions and Future Work ...... 134

Chapter 7. Experimental ...... 135

General experimental ...... 135

Chapter 2. SmI2–H2O ...... 138

Chapter 2.0 Preliminary studies of the SmI2–H2O system ...... 138

Chapter 2.1 Directing group effects ...... 139

Chapter 2.3 Mechanistic studies of lactone reduction using SmI2–H2O ...... 159

Chapter 2.4 Aromatic Reductions ...... 169

Chapter 3. SmI2–amine–H2O ...... 175

Chapter 3.1 Ester Reduction ...... 175

Chapter 3.2 Acid Reduction ...... 195

Chapter 4. New divalent lanthanide complexes ...... 211

Chapter 5. Synthesis of samarium diiodide...... 214

Malcolm Spain PhD Thesis References ...... 217

Malcolm Spain PhD Thesis Abstract

The University of Manchester School of Chemistry Malcolm Peter Spain Doctor of Philosophy

The First General Electron Transfer Reductions of Carboxylic Acid Derivatives Using Samarium Diiodide

2014

The development of new methods for the reduction of carboxylic acid derivatives is described. The ability to reduce these carbonyl derivatives through radical intermediates provides an orthogonal approach as compared with hydride based reductions.

Initial experiments focused on the development of the SmI2–H2O system, where we have shown that chelation effects can be utilised to facilitate reduction of cyclic esters. Furthermore, a revised mechanism for the SmI2–H2O mediated reduction of lactones is discussed, and the effective reduction potential of the system determined. Also described is the optimisation of barbituric acids using SmI2–H2O to give the corresponding hemiaminal product.

Next, experiments towards the development of a more reactive SmI2-based system are presented; where we have demonstrated that the SmI2–amine–H2O system is capable of the reduction unactivated carboxylic acid derivatives. The reductions of carboxylic esters and acids are described with mechanistic discussions. In addition, the design of a new divalent lanthanide system based on thulium diiodide is described. The addition of proton sources to TmI2 increases the effective reduction potential and facilitates unprecedented reactivity with amides. An investigation into the preparation of the reagent is also described, which has been one of the key factors developing all of the chemistry presented.

Malcolm Spain PhD Thesis Declaration

No portion of the work referred to in the thesis has been submitted in support of an application for another degree or qualification at this or any other university or other institute of learning.

Part of this work has been published in peer‐reviewed journals:

Parmar, D.; Price, K.; Spain, M.; Matsubara, H.; Bradley, P. A.; Procter, D. J. J. Am. Chem. Soc. 2011, 133, 2418.

Szostak, M.; Spain, M.; Procter, D. J. Chem. Commun. 2011, 47, 10254.

Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem Commun. 2012, 48, 330.

Szostak, M.; Spain, M.; Procter, D. J. Org. Lett. 2012, 14, 840.

Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2012, 77, 3049.

Szostak, M.; Spain, M.; Procter, D. J. Nat. Protoc. 2012, 7, 970.

Szostak, M.; Collins, K. D.; Fazakerley, N. J.; Spain, M.; Procter, D. J. Org. Biomol. Chem. 2012, 10, 5820.

Parmar, D.; Matsubara, H.; Price, K.; Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2012, 134, 12751.

Szostak, M.; Spain, M.; Procter, D. J. Angew. Chem. Int. Ed. 2013, 52, 7237.

Szostak, M.; Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155.

Szostak, M.; Sautier, B.; Spain, M.; Behlendorf, M.; Procter, D. J. Angew. Chem. Int. Ed. 2013, 52, 12559.

Szostak, M.; Spain, M.; Choquette, K. A.; Flowers, II, R. A.; Procter, D. J. J. Am. Chem. Soc.2013, 135, 15702.

Szostak, M.; Sautier, B.; Spain, M.; Procter, D. J. Org. Lett. 2014, 16, 1092.

Szostak, M.; Spain, M.; Eberhart, A. J.; Procter, D. J. J. Am. Chem. Soc. 2014, 136, 2268.

Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2014, 79, 2522.

Szostak, M.; Spain, M.; Procter, D. J. Chem. Eur. J. 2014, doi:10.1002/chem.201400295.

Malcolm Spain PhD Thesis Copyright statement

i. The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and s/he has given The University of Manchester certain rights to use such Copyright, including for administrative purposes.

ii. Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made. iii. The ownership of certain Copyright, patents, designs, trade marks and other intellectual property (the “Intellectual Property”) and any reproductions of copyright works in the thesis, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property and/or Reproductions. iv. Further information on the conditions under which disclosure, publication and commercialisation of this thesis, the Copyright and any Intellectual Property and/or Reproductions described in it may take place is available in the University IP Policy (see http://documents.manchester.ac.uk/DocuInfo.aspx?DocID=487), in any relevant Thesis restriction declarations deposited in the University Library, The University Library’s regulations (see http://www.manchester.ac.uk/library/aboutus/regulations) and in The University’s policy on Presentation of Theses.

Malcolm Spain PhD Thesis

Malcolm Spain PhD Thesis Acknowledgements

I would like to thank my supervisor Professor David J. Procter for giving me the opportunity to work in the Procter group, not only during my PhD but for giving me the opportunity to get a taste of research earlier in my undergraduate course. His support and guidance have been invaluable, especially during both undergraduate and postgraduate studies. I wish you all the best for your future research projects.

I would like to thank all of the Procter members past and present, that have contributed greatly to the research during and before my PhD: Ailsa, Andrew, An Jie, Beatrice, Brice,

Caroline, Craig, Claudio, Dixit, Estella, Guidi, Hassan, Irem, Iris, James, Karl, Laura, Lorna,

Matt Helm, Matt Levick, Michal, Neal, Paula, Pierre Sara, Seidjolo, Susannah, Sylvia, Tom

Baker, Tom Findley, Trung, Vagner and Vittorio.

I would particularly like to thank Michal for proofreading this thesis and for all of his help and advice throughout. It has been a great pleasure to work with you.

I would like to extend my thanks to Dr. Ian Watt, for helpful advice regarding kinetics, Prof.

Mike Turner and Ben Lidster, for the use of their glovebox. I would also like to thank Chris and Inigo for advice regarding X-ray crystallography, Carole for the use of GC-MS, and

Gareth, Rehana and Mo for mass spectrometry. In addition, I would like to thank my industrial supervisor, Manu, and GSK and the EPSRC for their financial support.

Finally, but not at all least, I would like to thank my family and friends. I am sorry for all the occasions I have not been myself, and not been reliable.

Malcolm Spain PhD Thesis Abbreviations

Μ micro (1 x 10-6 units)

AAPL Aldrich-APL (company)

1,3 A strain Allylic 1,3 strain

Ac Acetyl

Ar Aryl

Boc tert-butyloxycarbonyl

Bn Benzyl

Bu Butyl

Calcd Calculated

D doublet (bd- broad doublet)

DCM Dichloromethane

DIPA Diisopropylamine

DMF Dimethylformamide

DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-

pyrimidinone dr diastereomeric ratio ee enantiomeric excess

EG ethylene glycol

Equiv Equivalents

Et Ethyl

G gram (SI unit)

GC Gas chromatography

H Hours

HMPA Hexamethylphosphoramide

Malcolm Spain PhD Thesis HPLC high-performance liquid chromatography

Hz Hertz (s-1, SI unit)

IR Infrared

K Rate constant

K kilo (1 x 103 units)

KIE Kinetic isotope effect

L Litre (SI unit)

LDA Lithium diisopropylamide

M Mega (1 x 106 units)

M milli (1 x 10-3 units)

M molarity (non SI unit, mol/L)

Me Methyl

Min Minutes

MEM Methoxyethoxymethyl ether

MOM Methoxymethyl ether

MS Mass spectra/spectrometry

Mol mole (SI unit, approx. 6.022 x 1023)

N normality (equivalent concentration)

NHE standard hydrogen electrode

NMR Nucleomagnetic resonance

Ph Phenyl pKa –log10 (Ka), the negative logarithm, to the base

10, of the acid dissociation constant (Ka).

Pr Propyl

RT room temperature

S singlet (NMR)

Malcolm Spain PhD Thesis SCE standard calomel electrode

T triplet (NMR)

TBAI Tetrabutylammonium iodide

TBDMS tertiary-butyldimethylsilyl tert- or t-butyl tertiary-butyl

THF Tetrahydrofuran

TMSCl Trimethylsilyl chloride

V Volts

Malcolm Spain PhD Thesis Chapter 1. Introduction

1.1 Introduction to samarium diiodide

Since the introduction of samarium(II) iodide (SmI2; Kagan’s reagent) to the organic community by Kagan in 1977,1 it has become one of the most important single electron transfer reagents available in the laboratory. Reactions using SmI2 are often typified by their high chemo-, regio- and stereo-control, and as such often play an important role in challenging synthesis of natural products, or biologically active compounds.2,3,4 One of the most attractive features of SmI2 is the ability to fine-tune its reactivity and selectivity by the

5 , 6 , 7 , 8 appropriate use of co-solvents and additives. As such, the advancement of SmI2 chemistry is closely linked with the development of additives to modify the reactivity of the parent SmI2–THF system (Table 1.1).

5 Generally, additives used in conjunction with SmI2 can be classified into three categories: proton donors, such as t-BuOH, MeOH and H2O; Lewis basic additives, including HMPA

9 and DMPU; and metal salts, such as FeCl3, NiI2 and LiCl. Seminal work by Curran, demonstrated that H2O not only acts as a proton source but also accelerates reactions; later,

Flowers has determined that water coordinates to the metal centre, forming a SmI2‒H2O complex which has an increased redox potential (Table 1.1, entries 8 and 9),10 with respect to

11 SmI2–THF (entry 1). Similarly, Inanaga demonstrated that the addition of HMPA, as a

Lewis base, increases the reactivity of the parent reductant,12 which has been correlated with the formation of a SmI2–HMPA complex, which has a high reduction potential (entry 2). In addition, Flowers has demonstrated that the addition of excess LiCl or LiBr salts, to solutions of SmI2, forms a Sm(II) reductant characterised by a much higher redox potential than the parent reagent (entry 4 and 5); 13 UV-Vis experiments demonstrated that this reagent

13 combination is equivalent to SmBr2 and SmCl2, which has low solubility in THF. In addition, a number of other redox potentials have been determined for other common Sm(II)

Malcolm Spain PhD Thesis reagents, demonstrating that the coordinating ligands (DMPU, HMDS) lead to higher

14,15,16 reduction potentials than SmI2–THF (entries 3 and 6). Notably, increased reduction potential is not the only factor influencing the reactivity of SmI2; for example, catalytic amounts of transition metal salts are added to improve reactivity, which appears to facilitate an alternative mechanistic pathway.17

Table 1.1. Summary of redox potentials of common Sm(II) reductants determined by electrochemical methods.

a entry Sm(II) reductant –E1/2 electrode solvent reference b 1 SmI2 0.89±0.08 SCE THF 11 2 SmI2 + n HMPA (n = 4) 1.79±0.08 SCE THF 11 c 3 SmI2 + n DMPU (n = 30) 1.61±0.01 SCE THF 14 d 4 SmI2•12LiBr 1.55±0.07 SCE THF 13 e 5 SmI2•12LiCl 1.78±0.10 SCE THF 13 f 6 Sm(HMDS)2 1.5±0.1 SCE THF 15 g 7 SmBr2 + n HMPA (n = 50) 2.03±0.01 SCE THF 16 h 8 SmI2 + n H2O (n = 60) 1.0±0.1 SCE THF/DME 10 i 9 SmI2 + n H2O (n = 500) 1.3±0.1 SCE THF/DME 10 a In volts vs. SCE. -E1/2 describes the half-reduction potential measured in DMF. The accuracy is approx. ±0.1 V due to solvent effects. bRecalculated from -1.41±0.08 vs. Fe+/Fe according to ref. 21. cRecalculated from - 18 d 2.21±0.01 vs. Ag/AgNO3; the difference between the SCE and Ag/AgNO3 is 0.6 V. Note that the value based e on ref. 14 recalculated from -1.98±0.01 vs. Ag/AgNO3 is -1.38±0.01 vs. SCE. Note that the value based on ref. f 14, recalculated from -2.11±0.01 vs. Ag/AgNO3 is -1.51±0.01 vs. SCE. Recalculated from -2.1±0.1 vs. g h Ag/AgNO3. Recalculated from -2.63±0.01 vs. Ag/AgNO3. Recalculated from -1.6±0.1 vs. Ag/AgNO3. i Recalculated from -1.9±0.1 vs. Ag/AgNO3.

In addition, the reduction potential of a number of other Sm(II) based reductants has been determined, through estimation of the effective redox potential through reactions with unsaturated hydrocarbons (Table 1.2). This indirect method of determining redox potentials has been utilised as it is more general allowing estimation of the redox potentials for reductants with limited solubility, irreversible oxidation, precipitation or instability. Notably,

Evans has demonstrated that Sm(CpMe5)2 (entry 2) is one of the strongest Sm(II) reductants, reducing unsaturated hydrocarbons with reduction potentials more positive than -2.22 V (vs.

19 SCE). In addition, Cabri discovered that the combination of amine Lewis bases and H2O results in a significant rate enhancement;20 using the reduction of unsaturated hydrocarbons,

Hilmersson was able to determine that this SmI2–amine–H2O forms a powerful reductant, capable of reducing hydrocarbons with reduction potentials more positive than -2.80 V (vs.

Malcolm Spain PhD Thesis SCE).21 Besides, Sm(II)-reductants this method has been utilised by Chauvin to demonstrate that the reduction potential of Sm(0) (entry 1), 22 which interestingly is lower than

Sm(CpMe5)2 and SmI2–amine–H2O. Furthermore, using the same method, Fedushkin measured the effective redox potential of thulium(II) iodide (TmI2), a non-classical divalent lanthanide, which was shown to have a high reduction potential (entry 3).23

Table 1.2. Summary of redox potentials of common Ln(0) and Ln(II) reductants determined by reduction of aromatic hydrocarbons. a entry Ln reductant –E1/2 electrode solvent Reference 1 Sm(0) metal 2.02 SCE DME 22 2 Sm(Cp5Me5) 2 2.22 SCE toluene 19 3 TmI2 2.00 SCE THF 23 4 SmI2/amine/H2O 2.80 SCE THF 21 a In volts vs. SCE. -E1/2 describes the half-reduction potential measured in DMF. The accuracy is approx. ±0.1 V due to solvent effects. 1.2 Reduction of ketones and aldehydes

The reduction of simple carbonyl derivatives, such as ketones and aldehydes, is one of the

24,25 fundamental reactions mediated by SmI2. Single electron transfer results in the formation of a ketyl radical, which can be used to mediate a number of reactions, including pinacol coupling, ketyl-olefin coupling or fragmentation reactions. In this introduction the focus is on the ability of additives to facilitate the reduction of carbonyl derivatives to the corresponding alcohols.

In 1977, Kagan reported the first reduction of ketones and aldehydes using SmI2 in the presence of methanol.1 Notably, a proton source is required to achieve the reduction, otherwise pinacol coupling can be observed; pinacol coupling is fast with aliphatic aldehydes

(<1 min), however, it is slow with aliphatic ketones (ca. 24 h).26 Later, seminal work by

Curran demonstrated that the role of H2O is not only to act as a proton source, but it also accelerates the reduction.9

The first example of a ketone reduction in target-orientated synthesis was reported by Corey,

27 in 1987. Utilising the SmI2–H2O system (THF:H2O, 5:1), a ketone was reduced to the

Malcolm Spain PhD Thesis corresponding equatorial alcohol (dr = 93:7) in the total synthesis of (+)-atractyligenin

(Scheme 1.1). This discovery, that SmI2–H2O can reduce ketones with high chemo- and diastereocontrol, has led to SmI2 systems becoming useful reagents for the synthesis of alcohols.

Scheme 1.1. Highly stereoselective ketone reduction in the total synthesis of atractyligenin, SmI2–H2O system (Corey, 1987).

In 1993, Inanaga investigated the diastereoselectivity of SmI2-mediated ketone reduction in the conformationally-locked 4-tert-butylcylohexanone system (Scheme 1.2A). 28 Anion trapping experiments with pivalic acid were used to probe the stereochemistry of protonation of the radical anion intermediate, and showed good selectivity for the equatorial alcohol

(entry 1, dr = 74:26). By contrast, radical trapping experiments using Bu3SnH resulted in a much higher preference for the axial radical (entry 2, dr = 93:7). The obtained results compare favourably with diastereoselectivities afforded by alkali metal hydrides (entries 3-

5).29 Further studies by Corey,30 on a similar conformationally-locked cyclohexanone system

(Scheme 1.2B), demonstrated that chelation enhances the diastereoselectivity of the SmI2–

H2O mediated reduction, affording the equatorial alcohol with very high selectivity (dr =

96:4). Furthermore, calculations by Houk on the geometry of ketyl radicals and ketyl anions in cyclohexanones, have confirmed the conformational preference for axial radicals and anions in these systems.31

Malcolm Spain PhD Thesis Scheme 1.2. Stereoselective ketone reduction: a) radical vs. anion trapping (Inanaga); b) directed ketone reduction (Corey).

Notably, SmI2 based reagents can be used to achieve results unattainable using hydride-based reagents. In 2011, Smith reported that reduction of 2,6-disubstituted-4-piperidinones using

SmI2–H2O affords the opposite diastereoisomer to that formed using hydride-based reagents

(Scheme 1.3A).32 A mechanistic model involving pseudo-A1,3 strain was proposed to explain the diastereoselectivity, steric hindrance prevents the hydride attack from axial direction, whilst SmI2-mediated reduction forms the energetically-accessible axial radical to afford the equatorial alcohol after protonation. Similarly, in 2010 Scheidt reported the use of SmI2–H2O mediated ketone reduction in the total synthesis of (–)-bakkenolide S, a potent inhibitor of a variety of cancer cell lines (Scheme 1.3B).33 A similar approach was developed earlier in the synthesis of bakkane sesquiterpenoids by Deprés and Greene.34 Reduction of the sterically hindered cyclopentanone intermediate using hydride reagents did not provide the desired product. In contrast, the SmI2–H2O system provided a single diastereoisomer of the alcohol in

Malcolm Spain PhD Thesis excellent yield. Of note is the chemoselectivity of the SmI2 reduction in that the 5-membered lactone was unreactive under the reaction conditions.

Scheme 1.3. Chemoselective ketone reduction, SmI2–H2O systems: a) 2,4,6-trisubstituted piperidines (Smith, 2011); b) (–)-bakkenolide S (Scheidt, 2010).

Malcolm Spain PhD Thesis In 1998, Keck hypothesised that -directing groups could be used to facilitate diastereoselective ketone reduction through 1,3-induction (Scheme 1.4). Using -

35 hydroxyketone, optimal conditions were found using SmI2–MeOH. The reaction was proposed to proceed via a Sm(II) chelated chair conformation to afford the corresponding anti-1,3-diol. Interestingly, chelating β-alkoxy groups (OAlkyl, OMOM, OMEM) also yield the corresponding anti-products (Scheme 1.4B);36 however, ketones with non-chelating β- alkoxy groups (OBn and OTBS) were not reduced under the conditions, demonstrating that chelation leads to a significant rate enhancement. In addition, Keck studied the effect of β- amino directing groups on the diastereoselectivity (Scheme 1.4C). 37 Interestingly, the substituent on nitrogen was found to be critical. Simple, N-alkyl substituents led to low levels of stereocontrol, however, electron-rich aryl substituents facilitated the reduction to the corresponding anti-product. By contrast, N-acyl directing groups resulted in the syn-1,3- products, which was proposed to proceed through a larger 8-membered chelate, involving coordination to the carbonyl oxygen of the amide.

Malcolm Spain PhD Thesis

Scheme 1.4. Highly diastereoselective β-directed ketone reduction, SmI2–MeOH systems (Keck).

Furthermore, with respect to rate enhancement using directing groups, in 1987 Molander observed that in challenging intramolecular Barbier reactions, side-products from reduction of the carbonyl group of β-ketoamides are obtained following aqueous work-up, even in the presence of the more easily reduced alkyl halides (Scheme 1.5A). 38 This indicates that chelation, to the Lewis basic amide carbonyl, may enhance the rate of ketone reduction.

Further investigations by Flowers have shown that in the absence of proton sources reactions of β-ketoesters and β-ketoamides are much faster than butanone (Scheme 1.5B).39 Notably, under these conditions, in the absence of proton sources, dialkyl ketones are typically not reduced to the corresponding alcohol, but undergo slow pinacol coupling.

Malcolm Spain PhD Thesis

Scheme 1.5. Observations of directed reductions of ketones using SmI2: a) Directed ketone reduction (Molander, 1987); b) Rate study of directed reduction of ketones (Flowers, 2002).

Importantly, the mechanism of aliphatic ketone reduction using SmI2 involves rapid reversible electron transfer to the ketone, generating a low concentration of ketyl radical,40 in the presence of proton sources this can be reduced further to the corresponding alcohol. By contrast, unsaturated ketones are not good substrates for reductions using SmI2 even in the presence of proton sources, as a large concentration of stabilised ketyl radical is formed, promoting pinacol coupling as a major side reaction; in the absence of proton sources, pinacol coupling for aromatic ketones is very fast (<1 min).26

Studies by Hoz,41 have shown that proton donors can influence the diastereoselectivity and product distribution of ketone reduction, with the concentration of alcohol additive being critical. Interestingly, using norcamphor as a model substrate (Scheme 1.6A), Hoz was able to demonstrate that both the proton source, and its concentration, can significantly affect the diastereoselectivity of the reduction. Notably, a 10-fold change in the concentration of methanol (from 1.0 M to 0.1 M) resulted in a dramatic increase in diastereoselectivity (55:45 to 81:19). In addition, Hoz studied the influence of proton donors on the reduction of diaryl ketones (Scheme 1.6B).42 The presence of proton sources facilitates competing reduction of the ketyl radical, thus affecting the alcohol to pinacol ratio. Interestingly, increasing amounts

Malcolm Spain PhD Thesis of alcohol were observed with more Lewis basic alcohol additives (inversely proportional to alcohol acidity), which was hypothesised to result from decrease of the dimer concentration; the dimer being required for pinacol coupling.

Scheme 1.6. The influence of proton donors on diastereoselectivity and product distribution: a) aliphatic ketones; b) aromatic ketones (Hoz).

In addition, Flowers examined the role of alcohol additives in the SmI2-mediated reduction of acetophenone (Scheme 1.7).10 Among the proton donors that were found to increase the rate of reduction (H2O, MeOH, EtOH, TFE), a small kinetic isotope effect (kH/kD = 1.8-2.0) was observed, suggesting that proton transfer may be involved in the rate determining step.

Furthermore, the rate of the reduction increased linearly with acidity of the proton donor; however, the SmI2–H2O system showed a significantly higher reactivity. These mechanistic studies quantified for the first time the unique rate enhancement of the SmI2–H2O system in the reduction of ketones.

Malcolm Spain PhD Thesis

Scheme 1.7. The influence of proton donors on the mechanism of the SmI2-mediated ketone reduction (Flowers).

1.3 Reduction of carboxylic acid derivatives

As expected, from the increased redox potentials, the reduction of carboxylic acid derivatives using SmI2 is much more difficult that the reduction of ketones and aldehydes. In 1993,

Kamochi and Kudo reported the reduction of activated aromatic esters to primary alcohols

43 using the SmI2–H2O system (Scheme 1.8A). Interestingly, conditions similar to Corey’s for the reduction of ketones (approx. 4:1, THF: H2O) were found to be optimal. Moreover, using the same SmI2–H2O system, activated aromatic carboxylic acids, amides and nitriles could be reduced in high yield. By contrast, in 2008 Markó and co-workers observed different

44 reactivity of activated esters, can be achieved using SmI2–HMPA systems; reduction results in Csp3–O bond cleavage to give hydrocarbon products in a formal deoxygenation process

(Scheme 1.8B). Interestingly, even simple unactivated primary esters are good substrates for the Sm(II) reaction, whilst primary xanthates do not undergo typical Barton-McCombie deoxygenation processes.45

Malcolm Spain PhD Thesis Scheme 1.8. Chemoselective reduction of activated carboxylic acid derivatives: a) Kamochi and Kudo, SmI2–H2O; b) Markó, SmI2–HMPA.

In 2008, Procter developed the first SmI2-mediated reduction of lactones to the corresponding diols (Scheme 1.9A).46 Remarkably, this reaction is selective for 6-membered lactones, over acyclic carboxylic acid derivatives and even other ring sizes of lactones. Experimental studies suggested that the high selectivity originates from the initial electron transfer to the lactone carbonyl to give an acyl-type radical anion stabilised by anomeric effects, which are higher in six-membered rings, than in other ring systems. Subsequently, Procter has demonstrated that

SmI2–H2O is capable of reducing cyclic 1,3-diesters (Meldrum’s acids) to the corresponding

3-hydroxy acids (Scheme 1.9B): 47 The first example of selective mono-reduction of

Meldrum’s acids. In analogy to the reduction of lactones, anomeric effects are thought to stabilise the acyl-type radical anion, following reduction of the cyclic ester carbonyl the tetrahedral intermediate collapses resulting in the 3-hydroxy acid after further reduction.

Notably, no over-reduction of the products was observed.

Malcolm Spain PhD Thesis

Scheme 1.9. Highly chemoselective reduction of cyclic esters and diesters, using the SmI2–

H2O system (Procter).

In addition, Procter has demonstrated that the acyl-type radicals from cyclic ester derivatives can be utilised in C-C bond forming reactions to form carbocyclic products (Scheme

1.10).48,49,50,51,52 Interestingly, lactones bearing two olefins positioned for 5-exo cyclisation selectively cyclised onto one of the alkenes followed by 5-exo cyclisation of the intermediate ketone with the remaining alkene to form bicyclic products in one step.

Malcolm Spain PhD Thesis Scheme 1.10. Reductive cyclisations of 6-membered lactones and Meldrum’s acids.

Malcolm Spain PhD Thesis

Chapter 2. Investigations of the SmI2–H2O system

Samarium diiodide can be transformed by the addition of water into a more useful and chemoselective single electron transfer reagent. Upon addition of approximately 50 equivalents of water (approx. 0.3 M when using 0.1 M solutions of SmI2 in THF) a visible colour change is observed from the dark blue SmI2–THF complex into a burgundy-red SmI2–

H2O complex. The effects of water concentration on the redox potential of SmI2–H2O, shows that addition of 60 equiv (approx. 0.3 M, 0.1 M SmI2 in THF or DME) results in an increase in the redox potential from -1.5 ± 0.1 V to -1.6 ± 0.1 V (vs. Ag/AgNO3), while addition of

500-1000 equivalents of water (2.5-5 M, 0.1 M SmI2 in THF or DME) results in a thermodynamically stronger reductant (-1.9 ± 0.1 V).53

2.0 Preliminary studies of the SmI2–H2O system

The selective reduction of 6-membered lactones using SmI2–H2O is achieved at high concentration of water (>5 M),46,48 which is consistent with the increased redox potential of

SmI2 at this concentration. For our preliminary studies on the SmI2–H2O system we studied the reduction of 5-decanolide 1 (Table 2.1), which has been shown to have a low rate of reduction (rate constant of 7.4 ± 0.1 × 10-3 M-1s-1).48 Initial results confirmed that the reduction of this substrate is slow, with low conversion after typically 1-2 h. We hypothesised that competing reduction of water by Sm(II) may be slowing the reaction in accordance with

9 Curran’s studies into the SmI2–H2O system under extended reaction times. With this in mind, we performed a comprehensive study modifying the concentration of water used to enhance the rate of the reduction of 5-decanolide 1 (Table 2.1).

The initial optimisation studies were carried out with Dr. M. Szostak, using a protocol to ensure maximum reproducibility of results with Sm(II). The reactions were typically carried out in quadruple; under the optimised protocol, <5% variation in terms of reaction progress, efficiency, and reagent stability was observed between the runs. To ensure a consistent

Malcolm Spain PhD Thesis quality of SmI2, SmI2 powder was used to avoid variations due to lack of homogeneity of

SmI2 solutions (Table 2.1 and Figure 2.1).

a Table 2.1. Influence of water on the reduction of 5-decanolide 1 with SmI2–H2O.

b c c entry source of SmI2 time H2O conversion yield notes (h) (equiv) (%) (%) 1 solution, Sm(0) 2 800 33 31 Sm(0) from Acros weighed in a glove box. 2 powder, Aldrichd 2 800 47 47 3 powder, Aldrichd 2 800 46 43 reverse addition 4 powder, Aldrichd 24 800 88 72 5 powder, AAPLd 2 800 8 8 6 powder, AAPLd 2 800 nd 6 7 powder, AAPLd 2 800 nd 6 8 powder, AAPLd 1 400 26 24 9 powder, AAPLd 1 400 23 21 10 powder, AAPLd 1 400 20 17 11 powder, AAPLd 2 200 58 57 12 powder, AAPLd 2 200 56 55 13 powder, AAPLd 2 200 63 61 14 powder, AAPLd 2 50 48 48 15 powder, AAPLd 24 50 57 57 16 powder, AAPLd 72 50 47 47 17 powder, AAPLd 2 25 <5 <5 18 powder, AAPLd 2 25 7 6 19 powder, AAPLd 24 25 11 11 20 powder, AAPLd 24 25 12 12 aAll reactions carried out with strict exclusion of oxygen, using standard Schlenk techniques for handling air- b c 1 d sensitive reagents. Quenched with air after the specified time. Determined by H NMR. SmI2 powder was weighed out in a glovebox and stored in sealed vials under an argon atmosphere (in a disposable glovebag).

Malcolm Spain PhD Thesis

Figure 2.1. Conversion in the reduction of 5-decanolide 1 with SmI2–H2O with varying equivalents of water after 2 h.

The influence of water on the conversion of 1 using SmI2 powder after 2 h

70 60 50 40 30

conversion (%) conversion 20 10 0 0 200 400 600 800 water (equiv)

As shown in Table 2.1, we determined that the order of addition of lactone to SmI2–H2O

(entry 2), versus the reverse addition (entry 3) has little impact upon the reaction.

Furthermore, variation between SmI2 powders from different suppliers (Sigma Aldrich and

Aldrich-APL) was observed, resulting in approximately 5-fold difference in reactivity

(entries 2 and 3 versus entries 5, 6 and 7). Therefore, all subsequent comparisons were made when using the same batch of SmI2 powder. We determined that even with the higher quality

SmI2 the reaction was incomplete after 24 hours, further highlighting that the reaction is slow.

Notably, visual observation revealed that the more active SmI2 powder was a dark green colour, however, the less active SmI2 powder was a lighter yellow-green colour, indicative of containing Sm(III) and Sm(0) impurities.

To investigate the influence of water upon the reaction, different conditions were screened using a single batch of SmI2 powder. A non-linear dependence of the concentration of water upon conversion was found (Figure 2.1 and Table 2.1), in contrast to the earlier kinetic studies that indicated that the reaction is zero order in water. Increasing the equivalents of water has a positive impact upon the conversion up to 200 equivalents (approx. 1 M, 0.1 M

SmI2 in THF); however, further increases in the concentration of water (up to 800

Malcolm Spain PhD Thesis equivalents, >1 M, 0.1 M SmI2 in THF) results in lower conversions represented in Figure

2.1. We hypothesise that the stability of SmI2–H2O is influenced by Sm(0) and/or Sm(III) species, present in lower quality SmI2 solutions. Therefore to achieve good reactivity with

SmI2–H2O, SmI2 solutions of high purity of the divalent lanthanide are required.

In addition to water, other proton sources commonly used in SmI2 reductions were tested for comparison of SmI2–H2O with other Sm(II) based reductants, including representative additives methanol, ethylene glycol and an amine–H2O (Table 2.2). Methanol is commonly used in SmI2 reactions as a proton source, however, we found it gives no conversion in the reduction of 1 (entries 2 and 3). Interestingly, the use of a thoroughly dried (azeotroping with benzene) ethylene glycol as an additive (entries 4 and 5) gave low conversions, in contrast to previous reports on the use of this additive in the reduction of lactones,54 Importantly, the use of the SmI2–amine–H2O system, gave full conversion to the diol (entry 1) in agreement with a higher redox potential of SmI2–amine–H2O than SmI2–H2O systems, at much lower concentrations of water.21

a Table 2.2. Influence of additives on the reduction of 5-decanolide 1 with SmI2.

b c c entry source of SmI2 time additive equiv conv. yield (h) (%) (%) 1 powder, AAPL 2 Et3N/H2O 16/24 >95 >95 2 powder, AAPL 2 MeOH 50 <5 - 3 powder, AAPL 2 MeOH 800 <5 - 4 powder, AAPL 2 EG 32 5 5 5 powder, AAPL 24 EG 32 nd 27 aAll reactions carried out with strict exclusion of oxygen, using standard Schlenk techniques for handling air- sensitive reagents. bQuenched with air after the specified time. cDetermined by 1H NMR.

Malcolm Spain PhD Thesis 2.1 Directing group effects

The reduction of lactones using SmI2–H2O is restricted to electronically activated and sterically-accessible 6-membered lactones.46,48 Moreover, the reaction typically requires long reactions times, which are typically difficult to achieve with the SmI2–H2O system. We hypothesised that a suitably placed directing group could be used to facilitate electron transfer in the rate determining step by chelating Sm(II). If successful, this would reduce the barrier to electron transfer, thus increasing the rate of lactone reduction and enabling electron transfer to less reactive lactones, such as 5- and 7-membered lactones.55

Preliminary results using an ester directing group in the alpha position, demonstrated that directing groups could allow the selective reduction of previously unreactive ring-sizes of lactones to the corresponding diols (Scheme 2.1). These experiments demonstrated the positive impact of directing groups in Sm(II) chemistry to increase substrate scope and increase the rate of reaction, thus allowing SmI2–H2O reductions to proceed within feasible reaction times.

Malcolm Spain PhD Thesis Scheme 2.1. Initial studies of directing group effects on lactone reduction.a

a Using standard Schlenk techniques. Conditions: Lactone (1 equiv), SmI2 (8 equiv), H2O (800 equiv), THF, RT, 15 min to 8 h. Conversion and selectivity determined by 1H NMR, selectivity refers to lactone reduction vs. ester reduction. 2.1.1 Optimisation

Optimisation of the reaction conditions (Table 2.3) revealed the unique effect of water as an additive; only minor conversion was observed in the absence of water (entry 1) and with lithium chloride (entry 2). Other common additives for SmI2 reactions, such as methanol

(entry 3) do not afford any conversion and additive systems that result in a higher redox potential such as HMPA (entry 4) and the combination of Lewis acid with proton source

(Et3N–H2O, entries 5-6) are unable to achieve selective reduction. Full conversion of the starting material, within 60 seconds, was observed for a range of equivalents of water (200-

1600 equiv, ca. 0.3-8 M, entries 7-13) giving predominantly the lactol intermediate. Build up

Malcolm Spain PhD Thesis of this intermediate requires that the rate determining step does not precede lactol formation in this system. Furthermore, under limiting conditions of SmI2 (entry 14), almost exclusive formation of the lactol is observed, demonstrating that its formation is facile. Interestingly, even at low equivalents of water (25 equiv, entry 16), conversion of the lactol to the desired diol occurs over extended reaction times. In contrast to our expectations, these results suggest that the rate determining step in this reduction is the collapse of the stabilised lactol tetrahedral intermediate. Notably, the formation of lactol intermediates has not been previously observed in the reduction of lactones using SmI2.

Table 2.3. Optimisation of the reduction of ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate 7 a using SmI2.

b c c,e entry SmI2 additive additive time conversion (%) yield 8:9 (equiv) (equiv) (%)c,d 1 6 - - 6 h <15 12 >95:5 2 6 LiCl 72 6 h 62 23 25:75 3 6 MeOH 500 2 h <5f <2 - 4 8 HMPA 180 2 h 50g <2 - g 5 4 H2O/Et3N 24/24 5 min 58 <2 - g 6 6 H2O/Et3N 36/36 5 min 88 <2 - 7 6 H2O 25 60 s 36 36 >95:5 8 6 H2O 50 60 s 90 85 93:7 9 6 H2O 100 60 s >98 87 93:7 10 6 H2O 200 60 s >98 99 94:6 11 6 H2O 400 60 s >98 95 95:5 12 6 H2O 800 60 s >98 93 94:6 13 6 H2O 1600 60 s >98 90 95:5 h 14 2 H2O 200 30 s >95 90 (86) 95:5 15 8 H2O 800 1 h >95 96 <5:95 16 6 H2O 25 6 h >95 45 62:38 a All reactions carried out using standard Schlenk techniques. SmI2 in THF (freshly prepared from Sm and ICH2CH2I) was used. bQuenched with air after the indicated time cDetermined by 1H NMR. dRefers to the combined yield of 8 and 9. eIn all cases 45:55 to 50:50 dr of 8 was observed. fPartial transesterification to methyl ester was observed (methyl:ethyl ester = 37:63). gComplex mixture. hIsolated yield in brackets. Conversion = (100-SM).

Malcolm Spain PhD Thesis 2.1.2 Rates of directed reductions

To gain insight into the degree of rate enhancement possible using directing groups, a collaborative study with Professor Robert Flowers at Lehigh University was performed. We designed and synthesised a series of simple lactones containing a range of directing groups, and conducted initial reactivity studies. The rate studies were performed by Dr. K. Choquette

(Lehigh U.) using a stopped-flow spectrophotometer under pseudo-first order conditions with monitoring the decay of the SmI2–H2O complex (Table 2.4). As expected, the rate of reactions for unsubstituted lactones are low (10a-c); the unsubstituted 6-membered lactone was found to react 2 orders of magnitude faster than 7-membered lactone and the reduction of

5-membered lactones were below the lower limit of measurement, consistent with anomeric stabilisation of the radical anion being highest in the 6-membered ring. The addition of an ethyl ester directing group (10d-e, 7) was found to increase the rate of reduction for all ring- sizes by 4-7 orders of magnitude. As anticipated, the reduction of the 6-membered lactone is still fastest; however, the reduction of 5-membered lactone is similar in rate to this substrate and faster than the 7-membered lactone, thus showing a different trend to that seen with unsubstituted lactones.

Malcolm Spain PhD Thesis Table 2.4. Observed rate constants and reaction orders for the reduction of lactones using a SmI2–H2O.

rate order -1 -1 entry n R1, R2 k [M s ] lactone SmI2 1 10a 0 H, H <1.0 x 10-5 - - 2 10b 1 H, H 0.014±0.001 0.82±0.03 1.0 3 10c 2 H, H 3.0 x 10-4 - -

4 10d 0 H, CO2Et 419±45 1.1±0.1 1.0

5 7 1 H, CO2Et 610±10 1.0±0.1 1.0

6 10e 2 H, CO2Et 0.91±0.05 1.3±0.1 1.0

7 10f 0 H, CO2t-Bu 0.32±0.03 0.97±0.1 1.0 8 10g 0 H, C(OH)R 0.34±0.03 2.2±0.2 1.0 9 10h 0 H, CONHCy >1.0 x 104 - - 10 10i 1 H, Ph 0.012±0.001 0.9±0.1 1.0

11 1 1 C5H11, H 0.0074±0.001 1.1±0.1 1.0 a Reactions run by Dr. K. Choquette (Lehigh U.). Conditions: [SmI2] = 10 mM; H2O = 150 equiv; lactone = 10- 55 48 50 equiv, T = 30.0 ± 0.1 °C. Entry 11, 1, R = C5H10. Next, for the 5-membered lactones (6- and 7-membered lactones were observed to decompose over time through polymerisation) the impact of other directing groups upon the rate was studied. The rate of reduction of substrates bearing a sterically demanding tert-butyl ester directing group (10f) was slower than those reactions involving the ethyl ester, correlating with coordination to the Sm(II)-centre being more difficult. Furthermore, the rate enhancement was found to correlate with Lewis basicity of the directing group; for example, alcohol directing groups (10g) which are less Lewis basic were found to give slower rates than amide directing groups (10h), which are more Lewis basic and highly effective with the rate of reductions being beyond the upper limit of measurement. In addition, the rates were measured for the 6-membered lactone with an alpha electron-withdrawing phenyl group (10i) and was found to be within error of the unsubstituted lactone, supporting that coordination effects are important in the reduction (cf. an electron-withdrawing effect). Interestingly, δ-

Malcolm Spain PhD Thesis substitution in the 6-membered lactone (1) had a significant impact on the rate: the reduction of 5-decanolide was determined to be 2-orders of magnitude lower than that of 10b, correlating with the difficulty in reducing this substrate and showing that steric effects at this position affect coordination of Sm(II).

2.1.3 Substrate scope

Under optimised reaction conditions we explored the substrate scope in terms of directing groups and functional group compatibility (Table 2.5). From the rate studies (Table 2.4), the unsubstituted 5-membered lactone was the slowest substrate to reduce in the series therefore we investigated the suitability of directing groups using this substrate. Impressively, even sterically demanding tert-butyl esters (12b) are suitable directing groups and, as expected, amides (12c-d) are very good directing groups providing the corresponding diols in high yield. Furthermore, over-reduction was not observed in any of the acyclic directing groups demonstrating the mild reaction conditions and high chemoselectivity of SmI2–H2O. In addition, functional groups that are prone to reduction under other SET conditions, such as acetates, aromatic rings, nitriles and terminal olefins are tolerated (14c, 16b-e and 18a-c).

Interestingly, under these optimised reaction conditions, 5-exo cyclisation was not observed, demonstrating that the reduction is fast (18a-c).

Malcolm Spain PhD Thesis a Table 2.5. Chelation-enabled reduction of lactones using SmI2–H2O.

entry lactone diol yield, %

b 1 3b (12a), R= CO2Et 4 b (13a) 83 b 2 12b, R = CO2t-Bu 13b 87 3 12c, R = C(O)NHCyc 13c 94 4 12d, R = C(O)NHPhc 13d 77

5 7 (14a), R = Hb 9 (15a) 96 d 6 14b, R = C5H11 15b 72 7 14c, R = Phe 15c 68

8 5b (16a), R = Hb 6b (17a) 87 9 16b, R = Bnc 17b 85 c 10 16c, R = (CH2)3CN 17c 92 c 11 16d, R = (CH2)4OAc 17d 95 c 12 16e, R = (CH2)4Ph 17e 99

c 13 18a, n = 0, R =(CH2)2CH=CH2 19a 79 c 14 18b, n = 1, R = (CH2)2CH=CH2 19b 87 c 15 18c, n = 2, R = (CH2)2CH=CH2 19c 88 a b Using standard Schlenk techniques. Conditions: SmI2 (6-8 equiv), THF, H2O, 23 °C. SmI2 (8 equiv), H2O (800 equiv), c d THF, 23 °C, 30 min - 2 h. SmI2 (8 equiv), H2O (200 equiv), THF, 23 °C, 30 min - 5 h. SmI2 (6 equiv), H2O (800 equiv), e THF, 23 °C, 30 min. SmI2 (4.5 equiv), H2O (200 equiv), THF, 23 °C, 10 min.

Malcolm Spain PhD Thesis 2.1.4 Mechanistic studies

2.1.4.1 Competition studies

To investigate the relative reactivity of the activated lactones with respect to other functional groups, we performed a series of intermolecular competition experiments (Table 2.6). The reduction of activated lactones was found to be similar in rate to the reduction of activated aromatic acids. As expected, aldehydes and ketones were selectively reduced in the presence of the lactone; however, the directed reduction was completely selective in the presence of aromatic esters. Remarkably, the reaction tolerates aliphatic iodides (which can be reduced

56 quantitatively by SmI2–THF without additives in 6 h).

a Table 2.6. Selectivity study in the reduction of activated lactones using SmI2–H2O.

conv.b,c conv.b,c entry R-FG (20) k /k (7, %) (20, %) 7 20 1 <2 49 <1:20

2 <2 21 <1:20

3 >98 <5 >20:1

4 9.6 4.2 69:31

5 >98 <2 >50:1 a All reactions carried out using standard Schlenk techniques. Conditions: entries 1, 2, 5: SmI2 (1 equiv), H2O (200 equiv); entry 3: SmI2 (2 equiv), H2O (200 equiv); entry 4: SmI2 (0.5 equiv), H2O (200 equiv), THF, room temperature, 10 s to 3 min. All reactions carried out using standard Schlenk techniques. bDetermined by 1H NMR (500 MHz) and/or GC-MS. Conversion = (100-SM). In all cases, rapid injection of substrate (THF solution) to the preformed SmI2–H2O complex was used. Product distribution: entry 1: 3-phenylpropan-1-ol, 44% yield; entry 2: 4-phenylcyclohexanol, trans: cis = 1.85:1; entry 3: lactol 80%, dr = 47:53 (<2% of diol); entry 4: lactol 9.6%, dr = 47:53, (4-methoxyphenyl)methanol 4.2%; entry 5: lactol >98% conv., dodecane <2%.

Several mechanistic studies were performed (Scheme 2.2), Reduction of 14b with SmI2–D2O gave the corresponding deuterium labelled diol, consistent with the generation of anions in

Malcolm Spain PhD Thesis the reaction. Furthermore, the kinetic isotope effect was measured for both the formation of the lactol intermediate and diol product through intermolecular competition experiments

57 (H2O:D2O = 1:1); the low kinetic isotope effect (kH/kD = 1.24±0.1, diol) demonstrates that protonation is not involved in the rate determining step.58

Scheme 2.2. Determination of deuterium incorporation and the kinetic isotope effect for the a reduction of 14b using SmI2–H2O/D2O.

a Using standard Schlenk techniques. Conditions: Lactone (1 equiv), SmI2 (6-8 equiv), D2O (200 equiv) or H2O/D2O (1:1, 200 equiv), THF, RT, 15 min to 1 h. Deuterium incorporation and kinetic isotope effect determined by 1H NMR. 2.1.4.2 Selectivity studies

To gain further evidence on the origin of the selectivity the reduction of macrocyclic (23) and acyclic esters (25, 27) with ester directing groups in the alpha position (was investigated

Scheme 2.3). No reaction was observed with SmI2–H2O, demonstrating that anomeric stabilisation in the radical intermediates facilitates a successful reduction.

Malcolm Spain PhD Thesis a Scheme 2.3. Investigating the origin of selectivity in reduction of lactones using SmI2–H2O.

a Using standard Schlenk techniques. Conditions: lactone (1 equiv), SmI2 (6 equiv), H2O (200 equiv), THF, RT, 3 h. Conversion determined by 1H NMR. 2.1.4.3 Studies on the stability of acyl-type radicals

Having determined that directing groups can be utilised to facilitate electron transfer reduction of lactones we hypothesised that the resulting acyl-type radical intermediates could be used in C-C bond forming reactions. Furthermore, on the basis of previous studies,40, 59 a protocol involving slow addition of SmI2 would lead to an increased lifetime of the acyl-type radical as SmI2 concentration would be lower, thus disfavouring the bimolecular electron transfer. Pleasingly, we determined that slow addition of SmI2 afforded the cyclised products in good yield and diastereoselectivity (Table 2.7). As expected from the well-defined conformation of 6-membered lactones, the highest diastereoselectivity is observed in 18b.

Malcolm Spain PhD Thesis

Table 2.7. Reductive cyclisation of lactones 18 using SmI2–H2O, enabled by the directing group effect (slow addition of SmI2).

entry 1 timeb yieldc drd 19:30d (h) (30, %) (30) 1 n = 0 (18a) 1 77 91:9 <5:95 2 n = 1 (18b) 1 88 92:8 <5:95 3 n = 2 (18c) 1 92 64:36 <5:95 a All reactions carried out using standard Schlenk techniques. Conditions: substrate (1 equiv), SmI2 (6-7 equiv), H2O (1200 equiv), THF, RT, 1 h, addition of SmI2 via syringe pump over 1 hour to a mixture of substrate in b c d 1 THF-H2O. Quenched with air after the indicated time. Isolated yields. Determined by H NMR. To probe the mechanism further, we examined the approximate rate of the reduction of acyl- type radicals versus ring size (Table 2.8). The rate was estimated using a non-calibrated 5-exo

5 -1 40,60,61,62 radical clock (k5-exo = ca. 2.3 x 10 s at 25 °C), at high concentration of water (10 M, see section 2.2 for a discussion on water concentration). Typically, radical clock experiments involve competition between a unimolecular radical reaction, with a known rate constant, and a bimolecular reaction with an unknown rate constant; determination of the product distribution allows the rate constant of the bimolecular reaction to be estimated.61

Interestingly, under these conditions (water = 10 M, approx. 0.1 M SmI2) the radical obtained from the 5-membered lactone (n = 0) is reduced slowest, resulting in >20:1 selectivity for the cyclised product. In agreement with higher anomeric stabilisation of intermediates, the acyl- type radical obtained from the 6-membered lactone (n = 1) is reduced fastest, with reduction of the 7-membered lactone being intermediate. Interestingly, the diastereoselectivity was found to be inversely proportional to the rate of acyl-type radical reduction. The increase in ratio of cyclised products with water concentration and increased diastereoselectivity is in accordance with the Hammond postulate.63

Malcolm Spain PhD Thesis a Table 2.8. Determination of the reduction rate of acyl-type radicals using SmI2–H2O.

conv.b,c yieldb yieldb drb 19:30b [SmI ] k d entry 1 2 2nd ET (%) (19, %) (30, %) (30) (106 x M-1s-1) n = 0 18a 61 <2 55 57:43 <5:95 0.040 <0.30 n = 1 18b >98 37 52 88:12 41:59 0.040 4.00 n = 2 18c >98 32 68 62:38 32:68 0.040 2.71 a Conditions: substrate (1 equiv), SmI2 (6 equiv), H2O (1600 equiv, 10 M), THF, room temperature, 30 min. All reactions carried out using standard Schlenk techniques. bDetermined by 1H NMR (500 MHz). cQuenched with air after 30 min. All reactions carried out with 0.060 M SmI2 in THF (prepared from Sm and ICH2CH2I). Conversion = (100-SM). In all cases, rapid injection of substrate (THF solution) to the preformed SmI2–H2O complex was applied. dApproximation calculated using the rate constant for cyclisation of the 5-hexenyl radical: -1 5 -1 60,61,62 kSmI2 = (red/cycl) x k5-exo x [SmI2] ; (k5-exo = ca. 2.3 x 10 s at 25 °C). In addition, through the use of cyclopropyl clocks it was shown that activated acyclic esters

(31c) are reduced to the acyl-type radical by SmI2–H2O (Scheme 2.4) as demonstrated by cyclopropyl ring-opening. Experiments with 31b (R = Ph) show that the enhanced reduction is not simply an electron withdrawing effect. This indicates that the first electron transfer is favourable, however, SmI2–H2O is not capable of the reduction of acyl-type radicals (second

ET) in acyclic systems.

Scheme 2.4. Investigating the directing group effect on the stability of acyl-type radicals.

a All reactions carried out using standard Schlenk techniques. Conditions: substrate (1 equiv), SmI2 (8 equiv), 1 H2O (200 equiv), THF, RT, 30 min to 2 h. Conversion determined by GC-MS or H NMR. 2.2 Mechanistic studies of lactone reduction

During our preliminary studies on the SmI2–H2O-mediated reduction of lactones, we noticed a significant non-linear dependence of the reaction rate upon the concentration of water. This

Malcolm Spain PhD Thesis finding was contrary to kinetics studies conducted earlier, which determined that the reaction was zero order with respect to water (range of 100-180 equivalents of water (>5.0 M) with respect to SmI2). In addition, our preliminary studies suggested that the stability of the SmI2–

H2O system does not appear to be the major factor contributing to the variation in reaction conversion, which prompted us to investigate the effects of water in more detail.

2.2.1 Dependence of lactone reduction on water concentration

The non-linear dependence of the reduction of 1 upon H2O equivalents, observed in the preliminary studies with SmI2 powder (see Table 2.1), was also observed using SmI2–THF solutions (Table 2.9). Overlay of the results (Figure 2.2), demonstrates there are minor differences in the dependence on water between reductions of 1 performed with SmI2-powder and freshly prepared SmI2 solutions, potentially due to Sm(III) and Sm(0) impurities in the

SmI2-powder, but it follows the same trend with optimal conversion at 150-200 equivalents of water (ca. 1 M, 0.1 M SmI2). Overall, these results indicated that significant changes in the rate of electron transfer steps can be achieved by modifying the concentration of water additive. In addition, comparing the 1 hour and 18 hour points, demonstrates the relative reactivity of the SmI2–H2O system (Table 2.9).

Malcolm Spain PhD Thesis a Table 2.9. Reaction profiles for the reduction of 1 using SmI2 (THF solution).

b b entry H2O SmI2 time conversion time conversion (equiv) (equiv) (h) (%) (h) (%) 1 50 6 1 2.9 18 20 2 100 6 1 12.5 18 67 3 200 6 1 36.2 18 74 4 400 6 1 24.8 18 58 5 800 6 1 5.3 18 37 6 1600 6 1 <2 18 16 7 3200 6 1 <2 18 6 a All reactions carried out using standard Schlenk techniques. Conditions: under argon, to SmI2 (0.60 mmol) in THF (0.052 M), H2O (50-3200 equiv) was added ester substrate (1 = decanolide, 0.10 mmol) in THF (typically, 1.0 mL), RT, 18 h. In all entries, yield >95% based on recovered SM. bConversion by 1H NMR and/or GC of crude reaction mixtures and comparison with authentic samples.

Figure 2.2. Reaction profiles in the reduction of 1 using SmI2–H2O.

Influence of water on the conversion of 1 using SmI2-H2O (SmI2 solution, 18 h; SmI2 powder, 2 h) 80

60 5-decanolide (SmI2 solution) 5-decanolide (SmI2 40 powder)

conversion (%) conversion 20

0 0 1000 2000 3000

H2O (equiv)

Conditions: (5-decanolide 1, SmI2 solution, see Table 2.9): lactone (0.10 mmol), SmI2 (6 equiv, THF solution), H2O (50-3200 equiv), RT, 18 h. (5-decanolide 1, SmI2 powder, AAPL, see Table 2.1): lactone (0.10 mmol), SmI2 powder (8 equiv), THF, H2O (25-800 equiv), RT, 2 h.

Having established a non-linear trend in SmI2–H2O reduction of lactones, we examined the variation of the initial rates of the reaction versus water concentration to determine the cause of the non-linearity (Figure 2.3). At low concentrations of up to 1.5 M (circa 15 equiv wrt

[SmI2]) the rate was found to increase, with a slope consistent with saturation behaviour between 1.5 M and 1.9 M (15-25 equiv wrt [SmI2]). However, at higher concentrations (5 M, circa 50 equiv wrt [SmI2]) the rate decreased dramatically (>10-fold decrease in rate for a 4- fold change in [H2O]), consistent with dissociation of the substrate from the inner

Malcolm Spain PhD Thesis coordination sphere of Sm(II) caused by water. Above 5 M, the reaction rate slowly decreases with increasing water concentration. These results show that the reduction of lactones using

SmI2–H2O is slow at the concentration of water where the reduction potential of the system is highest as determined by CV studies.53

Figure 2.3. Plot of concentration of H2O versus kobs for the reduction of 1. [H2O] = 0-10 M (0-800 equiv). The inset shows the same up to [H2O] = 2 M. SmI2 = (6 equiv), lactone 1 = (1 equiv), T = 23 °C.

Rate dependence upon the concentration of H2O

0.5 0.16

0.14

0.12

0.10 0.4 0.08

rate (M/s) rate 0.06

0.04 0.3 0.02 0.00 0.8 1.0 1.2 1.4 1.6 1.8 2.0

[H2O]

0.2 rate (M/s) rate 0.1

0.0

0 5 10

[H2O] in M

The rate of the reaction is optimal with approximately 30 equivalents of water (wrt [SmI2]) and therefore is better represented by the kinetic study at low concentration of water. Kinetic experiments were performed with Dr. M. Szostak to ensure maximum reliability of the results in light of the previously noted difficulties with respect to homogeneity and air-sensitivity of lanthanide(II) reagents, especially in the presence of external oxidants, such as alcohols. We determined the reaction kinetics at low equivalents of water (15-35 equiv wrt [SmI2]) (Table

2.10, Figures 2.4-7). The kinetics at high concentration of water (100-180 equiv wrt [SmI2]), were earlier determined.48 Comparison of the results confirms that there is a change in

nd mechanism: at low concentration of water the reaction is 2 order in both H2O and substrate; however, at higher concentrations the reaction rate is 1st order in substrate and zero order in

Malcolm Spain PhD Thesis water. At this stage, the change of the obtained rate orders due to differences in carrying out the experiments cannot be excluded. This point is currently under further investigation. The rate order of two for lactone, may result from the formation of a SmI2-lactone complex, at low concentrations of water, where one of the lactones serves as a ligand for Sm(II). In addition, we measured the kinetic isotope effect at low concentration which shows that there is no significant kinetic isotope effect; the kinetic isotope effect was measured by comparing

57 the rate of reduction of 1 in H2O versus D2O in intermolecular experiments.

Table 2.10. Rate constant and reaction orders for the reduction of 1 using the SmI2–H2O system.

entry H2O (equiv) rate order kH/kD a b c substrate SmI2 H2O 1 15-35 2.2±0.1 1.1±0.1 2.1±0.1 1.33 248 >100 1.1±0.1 1.3±0.1 0 1.5 a [SmI2] = 70 mM, [H2O] = 15 equiv, [ester] = 0.05-0.15 mmol; [SmI2] = 10 mM, [H2O] = 150 equiv, [ester] = b 45-70 equiv. [SmI2] = 50-70 mM, [H2O] = 15 equiv, [ester] = 1 equiv; [SmI2] = 5-10 mM, [H2O] = 150 equiv, c [ester] = 5 mM. [SmI2] = 70 mM, [H2O] = 15-35 equiv, [ester] = 1 equiv; [SmI2] = 10 mM, [H2O] = 100-180 equiv, [ester] = 650 mM. Values for entry 1 are listed first. Figure 2.4. Determination of lactone rate order in the reduction of 5-decanolide 1 using a SmI2–H2O.

Lactone rate order for the reduction of 5-decanolide 1

using SmI2H2O

-1

-2

-3

ln(rate) y = 2.1823x - 8.0747 R² = 0.9353 -4

-5 1.5 2 ln[lactone] 2.5 3

a Lactone rate order. Conditions: SmI2 (6.0 equiv), H2O (100 equiv), lactone (0.5-1.5 equiv).

Malcolm Spain PhD Thesis Figure 2.5. Determination of samarium(II) iodide rate order in the reduction of 5-decanolide a 1 using SmI2–H2O.

SmI2 rate order for the reduction of 5-decanolide 1 using SmI2H2O

-3.4

-3.6

y = 1.083x - 8.1261 ln(rate) R² = 0.959 -3.8

-4 3.8 4 4.2 4.4 ln[SmI2] a Samarium(II) iodide rate order. Conditions: SmI2 (5.0-7.0 equiv), H2O (100 equiv), lactone (1.0 equiv).

Figure 2.6. Determination of H2O rate order in the reduction of 5-decanolide 1 using SmI2– a H2O.

Water rate order for the reduction of 5-decanolide 1

using SmI2H2O

-1.7

-1.9

-2.1

-2.3 y = 2.0902x - 2.8427

R² = 0.9008 ln(rate) -2.5

-2.7

-2.9 0 0.1 0.2 0.3 0.4 0.5 0.6 ln[H2O] a Water rate order. Conditions: SmI2 (6.0 equiv), H2O (90-150 equiv), lactone (1.0 equiv).

Malcolm Spain PhD Thesis a Figure 2.7. Determination of the KIE in the reduction of 1 using SmI2–H2O/D2O.

Initial rates for the reduction of 5-decanolide 1

using SmI2H2O and SmI2D2O

0.7 0.6 y = 0.0373x + 0.0107 R² = 0.9966

0.5

mol) 0.4 y = 0.0281x + 0.014 R² = 0.9869

0.3 yield (µ yield 0.2 0.1 0 0 5 10 15 time (min)

a Kinetic isotope effect. Conditions: SmI2 (6.0 equiv), H2O (100 equiv) or lactone (1.0 equiv); SmI2 (6.0 equiv), D2O (100 equiv), lactone (1.0 equiv). 2.2.2 Dependence of radical stability upon water concentration

To further the investigation on the rate of lactone reduction, we studied the dependence of the reduction of the corresponding acyl-type radicals upon water concentration by means of

5 -1 radical clock experiments. Using a non-calibrated 5-exo radical clock (kcycl = ca. 2.3 x 10 s , at 25 oC)60,61,62 we determined the approximate rate of the reduction in 18b (Table 2.11 and

Figure 2.8). Interestingly, we found that the ratio of the cyclised product increases with water concentration, indicating there is an increase in radical stability at high concentration of water. Control experiments with a varied concentration of SmI2, at the same concentration of water (entry 6 vs. entry 11) demonstrated that increasing SmI2 concentration increases the rate of reduction, consistent with a bimolecular step for the acyl-type radical reduction. In addition, lactol products were not observed in the reduction of activated lactone 18b, most likely due to the higher steric bulk. In comparison to 7, this reaction favours collapse of the tetrahedral intermediate. Furthermore, this demonstrates the unique ability of SmI2–H2O systems to be fine-tuned to alter the rate of the 2nd electron transfer and favour either the reduction product or the cyclised product, depending upon the concentration of water. This

Malcolm Spain PhD Thesis has been demonstrated in the ability to favour either the reduction product 19b, at low water concentration, or the cyclised product 30b at higher water concentration (Table 2.11).

Table 2.11. Effect of concentration of water on the rate of reduction of acyl-type radicals derived from lactone 18b.a

7 -1 -1 entry H2O (equiv) 19b:30b [SmI2] [H2O] rate [10 x M s ] 1 0 >98:2 0.053 - >21.3 2 25 >98:2 0.053 0.22 >21.3 3 50 >98:2 0.053 0.44 >21.3 4 100 >98:2 0.053 0.88 >21.3 5 200 97:3 0.052 1.73 14.30 6 400 94:6 0.050 3.33 7.21 7 800 77:23 0.048 6.40 1.60 8 1600 42:58 0.042 11.20 0.39 9 3200 30:70 0.035 18.67 0.28 10 6400 22:78 0.026 27.75 0.25 11 800 81:19 0.025 3.33 3.92 12 800 86:14 0.015 2.00 9.41 a All reactions carried out using standard Schlenk techniques. Conditions: under argon, to SmI2 (0.60 mmol) in THF, H2O (0-6400 equiv) and ester substrate (0.050 mmol) in THF (typically, 1.0 mL) were added, and the reaction mixture was vigorously stirred for 15 min – 3 hours. Conversion = (100-SM). In all cases, rapid b injection of substrate (THF solution) to the preformed SmI2–H2O complex was applied. Relative reactivity values determined from product distribution by 1H NMR and/or GC of crude reaction mixtures and comparison with authentic samples. cApproximation calculated using the rate constant for cyclisation of the 5-hexenyl -1 5 -1 60,61,62 radical: kSmI2 = (red/cycl) x k5-exo x [SmI2] ; (k5-exo = ca. 2.3 x 10 s at 25 °C).

Malcolm Spain PhD Thesis Figure 2.8. Cyclisation of acyl-type radical derived from 18b as a function of concentration of water (see Table 2.11).

Ratio of cyclised to reduced products from reduction of 18b using SmI2-H2O 90

80 70 60 50 40 30 20

cyclised: reduced productreduced cyclised: 10 0 0 2000 4000 6000 8000 H O (equiv) 2 As a follow up study, we investigated the application of our findings using a different 5-exo radical clock based on a 5-decanolide scaffold (Table 2.12). Similarly, the trend in increased ratios of cyclised products at higher water concentration was observed. Moreover, the results show that the cyclisation shows a preference for the Ph-substituted acceptor (34b). This dependence on the radical accepting group demonstrates that the cyclisation occurs through a late-transition state. Interestingly, the 5-exo product is predominant even at lower concentrations of water, suggesting that the pendant olefin is well positioned for cyclisation.

This is expected from its lower degree of freedom. Moreover, higher levels of cyclisation are promoted at higher concentrations of water, indicating a higher effective stability of the acyl- type radical.

Malcolm Spain PhD Thesis Table 2.12. Effect of concentration of water on the rate of reduction of acyl-type radicals derived from lactone 34.a

b b c Entry R H2O time conv. 35:36 [H2O] rate (equiv) (min) (%) (105 x M-1s-1) 1 H 200 60 86 66:34 2.02 19.42 2 H 800 60 67 91:9 7.36 4.14 350 H 2200 120 55 95:5 20.07 2.30 4 Ph 200 30 79 93:7 2.54 2.27 5 Ph 800 30 81 99:1 8.95 0.35 a All reactions carried out using standard Schlenk techniques. Conditions: under argon, to SmI2 (0.60 mmol) in THF, H2O (0-6400 equiv) and ester substrate (0.050 mmol) in THF (typically, 1.0 mL) were added, and the reaction mixture was vigorously stirred for 5 min. In all cases, rapid injection of substrate (THF solution) to the b preformed SmI2–H2O complex was applied. Relative reactivity values determined from product distribution by 1H NMR and/or GC of crude reaction mixtures and comparison with authentic samples. cApproximation -1 calculated using the rate constant for cyclisation of the 5-hexenyl radical: kSmI2 = (red/cycl) x k5-exo x [SmI2] ; 5 -1 60,61,62 (k5-exo = ca. 2.3 x 10 s at 25 °C). Quenched with air after the indicated time. In all cases yields >85% based on recovered starting material. Conditions (entries 1-2, 4-5): SmI2 (6 equiv, 0.063 M, entries 1-2; 0.080 M, entries 4-5, 0.10 mmol scale), H2O 0.36 or 1.44 mL. Rapid addition of H2O to the preformed solution of ester and SmI2 in THF. [SmI2] = 0.061, 0.055, 0.060, 0.076, 0.067 M (entries 1, 2, 3, 4, 5). Having established that acyl-type radical stability could be influenced by water, we hypothesised that 6-membered lactones bearing a suitable radical stabilising group at the 5- position could undergo a C-O fragmentation reaction (Table 2.13 and Figure 2.9). Moreover, we proposed that acyl-type radicals capable of fragmentation could be formed under SmI2–

H2O conditions from 5- and 7-membered lactones without directing groups. For each of the substrates, a wide range of SmI2–H2O conditions were tested in order to compare the radical stability at low concentration of water, where the radical has a shorter lifetime, and higher concentration of water, where the acyl-type radical should have an extended lifetime.

Interestingly, 5-, 6- and 7-membered lactones (37a-37c, 10j) undergo C-O fragmentation, demonstrating that the first electron transfer is not limited to activated 6-membered lactones.

In the case of the 5-membered lactone 37a, conversion of the starting material is lower at

Malcolm Spain PhD Thesis both high and low concentrations of water, however, the ratio of fragmented product is increased at high concentration of water. By comparison, 7-membered lactone 37c achieves higher conversion at both high and low concentration of water, with almost exclusive formation of the fragmented product 38c. This demonstrates that 5- and 7-membered lactones can be reduced to acyl-type radicals by SmI2–H2O. In addition, these findings suggest that the first electron transfer is reversible. Moreover, the selectivity in the reduction of 6-membered lactone 10j (37b) is almost completely reversed from low concentration of water favouring the diol 39b, to the acid 38b at higher concentrations of water. Comparison of the ratio of 38 to 39 (Figure 2.9) demonstrates the higher stability of this radical at high concentration of water, In addition, the high selectivity of the fragmentation of the 7-membered ring suggests that the conformation of this lactone is well-aligned for C-O fragmentation reactions.

Malcolm Spain PhD Thesis Table 2.13. Effect of concentration of water on the stability of acyl-type radicals derived from lactone 37.a

b b entry n H2O (equiv) time (h) conversion (%) [SmI2] [H2O] 38:39 1 0 200 5 35 0.070 1.93 41:59 2 0 800 5 9 0.077 6.99 77:23 3 1 200 5 96 0.070 1.93 34:66 4 1 800 5 92 0.077 6.99 72:28 5 2 200 5 >98 0.070 1.93 96:4 6 2 800 5 >98 0.077 6.99 99:1 7 0 200 2 22 0.144 2.39 62:38 8 1 200 1 95 0.144 2.39 39:61 aAll reactions carried out using standard Schlenk techniques. Quenched with air after the indicated time. In all cases yields >95% based on recovered SM. Conditions: Entries 1-6: 0.10 mmol of substrate, 8 equiv of SmI2 in THF (0.080 M), H2O: 0.36 mL or 1.44 mL. [SmI2] = 0.070 M (entries 1, 3, 5), 0.077 M (entries 2, 4, 6). Entries b 7-8, SmI2 powder AAPL, 1.2 mmol in 8.0 mL of THF. [SmI2] = 0.144 (entries 7-8). Relative reactivity values (RV) determined from product distribution by 1H NMR and/or GC of crude reaction mixtures and comparison c with authentic samples. Control reactions: SmI2/H2O/Et3N system, SmI2 (0.10 M), 42% yield, hydroxyacid d 13%, starting material 41%, 4-phenylbutan-1-ol <2%. SmI2/H2O/Et3N system (SmI2 0.10 M), 4-phenylbutan-1- ol formed in 92% yield. Figure 2.9. Fragmentation of lactone 37, as a function of lactone ring size versus concentration of H2O.

Fragmentation of acyl-type radicals with SmI2-H2O as a function of lactone 37 ring system (n) 100

80 800 equiv

200 equiv

60 38:39

40 ratio of ratio 20

0 0 1 2 3 4 lactone 37 (ring size, n)

Several control experiments indicated that conformational alignment of the phenyl ring to stabilise the fragmenting C-O bond is crucial for the successful reaction (Scheme 2.5). In the

Malcolm Spain PhD Thesis case of lactone 40, the phenyl ring is unable to stabilise the fragmenting C-O bond as its π- system does not provide sufficient stabilisation to the developing radical. Furthermore, the cyclic nature of the lactones is crucial for the fragmentation as acyclic esters do not react under these conditions (note that benzylic alcohols are stable to deoxygenation under these conditions).

Scheme 2.5. Mechanistic probes for the fragmentation of acyl-type radicals using SmI2– a H2O.

a Using standard Schlenk techniques. Conditions: substrate (1 equiv) SmI2 (6 equiv), H2O (200 equiv), RT, 3 h; quenched with air after the indicated time. Conversion determined by 1H NMR and GC-MS analysis: <2% by GC-MS; >95% recovery of ester 43 (SM). As previously discussed, our results strongly indicate that in the reduction of lactones the 2nd electron transfer is more difficult than the 1st electron transfer, and as such is not the rate determining step. As 5-exo cyclisation (ca. 105 s-1) competes with the reduction, we used a faster radical clock in order to verify that acyl-type radicals are formed easily under SmI2–

11 -1 o H2O conditions (kfrag = ca. 3 x 10 s , at 25 C) (Table 2.14). Furthermore, the study on the fragmentation of lactones suggested that the acyl-type radicals of 5-membered ring lactones are formed reversibly, but we required another evidence to prove the formation of the acyl- type radical. As indicated in Table 2.14, using excess SmI2, the reduction of the 5-membered 54

Malcolm Spain PhD Thesis lactone 46a (entry 1) resulted in the formation of the corresponding ring-opened lactone product (47a), demonstrating that the first electron transfer occurs under these conditions and is reversible. Furthermore, the reduction of 6-membered lactone (46b) to the corresponding ring-opened lactone (47b) is fast under the reaction conditions (entry 4). Importantly, in all cases the rearranged products are formed exclusively under a range of reaction conditions, including those with SmI2–amine–H2O, consistent with the proposed mechanism (see

Scheme 2.6 for a control reaction to this Sm(II) system).

Malcolm Spain PhD Thesis a Table 2.14. Radical clock experiments in the reduction of 46 using SmI2–H2O complexes.

b b,c entry n SmI2 H2O Et3N time conv. yield 47:48 49 (equiv) (equiv) (equiv) (%) (%)

1d 0 46a 8 200 - 3 h >98 99 >98:2 <2 2e 0 46a 2 24 24 < 1 52 52 96:4 <2 3f 0 46a 8 48 48 min1 h >98 98 <2:98 <2 4g 1 46b 2 200 - < 1 51 44 >98:2 <2 5h 1 46b 8 200 - min3 h >98 95 91:9 <2 6i 1 46b 2 24 24 < 1 37 36 >95:5 <2 7j 1 46b 8 48 48 min1 h >98 99 <2:98 <2 8k 1 46b 8 - - 3 h >98 <5 - - a All reactions carried out using standard Schlenk techniques. In all cases SmI2–H2O system had been preformed prior to the addition of substrate (as a solution in THF). SmI2 (0.085 M in THF) was used. All reactions were quenched with air after the indicated time. Relative reactivity values were determined from product distribution by 1H NMR (500 MHz) of crude reaction mixtures and comparison with authentic samples. bDetermined by 1H NMR using internal standard added after aqueous work-up. cCombined yield of lactone and diol. dFor entries 1- 3 46a used with dr >95:5. Lactone formed as 71:29 dr (crude rxn mixture analysis), 74:26 after chromatographic purification. eLactone formed as 77:23 dr (crude rxn mixture analysis); 1.9-2.4% of diol formed (52% yield of reduction products, 48% recovered yield of SM). fDiol formed as 77:23 dr (crude rxn mixture analysis), 79:21 after chromatographic purification. gFor entries 4-8, lactone used as 83:17 dr. SM recovered as 72:28 dr; 44% yield of lactone and 43% of SM. hLactone formed as ca. 1:1 dr (by 13C NMR analysis, crude rxn mixture and after purification); 55:45 purified by 1H NMR analysis. iSM recovered as 78:22 dr; 62% yield of SM, 36% of lactone, ca. 2% of diol. jDiol formed as ca. 1:1 dr (13C NMR analysis of crude rxn mixture and after purification). kDecomposition.

Scheme 2.6. Reductive opening of cyclopropyl diols 49a and 49b using SmI2–Et3N–H2O control experiment to C–C bond cleavage post-lactone reduction.

a Using standard Schlenk techniques. Conditions: SmI2–Et3N–H2O (6-48-48 equiv), RT, 18 h; quenched with air after the indicated time. Conversion determined by 1H NMR.

In summary, the reduction of lactones with SmI2–H2O proceeds through reversible electron transfer to generate an acyl-type radical, which can be trapped by fragmentation or

Malcolm Spain PhD Thesis cyclisation reactions (Scheme 2.7). Furthermore, we have demonstrated that the lifetime of the radical can be effectively increased through increasing the concentration of water, thus modifying the ratio of the rearranged products. We have been able to determine that the 2nd electron transfer is higher in energy than the 1st electron transfer, and furthermore that the 1st electron transfer occurs reversibly. In addition, primary kinetic isotope effect has not been observed and intermediates such as lactols have not been generally observed (except in the case of 7, in which collapse of the lactol intermediate appears to be the rds). From this

nd evidence, we proposed that the 2 electron transfer is the rate determining step in all SmI2–

nd H2O-mediated lactone reductions. Due to the mechanism involving the 2 step as the rate determining step, a variety of reactions intercepting the acyl-type radical is feasible, including fragmentation and radical additions.

Scheme 2.7. Summary of mechanistic pathways for the reactivity of acyl-type radicals generated from lactones using SmI2–H2O.

Malcolm Spain PhD Thesis 2.3 Aromatic reductions

64,65 The reduction of the lactone carbonyl (E1/2 = ca. -3.0 V vs. SCE) by SmI2 + n H2O (E1/2 = ca. -0.89 V vs. SCE, n = 0, ca. -1.0 V vs. SCE, n = 60, E1/2 = ca. -1.3 V vs. SCE, n =500) is inconsistent with the thermodynamic redox potentials determined by cyclic voltammetry studies.53 Studies by Hoz have suggested that electrostatic interaction plays an important part in the reduction of the carbonyl group in benzophenone, however, this explanation alone

66 cannot account for all the difference. To investigate the redox potential of SmI2–H2O, we measured its effective reduction potential against a set of hydrocarbon substrates,67 which react through outer-sphere electron transfer mechanisms.13 This protocol is a standard method of determining redox potentials of systems that are difficult to measure due to poor solubility, very high reactivity or formation of heterogeneous solutions.19,21,22,23 We therefore selected a series of unsaturated hydrocarbons with reduction potentials ranging from -1.6 V to -3.4 V vs. SCE (Figure 2.10),21 and a series of alkyl halides to gain insight into the chemoselectivity

68,69,70,71,72,73 of the SmI2–H2O system.

During our studies on the reductions of lactones using SmI2–H2O systems, we noticed that the system performs differently at low and high concentrations of water (see part 2.1).

Furthermore, the increased reactivity observed at low concentrations of water is in contrast with the trend in the thermodynamic redox potentials. In 2004, Flowers determined that addition of 60 equiv (approx. 0.3 M) results in an increase in redox potential from -1.5 ± 0.1

V to -1.6 ± 0.1 V (vs. Ag/AgNO3), which at higher equivalents of water (500-1000 equiv,

2.5-5 M) forms a thermodynamically stronger reductant (-1.9 ± 0.1 V).53 As a result, we determined the effective redox potential of SmI2–H2O at both low (n = 50) and high (n = 500) concentrations of water, using SmI2–THF solutions as a control.

Malcolm Spain PhD Thesis Figure 2.10. Structures of aromatic and unsaturated hydrocarbons19,21,22,23 and alkyl halides68,69,70,71,72,73

with their half-reduction potentials (E1/2 in volts in DMF vs. SCE).

2.3.1 Determination of the effective redox potential of SmI2–H2O systems

In this study, all of the reactions were carried out using 3 equivalents of SmI2 (1.5 molar equivalents) with the emphasis on determining the effective redox potential (Table 2.15). For comparison, all runs were performed in parallel, using stock solutions of titrated SmI2 prepared immediately prior to use. Reactions using SmI2 were quenched with air after 4-6 h, whilst reactions with SmI2–H2O were quenched after 2 h unless decolourisation occurred earlier (from burgundy red to a white emulsion or clear colourless solution).

Malcolm Spain PhD Thesis

Table 2.15. Determination of the effective redox potential of SmI2–H2O by reduction of aromatic hydrocarbons.a

b entry hydrocarbon -E1/2 reaction reaction with reaction with with SmI2 + n H2O SmI2 + n H2O SmI2–THF (n = 50) (n = 500) 1 acenaphtylene 1.65 52.6 (6 h) 73.4 (22 min) 51.9 (16 min) 2 cyclooctatetraene 1.83 >98 (6 h) >98 (21 min) >98 (9 min) 3 anthracene 1.98 <2 (6 h) 93.2 (37 min) 86.8 (6 min) 4 diphenylacetylene 2.11 <2 (6 h) 0.9c (2 h) <2 (48 min) 5 trans-stilbene 2.21 0.8 (5 h) 53.1 (2 h) 4.9 (20 min) 6 1,4-diphenylbenzene 2.40 <2 (5 h) <2 (2 h) <2 (11 min) 7 1,3,5-triphenylbenzene 2.51 <2 (5 h) <2 (2 h) <2 (24 min) 8 naphthalene 2.61 <2 (4 h) <2 (2 h) <2 (2 h) 9 styrene 2.65 <2 (4 h) 1.3 (2 h) 0.5 (2 h) 10 benzene 3.42 <2 (4 h) <2 (2 h) <2 (2 h) aAll reactions carried out using standard Schlenk techniques. All conversions in %, determined by GC or 1H NMR. Conditions: substrate (1 equiv, 0.05 mmol) SmI2 (3 equiv). All reactions quenched with air after the indicated time. In cases when time is < 2 h SmI2‒H2O complexes were oxidised by excess of water to b c Sm(III). In volts vs. SCE; -E1/2 describes half-reduction potential. 0.4% of bibenzyl and 0.5% of stilbene. In cases when conversion is <2%, only starting material was detected in the reaction mixtures.

It is clear from the results presented in Table 2.15 that water has a profound effect on the effective redox potential of SmI2. Remarkably, both SmI2–H2O systems can reduce trans- stilbene 68 (E1/2 = -2.21 V), whilst under the same conditions SmI2–THF is unreactive. All three systems reduced acenaphthylene 64 (E1/2 = -1.65 V) and cyclooctatetraene 65 (E1/2 = -

1.83 V), which was the limit for SmI2–THF, demonstrating an increase in the effective reduction potential on the addition of water by approximately 0.38 V. Interestingly, the effective redox potentials of SmI2–THF (-Eeff = ca. 1.83 V, increase by ca. 0.94 V) and SmI2

+ n H2O (-Eeff = ca. 2.21 V, increase by ca. 0.91 V (n = 500) or ca. 1.21 V (n = 50)) systems are higher than the thermodynamic reduction potential. In addition, the conversions are consistently higher at the lower concentration of water, SmI2 + 50 H2O, in contrast to its lower thermodynamically determined redox potential.53

Malcolm Spain PhD Thesis a Table 2.16. Determination of redox potential of SmI2–H2O by reduction of alkyl halides.

b entry alkyl halide -E1/2 reaction with reaction with reaction with SmI2 SmI2 + n H2O SmI2 + n H2O (n = 50) (n = 500) 1 C12H25I 1.30 4.6 (2 h) 94.0 (2 h) 90.7 (2 h) 2 C14H29Br 2.29 14.2 (2 h) 50.6 (2 h) 41.9 (2 h) 3 C14H29Cl 2.79 2.3 (2 h) <2 (2 h) <2 (2 h) c 4 C14H29F 2.97 <2 (2 h) <2 (2 h) <2 (35 min) aAll reactions carried out using standard Schlenk techniques. All conversions in %, determined by GC or 1H b NMR. Conditions: substrate (1 equiv, 0.05 mmol) SmI2 (3 equiv), H2O (0-1500 equiv). In volts vs. SCE; -E1/2 describes half-reduction potential. cDetermined for ArF.

Similarly to the hydrocarbons, the efficiency of the reduction of alkyl halides is improved by the addition of water (Table 2.16). Both SmI2–H2O systems reduce alkyl halides with a similar efficiency. The reduction potential based upon alkyl halide reduction is -2.29 V, which is in agreement with that determined with respect to hydrocarbon reduction. The low reactivity with alkyl halides demonstrates that high levels of chemoselectivity could be possible when using SmI2–H2O, with respect to alkyl fluorides, chlorides and bromides.

2.3.2 Optimisation of hydrocarbon reductions

Having determined that SmI2 + n H2O complexes are capable of reducing aromatic hydrocarbons with redox potentials up to -2.21 V (vs. SCE), we examined the reduction of 66 and 68 in more detail (Table 2.17-18). Extended reaction times with SmI2–THF did not reduce anthracene (entry 6); however, addition of as little as 3 equivalents of water promotes the reaction (entry 2). Increasing the equivalents of water to 10, and doubling the SmI2 equivalents, forms the Birch reduction product in excellent yield (entry 7), but the rate of reaction was much faster with 50 equivalents (ca. 0.3 M, entry 8). Further, we found that the stoichiometry of SmI2 could be reduced to 3 equivalents, to achieve excellent yield within a relatively short reaction time (entry 10).

Malcolm Spain PhD Thesis

Table 2.17. Optimisation of the reduction of anthracene 66 with SmI2–H2O.

entry SmI2 (equiv) H2O (equiv/SmI2) Time conversion (%) 1b 3 - 2 h <2 2b 3 3.3 2 h 8.2 3 3 - 6 h <2 4 3 50 37 min 93.2 5 3 500 6 min 86.8 6 6 - 24 h <2 7 6 10 24 h 99.5 (98) 8 6 50 2 h >98 (99) 9 3 10 2 h 67.6 (67) 10 3 50 2 h >98 (99) aAll reactions performed using standard Schlenk techniques. All conversions in %, determined by GC or 1H 1 NMR, yields (determined by H NMR) in brackets. Conditions: substrate (1 equiv, 0.05 mmol) SmI2 (3-6 b equiv), H2O (0-1500 equiv). Side-by-side reactions. As expected, from the thermodynamic redox potentials, the reduction of trans-stilbene (68-E) is more challenging than anthracene. Similarly to the reduction of anthracene, water is critical, and the rate of the reaction increased upon increasing the equivalents of water from

10 to 50. Increasing the equivalents of SmI2, with 50 equivalents of water (ca. 0.3 M) improved the conversion; however, optimal conditions involved carrying the reaction out in two iterations. Furthermore, no isomerisation of cis-stilbene to trans-stilbene was observed under the reaction conditions, indicating that reversible electron transfer does not occur in this substrate as the radical isomerisation of cis-stilbene is a very fast process.74 Interestingly, the reduction of cis-stilbene (68-Z) is slower the 68-E under identical reaction conditions.

This trend has been ascribed to the higher redox potential of 68-Z (68-Z, -E1/2 = -2.15 V; 68-

E, -E1/2 = -2.18 V, versus SCE under identical conditions (DMF, TBAI), however, coordination effects cannot be excluded at this point.75,76

Malcolm Spain PhD Thesis a Table 2.18. Optimisation of the reduction of stilbene 68 with SmI2–H2O.

entry stilbene SmI2 (equiv) H2O (equiv/SmI2) time conversion (%) 1b E 3 - 5 h 0.8 2 E 3 25 2 h 20.7 3 E 3 50 2 h 53.1 4 E 6 - 24 h 0.8 5 E 6 10 24 h 2.4 6 E 6 25 2 h 37.5 7 E 6 50 2 h 47.0 8 E 6 100 2 h 40.0 9 Z 6 25 2 h 3.9 10 Z 6 50 2 h 14.7 11 E 10 25 3 h 35.1 12 E 10 50 3 h 75.0 13b E 3 50 2 h 74.9 14b E 3 100 2 h 92.7 aAll reactions performed using standard Schlenk techniques. Conversions determined by GC or 1H NMR. Conditions: 0.05 mmol of substrate, 3 equiv of SmI2. In all entries, >95% yield based on recovered starting material. bTwo iterations. Entry 13, 57.5% conv. after first iteration; entry 14, 56.9%, after first iteration. 2.3.3 Mechanism of hydrocarbon reductions

To elucidate the mechanism of the Birch reduction, we determined the deuterium incorporation and kinetic isotope effects of the reductions (Schemes 2.8-10). Interesting, for both 66 and 68, the results indicate that a series of anions are generated that are protonated by water which is not rate determining step, due to the lack of a significant primary kinetic isotope effect. This finding is in contrast to the normal Birch reduction conditions, where the first protonation is rate determining.77 Furthermore, intermolecular competition experiments

(Scheme 2.10) show that trans-stilbene is reduced 4-times faster than cis-stilbene. We propose that this rate may be due to better coordination of the planar π-system as opposed to the redox potential argument. Notably, coordination complexes of Sm(II) (Sm(C5Me5)2) with weakly coordinating neutral π-systems including stilbene and styrene, have been reported.78

We propose that the large difference between the effective and thermodynamic redox potentials may be due to a partial inner-sphere electron transfer mechanism, which is

Malcolm Spain PhD Thesis sensitive to sterics, as opposed to the outer sphere mechanism expected.79 Interestingly, the

80,81 reduction of triphenylethylene 95 (-E1/2 = -1.97 V, vs. SCE) correlates very well with this concept, requiring harsher reducing conditions to achieve a good yield.

Scheme 2.8. Determination of deuterium incorporation and kinetic isotope effect in the a reduction of anthracene 66 with SmI2–H2O.

a Using standard Schlenk techniques. Conditions: substrate (1 equiv), SmI2–D2O (3–150 equiv), RT, 1 h; substrate (1 equiv), SmI2–H2O/D2O (3–75/75 equiv) quenched with air after the indicated time. Yield, deuterium incorporation and kinetic isotope effect determined by 1H NMR.

Scheme 2.9. Determination of deuterium incorporation and kinetic isotope effect in the a reduction of stilbene 68 with SmI2‒H2O.

a Using standard Schlenk techniques. Conditions: substrate (1 equiv), SmI2–D2O (3–150 equiv), RT, 1 h; substrate (1 equiv), SmI2–H2O/D2O (3–75/75 equiv) RT, 1 h; quenched with air after the indicated time. Yield, deuterium incorporation and kinetic isotope effect determined by 1H NMR.

Malcolm Spain PhD Thesis Scheme 2.10. Determination of relative rates of the reduction of E- and Z-stilbene 68 with SmI2‒H2O.

a Using standard Schlenk techniques. Conditions: substrate (1 equiv), SmI2–H2O (3–150 equiv), RT, 2 h; quenched with air after the indicated time. Conversion determined by GC-MS and 1H-NMR analysis: Run 1. cis-stilbene 91.7%, trans-stilbene 69.2%, bibenzyl 39.1%, kZ/kE = 3.71. Run 2. cis-stilbene 91.8%, trans-stilbene 72.4%, bibenzyl 35.8%, kZ/kE = 3.37. Average kZ/kE = 3.54. In addition, we examined the protonation step for the reduction of trans-stilbene 68-Z and the stereochemistry of the reduction of 80 with respect to the outcome of related SET reductants

(Scheme 2.11). Both SmI2‒D2O and the more thermodynamically powerful SmI2‒Et3N‒ D2O system gave 79 with >98% D incorporation; however, Na(silica) resulted in a significant loss of D incorporation. Next we investigated the stereochemistry of the protonation of 9,10- diphenylanthracene 80 with SmI2‒H2O, SmI2‒Et3N‒H2O ( and Na(silica) and observed to a gradual decrease in stereoselectivity of the protonation. These results suggest a significant difference in stereoselectivity versus more conventional Birch reductions, which create the

82 dianion which is then protonated; SmI2‒H2O shows excellent selectivity for the trans- product 81a, which may be due to a lower steric size of this reductant in comparison to

SmI2‒Et3N‒H2O.

Malcolm Spain PhD Thesis Scheme 2.11. Investigating the protonation step in the reduction of aromatic hydrocarbons a with SmI2‒H2O and related SET reductants.

a Using standard Schlenk techniques. Conditions: SmI2–water, substrate (1 equiv), SmI2 (3 equiv), H2O or D2O

(150 equiv), RT, 1 h; SmI2–Et3N–water, substrate (1 equiv), SmI2 (3 equiv), Et3N (24 equiv), H2O or D2O (24 equiv), RT, 1 h; Na(silica), substrate (1 equiv), Na(silica) (2.5 equiv), THF, RT, 5 h, quenched with D2O or 1 H2O. Product distribution and deuterium incorporation determined by H NMR.

Competition studies on the reduction of anthracene (Table 2.19) demonstrate the selectivity possible with SmI2‒H2O. In all cases, no reduction products arising from naphthalene, alkyl chloride or aryl bromides were observed despite excess reagent and long reaction times.

Furthermore, the reduction of 9-anthracene carboxylic acid 84 derivatives proceeds with complete selectivity over the corresponding benzoic acid analogues 85 (Scheme 2.12) (note

83 that the latter undergo instantaneous reduction with SmI2‒H2O systems).

Malcolm Spain PhD Thesis

Table 2.19. Chemoselectivity in Birch reductions of aromatic hydrocarbons using SmI2‒H2O complexes.a

entry substrates conv./ conv./ 66:83 product yield SM yield (78, %) (82, %) 1 >98/94 <2/>98 >98:2

2 >98/95 <2/>98 >98:2

3 >98/93 <2/>98 >98:2

aAll reactions performed using standard Schlenk techniques. Conversion determined by GC-MS and 1H NMR, yield determined by 1H NMR. Reduction products from competition substrates 83 <2% in all entries. Conditions: 66 (1 equiv), 82 (1 equiv), SmI2 (3 equiv), H2O (50 equiv/SmI2), THF, RT, 1 h.

Scheme 2.12. Investigating the origin of selectivity in reduction of 9-anthracene carboxylic a acid derivatives 84 with SmI2‒H2O.

a Using standard Schlenk techniques. Conditions: 84 (1 equiv), 85 (1 equiv), SmI2 (3 equiv), H2O (50 1 equiv/SmI2), THF, RT, 1 h. Yield and conversion determined by GC-MS and H NMR.

Based upon our studies on the reduction of aromatic hydrocarbons, we suggest that the mechanism proceeds through a partial inner-sphere mechanism, involving a rate-determining first electron transfer to give the radical anion, which is protonated rapidly by water (Scheme

2.13). A second electron transfer followed by protonation yields the reduced product.

Malcolm Spain PhD Thesis Notably, this reaction mechanism is different to the Birch reduction and therefore may show preferable selectivity in certain cases.84,85

Scheme 2.13. Proposed mechanism for the reduction of aromatic hydrocarbons using SmI2‒H2O complexes.

2.3.2 Substrate scope

Based on the mechanistic studies described above, we investigated the scope of the Birch reaction mediated by SmI2–H2O (Table 2.20). As expected, the Birch reduction of substrates containing 3 or more aromatic rings proceeded efficiently (entries 1-4, 7-10) in high yields and selectivity. Over-reduction was not observed, even when using excess reagent. In addition, aromatic acids, esters and amides 84a-c undergo clean hydrocarbon reduction even in the presence of excess Sm(II). As shown above, acids and esters are reduced faster than the corresponding aromatic carboxylic acid derivatives. Furthermore, SmI2‒H2O can be utilised to reduce conjugated alkenes and in tandem processes to effect benzylic chloride reduction and anthracene reduction in one-pot process (entry 7).

Malcolm Spain PhD Thesis a Table 2.20. Birch reductions of aromatic hydrocarbons using SmI2‒H2O complexes.

entry substrate product SmI2/H2O time yield (equiv) (%) 1 3-50 0.5 h 96b

2 3-50 2 h 99

3 3-50 2 h 98 (trans: cis >98:2)

4 3-50 10 min 99c

5 6-100 4 h 72

6 3-24-24c 2 h 97

7 5-50 2 h 74

8 84a, R = CO2H 86a, R = CO2H 3-50 2 h 94 9 84b, R = CO2Me 86b, R = CO2Me 3-50 15 min 99 10 84c, R = C(O)NEt2 86c, R = C(O)NEt2 3-50 5 min 98 aAll reactions performed using standard Schlenk techniques Yield determined by 1H NMR. In all entries, over- reduction was not detected by 1H NMR and GC-MS analysis of reaction mixtures. In addition, over-reduction b using large excess of SmI2–H2O (10-50 equiv) was not observed (Entry 8). Isolated yield, 1.0 mmol scale. c Reaction using SmI2 (3 equiv), H2O (24 equiv) and Et3N (24 equiv); 34% yield using SmI2/H2O (3-50, 2 h).

Malcolm Spain PhD Thesis 2.4 - Reductions of barbituric acids

Following the successful reduction of 6-membered lactones, the principle of the higher reactivity of cyclic ester carbonyls was applied to Meldrum’s acids. This study resulted in the first selective mono-reduction of cyclic 1,3-diesters to the corresponding 3-hydroxy acids

(Figure 2.11). Furthermore, it was found that the reduction of related barbituric acids with

SmI2–H2O could be achieved by optimising the conditions. We proposed that in the barbituric acid scaffold, one of the imide carbonyls is more prone to the reduction due to the lower

* energy of  CO orbital and the formed radical anion intermediate would be stabilised by anomeric effects.86 Preliminary results for barbituric acid reductions were performed by M.

Behlendorf (a visiting student from Universität Bonn). Competition cyclisation experiments were conducted by Dr. M. Szostak and Dr. B. Sautier.

Figure 2.11. Selective reduction of Meldrum’s acids and the proposed expansion to barbituric acids.

Malcolm Spain PhD Thesis 2.4.1 Optimisation

Interestingly, we found that the tetrahedral intermediate from 2 electron reduction of barbituric acids could be isolated, x-ray studies suggest that the stabilisation results from

* nN→ CO delocalisation into the remaining urea-type carbonyl providing unusual hemiaminal products.86 Our optimisation results are presented in Tables 2.21-23. After extensive studies, we were able to find conditions under which hemiaminal 103a was formed in good yield. Interestingly, degradation of the product was decreased through optimisation of the reaction and work-up conditions. For example, elimination of water is thermodynamically favoured resulting in an aromatic product, however with the optimal concentration of water

(1000 equivalents, ca. 5 M, 0.1 M SmI2 in THF), saturation of Lewis acidic Sm(II/III) prevents dehydration. Furthermore, the high selectivity achieved by SmI2–H2O was not achievable by a range of additives commonly used with SmI2, including those with higher and lower reduction potentials, such as metal salts (LiCl), Lewis bases (HMPA) proton sources and combination of Lewis base and proton source. It is noteworthy that only a few hemiaminals have been successfully isolated to date due to their lability. We determined that the use of an excess of SmI2 to facilitate the reaction, followed by quenching with air and immediate work-up, provided optimal conditions for the isolation of hemiaminal 103a (Table

2.22-23).

Malcolm Spain PhD Thesis a Table 2.21. Effect of additives on the reduction of barbituric acids using SmI2.

b c,d c c entry SmI2 additive additive time conv. yield dr (equiv) (equiv) (%) (%) 1 6 - - 24 h <5 (83 SM) - - 2 6 MeOH 4/1 v/v 2 h <5 (81 SM) - - 3 4 t-BuOH 24 2 h <5 (85 SM) - - 4 4 HMPA 24 2 h >95 (<5 SM) - - 5 4 LiCl 48 2 h 27 (73 SM) 8.6 81:19 6 4 HO(CH2)2O 24 2 h >95 (<5 SM) 11 81:19 7 2 Et3N-HMeOH 12-18 2 h <5 (69 SM) <2 - 9 2 Et3N-H2O 12-18 <30 s 49 (51 SM) 7.2 86:14 10 4 H2O 10 2 h 24 <5 - 11 4 H2O 50 10 s 79 <5 - 12 4 H2O 200 10 s 84 57 82:18 13 4 H2O 1000 10 s 93 (7 SM) 84 86:14 14 4 H2O 2500 10 s 66 49 88:12 aAll reactions carried out using standard Schlenk techniques. bQuenched with air after the indicated time. cDetermined by 1H NMR. dConversion to desired product is shown. The remaining starting material is shown in parentheses. In all entries, SmI2 prepared from Sm metal and ICH2CH2I was used. Conditions for SmI2–H2O reactions: barbituric acid, followed by H2O and SmI2; work-up using 0.1 M HCl. Table 2.22. Effect of addition sequence and work-up conditions on the reduction of a barbituric acids using SmI2.

b c c c entry SmI2 H2O time conv. yield dr addition/work-up (equiv) (equiv) (%) (%) 1 3 1000 5 min 91 81 88:12 Conditions A 2 3 1000 5 min 92 80 88:12 Conditions B 3 6 1000 3 min >95 52 77:23 Conditions C aAll reactions carried out using standard Schlenk techniques. bQuenched with air after the indicated time. c 1 d Determined by H NMR. Addition and work-up conditions: A) barbituric acid, followed by H2O and SmI2; work-up using 0.1 M HCl. B) SmI2, followed by H2O and barbituric acid; work-up using 0.1 M HCl. C) barbituric acid, followed by SmI2 and H2O work-up using 1.0 M HCl. In all entries, SmI2 prepared from Sm metal and ICH2CH2I was used.

Malcolm Spain PhD Thesis

Table 2.23. Effect of SmI2 stoichiometry on the reduction of barbituric acid 101a using a SmI2.

b entry SmI2 H2O time conv. yield dr 1 (equiv)3 (equiv)1000 60 s (%)91 (%)76 88:12 2 6 1000 10 s >95 82 88:12 (88:12) 3 12 1000 15 min >95 49 86:14 aAll reactions carried out using standard Schlenk techniques. bQuenched with air after the indicated time. c 1 Determined by H NMR. Conditions: barbituric acid, followed by H2O and SmI2; work-up using 0.1 M HCl. In all entries, SmI2 prepared from Sm metal and ICH2CH2I was used. 2.4.3 Mechanistic studies

Using deuterium labelling experiments we determined that in the reduction of barbituric acids with SmI2–H2O the proton incorporated into the hemiaminal product comes from water

(Scheme 2.14). This suggests that a radical anion is formed in the reaction, which is subsequently protonated by water. Further, through intramolecular competition experiments, we determined that proton transfer is not involved in the rate determining step.

Scheme 2.14. Determination of deuterium incorporation and kinetic isotope effect.a

a Using standard Schlenk techniques. Conditions: Deuterium incorporation, barbituric acid (1 equiv) SmI2 (3 equiv), D2O (1000 equiv), THF, RT, 60 s; kinetic isotope effect, barbituric acid (1 equiv) SmI2 (3 equiv), 1 H2O/D2O (500/500 equiv), THF, RT, 60 s. Deuterium incorporation and kinetic isotope effect determined by H NMR.

Furthermore, we determined that cyclic ureas and cyclic-1,3-malonamides are not reduced under SmI2–H2O conditions (Scheme 2.15), which indicates high selectivity in the reduction.

Malcolm Spain PhD Thesis Moreover, to observe the relative reactivity of the reduction of barbituric acids with respect to other functional groups, we performed a series of intermolecular competition experiments

(Table 2.24). The reduction of barbituric acids was found to be slower than the reduction of cyclic 1,3-diesters (entry 1), however, more facile than lactone reduction (entry 2). Thus, with

SmI2–H2O, cyclic 1,3-diesters are the most reactive substrates followed by barbituric acids and finally lactones. Furthermore, the reduction of barbituric acids is favoured by electron withdrawing groups (entry 5) and slowed down by steric substitution at the alpha carbon

(entry 4), suggesting a build-up of electron density and importance of sterics in the rate determining step.

Scheme 2.15. Selectivity studies in the reduction of barbituric acids.

a Using standard Schlenk techniques. Conditions: Substrate (1 equiv) SmI2 (4 equiv), H2O (200 equiv), THF, RT, 2 h. Conversion determined by 1H NMR.

Malcolm Spain PhD Thesis a Table 2.24. Selectivity study in the reduction of barbituric acids using SmI2–H2O.

b b entry 101 107 (R-FG) conv. conv. k101/k107 (101, %) (107, %)

1 <2 13 <1:20 101b 107a

2 24 2 >20:1 101b 107b

3 18 <2 >20:1 107a 107b

4 30 6.5 82:18 101a 107c

5 53 <2 >20:1 101c 107d a All reactions carried out using standard Schlenk techniques. Conditions: SmI2 (1 equiv), H2O (200 equiv), THF, RT, 10 s to 1 min. bDetermined by 1H NMR (500 MHz) and/or GC-MS. Conversion = (100-SM). In all cases, rapid injection of the equimolar mixture of substrate (THF solution) to the preformed SmI2–H2O complex was applied. Several intermolecular competition experiments involving cyclisation substrates were conducted (Table 2.25). Interestingly, these results demonstrate the reversibility of the first electron transfer and a high preference towards radical stabilising acceptors demonstrating that the cyclisation occurs through a late-transition state. Interestingly, 5-exo-dig cyclisations occurs in preference to 5-exo-trig (109a vs. 105a),87 despite the lower stability of vinyl radicals.88 A mechanism that is consistent with these observations is presented in Scheme

2.16.

Malcolm Spain PhD Thesis a Table 2.25. Selectivity study in the cyclisation of barbituric acids using SmI2–H2O.

b,c b,c entry 109 110 (R-FG) conv. conv. k109/k1 (109, %) (110- 10 red/cycl, %)

1 <2 33 <1:20c 109b, 109a, R = H R = 4-MeO-C6H4

2 2.7 14 16:84d

109a 105a

3 3.5 12 23:77d

109a 105b

4 <2 23 <1:20d

109a 101j

5 25 3.0 89:11c

109b, 101j R = 4-MeO-C6H4 a Reactions in Table 2.25 performed by Dr. M. Szostak and Dr. B. Sautier. Conditions: SmI2 (1 equiv), H2O (200 equiv), THF, RT, 10 s to 1 min. Conversion = (100-SM). In all cases, rapid injection of substrate (THF solution) c d to the preformed SmI2–H2O complex was applied. By Dr. M. Szostak. By Dr. B. Sautier.

Malcolm Spain PhD Thesis

Scheme 2.16. Mechanism of the Reduction of barbituric acids using SmI2–H2O.

In summary, optimisation of the reduction of barbituric acids and mechanistic studies on the system has been carried out. The reaction proceeds via reversible electron transfer to form the radical anion followed by proton transfer from water. In the rate determining step, SmI2 reduces the ketyl radical which is subsequently protonated to yield the corresponding hemiaminal product.

Malcolm Spain PhD Thesis

Chapter 3. Investigations of the SmI2–amine–H2O system

Historically, the use of additives in modifying SmI2 has played a major part in facilitating new reactivity with the reagent. More recently, the field of SmI2 chemistry has been significantly progressed through the use of a combination of water and Lewis basic amines, which forms a powerful reductant.20,21 Due to this increased reactivity, we hypothesised that this system would be capable of reducing carboxylic acid derivatives that have previously been considered inert to other SmI2 systems.

3.1 Ester Reduction

The initial discovery that the SmI2–amine–H2O reducing system can reduce lactones is described in Chapter 2, Table 2.1. The system provides a significant rate enhancement over

SmI2–H2O systems. Accordingly, we hypothesised that this higher reactivity may extend to the reduction of less activated carboxylic esters. Our investigation started with a study of the reactivity of SmI2–amine–H2O with a 7-membered lactone 5, which undergoes less that 5% conversion with SmI2–H2O (Scheme 3.1, see Chapter 1.1 for comparison with SmI2–H2O).

For initial studies, triethylamine was selected as the Lewis base.20 We were delighted to find that the corresponding diol product was formed. Spurred on by this encouraging finding, we discovered that unactivated esters could be reduced using the SmI2–Et3N–H2O system.

Notably, this was the first reported reduction of unactivated ester carbonyls using SmI2, despite the extensive use of this reagent over the past 30 years.89,90

Malcolm Spain PhD Thesis

Scheme 3.1. SmI2–Et3N–H2O reduction of a 7-membered lactone and the first reduction of an a unactivated carboxylic acid ester with SmI2.

a Using standard Schlenk techniques. Conditions: ester (1 equiv), SmI2 (8 equiv), Et3N (16 equiv), H2O (24 equiv), RT, 2 h. Conversion determined by 1H NMR. 3.1.1 Ester reduction optimisation studies

Having determined that the SmI2–H2O–Lewis base system is capable of reducing carbonyl groups of esters, next we carried out extensive optimisation of the reaction using hydrocinnamic methyl ester as a model system (Table 3.1). The results demonstrate the requirement for both amine and H2O. A variety of amines can be used, however, water is critical as the additive. Other proton sources, such as methanol and tert-butanol do not promote the reduction. In addition, we found that ethylene glycol, which has been reported to be an alternative to water in the SmI2–H2O mediated reduction of lactones, did not work in the present case. We determined that the rate of reduction is enhanced by increasing the concentration of amine; however, the dependence on water was found to be non-linear

(entries 19-23). Finally, we determined that SmI2–Et3N–H2O in a 1:2:3 ratio was required to reduce the hydrocinnamic methyl ester, even when using just 4 equivalents of SmI2 (entry

18), resulting in high yield (the reduction of esters to the corresponding alcohols is a 4 electron process).

Malcolm Spain PhD Thesis

Table 3.1. Optimisation of the reduction of hydrocinnamic methyl ester 115 with SmI2.

entry Amine proton source equiv proton source timea conv.b (amine) (equiv) (%) 1 Et3N H2O 12 18 5 min 96 2 Et3N - 12 - 24 h 6 3 - H2O - 12 72 h <2 4 - H2O - 800 24 h <2 2 i-Pr2NH H2O 12 18 5 min 86 3 n-BuNH2 H2O 12 18 5 min >98 4 pyrrolidine H2O 12 18 5 min >98 5 piperidine H2O 12 18 5 min 94 6 morpholine H2O 12 18 5 min 90 7 N-methylmorpholine H2O 12 18 24 h 91 8 Me2N(CH2)2OH H2O 12 18 24 h 74 9 DABCO H2O 12 18 5 min >98 10 Et3N H2O 3 18 5 min 36 11 Et3N H2O 6 18 5 min 64 12 Et3N H2O 24 18 1 min >98 13 pyrrolidine - 12 - 18 h <2 14 Me2N(CH2)2OH - 12 - 24 h <2 15 Et3N MeOH 12 18 24 h 9 16 Et3N t-BuOH 12 18 24 h <2 17 Et3N (HOCH2)2 12 9 24 h 94 c 18 Et3N H2O 8 12 10 min 96 19 Et3N H2O 12 6 30 s 20 20 Et3N H2O 12 12 30 s 68 21 Et3N H2O 12 18 30 s 83 22 Et3N H2O 12 48 30 s 67 23 Et3N H2O 12 96 30 s 31 All reactions carried out with strict exclusion of oxygen, using standard benchtop techniques for handling air- sensitive reagents. aQuenched by bubbling air through reaction mixtures until decolourisation occurred. b 1 c Determined by GC or H NMR. Using 4 equivalents of SmI2.

To investigate the ability of the SmI2–amine–H2O system to reduce more sterically hindered esters, we studied the reduction of hydrocinnamic acid tert-butyl ester and methyl adamantane-1-carboxylate in detail (Tables 3.2 and 3.3). From the optimisation studies it is clear that the SmI2–amine–H2O system is more reactive when more equivalents of amine are used. Accordingly, using the more reactive ratio of SmI2–amine–H2O (1:3:3), high

Malcolm Spain PhD Thesis conversion could be achieved for sterically encumbered esters by increasing the equivalents of the SmI2–Et3N–H2O system. In addition, pyrrolidine as the amine leads to a faster reaction rate. Notably, reaction systems using increased equivalents of amine are more reactive but appear to be more prone to oxidation of Sm(II). Our optimised conditions therefore involve the use of SmI2–amine–H2O in a ratio of 1:3:3 and the use of standard protocols for the handling of air-sensitive reagents (Schlenk techniques).

Table 3.2. Optimisation of the reduction of hydrocinnamic acid tert-butyl ester 115d with

a SmI2–amine–H2O.

b c entry amine SmI2 (equiv) H2O amine time conversion 1 Et3N 6 (equiv)18 (equiv)18 24 h [%]56 2 pyrrolidine 6 18 18 24 h 74 3 Et3N 6 18 36 24 h 60 4 pyrrolidine 6 18 36 24 h 87 5 Et3N 10 30 30 24 h 81 6 Et3N 16 48 48 24 h >98 7 Et3N 8 24 192 24 h 88 8 Et3N 8 192 192 24 h 50 aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. bQuenched by bubbling air through the reaction mixture after the specified time. cDetermined by GC or 1H NMR.

Malcolm Spain PhD Thesis

Table 3.3. Optimisation of reduction of methyl adamantane-1-carboxylate 118 with SmI2– a amine–H2O.

b c entry amine SmI2 (equiv) H2O amine time conversion 1 Et3N 6 (equiv)18 (equiv)18 24 h [%]77 2 pyrrolidine 6 18 18 24 h 93 3 Et3N 6 18 36 24 h 91 4 pyrrolidine 6 18 36 24 h 88 5 Et3N 10 30 30 24 h >98 6 Et3N 8 24 96 24 h >98 7 Et3N 8 96 96 24 h >95 8 Et3N 8 192 192 24 h 84 aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. bQuenched by bubbling air through reaction mixtures. cDetermined by GC or 1H NMR. 3.1.2 Substrate scope of the ester reduction

Having determined that SmI2–amine–H2O can be optimised to reduce even sterically hindered esters, we moved onto exploring the substrate scope with respect to the ester component. For this study a wide-range of esters derived from hydrocinnamic acid was used

(Table 3.4). Pleasingly, all esters were reduced easily under the standard conditions, with more hindered esters requiring extended reaction times and slightly more reducing conditions

(entries 3, 4 and 6).

Malcolm Spain PhD Thesis a Table 3.4. Reduction of hydrocinnamic esters 115 with SmI2–H2O–amine.

entry ester R amine time (h) product yield (%) 1 115a Me Et3N 2 116 97 2 115b Et Et3N 2 116 99 b 3 115c i-Pr Et3N 5 116 88 4c 115d t-Bu pyrrolidine 5 116 83 5 115e Ph Et3N 2 116 94 d 6 115f Bn Et3N 2 116 97 aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. Conditions: b ester (1 equiv), SmI2 (6 equiv), Et3N (18 equiv), H2O (18 equiv). Ester (1 equiv), SmI2 (8 equiv), Et3N (24 c d equiv), H2O (24 equiv). Ester (1 equiv), SmI2 (12 equiv), pyrrolidine (36 equiv), H2O (36 equiv). Ester (1 equiv), SmI2 (10 equiv), Et3N (30 equiv), H2O (30 equiv).

Next, we examined the scope of the reaction using a variety of esters differentiated on the carbonyl side (Table 3.5). Pleasingly, primary, secondary and tertiary esters provide the corresponding alcohols in high yield (entries 1-4). Furthermore, phenylacetic and hydrocinnamic acid derivatives with substituents in the α-position were tolerated (entries 5-

9), as well as aromatic (entry 14) and heteroaromatic esters (entry 15). In addition, the methodology can be applied to diesters, lactones and coumarins providing the corresponding diols (entries 10-13).

Malcolm Spain PhD Thesis a Table 3.5. Reduction of unactivated esters with SmI2–Et3N–H2O.

entry 121 ester 122 alcohol yield (%) 1 121a 122a 95

2 121b 122b 98

3 121c 122c 87

4 118 119 80b

5 121d 122d 99

6 121e 122e 97

7 121f 122f 95

8 121g 122g 85

9 121h 122h 88

10 121i 122i 87c

11 121j 122j 76c

Malcolm Spain PhD Thesis

12 1 1302 97

13 121k 122k 92

14 121l 122l 90

15 121m 122m 81

16 121n 122n 97

17 121o 122o (65)d aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. Conditions: b ester (1 equiv), SmI2 (6 equiv), Et3N (16-24 equiv), H2O (24 equiv), RT, 2-24 h. Conditions: SmI2 (10 equiv), c Et3N (30 equiv), H2O (30 equiv). Conditions: diester (1 equiv), SmI2 (12 equiv), Et3N (36 equiv), H2O (36 d equiv). Conditions: ester (1 equiv), SmI2 (16 equiv), Et3N (48 equiv), H2O (48 equiv), not an isolated yield, conversion (73%) and yield (65%) determined by 1H NMR.

Finally, we determined that the reduction of esters using SmI2–Et3N–H2O can be a very selective process as demonstrated in the chemoselective monoreduction of lovastatin

(Scheme 3.2). The more reactive, cyclic ester proceeds via an anomerically stabilised radical and is reduced selectively in the presence of the acyclic ester. In addition, it was found that using the SmI2–Et3N–H2O system, no epimerisation occurs, even in the reduction of readily epimerisable stereocentres (Scheme 3.3), thus demonstrating the utility of the reductant for the synthesis of optically-active alcohols.

Malcolm Spain PhD Thesis

Scheme 3.2. Selective reduction of lovastatin using SmI2–Et3N–H2O.

a Using standard Schlenk techniques. Conditions: Lactone (1 equiv), SmI2 (5 equiv), Et3N (30 equiv), H2O (30 equiv), THF, RT, 1 h. Selectivity determined by 1H NMR.

Scheme 3.3. Epimerisation study of enantioenriched ester under SmI2–Et3N–H2O conditions.

a Using standard Schlenk techniques. Conditions: ester (1 equiv), SmI2 (8 equiv), Et3N (48 equiv), H2O (48 equiv), RT, 2h. Conversion and optical purity determined by 1H NMR or HPLC. 3.1.3 Mechanism of ester reduction

To gain more insight into the mechanism, we utilised isotope labelling experiments to probe key steps of the reduction (Scheme 3.4).91 Reduction of hydrocinnamic acid methyl ester with

SmI2–Et3N–D2O gave the corresponding deuterium labelled alcohol (>97 % deuterium incorporation) suggesting anions are protonated by water in a series of electron transfer steps

(Scheme 3.4). Furthermore, through both parallel kinetics runs and intramolecular competition experiments, we determined a small kinetic isotope effect of 1.4-1.5, consistent with protonation not being involved in the rate determining step (Scheme 3.4). In addition,

18 H2 O labelling experiments demonstrated that hydrolysis does not occur in the reduction of several esters, including the standard methyl ester, sterically-hindered, iso-propyl, and electronically-activated phenyl esters (Table 3.6).

Malcolm Spain PhD Thesis Scheme 3.4. Deuterium incorporation and kinetic isotope effect experiments in the reduction of hydrocinnamic esters using SmI2–amine–water.

a Using standard Schlenk techniques. Conditions: deuterium incorporation, ester (1 equiv), SmI2 (6 equiv), Et3N (12 equiv), D2O (18 equiv), RT, 3 h; kinetic isotope effect, ester (1 equiv), SmI2 (6 equiv), Et3N (12 equiv), D2O/H2O (9/9 equiv) or by comparison of the initial rates of the ester reduction using SmI2 (6 equiv), Et3N (12 1 equiv), D2O or H2O (18 equiv). Deuterium incorporation and kinetic isotope effect determined by H NMR or rate study using GC.

18 Table 3.6. Determination of H2 O incorporation in the reduction of esters of hydrocinnamic 18 acid using SmI2–Et3N–H2 O.

18 a b b 18 c entry R SmI2 Et3N H2 O time conv. yield O (equiv) (equiv) (equiv) (h) (%) (%) (%) 1 115a Me 6 48 48 18 h >98 99 <2 2 115c i-Pr 6 48 48 18 h >98 92 <2 3 115e Ph 6 48 48 18 h >98 98 <2 All reactions carried out using standard Schlenk techniques. aQuenched with air after the indicated time. bDetermined by 1H NMR. cDetermined by HRMS.

Moreover, the required stoichiometry of the reagent for the reduction was investigated, through a range of experiments (Table 3.7). This study showed that SmI2–Et3N–H2O systems with at least 4 equivalents of SmI2, 8 equiv of amine and 12 equiv of H2O are required for the

92,93 reduction. This is in agreement with previous studies on SmI2–amine–H2O systems.

Malcolm Spain PhD Thesis Table 3.7. Determination of the reagent stoichiometry required for the reduction of esters of a using SmI2–Et3N–H2O.

b entry Et3N (equiv) H2O (equiv) conv. (%) 1 4 4 21.1 2 4 8 17.1 3 8 4 10.0 4 8 8 52.3 5 8 12 82.7 6 12 8 52.8 7 12 12 86.4 8b 12 18 96.4 9 24 24 >98 10 12 4 7.4 11 4 12 17.1 12 12 - <2 13 - 12 <2 a All reactions carried out using standard Schlenk techniques. Conditions: SmI2 (4.5 equiv), Et3N (12 equiv), b D2O (18 equiv), THF, RT, 24 h. Quenched with air after the indicated time. SmI2 (4 equiv) was used, determined at 10 min by GC-MS. Conversion determined by GC or GC-MS.

Next, we carried out kinetic studies (Table 3.8 and Figure 3.2). Kinetic experiments were performed with Dr. M. Szostak to ensure maximum reliability of the results in light of the previously noted difficulties with respect to homogeneity and air-sensitivity of lanthanide(II) reagents, especially in the presence of external oxidants, such as alcohols or water. The rate orders were determined by the initial rates method in the reduction of tert-butyl 3- phenylpropanoate, which reacts at a convenient rate to determine initial rates. The rate orders for ester, SmI2 and amine are 1, within experimental error, in the concentration range studied

(Table 3.8). In contrast, water shows complex behaviour, the rate order is 1 up to 0.3 M of water, however, further increasing the water concentration decreases the reaction rate (Figure

3.2). This suggests that coordination of water to Sm(II) is inhibiting coordination of the ester substrate, therefore slowing inner-sphere electron transfer. Importantly, these results suggest that all the reaction components are involved in the rate equation. Note that the complex

Malcolm Spain PhD Thesis behaviour of water concentration has been observed in a related SmI2–amine–H2O reduction of benzyl alcohols.94

Table 3.8. Rate constant and reaction orders for the reduction of 115d using the SmI2–Et3N–

H2O system.

a -3 -1 k (M s ) rate order a b c d substrate SmI2 Et3N H2O 1.4 x 101 0.96±0.10 1.09±0.10 1.18±0.10 0.92±0.10 a b [SmI2] = 75 mM, [H2O] = 250 mM, [Et3N] = 150 mM, [ester] = 5-20 mM. [SmI2] = 50-100 mM, [H2O] = 250 c mM, [Et3N] = 150 mM, [ester] = 12.5 mM. [SmI2] = 75 mM, [H2O] = 250 mM, [Et3N] = 75-250 mM, [ester] d =`12.5 mM. [SmI2] = 75 mM, [H2O] = 75-300 mM, [Et3N] = 150 mM, [ester] = 12.5 mM. T = 23 °C.

Figure 3.1. Influence of water concentration on the rate of the reduction of 115d using SmI2– Et3N–H2O.

Influence of [H2O] on the rate of reduction of 115d 0.04

0.03

)

- (s

0.02

obs k

0.01

0 0 0.5 1 1.5

[H2O] (M)

During our optimisation studies, we observed that various amines can be used to facilitate the reduction (see discussion at the beginning in Chapter 3). Rate studies using a variety of amines confirmed that amines dramatically influence the rate of reduction with over 2 magnitudes of variation in the initial rates (Table 3.9 and Figure 3.2). Furthermore, the influence of amines correlates with their basicity; more basic amines facilitate a faster reduction. Interestingly, by plotting kobs versus pKBH+ a linear correlation is observed

(gradient = 0.80), which corresponds very well to the relationship observed for the same

Malcolm Spain PhD Thesis amines in Hilmersson’s reduction of 1-chlorodecane (gradient = 0.79), despite the difference in mechanism (inner- vs. an outer-sphere process).92 This appears to demonstrate that the role of amine is independent of the nature of the electron transfer process.

a Table 3.9. Initial rates for the reduction of 115d using SmI2–amine–H2O versus pKBH+.

-1 b entry amine vinitial(mM s ) pKBH+ 1 morpholine 2.4 x 10-4 9.0±0.2 -5 2 n-Bu3N 3.9 x 10 10.0±0.5 -4 3 Et3N 5.0 x 10 10.6±0.3 -3 4 n-BuNH2 6.8 x 10 10.7±0.1 5 pyrrolidine 8.8 x 10-3 11.3±0.2 a b [SmI2] = 75 mM, [H2O] = 250 mM, [ester] = 12.5 mM, [amine] = 150 mM. T = 23 °C. Determined from ACD lab prediction algorithm.

Figure 3.2. Comparison of the correlation of log(kobs) versus pKBH+ in the reduction of esters and 1-chlorodecane using SmI2–amine–H2O from ref. 92.

Plot of log(kobs) vs pKBH+ in the reduction of tert-butyl 3-phenylpropanoate and 1-chlorodecane using SmI2/amine/H2O

2 1.5 y = 0.7929x - 7.5055 R² = 0.596 1 0.5

halide ) 0 obs -0.5 ester

log(k -1 -1.5 y = 0.7997x - 9.5963 -2 R² = 0.4682 -2.5 -3 8 9 10 11 12 pK BH+

To gain insight into the relative rates of ester reduction we conducted a number of competition experiments (Table 3.10). Competitions experiments using a series of esters with varying steric and electronic properties demonstrate that there is a large variation of over 3 orders of magnitude in the rate of reduction, with the sterically congested secondary ester being reduced slowest and, as expected, electronically activated aromatic esters being reduced fastest. This demonstrates that the ester reduction is sensitive to both electronic and steric effects, which could be exploited in chemoselective reductions.

Malcolm Spain PhD Thesis Table 3.10. Steric and electronic influence on the relative rates in the reduction of esters.a

entry 121a, R RV (122/116)b

1 >100 121p

2 121q 9.14

3 115a 4.29

4 1.00 121a 0.41 5 121c

0.26 6 118

0.91 7 121g

0.05 8 121o

entry RVb

9 115a R = OMe 1.00 10 115e R = OPh 6.88 11 115g R = Opfp 9.15 12 115h R = SEt 5.78 a All reactions carried out using standard Schlenk techniques. Conditions: under argon, to SmI2 (typically, 0.20 mmol), Et3N (typically, 2.4 mmol) and H2O (typically 2.4 mmol) an equimolar amount of the competition substrates (typically, 0.10 mmol) in THF (typically, 1 mL) was added, and the reaction mixture was vigorously stirred until decolourisation to white had occurred. bRelative reactivity values (RV) determined from product distribution by 1H NMR and/or GC of crude reaction mixtures and comparison with authentic samples. All data represent average of at least two experiments. To gain further mechanistic information, we investigated the electronic and steric requirements of the transition state, through Hammett and Taft correlation studies respectively (Tables 3.11 and 3.12). Hammett correlation studies, in a series of para- substituted phenyl acetic methyl esters (Table 3.11), showed an increase in rate with

Malcolm Spain PhD Thesis increasingly electron withdrawing substituents, demonstrating a build up of negative charge in the rate determining step. Furthermore, the rho value (ρ = +0.43) is similar to that observed in the ionisation of phenyl acetic acids (ρ = 0.49),95 consistent the build up of significant negative charge in the rate determining step.

Table 3.11. Hammett correlation study, electronic influence on the relative rates in the reduction of esters.a

Hammett electronic sensitivity (ρ) equation (Eq 1):

a entry X kX/kH Hammett constant (σpara) 1 123a CF3 1.79 0.54 2 123b Cl 1.44 0.23 3 123c F 1.22 0.06 4 121q H 1.00 0 5 123d MeO 0.81 -0.27 a Relative reactivity values (kX/kH) determined from product distribution (relative to X=H, through competition experiment with a equimolar mixture of 123 and 123q)) by 1H NMR and/or GC of crude reaction mixtures.

The effects of sterics upon the transition state were determined in a series of esters derived from hydrocinnamic acid (Table 3.12). Notably, the Taft correlation study (δ = +0.97) indicates that the steric requirements of the transition structure are similar to the tetrahedral intermediate formed in hydrolysis of esters (δ = +1.00). In summary, these studies demonstrate that there is a significant build up of negative charge in the transition state, and that an sp3-hybridised intermediate is formed in the rate determining step.

Malcolm Spain PhD Thesis

Table 3.12. Steric influence on the relative rates in the reduction of esters – Taft ES correlation study.a

Taft steric sensitivity (δ) equation (Eq 2):

a entry R kX/kMe Taft ES parameter 1 115a Me 1.00 0 2 115b Et 0.55 -0.07 3 115c i-Pr 0.19 -0.47 4 115d t-Bu 0.026 -1.54 5 115e Ph 6.20 -2.55 a Relative reactivity values (kX/kMe) determined from starting material distribution (relative to R = Me, through competition experiment with a equimolar mixture of 115:115a) by 1H NMR and/or GC of crude reaction mixtures.

The reduction of esters using SmI2 proceeds via single electron transfer through a radical pathway. Using radical clock experiments, we investigated the role of the acyl-type radicals generated in the initial electron transfer (Table 3.13). To this end, we investigated the products from the reduction of phenyl-substituted cyclopropyl radical clocks (kfrag = ca. 3 x

11 -1 10 s , at 25 °C). Interestingly, using approx. 4 equiv of SmI2 (entry 1) resulted in no cyclopropyl containing alcohol products, instead yielding the fragmented ester and fragmented alcohol in a 94:6 ratio. Furthermore, SmI2–H2O, which has a lower thermodynamic redox potential, is capable of the first electron transfer to acyclic esters

(shown by fragmenting the ester radical clock), but is unable to reduce the acyl-type radicals further to form the corresponding alcohol. Taken together, these results indicate that the first electron transfer to ester carbonyls is lower in energy than the second electron transfer. This is in agreement with cyclic voltammetry studies conducted for the reduction of aromatic esters, which shows that the first electron transfer is reversible and lower in energy than the second electron transfer.96,97,98

Malcolm Spain PhD Thesis

Table 3.13. Radical clock experiments using SmI2–Et3N–H2O and SmI2–H2O complexes in the reductive opening of ester 125.

a b b b c entry SmI2 Et3N H2O time conv. 126 127 yield (equiv) (equiv) (equiv) (h) (%) (%) (%) (%) 1 4 24 24 1 min 80 75 5 80 2 8 48 48 2 h >98 <2 98 98 3 2 - 415 1 min 1.7 1.7 - 1.7 4 4 - 833 15 min 4.1 4.1 - 4.1 5 4 - 200 5 min 11 11 - 11 6 8 - 200 2 h 53 53 - 53 All reactions carried out using standard Schlenk techniques. aQuenched with air after the indicated time. bDetermined by 1H NMR and/or GC-MS of crude reaction mixtures and comparison with authentic samples. cCombined yield of 126 and 127. Conversion = (100-SM). In all entries 128 was not detected (<2.0%).

We propose that the mechanistic pathway to the reduction involves reversible reduction to form the acyl-type radical, followed by formal exchange of Sm(III) with Sm(II), which likely occurs by proton-metal exchange with respect to the acyl-type radical 129c (Scheme 3.5-6).

Then, the Sm(II)-complex, activated by both amine and water reduces the acyl-type radical, in the rate determining step, producing an sp3-hybridised anion which undergoes protonation.

After collapse of the tetrahedral hemiacetal, facile reduction of the aldehyde occurs yielding the corresponding alcohol. Based upon all the components being involved in the rate equation, and the rate determining step being influenced by the basicity of amines, we propose that the amine is involved in the deprotonation of the active Sm(II) complex. It is likely that the Sm(II)-acyl-type radical complex coordinates one or more molecules of water that are deprotonated, further activating the complex.

Malcolm Spain PhD Thesis

Scheme 3.5. Proposed mechanism for the reduction of esters using SmI2–amine–H2O.

Scheme 3.6. Active complex in the rate determining step.

In summary, we determined that the mechanism of the reduction of esters using SmI2–amine–

H2O is first order in all components (under the optimum reaction conditions). The reaction mechanism does not involve hydrolysis as the major pathway and proton transfer is not rate limiting. Moreover, the first electron transfer to esters can be achieved with SmI2–H2O, thus giving an indication that the first electron transfer is energetically-favourable. Furthermore,

Malcolm Spain PhD Thesis we have shown that the rate determining step involves the buildup of negative charge and involves steric requirements similar to the tetrahedral intermediate in ester hydrolysis with the rate determining step prior to collapse of the tetrahedral intermediate. In light of the radical clock experiments and the precedence for reversible electron transfer in ester reductions from CV studies, we propose that the mechanism involves a reversible first electron transfer, and that the second electron transfer is the rate limiting step.

3.2 Acid Reduction

On the basis of the ability of SmI2–amine–H2O systems to reduce a range of carboxylic acid esters, we hypothesised that this system could also be used for the reduction of carboxylic acids despite their lower electrophilicity.99

3.2.1 Acid reduction optimisation studies

As shown in Table 3.1 at the beginning of this chapter, we found that an increased amine concentration led to a more reactive system in ester reduction using SmI2–amine–H2O. Since carboxylic acids are less electrophilic and contain an acidic proton, in the optimisation of acid reduction we utilised SmI2–amine–H2O with increased amine equivalents (Table 3.14).

Pleasingly, under these conditions carboxylic acids are reduced to the corresponding alcohols. In agreement with our previous study both amine and water were required to achieve high conversion. Reduced equivalents of water or amine gave lower conversions.

These findings are in agreement with a SmI2–amine–H2O ratio of 1:2:3 being required.

Malcolm Spain PhD Thesis

Table 3.14. Effect of additives on the reduction of unactivated carboxylic acids with SmI2– amine–H2O

entry proton source amine proton amine time conversionb yieldb source (equiv) (h) (%) (%) (equiv) 1 H2O Et3N 18 18 2 >95 99 2 H2O - 18 - 18 <5 <5 3 H2O - 800 - 18 <5 <5 4 H2O Et3N 6 18 18 51 48 5 H2O Et3N 18 6 18 28 28 6 H2O Et3N 12 12 18 78 78 7 - Et3N - 18 18 <5 <5 8 MeOH Et3N 18 18 18 15 15 9 t-BuOH Et3N 18 18 18 11 11 10 (HOCH2)2 Et3N 9 18 18 45 25 11 H2O n-BuNH2 18 18 2 86 86 12 H2O i-Pr2NH 18 18 2 97 96 13 H2O pyrrolidine 18 18 2 96 67 14 H2O morpholine 18 18 2 98 88 15 H2O piperidine 18 18 2 95 53 aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. bDetermined by GC or 1H NMR. 3.2.2 Substrate scope of the acid reduction

We next turned our attention to the scope of the carboxylic acid reduction (Table 3.15).

Primary, secondary and sterically hindered tertiary aliphatic carboxylic acids proved to be successful substrates (entries 1-4). Notably, the reaction is less sensitive to sterics than the ester reduction as 2-butyloctanoic acid was reduced to the corresponding alcohol under standard conditions (entry 2, compare with Table 3.5, entry 17). Terminal olefins were tolerated and olefin isomerisation was not observed with internal alkenes (entries 5-6). As expected, diacids afforded the corresponding diols (entry 7). In addition complex substrates, such as ursodeoxycholic acid containing free-hydroxyl groups (entry 8) and carboxylate salts, such as Ibuprofen sodium salt (entry 17) were readily reduced. Interestingly, carboxylate salts

Malcolm Spain PhD Thesis are often more difficult to reduce than acids especially under SET conditions, due to the problem of electron transfer to a negatively charged intermediate.100

a Table 3.15. Reduction of unactivated acids with SmI2–Et3N–H2O.

entry acid alcohol yield (%) 1 131a 122a 98

2 131b 122o 94

3 131c 122c 96

4 131d 119 94b

c 5 131e 122p 90

6 131f 122q 97

7 131g 122i 88d

8 131h 122r 94

9 131i 116 92

10 131j 122g 97

11 131k 122s 88

Malcolm Spain PhD Thesis

12 131l 122e 95

13 131m 122t 98

14 131n 122f 94

15 131o 122h 91

16 131p 122m 82e

17 131q 122h 97f aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. Conditions: acid b (1 equiv), SmI2 (6 equiv), Et3N (16-24 equiv), H2O (24 equiv), RT, 2-24 h. Conditions: acid (1 equiv), SmI2 (8 c equiv), Et3N (24 equiv), H2O (24 equiv). Conditions: acid (1 equiv), SmI2 (4 equiv), Et3N (24 equiv), H2O (24 d e equiv). Conditions: diacid (1 equiv), SmI2 (12 equiv), Et3N (72 equiv), H2O (72 equiv). Conditions: acid (1 f equiv), SmI2 (4.5 equiv), Et3N (24 equiv), H2O (24 equiv). Conditions: carboxylate salt (1 equiv), SmI2 (6 equiv), Et3N (72 equiv), H2O (72 equiv), RT, 2 h.

Next, we examined the functional group tolerance of the reduction (Table 3.16). Aryl fluorides and chlorides were well-tolerated under the reaction conditions. However, for aryl bromides dehalogenation was observed. In addition, trifluoromethyl groups were tolerated showing an interesting advantage over related SET reductions, which suffer from benzylic elimination of fluoride. 101 In addition, ethers and thioethers were tolerated; however, unprotected phenols and anilines give slightly lower yields due to a reductive dearomatisation pathway.

Malcolm Spain PhD Thesis Table 3.16. Effect of substitution on the reduction of unactivated carboxylic acids with SmI2–Et3N–H2O.

entry R R yield (%) 1 132a F 133a F 93 2 132b Cl 133b Cl 86 3 132c Br 116 H 86a 4 132d CF3 133d CF3 98 5 132e MeO 133e MeO 94 6 132f SMe 133f SMe 96 7 132g HO 133g HO 71b 8 132h H2N 133h H2N 73 aComplete debromination was observed. b2:1 ratio of 132g to 4-(3-hydroxypropyl)cyclohex-3-enol. The reduction of enantioenriched acid 131n-(R) under the reaction conditions demonstrates that significant epimerisation does not occur in the reduction (Scheme 3.7), however note that the acid is more sensitive to racemisation than the corresponding methyl ester (Scheme 3.3).

Scheme 3.7. Epimerisation study using an enantioenriched acid under SmI2–Et3N–H2O conditions.a

a Using standard Schlenk techniques. Conditions: acid (1 equiv), SmI2 (8 equiv), Et3N (48 equiv), H2O (48 equiv), RT, 2h. Conversion and optical purity determined by 1H NMR or HPLC. 3.2.3 Mechanism of acid reduction

Several experiments were performed to determine the mechanism of acid reduction using

SmI2–amine–H2O. Firstly, through deuterium incorporation we determined that a series of anions is generated in the reduction and that the anions are protonated from the water co- solvent (Scheme 3.8). Similarly to the ester reduction, a significant kinetic isotope effect is not observed showing that protonation of the substrate is not involved in the rate determining step (Scheme 3.8).

100

Malcolm Spain PhD Thesis Scheme 3.8. Deuterium incorporation and kinetic isotope effect experiments in the reduction of hydrocinnamic acid.

a Using standard Schlenk techniques. Conditions: deuterium incorporation, acid (1 equiv), SmI2 (6 equiv), Et3N (12 equiv), D2O (18 equiv), RT, 3 h; kinetic isotope effect, acid (1 equiv), SmI2 (6 equiv), Et3N (12 equiv), 1 D2O/H2O (9/9 equiv). Deuterium incorporation and kinetic isotope effect determined by H NMR. Next, rate orders for all the components of the reaction were determined by the initial rates method in the reduction of 2-butyloctanoic acid, using tributylamine as a Lewis base (Table

3.17). This combination resulted in a reduction at a convenient rate for the kinetic studies.

The rate orders were determined over a concentration range representative of the preparative reaction conditions. Within experimental error, for acid, H2O and amine a rate order of 1 was found, with SmI2 having a rate order 2. Similar to the ester reduction, water concentration shows a more complex behaviour, inhibiting the reduction at increased concentrations of approx. 0.3 M and demonstrating similarities to the reduction of esters, where coordination of the substrate to SmI2 competes with H2O. Furthermore, the kinetic studies with acids show that all reaction components are involved in the rate determining step (as for the reduction of esters).

101

Malcolm Spain PhD Thesis Table 3.17. Rate constant and reaction orders for the reduction of 2-butyloctanoic acid 131b using the SmI2–Bu3N–H2O system.

a -3 -1 k (M s ) rate order a b c d substrate SmI2 Bu3N H2O 2.5 x 102 0.93±0.10 1.93±0.10 0.94±0.10 1.01±0.10 a b [SmI2] = 75 mM, [H2O] = 250 mM, [Et3N] = 150 mM, [ester] = 5-15 mM. [SmI2] = 50-100 mM, [H2O] = 250 c mM, [Et3N] = 150 mM, [ester] = 12.5 mM. [SmI2] = 75 mM, [H2O] = 250 mM, [Et3N] = 75-250 mM, [ester] d =`12.5 mM. [SmI2] = 75 mM, [H2O] = 75-150 mM, [Et3N] = 150 mM, [ester] = 12.5 mM. T = 23 °C. Next, we studied the influence of sterics and electronics on the acid reduction using relative reactivity studies (Table 3.18). Interestingly, the results presented in Table 3.18 demonstrate that when electron withdrawing groups are closer to the carboxylate the rate is not significantly enhanced, in particular as compared to ester reduction (see Table 3.10). In addition, the reduction is less sensitive to sterics than the ester reduction. Overall, the range of reactivity in the substrates in Table 3.18 is approx. 30, as compared with more than 3 orders of magnitude for ester reduction. We hypothesise that the lower sensitivity towards sterics is likely due to the decreased sterics of acids and could be related to the formation of the carboxylate acting as an effective ligand for Sm(II).

102

Malcolm Spain PhD Thesis Table 3.18. Relative rates study for the reduction of acids.

entry 135 R RV (122/122a)a 1 5.73 135a 2 135b 1.48 3 130 1.47 4 1.00 131a 0.83 5 131c

0.58 6 131d

0.87 7 131j

0.17 8 131b aConditions: Relative reactivity values (RV) (RV = 122/122a) determined from product distribution by 1H NMR and/or GC of crude reaction mixtures. All data are average of two experiments.

To further investigate the differences between ester and acid reduction we used radical clock experiments (Table 3.19). Interestingly, the SmI2–H2O system is also capable of the first electron transfer to carboxylic acids, however, the reagent is unable to reduce the acyl-type radical (compare with Table 3.13 for ester reduction). In similarity to the ester reduction, cyclopropylcarbinol product is not observed, however the ratio of the acyclic ester to the alcohol is significantly higher. In summary, these results suggest that the relative barriers for the first and second electron transfer are different in the reduction of carboxylic acids and esters, with the second electron transfer being relatively lower in the reduction of acids when compared to the analogous electron transfer step in ester reduction using SmI2–amine–H2O.

103

Malcolm Spain PhD Thesis

Table 3.19. Radical clock experiments using SmI2–Et3N–H2O and SmI2–H2O complexes in the reductive opening of acid 137.

entry SmI2 Et3N H2O time conv. 138 127 yield (equiv) (equiv) (equiv) (h)a (%)b (%)b (%)b (%)b 1 1.5 24 24 1 min 44 34 9.5 44 2 8 48 48 2 h >95 - 96 96 3 8 - 200 2 h 15 15 - 15 4 8 - 615c 2 h <5 - - <5 aQuenched with air after the indicated time. bDetermined by 1H NMR. cMeOH used instead of water.

Finally, we determined the relative rates of acid reduction with SmI2 with respect to the reduction of other carboxylic acid derivatives (Table 3.20). Competition experiments between esters and acids, show that methyl and ethyl esters are reduced faster than carboxylic acids, however, increasing the steric size of the ester moiety further favours preferential acid reduction. These results correlate with the lower steric sensitivity observed in the reduction of acids compared to esters. In addition, primary amides and nitriles can be reduced with high selectivities in the presence of acids, demonstrating that these reductions occur at a faster rate

102,103 than both acid and ester reduction using SmI2–Et3N–H2O.

104

Malcolm Spain PhD Thesis Table 3.20. Competition experiments between carboxylic acid 131l and other carboxylic acid derived functional groups 131l.

entry X Y 140a/140b 122e 1 CO2Me OH 62 38 2 CO2Et OH 53 47 3 CO2i-Pr OH 28 72 4 CO2t-Bu OH 11 89 5 C(O)NH2 OH 95 5 6 CH2CN CH2NH2 91 9 a 1 Determined by GC and H NMR. Conditions: 139 (1 equiv), 131l (1 equiv), SmI2 (4 equiv), Et3N (24 equiv), H2O (24 equiv), RT, 5 min.

The proposed mechanism for the reduction of carboxylic acids with SmI2 is presented in

Scheme 3.10 and is analogous to the reduction of esters (see Scheme 3.5). The mechanism involves reversible reduction to form the acyl-type radical, followed by exchange of Sm(III) to Sm(II), which most likely involves a protonated acyl-type radical intermediate. Then, the active Sm(II)-complex, activated by both amine and water reduces the acyl-type radical, in the rate determining step, producing an sp3-hybridised anion which undergoes protonation.

After collapse of the tetrahedral acetal, facile reduction of the aldehyde occurs yielding the corresponding alcohol.

105

Malcolm Spain PhD Thesis

Scheme 3.9. Proposed mechanism for the reduction of acids using SmI2–amine–H2O.

For simplicity the acid is shown, however, the reduction of the carboxylate could be more important.

In summary, the first reduction of unactivated carboxylic acids with SmI2 has been achieved.

As demonstrated by the rate studies, the reduction of acids is influenced by all reaction components (under the optimum reaction conditions). Despite the presence of an acidic proton, protonation occurs predominantly from water (deuterium incorporation) and is not rate limiting. Moreover, we have demonstrated that the first electron transfer to acids can be achieved with SmI2–H2O. Interestingly, the reduction of acids is less sensitive to steric and electronic effects than the reduction of esters. This process is advantageous due to the commercial availability of carboxylic acid starting materials and the general lack of methods for the reduction of this important functional group that proceed through radical mechanisms.

106

Malcolm Spain PhD Thesis Chapter 4. New divalent lanthanide complexes

Building upon our work uncovering the beneficial roles of proton donors in SmI2 reductions, we hypothesised that the same principles could be applied to other divalent lanthanide complexes to create new complexes capable of single electron transfer reduction of carboxylic acid derivatives. Initially we were interested in exploring the possibility of activating the classical divalent lanthanide, europium(II) iodide (EuI2, E1/2= -0.35 V, vs.

NHE).104 Unfortunately, however, activation with Lewis bases and/or water was unfruitful, and we were unable to reduce aldehydes and ketones. However, in light of developments in the field of non-classical divalent lanthanides (TmI2, E1/2 = -2.3 V; DyI2, E1/2 = -2.5 V; NdI2,

104 105 E1/2 = -2.7 V, vs. NHE) which are now commercially available, we hypothesised that we could activate TmI2 (the first reagent in the series in terms of redox potentials) with proton donors.106

4.1 Effective redox potential of TmI2–MeOH

The effective reduction potential of TmI2–THF was investigated by Fedushkin et al., by using

107 a series of aromatic hydrocarbons. They found that TmI2 reacts with unsaturated cyclic hydrocarbons that have reduction potentials more positive than -2.0 V, which is consistent with the reduction potential of -2.3 V (vs. NHE; approx. -2.0 V vs. SCE) 108 previously determined for thulium(II) from spectroscopic data.107 To determine whether proton donors could increase the effective reducing power of TmI2, we investigated the reduction of aromatic hydrocarbons usingTmI2–ROH reagents (Table 4.1).

107

Malcolm Spain PhD Thesis

Table 4.1. Determination of redox potential of TmI2 by reduction of aromatic and unsaturated hydrocarbons.

a entry hydrocarbon -E1/2 major product conv. (%) 1b cyclooctatetraene 1.83 cyclooctadiene >98 2 anthracene 1.98 9,10-dihydroanthracene 84 3 trans-stilbene 2.21 bibenzyl >98 4 1,4-diphenylbenzene 2.40 dihydro-1,4-diphenylbenzene 40 5 1,3,5-triphenylbenzene 2.51 dihydrotriphenylbenzene 15 6 naphthalene 2.61 1,4-dihydronaphthalene 1.8 7 styrene 2.65 ethylbenzene 46 8 benzene 3.42 1,4-cyclohexadiene <2

All reactions carried out using standard Schlenk techniques. Conditions: under argon, to TmI2, substrate (0.05 mmol) in THF (typically, 1 mL) was added, followed by methanol (0.20 mL, 100 equiv) at RT for 2-3 min, after which decolourisation from deep green (TmII) to transparent, yellow or milky-white (TmIII) had occurred. aIn volts vs. SCE; -E1/2 describes half-reduction potential.

Gratifyingly, the addition of MeOH to TmI2 allowed the reduction of aromatic hydrocarbons with reduction potentials more positive than -2.6 V (vs. SCE). This demonstrates that the addition of MeOH facilitates the reduction of aromatic hydrocarbons 0.6V higher than TmI2–

THF alone. This confirmed our hypothesis that addition of proton sources could increase the redox potential of TmI2. The use of other proton donors with TmI2 was less successful (see, part 4.2).

4.2 The role of proton donors

We hypothesised that the difference in reduction potential could arise from MeOH acting as a ligand to TmI2. To investigate the role of MeOH in promoting the reaction we investigated the reduction of trans-stilbene (E1/2 = -2.22 V, vs. SCE) with a range of proton sources.

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Malcolm Spain PhD Thesis Table 4.2. Investigation of the Role of Proton Donor (Reduction of trans-Stilbene 68).

b c c entry TmI2 ROH ROH time conv. yield notes (equiv)a (equiv)a (%) (%) 1 3 - - 3 min <5 <5 - 2d 3 - - 1 h <5 <5 - 3 3 MeOH 100 3 min >95 96 - 4 3 H2O 150 3 min 86 81 - 5 3 MeOH 10 3 min >95 99 - 6 3 H2O 10 3 min >95 99 - 7 3 t-BuOH 10 3 min <5 <5 - 8 3 TFE 10 3 min 28 28 - 9 3 Et3N/H2O 18/18 <5 s 20 20 - 2 10 3 MeOD-d4 100 1.5 >95 93 96.5% D - min purity e 11 3 MeOD-d4 100 1.5 >95 72 kH/kD = /MeOH min 1.13±0.1 2 12 3 D2O 100 1 min >95 94 98.0% D - purity e 13 3 D2O /H2O 100 1 min >95 91 kH/kD = 1.27±0.1

All reactions carried out using standard Schlenk techniques. Conditions: under argon, to 3 equiv of TmI2, substrate (0.050 mmol) in THF (typically, 1 mL) was added, followed by an alcohol. Conversion = (100-SM). aWith respect to trans-stilbene. bIndicates time after which decolourisation from deep green (TmII) to transparent, yellow or milky-white (TmIII) had occurred. cDetermined by 1H NMR analysis by comparison with d e authentic samples. Reaction carried out in the dark. 1:1 mixture of MeOD-d4/MeOH or D2O/H2O was used.

As presented in Table 4.2, clearly, there is a difference between coordinating proton donors

(MeOH and H2O) and non-coordinating proton sources (t-BuOH). In addition, the use of TFE demonstrates that the increased rate is not simply an effect of increased acidity. Furthermore, deuterium incorporation was determined to occur from the acidic solvent indicating that anions formed in the reduction are protonated by the protic co-solvent. Low kinetic isotope effect was determined for this reaction (MeOD-d4, kH/kD = 1.1; D2O, kH/kD = 1.3).

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Malcolm Spain PhD Thesis

4.3 TmI2-mediated reduction of carboxylic acid derivatives

Having determined the beneficial role of proton sources on the reduction of aromatic hydrocarbons using TmI2, next we evaluated its ability to reduce unactivated carboxylic acid derivatives (Table 4.3).

a Table 4.3. Reduction of esters and carboxylic acids with TmI2–ROH. entry ester/acid product ROH ROH conv.b yieldb (equiv) (%) (%) 1 H2O 150 >95 88

1 2 c 2 H2O 150 >95 83

121a 122a 3 MeOH 100 >95 99

121a 122a 4 MeOH 100 >95 96

115a 116 5d MeOH 100 63 63

121o 122o 6d MeOH 100 >95 94

121c 122c 7 MeOH 100 86 85

121h 122h 8 MeOH 100 59 58

118 119 9 MeOH 100 >95 34d

115c 116 10 - - 7 <10

121a 122a

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Malcolm Spain PhD Thesis 11 MeOH 100 <5 <5d

131a 122a All reactions carried out using standard Schlenk techniques. Conditions: under argon, to 6 equiv of TmI2, substrate (typically, 0.050 mmol) in THF (typically, 1 mL) was added, followed by H2O or MeOH (150 or 100 equiv). Conversion = (100-SM). aTime elapsed until colour change from characteristic Tm(II) to Tm(III), 2-3 b 1 c d min. Determined by H NMR and/or GC-MS. 61:39 ratio of 1-decanol/1-decanal. 8 equiv of TmI2 was used. d 62% yield (77% conv.) with TmI2–H2O.

Treatment of 5-decanolide (entry 1) with TmI2–H2O afforded the corresponding diol. In comparison to SmI2–H2O this reaction is much faster; >95% conversion in 2-3 min.

Impressively, this TmI2–H2O system is also capable of the reduction of unactivated acyclic esters within the same reaction time, further demonstrating an increase in reactivity vs. SmI2–

H2O systems; however, we found conditions using TmI2–MeOH were optimal to achieve efficient ester reduction. High reactivity was observed, using TmI2–MeOH, in the reduction of aliphatic, aromatic, alpha-substituted and sterically-demanding esters. Interestingly, this process demonstrates a higher tolerance of sterics than SmI2–Et3N–H2O, with regards to sterically demanding substrate (entry 5); with SmI2–Et3N–H2O, 8:24:24 equiv, 3h, 42% conv., 42% yield. Control reactions demonstrated that esters are not reduced in the absence of proton sources, and carboxylic acids are inert to TmI2–MeOH. This demonstrates that useful levels of chemoselectivity can be achieved using TmI2–MeOH.

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Malcolm Spain PhD Thesis

Table 4.4. C-N Bond Cleavage in Amides using TmI2–ROH – Optimisation Study.

a b entry n LnI2–ROH LnI2 ROH time conv. (%) yield (equiv) (equiv) (%) c 1 1 TmI2 3 - 2 h 47 <2 2 1 TmI2–MeOH 3 10 2-3 min <2 <2 d 3 1 TmI2–MeOH 3 100 2-3 min 55 48 (77) 4 1 TmI2–H2O 3 150 2-3 min 82 <2 e 5 1 TmI2–MeOH 3 100 2-3 min <2 <2 6 0 SmI2 3 - 3 h <2 <2 7 0 SmI2–MeOH 3 100 3 h <2 <2 8 0 SmI2–H2O 3 100 1 h <2 <2

All reactions carried out using standard Schlenk techniques. Conditions: under argon, to TmI2, substrate (0.05 mmol) in THF (typically, 1 mL) was added, followed by a proton source. Conversion = (100-SM). Yield refers to C–N bond cleavage product. aIndicates time after which decolourisation from deep green (TmII) to transparent (TmIII) had occurred. bDetermined by 1H NMR and/or GC-MS analysis by comparison with authentic samples. cReaction carried out in the dark. dIn parentheses, yield based on the recovered starting e material. TmI2 (6 equiv) afforded 2a in 45% yield. 1-(3-Phenylpropyl)pyrrolidine used instead of the amide.

Due to the high reactivity of TmI2–MeOH systems with ester carbonyls, we hypothesised that the reagent system would be capable of electron transfer reduction of amide carbonyls.

Remarkably, activation of TmI2 with MeOH (100 equiv) results in the product of unactivated sigma C-N bond cleavage in amides; whilst the reaction did not proceed in the absence of proton sources, at low methanol concentration or with H2O as an additive. Notably, C-N bond cleavage was not observed in the corresponding amine (entry 5), in a more activated azetidinyl amide, and with a variety of SmI2 systems. This demonstrates that TmI2–MeOH is capable of unprecedented reactivity in the reduction of amides. With the optimised conditions in hand, a series of amides were subjected to the reaction conditions to investigate the scope.

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Malcolm Spain PhD Thesis

Scheme 4.1. Cleavage of unactivated  C–N bonds in amides using TmI2–MeOH.

a Using standard Schlenk techniques. Conditions: substrate (1 equiv), TmI2 (3 equiv), MeOH (100 equiv), THF, RT, 2-3 min, after which decolourisation from deep green (TmII) to transparent (TmIII) occured. Yield determined by 1H NMR by comparison with authentic samples. Pleasingly, both unhindered and sterically-bulky pyrrolidinyl amides also underwent successful sigma C-N bond cleavage. Furthermore, this reactivity is not limited to the pyrrolidinyl amides, both azetidinyl amide and acyclic amides undergo C-N bond cleavage.

In addition, we hypothesised that the cleavage of sterically-biased aziridinyl amide, would give insight into the mechanism. The reaction afforded an approximate 1.6:1.0 ratio, favouring cleavage at the less substituted carbon. Given the instability of primary radicals, we suggest that to some degree direct insertion into the C-N bond may occur.

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Malcolm Spain PhD Thesis a Table 4.5. Sigma C–N bond cleavage of amides using TmI2–ROH at fragmentation study.

b b c entry R TmI2 ROH conversion (%) yield SE (equiv) (equiv) (%) (kcal/mol) 1 150 t-Bu 3 100 >95 71 4.35 2 157a i-Pr 3 100 52 29 2.57 3 157b Me 3 100 33 <2 -1.67 4 157c Ph 3 100 23 <2 -10.27

All reactions carried out using standard Schlenk techniques. Conditions: under argon, to TmI2, substrate (0.05 mmol) in THF (typically, 1 mL) was added, followed by a MeOH (100 equiv), 2-3 min after which decolourisation from deep green (TmII) to transparent (TmIII) had occurred. Conversion = (100-SM). Yield refers to C–N bond cleavage product. Yield and conversion determined by 1H NMR and/or GC-MS analysis by comparison with authentic samples. cSE = Thermochemical stabilisation energy of the corresponding radical (t- Bu, i-Pr, Me, Ph) as defined by Ref. 109. To gain further insight on the mechanism of sigma C-N bond cleavage a selection of secondary amides were subjected to the reaction conditions (Table 4.5). The degree of fragmentation correlates with the thermochemical stabilisation energy (SE) of the fragmenting radical (t-Bu (71%, SE = 4.35 kcal/mol) > i-Pr (29%, SE = 2.57 kcal/mol) > Me

(<2%, SE = -1.65 kcal/mol)).109 Therefore, the mechanism of the C-N bond cleavage may occur predominantly via radical fragmentation (Scheme 4.2). An alternative mechanism involving direct insertion may be possible and would explain the opening via formal primary radical fragmentation in the methyl-aziridinyl amide.

Scheme 4.2. Mechanism of the  C–N bond cleavage in unactivated amides using TmI2‒ROH.

114

Malcolm Spain PhD Thesis Furthermore, to investigate the possibility of a formal C-O fragmentation pathway in esters, we conducted several detailed mechanistic experiments (Scheme 4.3).

Scheme 4.3. Investigating the mechanism of ester reduction with TmI2–ROH.

Treatment of decyl and 1-phenylethyl acetate with TmI2–MeOH, demonstrated that the fragmentation does occur under these conditions; further, it correlates with the stability of the fragmenting radical. Furthermore, even benzylic alcohols, which are known to fragment with other SET reagents, are not fragmented under the reaction conditions; this further demonstrates the unique reactivity possible with TmI2.

In conclusion, we have developed a new lanthanide reagent based on the activation of TmI2 with MeOH. The reagent promotes unique cleavage of unactivated sigma C-N bonds in amides.

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Malcolm Spain PhD Thesis Chapter 5. Synthesis of samarium diiodide

One of the key factors in developing the chemistry using divalent lanthanides has been our investigation into the preparation of samarium(II) iodide. To explore mechanisms of reactions using SmI2, we required solutions with high low-valent lanthanide purity that could be prepared consistently. The preparation of SmI2 is typically performed with carefully dried and deoxygenated solvents using Schlenk techniques.110 This demonstrates care and attention to the effects of water and oxygen, which can influence the formation of the reagent. In addition, peroxide-content resulting from the oxidation of THF has been reported to prevent the efficient synthesis of SmI2. It has also been recognised that the quality of samarium metal is important, occasionally completely preventing synthesis of the reagent. We hypothesised that the first quantitative evaluation of these factors would provide useful information, not only in our studies but to the wider organic community.111

To measure the divalent lanthanide content in samarium(II) iodide solutions, titration was performed according to the method developed by Hilmersson112 and by standard iodometric titration113 (notably, Hilmersson’s titration measures only the amount of active Sm(II) reagent and does not include concentration of other species). All studies were performed with Dr. M.

Szostak in duplicate to ensure maximum reliability of the obtained results in light of the contrasting literature evidence regarding preparation and stability of Sm(II) solutions.

Solutions of samarium(II) iodide were allowed to settle for at least 30 min prior to titration to reach homogeneity of solutions, and titration of each sample was performed in triplicate. All reactions were conducted using standard Schlenk techniques unless noted otherwise (i.e. the use of a Schlenk line with argon gas, using flame-dried glassware with attention to air tight seals using tight fitting suba-seals that are sealed using PTFE tape and parafilm).

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Malcolm Spain PhD Thesis 5.1 Investigation of commercially available samarium(II) iodide solutions

As a starting point to our investigation, we were interested in determining the quality of commercially available SmI2–THF solutions. Often SmI2–THF solutions are utilised by research groups in their first experience with SmI2-mediated reactions, due to the convenience of applying commercial chemicals. Therefore we first investigated the quality of these solutions in a series of selected reactions (Tables 5.1-3).

Table 5.1. Comparison of molarity of commercially available solutions of SmI2 (all advertised as 0.1 M solutions).

a b c entry SmI2 notes titration 1 ABCR w/o sure-seal 0.049 M 2 Aldrich w/ sure-seal 0.026-0.030 Md 3 Alfa-Aesar w/o sure-seal 0.041 M 4 Strem w/o sure-seal 0.044 M aReagents purchased between June-September 2011. Titration was performed immediately after a particular b bottle was received from the specified supplier. Bottles of SmI2 from supplier 1, 3 and 4 were not equipped with a sure-seal system. Note that opening of bottles of commercial SmI2 from suppliers 1, 3, 4 should be performed under strong flow of inert gas or in a glove box to ensure minimal decomposition of SmI2. cPerformed according to ref. 112 and 113. dAverage of two bottles, purchased in June-September 2011.

Contrary to our expectation, we found that many of the commonly used suppliers of SmI2–

THF solutions supplied the reagent in packaging that did not have a sure-seal system, despite wide-spread literature pertaining to the instability of SmI2 to air (i.e. reduction of dioxygen by

SmI2) (Table 5.1). We determined that these commercial bottles should be opened under a strong flow of inert gas and sealed, in order to ensure minimal decomposition of SmI2.

Titration of commercially available solutions revealed that the solutions contain much less divalent lanthanide content (<0.05 M) than advertised (0.1 M). As a result, we found that commercial solutions of SmI2–THF should be titrated prior to use.

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Malcolm Spain PhD Thesis a Table 5.2. Reduction of ester 115b using commercially available solutions of SmI2

c c entry SmI2 equiv of molarity of conv. yield b SmI2/H2O/Et3N SmI2 (%) (%) 1 Alfa 6/48/48 0.041 >95 99 2 Alfa 8/24/24 “0.10” 81 74 3 Aldrich 8/24/24 “0.10” 73 61 4 Aldrich 6/120/120 0.012 60 25 5 Aldrich 6/54/54 0.030 >95 93 6 ABCR 6/36/36 0.049 >95 99 7 ABCR 8/24/24 “0.10” 80 73 8 Strem 6/48/48 0.044 >95 99 9 Strem 8/24/24 “0.10” >95 99 aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. All reactions b carried out for 15-18 h at RT. Determined according to ref. 112 and 113. “0.10” indicates that SmI2 was used with the advertised molarity. cDetermined by 1H NMR.

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Malcolm Spain PhD Thesis Table 5.3. Reduction of aliphatic carboxylic acids using commercially available solutions of a SmI2.

entry acid product SmI2 yield (%)b 1 ABCR 96

131c 122c

2 Alfa 67

131e 122p

3 Alfa 99

131b 122o aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. Entry 1-2 conditions: ester or acid (1 equiv), SmI2 (6 equiv), Et3N (36 equiv), H2O (36 equiv), THF, RT, 15-18 h. Entry 1- b 2 conditions: acid (1 equiv), SmI2 (6 equiv), Et3N (48 equiv), H2O (48 equiv), THF, RT, 18 h. Determined by 1H NMR.

To investigate the ability of commercially available solutions to perform synthetic reactions, we considered that our own methodology would provide a perfect testing ground (Tables 5.2-

3). As indicated in Table 5.2, all commercial solutions perform well in the reduction of 115b.

Notably, SmI2 should be titrated before use, however, a large excess of the reagent can be used to ensure high conversions. Furthermore, titrated commercial solutions can be used in other reductions, such as the reduction of carboxylic acids (Table 5.3). Unfortunately, commercial solutions are not suitable for use in all reductions. For example they can be ineffective in effecting reactions using SmI2–H2O, where a high concentration of H2O is used

(not shown). We hypothesise that this is due to incompatibility of SmI2–H2O with the high concentration of Sm(III) species present in commercial solutions.

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Malcolm Spain PhD Thesis 5.2 Preparation of samarium diiodide solutions

To investigate the preparation of SmI2–THF solutions we identified that quantification of water, oxygen and peroxide content is important in understanding mechanisms of decomposition of the reagent. We were also aware that some batches of samarium metal could not be used to prepare samarium diiodide from. We also investigated methods to activate “inactive” samarium metal.

5.2.1 Methods of preparation

There are a number of procedures reported in the literature that may be used for the

114 preparation of SmI2–THF solutions (Figure 5.1). The procedures reported by Imamoto,

Flowers113 and Hilmersson112 which use molecular iodine as the oxidant, differing only in heating, the use of sonication or microwave heating of the suspension, respectively (note that

Imamoto’s procedure is sometimes performed at room temperature). The methods reported by Kagan,1,56 Kagan/Molander 115 and Concellón 116 also show similarities in having an organic oxidant which ultimately leads to volatile byproducts that are lost from the reaction.

Perhaps the most different method was reported by Ishii, in which TMSCl is used as the oxidant, in the presence of sodium iodide. 117 Examination of the literature revealed that

Kagan’s and Imamoto’s procedures have been the methods that have been used most frequently in the literature. Therefore we chose to examine these two methods with regards to the influence of water, oxygen, peroxides and samarium metal quality. In accordance with

Kagan’s original procedure an excess of samarium metal with regard to oxidant was used (2:1 ratio) to ensure reproducibility of the results.

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Malcolm Spain PhD Thesis Figure 5.1. Methods for the preparation of samarium(II) iodide.

5.2.2 The influence of water

Water has the potential to react with Sm metal, SmI3 or SmI2; therefore we considered it is one of the most likely factors affecting the preparation of samarium diiodide.118 To evaluate the influence of water on the formation of samarium(II) iodide, tetrahydrofuran with gradually increasing amounts of water was used, quantified by coulometric Karl-Fischer titration (Table 5.4). To ensure an accurate range of water concentration, tetrahydrofuran used in entries 1-3 was prepared by sequential dilution of the same batch of tetrahydrofuran.

For comparison, three other batches of tetrahydrofuran were also used. All reactions were carried out, with the exception of water content, using conditions prescribed in the literature for the synthesis of SmI2 (i.e. carefully degassed tetrahydrofuran, standard Schlenk techniques and samarium metal handled in a glove box).

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Malcolm Spain PhD Thesis a Table 5.4. Evaluation of water content on synthesis of SmI2 entry water tetrahydrofuran induction SmI2 contentb timec molarityd 1 15 ppm anhydrous, dried over MS 4 Å 15 min 0.076 M 2 167 ppm anhydrous, dried over MS 4Å + H2O 45 min 0.072 M 3 328 ppm anhydrous, dried over MS 4 Å + H2O > 2 h 0.073 M 4 59 ppm anhydrous 30 min 0.070 M 5 50 ppm HPLC grade 30 min 0.075 M 6 34 ppm HPLC grade, distilled from 10 min 0.075 M Ph2CO/Na aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents; samarium metal (ABCR) handled in a glove box; tetrahydrofuran purchased from Sigma-Aldrich; RT, 18-24 h, 5.5 mmol scale. bDetermined by coulometric Karl-Fischer titration. cInduction time indicates time after which colour of reaction mixture turned blue; note that induction time varies dependent on scale of the reaction. dRefers to solutions of SmI2, performed in triplicate according to Hilmersson’s protocol Water content was found to have little influence (within experimental error) on the synthesis of SmI2 under the conditions of our experiments (Table 5.4). Even in the extreme case, corresponding to wet THF (Table 5.4, entry 3), SmI2–THF was formed with similar efficiency. Interestingly, the induction time (time for the reaction to change to a dark blue colour) was found to correlate directly with the water content, with slower induction time corresponding to higher water concentration. From these experiments, it is evident that water is not a major factor limiting the synthesis of SmI2–THF solutions, and that commercially available anhydrous THF can be used. In the cases where wet THF was used, we hypothesise that the longer induction time is due to an initial reaction between samarium metal and water to give samarium(III) hydroxide, slowing down oxidation step with 1,2-diiodoethane.

5.2.3 The influence of oxygen

In addition to water, oxygen-content is likely to be a concern in the preparation of samarium(II) iodide. It is well-known that the most stable oxidation state of lanthanides is the

+3 oxidation state, consequently samarium(II) iodide is unstable when exposed to air favouring oxidation to samarium(III). To investigate the influence of oxygen on the preparation of samarium(II) iodide we used experimental protocols with gradually less rigorous care towards the exclusion of oxygen (Table 5.5). Using standard Schlenk techniques, we compared degassing of THF though freeze-pump thawing, one of the most

122

Malcolm Spain PhD Thesis effective methods to degas solvents and the use of commercial solvents without pretreatment.

In addition, we compared the preparation of SmI2 using Schlenk techniques with conditions under inert gas and finally with open flask conditions (i.e. w/o the use of an inert gas).

a Table 5.5. Evaluation of oxygen content on the synthesis of SmI2

entry degassing method reaction set-up method induction SmI2 of THFb timec Molarityc 1 freeze-pump standard Schlenk techniques 15 min 0.076 M thawing 2 distillation from standard Schlenk techniques 10 min 0.075 M Na/Ph2CO/N2 3 - standard Schlenk techniques 20 min 0.074 M 4 - Ar sparging, no vacuumd 15 min 0.060 M 5 - “open flask conditions”e 15 min 0.058 M aUnless noted otherwise, all reactions carried out using standard Schlenk techniques for handling air-sensitive reagents; samarium metal (ABCR) handled in a glove box; tetrahydrofuran purchased from Sigma-Aldrich; RT, 18-24 h, 5.5 mmol scale. bEntry 1, three cycles of freeze-pump-thawing; entry 2, freshly distilled prior to use, from sodium/benzophenone under nitrogen; entries 3-5, commercial THF w/o any pretreatment was used. cSee, Table 5.4. dReaction was carried out without the use of high-vacuum: in air, oven-dried flask was charged with samarium metal and 1,2-diiodoethane, sealed with septum and placed under argon atmosphere. Tetrahydrofuran was added in one portion, the flask was sealed with parafilm, and the reaction mixture was stirred for indicated time. eReaction was carried out without the use of high-vacuum or inert gas techniques: in air, oven-dried flask was charged with samarium metal and 1,2-diiodoethane, fitted with septum and tetrahydrofuran was added in one portion. The flask was sealed with parafilm, and the reaction mixture was stirred for the indicated time. Notably, similar results are obtained using thoroughly degassed solvents and commercially available solvents without degassing prior to use (Table 5.5, entries 1-3). Furthermore, argon sparging and even “open flask” conditions provides efficient synthesis of SmI2 (Table 5.5, entries 4-5). These results suggest that the exclusion of oxygen during the preparation of

SmI2 is not necessary for its formation; however, the use of standard Schlenk techniques is advantageous. We propose that in cases where oxygen was deliberately not removed from the reaction vessels, the reaction of the excess samarium metal removed oxygen allowing the efficient formation of SmI2.

5.2.4 The influence of peroxides

Ethereal solvents such as tetrahydrofuran are well-known to form explosive peroxides in air.119 As such commercial THF often contains BHT inhibitors to prevent their build-up.

Moreover, peroxides are known to breakdown initiating radical chain reactions, which have

120,121 been reported to affect the preparation of SmI2. To investigate the effect of peroxide

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Malcolm Spain PhD Thesis content on the synthesis of SmI2, we tested different sources of tetrahydrofuran with varying degrees of peroxide content (Table 5.6). The peroxide content was determined by the standard reaction with sodium thiosulfate followed by iodometric titration.

a Table 5.6. Evaluation of peroxide concentration on the synthesis of SmI2 entry peroxide tetrahydrofuran induction titrationc contentb timec 1 0.0015 M Aldrich, anh., 1 L, w/o BHT 30 min 0.070 M 2 0.002 M Aldrich, anh., 2 L, w/o BHT 15 min 0.076 M 3 0.002 M Acros, anh., 1 L, w/o BHT 30 min 0.069 M 4 < 0.001 M Aldrich, HPLC, w/BHT 20 min 0.074 M 5 < 0.001 M Fisher Sci., anh., w/BHT 15 min 0.071 M aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents; samarium metal (ABCR) handled in a glove box, RT, 18-24 h, 5.5 mmol scale. bDetermined by reaction with sodium thiosulfate, followed by iodometric titration. cSee, Table 5.4.

As indicated in Table 5.6, peroxide content is unlikely to interfere with the synthesis of THF.

Furthermore, this study demonstrates that both stabilised and unstabilised THF can be used for efficient synthesis of the reagent. During this work, various suppliers of THF were used and we have not found any evidence to suggest that the synthesis is dependent on source of

THF (Table 5.6).

5.2.5 Preparation procedure

Within the literature, there are three different methods of adding the reagents and solvents for

122,123,124 SmI2 preparation. Comparison of these three methods (Table 5.7), demonstrates that there is no significant impact on the synthesis of SmI2. From a practical point of view, we determined that adding tetrahydrofuran to a reaction vessel charged with samarium metal and

1,2-diiodethane is the most convenient and time-efficient method of synthesis (entry 1).

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Malcolm Spain PhD Thesis a Table 5.7. Evaluation of preparation procedure on the synthesis of SmI2 entry addition procedureb induction titrationc timec 1 addition of THF to Sm metal and ICH2CH2I 15 min 0.071 M 2 addition of ICH2CH2I in THF to Sm metal 20 min 0.072 M 3 addition of solid ICH2CH2I to Sm metal in THF 20 min 0.069 M aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents; samarium metal (ABCR) handled in a glove box, commercial tetrahydrofuran was used w/o special pretreatment, water content - 100 ppm; RT, 18-24 h, 5.5 mmol scale. bEntry 1: THF was added to a flask charged with Sm metal and 1,2- diiodoethane; Entry 2: a solution of 1,2-diiodoethane in THF was added to a flask charged with Sm metal; Entry 3: solid 1,2-diiodoethane was added to a flask charged with Sm metal and THF; see, experimental section for full experimental procedures. cSee, Table 5.4. 5.2.6 Imamoto’s procedure

Having examined potential factors affecting the synthesis of samarium(II) iodide from 1,2- diiodoethane, next we turned our attention to detailed investigation of the synthesis of SmI2 using iodine as the oxidant, namely Imamoto’s procedure.114 These results are summarised in

Table 5.8. As expected, the findings are consistent with results found for Kagan’s procedure using 1,2-diiodoethane; Rigorously dried solvents are not required, simple techniques in excluding oxygen are effective, and peroxide content is not a major contributing factor.

Notably, commercially available solutions of stabilised or non-stabilised THF are suitable for use without pre-treatment.

a Table 5.8. Evaluation of selected parameters affecting the synthesis of SmI2 using I2 entry water reaction set-up method peroxidesc induction titrationd contentb timed 1 100 Schlenk techniques <0.001 M 1 h 0.060 M 2 110 Schlenk techniques 0.002 M 1.5 h 0.062 M 3 110 Schlenk techniques/60 °Ce 0.002 M 30 min 0.066 M 4 100 Ar spargingf <0.001 M 2 h 0.061 M 5 100 “open flask”f <0.001 M > 5 h 0.061 M 6 380 Schlenk techniques <0.001 M 2 h 0.055 M aUnless noted otherwise, all reactions carried out using standard Schlenk techniques for handling air- sensitive reagents; samarium metal (ABCR) handled in a glove box; commercial THF w/o special pretreatment was used; RT, 18-24 h, 5.5 mmol scale. bDetermined by coulometric Karl-Fischer titration. cDetermined by reaction with sodium thiosulfate, followed by iodometric titration. dSee, Table 5.4. eReaction performed at 60 °C. fSee, Table 5.5.

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Malcolm Spain PhD Thesis 5.2.7 Effect of the quality of samarium metal on the preparation of samarium(II) iodide

The quality of samarium metal has been generally noticed as effecting the preparation of

SmI2. Whilst Sm metal is available from a variety of commercial suppliers, even with samarium metal from suppliers that had been found to supply good quality samarium metal, occasionally, bottles of “inactive” samarium metal have been encountered (these occasional batches failed to form SmI2 under standard conditions used for preparation of the reagent).

Since samarium metal, is well-known to oxidise in air, we hypothesised that the major factor preventing efficient formation of SmI2 from “inactive” batches originate from tarnishing of the metal surface with samarium oxide. To address the problem of samarium metal quality, we investigated the handling of samarium metal and the ability to activate “inactive” batches

(Tables 5.9-11).

a Table 5.9. Evaluation of quality of samarium metal on synthesis of SmI2 entry samarium metalb Notes induction titrationc timec 1 ABCR, glove- - 5 min 0.072 M box 2 Acros, glove-box - 5 min 0.065-0.073 M 3 Acros, aird - 15 min 0.069 M 4 ABCR, glove- kept in air for 10 dayse 15 min 0.062 M box 5 Acros, glove-box activated by flame- 5 min 0.068 M dryingf aUnless noted otherwise, all reactions carried out using standard Schlenk techniques for handling air-sensitive reagents; RT, 18-24 h, 5.5 or 16.5 mmol scale. cSee, Table 5.4.dStored in a closed container in air and frequently opened in air for use without any precautions to exclude oxygen. eSamarium metal removed from glove box, stored in air in open-vessel and mixed at least two times a day to ensure homogenous exposure of metal surface to oxygen. fVigorous flame-drying of samarium metal under high-vacuum.

To investigate the influence of handling of samarium metal, we compared the results of preparations using “active” batches of samarium metal weighed and stored in a glove-box and stored in air for a period of time (Table 5.9). Interestingly, there was no significant link between the efficiency of synthesis of SmI2 and the storage or handling of samarium metal.

These results suggest that samarium metal is not deactivated in air over short periods of time.

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Malcolm Spain PhD Thesis Therefore Sm metal can be stored in air without special precautions during weighing the samples for the reaction.

5.2.8 Activation of samarium metal

During our studies on properties of Sm metal, we noticed that “active” and “inactive” batches of samarium metal tend to differ in physical appearance. To address the problem of activating

“inactive” samarium metal, we proposed that the problem could be due to the deactivation of surface of the metal and that choosing appropriate procedure for cleaning the surface would restore properties required for the synthesis of Sm(II) (Table 5.10). For this study, we selected different batches of samarium metal that failed to form SmI2 under standard conditions using Kagan’s and Imamoto’s procedures (Table 5.10, entries 1-2). After experimentation, we determined that the “dry-stirring” protocol introduced by Brown, is applicable to activate “inactive” Sm metal by mechanical activation of the metal surface

(Table 5.10, entry 3).

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Malcolm Spain PhD Thesis a Table 5.10. Synthesis of SmI2 from “inactive” samarium metal. entry samarium activation of synthesis notesb activation titrationc metal samarium metal method timec 1 Strem - ICH2CH2I RT, 6 d - not formedd 2 Strem - I2 60 °C, 3 - not d formedd 3 Strem dry-stirring under I2 60 °C, 2 h 0.084 M Ar, 24 he 18 h 4 Strem dry-stirring under I2 60 °C, 5 h 0.081 M vacuum, 150 °C, 18 h 20 hf 5 Strem dry-stirring ICH2CH2I RT, 18 h - not under Ar, 24 he formedd g 6 Strem thermal activation ICH2CH2I RT, 18 h - not formedd h 7 Strem 10 to 55 mL ICH2CH2I RT, 2 > 5 h 0.057 M d→1d h 8 Strem 10 to 55 mL ICH2CH2I RT, > 5 h 0.072 M 1d→1d h 9 Strem 10 to 55 mL I2 RT, > 5 h 0.047 M 1d→1d 10 Alfa- - ICH2CH2I RT, 1 d - not Aesar formedd 11 Alfa- dry-stirring under I2 60 °C, 15 min 0.083 M Aesar Ar, 24 he 18 h 12 ABCR - ICH2CH2I RT, 1 d - not formedd 13 ABCR dry-stirring under I2 60 °C, 15 min 0.099 M Ar, 24 he 18 h aAll reactions carried out using standard Schlenk techniques for handling air-sensitive reagents. All reactions b c performed on 5.5 mmol scale. Refers to conditions of synthesis of SmI2. See, Table 5.4; molarity for entries 11 d and 13 was determined for suspensions of SmI2. Indicates that blue colour characteristic to SmI2 did not form. eSamarium metal was stirred under argon at RT for indicated time, followed by addition of THF and oxidant. fSamarium metal was stirred under high-vacuum at 150 °C for indicated time, followed by addition of THF and oxidant. gActivation of metal by vigorous flame-drying under vacuum. h1,2-Diiodoethane and samarium metal stirred in 10 mL of THF for indicated time, followed by addition of the remaining portion of THF.

Pleasingly, we were able to find that activation of one of the “inactive” batches of samarium metal by dry-stirring under argon, followed by oxidation with iodine, formed SmI2 in excellent yield. Furthermore, we applied the dry-stirring activation method to other “inactive” batches of samarium metal. The “dry-stir” activation was found to be ineffective when 1,2- diidoethane is used as oxidant (entries 5-6). We hypothesise that further activation of the samarium metal surface by iodine due to heating might be involved, resulting in this process being more effective. As such, we recognised that 1,2-diiodoethane at higher concentrations

128

Malcolm Spain PhD Thesis would also activate the metal surface; pleasingly this led to formation of active SmI2 solutions (entries 7-9); the reaction of samarium metal with 1,2-diiodoethane generates a significant exotherm, increasing the temperature of the reaction mixture. However, this protocol has not been found to be as general as the dry-stir method followed by the reaction with iodine. Importantly, the SmI2 solutions prepared from “inactive” samarium metal were capable of mediating a variety of SmI2 transformations (Table 5.11). In all cases, yields were comparable or higher to those previously reported, demonstrating the success of our activation protocol.

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Malcolm Spain PhD Thesis

Table 5.11. Single electron transfer reactions mediated by SmI2 prepared from “inactive” Sm metal.a

entry starting material product conditions time yield (h) (%)a 1 SmI – 2 1 65 H2O 40 41 2 SmI2– H2O– 18 97 118 119 Et3N 3 SmI2– H2O– 1 99 Et3N 121m 4 SmI2– H2O– 15 84 130 116 Et3N 5 SmI2– 131a 122a H2O– 15 89 Et3N 6

SmI – 2 1 98 H2O

166 167 7 88 SmI – 2 1 (7:1 H O 18b 2 dr) 30b a All reactions performed using standard Schlenk techniques. Conditions: entries 1-2, lactone (1 equiv), SmI2 (8 equiv), H2O (200 equiv), THF, RT, 30 min to 1 h; entry 3, ester (1 equiv), SmI2 (12 equiv), Et3N (72 equiv), H2O (72 equiv), THF, RT, 18 h; entry 4, ester (1 equiv), SmI2 (8 equiv), Et3N (36 equiv), H2O (36 equiv), THF, RT, 1 h; entries 5-6, acids (1 equiv), SmI2 (6 equiv), Et3N (36 equiv), H2O (36 equiv), THF, RT, 15 h; entry 7, cyclic-1,3-diester (1 equiv), SmI2 (8 equiv), H2O (1200 equiv), THF, RT, 1 h; entry 8, activated lactone (1 equiv), SmI2 (7 equiv), H2O (1200 equiv), THF, RT, SmI2 added to a THF solution of lactone and H2O over 1 h. Yields determined by 1H NMR by comparison with authentic samples.

5.2.9 Stability of solutions of samarium(II) iodide

Finally, it should be noted that our studies pertain to the concentration of samarium(II) iodide in solution, rather than the concentration of the samarium(II) iodide suspension. Our studies were focused on the solution properties as this allowed batch preparation of the reagent for set-up of multiple reactions. Moreover, it has been reported in the literature that suspensions

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Malcolm Spain PhD Thesis of samarium(II) iodide display different properties than solutions of samarium(II) iodide or pure samarium(II) iodide solid.28 For example, some reactions mediated by samarium(II) iodide are not compatible with samarium metal present in suspensions of samarium(II) iodide

(i.e. suspensions of SmI2 cannot be used for these reactions). In all reactions presented in the current study (except some entries in Table 5.10), reactions between samarium metal and the oxidant proceed quantitatively to yield suspensions of samarium(II) iodide. Furthermore, we confirmed the molarity of suspensions of samarium(II) iodide generated by our method by titration of the entire solution (1H NMR assay according to the procedure reported by

Hilmersson).

With regard to the stability of the solutions generally it is recommended that samarium diiodide should be freshly prepared before each use, due to problems in storing the solutions.

To examine the effects of storing on the quality of SmI2 solutions prepared by Kagan’s method, we sealed a solution of SmI2 under argon and stirred it at room temperature. Over the period of one month, no significant decomposition of the reagent was detected. Notably, we have noticed that SmI2 tends to precipitate from unstirred THF solutions over time.

Furthermore, we found that SmI2 can be stored at room temperature under inert atmosphere without stirring for long periods of time (>2 weeks), stirring of the suspension for at least 1 h prior to use results in full restoration of the properties of the reagent. By contrast, SmI2 prepared by Imamoto’s procedure is much less stable. In these solutions, precipitation of yellow samarium(III) can be observed after several days.

131

Malcolm Spain PhD Thesis 5.3 Reduction of Meldrum’s acids (practical protocol for the use of SmI2–H2O Solutions)

The Procter group have previously reported the reduction of Meldrum’s acid using SmI2–H2O which affords the corresponding 3-hydroxyacid. This process offers a significant advantage over the typically used multi-step protocol involving conversion of a Meldrum’s acid to the monoacid, activation of the monoacid as a mixed anhydride, reduction and hydrolysis. 125

Since the cyclic nature of the substrate is required, no over-reduction is observed even in the presence of excess reagent. Furthermore, 3-hydroxy acids constitute an important class of compounds in medicinal chemistry, and as valuable intermediates. In light of our work on the preparation of SmI2 solutions, we developed a user-friendly procedure for the synthesis of 3- hydroxyacids which can be carried out using standard Schlenk techniques, or simple degassing techniques involving sparging of reaction vessels and solvents with inert gas. This

9.126 method presents a convenient protocol for the use of SmI2–H2O solutions (Scheme 5.1).

Scheme 5.1. 2.5 mmol synthesis of 3-hydroxacids (167 and 169) from α,β-unsaturated and saturated Meldrum’s acids (166 and 169, respectively).a

a Using standard Schlenk techniques. Conditions: 166 (1 equiv), SmI2 (8 equiv), H2O (1000 equiv), 15 min; 168 (1 equiv), SmI2 (6 equiv), H2O (1000 equiv), 15 min. When developing the protocol, we determined that the reduction of Meldrum’s acids requires a high concentration of water. Therefore, the reaction requires SmI2 solutions with a high divalent lanthanide content as prepared by the method described in the first part of this

132

Malcolm Spain PhD Thesis chapter. Furthermore, we found it beneficial to remove SmI2 solutions from the flask used in the preparation of SmI2, due to the presence of activated samarium metal, which can react with H2O. The reduction of Meldrum’s acids exemplifies a SmI2 reaction that requires good quality SmI2, prepared using standard procedures for the exclusion of oxygen. Using these techniques, a one-step synthesis of -hydroxy acids with SmI2 was found to proceed reliably on smaller or larger scales. This is the first large scale application of the useful SmI2–H2O complex in organic synthesis.

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Malcolm Spain PhD Thesis Chapter 6. Conclusions and Future Work

The reduction of unactivated carboxylic acids derivatives has been developed. Using the

SmI2–H2O system chelation can be used to increase the rate of reductions to achieve reductions in feasible reaction times (Chapter 2.1). Furthermore, this has allowed us to facilitate electron transfer to previously unreactive substrates, allowing them to be used as acyl-type radical equivalents. In addition, the concentration of water is critical and can significantly affect the effective lifetime of acyl-type radical equivalents (Chapter 2.1).

Experimental studies on the reduction of lactones, suggest that the mechanism involves reversible first electron transfer contrary to the previous mechanism proposed (Chapter 2.2).

Furthermore, the different behaviour at low and high water concentration has been shown to apply to the reduction of aromatic hydrocarbons (Chapter 2.3) and the reduction of barbituric acids (Chapter 2.4).

Optimisation of the divalent samarium systems, by means of protic and Lewis basic additives, has been demonstrated to allow the reduction of unactivated carboxylic esters and acids (Chapter 3). In addition, this concept has been shown to apply to TmI2, where the addition of proton donors significantly affects the reactivity (Chapter 4). Notably, the divalent thulium system (TmI2–MeOH) is capable of unprecedented reactivity achieving C-N bond cleavage in unstrained amides.

Finally, we have demonstrated a practical procedure for the synthesis of samarium diiodide which can be prepared using simple laboratory equipment, and that reactions using SmI2–

H2O can be achieved on a large scale (Chapter 5).

The future goals are to use carboxylic acid derivatives, to generate acyl-type radicals which are possible to achieve the complex chemistry achieved using SmI2 derived ketyl radicals.

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Malcolm Spain PhD Thesis Chapter 7. Experimental

General experimental

All experiments were performed under an atmosphere of argon at room temperature using standard Schlenk techniques, with anhydrous solvents, unless stated otherwise. Reaction flasks were over dried overnight and cooled under vacuum then purged with argon, reaction vials were flushed with argon for 2-3 min before use. For SmI2 reactions all syringes used were flushed with argon (3 times), by evacuation backfill cycles, except when very low water content was required.

1H NMR and 13C NMR were recorded using 300, 400 and 500 MHz spectrometers. Unless otherwise noted, all samples were dissolved in CDCl3 and the chemical shift values are reported in ppm relative to residual CHCl3 (δH = 7.27 or δC = 77.2) as an internal standard.

Abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet; br. s, broad singlet. Mass spectra were obtained using positive and negative electrospray (ES±) or gas chromatography (GC-

MS) methodology. Infra-red spectra were recorded as evaporated films or neat using a FT/IR spectrometer and are expressed in wave numbers (cm-1). All column chromatography was carried out using 35 – 70 mesh ASTM, 60 Ǻ silica gel. Routine TLC analysis was carried out on aluminium sheets coated with 35 – 70 mesh ASTM, 60 Ǻ silica gel, with fluorescent indicator F254 (zinc silicate), 0.2 mm thickness. Plates were viewed using a 254 nm ultraviolet lamp or stained in aqueous potassium permanganate.

GC-MS chromatography was performed using Agilent 7890A GC System and Agilent 5975C inert XL EI/CI MSD with Triple Axis Detector equipped with Agilent HP-5MS column

(19091S-433) (length 30 m, internal diameter 0.25 mm, film 0.25 m) using helium as the carrier gas at a flow rate of 1 mL/min, injection time of 2 min and an initial oven temperature of 40 °C or 50 °C. The injector temperature was 250 °C. The detector temperature was 250

°C. Method A (Standard GC-MS conditions): initial oven temperature 50 °C, hold 3 min, 135

Malcolm Spain PhD Thesis ramped to 300 °C at 25 °C/min, hold 5 min (splitless mode of injection, total run time of 18 min). Method B (GC-MS conditions): initial oven temperature 40 °C, hold 3 min, ramped to

300 °C at 15 °C/min, hold 5 min (splitless mode of injection, total run time of 25.33 min).

GC chromatography was performed using DANI Master GC Fast Gas Chromatograph

System equipped with Varian VF-1m column (length 30 m, internal diameter 0.25 mm, film

0.25 m) using hydrogen as the carrier gas at a flow rate of 1 mL/min and an initial oven temperature of 40 °C or 70 °C. The injector temperature was 250 °C. The detector temperature was 250 °C. The temperature was increased with a 10 °C/min ramp to a final temperature of 150 °C or 220 °C (splitless mode of injection). Method A (Standard GC conditions): initial oven temperature of 70 °C, ramped to 220 °C at 10 °C/min with no hold time (splitless mode of injection, total run time of 15 min). Method B (GC-MS conditions): initial oven temperature of 40 °C, hold 3 min, ramped to 150 °C at 10 °C/min, hold 3 min

(total run time of 17 min).

Preparation of SmI2

Samarium diiodide was prepared by a modification of the procedure of Kagan,1 using 1,2- diiodoethane, unless stated otherwise. To a oven-dried (overnight, or flame-dried) flask under argon was added samarium metal (6.02 g, 40.0 mmol, 2 equiv,–40 mesh, Acros Organics, cat. no. 294780500; stored at room temperature in air) and 1,2-diiodoethane (5.65 g, 20.0 mmol,

Aldrich, cat. no. D122807; stored at 2-8 °C, freshly purified (see below)) was added tetrahydrofuran (4 x 50 mL, anhydrous, >99.9%, Sigma-Aldrich, cat. no. 186562 or anhydrous, >99.9%, inhibitor-free, Sigma-Aldrich, cat. no. 401757, without degassing).

Typically after 2-3 min a colour change to green-blue is observed (associated with a reasonably strong exotherm) at the reaction flask is backfilled with argon to remove ethylene followed by addition of the remainder of the THF. The reaction was stirred overnight, yielding a deep blue suspension of SmI2, the suspension of SmI2 was allowed to settle for 30 min then titrated (see below).

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Malcolm Spain PhD Thesis Purification of 1,2-diiodoethane

Commercial 1,2-diiodoethane is contaminated with iodine and should be purified before use.

1,2-diiodoethane (20g) dissolved in diethyl ether (approx. 400 mL) and washed with aqueous saturated sodium thiosulfate solution (5 x 100 mL, prepared by dissolving 100 g of sodium thiosulfate in 500 mL of water), then water (100 mL). The diethyl ether layer was dried over sodium sulfate (50 g), and concentrated in vacuo to give 1,2-diiodoethane white solid, then protected from light by aluminium foil it was dried under vacuum for 15-30 min.

Titration of SmI2

According to the literature procedure.7 An oven-dried four-dram vial equipped with a stirring bar and septum was placed under high-vacuum line, subjected to three evacuation/backfilling cycles with argon, and left under positive pressure of argon. SmI2 (typically 1.0 mL, solution in THF, the exact volume of SmI2 was recorded) was added, followed by triethylamine (0.21 mL), H2O (33 mg), resulting in a colour change to a dark brown solution. A solution of cyclohexanone (85 mg, 0.87 mmol) in THF (5 mL) was added dropwise until the endpoint, when the solution turns white. The procedure was repeated at least 3 times and the concentration was determined accordingly (ketone reduction requires 2 equiv of SmI2). Note: all syringes and solvents used in the procedure should be flushed with argon (3 times) and degassed prior to use to obtain reproducible results. The titration should be repeated to give the average of three experiments.

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Malcolm Spain PhD Thesis

Preparation of solvents and additives for use with LnI2

When used in conjunction with SmI2 solutions, SmI2 powder or TmI2, THF (anhydrous,

>99.9%, Sigma-Aldrich, cat. no. 186562 or anhydrous, >99.9%, inhibitor-free, Sigma-

Aldrich, cat. no. 401757), triethylamine (anhydrous, >99.5%, Sigma-Aldrich, cat. no.

471283), water (deionised Water, Fluka, cat. no. 99053) and methanol (anhydrous, 99.8%,

Sigma-Aldrich, cat. no. 322415) were deoxygenated by sparging with Ar for 15 min immediately prior to use and stored under an Ar atmosphere. For TmI2 or kinetic experiments with SmI2 fresh bottles of Et3N, MeOH and THF (>99.9%, inhibitor-free, Sigma-Aldrich, cat. no. 401757) were used.

Determination of yields by 1H NMR

Following the work-up of the reaction the crude yields were determined by 1H-NMR using an internal standard (typically a freshly prepared solution of nitromethane in CDCl3), and comparison with authentic samples; either commercially available samples, samples prepared according to standard literature procedures, or where unavailable samples of fully characterised isolated compounds.

Chapter 2. SmI2–H2O

Chapter 2.0 Preliminary studies of the SmI2–H2O system

General procedure A for the reduction of lactones using SmI2 (powder).

An oven-dried vial containing a stir bar was charged with SmI2 powder (8 equiv) in a glovebox (argon), then sealed and stored in a disposable glovebag before use. Under a positive pressure of argon, THF solution (8 mL) was added followed by additive(s) (as specified in Tables 2.1 and 2.2) with vigorous stirring, then lactone (1.0 equiv, stock solution in THF, 1.0 mL). After the specified time, the excess of SmI2 was oxidised by bubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2 or EtOAc (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 or EtOAc (3 × 30

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Malcolm Spain PhD Thesis mL), and the organic layers were combined, dried over Na2SO4, filtered, and concentrated.

The sample was analyzed by 1H NMR to obtain conversion and yield using internal standard and comparison with authentic samples.

Chapter 2.1 Directing group effects

General procedure B for the chelation-enabled reduction of lactones using SmI2–H2O

An oven-dried vial containing a stir bar was charged with a lactone (1 equiv), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. SmI2 (THF solution, typically 8 equiv) was added, followed by a rapid injection of

H2O (typically, 800 equiv, 1.44 mL) under inert atmosphere at room temperature with vigorous stirring. After the specified time, the excess of SmI2 was oxidised by bubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2 (30 mL) and HCl

(1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The sample was analyzed by

1 H NMR (CDCl3) and/or GC-MS (neat) to determine the product distribution and diastereoselectivity from the crude reaction mixture. The crude product was purified by chromatography on silica gel and concentrated under reduced pressure.

Ethyl 4-hydroxy-2-(hydroxymethyl)butanoate (4b (13a)). (Table 2.5, entry 1)

1 Ethyl 2-oxotetrahydrofuran-3-carboxylate (3b (12a)) Rf (1/4 EtOAc/hexanes) = 0.21. H

NMR (300 MHz, CDCl3)  1.25 (t, J = 6.9, 3 H), 2.38-2.51 (m, 1 H), 2.56-2.68 (m, 1 H), 3.58

(dd, J = 7.8, 9.3 Hz, 1 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.22-4.31 (m, 1 H), 4.38-4.56 (m, 1 H).

Spectroscopic data matched literature values.127 According to the general procedure C, the

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Malcolm Spain PhD Thesis reaction of 3b (12a) (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 8.0 mL, 0.10 M) and H2O (1.44 mL, 800 equiv) for 2 h at room temperature afforded after purification by chromatography

(100% EtOAc) the title compound as a colourless oil. Note that the title compound is

1 unstable. Yield 83%. Rf (100% EtOAc) = 0.22. H NMR (300 MHz, CDCl3)  1.21 (t, J = 7.2

Hz, 3 H), 1.74-1.96 (m, 2 H), 2.64-2.72 (m, 1 H), 2.45-3.05 (br, 2 H), 3.59-3.68 (m, 2 H),

13 3.73-3.77 (m, 2 H), 4.11 (q, J = 7.2 Hz, 2 H); C NMR (75 MHz, CDCl3)  14.2, 31.7, 44.9,

60.5, 60.9, 63.0, 175.0. IR (neat) 3377, 2979, 2933, 1708, 1466, 1444, 1396, 1260, 1178,

-1 + 1049, 1022, 908, 859 cm . HRMS calcd for C7H14O4Na (M + Na) 185.0785, found

185.0787.

tert-Butyl 4-hydroxy-2-(hydroxymethyl)butanoate (13b). (Table 2.5, entry 2)

1 tert-Butyl 2-oxotetrahydrofuran-3-carboxylate (12b) Rf (1/4 EtOAc/hexanes) = 0.30. H

NMR (300 MHz, CDCl3)  1.40 (s, 9 H), 2.31-2.42 (m, 1 H), 2.43-2.58 (m, 1 H), 3.34 (dd, J

13 = 7.5, 9.3 Hz, 1 H), 4.17-4.25 (m, 1 H), 4.31-4.40 (m, 1 H). C NMR (75 MHz, CDCl3) 

26.5, 27.9, 46.9, 67.3, 82.9, 166.9, 172.7. Spectroscopic data matched literature values.128

According to the general procedure C, the reaction of 12b (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 8.0 mL, 0.10 M) and H2O (1.44 mL, 800 equiv) for 2 h at room temperature afforded after purification by chromatography (100% EtOAc) the title compound as a colourless oil.

1 Yield 87%. H NMR (500 MHz, CDCl3)  1.41 (s, 9 H), 1.75-1.91 (m, 2 H), 2.18 (br, 1 H),

2.55-2.61 (m, 1 H), 2.63 (br, 1 H), 2.62-2.72 (m, 3 H), 3.72-3.77 (m, 1 H); 13C NMR (125

MHz, CDCl3)  28.1, 31.9, 45.5, 60.6, 63.2, 81.5, 174.5. IR (neat) 3348, 2925, 1721, 1705,

-1 + 1457, 1392, 1367, 1252, 1051, 886, 846, 747, 652 cm . HRMS calcd for C9H18O4Na (M +

Na) 213.1098, found 213.1090.

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N-Cyclohexyl-4-hydroxy-2-(hydroxymethyl)undecanamide (13c). (Table 2.5, entry 3)

N-Cyclohexyl-5-heptyl-2-oxotetrahydrofuran-3-carboxamide 12c 1H NMR (300 MHz,

CDCl3)  (mixture of diastereoisomers and rotamers) 0.89 (t, J = 7.2 Hz, 3 H), 1.12-1.54 (m,

15 H), 1.55-1.79 (m, 5 H), 1.82-2.01 (m, 2 H), 2.04-2.14 (m, 0.40 H), 2.21-2.33 (m, 0.50 H),

2.38-2.54 (m, 0.40 H), 2.57-2.68 (m, 0.40 H), 2.85-2.93 (m, 0.30 H), 3.41-3.51 (m, 1 H),

3.68-3.85 (m, 1 H), 4.42-4.53 (m, 0.40 H), 4.55-4.74 (m, 0.60 H), 6.68 (d, J = 7.8 Hz, 0.30

13 H), 6.78 (d, J = 8.1 H, 0.20 H), 7.13 (d, J = 7.2 Hz, 0.50 H); C NMR (75 MHz, CDCl3) 

(mixture of diastereoisomers and rotamers) 14.1, 22.6, 24.6, 25.1, 25.5, 29.1, 29.2, 30.0, 30.9,

31.7, 32.7, 35.3, 35.6, 46.1, 46.3, 48.5, 48.8, 79.9, 80.9, 164.0, 164.5, 175.4, 175.6. IR (neat)

-1 2928, 2855, 1756, 1651, 1538, 1432, 1180, 912, 742, 646 cm ; HRMS calcd for C18H32O3N

(M+ + H) 310.2377, found 310.2377. According to the general procedure C, the reaction of

12c (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 2 h at room temperature afforded after purification by chromatography (100%

EtOAc) the title compound as a colourless oil. Yield 94%. Rf (100% EtOAc) = 0.53. Dr =

1 85:15. H NMR (400 MHz, CDCl3)  (mixture of diastereoisomers) 0.81 (t, J = 6.8 Hz, 3 H),

; 1.04-1.46 (m, 18 H), 1.54 (dt, J = 3.6, 12.8 Hz, 1 H), 1.59-1.68 (m, 2 H), 1.79-1.92 (m, 3

H), 2.31 (br, 2 H), 2.49-2.57 (m, 1 H), 3.52-3.60 (m, 1 H), 3.63-3.78 (m, 3 H), 6.31 (d, J =

13 7.6 Hz, 1 H, major), 6.41 (d, J = 6.8 Hz, 1 H, minor). C NMR (100 MHz, CDCl3) 

(mixture of diastereoisomers) (major) 14.1, 22.6, 24.8, 25.5, 25.6, 29.2, 29.5, 31.8, 33.0, 36.5,

38.2, 44.7, 48.1, 64.1, 69.7, 174.6. (minor, diagnostic peaks only) 25.0, 36.7, 38.2, 45.0, 63.3,

70.4, 175.2. IR (neat) 3295, 2927, 2859, 1636, 1541, 1448, 1366, 1214, 1058 cm-1. HRMS

+ calcd for C18H35NO3Na (M + Na) 336.2510, found 336.2504.

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4-Hydroxy-2-(hydroxymethyl)-N-phenylundecanamide (13d). (Table 2.5, entry 4)

5-Heptyl-2-oxo-N-phenyltetrahydrofuran-3-carboxamide (12d) 1H NMR (300 MHz,

CDCl3)  (mixture of diastereoisomers and rotamers) 0.90 (t, J = 6.6 Hz, 3 H), 1.05-1.51 (m,

10 H), 1.55-1.84 (m, 2 H), 2.06-2.17 (m, 0.40 H), 2.28-2.40 (m, 0.60 H), 2.58-2.68 (m, 0.60

H), 2.86-2.97 (m, 0.40 H), 3.63-3.72 (m, 1 H), 4.41-4.53 (m, 0.60 H), 4.60-4.61 (m, 0.40 H),

13 6.95-7.60 (m, 5 H), 8.67 (br, 0.40 H), 9.21 (br, 0.60 H); C NMR (75 MHz, CDCl3) 

(mixture of diastereoisomers and rotamers) 14.1, 22.6, 25.2, 29.1, 29.2, 30.5, 31.1, 31.7, 35.2,

35.6, 47.5, 47.5, 80.0, 81.0, 120.0, 120.2, 122.7, 124.5, 128.8, 128.9, 137.6, 139.9, 164.3,

175.1. IR (neat) 2928, 1755, 1635, 1600, 1524, 1498, 1443, 1331, 1173, 1053, 912, 744, 691

-1 + cm ; HRMS calcd for C18H25O3NNa (M + Na) 326.1727, found 326.1729. According to the general procedure C, the reaction of 12d (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL,

0.080 M) and H2O (0.36 mL, 200 equiv) for 2 h at room temperature afforded after purification by chromatography (100% EtOAc) the title compound as a colourless oil. Yield

1 77%. Rf (100% EtOAc) = 0.65. Mixture of diastereoisomers. H NMR (300 MHz, CDCl3) 

(major diastereoisomer) 0.80 (t, J = 6.9 Hz, 3 H), 1.07-1.54 (m, 13 H), 1.87-1.98 (m, 1 H),

2.31 (br. s, 2 H), 2.73-2.84 (m, 1 H), 3.59-3.69 (m, 1 H), 3.73-3.82 (m, 2 H), 7.03 (t, J = 7.2

Hz, 1 H), 7.23 (t, J = 7.8 Hz, 2 H), 7.47 (d, J = 7.8 Hz, 2 H), 8.58 (br. s, 1 H). 13C NMR (100

MHz, CDCl3)  (major diastereoisomer) 14.1, 22.6, 25.6, 29.2, 29.5, 31.8, 36.3, 38.1, 45.8,

64.0, 70.0, 120.0, 124.4, 129.0, 137.9, 173.8. IR (neat) 3338, 2922, 2853, 1626, 1559, 1446,

-1 + 1307, 1268, 1207, 1132, 1052, 1028, 889, 621 cm . HRMS calcd for C18H30NO3 (M + H)

308.2221, found 308.2221.

142

Malcolm Spain PhD Thesis Ethyl 5-hydroxy-2-(hydroxymethyl)pentanoate (9 (15a)). (Table 2.5, entry 5)

1 Ethyl 2-oxotetrahydro-2H-pyran-3-carboxylate 7(14a) Rf (1/4 EtOAc/hexanes) = 0.29. H

NMR (300 MHz, CDCl3)  1.30 (t, J = 7.2 Hz, 3 H), 1.83-2.06 (m, 2 H), 2.12-2.33 (m, 2 H),

3.56 (t, J = 7.5 Hz, 1 H), 4.25 (q, J = 7.2 Hz, 2 H), 4.32-4.43 (m, 2 H). 13C NMR (75 MHz,

CDCl3)  14.0, 20.9, 22.8, 47.4, 61.9, 69.4, 167.4, 169.1. Spectroscopic data matched literature values.48 According to the general procedure C, the reaction of 7 (14a) (0.10 mmol),

SmI2 (0.80 mmol, 8 equiv, 8.0 mL, 0.10 M) and H2O (1.44 mL, 800 equiv) for 1h at room temperature afforded the title compound. Yield 96% (determined by 1H NMR analysis v.

1 internal standard after the aqueous work-up as described above). H NMR (400 MHz, CDCl3)

 1.22 (t, J = 7.2 Hz, 3 H), 1.50-1.73 (m, 4 H), 2.35 (br. s, 2 H), 2.49-2.56 (m, 1 H), 3.59 (t, J

13 = 6.4 Hz, 2 H), 3.69-3.73 (m, 2 H), 4.11 (q, J = 6.8 Hz, 2 H). C NMR (100 MHz, CDCl3) 

14.2, 24.7, 30.1, 47.2, 60.8, 62.4, 63.0, 175.3. Spectroscopic data matched literature values.48

Ethyl 5-hydroxy-2-(hydroxymethyl)decanoate (15b). (Table 2.5, entry 6)

Ethyl 2-oxo-6-pentyltetrahydro-2H-pyran-3-carboxylate (14b) Rf (1/4 EtOAc/hexanes) =

1 0.49. H NMR (300 MHz, CDCl3)  (1:1 mixture of diastereoisomers) 0.89 (t, J = 6.6 Hz, 3

H), 1.14-1.81 (m, 12 H), 1.85-2.06 (m, 1 H), 2.06-2.32 (m, 2 H), 3.48 (t, J = 7.5 Hz, 0.50 Hz),

13 3.56 (t, J = 7.5 Hz, 0.50 Hz), 4.16-4.41 (m, 3 H). C NMR (75 MHz, CDCl3)  (1:1 mixture of diastereoisomers) 14.0, 14.0, 14.1, 21.7, 22.5, 22.9, 24.4, 25.6, 25.7, 27.1, 31.5, 35.4, 35.8,

46.1, 48.0, 61.8, 61.9, 80.5, 81.1, 167.4, 168.4, 169.2, 169.4. IR (neat) 2932, 2861, 1724,

-1 1458, 1373, 1313, 1253, 1174, 1098, 1039, 944, 857, 728 cm . HRMS calcd for C13H23O4

143

Malcolm Spain PhD Thesis (M+ + H) 243.1591, found 243.1603. According to the general procedure C, the reaction of

14b (0.10 mmol), SmI2 (0.60 mmol, 6 equiv, 10.0 mL, 0.060 M) and H2O (1.44 mL, 800 equiv) for 30 min at room temperature afforded after purification by chromatography (1/1

EtOAc/hexanes) the title compound as a colourless oil. Yield 72%. Rf (1/1 EtOAc/hexanes) =

0.33. Mixture of diastereoisomers, stereochemistry not assigned. Dr = 51:49. Note that the title compound is unstable and undergoes closure to 3-(hydroxymethyl)-6-pentyltetrahydro-

2H-pyran-2-one. Selected characterisation data for ethyl 5-hydroxy-2-(hydroxymethyl)

1 decanoate: H NMR (500 MHz, CDCl3)  1.17 (t, J = 7.0 Hz, 3 H), 2.22-2.29 (m, 1 H), 4.10

(q, J = 7.0 Hz, 2 H). The title compound has been fully characterised after the cyclisation to

1 3-(hydroxymethyl)-6-pentyltetrahydro-2H-pyran-2-one: H NMR (500 MHz, CDCl3) 

(mixture of diastereoisomers0.83 (t, J = 7.0 Hz, 3 H), 1.17-1.36 (m, 5 H), 1.37-1.68 (m, 5

H), 1.86-1.98 (m, 2 H), 2.46-2.52 (m, 0.5 H, major), 2.59-2.65 (m, 0.5 H, minor), 2.89 (br. s,

13 1 H), 3.64-3.76 (m, 2 H), 4.20-4.26 (m, 1 H). C NMR (75 MHz, CDCl3)  (mixture of diastereoisomers14.0, 14.0, 19.5, 22.5, 22.5, 22.8, 24.5, 24.8, 26.8, 28.6, 31.6, 31.6, 35.0,

36.1, 40.5, 43.4, 62.5, 63.6, 78.6, 82.1, 174.2, 176.1 IR (neat) 3446, 2931, 1715, 1558, 1540,

-1 + 1507, 1457, 1376, 1230, 1189, 1080, 1044, 930 cm . HRMS calcd for C11H20O3Na (M –

C2H5OH + Na) 223.1305, found 223.1296.

144

Malcolm Spain PhD Thesis Ethyl 5-hydroxy-2-(hydroxymethyl)-5-phenylpentanoate (15c). (Table 2.5, entry 7)

Ethyl 2-oxo-6-phenyltetrahydro-2H-pyran-3-carboxylate (14c) Rf (1/4 EtOAc/hexanes) =

1 0.38. H NMR (300 MHz, CDCl3)  (1:1 mixture of diastereoisomers) 1.32 (t, J = 7.2 Hz, 3

H), 1.83-2.14 (m, 4 H), 3.63 (dd, J = 7.2, 9.0 Hz, 0.50 H), 3.72 (t, J = 7.2 Hz, 0.50 H), 4.23-

13 4.34 (m, 2 H), 5.36-5.47 (m, 1 H), 7.31-7.45 (m, 5 H). C NMR (75 MHz, CDCl3)  (1:1 mixture of diastereoisomers) 14.1, 22.0, 23.1, 28.5, 29.7, 46.4, 47.9, 62.0, 62.1, 81.8, 82.1,

125.7, 125.8, 128.5, 128.7, 128.7, 139.1, 139.1, 166.9, 167.6, 169.1, 169.3. IR (neat) 2970,

1722, 1456, 1371, 1312, 1240, 1154, 1065, 1026, 913, 862, 748, 699, 652 cm-1. HRMS calcd

+ for C14H16O4Na (M + Na) 271.0939, found 271.0941. According to the general procedure C, the reaction of 15c (0.10 mmol), SmI2 (0.45 mmol, 4.5 equiv, 6.9 mL, 0.065 M) and H2O

(0.36 mL, 200 equiv) for 10 min at room temperature afforded after purification by chromatography (100% EtOAc) the title compound as a colourless oil. Yield 68%. Rf (100%

EtOAc) = 0.63. Dr = 94:6. Mixture of diastereoisomers, stereochemistry not assigned. 1H

NMR (500 MHz, CDCl3) (major diastereoisomer)  1.20 (t, J = 7.0 Hz, 3 H), 1.46-1.55 (m, 1

H), 1.64-1.79 (m, 3 H), 1.88 (br. s, 2 H), 2.50-2.56 (m, 1 H), 3.64-3.71 (m, 2 H), 4.10 (q, J =

7.0 Hz, 2 H), 4.61 (dd, J = 5.5, 7.5 Hz, 1 H), 7.19-7.23 (m, 1 H), 7.24-7.33 (m, 4 H). (minor,

13 diagnostic peaks only) 5.29 (dd, J = 3.5, 11.0 Hz, 1 H). C NMR (75 MHz, CDCl3) (major diastereoisomer)  18.4, 23.0, 31.0, 43.4, 58.5, 63.5, 83.0, 125.7, 128.5, 128.7, 139.4, 173.8.

IR (neat) 3422, 1716, 1540, 1507, 1456, 1362, 1267, 1233, 1194, 1071, 913, 747, 701 cm-1.

+ HRMS calcd for C12H14O3Na (M –C2H5OH + Na) 229.0835, found 229.0839.

145

Malcolm Spain PhD Thesis Ethyl 6-hydroxy-2-(hydroxymethyl)hexanoate (6b (17a)). (Table 2.5, entry 8)

1 Ethyl 2-oxooxepane-3-carboxylate 5b (16a). Rf (40% EtOAc/hexanes) = 0.53. H NMR

(300 MHz, CDCl3)  1.23 (t, J = 7.2 Hz, 3 H), 1.49-2.10 (m, 6 H), 3.64 (dd, J = 2.1, 10.5 Hz,

13 1 H), 4.01-4.29 (m, 4 H). C NMR (75 MHz, CDCl3)  14.1, 25.8, 26.9, 28.7, 50.9, 61.6,

69.4, 169.0, 172.0. IR (neat) 2938, 1736, 1722, 1474, 1446, 1392, 1371, 1321, 1306, 1231,

-1 + 1204, 1146, 1049, 1028, 912 cm . HRMS calcd for C9H14O4Na (M + Na) 209.0785, found

209.0779. According to the general procedure C, the reaction of 5b (16a) (0.10 mmol), SmI2

(0.8 mmol, 8.0 equiv, 8.0 mL, 0.10 M) and H2O (1.44 mL, 800 equiv) for 30 min at room temperature afforded after purification by chromatography (100% EtOAc) the title compound

1 as a colourless oil. Yield 87%. Rf (100% EtOAc) = 0.26. H NMR (400 MHz, CDCl3)  1.21

(t, J = 6.8 Hz, 3 H), 1.31-1.39 (m, 2 H), 1.46-1.55 (m, 3 H), 1.57-1.67 (m, 1 H), 1.84 (br. s, 1

H), 2.35 (br. s, 1 H), 2.47-2.54 (m, 1 H), 3.58 (t, J = 6.8 Hz, 2 H), 3.66-3.74 (m, 2 H), 4.11

13 (qd, J = 0.8, 7.2 Hz, 2 H). C NMR (100 MHz, CDCl3)  14.3, 23.4, 28.1, 32.5, 47.4, 60.7,

62.5, 63.0, 175.4. IR (neat) 3371, 2935, 1714, 1460, 1379, 1184, 1031, 911, 728 cm-1. HRMS

+ calcd for C9H18O4Na (M + Na) 213.1098, found 213.1091.

Ethyl 2-benzyl-6-hydroxy-2-(hydroxymethyl)hexanoate (17b). (Table 2.5, entry 9)

1 Ethyl 3-benzyl-2-oxooxepane-3-carboxylate 16b. Rf (30% EtOAc/hexanes) = 0.59. H

NMR (300 MHz, CDCl3)  1.20 (t, J = 7.2 Hz, 3 H), 1.45-1.92 (m, 5 H), 2.23 (dt, J = 3.0,

14.1 Hz, 1 H), 3.12 (d, J = 13.8 Hz, 1 H), 3.43 (d, J = 13.8 Hz, 1 H), 3.91-4.00 (m, 1 H),

146

Malcolm Spain PhD Thesis 13 4.01-4.28 (m, 3 H), 6.95-4.37 (m, 5 H). C NMR (75 MHz, CDCl3)  13.9, 24.1, 28.1, 31.3,

45.1, 58.6, 61.6, 68.4, 127.1, 128.0, 131.0, 135.9, 169.9, 172.5. IR (neat) 2934, 1718, 1455,

-1 + 1368, 1223, 1162, 1111, 1056, 1029, 913, 740, 700 cm . HRMS calcd for C16H21O4 (M +

H) 277.1435, found 277.1437. According to the general procedure C, the reaction of 16b

(0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 30 min at room temperature afforded after purification by chromatography (100% EtOAc)

1 the title compound as a colourless oil. Yield 85%. Rf (100% EtOAc) = 0.67. H NMR (400

MHz, CDCl3)  1.19 (t, J = 7.2 Hz, 3 H), 1.24-1.37 (m, 2 H), 1.39-1.52 (m, 3 H), 1.58-1.66

(m, 1 H), 1.81 (br. s, 2 H), 2.79 (d, J = 13.6 Hz, 1 H), 3.00 (d, J = 13.6 Hz, 1 H), 3.49 (d, J =

11.2 Hz, 1 H), 3.57 (t, J = 6.4 Hz, 2 H), 3.63 (d, J = 11.2 Hz, 1 H), 4.04-4.16 (m, 2 H), 7.08-

13 7.12 (m, 2 H), 7.14-7.22 (m, 3 H). C NMR (100 MHz, CDCl3)  14.2, 20.4, 32.9, 33.1,

39.4, 52.1, 60.7, 62.4, 63.6, 126.6, 128.2, 130.3, 136.9, 176.1. IR (neat) 3391, 2931, 1715,

-1 + 1455, 1373, 1210, 1049, 1026, 915 cm . HRMS calcd for C16H24O4Na (M + Na) 303.1567, found 303.1566.

Ethyl 2-(3-cyanopropyl)-6-hydroxy-2-(hydroxymethyl)hexanoate (17c). (Table 2.5, entry 10)

Ethyl 3-(3-cyanopropyl)-2-oxooxepane-3-carboxylate 16c. Rf (1/1 EtOAc/hexanes) = 0.64.

1 H NMR (300 MHz, CDCl3)  1.34 (t, J = 7.2 Hz, 3 H), 1.51-1.98 (m, 8 H), 2.03-2.19 (m, 2

H), 2.39 (t, J = 6.9 Hz, 2 H), 4.01 (dd, J = 10.2, 12.3 Hz, 1 H), 4.18-4.32 (m, 1 H), 4.28 (q, J

13 = 7.2 Hz, 2 H). C NMR (75 MHz, CDCl3)  14.2, 17.5, 21.1, 24.6, 28.1, 32.5, 39.2, 57.4,

62.0, 68.8, 119.2, 170.4, 171.9. IR (neat) 2939, 1716, 1456, 1360, 1293, 1217, 1167, 1122,

-1 + 1077, 1021, 953, 892, 915, 853, 741, 620 cm . HRMS calcd for C13H19O4NNa (M + Na)

147

Malcolm Spain PhD Thesis 276.1207, found 276.1201. According to the general procedure C, the reaction of 16c (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 1 h at room temperature afforded after purification by chromatography (100% EtOAc) the title

1 compound as a colourless oil. Yield 92%. Rf (100% EtOAc) = 0.32. H NMR (300 MHz,

CDCl3)  1.22 (t, J = 7.2 Hz, 3 H), 1.14-1.36 (m, 2 H), 1.42-1.73 (m, 9 H), 2.28 (t, J = 6.6

Hz, 2 H), 2.35 (br. s, 1 H), 3.58 (t, J = 6.3 Hz, 2 H), 3.66 (qd, J = 3.6, 11.4 Hz, 2 H), 4.12 (q,

13 J = 6.9 Hz, 2 H). C NMR (75 MHz, CDCl3)  14.3, 17.7, 20.2, 20.7, 32.8, 32.9, 33.2, 50.6,

60.9, 62.3, 64.8, 119.4, 175.9. IR (neat) 3405, 2939, 2872, 1719, 1457, 1425, 1371, 1297,

-1 + 1217, 1183, 1112, 1042, 935, 859, 814, 776, 736 cm . HRMS calcd for C13H24NO4 (M + H)

258.1700, found 258.1699.

Ethyl 6-acetoxy-2-(4-hydroxybutyl)-2-(hydroxymethyl)hexanoate (17d). (Table 2.5, entry 11)

Ethyl 3-(4-acetoxybutyl)-2-oxooxepane-3-carboxylate (16d) Rf (1/1 EtOAc/hexanes) =

1 0.72. H NMR (300 MHz, CDCl3)  1.25 (t, J = 7.2 Hz, 3 H), 1.35-1.93 (m, 11 H), 1.97 (s, 3

H), 2.08 (dt, J = 3.6, 14.7 Hz, 1 H), 3.87-4.02 (m, 3 H), 4.13-4.22 (m, 3 H). 13C NMR (75

MHz, CDCl3)  14.2, 21.0, 21.9, 24.5, 28.2, 28.8, 32.1, 39.8, 57.3, 61.6, 64.1, 68.6, 170.9,

171.2, 172.2. IR (neat) 2939, 1721, 1456, 1389, 1368, 1231, 1165, 1096, 1039, 914, 853, 745,

-1 + 619 cm . HRMS calcd for C15H25O6 (M + H) 301.1646, found 301.1638. According to the general procedure C, the reaction of 16d (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL,

0.080 M) and H2O (0.36 mL, 200 equiv) for 1 h at room temperature afforded after purification by chromatography (100% EtOAc) the title compound as a colourless oil. Yield

1 95%. Rf (100% EtOAc) = 0.29. H NMR (300 MHz, CDCl3)  1.21 (t, J = 7.2 Hz, 3 H), 1.06-

148

Malcolm Spain PhD Thesis 1.38 (m, 4 H), 1.42-1.61 (m, 8 H), 1.71 (br. s, 1 H), 1.98 (s, 3 H), 2.44 (br. s, 1 H), 3.58 (t, J =

6.3 Hz, 2 H), 3.59-3.66 (m, 2 H), 3.99 (t, J = 6.6 Hz, 2 H), 4.11 (q, J = 6.9 Hz, 2 H). 13C

NMR (75 MHz, CDCl3)  14.3, 20.2, 20.6, 21.0, 29.1, 32.9, 33.0, 33.2, 50.8, 60.6, 62.3, 64.1,

64.7, 171.3, 176.5. IR (neat) 3456, 2942, 2969, 1737, 1436, 1365, 1228, 1216, 1043, 912, 743

-1 + cm . HRMS calcd for C15H29O6 (M + H) 305.1959, found 305.1955.

Ethyl 6-hydroxy-2-(hydroxymethyl)-2-(4-phenylbutyl)hexanoate (17e). (Table 2.5, entry 12)

Ethyl 2-oxo-3-(4-phenylbutyl)oxepane-3-carboxylate (16e). Rf (30% EtOAc/hexanes) =

1 0.59. H NMR (300 MHz, CDCl3)  1.18 (t, J = 7.2 Hz, 3 H), 1.04-2.09 (m, 12 H), 2.53 (dd, J

= 6.9, 8.4 Hz, 2 H), 3.81-4.10 (m, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 7.02-7.21 (m, 5 H). 13C

NMR (75 MHz, CDCl3)  14.1, 24.2, 24.4, 28.2, 31.7, 32.1, 35.6, 40.0, 57.3, 61.5, 68.5,

125.7, 128.3, 128.4, 142.4, 170.9, 172.4. IR (neat) 2933, 1719, 1454, 1213, 1162, 1019, 912,

-1 + 730, 699 cm . HRMS calcd for C19H27O4 (M + H) 319.1904, found 319.1902. According to the general procedure C, the reaction of 16e (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 1 h at room temperature afforded after purification by chromatography (100% EtOAc) the title compound as a colourless oil. Yield

1 99%. Rf (100% EtOAc) = 0.71. H NMR (300 MHz, CDCl3)  1.17 (t, J = 7.2 Hz, 3 H), 1.06-

1.34 (m, 4 H), 1.42-1.64 (m, 8 H), 1.82 (br. s, 2 H), 2.53 (t, J = 7.5 Hz, 2 H), 3.57 (t, J = 6.3

Hz, 2 H), 3.57-3.66 (m, 2 H), 4.08 (q, J = 7.2 Hz, 2 H), 7.06-7.13 (m, 3 H), 7.16-7.24 (m, 2

13 H). C NMR (75 MHz, CDCl3)  14.2, 20.2, 23.7, 31.9, 32.9, 33.0, 33.5, 35.7, 50.8, 60.6,

62.4, 64.9, 125.7, 128.3, 128.4, 142.4, 176.8. IR (neat) 3368, 2935, 1715, 1455, 1369, 1296,

149

Malcolm Spain PhD Thesis -1 + 1216, 1176, 1041, 745, 699 cm . HRMS calcd for C19H30O4Na (M + Na) 345.2037, found

345.2027.

Ethyl 2-(2-hydroxyethyl)-2-(hydroxymethyl)hex-5-enoate (19a). (Table 2.5, entry 13)

Ethyl 3-(but-3-en-1-yl)-2-oxotetrahydrofuran-3-carboxylate (18a). Rf (1/4

1 EtOAc/hexanes) = 0.55. H NMR (400 MHz, CDCl3)  1.27 (t, J = 7.2 Hz, 3 H), 1.76-1.83

(m, 1 H), 1.93-2.03 (m, 1 H), 2.05-2.22 (m, 3 H), 2.66-2.72 (m, 1 H), 4.11-4.21 (m, 2 H),

13 4.25-4.29 (m, 2 H), 4.91-5.02 (m, 2 H), 5.67-5.77 (m, 1 H). C NMR (100 MHz, CDCl3) 

14.0, 29.0, 31.8, 33.2, 53.9, 62.2, 66.2, 115.6, 136.8, 169.4, 174.7. IR (neat) 2981, 1771,

-1 1726, 1449, 1376, 1260, 1209, 1164, 1027, 912, 728, 649 cm . HRMS calcd for C11H17O4

(M+ + H) 213.1122, found 213.1125 According to the general procedure C, the reaction of

18a (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 3 h at room temperature afforded after purification by chromatography (1/1 hexanes/EtOAc-100% EtOAc) the title compound as a colourless oil. Yield 79%. Rf (100%

1 EtOAc) = 0.55. H NMR (300 MHz, CDCl3)  1.30 (t, J = 6.9 Hz, 3 H), 1.62-1.70 (m, 2 H),

1.76-1.85 (m, 1 H), 1.91-2.04 (m, 2 H), 2.09-2.17 (m, 1 H), 3.10 (br. s, 2 H), 3.62 (d, J = 11.7

Hz, 1 H), 3.67-3.79 (m, 2 H), 3.97 (d, J = 11.7 Hz, 1 H), 4.21 (q, J = 7.2 Hz, 2 H), 4.94-5.07

13 (m, 2 H), 5.70-5.84 (m, 1 H). C NMR (75 MHz, CDCl3)  14.2, 28.6, 34.8, 38.1, 50.4, 59.3,

60.8, 65.8, 115.0, 137.8, 176.0. IR (neat) 3374, 2932, 1721, 1640, 1447, 1369, 1201, 1133,

-1 + 1041, 912, 860, 740 cm . HRMS calcd for C11H20O4Na (M + Na) 239.1254, found

239.1264.

150

Malcolm Spain PhD Thesis Ethyl 2-(hydroxymethyl)-2-(3-hydroxypropyl)hex-5-enoate (19b). (Table 2.5, entry 14)

Ethyl 3-(but-3-en-1-yl)-2-oxotetrahydro-2H-pyran-3-carboxylate (18b) Rf (1/4

1 EtOAc/hexanes) = 0.30. H NMR (300 MHz, CDCl3)  1.22 (t, J = 7.2 Hz, 3 H), 1.68-2.18

(m, 7 H), 2.27-2.42 (m, 1 H), 4.16 (q, J = 7.2 Hz, 2 H), 4.19-4.27 (m, 2 H), 4.84-5.03 (m, 2

13 H), 5.64-5.79 (m, 1 H). C NMR (75 MHz, CDCl3)  14.1, 20.7, 28.2, 28.8, 35.6, 53.9, 62.1,

68.6, 115.3, 137.4, 170.2, 171.3. Spectroscopic data matched literature values.48 According to the general procedure C, the reaction of 18b (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 3 h at room temperature afforded after purification by chromatography (1/1 hexanes/EtOAc-100% EtOAc) the title compound as a

1 colourless oil. Yield 87%. Rf (100% EtOAc) = 0.56. H NMR (300 MHz, CDCl3)  1.21 (t, J

= 7.2 Hz, 3 H), 1.36-1.74 (m, 7 H), 1.85-2.02 (m, 2 H), 2.35 (br. s, 1 H), 3.57 (t, J = 6.0 Hz, 2

H), 3.58-3.71 (m, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 4.89-4.99 (m, 2 H), 5.64-5.77 (m, 1 H). 13C

NMR (75 MHz, CDCl3)  14.3, 27.2, 28.5, 29.5, 33.0, 50.4, 60.7, 63.1, 64.8, 114.8, 138.1,

176.4. IR (neat) 3377, 2941, 1723, 1643, 1449, 1374, 1204, 1134, 1054, 911, 864, 746 cm-1.

+ HRMS calcd for C12H22O4Na (M + Na) 253.1411, found 253.1407.

151

Malcolm Spain PhD Thesis Ethyl 2-(4-hydroxybutyl)-2-(hydroxymethyl)hex-5-enoate (19c). (Table 2.5, entry 15)

Ethyl 3-(but-3-en-1-yl)-2-oxooxepane-3-carboxylate (18c). Rf (1/4 EtOAc/hexanes) =

1 0.52. H NMR (500 MHz, CDCl3)  1.25 (t, J = 7.0 Hz, 3 H), 1.50-1.58 (m, 1 H), 1.60-1.69

(m, 1 H), 1.74-1.82 (m, 4 H), 1.92-2.03 (m, 2 H), 2.06-2.17 (m, 2 H), 3.93 (t, J = 12.0 Hz, 1

H), 4.16-4.21 (m, 1 H), 4.20 (q, J = 7.5 Hz, 2 H), 4.87-4.99 (m, 2 H), 5.68-5.76 (m, 1 H). 13C

NMR (75 MHz, CDCl3)  14.2, 24.5, 28.2, 29.0, 32.2, 39.3, 57.2, 61.6, 68.6, 115.0, 137.7,

170.8, 172.2. IR (neat) 2939, 1716, 1448, 1446, 1389, 1359, 1285, 1236, 1167, 1071, 1031,

-1 + 911, 649 cm . HRMS calcd for C13H21O4 (M + H) 241.1435, found 241.1434. According to the general procedure B, the reaction of 18c (0.10 mmol), SmI2 (0.80 mmol, 8 equiv, 10.0 mL, 0.080 M) and H2O (0.36 mL, 200 equiv) for 5 h at room temperature afforded after purification by chromatography (1/1 hexanes/EtOAc-100% EtOAc) the title compound as a

1 colourless oil. Yield 88%. Rf (100% EtOAc) = 0.62. H NMR (300 MHz, CDCl3)  1.21 (t, J

= 7.2 Hz, 3 H), 1.14-1.38 (m, 2 H), 1.44-1.67 (m, 6 H), 1.75 (br. s, 1 H), 1.84-2.01 (m, 2 H),

2.47 (br. s, 1 H), 3.58 (t, J = 6.3 Hz, 2 H), 3.58-3.71 (m, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 4.86-

13 4.99 (m, 2 H), 5.64-5.78 (m, 1 H). C NMR (75 MHz, CDCl3)  14.3, 20.1, 28.6, 32.9, 32.9,

33.0, 50.6, 60.6, 62.3, 64.7, 114.7, 138.2, 176.5. IR (neat) 3364, 2936, 2868, 1709, 1636,

-1 + 1451, 1367, 1206, 1131, 1032, 908 866, 793 cm . HRMS calcd for C13H24O4Na (M + Na)

267.1567, found 267.1574.

152

Malcolm Spain PhD Thesis Mechanistic experiments

Ethyl 5-hydroxy-2-(hydroxymethyl-d2)pentanoate (22). (Scheme 2.2)

According to the general procedure B, the reaction of 14b (0.10 mmol), SmI2 (0.60 mmol, 6 equiv, 10.0 mL, 0.060 M) and D2O (0.36 mL, 200 equiv) for 1 h at room temperature afforded after purification by chromatography (1/1 EtOAc/hexanes) the title compound as a colourless oil. Yield 79%, 96.0% D2 incorporation. Mixture of diastereoisomers, stereochemistry not assigned. Dr = 52:48. 48.0% D1 at the acidic position. Note that the title compound is unstable and undergoes closure to 3-D2-3-(hydroxy)methyl-6-pentyltetrahydro-

2H-pyran-2-one during purification. 3-D2-3-(hydroxy)methyl-6-pentyltetrahydro-2H-pyran-

1 2-one: H NMR (500 MHz, CDCl3)  (mixture of diastereoisomers0.83 (t, J = 7.0 Hz, 3 H),

1.17-1.35 (m, 5 H), 1.38-1.68 (m, 5 H), 1.85-1.96 (m, 2 H), 2.45-2.50 (m, 0.5 H, major, ca.

50% exchange to D), 2.58-2.62 (m, 0.5 H, minor, ca. 50% exchange to D), 2.74 (br. s, 1 H),

13 3.63-3.72 (m, 0.08 H), 4.19-4.26 (m, 1 H). C NMR (75 MHz, CDCl3)  (mixture of diastereoisomers14.0, 14.0, 19.4, 22.5, 22.5, 22.7, 24.5, 24.8, 26.8, 28.6, 31.6, 31.6, 35.0,

36.1, 40.2, 43.3, 61.7 (t, J1 = 23.5 Hz), 78.6, 82.1, 174.2, 176.1 IR (neat) 3447, 2930, 2860,

1716, 1558, 1540, 1507, 1457, 1373, 1274, 1197, 113, 1073, 973 cm-1. HRMS calcd for

+ C11H19D1O3 (M –C2H5OH + H) 203.1611, found 203.1616.

153

Malcolm Spain PhD Thesis Kinetic isotope effect (Scheme 2.2)

According to modification of the general procedure B, the reaction of 14b (0.05 mmol), was added to a preformed solution of SmI2 (0.30 mmol, 6 equiv, 4.1 mL, 0.074 M) and deuterium oxide/water (1:1, 200 equiv) for 15 min at room temperature to afford ethyl 5-hydroxy-2-

(hydroxymethyl)decanoate (15b), ethyl 2-hydroxytetrahydro-2H-pyran-3-carboxylate-2-d and ethyl 5-hydroxy-2-(hydroxymethyl-d2)pentanoate (22) (>95% conversion). The amount of

1 each species was determined by H NMR (500 MHz, CDCl3,). Kinetic isotope effect, kH/kD =

1.08±0.1 (lactol) and kH/kD = 1.24±0.1 (diol).

General procedure C for the reductive cyclisation of lactones using SmI2–H2O.

An oven-dried vial containing a stir bar was charged with lactone (1 equiv), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. The lactone was dissolved in THF (typically, 2.0 mL) and water (typically, 1200 equiv) was added. Samarium(II) iodide (THF solution, typically 8 equiv) was added via syringe pump over 1 h under inert atmosphere at room temperature with vigorous stirring.

When the addition was complete, the excess of SmI2 was oxidised by bubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2 (30 mL) and HCl (1 N,

30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were

1 combined, dried over Na2SO4, filtered, and concentrated. The sample was analyzed by H

NMR (CDCl3) and/or GC-MS (neat) to determine the product distribution, diastereoselectivity, and yield using internal standard and comparison with authentic samples.

The crude product was purified by chromatography on silica gel. All compounds have been prepared as racemates.

154

Malcolm Spain PhD Thesis (1R,2S,3S)-Ethyl 2-hydroxy-1-(2-hydroxyethyl)-3-methylcyclopentanecarboxylate (30a). (Table 2.7, entry 1)

According to the general procedure C, the reaction of 18a (0.10 mmol), SmI2 (0.60 mmol, 6 equiv, 9.5 mL, 0.063 M) and H2O (2.16 mL, 1200 equiv) for 1 h at room temperature afforded after purification by chromatography (4/1-1/1 hexanes/EtOAc) the title compound as a colourless oil. Yield 53%, 77% based on unreacted lactone, 66% conv. Rf (EtOAc) = 0.63.

Diol:cyclisation product = 13:87. Dr = 91:9 (major:rest). Stereochemistry of the major

1 diastereoisomer was determined by 2 D NMR experiments. H NMR (300 MHz, CDCl3) 

(major diastereoisomer) 0.98 (d, J = 6.6 Hz, 3 H), 1.19 (t, J = 7.2 Hz, 3 H), 1.29-1.43 (m, 1

H), 1.58-1.75 (m, 2 H), 1.85-2.22 (m, 5 H), 2.62 (br. s, 1 H), 3.56-3.71 (m, 2 H), 4.07 (q, J =

13 7.2 Hz, 2 H), 4.22 (d, J = 3.9 Hz, 1 H). C NMR (75 MHz, CDCl3)  (major diastereoisomer)

14.2, 14.2, 29.4, 34.0, 36.6, 38.4, 58.7, 60.3, 60.7, 78.2, 176.7. IR (neat) 3389, 2955, 2927,

-1 + 1718, 1457, 1367, 1239, 1195, 1094, 1029, 992, 863 cm . HRMS calcd for C11H20O4Na (M

+ Na) 239.1254, found 239.1248.

155

Malcolm Spain PhD Thesis (1R,2S,3S)-Ethyl 2-hydroxy-1-(3-hydroxypropyl)-3-methylcyclopentanecarboxylate (30b). (Table 2.7, entry 2)

According to the general procedure C, the reaction of 18b (0.10 mmol), SmI2 (0.70 mmol, 7 equiv, 17.5 mL, 0.040 M) and H2O (2.16 mL, 1200 equiv) for 1 h at room temperature afforded after purification by chromatography (1/1 hexanes/EtOAc-100% EtOAc) the title compound as a colourless oil. Yield 88%. Rf (1/1 hexanes/EtOAc) = 0.29. Dr (crude) = 93:7.

Dr (purified) = 92:8. Diol:cyclised <5:95. Stereochemistry of the major diastereoisomer was

1 determined by 2 D NMR experiments. H NMR (300 MHz, CDCl3)  (major diastereoisomer) 0.97 (d, J = 6.6 Hz, 3 H), 1.19 (t, J = 7.2 Hz, 3 H), 1.24-2.02 (m, 10 H),

2.15-2.26 (m, 1 H), 3.49-3.65 (m, 2 H), 4.07 (q, J = 7.2 Hz, 2 H), 4.13 (d, J = 4.2 Hz, 1 H).

13 C NMR (75 MHz, CDCl3)  (major diastereoisomer) 14.2, 14.2, 28.8, 29.3, 29.9, 32.5, 38.1,

59.6, 60.6, 62.8, 78.7, 176.5. IR (neat) 3375, 2936, 2873, 1721, 1465, 1450, 1370, 1329,

-1 + 1237, 1187, 1102, 1059, 1029, 969, 913, 861 cm . HRMS calcd for C12H22O4Na (M + Na)

253.1411, found 253.1408.

156

Malcolm Spain PhD Thesis (1S,2S,3S)-Ethyl 2-hydroxy-1-(4-hydroxybutyl)-3-methylcyclopentanecarboxylate (30c). (Table 2.7, entry 3)

According to the general procedure C, the reaction of 18c (0.10 mmol), SmI2 (0.60 mmol, 6 equiv, 9.1 mL, 0.066 M) and H2O (2.16 mL, 1200 equiv) for 1 h at room temperature afforded after purification by chromatography (10/1-1/1 hexanes/EtOAc) the title compound as a colourless oil with >95% purity. Rf (1/1 hexanes/EtOAc) = 0.40. Yield 88%, Dr = 64:36

(determined by 1H NMR analysis vs. internal standard). Diol:cyclised <5:95. Stereochemistry of the major diastereoisomer was determined by 2 D NMR experiments. 1H-NMR (300 MHz,

CDCl3)  (mixture of diastereoisomers) 0.95 (d, J = 6.9 Hz, 3 H, major), 1.00 (d, J = 6.3 Hz,

3 H), 1.18 (t, J = 7.2 Hz, 3 H), 1.06-2.02 (m, 12 H), 2.03-2.24 (m, 1 H), 3.52-3.61 (m, 2 H),

13 4.07 (q, J = 7.2 Hz, 2 H), 4.08-4.12 (m, 1 H). C NMR (75 MHz, CDCl3)  (mixture of diastereoisomers) 14.2, 14.2, 14.3, 18.3, 21.0, 21.9, 28.4, 29.3, 29.7, 31.7, 32.0, 32.6, 33.1,

33.5, 37.9, 38.8, 55.6, 59.8, 60.5, 60.6, 62.4, 62.6, 79.0, 83.8, 176.6, 177.2. IR (neat) 3393,

2943, 2872, 1705, 1459, 1391, 1368, 1325, 1294, 1242, 1186, 1098, 1031, 1003, 974 cm-1.

+ HRMS calcd for C13H24O4Na (M + Na) 267.1567, found 267.1560. The title compound has been fully characterised after oxidation of the crude reaction mixture after standard work-up

(a separate run using 0.10 mmol of 18c, SmI2 (0.80 mmol, 8 equiv, 8.0 mL, 0.10 M) and H2O

(2.16 mL, 1200 equiv)) using DMP (5 equiv) in CH2Cl2 (10 mL) for 1 h at room temperature to give (1S,3S)-ethyl 3-methyl-2-oxo-1-(4-oxobutyl)cyclopentanecarboxylate (30c-[O]).

Purification by chromatography afforded the title compound as a colourless oil. Rf (1/1

157

Malcolm Spain PhD Thesis 1 hexanes/EtOAc) = 0.78. Yield 92% (2 steps), Dr = 66:34. H NMR (300 MHz, CDCl3) 

(mixture of diastereoisomers) 1.05 (d, J = 7.2 Hz, 3 H, major), 1.09 (d, J = 6.6 Hz, 3 H, minor), 1.18 (t, J = 7.2 Hz, 3 H), 1.35-1.69 (m, 5 H), 1.70-1.86 (m, 1 H), 1.88-2.01 (m, 1 H),

2.09-2.24 (m, 1 H), 2.32-2.43 (m, 3 H), 4.08 (q, J = 7.2 Hz, 2 H), 9.69 (t, J = 1.5 Hz, 1 H).

13 C NMR (75 MHz, CDCl3)  (major diastereoisomer) 14.1, 14.5, 17.5, 28.1, 30.3, 32.8, 43.7,

43.9, 59.8, 61.4, 171.4, 201.7, 215.9;  (minor, diagnostic peaks only) 15.0, 17.4, 29.0, 31.2,

34.0, 43.9, 44.2, 60.2, 61.4, 171.1, 201.7, 216.6. IR (neat) 3018, 1757, 1736, 1435, 1369,

-1 + 1230, 1214, 1144, 1019 cm . HRMS calcd for C13H20O4Na (M + Na) 263.1254, found

263.1267.

General Procedure D for the determination of the reduction rate of acyl-type radicals using SmI2–H2O. An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum.

Samarium(II) iodide (THF solution, 0.30 mmol, 6.0 equiv, 0.060 M) was added followed by

H2O (1.44 mL, 1600 equiv) with vigorous stirring, which resulted in the formation of a characteristic burgundy-red colour of the SmI2+ n H2O complex (n > 5 with respect to SmI2).

A preformed solution of the substrate 18 (0.05 mmol, 1.0 equiv, stock solution in THF, 1.0 mL, as specified in Table 2.8) was added rapidly and the reaction mixture was stirred for 30 min. The reaction mixture was quenched by bubbling air through the reaction mixture, diluted with CH2Cl2 (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with

CH2Cl2 (3 x 30 mL), and the organic layers were combined, dried over Na2SO4, filtered, and

1 concentrated. The sample was analyzed by H NMR (CDCl3, 500 MHz) to obtain conversion and yield using internal standard and comparison with authentic samples of 19 and 30 and the

-1 rate constant calculated according to kSmI2 (2nd ET) = (19/30) x k5-exo x [SmI2] .

158

Malcolm Spain PhD Thesis

Chapter 2.3 Mechanistic studies of lactone reduction using SmI2–H2O

Reaction profiles for the reduction of 1 using SmI2 (THF solution). An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide (THF solution) (6.0 mmol, 6 equiv) was added followed by H2O (as specified in Table 2.9) with vigorous stirring, which resulted in the formation of a characteristic burgundy-red colour of the SmI2 + n H2O complex (n > 5 with respect to SmI2). A solution of the 1 (0.1 mmol, stock solution in THF, 1 mL) was added and the reaction mixture was vigorously stirred under argon. Small aliquots

(typically, 0.25 mL) were removed from the reaction mixture at set time intervals (1, 2, 3, 4,

5 and 60 min, 1 hour point taken), immediately quenched by bubbling air through the reaction mixture, diluted with diethyl ether (2.0 mL) and HCl (0.1 N, 0.25 mL), and analyzed by GC (Method A) and GC-MS (to determine product distribution, method A) to obtain yield and product distribution using internal standard and comparison with authentic samples. After

18h, the reaction mixture was quenched by bubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2 (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were combined, dried over

1 Na2SO4, filtered, and concentrated. The sample was analyzed by H NMR (CDCl3, 500 MHz) to obtain conversion using internal standard and comparison with authentic samples. GC-MS

(Method A): Product: 10.416 min (decane-1,5-diol), starting material: 10.674 min (5- decanolide), standard: 10.178 min (1,3,5-trimethoxybenzene).

General procedure D for kinetic measurements using SmI2–H2O.

An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide

(THF solution, 0.085 M) was added followed by H2O with vigorous stirring, which resulted in the formation of a characteristic burgundy-red colour of the SmI2 + n H2O complex (n > 5

159

Malcolm Spain PhD Thesis with respect to SmI2). A solution of the 1 (stock solution in THF) was added and the reaction mixture was vigorously stirred under argon. Small aliquots (typically, 0.25 mL) were removed from the reaction mixture at 2.5, 5, 7.5, 10, 12.5 and 15 min, immediately quenched by bubbling air through the reaction mixture, diluted with diethyl ether (2.0 mL) and HCl (0.1

N, 0.25 mL), and analyzed by GC (Method A) and/or GC-MS (Method A) to obtain yield and product distribution using internal standard and comparison with authentic samples. The initial rates at various concentrations were converted into graphs to determine the rate order by plotting the natural logarithm of the rate vs. the natural logarithm of the concentration.

Figure 7.1. Determination of lactone rate order in the reduction of 5-decanolide using SmI2–

H2O.

According to the general procedure D, conditions: SmI2 (6.0 equiv), H2O (100 equiv), lactone

(0.5, 1.0, 1.5 equiv).

160

Malcolm Spain PhD Thesis Figure 7.2 Determination of samarium(II) iodide rate order in the reduction of 5-decanolide 1 using SmI2–H2O.

According to the general procedure D, conditions: SmI2 (5.0, 6.0, 7.0 equiv), H2O (100 equiv), lactone (1.0 equiv).

161

Malcolm Spain PhD Thesis Figure 7.3. Determination of rate order of water in the reduction of 5-decanolide 1 using

SmI2–H2O.

According to the general procedure D, conditions: lactone (1.0 equiv), SmI2 (6.0 equiv), H2O

(50-800 equiv).

General procedure E for the determination of acyl-type radical stability.

An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide

(THF solution) was added followed by H2O with vigorous stirring, which resulted in the formation of a characteristic burgundy-red colour of the SmI2 + n H2O complex (n > 5 with respect to SmI2). For reactions involving SmI2–amine–H2O system, Sm(II) reagent was preformed by adding amine, followed by H2O to SmI2 solution in THF under argon. A solution of the ester substrate (stock solution in THF) was added and the reaction mixture was vigorously stirred under argon. After indicated time, the reaction mixture was rapidly

162

Malcolm Spain PhD Thesis quenched by bubbling air though the reaction mixture. The reaction mixture was diluted with

CH2Cl2 (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The

1 sample was analyzed by H NMR (CDCl3, 500 MHz) and/or GC-MS to obtain conversion and yield using internal standard and comparison with authentic samples.

Effect of concentration of water on the rate of reduction of acyl-type radicals derived from lactone 18b. (Table 2.11)

According to the general procedure E, the reaction of lactone 18b (1 equiv), SmI2 (12 equiv) and H2O (0-6400 equiv, as specified in Table 2.11) at room temperature for 15 min - 3 hours.

After work-up the ratio of 19b and 30b was determined by 1H NMR using an internal standard and comparison with authentic samples. The rate was approximated using: kSmI2 =

-1 (19b/30b) x k5-exo x [SmI2] .

Effect of concentration of water on the stability of acyl-type radicals derived from lactone 34. (Table 2.12)

1 rac-(1S,3R,4R)-3-benzyl-1-methylcycloheptane-1,4-diol (35a) H NMR (400 MHz, CDCl3)

(mixture of diastereoisomers) δ 0.93 (d, J 6.8), 1.03 (d, J 7.1, 3H), 1.20-1.26 (m, 1H), 1.29 (s,

3H), 1.32 (s, 3H), 1.34-1.35 (m, 1H), 1.35-1.43 (m, 1H), 1.40-1.45 (m, 2H), 1.51-1.60 (m,

163

Malcolm Spain PhD Thesis 1H), 1.63-1.69 (m, 2H), 1.72-1.76 (m, 2H), 1.85-1.88 (m, 2H), 1.97-2.02 (m, 1H), 2.05-2.13

13 (m, 2H), 2.12-2.19 (m, 1H); C NMR (100 MHz, CDCl3) δ 13.0, 17.4, 18.7, 18.8, 27.2, 30.3,

30.9, 35.4, 35.7, 38.5, 41.5, 43.4, 44.3, 65.8, 79.2, 104.1, 105.1. 5-methyloct-7-ene-1,5-diol

1 (36a) H NMR (400 MHz, CDCl3) δ 1.18 (s, 3 H), 1.40-1.52 (m, 4 H), 1.58 ( q, J = 6.3 Hz,

2H), 2.23 (d, J = 7.3 Hz, 2H), 3.66 (t, J = 6.3 Hz, 2H), 5.09-5.16 (m, 2H), 5.86 (ddt, J = 16.9,

13 10.1, 7.3 Hz, 1H); C NMR (100 MHz, CDCl3) δ 20.0, 26.7, 33.0, 41.3, 46.3, 62.7, 72.2,

1 118.8, 134.0. 35b H NMR (400 MHz, CDCl3) 1.22 (s, 3H), 1.27-1.34 (m, 1H), 1.42 (dd, J =

12.9, 7.6 Hz, 1H), 1.54-1.62 (m, 1H), 1.64-1.67 (m, 1H), 1.68-1.77 (m, 3H), 1.80-1.91 (m,

1H), 2.24-2.31 (m, 1H), 2.58 (t, 1H, J = 13.4 Hz), 2.87 (dd, J 13.4 3.8 Hz, 1H, from major diastereoisomer) 3.06 (dd, J 12.6 3.3Hz from minor diastereoisomer), 7.11-7.24 (m, 5H); 13C

NMR (100 MHz, CDCl3) 18.9, 27.2, 31.4, 34.8, 35.6, 39.4, 50.7, 79.4, 104.6, 126.0, 128.4,

129.1, 140.9. According to the general procedure E, the reaction of lactone 34 (1 equiv), SmI2

(12 equiv), H2O (as specified in Table 2.12) at room temperature for 30 – 120 min. After work-up the ratio of 35 and 36 was determined by 1H NMR using an internal standard and comparison with authentic samples. The rate was approximated using: kSmI2 = (36/35) x k5-exo

-1 x [SmI2] .

164

Malcolm Spain PhD Thesis Effect of concentration of water on the stability of acyl-type radicals derived from lactone 37. (Table 2.13)

According to the general procedure E, the reaction of lactone 37 (1 equiv), SmI2 (8 equiv),

H2O (as specified in Table 2.13) at room temperature for 1-5 h. After work-up, the sample

1 was analyzed by H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion and yield using internal standard to determine the conversion and ratio of 38 to 39 by comparison with authentic samples.

Radical clock experiments in the reduction of 46. (Table 2.14)

6-Hexyl-1-phenyl-5-oxaspiro[2.4]heptan-4-one (46a). Single diastereoisomer, dr > 95:5,

1 stereochemistry not assigned. H NMR (500 MHz, CDCl3)  0.80 (t, J = 7.0 Hz, 3 H), 1.13-

1.28 (m, 7 H), 1.31-1.41 (m, 2 H), 1.48-1.55 (m, 1 H), 1.64-1.71 (m, 1 H), 1.73-1.78 (m, 2

H), 1.84 (dd, J = 7.5, 13.0 Hz, 1 H), 2.65 (dd, J = 7.0, 9.5 Hz, 1 H), 4.30-4.36 (m, 1 H), 7.04

(dd, J = 1.0, 7.0 Hz, 2 H), 7.19 (tt, J = 1.0, 8.0 Hz, 1 H), 7.27 (t, J = 7.5 Hz, 2 H); 13C NMR

(125 MHz, CDCl3)  14.1, 17.9, 22.5, 25.0, 28.4, 29.0, 31.4, 31.4, 31.7, 36.3, 78.5, 127.1,

128.1, 128.6, 136.1, 179.2. IR (neat) 2926, 2856, 1760, 1456, 1283, 1352, 1282, 1238, 1201,

-1 + 1177, 1119, 1090, 1004, 923, 875 cm . HRMS calcd for C18H25O2 (M + H) 273.1849 found

273.1848. 6-Pentyl-1-phenyl-5-oxaspiro[2.5]octan-4-one (46b). Mixture of

165

Malcolm Spain PhD Thesis 1 diastereoisomers, dr = 83:17, stereochemistry not assigned. H NMR (500 MHz, C6D6)  0.74

(t, J = 7.5 Hz, 3 H, major), 0.75 (t, J = 7.5 Hz, 3 H, minor), 0.88-1.14 (m, 10 H), 1.15-1.27

(m, 2 H), 1.31-1.39 (m, 1 H), 1.69 (dd, J = 4.5, 9.5 Hz, 1 H, minor), 1.83 (dd, J = 4.5, 9.5, 1

H, major), 2.82 (dd, J = 7.5, 8.5 Hz, 1 H, major), 2.96 (dd, J = 7.0, 9.0 Hz, 1 H, minor), 3.68-

3.74 (m, 1 H, minor), 3.74-3.81 (m, 1 H, major), 6.77 (d, J = 7.0 Hz, 2 H, major), 6.80 (d, J =

13 7.0 Hz, 2 H, minor), 6.91-7.03 (m, 3 H); C NMR (75 MHz, C6D6) (major)  14.2, 19.2,

22.9, 23.3, 25.0, 25.9, 28.4, 31.9, 35.3, 36.3, 80.7, 127.1, 128.5, 129.5, 136.4, 173.3; (minor, diagnostic peaks) 14.2, 19.2, 22.8, 24.6, 25.2, 25.6, 28.5, 31.8, 32.8, 36.1, 80.5, 127.0,

128.3, 129.3, 136.8, 172.8. IR (neat) 3028, 2929, 2859, 1717, 1456, 1299, 1262, 1216, 1198,

-1 + 1146, 1006, 932, 909, 811, 763 cm . HRMS calcd for C18H24O2Na (M + Na) 295.1669 found 295.1662. Note: the title compound is unstable. The title compound was contaminated with an inseparable impurity that could not be removed by all standard chromatographic methods. 5-Hexyl-3-phenethyldihydrofuran-2(3H)-one (47a). Mixture of diastereoisomers,

1 dr = 74:26, stereochemistry not assigned. H NMR (400 MHz, CDCl3)  0.82 (t, J = 7.5 Hz, 3

H), 1.16-1.54 (m, 10 H), 1.58-1.75 (m, 2 H), 1.99 (dd, J = 8.0, 10.5 Hz, 1 H, minor), 2.07-

2.14 (m, 1 H, minor), 2.15-2.25 (m, 1 H, major), 2.33-2.40 (m, 1 H, major), 2.44-2.54 (m, 1

H), 2.57-2.76 (m, 2 H), 4.20-4.28 (m, 1 H, major), 4.40-4.47 (m, 1 H, minor), 7.11-7.16 (m, 2

13 H), 7.20-7.25 (m, 3 H); C NMR (75 MHz, CDCl3) (major)  14.1, 22.5, 25.3, 29.0, 31.7,

32.0, 33.5, 35.4, 35.6, 40.2, 78.9, 126.2, 128.4, 128.5, 140.9, 178.8; (major, diagnostic peaks)

 14.1, 22.5, 25.3, 29.0, 32.6, 33.4, 33.6, 35.4, 35.6, 38.6, 78.8, 126.2, 128.5, 128.5, 140.8,

179.2. IR (neat) 3026, 2925, 2854, 1743, 1456, 1365, 1204, 996, 912 cm-1. HRMS calcd for

+ C18H26O2Na (M + Na) 297.1826 found 297.1839. 6-Pentyl-3-phenethyltetrahydro-2H- pyran-2-one (47b). Mixture of diastereoisomers, dr = 55:45, stereochemistry not assigned.

1 H NMR (500 MHz, CDCl3)  0.82 (t, J = 7.0 Hz, 3 H), 1.17-1.56 (m, 9 H), 1.58-1.68 (m, 1.5

H), 1.74-1.89 (m, 1.5 H), 1.98-2.06 (m, 1 H), 2.13-2.39 (m, 2 H), 2.57-2.73 (m, 2 H), 4.12-

13 4.23 (m, 1 H), 7.10-7.16 (m, 3 H), 7.19-7.24 (m 2 H); C NMR (100 MHz, CDCl3)  14.0,

166

Malcolm Spain PhD Thesis 14.0, 22.6, 23.5, 24.5, 24.8, 25.7, 25.7, 26.8, 28.9, 31.6, 31.6, 32.4, 32.8, 33.0, 33.6, 35.3,

36.2, 37.2, 40.1, 78.0, 81.4, 126.0, 126.0, 128.5, 128.5, 141.3, 141.5, 173.8, 175.7. IR (neat)

-1 + 3027, 2929, 2859, 1733, 1456, 1373, 1183, 935 cm . HRMS calcd for C18H26O2Na (M +

Na) 297.1826 found 297.1820. 2-Phenethyldecane-1,4-diol (48a). Mixture of

1 diastereoisomers, dr = 79:21, stereochemistry not assigned. H NMR (400 MHz, CDCl3) 

0.82 (t, J = 6.8 Hz, 3 H), 1.18-1.27 (m, 7 H), 1.31-1.43 (m, 4 H), 1.44-1.67 (m, 4 H), 2.37 (br. s, 2 H), 2.58 (t, J = 7.6 Hz, 2 H), 2.43 (dd, J = 7.2, 10.8 Hz, 1 H, major), 3.52-3.59 (m, 1 H, minor), 3.56-3.64 (m, 1 H), 3.67 (dd, J = 3.2, 10.8 Hz, 1 H, major), 3.69-3.77 (m, 1 H,

13 minor), 7.09-7.14 (m, 3 H), 7.19-7.24 (m, 2 H); C NMR (100 MHz, CDCl3) (major)  14.1,

22.6, 25.7, 29.3, 31.8, 33.4, 34.6, 38.7, 39.6, 41.3, 66.8, 71.7, 125.8, 128.3, 128.4, 142.3;

(minor, diagnostic peaks)  14.1, 22.6, 25.9, 33.5, 36.8, 37.9, 39.9, 125.8, 142.4. IR (neat)

-1 + 3302, 2925, 2854, 1456, 1362, 1216, 1030, 913 cm . HRMS calcd for C18H30O2Na (M +

Na) 301.2139 found 301.2129. 2-Phenethyldecane-1,5-diol (48b). Mixture of

1 diastereoisomers, dr = 1:1, stereochemistry not assigned. H NMR (400 MHz, CDCl3)  0.83

(t, J = 6.8 Hz, 3 H), 1.19-1.28 (m, 5 H), 1.32-1.41 (m, 5 H), 1.42-1.66 (m, 7 H), 2.58 (t, J =

7.6 Hz, 2 H), 3.48-3.59 (m, 3 H), 7.09-7.14 (m, 3 H), 7.19-7.24 (m, 2 H); 13C NMR (100

MHz, CDCl3)  14.1, 14.1, 22.7, 22.7, 25.4, 25.4, 26.6, 26.6, 31.9, 31.9, 32.8, 33.0, 33.3,

33.3, 34.1, 34.2, 37.6, 37.6, 39.9, 40.1, 65.1, 65.3, 72.1, 72.4, 125.8, 125.8, 128.3, 128.3,

128.4, 128.4, 142.5, 142.6. IR (neat) 3333, 2926, 2856, 1456, 1216, 1030 cm-1. HRMS calcd

+ for C18H30O2Na (M + Na) 301.2139 found 301.2135. 1-(1-(Hydroxymethyl)-2- phenylcyclopropyl)octan-2-ol (49a). Mixture of diastereoisomers, dr = 80:20,

1 stereochemistry not assigned. H NMR (500 MHz, CDCl3)  0.77 (t, J = 9.0 Hz, 3 H, minor),

0.79 (t, J = 7.0 Hz, 3 H, major), 0.85-0.92 (m, 2 H), 0.93-1.03 (m, 2 H), 1.03-1.29 (m, 9 H),

1.39 (ddd, J = 1.0, 10.0, 15.5 Hz, 1 H), 2.05 (dd, J = 6.0, 8.5 Hz, 1 H, major), 2.11 (dd, J =

6.5, 8.5 Hz, 1 H, minor), 2.58 (br. s, 2 H), 3.26 (d, J = 11.5 Hz, 1 H, major), 3.36 (d, J = 11.5

Hz, 1 H, minor), 3.35-3.42 (m, 1 H, minor), 3.56-3.62 (m, 1 H, major), 3.68 (d, J = 11.5 Hz, 1

167

Malcolm Spain PhD Thesis H, minor), 3.81 (d, J = 11.0 Hz, 1 H, major), 7.05 (d, J = 7.5 Hz, 2 H), 7.11-71.5 (t, J = 7.5

13 Hz, 1 H), 7.22 (t, J = 7.5 Hz, 2 H); C NMR (125 MHz, CDCl3) (major)  13.5, 14.1, 22.6,

25.6, 28.9, 29.2, 29.3, 31.8, 38.1, 38.7, 71.6, 72.1, 126.2, 128.2, 129.1, 138.3; (minor, diagnostic peaks)  14.1, 16.4, 22.5, 25.3, 27.0, 29.0, 31.7, 38.0, 39.4, 70.5, 71.4, 126.0,

128.0, 128.9, 138.3. IR (neat) 3286, 3027, 2928, 2856, 1455, 1366, 1228, 1217, 1206, 1031,

-1 + 908, 733 cm . HRMS calcd for C18H28O2Na (M + Na) 299.1982, found 299.1993. 1-(1-

(Hydroxymethyl)-2-phenylcyclopropyl)octan-3-ol (49b). Mixture of diastereoisomers, dr =

1 91:9, stereochemistry not assigned. H NMR (500 MHz, CDCl3)  0.79 (t, J = 7.0 Hz, 3 H),

0.82-0.90 (m, 2 H), 1.06-1.27 (m, 9 H), 1.27-1.37 (m, 3 H), 1.50 (br. s, 2 H), 2.00 (dd, J =

6.5, 8.5 Hz, 1 H), 3.23-3.28 (m, 1 H), 3.47 (d, J = 11.5 Hz, 1 H), 3.57 (d, J = 11.0 Hz, 1 H),

13 7.10-7.14 (m, 3 H), 7.19-7.23 (m, 2 H); C NMR (125 MHz, CDCl3) (major)  14.0, 14.6,

22.6, 24.7, 25.2, 27.4, 29.5, 31.8, 33.5, 37.1, 69.1, 71.9, 126.0, 128.0, 128.9, 138.5; (minor, diagnostic peaks)  14.0, 14.3, 22.6, 24.6, 25.4, 27.5, 29.3, 31.8, 33.4, 37.4, 68.9, 72.1, 125.9,

128.0, 129.1, 138.6. IR (neat) 3322, 2928, 2858, 1498, 1455, 1376, 1228, 1217, 1205, 1095,

-1 + 1072, 1032, 779 cm . HRMS calcd for C18H28O2Na (M + Na) 299.1982, found 299.1982.

According to the general procedure E, the reaction of lactone 46 (typically 0.1 mmol, 1 equiv, as specified in Table 2.14), SmI2 (2-8 equiv,0.085 M, as specified in Table 2.14), H2O (0-200 equiv, as specified in Table 2.14), Et3N (0-48 equiv, as specified in Table 2.14). After work-

1 up the sample was analyzed by H NMR (CDCl3, 500 MHz) and/or GC-MS to obtain conversion and yield using internal standard and comparison with authentic samples.

168

Malcolm Spain PhD Thesis Control reactions (Scheme 2.6)

According to the general procedure E, SmI2 (THF solution, 0.15 mmol, 6.0 equiv, 0.080 M),

Et3N (0.17 mL, 48 equiv) and H2O (0.022 mL, 48 equiv) were combined with vigorous stirring, which resulted in the formation of a characteristic dark brown colour of the SmI2–

Et3N–H2O complex. A solution of 49 (0.025 mmol, 1.0 equiv, stock solution in THF, 1.0 mL) was added and the reaction mixture was stirred for 18 h at room temperature. After work-up the sample was analyzed by 1H NMR to obtain conversion and yield using internal standard: conversion <5%; yield of recovered starting material 49: >95%, indicating that the reductive opening of phenyl-activated cyclopropyl diols with SmI2–Et3N–H2O is not operative under these reaction conditions.

Chapter 2.4 Aromatic Reductions

General procedure F reduction of aromatic hydrocarbons or alkyl halides.

Method A. An oven-dried vial containing a stir bar was placed under a positive pressure of argon. After three evacuation/backfilling cycles freshly prepared solution of SmI2 was added, followed by the addition of deoxygenated deionised water (typically n = 0, 50 or 500 equiv relative to SmI2). At this point a change of colour of SmX2 (X = I, Br, Cl) to burgundy red indicative of the formation of SmI2 + n H2O complex was observed (n>5). To the preformed

SmI2‒H2O complex (THF solution, typically 3 equiv) a solution of substrate (1 equiv) in THF

(1.0 mL) solution was added at room temperature under argon atmosphere and the mixture was stirred vigorously. After the specified time, the reaction was quenched by bubbling air through the reaction mixture until decolourisation had occurred. The sample was analyzed by

169

Malcolm Spain PhD Thesis GC and/or 1H NMR to obtain conversion using internal standard. For GC (Method A, confirmed by GC-MS, using Method A) analysis, a small aliquot (typically, 1.0 mL) was removed from the reaction mixture, diluted with diethyl ether (2.0 mL) and HCl (0.1 N, 0.25 mL) and analyzed by GC and/or GC-MS to obtain conversion. For 1H NMR analysis, the reaction mixture was diluted with CH2Cl2 (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (2 x 30 mL), organic layers were combined, dried over MgSO4, filtered and concentrated. The product distribution was analyzed after the addition of internal standard and comparison with authentic samples. Method B. An oven-dried vial was charged with a substrate (typically, 0.10 mmol) and placed under a positive pressure of argon.

Samarium(II) iodide (THF solution, typically 3 equiv), followed by H2O (typically, 50 equiv relative to SmI2) were added and the resulting mixture was stirred vigorously. Work-up and analysis was performed as described for Method A.

Determination of the effective redox potential of SmI2‒H2O by reduction of aromatic hydrocarbons and alkyl halides (Table 2.15 and Table 2.16). According to the general procedure F (Method A) to a preformed solution of SmI2 + n H2O complex (3 equiv, 0.15 mmol, n = 0, 50, or 500 equiv, relative to SmI2, based upon Table 2.15 and Table 2.16) was added a solution of substrate (1 equiv, 0.05 mmol, according to Table 2.15 and Table 2.16).

The product distribution was analysed by GC-MS (typically Method A and/or Method B), or

GC-MS (Method A) and 1H-NMR using internal standard, and comparison with authentic samples.

Determination of deuterium incorporation and kinetic isotope effect.

Modification of the general procedure F Method B. Conditions: Substrate (1 equiv), SmI2

(THF solution, typically 3 equiv), followed by D2O (typically, 50 equiv relative to SmI2; deuterium incorporation) or an equimolar mixture of D2O and H2O (typically, 50 equiv

170

Malcolm Spain PhD Thesis relative to SmI2; kinetic isotope effect) were added and the resulting mixture was stirred vigorously. After work-up as described above, the amount of each species was determined by

1 H NMR analysis (500 MHz, CDCl3).

Reduction of Aromatic Hydrocarbons using SmI2/Et3N/H2O Complexes. Modification of the general procedure F Method B. To a substrate (1 equiv), samarium(II) iodide (THF solution, typically 3 equiv), followed by amine (typically, 24 equiv) and water (typically, 24 equiv) were added under argon at room temperature, and the resulting solution was stirred vigorously. Work-up and analysis as described for the general procedure F.

Reduction of Aromatic Hydrocarbons using Na(silica). Modification of the general procedure F Method B. An oven-dried vial equipped was charged with Na(silica) (0.63 mmol,

2.5 equiv) and placed under a positive pressure of argon. A solution of substrate (0.25 mmol,

1 equiv) in THF (3.3 mL) was added, the resulting mixture was vigorously stirred for 5 h, followed by quenching with H2O (3.0 mL) or D2O (3.0 mL). Work-up and analysis as described above for the general procedure F.

171

Malcolm Spain PhD Thesis 9,10-Dihydroanthracene (78). (Table 2.20, entry 1).

According to the general procedure F, the reaction of anthracene (66) (178 mg, 1 mmol, 1 equiv), SmI2 (THF solution, 3 equiv) and H2O (2.7 mL, 150 equiv, 50 equiv relative to SmI2) afforded after purification by column chromatography (2% EtOAc/hexanes) and recrystallisation (EtOH) the title compound. Yield: 96% (172 mg) isolated. 1H NMR (500

13 MHz, CDCl3)  = 3.82 (s, 4 H), 7.07-7.11 (m, 4 H), 7.16-7.20 (m, 4 H). C NMR (125 MHz,

129 CDCl3)  = 36.3, 126.2, 127.5, 136.8.

General procedure G for monoreduction of cyclic 1,3-diimides using SmI2–H2O.

An oven-dried vial containing a stir bar was charged with a cyclic 1,3-diimide (1 equiv), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. THF (typically, 2.0 mL) and water (typically, 1000 equiv, ca. 1:1

THF/H2O v/v) were added, followed by a rapid injection of SmI2 (in THF, typically 4 equiv) with vigorous stirring. After the specified time (typically, 10-60 s), the reaction was quenched by bubbling air through the reaction mixture, diluted with CH2Cl2 (30 mL) and HCl (0.1 N,

20 mL), H2O (20 mL) or NaHCO3 (2% in H2O, 20 mL). The aqueous layer was extracted with CH2Cl2 (3 x 20 mL), organic layers were combined, dried over Na2SO4, filtered and

1 concentrated. The sample was analyzed by H NMR (CDCl3, C6D6 or CD3C(O)CD3) and/or

GC-MS (neat) to determine the product distribution and diastereoselectivity from the crude reaction mixture. The crude product was purified by chromatography on silica gel, concentrated under reduced pressure and stored neat or as a solution in acetone. All compounds have been prepared as racemates.

172

Malcolm Spain PhD Thesis (5S,6R)-6-Hydroxy-5-isobutyl-1,3-dimethyldihydropyrimidine-2,4(1H,3H)-dione (103a)

5-Isobutyl-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (101a) (Mp = 48-50 °C). 1H

NMR (400 MHz, CDCl3)  0.86 (d, J = 6.4 Hz, 6 H), 1.70-1.81 (m, 1 H), 1.87 (t, J = 6.4 Hz,

13 2 H), 3.23 (s, 6 H), 3.41 (t, J = 6.4 Hz, 1 H); C NMR (100 MHz, CDCl3)  22.2, 25.7, 28.6,

40.5, 47.8, 151.7, 169.0. Spectroscopic data matched literature values.130 According to the general procedure, the reaction of 101a (0.10 mmol), SmI2 (0.30 mmol, 3 equiv, 5.5 mL,

0.055 M) and H2O (1.8 mL, 1000 equiv) for 10 s afforded after purification by chromatography (1/1 EtOAc/hexanes) the title compound as a colourless oil. Yield 83%. Dr =

88:12 (crude), 88:12 (purified). Stereochemistry of the major diastereoisomer was determined by 2 D NMR experiments and confirmed by an X-ray analysis of a derivative. Rf (50%

1 EtOAc/hexanes) = 0.53. H NMR (500 MHz, C6D6)  (major diastereoisomer) 0.88 (d, J =

6.5 Hz, 3 H), 0.96 (d, J = 6.5 Hz, 3 H), 1.54-1.60 (m, 1 H), 1.69-1.78 (m, 1 H), 2.85-2.14 (m,

1 H), 2.23-2.27 (m, 1 H), 2.87 (s, 3 H), 3.20 (d, J = 6.0 Hz, 1 H), 3.32 (s, 3 H), 4.25 (dd, J =

4.5, 5.0 Hz, 1 H); (minor, diagnostic peaks only) 0.82 (d, J = 6.5 Hz, 3 H), 0.92 (d, J = 6.5

Hz, 3 H), 2.93 (s, 3 H), 3.31 (s, 3 H), 3.53 (d, J = 4.5 Hz, 1 H), 4.19 (d, J = 2.0 Hz, 1 H); 13C

NMR (75 MHz, C6D6)  (major diastereoisomer) 21.9, 23.3, 25.3, 27.7, 34.3, 34.8, 44.3,

80.5, 153.6, 170.4; (minor, diagnostic peaks only) 22.2, 22.4, 25.7, 27.5, 34.6, 39.0, 47.6,

82.6, 171.6. IR (neat) 3392, 2956, 2871, 1710, 1650, 1468, 1421, 1295, 1143, 1094, 1055,

-1 + 1031, 1000, 911, 793 cm . HRMS calcd for C10H18N2O3Na (M + Na) 237.1210, found

237.1217.

173

Malcolm Spain PhD Thesis (5S,6R)-5-decyl-6-hydroxy-1,3,5-trimethyldihydropyrimidine-2,4(1H,3H)-dione-6-d (103b-D).

According to the above procedure reaction of 101b (0.10 mmol), SmI2 (0.40 mmol, 3 equiv,

2.7 mL, 0.11 M) and D2O (1.8 mL, 1000 equiv) for 60 s afforded after purification by chromatography (1/1 EtOAc/hexanes) the title compound with >98% D1 incorporation as a colourless oil. Yield 57%. Dr = 77:23 (crude), >95:5 (after purification). The major diastereoisomer can be partially separated by chromatography on silica gel. 1H NMR (500

MHz, CD3C(O)CD3)  (major diastereoisomer) 0.88 (t, J = 6.9 Hz, 3 H), 1.15 (s, 3 H), 1.22 -

1.36 (m, 15 H), 1.36 - 1.46 (m, 2 H), 1.70 - 1.82 (m, 2 H), 3.05 (s, 3 H), 3.05 (s, 3 H), 5.48 (s,

1 H); (minor, diagnostic peaks only) 0.87 (t, J = 6.9 Hz, 3 H), 1.23 (s, 3 H), 1.42 - 1.50 (m, 1

13 H), 1.50 - 1.58 (m, 1 H), 5.47 (s, 1 H); C NMR (125 MHz, CD3C(O)CD3)  (major diastereoisomer) 14.4, 21.1, 23.3, 23.4, 27.7, 30.1, 30.2, 30.2, 30.4, 31.2, 32.7, 33.5, 34.6,

46.6, 84.8 (t, J = 23.6 Hz), 153.7, 175.6; (minor, diagnostic peaks only) 14.4, 17.8, 23.4,

24.7, 27.7, 32.7, 34.6, 37.5, 48.0, 153.7, 174.4. IR (neat) 764, 847, 965, 1064, 1316, 1384,

+ 1417, 1469, 1656, 1711, 2854, 2924, 3398. HRMS calcd for C17H30DN2O2 (M − OH)

296.2443, found 296.2432. Kinetic isotope effect was determined by reacting 101b (0.10 mmol), SmI2 (0.40 mmol, 3 equiv, 2.7 mL, 0.11 M) and D2O/H2O (1:1, 1.8 mL, 1000 equiv) for 60 s at room temperature, followed by standard work-up to give the title compound with

1 1 40.1% D incorporation as determined by H NMR (500 MHz) analysis (kH/kD = 1.49±0.1).

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Malcolm Spain PhD Thesis

Chapter 3. SmI2–amine–H2O

General procedure H for SmI2–amine–H2O reductions.

An oven-dried vial was placed under a positive pressure of argon. After three evacuation/backfilling cycles substrate (neat or dissolved in 1.0 mL of THF) and samarium(II) iodide (THF solution, typically 6 or 8 equiv) was added, followed by amine

(typically 18 or 24 equiv) and water (typically 18 or 24 equiv) at room temperature and stirred vigorously. After the specified time (typically 2-24 h), the excess of SmI2 was oxidised by bubbling air through the reaction mixture. The reaction mixture was diluted with

EtOAc (20 mL) and HCl (10 mL, 1.0 M). The aqueous layer was extracted with EtOAc (3 x

20 mL), organic layers were combined, washed with brine (1 x 10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography using a short plug of silica gel.

Chapter 3.1 Ester Reduction

Decane-1,6-diol (6a) (Scheme 3.1)

According to the general procedure H, the reaction of 7-butyloxepan-2-one (5) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (1.6 mmol) and triethylamine (2.4 mmol) for 2 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes-EtOAc) the title

1 compound in 87% yield. Oil (Rf = 0.56, EtOAc). H NMR (300 MHz, CDCl3)  0.84 (t, J =

7.2 Hz, 3H), 1.15-1.43 (m, 14H), 1.46-1.57 (m, 2H), 3.47-3.55 (m, 1H), 3.58 (t, J = 6.3 Hz,

13 2H); C NMR (75 MHz, CDCl3)  14.0, 22.8, 25.4, 25.8, 27.8, 32.7, 37.3, 37.4, 62.9, 71.9.

Spectroscopic data matched literature values.131

175

Malcolm Spain PhD Thesis 3-Phenylpropan-1-ol (116) (Table 3.4, entry 1)

According to the general procedure H, the reaction of methyl 3-phenylpropanoate (115a)

(0.25 mmol), samarium(II) iodide (1.5 mmol), water (4.5 mmol) and triethylamine (4.5 mmol) for 2 h at room temperature, afforded after chromatography (1/4-1/1 EtOAc/hexanes)

1 the title compound in 97% yield. Oil (Rf = 0.20, 1/4 EtOAc/hexanes). H NMR (500 MHz,

CDCl3)  1.27 (br. s, 1H), 1.80-1.86 (m, 2H), 2.64 (t, J = 7.5 Hz, 2H), 3.61 (t, J = 6.5 Hz,

13 2H), 7.10-7.24 (m, 5H); C NMR (125 MHz, CDCl3)  32.1, 34.3, 62.3, 125.9, 128.4, 128.5,

141.8. Spectroscopic data matched literature values.132

3-Phenylpropan-1-ol (Table 3.4, entry 2)

According to the general procedure H, the reaction of ethyl 3-phenylpropanoate (115b)

(0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.8 mmol) for 2 h at room temperature, afforded after chromatography (1/4-1/1 EtOAc/hexanes) the title compound in 99% yield. Oil (Rf = 0.20, 1/4 EtOAc/hexanes). Spectroscopic properties matched those previously described.

3-Phenylpropan-1-ol (Table 3.4, entry 3)

176

Malcolm Spain PhD Thesis According to the general procedure H, the reaction of isopropyl 3-phenylpropanoate

(115c) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine

(2.4 mmol) for 5 h at room temperature, afforded after chromatography (1/10-1/1

EtOAc/hexanes) the title compound in 88% yield. Oil (Rf = 0.20, 1/4 EtOAc/hexanes).

Spectroscopic properties matched those previously described.

3-Phenylpropan-1-ol (Table 3.4, entry 4)

According to the general procedure H, the reaction of tert-butyl 3-phenylpropanoate (115d)

(0.10 mmol), samarium(II) iodide (1.2 mmol), water (3.6 mmol) and pyrrolidine (3.6 mmol) for 5 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 83% yield. Oil (Rf = 0.20, 1/4 EtOAc/hexanes). Spectroscopic properties matched those previously described.

3-Phenylpropan-1-ol (Table 3.4, entry 5)

According to the general procedure H, the reaction of phenyl 3-phenylpropanoate (115e)

(0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.8 mmol) for 2 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 94% yield. Oil (Rf = 0.20, 1/4 EtOAc/hexanes). Spectroscopic properties matched those previously described.

3-Phenylpropan-1-ol (Table 3.4, entry 6)

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Malcolm Spain PhD Thesis

According to the general procedure H, the reaction of benzyl 3-phenylpropanoate (115f)

(0.10 mmol), samarium(II) iodide (1.0 mmol), water (3.0 mmol) and triethylamine (3.0 mmol) for 2 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 97% yield. Oil (Rf = 0.20, 1/4 EtOAc/hexanes). Spectroscopic properties matched those previously described.

Decan-1-ol (Table 3.5, entry 1)

According to the general procedure H, the reaction of methyl decanoate (121a) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine (1.8 mmol) for 15 h at room temperature, afforded after chromatography (1/1 EtOAc/hexanes-EtOAc) the title

1 compound in 95% yield. Oil (Rf = 0.24, 1/4 EtOAc/hexanes). H NMR (500 MHz, CDCl3) 

0.81 (t, J = 6.9 Hz, 3H), 1.15-1.33 (m, 15H), 1.47-1.52 (m, 2H), 3.57 (t, J = 5.8 Hz, 2H); 13C

NMR (125 MHz, CDCl3)  14.1, 22.7, 25.7, 29.3, 29.4, 29.6, 29.6, 31.9, 32.8, 63.1.

Cycloheptylmethanol (Table 3.5, entry 2)

According to the general procedure H, the reaction of methyl cycloheptanecarboxylate

(121b) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine

(2.4 mmol) for 3 h at room temperature, afforded after chromatography (CH2Cl2-1/4

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Malcolm Spain PhD Thesis

Et2O/CH2Cl2) the title compound in 98% yield. Note: work-up with CH2Cl2 (3 x 20 mL) and

1 1.0 M HCl (1 x 10 mL). Oil (Rf = 0.39, 1/4 Et2O/CH2Cl2). H NMR (500 MHz, CDCl3) 

1.08-1.15 (m, 2H), 1.30 (br. s, 1H), 1.34-1.46 (m, 5H), 1.48-1.64 (m, 4H), 1.65-1.71 (m, 2H),

13 3.35 (d, J = 6.6 Hz, 2H); C NMR (125 MHz, CDCl3)  26.5, 28.6, 30.8, 42.1, 68.7.

Spectroscopic data matched literature values. 133

trans-4-(Pentylcyclohexyl)methanol (Table 3.5, entry 3)

According to the general procedure H, the reaction of methyl trans-4- pentylcyclohexanecarboxylate (121c) (0.10 mmol), samarium(II) iodide (0.8 mmol), water

(2.4 mmol) and triethylamine (2.4 mmol) for 6 h at room temperature, afforded after chromatography (1/10-1/4 EtOAc/hexanes) the title compound in 87% yield. Oil (Rf = 0.43,

1 1/4 EtOAc/hexanes). H NMR (300 MHz, CDCl3)  0.77-0.92 (m, 7H), 1.06-1.28 (m, 10H),

1.35 (br. s, 1H), 1.71 (d, J = 8.7 Hz, 4H), 3.37 (d, J = 6.4 Hz, 2H); 13C NMR (75 MHz,

CDCl3)  14.1, 22.7, 26.6, 29.5, 32.2, 32.7, 37.4, 37.8, 40.7, 68.8. Spectroscopic data matched literature values.101

1-Adamantanemethanol 119 (Table 3.5, entry 4)

According to the general procedure H, the reaction of methyl adamantane-1-carboxylate

(118) (0.10 mmol), samarium(II) iodide (1.0 mmol), water (3.0 mmol) and triethylamine (3.0 mmol) for 20 h at room temperature, afforded after chromatography (1/10-1/1

1 EtOAc/hexanes) the title compound in 80% yield. Solid (Rf = 0.57, 1/4 EtOAc/hexanes). H

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Malcolm Spain PhD Thesis

NMR (500 MHz, CDCl3)  1.23 (br. s, 1H), 1.44 (m, 6H), 1.57 (m, 1H), 1.59 (m, 2H), 1.65

13 (m, 2H), 1.68 (m, 1H), 1.92 (m, 3H), 3.13 (s, 2H); C NMR (125 MHz, CDCl3)  28.2, 34.5,

37.2, 39.0, 73.9. Spectroscopic data matched literature values.101

3-(4-Methoxyphenyl)propan-1-ol (Table 3.5, entry 5)

According to the general procedure H, the reaction of methyl 3-(4- methoxyphenyl)propanoate (121d) (0.25 mmol), samarium(II) iodide (1.5 mmol), water

(4.5 mmol) and triethylamine (4.5 mmol) for 2 h at room temperature, afforded after chromatography (1/4-1/1 EtOAc/hexanes) the title compound in 99% yield. Oil (Rf = 0.62,

1 1/1 EtOAc/hexanes). H NMR (500 MHz, CDCl3)  1.55 (br. s, 1H), 1.75-1.81 (m, 2H), 2.57

(t, J = 7.5 Hz, 2H), 3.58 (t, J = 6.5 Hz, 2H), 3.71 (s, 3H), 6.75 (d, J = 8.5 Hz, 2H), 7.03 (d, J

13 = 8.5 Hz, 2H); C NMR (125 MHz, CDCl3)  31.2, 34.5, 55.3, 62.2, 113.8, 129.3, 133.9,

157.8. Spectroscopic data matched literature values.101

3-(p-Tolyl)propan-1-ol (122e) (Table 3.5, entry 6)

According to the general procedure H, the reaction of methyl 3-(p-tolyl)propanoate (121e)

(0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.8 mmol) for 3 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes)

1 the title compound in 97% yield. Oil (Rf = 0.63, 1/1 EtOAc/hexanes). H NMR (300 MHz,

CDCl3)  1.24 (br. s, 1H), 1.76-1.85 (m, 2H), 2.25 (s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 3.60 (t, J

180

Malcolm Spain PhD Thesis 13 = 6.6 Hz, 2H), 7.02 (s, 4H); C NMR (75 MHz, CDCl3)  21.0, 31.6, 34.4, 62.4, 128.3,

129.1, 135.3, 138.7. Spectroscopic data matched literature values.101

2-Phenylpropan-1-ol (122f) (Table 3.5, entry 7)

According to the general procedure H, the reaction of methyl 2-phenylpropanoate (121f)

(0.25 mmol), samarium(II) iodide (1.5 mmol), water (4.5 mmol) and triethylamine (4.5 mmol) for 24 h at room temperature, afforded after chromatography (1/10-1/1

1 EtOAc/hexanes) the title compound in 95% yield. Oil (Rf = 0.56, 1/1 EtOAc/hexanes). H

NMR (500 MHz, CDCl3)  1.21 (d, J = 7.0 Hz, 3H), 1.33 (br. s, 1H), 2.84-2.91 (m, 1H), 3.63

13 (d, J = 7.0 Hz, 2H), 7.14-7.18 (m, 3H), 7.24-7.28 (m, 2H); C NMR (125 MHz, CDCl3) 

17.6, 42.5, 68.7, 126.7, 127.5, 128.7, 143.7. Spectroscopic data matched literature values.101

2-Methyl-3-phenylpropan-1-ol (122g) (Table 3.5, entry 8)

According to the general procedure H, the reaction of methyl 2-methyl-3-phenylpropanoate

(121g) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine

(2.4 mmol) for 20 h at room temperature, afforded after chromatography (1/10-1/1

1 EtOAc/hexanes) the title compound in 85% yield. Oil (Rf = 0.66, 1/1 EtOAc/hexanes). H

NMR (500 MHz, CDCl3)  0.85 (d, J = 6.5 Hz, 3H), 1.35 (br. s, 1H), 1.83-1.92 (m, 1H), 2.36

(dd, J = 8.5, 13.5 Hz, 1H), 2.69 (dd, J = 6.5, 13.5 Hz, 1H), 3.38-3.49 (m, 2H), 7.09-7.14 (m,

181

Malcolm Spain PhD Thesis 13 3H), 7.19-7.23 (m, 2H); C NMR (125 MHz, CDCl3)  16.5, 37.8, 39.7, 67.7, 125.9, 128.3,

129.2, 140.6. Spectroscopic data matched literature values.101

2-(4-Isobutylphenyl)propan-1-ol (122h) (Table 3.5, entry 9)

According to the general procedure H, the reaction of methyl 2-(4- isobutylphenyl)propanoate (121h) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine (2.4 mmol) for 20 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 88% yield. Oil (Rf = 0.79,

1 1/1 EtOAc/hexanes). H NMR (500 MHz, CDCl3)  0.83 (d, J = 7.0 Hz, 6H), 1.19 (d, J = 7.0

Hz, 3H), 1.54 (br. s, 1H), 1.73-1.82 (m, 1H), 2.38 (d, J = 7.0 Hz, 2H), 2.81-2.89 (m, 1H),

13 3.61 (d, J = 6.5 Hz, 2H), 7.02-7.09 (m, 4H); C NMR (125 MHz, CDCl3)  17.6, 22.4, 30.3,

42.0, 45.0, 68.8, 127.2, 129.4, 140.1, 140.7. Spectroscopic data matched literature values.101

Heptane-1,7-diol (122i) (Table 3.5, entry 10)

According to the general procedure H, the reaction of diethyl heptanedioate (121i) (0.10 mmol), samarium(II) iodide (1.2 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for

20 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title

1 compound in 87% yield. Oil (Rf = 0.35, EtOAc). H NMR (500 MHz, CDCl3)  1.25 (br. s,

2H), 1.28-1.33 (m, 6H), 1.47-1.54 (m, 4H), 3.58 (t, J = 6.6 Hz, 4H); 13C NMR (125 MHz,

101 CDCl3)  25.7, 29.2, 32.7, 63.0. Spectroscopic data matched literature values.

182

Malcolm Spain PhD Thesis 2,2-Dibutylpropane-1,3-diol (122j) (Table 3.5, entry 11)

According to the general procedure H, the reaction of diethyl 2,2-dibutylmalonate (121j)

(0.10 mmol), samarium(II) iodide (1.6 mmol), water (4.8 mmol) and triethylamine (4.8 mmol) for 18 h at room temperature, afforded after chromatography (1/10-1/1

1 EtOAc/hexanes-EtOAc) the title compound in 76% yield. Oil (Rf = 0.64, EtOAc). H NMR

(300 MHz, CDCl3)  0.84 (t, J = 6.9 Hz, 6H), 1.05-1.31 (m, 12H), 2.36 (br. s, 2H), 3.50 (s,

13 4H); C NMR (75 MHz, CDCl3)  14.1, 23.6, 25.1, 30.6, 40.9, 69.5. Spectroscopic data matched literature values.134

183

Malcolm Spain PhD Thesis Decane-1,5-diol (2) (Table 3.5, entry 12)

According to the general procedure H, the reaction of 6-pentyltetrahydro-2H-pyran-2-one

(5-decanolide) (1) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine (1.6 mmol) for 2 h at room temperature, afforded after chromatography

1 (EtOAc) the title compound in 97% yield. Oil (Rf = 0.50, EtOAc). H NMR (500 MHz,

CDCl3)  0.82 (t, J = 6.9 Hz, 3H), 1.19-1.28 (m, 5H), 1.32-1.58 (m, 7H), 1.48-1.58 (m, 2H),

13 1.61 (br. s, 2H), 3.51-3.56 (m, 1H), 3.59 (t, J = 6.0 Hz, 2H); C NMR (125 MHz, CDCl3) 

14.0, 21.8, 22.6, 25.3, 31.9, 32.6, 37.0, 37.5, 62.7, 71.9. Spectroscopic data matched literature values.46

2-(3-Hydroxypropyl)phenol (122k) (Table 3.5, entry 13)

According to the general procedure H, the reaction of chroman-2-one (121k) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.8 mmol) for 2 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title

1 compound in 92% yield. Oil (Rf = 0.50, EtOAc). H NMR (500 MHz, CDCl3)  1.78-1.84

(m, 2H), 2.51 (br. s, 1H), 2.71 (t, J = 6.8 Hz, 2H), 3.57 (t, J = 5.8 Hz, 2H), 6.76-6.82 (m, 2H),

13 7.02-7.05 (m, 2H), 7.06 (br. s, 1H); C NMR (125 MHz, CDCl3)  25.1, 32.2, 60.8, 116.1,

120.8, 127.2, 127.6, 130.7, 154.6. Spectroscopic data matched literature values.46

184

Malcolm Spain PhD Thesis (4-Methoxyphenyl)methanol (122l) (Table 3.5, entry 14)

According to the general procedure H, the reaction of methyl 4-methoxybenzoate (122l)

(0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.8 mmol) for 1 h at room temperature, afforded after chromatography (4/1 EtOAc/hexanes) the

1 title compound in 90% yield. Oil (Rf = 0.54, 4/1 EtOAc/hexanes). H NMR (300 MHz,

CDCl3)  1.57 (br. s, 1H), 3.74 (s, 3H), 4.54 (s, 2H), 6.82 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7

13 Hz, 2H); C NMR (75 MHz, CDCl3)  55.3, 65.1, 114.0, 128.7, 133.2, 159.3. Spectroscopic data matched literature values.135

2-(1H-Indol-3-yl)ethanol (122m) (Table 3.5, entry 15)

According to the general procedure H, the reaction of ethyl 2-(1H-indol-3-yl)acetate (121m)

(0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine (2.4 mmol) for 20 h at room temperature, afforded after chromatography (1/10-1/1

1 EtOAc/hexanes) the title compound in 81% yield. Oil (Rf = 0.33, 1/1 EtOAc/hexanes). H

NMR (500 MHz, CDCl3)  1.47 (br. s, 1H), 2.97 (t, J = 6.3 Hz, 2H), 3.84 (t, J = 6.3 Hz, 2H),

7.01 (d, J = 1.5 Hz, 1H), 7.06 (t, J = 7.0 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.2 Hz,

13 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.99 (br. s, 1H); C NMR (125 MHz, CDCl3)  28.8, 62.6,

111.3, 112.3, 118.9, 119.5, 122.3, 122.5, 127.4, 136.5. Spectroscopic data matched literature values.101

185

Malcolm Spain PhD Thesis 5,7-Dimethyloct-7-ene-1,5-diol (122n) (Table 3.5, entry 16)

According to the general procedure H, the reaction of 6-methyl-6-(2- methylallyl)tetrahydro-2H-pyran-2-one (121n) (0.10 mmol), samarium(II) iodide (0.8 mmol), water (2.4 mmol) and triethylamine (1.8 mmol) for 2 h at room temperature, afforded after chromatography (EtOAc) the title compound in 97% yield. Oil (Rf = 0.41, 80/20

1 EtOAc/hexanes). H NMR (500 MHz, CDCl3)  1.19 (s, 3H), 1.43-1.53 (m, 4H), 1.55-1.62

(m, 2H), 1.64-1.69 (br. s, 2H) 1.85 (s, 3H), 2.10 (d, J = 13.0 Hz, 1H), 2.16 (d, J = 13.0 Hz,

1H), 3.67 (t, J = 6.5 Hz, 2H), 4.73-4.78 (m, 1H), 4.90-4.96 (m, 1H); 13C NMR (125 MHz,

CDCl3)  20.2, 25.1, 27.0, 33.1, 42.1, 49.4, 62.7, 72.3, 114.9, 142.8; IR (neat) 3336, 3072,

-1 + 2937, 2967, 1641, 1457, 1373 cm ; HRMS calcd for C10H20O2Na (M + Na) 195.1356, found

195.1356.

2-Butyloctan-1-ol (122o) (Table 3.5, entry 17)

According to the general procedure H, the reaction of methyl 2-butyloctanoate (121o) (0.10 mmol), samarium(II) iodide (1.6 mmol), water (4.8 mmol) and triethylamine (4.8 mmol) for

18 h at room temperature, After work-up the conversion (73%) and yield (65%) were determined by 1H NMR using an internal standard and comparison with authentic samples

1 (isolated in Table 3.15, entry 2). H NMR (500 MHz, CDCl3)  0.79-0.85 (m, 6H), 1.09-1.14

(br. s, 1H), 1.16-1.29 (m, 16H), 1.35-1.42 (m, 1H), 3.47 (t, J = 5.4 Hz, 2H); 13C NMR (100

MHz, CDCl3)  14.1, 22.7, 23.1, 26.9, 29.1, 29.8, 30.6, 30.9, 31.9, 40.5, 65.8. Spectroscopic data matched literature values.136

186

Malcolm Spain PhD Thesis

(1S,3R,7S,8S,8aR)-3,7-Dimethyl-8-((3R,5S)-3,5,7-trihydroxyheptyl)-1,2,3,7,8,8a- hexahydronaphthalen-1-yl 2-methylbutanoate (124) (Scheme 3.2)

According to the general procedure H, the reaction of (1S,3R,7S,8S,8aR)-8-(2-((2R,4R)-4- hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-3,7-dimethyl-1,2,3,7,8,8a- hexahydronaphthalen-1-yl (S)-2-methylbutanoate (lovastatin) (123) (0.10 mmol), samarium(II) iodide (0.5 mmol), water (3.0) and triethylamine (3.0 mmol) for 1 h at room temperature, afforded after purification by preparative thin layer chromatography (EtOAc) the title compound in 87% yield. Oil (Rf = 0.34, EtOAc). Note: a modified procedure was used. To samarium(II) iodide powder, substrate in 8.0 mL of THF was added, followed by amine and water. Products resulting from non-selective reduction were not detected by

1 137 1 analysis of crude reaction mixture by H NMR. H NMR (500 MHz, CDCl3)  0.79-0.83

(m, 6H), 1.01 (d, J = 7.5 Hz, 3H), 1.04 (d, J = 7.0 Hz, 3H), 1.08-1.22 (m, 2H), 1.32-1.41 (m,

1H), 1.42-1.61 (m, 6H), 1.64 (q, J = 5.5 Hz, 2H), 1.85-1.88 (m, 2H), 2.18 (dd, J = 2.5, 12.0

Hz, 1H), 2.23-2.32 (m, 2H), 2.34-2.41 (m, 1H), 3.00 (br. s, 1H), 3.60 (br. s, 1H), 3.69-3.83

(m, 3H), 4.02-4.07 (m, 1H), 4.28 (br. s, 1H), 5.35 (q, J = 3.0 Hz, 1H), 5.45 (t, J = 3.0 Hz,

13 1H), 5.72 (dd, J = 6.5, 9.5 Hz, 1H), 5.92 (d, J = 9.5 Hz, 1H); C NMR (125 MHz, CDCl3) 

11.7, 13.9, 16.3, 22.9, 24.2, 26.8, 27.5, 30.5, 32.9, 35.1, 36.2, 37.5, 38.8, 41.5, 43.0, 61.2,

68.1, 72.8, 73.0, 128.3, 129.6, 131.6, 133.3, 177.2; IR (neat) 3372, 3019, 2935, 2874, 1711,

-1 + 1462, 1373, 1264, 1195, 1158, 1125, 1081, 1056, 974 cm ; HRMS calcd for C24H41O5 (M +

H) 409.2949, found 409.2932.

187

Malcolm Spain PhD Thesis (R)-2-phenylpropan-1-ol (122f-(R)) (Scheme 3.3)

According to modification of the general procedure H using the preformed Sm(II) complex,

(R)-methyl 2-phenylpropanoate (0.10 mmol, >99.5% ee), was reacted with a preformed solution of samarium(II) iodide (0.8 mmol), water (4.8 mmol) and triethylamine (4.8 mmol) for 2 h at room temperature to afford the title compound in 99% yield. 1H NMR (500 MHz,

CDCl3)  1.21 (d, J = 7.0 Hz, 3H), 1.33 (br. s, 1H), 2.84-2.91 (m, 1H), 3.63 (d, J = 7.0 Hz,

13 2H), 7.14-7.18 (m, 3H), 7.24-7.28 (m, 2H); C NMR (125 MHz, CDCl3)  17.6, 42.5, 68.7,

126.7, 127.5, 128.7, 143.7. HPLC analysis (chiralpak IA 28C, hexanes/i-PrOH 99/1, 1.0 mL/min, 220 nm) indicated 98.4% ee: tR (minor) = 18.42 minutes, tR (major) = 19.48 minutes. In addition, the reaction of 121f-(R) (0.1 mmol, >99.5% ee) was stopped at half- conversion (conditions: SmI2 (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol), preformed Sm(II) complex, 5 min, room temperature) to give the title product in 44% yield

(44% conv.). HPLC analysis chiralpak IA 28C, hexanes/i-PrOH 99/1, 1.0 mL/min, 220 nm) indicated 98.9% ee: tR (minor) = 17.75 minutes, tR (major) = 19.02 minutes.

188

Malcolm Spain PhD Thesis Mechanistic experiments

3-phenylpropan-1,1-D2-1-ol (116-D,D) (Scheme 3.4)

According to the general procedure H, the reaction of methyl 3-phenylpropanoate (115a)

(0.10 mmol), samarium(II) iodide (0.6 mmol), deuterium oxide (1.8 mmol) and triethylamine

(1.2 mmol) for 3 h at room temperature, afforded 1,1-D,D-3-phenylpropan-1-ol with >97% deuterium incorporation. Yield 88% (1H NMR vs. internal standard). Purification by chromatography (1/4-1/1 EtOAc/hexanes) afforded the title product (Rf = 0.20, 1/4

1 EtOAc/hexanes). H NMR (500 MHz, CDCl3)  1.50 (br. s, 1H), 1.82 (t, J = 7.7 Hz, 2H),

13 2.64 (t, J = 7.5 Hz, 2H), 7.10-7.24 (m, 5H); C NMR (125 MHz, CDCl3)  32.0, 34.0, 61.6

(t, J1 = 21.3 Hz), 125.9, 128.4, 128.4, 141.8.

Determination of primary kinetic isotope effect (Scheme 3.4)

Method 1: According to the general procedure H, the reaction of isopropyl 3- phenylpropanoate (115c) (0.10 mmol), samarium(II) iodide (0.6 mmol), deuterium oxide/water (1:1, 1.8 mmol) and triethylamine (1.2 mmol) for 5 min at room temperature, afforded 1,1-D,D-3-phenylpropan-1-ol and 3-phenylpropan-1-ol (45% conversion). The

1 amount of each species was determined by H NMR (500 MHz, CDCl3,). Kinetic isotope effect, kH/kD = 1.4. Method 2: According to the general procedure, the reaction of isopropyl

3-phenylpropanoate (115c) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.2 mmol) and the reaction of isopropyl 3-phenylpropanoate (0.10 mmol), samarium(II) iodide (0.6 mmol), deuterium oxide (1.8 mmol) and triethylamine (1.2 mmol)

189

Malcolm Spain PhD Thesis were followed by GC (Method A) with undecane as the internal standard. Initial rates were determined from the slopes at low conversion. Kinetic isotope effect, kH/kD = 1.5.

18 H2 O Incorporation Studies (Table 3.6) According to modification of general procedure H using a preformed Sm(II) complex, methyl 3-phenylpropanoate (115a) (0.10 mmol), was reacted with samarium(II) iodide (0.6

18 mmol), H2 O (4.8 mmol) and triethylamine (4.8 mmol) for 18 h at RT to afford the title compound in 99% yield determined by 1H NMR (using an internal standard), <2.0% of 18O incorporation (determined by HRMS analysis) (Table 3.6, entry 1). In addition, the reaction of a hindered isopropyl 3-phenylpropanoate (115c) (Table 3.6, entry 2) and electronically- activated phenyl 3-phenylpropanoate (115e) (Table 3.6, entry 3) under the reaction conditions described above afforded the title compound in 92% and 98% yield (determined by 1H NMR using an internal standard), respectively, with <2.0% of 18O incorporation

(determined by HRMS analysis).

General Procedure I for SmI2–amine–H2O kinetic experiments

An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide

(THF solution, 0.10 M) was added followed by Et3N and H2O with vigorous stirring, which resulted in the formation of a characteristic dark brown colour of the SmI2–Et3N–H2O complex. Substrate (stock solution in THF) was added and the reaction mixture was vigorously stirred under argon. Small aliquots (typically, 0.25 mL) were removed from the reaction mixture at set time intervals, immediately quenched by bubbling air through the reaction mixture, diluted with diethyl ether (2.0 mL) and HCl (0.1 N, 0.25 mL), and analyzed by GC and/or GC-MS to obtain yield and product distribution using internal standard and comparison with authentic samples.

190

Malcolm Spain PhD Thesis Determination of the rate orders in the reduction of esters.

Ester rate order. According to general procedure I. Conditions: SmI2 (6.0 equiv), Et3N (12.0 equiv), H2O (18.0 equiv), ester (0.05-0.15 equiv).

Figure 7.4. Determination of ester rate order in the reduction of 115d using SmI2–Amine–

H2O.

Plot of ln(kobs) vs ln [ester] in the reduction of tert-butyl 3-phenylpropanoate using SmI2/Et3N/H2O -3

-3.2

-3.4

) y = 0.9613x + 0.6393

obs -3.6 R² = 0.9243 ln(k -3.8

-4 -4.7 -4.6 -4.5 -4.4 -4.3 -4.2 -4.1 -4 -3.9

ln [ester]

Samarium(II) iodide rate order. According to general procedure I. Conditions: SmI2 (5.0-8.0 equiv), Et3N (12.0 equiv), H2O (18.0 equiv), Ester (1.0 equiv).

Figure 7.5. Determination of SmI2 rate order in the reduction of 115d using SmI2–Amine–

H2O.

Plot of ln(kobs) vs ln [SmI2] in the reduction of tert-butyl 3-phenylpropanoate using SmI2/Et3N/H2O -3 -3.1 -3.2

y = 1.0945x - 0.3548 ) -3.3

obs R² = 0.9999

ln(k -3.4 -3.5 -3.6 -3.7 -3 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4

ln [SmI2]

Amine rate order. According to general procedure I. Conditions: SmI2 (6.0 equiv), amine

(6.0-96.0 equiv), H2O (18.0 equiv), Ester (1.0 equiv).

191

Malcolm Spain PhD Thesis

Figure 7.6. Determination of Amine Rate Order in the Reduction of 115d using SmI2–

Amine–H2O.

Plot of ln(kobs) vs ln [Et3N] in the reduction of tert-butyl 3- phenylpropanoate using SmI2/Et3N/H2O -1.5

-1.7

-1.9

) y = 1.177x + 2.1315

obs -2.1 R² = 0.9687

ln(k -2.3

-2.5

-2.7 -4 -3.8 -3.6 -3.4 -3.2 -3

ln [Et3N]

Water rate order. According to general procedure I. Conditions: SmI2 (6.0 equiv), amine

(12.0 equiv), H2O (6.0-96.0 equiv), Ester (1.0 equiv).

Figure 7.7. Determination of H2O Rate Order in the Reduction of 1 using SmI2–Amine–H2O.

Plot of ln(kobs) vs ln [H2O] in the reduction of tert-butyl 3-phenylpropanoate using SmI2/Et3N/H2O -3 -3.2 -3.4

-3.6 )

obs -3.8 y = 0.9227x - 2.0449 R² = 0.9844 ln(k -4 -4.2 -4.4 -4.6 -3 -2.5 -2 -1.5 -1

ln [H2O]

Hammett and Taft Studies

(Table 3.11-12)

An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide

192

Malcolm Spain PhD Thesis

(THF solution, 0.20 mmol, 2.0 equiv, 0.10 M) was added followed by Et3N (0.33 mL, 24 equiv) and H2O (0.043 mL, 24 equiv) with vigorous stirring, which resulted in the formation of a characteristic dark brown colour of the SmI2–Et3N–H2O complex. A preformed solution of two substrates (each 0.10 mmol, 1.0 equiv, stock solution in THF, 1.0 mL) was added and the reaction mixture was stirred until decolourisation to white had occurred. The reaction mixture was diluted with CH2Cl2 (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were combined, dried over Na2SO4,

1 filtered, and concentrated. The sample was analyzed by H NMR (CDCl3, 500 MHz) and GC-

MS to obtain conversion and yield using internal standard and comparison with authentic samples.

Figure 7.8 Hammett plot for the reduction of 4-phenylacetic methyl esters.

Hammett plot in the reduction of 4-phenylacetic methyl esters with SmI2/Et3N/H2O

0.3 y = 0.4281x + 0.0416 R² = 0.979

0.2

)

/k X

0.1 log(k

0 -0.4 -0.2 0 0.2 0.4 0.6

-0.1 Hammett  constant para

193

Malcolm Spain PhD Thesis Figure 7.9 Taft plot for the reduction of hydrocinnamic acid esters.

Taft steric constant ES in the reduction of hydrocinnamic acid esters with SmI2/Et3N/H2O

) Me

y = 0.969x - 0.1386 -1 /k X

R² = 0.9729 lg(k

-2 -2 -1.5 -1 -0.5 0 Taft ES constant

Radical Clock Experiments

(Table 3.13 and Table 3.19)

An oven-dried vial containing a stir bar was placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Samarium(II) iodide

(THF solution, typically 0.20-0.80 mmol, 2.0-8.0 equiv, 0.10 M) was added followed by Et3N

(0.33 mL, 24 equiv) and H2O (0.043 mL, 24 equiv) with vigorous stirring, which resulted in the formation of a characteristic dark brown colour of the SmI2–Et3N–H2O complex. A solution of ester substrate (0.10 mmol, 1.0 equiv, stock solution in THF, 1.0 mL) was added and the reaction mixture was stirred for the indicated time. The excess of Sm(II) was oxidised by bubbling air through the reaction mixture, and the reaction mixture was diluted with

CH2Cl2 (30 mL) and HCl (1 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 30 mL), the organic layers were combined, dried over Na2SO4, filtered, and concentrated. The

1 sample was analyzed by H NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion and yield using internal standard and comparison with authentic samples. In all other cases, the

Sm(II) reagent was pre-formed by adding the specified additive to the SmI2 solution prepared as described above, and stirring until the colour characteristic to the particular Sm(II)

194

Malcolm Spain PhD Thesis complex had appeared (SmI2–H2O: burgundy red; SmI2–MeOH: dark brown; SmI2–Et3N: dark blue).

Control Experiment

According to the general procedure, an oven-dried vial containing a stir bar was charged with samarium(II) iodide (THF solution, 0.40 mmol, 8.0 equiv, 0.085 M), Et3N (0.50 mL, 72 equiv) and H2O (0.065 mL, 72 equiv) with vigorous stirring, which resulted in the formation of a characteristic dark brown colour of the SmI2–Et3N–H2O complex. A solution of ((1R,2R)-2-phenylcyclopropyl)methanol (0.05 mmol, 1.0 equiv, stock solution in THF, 1.0 mL) was added and the reaction mixture was stirred for 18 h at room temperature. After the standard work-up as described above, the sample was analyzed by 1H NMR to obtain conversion and yield using internal standard: conversion <5%; yield of recovered starting material: 96%, indicating that the reductive opening of phenyl-activated cyclopropyl carbinols with SmI2–Et3N–H2O is not operative under these reaction conditions. Experiment suggested by Prof. Chaozhong Li (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences).

Chapter 3.2 Acid Reduction

Decan-1-ol (122a) (Table 3.15, entry 1)

According to the general procedure H, the reaction of decanoic acid (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for 3 h at room temperature, afforded after chromatography (1/10-1/4 EtOAc/hexanes) the title compound in 98% yield. Oil (Rf = 0.54, 1/4 EtOAc/hexanes. Spectroscopic properties matched those previously described.

195

Malcolm Spain PhD Thesis 2-Butyloctan-1-ol (122o) (Table 3.15, entry 2)

According to the general procedure H, the reaction of 2-butyloctanoic acid (131b) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (4.8 mmol) and triethylamine (4.8 mmol) for

18 h at room temperature, afforded after chromatography (1/10-1/4 EtOAc/hexanes-EtOAc)

1 the title compound in 94% yield. Oil. H NMR (500 MHz, CDCl3)  0.79-0.85 (m, 6H), 1.09-

1.14 (br. s, 1H), 1.16-1.29 (m, 16H), 1.35-1.42 (m, 1H), 3.47 (t, J = 5.4 Hz, 2H); 13C NMR

(100 MHz, CDCl3)  14.1, 22.7, 23.1, 26.9, 29.1, 29.8, 30.6, 30.9, 31.9, 40.5, 65.8.

Spectroscopic data matched literature values.138

trans-4-(Pentylcyclohexyl)methanol (Table 3.15, entry 3)

According to the general procedure H, the reaction of trans-4-pentylcyclohexanecarboxylic acid (131c) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for 18 h at room temperature, afforded after chromatography (1/10-

1/4 EtOAc/hexanes) the title compound in 96% yield. Oil (Rf = 0.60, 1/4 EtOAc/hexanes).

Spectroscopic properties matched those previously described.

196

Malcolm Spain PhD Thesis 1-Adamantanemethanol (Table 3.15, entry 4)

According to the general procedure H, the reaction of adamantane-1-carboxylic acid (131d)

(0.10 mmol), samarium(II) iodide (0.80 mmol), water (2.4 mmol) and triethylamine (2.4 mmol) for 3 h at room temperature, afforded after chromatography (1/10-1/4 EtOAc/hexanes) the title compound in 94% yield. Solid (Rf = 0.48, 1/4 EtOAc/hexanes). Spectroscopic properties matched those previously described.

Undec-10-en-1-ol (233p) (Table 3.15, entry 5)

According to the general procedure H, the reaction of undec-10-enoic acid (131e) (0.10 mmol), samarium(II) iodide (0.4 mmol), water (2.4 mmol) and triethylamine (2.4 mmol) for 2 h at room temperature, afforded after chromatography (1/10-4/1 EtOAc/hexanes) the title

1 compound in 90% yield. Oil (Rf = 0.50, 1/4 EtOAc/hexanes). H NMR (300 MHz, CDCl3) 

1.06-1.36 (m, 13H), 1.44-1.55 (m, 2H), 1.92-2.01 (m, 2H), 3.57 (t, J = 6.6 Hz, 2H), 4.83-4.96

13 (m, 2H), 5.67-5.82 (m, 1H); C NMR (75 MHz, CDCl3)  25.7, 28.9, 29.1, 29.4, 29.6, 32.8,

33.8, 63.1, 114.1, 139.2. Spectroscopic data matched literature values.139

197

Malcolm Spain PhD Thesis (Z)-Octadec-9-en-1-ol (233q) (Table 3.15, entry 6)

According to the general procedure H, the reaction of oleic acid (131f) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for 2 h at room temperature, afforded after chromatography (100/3-4/1 EtOAc/hexanes) the title

1 compound in 97% yield. Oil (Rf = 0.46, 1/4 EtOAc/hexanes). H NMR (400 MHz, CDCl3) 

0.81 (t, J = 7.2 Hz, 3H), 1.16-1.32 (m, 23H), 1.45-1.53 (m, 2H), 1.91-1.97 (m, 4H), 3.57 (t, J

13 = 6.8 Hz, 2H), 5.23-5.33 (m, 2H); C NMR (100 MHz, CDCl3)  14.1, 22.7, 25.7, 27.2, 27.2,

29.3, 29.3, 29.4, 29.5, 29.5, 29.8, 29.8, 31.9, 32.8, 63.1, 129.8, 130.0. Spectroscopic data matched literature values.140

Nonane-1,9-diol (122i) (Table 3.15, entry 7)

According to the general procedure H, the reaction of azelaic acid (131g) (0.10 mmol), samarium(II) iodide (1.2 mmol), water (7.2 mmol) and triethylamine (7.2 mmol) for 18 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 88% yield. Solid (Rf = 0.55, EtOAc). Spectroscopic properties matched those previously described.

198

Malcolm Spain PhD Thesis (3R, 5S, 7S, 8R, 9S, 10S, 13R, 14S, 17R)-17-((R)-5-Hydroxypentan-2-yl)-10,13- dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol (122r) (Table 3.15, entry 8)

According to the general procedure H, the reaction of ursodeoxycholic acid (131h) (CAS:

128-12-2) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine

(9.0 mmol) for 4 h at room temperature, afforded after chromatography (1/10-1/1

1 EtOAc/hexanes-EtOAc) the title compound in 94% yield. Solid (Rf = 0.33, EtOAc). H NMR

(500 MHz, CDCl3)  0.61 (s, 3H), 0.88 (s, 6H), 0.91-1.11 (m, 4H), 1.13-1.27 (m, 4H), 1.29-

1.46 (m, 11H), 1.49-1.63 (m, 5H), 1.68-1.76 (m, 3H), 1.77-1.86 (m, 1H), 1.94 (dt, J = 3.2,

13 12.5 Hz, 1H), 3.48-3.59 (m, 4H); C NMR (125 MHz, CDCl3)  12.1, 18.8, 21.2, 23.4, 26.9,

28.8, 29.4, 30.3, 31.9, 34.1, 34.9, 35.5, 36.8, 37.2, 39.2, 40.2, 42.4, 43.8, 43.8, 55.1, 55.7,

63.6, 71.4, 71.5. Spectroscopic data matched literature values.141

3-Phenylpropan-1-ol (116) (Table 3.15, entry 9)

According to the general procedure H, the reaction of 3-phenylpropanoic acid (131i) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (1.8 mmol) and triethylamine (1.8 mmol) for 3 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 92% yield. Oil (Rf = 0.56, 1/1 EtOAc/hexanes). Spectroscopic properties matched those previously described.

199

Malcolm Spain PhD Thesis 2-Methyl-3-phenylpropan-1-ol (122g) (Table 3.15, entry 10)

According to the general procedure H, the reaction of 2-methyl-3-phenylpropanoic acid

(131j) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for 16 h at room temperature, afforded after chromatography (1/10-4/1

EtOAc/hexanes) the title compound in 97% yield. Oil (Rf = 0.37, 1/4 EtOAc/hexanes).

Spectroscopic properties matched those previously described.

3-Phenylbutan-1-ol (122s) (Table 3.15, entry 11)

According to the general procedure H, the reaction of 3-phenylbutanoic acid (131k) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine (9.0 mmol) for 3 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title

1 compound in 88% yield. Oil (Rf = 0.60, 1/1 EtOAc/hexanes). H NMR (500 MHz, CDCl3) 

1.21 (d, J = 7.0 Hz, 3H), 1.24 (br. s, 1H), 1.75-1.82 (m, 2H), 2.77-2.85 (m, 1H), 3.43-3.54

13 (m, 2H), 7.10-7.25 (m, 5H); C NMR (125 MHz, CDCl3)  22.4, 36.5, 41.0, 61.2, 126.1,

127.0, 128.5, 146.8. Spectroscopic data matched literature values.142

3-(p-Tolyl)propan-1-ol (122e) (Table 3.15, entry 12)

According to the general procedure H, the reaction of 3-(p-tolyl)propanoic acid (131l) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for

18 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title

200

Malcolm Spain PhD Thesis compound in 95% yield. Oil (Rf = 0.31, 1/4 EtOAc/hexanes). Spectroscopic properties matched those previously described.

3-(o-Tolyl)propan-1-ol (122t) (Table 3.15, entry 13)

According to the general procedure H, the reaction of 3-(o-tolyl)propanoic acid (131m)

(0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for 18 h at room temperature, afforded after chromatography (1/10-1/4

1 EtOAc/hexanes) the title compound in 98% yield. Oil (Rf = 0.36, 1/4 EtOAc/hexanes). H

NMR (300 MHz, CDCl3)  1.27 (br. s, 1H), 1.73-1.84 (m, 2H), 2.25 (s, 3H), 2.59-2.66 (m,

13 2H), 3.64 (t, J = 6.6 Hz, 2H), 7.00-7.11 (m, 4H); C NMR (75 MHz, CDCl3)  19.3, 29.5,

33.1, 62.6, 126.0, 126.0, 128.8, 130.3, 136.0, 140.0. Spectroscopic data matched literature values.143

2-Phenylpropan-1-ol (122f) (Table 3.15, entry 14)

According to the general procedure H, the reaction of 2-phenylpropanoic acid (131n) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine (3.6 mmol) for

16 h at room temperature, afforded the title compound in 94% yield (1H NMR vs. internal standard). Note: the product is volatile. Spectroscopic properties matched those previously described.

201

Malcolm Spain PhD Thesis 2-(4-Isobutylphenyl)propan-1-ol (122h) (Table 3.15, entry 15)

According to the general procedure H, the reaction of 2-(4-isobutylphenyl)propanoic acid

(131o) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (3.6 mmol) and triethylamine

(3.6 mmol) for 16 h at room temperature, afforded after chromatography (1/10-1/4

EtOAc/hexanes) the title compound in 91% yield. Oil (Rf = 0.44, 1/4 EtOAc/hexanes).

Spectroscopic properties matched those previously described.

2-(1H-Indol-3-yl)ethanol (122m) (Table 3.15, entry 16)

According to the general procedure H, the reaction of 2-(1H-indol-3-yl)acetic acid (131p)

(0.25 mmol), samarium(II) iodide (1.12 mmol), water (6.0 mmol) and triethylamine (6.0 mmol) for 5 h at room temperature, afforded after purification by preparative thin layer chromatography (EtOAc) the title compound in 82% yield. Oil (Rf = 0.71, EtOAc).

Spectroscopic properties matched those previously described.

2-(4-Isobutylphenyl)propan-1-ol (122q) (Table 3.15, entry 17)

According to the general procedure H, the reaction of sodium 2-(4- isobutylphenyl)propanoate (131q) (0.10 mmol), samarium(II) iodide (0.6 mmol), water (7.2 mmol) and triethylamine (7.2 mmol) for 18 h at room temperature, afforded after chromatography (1/10-1/4 EtOAc/hexanes) the title compound in 97% yield. Oil (Rf = 0.15,

1/10 EtOAc/hexanes). Spectroscopic properties matched those previously described.

202

Malcolm Spain PhD Thesis 3-(4-Fluorophenyl)propan-1-ol (133a) (Table 3.16, entry 1)

According to the general procedure H, the reaction of 3-(4-fluorophenyl)propanoic acid

(132a) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine

(9.0 mmol) for 1 h at room temperature, afforded after chromatography (1/4-1/1

1 EtOAc/hexanes) the title compound in 93% yield. Oil (Rf = 0.53, 1/1 EtOAc/hexanes). H

NMR (300 MHz, CDCl3)  1.47 (br. s, 1H), 1.74-1.84 (m, 2H), 2.61 (t, J = 7.8 Hz, 2H), 3.59

13 (t, J = 6.6 Hz, 2H), 6.84-6.93 (m, 2H), 7.03-7.11 (m, 2H); C NMR (75 MHz, CDCl3) 

31.2, 34.3, 62.1, 115.1 (d, J2 = 21.0 Hz), 129.7 (d, J3 = 8.3 Hz), 137.4 (d, J4 = 3.0 Hz), 161.3

1 19 (d, J = 241.5 Hz); F (376 MHz, CDCl3)  -117.7. Spectroscopic data matched literature values.144

3-(4-Chlorophenyl)propan-1-ol (133b) (Table 3.16, entry 2)

According to the general procedure H, the reaction of 3-(4-chlorophenyl)propanoic acid

(132b) (0.25 mmol), samarium(II) iodide (2.5 mmol), water (15 mmol) and triethylamine (15 mmol) for 3 h at room temperature, afforded after chromatography (1/0-1/1 EtOAc/hexanes)

1 the title compound in 86% yield. Oil (Rf = 0.59, 1/1 EtOAc/hexanes). H NMR (300 MHz,

CDCl3)  1.59 (br. s, 1H), 1.83-1.93 (m, 2H), 2.70 (t, J = 7.5 Hz, 2H), 3.68 (t, J = 6.3 Hz,

13 2H), 7.15 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.4 Hz); C NMR (75 MHz, CDCl3)  31.4, 34.1,

62.0, 125.9, 129.8, 131.6, 140.3. Spectroscopic data matched literature values. 145

203

Malcolm Spain PhD Thesis 3-Phenylpropan-1-ol (116) (Table 3.16, entry 3)

According to the general procedure H, the reaction of 3-(4-bromophenyl)propanoic acid

(132c) (0.25 mmol), samarium(II) iodide (2.0 mmol), water (12 mmol) and triethylamine (12 mmol) for 1 h at room temperature, afforded after chromatography (1/10-1/1 EtOAc/hexanes) the title compound in 86% yield. Oil (Rf = 0.48, 1/1 EtOAc/hexanes). Spectroscopic properties matched those previously described.

3-(4-(Trifluoromethyl)phenyl)propan-1-ol (133d) (Table 3.16, entry 4)

According to the general procedure H, the reaction of 3-(4-

(trifluoromethyl)phenyl)propanoic acid (132d) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine (9.0 mmol) for 5 h at room temperature, afforded after chromatography (1/4-1/1 EtOAc/hexanes) the title compound in 98% yield. Oil (Rf =

1 0.62, 60/40 EtOAc/hexanes). H NMR (500 MHz, CDCl3)  1.45 (br. s, 1H), 1.80-1.86 (m,

2H), 2.70 (t, J = 7.5 Hz, 2H), 3.61 (t, J = 6.3 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.47 (d, J =

13 3 7.9 Hz, 2H); C NMR (125 MHz, CDCl3)  31.9, 33.9, 61.9, 123.3, 125.3 (q, J = 3.6 Hz),

2 19 128.3 (q, J = 32.5 Hz), 128.8, 146.0; F (470 MHz, CDCl3)  -62.3. Spectroscopic data matched literature values.146

204

Malcolm Spain PhD Thesis 3-(4-Methoxyphenyl)propan-1-ol (133e) (Table 3.16, entry 5)

According to the general procedure H, the reaction of methyl 3-(4- methoxyphenyl)propanoic acid (132e) (2.5 mmol), samarium(II) iodide (12.5 mmol), water

(75 mmol) and triethylamine (75 mmol) for 2 h at room temperature, afforded after chromatography (1/0-1/1 EtOAc/hexanes) the title compound in 94% yield. Oil (Rf = 0.52,

1/1 EtOAc/hexanes). Note: the following extraction procedure was used: 1 N HCl/CH2Cl2

1 (200 mL/200 mL, 4 x 50 mL). H NMR (300 MHz, CDCl3)  1.33 (br. s, 1H), 1.74-1.84 (m,

2H), 2.58 (t, J = 7.5 Hz, 2H), 3.59 (t, J = 6.3 Hz, 2H), 3.72 (s, 3H), 6.76 (d, J = 8.7 Hz, 2H),

13 7.04 (d, J = 8.4 Hz, 2H); C NMR (75 MHz, CDCl3)  31.2, 34.5, 55.3, 62.3, 113.9, 129.3,

133.9, 157.8. Spectroscopic data matched literature values.101

3-(4-(Methylthio)phenyl)propan-1-ol (133f) (Table 3.16, entry 6)

According to the general procedure H, the reaction of 3-(4-(methylthio)phenyl)propanoic acid (132f) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine (9.0 mmol) for 1 h at room temperature, afforded after chromatography (1/0-1/1

EtOAc/hexanes) the title compound in 96% yield. Oil (Rf = 0.50, 1/1 EtOAc/hexanes). Note:

1 the product is unstable. H NMR (300 MHz, CDCl3)  1.52 (br. s, 1H), 1.74-1.84 (m, 2H),

2.39 (s, 3H), 2.59 (t, J = 7.2 Hz, 2H), 3.58 (t, J = 6.3 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.13

13 (d, J = 8.1 Hz, 2H); C NMR (75 MHz, CDCl3)  16.4, 31.5, 34.2, 62.2, 127.3, 129.0, 135.4,

139.0. Spectroscopic data matched literature values.147

205

Malcolm Spain PhD Thesis 4-(3-Hydroxypropyl)phenol (133g) (Table 3.16, entry 7)

According to the general procedure H, the reaction of 3-(4-hydroxyphenyl)propanoic acid

(132g) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine

(9.0 mmol) for 3 h at room temperature, afforded after chromatography (1/10-2/1

EtOAc/hexanes-EtOAc) the title compound and 4-(3-hydroxypropyl)cyclohex-3-enol in 71%

1 yield. 4-(3-Hydroxypropyl)phenol: 48%, oil (Rf = 0.33, 1/1 EtOAc/hexanes). H NMR (300

MHz, CDCl3)  1.49 (br. s, 1H), 1.74-1.84 (m, 2H), 2.57 (t, J = 7.2 Hz, 2H), 3.61 (t, J = 6.6

Hz, 2H), 4.97 (br. s, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H); 13C NMR (75

MHz, CDCl3)  31.1, 34.4, 62.3, 115.3, 129.5, 133.9, 153.8. 4-(3-Hydroxypropyl)cyclohex-3-

1 enol: 23%, oil (Rf = 0.13, 1/1 EtOAc/hexanes). H NMR (300 MHz, CDCl3)  1.45-1.67 (m,

5H), 1.74-1.84 (m, 1H), 1.87-2.07 (m, 5H), 2.21-2.34 (m, 1H), 3.57 (t, J = 6.6 Hz, 2H), 3.84-

13 3.92 (m, 1H), 5.24-5.29 (m, 1H); C NMR (75 MHz, CDCl3)  26.2, 30.6, 31.0, 33.8, 34.3,

62.8, 66.8, 118.1, 137.2. Spectroscopic data matched literature values.148

3-(4-Aminophenyl)propan-1-ol (133h) (Table 3.16, entry 8)

According to the general procedure H, the reaction of 3-(4-aminophenyl)propanoic acid

(132h) (0.25 mmol), samarium(II) iodide (1.5 mmol), water (9.0 mmol) and triethylamine

(9.0 mmol) for 5 h at room temperature, afforded after chromatography (1/10-1/1

EtOAc/hexanes-EtOAc) the title compound in 73% yield. Oil (Rf = 0.60, EtOAc). Note: the

1 following extraction procedure was used: 1 N NaOH/CH2Cl2 (50 mL/30 mL, 4 x 30 mL). H

NMR (300 MHz, CDCl3)  1.71-1.81 (m, 2H), 2.52 (t, J = 7.2 Hz, 2H), 3.34 (br. s, 2H), 3.58

(t, J = 6.3 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz,

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Malcolm Spain PhD Thesis

CDCl3)  31.2, 34.5, 62.4, 115.4, 129.2, 131.9, 144.3. Spectroscopic data matched literature values.149

(R)-2-Phenylpropan-1-ol (122f-(R)) (Scheme 3.7)

According to the modified general procedure H, using the preformed Sm(II) complex, (R)- methyl 2-phenylpropanoic acid 131n-(R) (0.10 mmol, >99.5% ee), was reacted with samarium(II) iodide (0.8 mmol), water (4.8 mmol) and triethylamine (4.8 mmol) for 2 h at

1 room temperature to afford the title compound in 91% yield. H NMR (500 MHz, CDCl3) 

1.21 (d, J = 7.0 Hz, 3H), 1.33 (br. s, 1H), 2.84-2.91 (m, 1H), 3.63 (d, J = 7.0 Hz, 2H), 7.14-

13 7.18 (m, 3H), 7.24-7.28 (m, 2H); C NMR (125 MHz, CDCl3)  17.6, 42.5, 68.7, 126.7,

127.5, 128.7, 143.7. HPLC analysis (chiralpak IA 28C, hexanes/i-PrOH 99/1, 1.0 mL/min,

220 nm) indicated 93.5% ee: tR (minor) = 18.42 minutes, tR (major) = 19.48 minutes.

Mechanistic experiments

3-Phenylpropan-1,1-d2-1-ol (116-D,D) (Scheme 3.8)

According to the general procedure H, the reaction of methyl 3-phenylpropanoic acid (0.10 mmol), samarium(II) iodide (0.6 mmol), deuterium oxide (1.8 mmol) and triethylamine (1.2 mmol) for 2 h at room temperature, afforded 1,1-D,D-3-phenylpropan-1-ol (96% deuterium incorporation). Yield 80% (1H NMR vs. internal standard). Purification by preparative thin layer chromatography (60/40 EtOAc/hexanes) afforded the title product (Rf = 0.58, 1/1

207

Malcolm Spain PhD Thesis 1 EtOAc/hexanes). H NMR (400 MHz, CDCl3)  1.24 (br. s, 1H), 1.82 (t, J = 7.6 Hz, 2H),

13 2.64 (t, J = 7.6 Hz, 2H), 7.10-7.24 (m, 5H); C NMR (100 MHz, CDCl3)  32.0, 34.0, 61.6

(t, J1 = 21.1 Hz), 125.9, 128.4, 128.4, 141.8.

Determination of primary kinetic isotope effect (Scheme 3.8)

According to the general procedure, the reaction of 3-phenylpropanoic acid (0.10 mmol), samarium(II) iodide (0.6 mmol), D2O/H2O (1:1, 1.8 mmol) and triethylamine (1.2 mmol) for

2 h at room temperature, afforded 1,1-D,D-3-phenylpropan-1-ol and 3-phenylpropan-1-ol. The

1 amount of each species was determined by H NMR (500 MHz, CDCl3,). Kinetic isotope effect, kH/kD = 1.1.

208

Malcolm Spain PhD Thesis Determination of the rate orders in the reduction of acid (131b).

Samarium(II) iodide rate order. According to the general procedure I. Conditions: SmI2 (5.0-

7.0 equiv), Bu3N (12.0 equiv), H2O (18.0 equiv), acid (1.0 equiv).

Figure 7.10. Determination of SmI2 rate order in the reduction of 131b using SmI2–amine–

H2O.

Plot of ln(kobs) vs ln [SmI2] in the reduction of 2-butyloctanoic acid using SmI2/Bu3N/H2O 0

-0.2

-0.4

) -0.6

obs y = 1.9329x + 4.6682 R² = 0.9999 ln(k -0.8

-1

-1.2 -3 -2.95 -2.9 -2.85 -2.8 -2.75 -2.7 -2.65 -2.6 -2.55

ln [SmI2]

. According to the general procedure I. Conditions: SmI2 (6.0 equiv), Bu3N (12.0 equiv),

H2O (18.0 equiv), Acid (0.05-0.15 equiv).

Figure 7.11. Determination of acid rate order in the reduction of 131b using SmI2–Amine–

H2O.

Plot of ln(kobs) vs ln [acid] in the reduction of 2-butyloctanoic acid using SmI2/Bu3N/H2O 0 -0.2 -0.4

y = 0.9285x + 1.638

) -0.6 R² = 0.9997 obs

-0.8 ln(k -1 -1.2 -1.4 -3.1 -2.9 -2.7 -2.5 -2.3 -2.1 -1.9 -1.7 -1.5 ln [acid]

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Malcolm Spain PhD Thesis

Amine Rate Order. According to the general procedure I. Conditions: SmI2 (6.0 equiv), Bu3N

(6.0-18.0 equiv), H2O (18.0 equiv), acid (1.0 equiv).

Figure 7.12. Determination of amine rate order in the reduction of 131b using SmI2–amine–

H2O.

Plot of ln(kobs) vs ln [Bu3N] in the reduction of 2-butyloctanoic acid using SmI2/Bu3N/H2O 0 -0.2 -0.4

-0.6

) -0.8 y = 0.9378x + 1.2062

obs R² = 0.987

-1 ln(k -1.2 -1.4 -1.6 -3 -2.5 -2 -1.5 -1

ln [Bu3N]

Water Rate Order. According to the general procedure I. Conditions: SmI2 (6.0 equiv), Bu3N

(12.0 equiv), H2O (6.0-18.0 equiv), acid (1.0 equiv).

Figure 7.13. Determination of H2O rate order in the reduction of 131b using SmI2–amine–

H2O.

Plot of ln(kobs) vs ln [H2O] in the reduction of 2-butyloctanoic acid using SmI2/Bu3N/H2O 0.1 -6E-16 -0.1

-0.2

)

obs -0.3 y = 1.0134x + 2.3049 ln(k -0.4 -0.5 -0.6 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3

ln [H2O]

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Malcolm Spain PhD Thesis Chapter 4. New divalent lanthanide complexes

General procedure J for reductions using the TmI2 system

In an argon-filled glove box, TmI2 powder was weighed out into a vial equipped with a magnetic stir bar, transferred out of the glove box, and placed under a positive pressure of argon using standard Schenk techniques. Substrate (as a THF solution) was added, followed by a rapid injection of additives (typically H2O or MeOH, as specified), with vigorous stirring. After the specified time, the excess of TmI2 was oxidised by bubbling air through the reaction mixture. The reaction mixture was diluted with CH2Cl2 (20 mL) and HCl (1.0 N, 30 mL). The aqueous layer was extracted with CH2Cl2 (3 x 20 mL), organic layers were combined, dried over Na2SO4, filtered and concentrated. All products were identified using

1H NMR (400 and 500 MHz) analysis and comparison with authentic samples. GC, GC/MS analysis was used for volatile products. In all cases, GC, GC/MS or LC/MS analysis was used as a complementary method of analysis to confirm the product distribution. All yields refer to yields determined by 1H NMR using an internal standard unless stated otherwise. Reactions involving lanthanides(II) can typically be followed by visual observation of the changes in

1 colour of the respective reaction mixtures. In the case of TmI2‒THF, the colour changes from TmII (dark green) to TmIII (oxidised, solvated: transparent colour; oxidised, w/o protic

150 additives: yellow colour). It should be noted that the instability of TmI2‒THF to light has been reported; it is recommended that the reactions involving TmI2‒THF are carried out in the dark.151

Determination of the Redox Potential of TmI2–MeOH. (Table 4.1) According to the general procedure J, an aromatic hydrocarbon as indicated in Table 4.1

(0.05 mmol) was reacted with thulium(II) iodide (0.15 mmol) and methanol (0.20 mL, 100 equiv) in THF (1.0 mL) at RT for 2-3 min. A small portion of the reaction mixture (200-500

L) was transferred to a GC vial and analyzed directly by GC (Method 2) and GC-MS

211

Malcolm Spain PhD Thesis (Method 2) to obtain the product distribution by comparison with authentic samples. In case of non-volatile products, 1H NMR analysis using an internal standard was used to obtain the yield after the work-up as described in the general methods.

Reduction of esters and carboxylic acids (Table 4.3)

According to the general procedure J, an ester or carboxylic acid as indicated in Table 4.3

(typically, 0.05 mmol) was reacted with thulium(II) iodide (0.30 mmol) and methanol (0.20 mL, 100 equiv) or water (0.14 mL, 150 equiv) in THF (typically, 1.0 mL) at RT until decolourisation to transparent indicative of the formation of TmIII species had occurred

(typically 2-3 min). All compounds matched the spectroscopic properties matched those previously described.

C–N bond cleavage in amides (Scheme 4.1)

According to the general procedure J, amide as indicated in Table SI-5 (typically, 0.05 mmol) was reacted with thulium(II) iodide (0.15-0.30 mmol) and a proton source in THF (typically,

1.0 mL) until decolourisation to transparent indicative of formation of TmIII species had occurred. All compounds have been previously reported. N-Butyl-3-phenylpropanamide

1 (143). H NMR (500 MHz, CDCl3)  0.80 (t, J = 7.0 Hz, 3H), 1.13-1.21 (m, 2H), 1.29-1.35

(m, 2H), 2.39 (t, J = 7.5 Hz, 2H), 2.87 (t, J = 8.5 Hz, 2H), 3.09-3.13 (m, 2H), 5.79 (br, 1H),

13 7.09-7.13 (m, 3H), 7.16-7.21 (m, 2H); C NMR (125 MHz, CDCl3)  13.7, 20.0, 31.6, 31.9,

38.4, 39.3, 126.2, 128.4, 128.5, 140.9, 172.4. N-Butyldecanamide (145). 1H NMR (500

MHz, CDCl3)  0.80 (t, J = 7.0 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H), 1.14-1.31 (m, 14H), 1.37-

1.44 (m, 2H), 1.51-1.58 (m, 2H), 2.10 (t, J = 7.5 Hz, 2H), 3.13-3.17 (m, 2H), 6.40 (br, 1H);

13 C NMR (125 MHz, CDCl3)  13.7, 14.0, 20.1, 22.6, 25.9, 29.2, 29.3, 29.4, 29.4, 31.7, 31.8,

1 36.7, 39.1, 173.4. N-Butyladamantane-1-carboxamide (147). H NMR (300 MHz, CDCl3)

212

Malcolm Spain PhD Thesis  0.77 (t, J = 7.5 Hz, 3H), 1.15-1.27 (m, 2H), 1.31-1.41 (m, 2H), 1.53-1.66 (m, 6H), 1.71-

1.76 (m, 6H), 1.87-1.94 (m, 3H), 3.07-3.14 (m, 2H), 5.80 (br, 1H); 13C NMR (75 MHz,

CDCl3)  13.7, 20.0, 28.1, 31.7, 36.5, 38.9, 39.2, 40.4, 177.7. 3-Phenyl-N-

1 propylpropanamide (149). H NMR (500 MHz, CDCl3)  0.72 (t, J = 7.5 Hz, 3H), 1.30-

1.37 (m, 2H), 2.36 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 3.01 (q, J = 7.0 Hz, 2H), 6.60

13 (br, 1H), 7.02-7.06 (m, 3H), 7.09-7.13 (m, 2H); C NMR (125 MHz, CDCl3)  11.4, 22.8,

31.9, 38.2, 41.3, 126.1, 128.3, 128.4, 141.0, 172.5. 3-Phenylpropanamide (151). 1H NMR

(500 MHz, CDCl3)  2.40 (t, J = 7.5 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 5.76 (br, 1H), 6.26 (br,

13 1H), 7.08-7.12 (m, 3H), 7.16-7.20 (m, 2H); C NMR (125 MHz, CDCl3)  31.4, 37.5, 126.3,

128.3, 128.6, 140.7, 175.5. N-Ethyladamantane-1-carboxamide (153). 1H NMR (300 MHz,

CDCl3)  1.05 (t, J = 7.2 Hz, 3H), 1.58-1.70 (m, 6H), 1.74-1.81 (m, 6H), 1.91-1.99 (m, 3H),

13 3.15-3.24 (m, 2H), 5.81 (br, 1H); C NMR (75 MHz, CDCl3)  14.9, 28.1, 34.1, 36.5, 39.2,

1 40.4, 177.8. N-Isopropyl-3-phenylpropanamide (155). H NMR (500 MHz, CDCl3)  0.96

(d, J = 7.0 Hz, 6H), 2.33 (t, J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 3.87-3.96 (m, 1H), 6.14

13 (d, J = 7.0 Hz, 1H), 7.03-7.07 (m, 3H), 7.11-7.15 (m, 2H); C NMR (125 MHz, CDCl3) 

22.6, 31.9, 38.4, 41.2, 126.1, 128.3, 128.4, 141.0, 171.4.

213

Malcolm Spain PhD Thesis Chapter 5. Synthesis of samarium diiodide

Iodometric titration.113

Note: Iodine also reacts with Sm(0), therefore there may be differences between this titre and the one obtained using the standard method, if the suspensions of SmI2 are not allowed to settle for long enough. An oven-dried four-dram vial equipped with a stirring bar and septum was charged with iodine (typically 53.0 mg), placed under high-vacuum line, subjected to three evacuation/backfilling cycles with argon, and tetrahydrofuran was added (4.0 mL) giving a solution of iodine in THF (ca. 0.1 mmol/mL). Another vial, equipped with a stirring bar and septum was placed under high-vacuum line, subjected to three evacuation/backfilling cycles with argon, and charged with solution of SmI2 (typically, 1.0 mL, the exact volume of added SmI2 has to be carefully noted). The solution of SmI2 was titrated with iodine solution, prepared as described above. The end point is reached when the solution changes to yellow colour. Note: all syringes and solvents used in the procedure should be flushed with argon (3 times) and degassed prior to use to obtain reproducible results. The titration should be repeated to give the average of three experiments.

3-hydroxy-2-(4-methoxybenzyl)propanoic acid (167). (Scheme 5.1)

According to the general procedure for the preparation of SmI2, samarium metal (12.0 g), freshly purified 1,2-diidodoethane (11.28 g), THF (400 mL, 8 x 50 mL), was stirred at RT for

18h. After settling the solution was titrated and transferred to a reaction flask. To a solution of SmI2 (267 mL, 0.075 M) was freshly degassed deionised water (45 mL) over 10-15 s.

Addition of water results in a characteristic colour change from deep blue (samarium diiodide) to burgundy red, indicating formation of samarium diiodide-water complex. To the

214

Malcolm Spain PhD Thesis pre-formed SmI2–H2O complex was added a solution of 5-(4-methoxybenzylidene)-2,2- dimethyl-1,3-dioxane-4,6-dione (0.656 g) in freshly degassed THF (20 mL) dropwise over

30s. The reaction was left to stir at RT for 15 min and quenched with air. The reaction was quenched by bubbling with air until a milky-white suspension was formed. The quenched reaction mixture was diluted with CH2Cl2 (400 mL) and HCl (0.1 N, 500 mL). The aqueous layer was extracted with CH2Cl2 (5 x 250 mL), organic layers were combined, dried over

Na2SO4, filtered and concentrated to give the crude product as a brown oil. The crude product was purified by chromatography ((1:10 EtOAC/hexanes) followed by (1:1 EtOAC/hexanes, with 0.033% of AcOH) then EtOAc (with 0.033% of AcOH) and concentrated under reduced pressure to afford the title compound as a white solid (mp = 80-82 °C), which was stored neat

1 or as a solution in acetone. Yield 84% (442 mg). Rf (0.1% AcOH in EtOAc) = 0.36. H NMR

(500 MHz, CDCl3):  2.81-2.90 (m, 2H), 2.99-2.08 (m, 1H), 3.72-3.77 (m, 1H), 3.79-3.83 (m,

13 1H), 3.81 (s, 3H), 6.86 (d, J = 8.8 Hz), 7.15 (d, J = 8.8 Hz). C NMR (125 MHz, CDCl3): 

33.2, 49.0, 55.3, 61.9, 114.0, 130.0, 130.2, 158.3, 179.7. IR (neat, cm-1): 3415, 3335, 2908,

2611, 1695, 1612, 1513, 1470, 1414, 1349, 1298, 1246, 1219, 1177, 1113, 1060, 1034, 1004,

+ 930, 906, 841, 802, 770. HRMS calcd for C11H14O4Na: (M + 23) 233.0785, found 233.0786.

2-(4-bromobenzyl)-3-hydroxypropanoic acid (Scheme 5.1)

According to the general procedure for the preparation of SmI2, samarium metal (12.0 g), freshly purified 1,2-diidodoethane (11.28 g), THF (400 mL, 8 x 50 mL), was stirred at RT for

18h. After settling the solution was titrated and transferred to a reaction flask. To a solution of SmI2 (197 mL, 0.076 M) was added a solution of 5-(4-bromobenzyl)-2,2-dimethyl-1,3- dioxane-4,6-dione (168) (0.783 g) in freshly degassed THF (20 mL) followed by freshly degassed deionised water (50 mL) over 10-15 s. Addition of water results in a characteristic

215

Malcolm Spain PhD Thesis colour change from deep blue (samarium diiodide) to burgundy red, indicating formation of samarium diiodide-water complex The reaction was left to stir at RT for 15 min and quenched with air. The reaction was quenched by bubbling with air until a milky-white suspension was formed. The quenched reaction mixture was diluted with CH2Cl2 (400 mL) and HCl (0.1 N, 500 mL). The aqueous layer was extracted with CH2Cl2 (5 x 250 mL), organic layers were combined, dried over Na2SO4, filtered and concentrated to give the crude product as a brown oil. The crude product was purified by chromatography ((1:10

EtOAC/hexanes) followed by (1:1 EtOAC/hexanes, with 0.033% of AcOH) then EtOAc

(with 0.033% of AcOH) and concentrated under reduced pressure to afford the title compound as a white solid (mp = 84-86 °C), which was stored neat or as a solution in

1 acetone. Yield 82% (528 mg). Rf (0.1% AcOH in EtOAc) = 0.27. H NMR (500 MHz,

CDCl3):  2.72-2.80 (m, 2H), 2.88-2.96 (m, 1H), 3.61-3.65 (m, 1H), 3.70-3.74 (m, 1H), 7.01

13 (d, J = 8.2 Hz), 7.34 (d, J = 8.5 Hz). 6.5-7.5 (1H, br). C NMR (125 MHz, CDCl3):  33.3,

48.7, 61.8, 120.6, 130.7, 131.7, 137.2, 179.4. IR (neat, cm-1): 3333, 2944, 2603, 1693, 1489,

1403, 1346, 1293, 1244, 1207, 1166, 1112, 1097, 1061, 1013, 951, 929, 906, 843, 832, 795,

+ 764, 714. MS (ES) m/e calculated for C10H11O3BrNa: (M + 23) 280.9784, found 280.9780.

216

Malcolm Spain PhD Thesis References

1 Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5. 2 Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371. 3 Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem. Int. Ed. 2009, 48, 7140. 4 Szostak, M.; Procter, D. J. Angew. Chem. Int. Ed. 2011, 50, 7737. 5 Procter, D. J.; Flowers, R. A. II; Skrydstrup, T., Organic Synthesis Using Samarium Diiodide: A Practical Guide, RSC Publishing, Cambridge: 2009. 6 Kagan, H. B.; Namy, J. L., Lanthanides: Chemistry and Use in Organic Synthesis, Kobayashi, S., Ed. Springer, New York: 1999; pp 155. 7 Dahlén, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393. 8 Flowers, R. A., II Synlett 2008, 1427. 9 Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008. 10 Chopade, P. R.; Prasad, E.; Flowers, R. A., II J. Am. Chem. Soc. 2004, 126, 44. 11 Shabangi, M.; Flowers, R. A., II Tetrahedron Lett. 1997, 38, 1137. 12 Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485 13 Miller, R. S.; Sealy, J. M.; Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II J. Am. Chem. Soc. 2000, 122, 7718. 14 Shabangi, M.; Sealy, J. M.; Fuchs, J. R.; Flowers, R. A., II Tetrahedron Lett. 1998, 39, 4429. 15 Prasad, E.; Knettle, B. W.; Flowers, R. A., II J. Am. Chem. Soc. 2004, 126, 6891. 16 Knettle, B. W.; Flowers, R. A., II Org. Lett. 2001, 3, 2321. 17 Choquette, K. A.; Sadasivam, D. V.; Flowers, R.A., II J. Am. Chem. Soc. 2011, 133, 10655. 18 Kuhlman, M. L.; Flowers, R. A., II Tetrahedron Lett. 2000, 41, 8049. 19 Evans, W. J.; Gonzales, S. L.; Ziller, J. W. J. Am. Chem. Soc. 1994, 116, 2600. 20 Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron Lett. 1995, 36, 949. 21 Dahlén, A.; Nilsson, Å.; Hilmersson, G. J. Org. Chem. 2006, 71, 1576. 22 Chauvin, Y.; Olivier, H.; Saussine, L. Inorg. Chim. Acta. 1989, 161, 45. 23 Fedushkin, I. L.; Bochkarev, M. N.; Dechert, S.; Schumann, H. Chem. Eur. J. 2001, 7, 3558. 24 Szostak, M.; Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155. 25 Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem. Commun. 2012, 48, 330.

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