Palladium-Catalyzed Reactions of Enol Ethers THESIS Presented In

Palladium-Catalyzed Reactions of Enol Ethers

THESIS

Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University

Amneh Awad

Graduate Program in Chemistry

The Ohio State University

2014

Master's Examination Committee:

Professor Christopher M. Hadad, Advisor

Professor James P. Stambuli

Professor Jovica D. Badjic

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! Copyright by

Amneh Awad

2014

! ! ! ! ! ! Abstract

Enals were accessed via a palladium-catalyzed oxidation of enol ethers using lower palladium loadings than traditional Saegusa oxidations of silyl enol ethers. In addition to functional group tolerance, the conditions allow the access of di-, tri-, and tetrasubstituted olefins. This methodology was extended to the intramolecular cyclization of 4-hydroxy-

1-enol ethers to give furans and dihydrofurans which are prevalent in biologically active compounds. The extension of the methodology to synthesize pyrroles from 4-amino-1- enol ethers was also successful.

Dedication

This document is dedicated to my friends and family.

iii

Acknowledgments

I would like to thank Professor James P. Stambuli for accepting me into his group. His mentorship and guidance taught me to love chemistry and to become a better problem solver. He is driven when it comes to his work but, above all, he cares about his students.

I would like to thank him for creating a group dynamic that fostered a good team spirit where everyone was always willing to assist each other however possible. More than anything else, I want to thank him for always having his door open for me and for always looking out for my best interest. All the Stambuli group members have my appreciation and gratitude for making work a fun and intellectually stimulating environment. Special thanks to Dr. Matt Lauer and Dr. William Henderson for serving as my mentors on the enol ether project and beyond. Luke A. Baldwin, Jon W. Crowe, and I joined the group at the same time and I would like to thank them for being my friends as well as co-workers.

I would like to thank Professor Christopher M. Hadad for giving me a place in his group and mentoring me for the past year. Special thanks to Ryan K. McKenney, Ben R.

Garrett, and Tom S. Corrigan from the Hadad group as well as Chi “Chip” Le from the

Stambuli group for the work we did on the Hapten project. Finally, I would like to thank

Professor Jovica Badjic for serving on my Examination Committee.

Vita

December 12, 1989...... Born – Detroit, Michigan

May 2007 ...... Fordson High School

May 2011 ...... B.S. Chemistry, Biochemistry, University of

Michigan-Dearborn

2011 to present ...... Graduate Teaching Associate, Department

of Chemistry and Biochemistry, The Ohio

State University

Publications

Lauer, M. G.; Henderson, W. H.; Awad, A.; Stambuli, J. P. “Palladium-Catalyzed

Reactions of Enol Ethers: Access to Enals, Furans, and Dihydrofurans.” Org. Lett. 2012,

14, 6000-6003.

Fields of Study

Major Field: Chemistry

Table of Contents

Abstract...... ii!

Dedication...... iiii!

Acknowledgments...... iv!

Vita ...... v

Table of Contents ...... vi

List of Tables ...... viii!

List of Figures...... x

List of Schemes...... xi!

List of Abbreviations...... xii!

Chapter 1: Enals from the Saegusa-Type Oxidations of Enol Ethers ...... 1

1.1 Abstract ...... 1!

1.2 Background...... 1!

1.3 Introduction ...... 5!

1.4 Results and Discussion ...... 7

1.5 Conclusions...... 18

Chapter 2: Furans and Dihydrofurans from 4-Hydroxy Enol Ethers...... 19!

2.1 Abstract ...... 19!

2.2 Background...... 19!

2.3 Results and Discussion...... 23!

2.4 Conclusions and Future Work ...... 38

Chapter 3: Pyrroles from 4-Amino Enol Ethers...... 39!

3.1 Abstract ...... 39!

3.2 Background...... 39!

3.3 Results and Discussion...... 41!

3.4 Conclusions and Future Work ...... 46!

Chapter 4: Experimental Details...... 47!

4.1 General Methods...... 47!

4.2 Chapter 1 Experimental Details...... 48!

4.3 Chapter 2 Experimental Details...... 69!

4.4 Chapter 3 Experimental Detials...... 86!

References and Notes ...... 88

Appendix A: 1H NMR and 13C NMR Spectra for Selected Compounds ...... 93

vii

List of Tables

Table 1.1 Larock Optimization Conditions 3

Table 1.2 Takayama Optimization Conditions 4

Table 1.3 Initial Reaction Optimization 9

Table 1.4 Enal Solvent Screen 10

Table 1.5 Enal Substrate Scope 12

Table 1.6 Greener Optimization Conditions 14

Table 1.7 Initial Enone Optimization 16

Table 2.1 Yields of 4-Hydroxy Methyl Enol Ethers Using Reissig’s Synthesis 24

Table 2.2 Optimization of 4-Hydroxy Methyl Enol Ether Synthesis 26

Table 2.3 Acetic Acid and Water Screen 27

Table 2.4 Effect of Alkyl Enol Ether of Furan Yield 30

Table 2.5 Furan Acetic Acid Screen 32

Table 2.6 Furan Solvent Screen 33

Table 2.7 Furan Ligand Screen 34

Table 2.8 Furan Substrate Scope 35

Table 2.9 Conversion of Enol Ethers to 2,5-Dihydrofurans 36

Table 3.1 General Pyrrole Cyclization Conditions Screen 43

Table 3.2 Pyrrole Solvent Screen 44 viii

Table 3.3 Acetic Acid and Triphenylphosphine Screen 45

List of Figures

Figure 1.1 Saegusa Oxidation Mechanism 2

Figure 1.2 Possible Oxidation Mechanisms 17

Figure 2.1 Proposed Oshima-Utimoto Reaction Mechanism 21

Figure 2.2 Furan % Yield vs Hydrolysis Rate of Alkyl Vinyl Ether 31

List of Schemes

Scheme 1.1 Oxidant Controlled Stereoselectivity 6

Scheme 1.2 Conversion of Vinyl Fluorides to !,"-Unsaturated Aldehydes 7

Scheme 1.3 Methods for Enol Ether Synthesis 8

Scheme 1.4 Stellettadine A Intermediate Synthesis 13

Scheme 2.1 Paal-Knorr Furan Synthesis 20

Scheme 2.2 Catalytic Oshima-Utimoto Reaction 21

Scheme 2.3 Reisigg’s Dihydrofuran Synthesis 22

Scheme 2.4 Allyl Methyl Ether Addition to Aldehydes and Ketones 25

Scheme 2.5 One-Pot Cyclization/Sakurai Allylation 28

Scheme 2.6 Conversion of 2,5-Dihydrofurans to Furans 28

Scheme 2.7 2,3-Disubstituted Furan Synthesis 37

Scheme 2.8 2,4-Diphenylfuran Substrate Synthesis 38

Scheme 3.1 Paal-Knorr Pyrrole Synthesis 40

Scheme 3.2 Synthesis of 1,2-Diarylpyrroles 40

Scheme 3.3 Possible Mechanism for the Formation of 1,2-Diarylpyrroles 41

Scheme 3.4 Pyrrole Substrate Synthesis Attempts 42

List of Abbreviations

°C degrees Celsius

! alpha

Å angstrom

" beta

# gamma

$ heat (reflux)

% chemical shift in parts per million

µ micro

1H NMR proton nuclear magnetic resonance

13C NMR carbon 13 nuclear magnetic resonance

Ac acetyl

AcOH acetic acid aq aqueous atm atmosphere(s)

Bn benzyl

Bt benzotriazole

BQ 1,4-benzoquinone

xii br broad nBu normal-butyl sBu sec-butyl tBu tert-butyl

Bz benzoyl c centi c concentration calcd calculated

CAM ceric ammonium molybdate cat catalytic

COSY correlation spectroscopy

CSA camphorsulfonic acid

D dextrorotatory d day(s); doublet dba dibenzylideneacetone

DCM dichloromethane dd doublet of doublets

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(DHQ)2PHAL dihydroquinine 1,4-phthalazinediyl diether

(DHQD)2PHAL dihydroquinidine 1,4-phthalazinediyl diether

DIAD diisopropyl azodicarboxylate

DIBAL diisobutylaluminum hydride

xiii

DIPEA diisopropylethylamine

DMAP N,N-dimethylaminopyridine

DME 1,2-dimethoxymethane

DMF N,N-dimethylformamide

DMP Dess-Martin periodinane

DMSO dimethylsulfoxide dppe 1,2-bis(diphenylphosphino)ethane dt doublet of triplets

E entgegen ee enantiomeric excess equiv equivalent(s)

ESI electrospray ionization

Et ethyl

FTIR Fourier transform infrared spectroscopy g gram(s)

GC gas chromatography h hour(s)

HMPA hexamethylphosphoramide

HPLC high performance liquid chromatography

HRMS high resolution mass spectrometry

HWE Horner-Wadsworth-Emmons

Hz hertz

xiv

IR infrared iPr iso-propyl

J coupling constant in Hertz

L liter(s)

L levorotatory

LDA lithium diisopropylamide

LiHMDS lithium hexamethyldisilazide lut 2,6-lutidine m meta m milli; multiplet

M molarity m-CPBA meta-chloroperoxybenzoic acid

Me methyl

MeCN acetonitrile

MeOH methanol min minute(s) mol mole(s)

MOM methoxymethyl

MS mass spectrometry; molecular sieves

Ms mesyl/methanesulfonyl

MTBE methyltert-butyl ether

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NMP N-methyl-2-pyrrolidone

NOESY nuclear Overhauser effect spectroscopy

NR no reaction o ortho p para p pentet

Pd(OAc)2 palladium (II) acetate pdt product

PEG polyethylene glycol

Ph phenyl

PIDA phenyliodine diacetate

PMB para-methoxybenzyl ppm parts per million p-TSA para-toluenesulfonic acid pyr pyridine q quartet

R rectus rt room temperature s sec/secondary s singlet

S sinister

xvi sat. saturated sep septet sext sextet

SM starting material t/tert tertiary t triplet

TBAB tetrabutylammonium bromide

TBAC tetrabutylammonium chloride

TBAF tetrabutylammonium fluoride

TBAI tetrabutylammonium iodide

TBDPS tert-butyldiphenylsilyl

TBS tert-butyldimethylsilyl

TES triethylsilyl

TEA triethylamine

TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl

Tf triflyl/(trifluoromethanesulfonyl)

THF tetrahydrofuran

TFA trifluoroacetic acid

TLC thin layer chromatography

TMEDA tetramethylethylenediamine

TMS trimethylsilyl

TMSE 2-(trimethylsilyl)ethyl

xvii

Ts tosyl/(p-toluenesulfonyl)

UV ultraviolet

Z zusammen

xviii

Chapter 1: Enals from the Saegusa-Type Oxidation of Enol Ethers

1.1 Abstract

A methyl enol ether Saegusa-type oxidation was developed using lower palladium loadings than the current oxidation of methyl enol ethers which uses 0.5-1 equivalents of palladium (II) acetate.1 The wide variety of functional groups tolerated expands the substrate scope of the reaction which produces !,"-unsaturated aldehydes in moderate to good yield.

1.2 Background

Saegusa and coworkers reported in 1978 that silyl enol ethers could be oxidized to the corresponding !,"-unsaturated carbonyl compounds using 0.5 equivalents of palladium

(II) acetate and 0.5 equivalents of BQ as a co-oxidant at room temperature.2 Decreasing the palladium loadings to 0.25 equivalents or less results in a decreased reaction rate and yield. Thus, stoichiometric amounts of palladium (II) acetate are often used to form !,"- unsaturated carbonyls in natural product synthesis.3

Mechanistically speaking, the Saegusa oxidation occurs by coordination of Pd(OAc)2 to the TMS enol ether (1.1) to make an alkene-Pd complex (1.2) (Figure 1.1). An acetate

1 ion attacks the TMS group to give a palladium-enolate species (1.3), which undergoes !- hydride elimination to form the enone (1.4), palladium (0), and acetic acid. An oxidant is used if substoichiometric amounts of palladium are used to reoxidize the palladium (0) into palladium (II).

TMSO

OAc Pd (II) R 1.1 OAc

TMSO OAc (II) Pd (0) Pd OAc R

Me SiOAc AcOH 3

(II) (AcO)Pd H(OAc)Pd(II) R 1.3

O 1.4

Figure 1.1: Saegusa Oxidation Mechanism

The high cost of palladium (II) acetate inspired several modifications and improvements of the method but they still suffer from low yields and often have a limited substrate scope. Tsuji modified the traditional Saegusa conditions to lower palladium loadings to 5 mol% using dppe as a ligand with 2 equivalents of diallyl carbonate as the reoxidant.4 While this method is a great improvement on traditional Saegusa oxidations, it relies on superstoichiometric reoxidant which makes it less attractive. An environmentally friendly modification was later developed by Larock using the taxol model system (1.5) where oxygen is the reoxidant in DMSO using 10 mol% Pd(OAc)2

(Table 1.1).5 This method unfortunately requires long reactions times or higher temperatures to give good yields of the enone product (1.6). Another drawback is the production of the undesired ketone (1.7) as the major product when the palladium loadings are lowered to 3 mol %.

Table 1.1: Larock Optimization Conditions

OTMS O O

Pd(OAc)2 + DMSO, O O 2 O O O O O

1.5 1.6 1.7

o Entry Pd(OAc)2 (mol%) Time (h) Temp ( C) Ratio (1.6:1.7) % Yield (1.6+1.7)

1 10 72 25 100:0 86

2 10 16 80 100:0 80

3 3 16 80 33:67 -

Other Saegusa modifications allow for the use of enol acetates or allyl enol carbonates as the substrate for the oxidation; however, these methods suffer from similar drawbacks as previously discussed.6-8 Takayama recently used methyl enol ethers are precursors to access enals in good yields (Table 1.2).1 Using Saegusa’s conditions did not lead to any product formation from methyl enol ether 1.8 (entry 1). Addition of 1.2 equivalents of water to the reaction gave the product enal 1.9 in 56% yield (entry 2).

Using 5% aqueous NaHCO3 instead of water to make the reaction moderately basic improved the yield to 88% (entry 3). The best conditions employed 5% aqueous

NaHCO3, 0.5 equivalents Pd(OAc)2, and 1 equivalents Cu(OAc)2•H2O to reoxidize palladium (0) to palladium (II) to give the desired enal in 92% yield (entry 4). Trying to reduce the palladium loadings to 10 mol% drastically reduced the yield (entry 5).

Table 1.2: Takayama Optimization Conditions

OMe Pd(OAc)2 O

o CH3CN, 0-24 C

1.8 1.9

Entry Pd(OAc)2 (mol%) Time (h) Addiditve (equiv) % Yield

1 100 6 - NR

2 100 6 H2O (1) 56

3 50 0.5 5% NaHCO3 88

5% NaHCO3 4 50 1 92 Cu(OAc)2•H2O (1)

5% NaHCO3 5 10 6 49 Cu(OAc)2•H2O (1.9)

With optimized conditions in hand, Takayama explored the substrate scope of the reaction and found it to be general; giving mostly E enals from isomeric mixtures of methyl enol ethers in good yield. Regardless of the substrate however, the method required at least 0.5 equivalents of Pd(OAc)2 to give good yields.

1.3 Introduction9

A major interest in our lab is the development of allylic C-H oxidation of acyclic olefins. Recently we reported the allylic oxidation of terminal olefins into allylic acetates using Pd(OAc)2, a thioether ligand, and BQ as a reoxidant in AcOH. Disubstituted olefins such as 2-hexene however, were unreactive.10 We hypothesized that the increased steric interactions around the double bond made metal coordination to the olefin (a process we deemed crucial to the reaction mechanism) more difficult. To circumvent this, we sought to decrease the steric effects by using vinylsilanes since the C-Si bond length (~1.8 Å) is

0.3 Å shorter than the C-C bond length (~1.5 Å).11 The vinylsilanes could be quickly accessed through hydrosilylation of the corresponding alkyne and the oxidized allylic acetate would have two functional handles for further synthetic transformations. Both cis and trans-vinylsilanes were synthesized and subjected to the reaction conditions. Trans- vinylsilanes did not react presumably because they are still too sterically encumbered for metal coordination, but subjecting cis-vinylsilanes to Pd(OAc)2 loadings as low as 2 mol

% in neat AcOH at 90 oC led to the formation of branched allylic acetates with high diastereo- and regioselectivity. Surprisingly, the stereoselectivity of the reaction was controlled by the choice of oxidant. When the cis-vinylsilane 1.10 was exposed to the

5 reaction conditions using BQ as the oxidant, the trans-allylic acetate 1.11 was produced

(Scheme 1.1). However, when PIDA was used as an oxidant, the cis-allylic acetate 1.12 was the major product. Thus the reaction is quite versatile since either isomer could be accessed from the same starting material depending on the choice of oxidant.

BQ OAc AcO SiEt3

2 mol %Pd(OAc)2 1.11 SiEt3 AcO AcOH, 90 oC OAc SiEt 1.10 PIDA 3 AcO

1.12

Scheme 1.1 Oxidant Controlled Stereoselectivity

Encouraged by the success of the use of cis-vinylsilanes as unhindered disubstituted olefins, we sought to explore other possible substrates for allylic oxidations.

Vinyl fluorides were selected as possible substrates due to the small atomic radius of fluorine. Surprisingly, exposure of vinyl fluoride 1.13 to our allylic oxidation conditions gave no allylic acetate 1.14, but produced the corresponding !,"-unsaturated aldehyde

1.15 as the product (Scheme 1.2).12 The enal product 1.15 presumably arises from hydrolysis of the allyl acetate 1.16 with fluoride as the leaving group.13 Since the fluoride was only acting as leaving group, we thought we could use a different vinyl-leaving group substrate, preferably one that is more synthetically accessible. Vinyl ethers seemed like a good substitute since the substrates could be accessed quickly through a Wittig olefination reaction and the alkoxy group is a better leaving group than fluoride.

OAc 5 mol% Pd(OAc) 2 X F BQ (2 equiv) 7 1.14 F

o 7 AcOH, 40 C 1.13 7 O 1.15

H F O F OH

7 O 7 O Nu 1.16 1.17 Nu

Scheme 1.2: Conversion of Vinyl Fluorides to !,"-Unsaturated Aldehydes

1.4 Results and Discussion

To begin our exploration of vinyl ethers as precursors to enals, we investigated different commercially available phosphonium salts.

(Methoxymethyl)triphenylphosphonium chloride is commercially available and easily synthesized from acetic anhydride, acetyl chloride, dimethoxymethane, and triphenylphosphine.14 We found that upon reaction with an aldehyde 1.18,

(methoxymethyl)triphenylphosphonium chloride gave the one-carbon elongated methyl enol ether 1.19 (Scheme 1.3).1 Alternatively, methyl enol ethers without one-carbon elongation 1.20 can be prepared by conversion of ketones into the dimethyl acetal followed by elimination of methanol with trimethylorthoformate and p-TSA.15

Additionally, methyl enol ethers 1.20 can be prepared by O-alkylation of the enolate with methyl triflate.16

Cl Ph P O 3 , base MeO THF 1.19 R R 1 O trimethylorthoformate, p-TSA R R 1 OMe 1.20 1.18 base, HMPA, THF R R 1 then MeOTf

Scheme 1.3: Methods for Methyl Enol Ether Preparation

With several methods to synthesize various methyl enol ethers at hand, we began our investigations into the Saegusa-type oxidation. Reaction optimization was conducted using (4-methoxymethylene)cyclohexylbenzene (1.21) as the substrate (Table 1.3). First, we tried the reaction in the absence of Pd(OAc)2 which produced none of the desired enal

(1.22) product (entry 1). Using our allylic oxidation conditions for terminal olefins with 5 mol % of an external sulfide ligand gave the desired product in 39% yield (entry 2).

Excluding the sulfide ligand however, had no effect on the yield (entry 3). Reducing the

Palladium loading down to 0.5 mol % decreased the yield (entry 4). A surprising improvement was found upon addition of 1.1 equivalents of water to the reaction (entry

5). Increasing the Palladium loading to 2 mol % improved the yield to 82% (entry 6).

Finally, decreasing the temperature had no effect on the yield (entry 7).

Table 1.3 Initial Reaction Optimizations

OMe OMe X mol % Pd(OAc)2, X equiv BQ AcOH, X equiv Additive, T, 8h

Ph Ph 1.21 1.22

a Entry Pd(OAc)2 (mol %) BQ (equiv) Temp (°C) Additive GC Yield (%)

1 0 2 40 - 0

2 5 2 40 5 mol % Lb 39

3 5 2 40 - 38

4 2 40 - 27 0.5

5 0.5 2 40 1.1 equiv H2O 69

6 2 1.2 40 1.1 equiv H2O 82

7 2 1.2 23 1.1 equiv H2O 85

a b Nitrobenzene used as internal standard L = PhSCH2CH2O(p-tolyl)

A solvent screen was conducted next to see if other solvents were competent in the reaction using our optimized reaction conditions and 4 equivalents of AcOH (Table

1.4). Dichloromethane (entry 2), toluene (entry 3), acetone (entry 4), and dioxane (entry

5) all gave similar yields, whereas acetonitrile (entry 6) gave severely diminished yields presumably by coordinating strongly to the palladium catalyst. Dichloromethane was chosen as the solvent for the reaction since it is less hygroscopic than acetone and dioxane, and it is easier to remove from the reaction than toluene.

Table 1.4: Enal Solvent Screen

OMe

Pd(OAc)2 (2 mol %), BQ (1.2 equiv) O Ph AcOH (4 equiv), H2O (1.1 equiv), 23 °C, 8h Ph

1.21 1.22

Entry Solvent GC Yield (%)a

1 acetic acid 85

2 dichloromethane 81

3 acetone 78

4 toluene 74

5 77 dioxane

6 acetonitrile 42

a Nitrobenzene used as Internal Standard

Once we optimized our conditions, we sought to explore the substrate scope of the reaction (Table 1.5). Alkyl substrates were well tolerated to give the corresponding enals in good yields (entries 1-3). The reaction conditions tolerated acetate esters, silyl ethers, as well as vinylsilanes (entries 4-6). Trisubstituted enals were produced in good yields

(entries 1, 7-8, 11) and the first example of a tetrasubstituted enal (entry 12) from a

Saegusa-type oxidation of an alkyl enol ether was successfully achieved with the help of

10 longer reaction time and higher catalyst loading. Nitrogen containing derivatives of phthalimides, succinimides, and indoles were tolerated as well (entries 9-10, 13).

Table 1.5: Enal Substrate Scope

R1 R1 Pd(OAc)2 (1-5 mol %), BQ (1.2 equiv), DCM R2 OMe R2 O AcOH (4 equiv), H2O (1.1 equiv), 23 °C, time

a Entry Enol Ether Time (h) Pd(OAc)2 (mol %) Enal Yield (%) OMe O 1 Ph 1.21 8 2 Ph 1.22 80

O 2 OMe 1.23 4 2 1.24 65 9 9

OMe O 3 1.25 4 1 1.26 63

OMe O 4 TBSO 1.27 8 2.5 TBSO 1.28 57 3 3

OMe O 5 AcO 1.29 12 1 AcO 1.30 79 3 3 SiEt3 SiEt3 6 OMe 1.31 24 4 O 1.32 67 2 2 O OMe O O 7 1.33 18 2.5 1.34 76 O O OMe O 8 1.35 6 2 1.36 90 O O

N OMe N O 9 3 1.37 7 2.5 3 1.38 72 O O O O N OMe N O 10 3 1.39 8 2.5 3 1.40 72 OMe O O O

11 1.41 16 5 1.42 73b

OMe O 12 1.43 96 10 1.44 57c

13 OMe 1.45 16 5 3 O 1.46 44 NBoc3 NBoc OMe 14 1.47 16 5 O 1.48 72

a Yields are average of two one mmol reactions. bReaction was conducted in neat AcOH at 40 °C cReaction was conducted in neat AcOH at 23 °C

The utility of the reaction is demonstrated by a substrate (1.47) derived from citronellal (entry 14) to produce an enal (1.48) that is an intermediate in Mori’s synthesis of stellettadine A (1.49).17 Beginning from citronellal (1.50), Mori uses a Wittig reaction to make the one carbon elongated methyl enol ether and uses Takayama’s conditions to oxidize it to the enal (1.51) in 61% yield over two steps. These conditions however, required 56 mol % of Palladium and therefore has room for improvement. Application of our conditions using only 5 mol % Palladium gave us a comparable yield of 65% over two steps (Scheme 1.4).

O NH Cl 2 H N NH N N 2 H NH2 Cl Stellettadine A 1.49

Mori's Work: Cl 1. Ph3P (1.2 equiv), PhLi (1.2 equiv), O O Et2O O 2. Pd(OAc)2 (56 mol %), Cu(OAc)2 (1.1 equiv) 1.50 (15 : 1) MeCN : 5% NaHCO3 (aq) 1.51

Our Work: Ph P Cl 1. 3 (1.3 equiv), KOtBu (1.3 equiv) O O THF, 90% O 2. Pd(OAc) (5 mol %), BQ (1.2 equiv), DCM 2 1.48 1.50 AcOH (4 equiv), H2O (1 equiv), 72%

Scheme 1.4: Stellettadine A Intermediate Synthesis

One drawback of the method is that we are required to use stoichiometric amounts of the reoxidant p-benzoquinone. A greener reoxidant would be the use of oxygen such as

13 the one that worked for the allylic oxidation of terminal olefins.10 This alternative reoxidation method utilizes 10 mol % dihydroquinone and 5 mol % copper (II) acetate under an atmosphere of oxygen to complete the catalytic cycle. Although this method worked, it required higher palladium loadings and the yields of enals were lower than those using BQ as a reoxidant (Table 1.6)

Table 1.6: Greener Oxidation Conditions

Pd(OAc) (5 mol %), BQ (1.2 equiv), DCM R 2 R 1 Cu(OAc)2 (5 mol %), hydroquinone (10 mol %), 1 R2 OMe R2 O AcOH (4.2 equiv), H2O (1.1 equiv), 23 °C, 18-25 h

O O 1.22 66% 1.24 64% Ph 9

O O 1.26 60% AcO 1.30 30% 3

In Takayama’s original report, there were no examples of enones as the product of oxidation of methyl enol ethers.1 Hoping to expand the scope of our method further, we investigated such an oxidation. Our optimizations (Table 1.7) began with 1- methoxycyclohexene (1.52). Under our oxidation conditions with acetic acid as the solvent (entry 1), the reaction produced some of the desired cyclohexeneone (1.53) but the majority of the product was the cyclohexanone (1.54) that presumably forms from hydrolysis of the enol ether. Changing the solvent to THF (entry 2) gave more of our desired enone product 1.53, but the major product was still 1.54 and this reaction was sluggish. Increasing the equivalents of water from 1.1 to 5.5 equivalents (entry 3) resulted

14 in an incomplete reaction, but the major product was the desired enone 1.53. Changing the solvent to dichloromethane (entry 4) let to a complete reaction, but the amount of desired 1.53 dropped once again. Another change in the solvent, this time to acetone

(entry 5) once again resulted in incomplete conversion, which is surprising since acetone and DCM were both competent solvents for enal formation. Adding acetic acid formed more of the undesired side product 1.54, however the reaction was faster with more acetic acid. We currently do not have synthetically useful conditions for the formation of enones from alkyl enol ethers.

Table 1.7: Initial Enone Optimizations

OMe O O

Pd(OAc)2 (5 mol %), BQ (1.2 equiv) + X equiv AcOH, X equiv H2O, 23 °C, 17h 1.52 1.53 1.54

Entry H2O (equiv) AcOH (equiv) Solvent % Converstion Ratio 1.53 : 1.54

1 1.1 N/A AcOH 100 0.1 : 1

2a 1.1 - THF 99 0.5 : 1

3 5.5 - THF 36 2 : 1

4 5.5 - DCM 100 0.1 : 1

5 5.5 - Acetone 57 0.3 : 1

6 5.5 THF 100 1 1 : 1

7 5.5 0.5 THF 84 1 : 1

8 5.5 0.07 THF 70 2 : 1

a 72 h to completion

A number of different mechanisms for the oxidation are possible (Figure 1.2).

The first two pathways involve a Wacker type oxidation or acetoxypalladation across the double bond where palladium and either water or acetate add across the double bond

(pathways 1-2). A !-hydride elimination gives the hemi-acetal 1.56 or the acetal 1.59.

Hydrolysis of the hemi-acetal or acetal with concomitant elimination of methanol gives the enal product 1.57. The other possible mechanisms could go through a "-allyl palladium species (1.60) via palladium insertion into the allylic C-H bond. Regioselective

16 nucleophilic attack followed by !-hydride elimination gives the same hemi-acetal 1.56 or acetal 1.59 depending on the nucleophile. Finally, hydrolysis with methanol elimination gives the ",!-unsaturated aldehyde.

Pathway Pd R OMe R OMe R O 1

OH OH 1.55 1.56 1.57

Pd Acetoxypalladation/Wacker R OMe R OMe R O 2

OAc OAc R OMe 1.58 1.59 1.57 1.54 R OMe R O 3 !-Allyl Palladium OH R OMe 1.56 1.57

Pd R OMe 4 1.60 R O OAc 1.59 1.57

Figure 1.2: Possible Oxidation Mechanisms

Experimental observations support pathways 1 and 3. Water is crucial to the reaction, as no product is produced in its absence, which supports water as the nucleophile to make the hemi-acetal 1.56. The potentially stable acetal 1.59 is never observed nor isolated from the reaction. This could mean that acetate is not the nucleophile in the reaction, which is supported by the fact that trace amounts of product could still be formed in the absence of acetic acid. The yield is low because benzoquinone cannot oxidize palladium (0) to palladium (II) without acetic acid present.

1.5 Conclusions

A new method for the conversion of methyl enol ethers in to !,"-unsaturated aldehydes was developed. The method uses lower palladium loadings and has comparable yields and functional group tolerance as the method developed by

Takayama.1 Extension of the oxidation to produce enones resulted in low yields. Further improvement of the method is needed to produce enones and to allow a one-pot reaction to produce and oxidize methyl enol ethers.

Chapter 2: Furans and Dihydrofurans from 4-Hydroxy-1-Enol Ethers

2.1 Abstract

An intramolecular cyclization reaction to produce 2,5-dihydrofurans or furans from 4- hydroxy-1-enol ethers was developed. This reaction is an extension of the methodology developed to produce !,"-unsaturated aldehydes. The mild reaction conditions display wide functional group tolerance and the ease of preparation of the 4-hydroxy-1-enol ethers allows rapid access to substituted furans and 2,4-dihydrofurans heterocycles.

2.2 Background

Natural products are abundant in heterocycles including furan and furan derivatives which serve as common versatile synthetic building blocks.18-19 The most common way to synthesize furans is via the Paal-Knorr furan synthesis which is an acid- catalyzed dehydration of 1,4-diketones (Scheme 2.1).20, 21 The limitation of this method is the need for 1,4-diketones, or 1,4-diketone surrogates, and the strongly acidic or Lewis acidic conditions needed for the cyclization.22-25 This limits the reaction to substrates that can tolerate the harsh conditions which limits the substrate scope. To address these shortcomings, metal catalysis has recently been used in the literature to form furans.26-28

O R3 O R3 H+ R + R 1 O H R R 4 4 1 R4 R1 or or OR5 R2 O R OR Lewis Acid R2 Lewis Acid 2 5 R3 2.1 2.2 2.3

Acid or Base

O R3 R R 4 1 O R2 2.4

Scheme 2.1: Paal-Knorr Furan Synthesis

Oshima and Utimoto developed a method for the intermolecular cyclization of allyl alcohols (2.5) with 10 equivalents of vinyl ethers (2.6) (Figure 2.1).29

Stoichiometric amounts of palladium were required for the reaction which gives mixtures of the tetrahydrofuran (2.7) and 2,3-dihydrofuran (2.8) products. Any substitution on the vinyl group was not tolerated by the reaction conditions. The proposed mechanism begins with coordination of the vinyl ether to palladium followed by regioselective nucleophilic attack of the allyl alcohol to give the alkyl palladium intermediate (2.9). The intermediate

2.9 undergoes intramolecular alkene insertion to give the cyclic intermediate 2.10 which can then undergo !-hydride elimination to form either the tetrahydrofuran products 2.7 or

2.11. The exo-methylene 2.11 is not isolated but is isomerized to the dihydrofurans 2.8.

O O Pd(OAc)2 (1 equiv) OBu OBu + + OH OBu 2.5 2.6 2.7 2.8 1 equiv 10 equiv

PdII PdII

OBu OBu OBu O O O 2.9 2.10 2.11

Figure 2.1: Proposed Oshima-Utimoto Reaction Mechanism

In 2005, Hosokawa discovered a catalytic version of the Oshima-Utimoto reaction using 5 mol % Pd(OAc)2, 5 mol % Cu(OAc)2, and catechol in acetonitrile under an atmosphere of oxygen (Scheme 2.2).30 The regioselectivity of the reaction were controlled by the R group on the allylic alcohols (2.12). When the R group was aromatic or hydrogen, the product was the exo-methylene product (2.13), but when R was alkyl, the product was the vinyl tetrahydrofuran (2.14) (Scheme 2.2). An asymmetric version using a chiral bisoxazoline ligand and toluene as the solvent was developed but enantiomeric excesses of only about 20-50% were obtained.31 Hosokawa’s methodology was utilized in several natural product syntheses.32-34

Pd(OAc)2 (5 mol %) Cu(OAc)2 (5 mol %) catechol (10 mol %) O O + OBu OBu OBu R OH R + R O2 (1 atm), MeCN 24 °C 2.12 2.6 2.13 2.14 1 equiv 10 equiv R = Ph or H R = alkyl

Scheme 2.2: Catalytic Oshima-Utimoto Reaction

Reissig and coworkers developed an intramolecular variant of the Oshima-

Utimoto reaction by utilizing 4-hydroxy methyl enol ethers.35 They showed that 2,5- dihydrofurans could be made by utilizing Takayama’s modified Saegusa-type conditions with 50 mol % palladium (II) acetate, one equivalents of copper (II) acetate, and sodium bicarbonate in acetonitrile under an atmosphere of oxygen. When 4-hydroxy methyl enol ether 2.15 was subjected to Takayama’s conditions, the 2,5-dihydrofuran (2.16) was obtained as a mixture of the acetal and hemiacetal (Scheme 2.3). The mixture was subjected to a Sakurai reaction to give the allyl-substituted dihydrofurans (2.17) in 86% yield over two steps.

RO OMe Pd(OAc)2 (50 mol %) T M S (3.7 equiv) HO O O Cu(OAc)2 (1 equiv) NaHCO 3 BF3OEt2 (5.5 equiv)

H2O, MeCN DCM 0 °C, 1 h -78 °C, 45 min then 24 °C, 1 h then 24 °C, 5 h

2.15 2.16 2.17 R = H or Me 86 % two steps

Scheme 2.3: Reissig’s Dihydrofuran Synthesis

The 4-hydroxy methyl enol ethers are also useful precursors to tetrahydrofurans since treatment with acid hydrolyzes the enol ether to give the !–hydroxy aldehydes which cyclize to the tetrahydrofuran.36

2.3 Results and Discussion37

Since Reissig was able to synthesize 2,5-dihydrofurans using Takayama’s conditions on 4-hydroxy methyl enol ethers, we wanted to see if we could apply our methodology to achieve the same transformation. To accomplish this goal, we first had to synthesize 4-hydroxy methyl enol ethers. Reissig’s method to produce 4-hydroxy methyl enol ethers used samarium diiodide (2.5 equivalents) in a solution of THF, tert-butanol, and HMPA to achieve reaction between aldehyde or ketone 2.18 and methoxyallene 2.19 to give 4-hydroxy methyl enol ether 2.20 in low to moderate yields (Table 2.1).36 This method was attempted for the synthesis of four substrates. The cyclohexanone (2.21,

2.23, 2.25) substrates reacted to give the desired 4-hydroxy methyl enol ethers (2.22,

2.24, 2.26) in poor to moderate yields while the benzaldehyde substrate (2.27) did not give any of the desired product (2.28).

Table 2.1: Yields of 4-Hydroxy Methyl Enol Ethers Using Reissig’s Synthesis

Sm (2.5 equiv) ICH2CH2I (2.1 equiv) HMPA (18 equiv) t R R O BuOH (2 equiv) 1 2 + OMe • HO R R THF, 24 °C 1 2 OMe 2.18 2.19 16-18 h 2.20 (2 equiv) Entry Starting Material Product % Yield

1 2.21 O 2.22 MeO 51 HO

2 2.23 O 2.24 MeO 18 HO O O 3 2.25 O 2.26 MeO 34 HO Ph 4 2.27 O 2.28 MeO 0 OH

An alternative route to access 4-hydroxy methyl enol ethers was examined that avoided using super stoichiometric quantities of the costly metal samarium or the highly carcinogenic additive HMPA. Addition of the allyl methyl ether anion to aldehydes and ketones gives two regioisomers of the homoallylic alcohol (Scheme 2.4) where the desired isomer is produced in comparable yields to Reissig’s method.

sBuLi (1.3 equiv) R R R R O -78 °C, THF 1 2 1 2 OMe + HO + HO R R 1 2 OMe OMe 2.18 2.29 2.20 2.30 (1.3 equiv) 15-43 %

Scheme 2.4: Allyl Methyl Ether Addition to Aldehydes and Ketones

To improve the selectivity for the desired homoallylic alcohol 2.20, a limited number of bases and additives were screened (Table 2.2). For all the optimization reactions, 3-phenylpropionaldehyde (2.31) was used along with methyl allyl ether (2.29).

The ether was stirred in a THF solution at -78 °C with the base for an hour after which the aldehyde was added. The resulting solution was allowed to warm to 0 °C and stirred for an additional hour before quenching with a saturated solution of ammonium chloride.

The base that gave the best ratio of the desired (2.32) to undesired (2.33) homoallylic alcohol was sBuLi (entry 1). Changing the base to tBuLi or a mixture of nBuLi and tetramethylethylenediamine as an additive gave a nearly 1:1 ratio of the desired and undesired isomers (entries 2, 3). Adding titanium isopropoxide increased the steric effects around the terminal carbon and led exclusively to the undesired isomer 2.33 (entry 4).

Table 2.2: Optimization of 4-Hydroxy Methyl Enol Ether Synthesis

OMe OMe Conditions Ph Ph Ph O + OMe + OH OH 2.31 2.29 2.32 2.33 Entry Conditions Ratio 2.33 : 2.34a

1 sBuLi (1.3 equiv), THF 0.69 : 0.31

2 tBuLi (1.3 equiv), THF 0.53 : 0.47

3 nBuLi (1.3 equiv), TMEDA (1.3 equiv), pentane 0.54 : 0.46

n 4 BuLi (1.3 equiv), TMEDA (1.3 equiv), Ti(OiPr)4, pentane 0.00 : 1.00

a 1 Ratio determined by H NMR spectroscopy after aqueous work-up

To test if we could extend our conditions for enal formation to the intramolecular cyclization to produce 2,5-dihydrofurans, we used the substrates we synthesized either using Reissig’s method or via allyl methyl ether addition to aldehydes and ketones. When we subjected 2.22 to our standard enal conditions, the desired 2,5-dihydrofuran product

(2.34) along with the undesired tetrahydrofuran product (2.35) were obtained (Table 2.3, entry 1). Using neat acetic acid as the solvent decreased the ratio of the desired to undesired product presumably because too much acetic acid could lead to hydrolysis of the enol ether leading to production of the saturated product (entry 2). Excluding water from the reaction improved the ratio of dihydrofuran to tetrahydrofuran (entry 3).

Without acetic acid, there was no reaction since acidic conditions are needed for the benzoquinone to oxidize palladium (0) (entry 4). Reducing the amount of acetic acid to only 1 equivalent also improved the ratio of the dihydrofuran product (entry 5).

Table 2.3: Acetic Acid and Water Screen

Pd(OAc)2 (5 mol %) BQ (1.2 equiv) AcOH (4.2 equiv) H2O (1.1 equiv) O O OMe + OMe OMe OH CH2Cl2, 23 °C, 2 h 2.22 2.34 2.35

Entry Change from Scheme Ratio 2.34 : 2.35a

1 - 0.81 : 0.19

2 Solvent neat AcOH 0.53 : 0.46

3 No H2O 0.86 : 0.14

4 No AcOH NR

5 Only 1 equiv AcOH 0.88 : 0.12

a 1 Ratio determined by H NMR spectroscopy after aqueous work-up

The acetals of the dihydro- and tetrahydrofuran derivatives can act as electrophiles to allylsilane nucleophiles under lewis acidic conditions to form a new carbon-carbon bond in a reaction known as the Sakurai allylation.38 We envisioned that we could subject our 4-hydroxymethylenol ether substrates to a one-pot cyclization/allylation sequence by taking advantage of the potential instability of the acetal products (Scheme 2.5). To effect this transformation, we subjected 2.22 to the optimized cyclization conditions followed with treatment of the acetals (2.34, 2.35) with allyltrimethylsilane and boron trifluoride diethyl etherate as the Lewis acid to give the desired allylated products as a 9:1 mixture of the 2,5-dihydro- and tetrahydrofuran (2.36,

2.37).

OMe then: Pd(OAc)2 (5 mol %) T M S BQ (1.2 equiv) O (1.6 equiv) O O AcOH (1 equiv) BF •OEt (1.6equiv) 3 2 + OMe OH CH2Cl2, 23 °C, 1 h 0-24 °C, 17 h

2.22 2.34 + 2.35 2.36 2.37 sat. pdt 9 : 1 74 % two steps

Scheme 2.5: One-Pot Cyclization/Sakurai Allylation

During cyclization of a 4-hydroxy methyl enol ether derived from an aldehyde

(2.28), we observed the formation of two peaks on the GC from the syn and anti isomers of the dihydrofuran (2.38), which slowly converted into a new peak. Analysis of the product by GC-MS and 1H NMR spectroscopy indicated that the new product was the furan (2.39). We postulated that under the acidic reaction conditions, aromatization via acid-catalyzed elimination of methanol from the dihydrofuran intermediates could lead to the formation of the furans (Scheme 2.6). Treatment of the 2,5-dihydrofuran 2.38 with

2M hydrochloric acid facilitated aromatization to the corresponding furan 2.39 and shortened the reaction time.

Pd(OAc)2 (5 mol %) OH BQ (1.2 equiv) AcOH (4 equiv) H O OMe O OMe DCM, 5 h 2.28 2.38 2.39

Scheme 2.6: Conversion of 2,5-Dihydrofuran to Furan

After the acidic work-up, the furan products were relatively pure except for a minor amount of the tetrahydrofuran by-product. The yields of the furan product however were lower than desired, with the highest GC yield being 60% and the isolated yield around 50% (Table 2.4, entry 1). Based on the vibrantly colored reaction mixtures we obtained such as green, purple, or red, we concluded that either the starting material or the product were likely polymerizing. To try to avoid polymerization, we sought to change the R group on the enol ether. Instead of reacting our aldehydes and ketones with allyl methyl ether, we just had to change the alkyl group on the ether to obtain our new substrates. Using the commercially available allyl ethyl ether, we prepared the 4-hydroxy ethyl enol ether and subjected it to the furan cyclization conditions (Table 2.4 entry 2).

The isolated yield of the furan using the ethyl enol ether improved to 59% yield, which is a 10% improvement over the methyl enol ether (entry 1). Increasing the sterics of the alkyl group was accomplished by making the isopropyl and neopentyl enol ethers. The isopropyl group increased the isolated yield to 73% (entry 3) but the neopentyl group decreased the yield to 64% (entry 4). The phenyl ether did not improve the yield over the isopropyl substituent and the thiomethyl ether failed to react (entries 5-6).

Table 2.4: Effect of Alkyl Enol Ether on Furan Yield

Pd(OAc)2 (2.5 mol %) BQ (1.1 equiv) OH AcOH (4 equiv) DCM, 0.5 h O then 2M HCl R 2.40 2.41 Entry R Isolated Yield (%)a GC Yield (%)b

1 OMe 47 60

2 OEt 59 75

3 OiPr 73 81

4 - 64 O

5c OPh - 68

6c SMe NR 0

aIsolated yields are an average of two trials bNitrobenzene used as an internal standard c Reaction time 12 h

In an attempt to find a trend in the dependence of the yield of the furan on the alkyl substituent, the rates of hydrolysis for various alkyl vinyl ethers were compared

(Figure 2.2). The rates of hydrolysis for the vinyl ethers were taken from the work of

Jones39 and Kresge.40 Unfortunately, there was no direct correlation between the yield of the furan and the rate of hydrolysis of the ethers which leads us to believe that there are multiple factors affecting the yield such as steric and electronic effects on the 2,5- dihydrofuran intermediate.

Figure 2.2: Furan % Yield vs Hydrolysis Rate of Alkyl Vinyl Ether

In an attempt to improve the yield of the reaction, we conducted an acetic acid screen to determine the number of equivalents needed in the reaction (Table 2.5). The reaction gave poor yields in the absence of acetic acid (entry 1) probably because acetic acid is needed for benzoquinone to oxidize palladium (0). With one equivalent of acetic acid, the yield improved significantly and the reaction time was shortened to two hours

(entry 2). Using two or four equivalents of acetic acid decreased the reaction time to one hour but had no affect on the yield of the furan (entries 3-4). Finally, using acetic acid as the solvent lowered the reaction time even further, but decreased the yield to 60% (entry

5). Since both one, two, and four equivalents all gave similar yields of the furan, one equivalent of acetic acid was selected as the optimal amount to decrease the likelihood of starting material or product decomposition.

Table 2.5: Furan Acetic Acid Screen

Pd(OAc)2 (2.5 mol %) BQ (1.1 equiv) OH AcOH ( equiv) DCM, time h O then 2M HCl OiPr 2.42 2.41 Entry AcOH (equiv) Time (h) GC Yield (%)a

1 0 24 20

2 1 2 85

3 2 1 83

4 4 1 85

5 solvent (1 M) 0.5 60

a Nitrobenzene used as internal standard

Next, a solvent screen was conducted to determine the optimal solvent (Table.

2.6). Several solvents allowed the reaction to progress with good yields of the furan 2.41, but just as with the enal solvent screen, dichloromethane proved to be the optimal solvent

(entry 1) as opposed to acetone, diethyl ether, toluene, or tetrahydrofuran (entries 2-5).

Once again, strongly coordinating solvents such as dimethylformamide, acetonitrile, and dimethyl sulfoxide gave significantly lower yields of the desired product (entries 6-8).

Table 2.6: Furan Solvent Screen

Pd(OAc)2 (2.5 mol %) BQ (1.1 equiv) OH AcOH (1 equiv) solvent, 13 h O then 2M HCl OiPr 2.42 2.41 Entry Solvent GC Yield (%)a

1 DCM 86

2 Acetone 78

3 Diethyl ether 76

4 Toluene 74

5 THF 73

6 DMF 43

7 MeCN 30

8 DMSO 28

a Nitrobenzene used as internal standard

Different ligands were tested to see if the yield of the furan 2.41 could be improved (Table 2.7). Sulfoxides and sulfides as ligands decreased the reaction rate and lowered the yield of the furan product (entries 2-4). Small amounts of triphenylphosphine improved the yield with 10 mol % being the optimal amount to give a 90% yield (entries

5-6). Too much of the phosphine ligand however, likely saturates the metal center since

33 the yield decreased to 66% when half an equivalent of triphenylphosphine was used

(entry 7).

Table 2.7 Furan Ligand Screen.

Pd(OAc)2 (2.5 mol %) BQ (1.1 equiv) OH AcOH (1 equiv) DCM, time h O then 2M HCl OiPr 2.42 2.41 Entry Ligand (mol %) Time (h) GC Yield (%)a

1 no ligand 1 85

2 DMSO (20) 16 37

3 diethyl sulfide (20) 2 77

4 allyl sulfide (20) 16 43

5 PPh3 (20) 1 88

6 PPh3 (10) 1 90

7 PPh3 (50) 5 66

a Nitrobenzene used as internal standard

With optimized conditions in hand, we sought to explore the substrate scope of the reaction (Table 2.8). The reaction tolerated aromatic (entries 1-3) and alkyl (entries

4-5) substituents in the 2-position to produce 2-susbtituted furans in good yields.

Table 2.8 Furan Substrate Scope

Pd(OAc)2 (2.5 mol %) PPh3 (10 mol %) OH BQ (1.1 equiv) R O R AcOH (1 equiv) OiPr DCM, 24 °C, 2 h 2.43 then 2M HCl 2.44

Entry Enol Ether Product Yield (%)a OH 1 2.45 2.39 O 82

OiPr OH MeO 2 2.46 MeO 2.47 89 O OiPr OMe OMe OH 3 2.48 2.49 72 O i S O Pr S OH 4 2.42 2.41 O 82 OiPr OH O b 5 2.50 TBSO 2.51 TBSO 78 OiPr

aIsolated yields are an average of two 1 mmol reactions b Reaction conducted for 6 h

During our furan optimizations, we noticed that using one equivalent of acetic acid produced minimal amounts of the furan until the acidic work-up. If the reactions were quenched with water instead of acid, the 2,5-dihydrofurans could be isolated instead

(Table 2.9). The 2,5-dihydrofurans obtained from secondary (entries 1-2) as well as tertiary alcohols (entry 3) could be isolated in good yields. In contrast to the enal

35 conditions, the 2,5-dihydrofurans obtained under furan cyclization conditions had no contamination from the tetrahydrofuran side products.

Table 2.9: Conversion of Enol Ethers to 2,5-Dihydrofurans

Pd(OAc)2 (2.5 mol %) PPh3 (10 mol %) OH BQ (1.1 equiv) R O OiPr R AcOH (1 equiv) OiPr DCM, 24 °C, 2 h 2.43 2.52

Entry Enol Ether Product Yield (%)a OH MeO 1 2.46 MeO 2.53 82b O OiPr OiPr OMe OMe OH b 2 2.48 2.54 O OiPr 89 S S OiPr

OH i O Pr c 3 2.55 OiPr 2.56 O O 72 O

aIsolated yields are an average of two 1 mmol reactions bProduct isolated as a 1:1 mixture of diastereomers c Product isolated as a 3:1 mixture of diastereomers

With improved conditions for making 2,5-disubstituted dihydrofurans, attempts were made at making other disubstituted dihydrofurans. Unfortunately, using 4-hydroxy isopropyl enol ether 2.57, only 31% of the desired furan 2.61 was obtained using our optimized cyclization conditions for 17 hours (Scheme 2.7). Attempts at altering the temperature, equivalents of acetic acid or equivalents of triphenylphosphine resulted in

36 the same or lower yields. Although the side products were not isolated, one potential side product could be the exomethylene tetrahydrofuran 2.59 which could result form !- hydride elimination of the organopalladium (II) species 2.58.

Pd(OAc)2 (2.5 mol %) PPh3 (10 mol %) OH BQ (1.1 equiv) O AcOH (1 equiv) OiPr DCM, 24 °C, 17 h 2.61 2.57 then 2M HCl

H+ Pd

O OiPr

O 2.60 OiPr !-hydride elimination Pd 2.58 O OiPr

2.59

Scheme 2.7: 2,3-Disubstituted Furan Synthesis

In an attempt to avoid the potential !-hydride elimination problem, the methyl substituent was replaced with a phenyl group in substrate 2.63. Unfortunately, the reaction between benzaldehyde 2.27 and the allyl alcohol 2.62 did not work to produce any desirable products (Scheme 2.8).

sBuLi (1.3 equiv) OH O i + O Pr X THF -78 to 24 °C OiPr 2.27 2.62 2.63 1.3 equiv

Scheme 2.8: 2,4-Diphenyl Furan Substrate Synthesis

2.4 Conclusions and Future Work

Furans or 2,5-dihydrofurans can be produced from the same 4-hydroxy enol ether substrates under mild conditions with short reaction times. This methodology allows access to furans or dihydrofurans in just two steps from aldehydes and ketones. The methodology would be far more practical if a more efficient synthesis of 4-hydroxy enol ethers could be developed which would improve the overall yield of the method. The addition of the alkyl enol ether to aldehydes and ketones has the greatest room for improvement and screening additives to improve the regioselectivity of the addition would improve the yield tremendously. Additionally, expanding the methodology to include polysubstituted furans and 2,5-dihydrofurans needs to be explored.

Chapter 3: Pyrroles from 4-Amino Enol Ethers

3.1 Abstract

An intramolecular reaction to produce pyrroles from 4-amino-1-enol ethers was developed. This methodology was inspired by our previous work in the synthesis of furans from 4-hydroxy-1-enol ethers. The reaction provides an alternative procedure for producing 2-aryl pyrroles in modest yield using mild conditions.

3.2 Background

Pyrrole derived alkaloids are abundant in nature and posses relevant biological activity.41-42 One of the most employed methods to prepare pyrroles is the Paal-Knorr pyrrole synthesis (Scheme 3.1). The Paal-Knorr reaction is the condensation of 1,4- dicarbonyls or their surrogates with ammonia or a primary amine to give substituted pyrroles.20-21 This methodology is limited by the same factors that limit the Paal-Knorr furan synthesis; namely, the synthetic challenge of producing 1,4-diketones. Alternative methods to produce pyrroles from a variety of synthetically accessible precursors using transition metal catalysis were developed to address this shortcoming.43

O R3 R5 + R H+ MeO R H 1 N O NH R + 4 + NH R 2 5 R1 R OMe 2 5 or 4 or R2 O Lewis Acid Lewis Acid R2 R2 R3 R3 3.1 3.2 3.3 R1, R4 = H 3.1 3.4

Scheme 3.1: Paal-Knorr Pyrrole Synthesis

In 2000, Katritzky reported the preparation of 1,2-diarylpyrroles (3.6) from N- allylbenzotriazole (3.5) in mediocre yields (Scheme 3.2).44 The reaction used catalytic amounts of palladium (II) acetate, but required superstoichiometric amounts of the copper

(II) chloride reoxidant and potassium carbonate base.

H Pd(OAc)2 Ar Ar NHAr Ar PPh3 N Bt CuCl2 K2CO3, THF 3.5 3.6

Scheme 3.2: Synthesis of 1,2-Diarylpyrroles

Although there is no proposed mechanism in the report, a possible mechanism is illustrated in Scheme 3.3 that proceeds by initial metal coordination to the olefin.

Nucleophilic attack of the amine onto the olefin produces the alkyl-palladium intermediate 3.8. !-Hydride elimination, followed by elimination of the leaving group would furnish the pyrrole product 3.6.

H H Ar Ar Ar Ar NHAr H H Ar NH2Ar Ar Pd Ar N Ar N N Bt Bt Pd Bt Bt Pd 3.5 3.7 3.8 3.9 3.6

Scheme 3.3: Possible Mechanism for the Formation of 1,2-Diarylpyrroles

Given our success using 4-hydroxy alkyl enol ethers to make furans, we thought we could use a similar strategy to make pyrroles. In comparison to Katritzky’s approach, our precursor would utilize an atom economical alkoxy leaving group as opposed to a benzotriazole leaving group.

3.3 Results and Discussion

Our initial investigations into the pyrrole synthesis began with developing a method to efficiently prepare the 4-amino alkyl enol ether starting materials. Due to the basicity of the nitrogen atom and its ability to strongly coordinate to palladium, we decided to protect our amine prior to cyclization. In 1983, Hegedus reported the intramolecular aminopalladation of aminoolefins.45 In this report, unprotected amines were good ligands for palladium and did not readily undergo cyclization. Protecting the amine as an acetamide also did not give the desired reactivity. Changing the protecting group into a tosyl group gave excellent yields of the cyclized product under mild reaction conditions. Given that the pKa of tosyl amides is around 16 compared to the pKa of carbamates, which is around 24, we sought to synthesize the tosyl protected 4-amino alkoxy enol ethers since the less basic amine is a worse ligand for palladium. Initial

41 attempts to make the substrate 3.9 from the commercially available aminoalcohol 3.7 proved unsuccessful due to the instability of the aldehyde 3.8 (Scheme 3.5). Therefore, the same approach to make the pyrrole substrates as was used for making furans was utilized. Since the isopropoxy group preformed best for the cyclization of the furans, it was used for the pyrrole cyclization. We were pleased to find that addition of allyl anion to protected imines 3.11 gave the desired 4-amino isopropyl enol ethers 3.12 in yields comparable to their hydroxy counterparts.

Unsuccessful Approach Cl Ph P OiPr 1. TsCl, Et3N, DCM, 0 °C 3 TsHN H2N OH 2. DMSO, (COCl) , Et N TsHN O 2 3 t OiPr 3.7 DCM, -78 °C 3.8 KO Bu, THF, 23 °C 3.9

Current Approach Ph TsNH OiPr O 2 NTs TsHN Toluene, reflux sBuLi, THF, -78 °C OiPr 3.12 3.10 3.11

Scheme 3.5: Pyrrole Substrate Synthesis Attempts

With our desired substrate in hand, we performed a general screen of multiple cyclization conditions to determine if any of the desired pyrrole product 3.13 would form

(Table 3.1). We were pleased to find that in addition to our furan cyclization conditions

(entry 1) numerous conditions (entries 2-5) produced the desired product.

Table 3.1: General Pyrrole Cyclization Condition Screen

Ph Ts Ph N Conditions TsHN OiPr 25 °C, 72h 3.12 3.13

Entry Conditions Product Formed (Y/N)

1 Pd(OAc)2 (5 mol%), PPh3, AcOH, BQ, DCM Y

2 Pd(OAc)2 (5 mol%), Cu(OAc)2, catechol, O2, 3 Å MS, MeCN Y

3 Pd(TFA)2 (5 mol%), PPh3, toluene, O2 Y

4 Pd(OAc)2 (5 mol%), PPh3, toluene, O2 Y

5 Pd(OAc)2 (5 mol%), DMSO, O2 Y

6 Pd(OAc)2 (5 mol%), pyridine, toluene, O2 N

Since our furan cyclization conditions produced the desired product, we sought to optimize those reaction conditions. A solvent screen was conducted and showed that dichloromethane was the ideal solvent (Table 3.2).

Table 3.2: Pyrrole Solvent Screen

Ph Pd(OAc) (5 mol%), PPh3 (20 mol%) Ph Ts BQ (1.1 equiv), AcOH (1 equiv) N TsHN OiPr Solvent, 40 °C, 24 h 3.12 3.13

Entry Solvent GC Yield (%)a

1 DCM 66

2 MeCN 51

3 Toluene 50

4 Acetone 29

5 EtOAc 40

6 THF 15

7 DMF 14

a Nitrobenzene used as internal standard

In an attempt to improve the reaction yield, the equivalents of acetic acid and benzoquinone were modified (Table 3.3). As previously observed, the reaction does not proceed in the absence of acetic acid, which is required in the reoxidation of the palladium catalyst (entry 1). Increasing the equivalents of acetic acid improves the yield

(entries 2-5), but too much acetic acid has a negative impact on the reaction (entry 6).

Reducing the amount of the triphenylphosphine ligand decreases the yield (entries 7-10).

The highest yield of 72% was obtained using four equivalents of acetic acid and 20 mol% of the triphenylphosphine ligand (entry 4).

Table 3.3: Acetic Acid and Triphenylphosphine Screen

Ph Pd(OAc) (5 mol%), PPh3 (x mol%) Ph Ts BQ (1.1 equiv), AcOH (x equiv) N TsHN OiPr Solvent, 40 °C, 24 h 3.12 3.13

a Entry AcOH (equiv) PPh3 (mol %) GC Yield (%)

1 0 20 0

2 0.5 20 26

3 1 20 52

4 2 20 58

5 4 20 72

6 8 20 44

7 4 10 48

8 1 10 56

9 1 5 69

10 1 0 53

a Nitrobenzene used as internal standard

Other conditions that were screened failed to improve the yield of the pyrrole

3.13. In addition, different 2-aryl and 2-alkyl substrates were subjected to the optimized cyclization conditions but failed to yield any of the desired product in appreciable quantities.

3.4 Conclusions and Future Work

A procedure to produce 2-phenyl pyrrole in moderate yield was developed. The reaction proved to not be general and further improvements on the yield were not obtained. The practicality of the method would be improved if the cyclization substrates could be synthesized in a more efficient manner, if the reaction could tolerate different functional groups, and if the yield of the desired pyrroles was improved. To improve the reaction, a detailed study of the effects of different ligands should be conducted.

Additionally, other substrates with various substituents should be synthesized to see if the generality and yield of the reaction can be improved.

Chapter 4. Experimental Details

4.1 General Methods

All reactions were performed in flame-dried glassware or new 4 mL borosilicate glass vials. All palladium-catalyzed enal, furan, 2,5-dihydrofuran, and pyrroles reactions were performed under an air atmosphere. All other reactions were performed under an atmosphere of nitrogen unless otherwise stated. Dichloromethane, diethyl ether, toluene, and tetrahydrofuran were obtained from a solvent purification system (activated alumina columns) and used without further drying. Triethylamine, diisopropylamine, pyridine,

TMEDA, and HMPA were freshly distilled over calcium hydride prior to use. Palladium acetate was purified by recrystallization from hot benzene. 1,4-Benzoquinone was sublimed before use in reactions. all other commercially obtained reagents were used as received. Allyl methyl ether,46 allyl phenyl ether,47 dihydro-2H-pyran-3(4H)-one,48 methoxyallene,49 1-(3-methoxyallyl)cyclohexanol,35 6-methoxyhex-5-en-1-ol,50 5-((tert- butyldimethylsilyl)oxy)pentanal,54 4-(tert-buty)-1-(3-methoxyallyl)cyclohexanol,35 tert- butyl 2-(5-oxopentyl)-1H-indole-1-carboxylate,51 (Z)-6-(triethylsilyl)hex-5-enal11 N-(3- oxo-1,3-diphenylpropyl)acetamide,64 N-(3-hydroxypropyl)-4- methylbenzenesulfonamide,65 4-methyl-N-(3-oxopropyl)benzenesulfonamide,66 and N- benzylidene-4-methylbenzenesulfonamide,67 were prepared according to known literature

47 procedures. Thin-layer chromatography (TLC) was conducted with SiliCycle glass backed 60 Å UV254 plates (0.25 mm) and visualized with UV lamps or KMnO4 or ceric ammonium molybdate (CAM) stain followed by heating. Flash chromatography was performed using normal phase Aldrich 40-63 µm 60 Å silica gel. NMR spectra were obtained on a 400 MHz Bruker spectrometer and reported relative to TMS. IR spectra were recorded on a PerkinElmer Spectrum RX1 FTIR spectrometer. High-resolution mass spectra were obtained on a Bruker MicrOTOF II instrument from the mass spectrometry facility at The Ohio State University.

4.2 Chapter 1 Experimental Details

acetyl chloride acetic anhydride Cl PPh3 + O O toluene, 65 °C Ph3P O 20 h

(Methoxymethyl)triphenylphosphonium chloride: Closely following the known

13 procedure, to a solution of PPh3 (75.4 g; 287 mmol) in toluene (35 mL) was added acetic anhydride (2.70 mL, 28.6 mmol, 0.1 equiv), dimethoxy methane (31 mL, 350 mmol, 1.2 equiv), and acetyl chloride (23.0 mL, 323 mmol, 1.1 equiv). The solution was heated to 65 !C for 20 h. The resulting white suspension was cooled to 0 !C and filtered; the solid was thoroughly washed with Et2O. The solid was left to dry on the Buchner funnel and then dried under reduced pressure giving a white power (93.15g, 271.7 mmol,

95%).

Spectral data matched that of the known compound.

t 1. [Ph3PCH2OCH3]Cl (1.3 equiv), KO Bu (1.3 equiv) THF, 23 °C, 45 min R1 R1 R 2. Aldehyde or ketone, THF, 23 °C, 4 h R O 2 O 2

General Procedure for the Synthesis of Enol Ethers: Potassium tert-butoxide (1.3 equiv) in THF was slowly added to a rapidly stirring solution of

(methoxymethyl)triphenylphosphonium chloride (1.3 equiv) in THF. The deep red solution was allowed to stir at 23 °C for 45 min before slowly adding a solution of the aldehyde (1 equiv) in THF. The solution turned from deep red to orange and was allowed to stir for an additional 4 h. The solvent was reduced under vacuum and diluted with hexanes. The organic layer was washed with water and brine followed by drying the organic layer over MgSO4. The organic layer was removed under vacuum and the resulting oil purified by Kugelrohr distillation under reduced pressure or by flash chromatography on silica gel.

OMe Ph

(4-(Methoxymethylene)cyclohexyl)benzene (1.21): The above general procedure was followed using 4-phenylcyclohexanone (707 mg, 4.05 mmol) and (2- methoxymethyl)triphenylphosphonium chloride (1.90 g, 5.54 mmol, 1.35 equiv) with potassium tert-butoxide (614 mg, 5.47 mmol, 1.35 equiv). The crude oil was purified by

Kugelrohr distillation under reduced pressure to give (4-

(methoxymethylene)cyclohexyl)benzene (791 mg, 3.91 mmol, 96%) a clear, colorless oil.

Spectral data of the product matched reported literature values.53

OMe 9

1-Methoxytridec-1-ene (1.23): The above general procedure was followed using 1- dodecanal (1.70 mL, 7.85 mmol) and (2-methoxyethyl)triphenylphosphonium chloride

(2.69 g, 7.85 mmol, 1.02 equiv) with potassium tert-butoxide (1.00 g, 8.88 mmol, 1.16 equiv). The resulting oil was purified by Kugelrohr distillation under reduced pressure to give 1-methoxytridec-1-ene (1.35 g, 7.66 mmol, 83%) as a clear, colorless oil. The product was isolated as a 1.6:1 (E:Z) mixture isomers.

Spectral data of the product matched reported literature values.52

OMe

(4-Methoxybut-3-en-1-yl)benzene (1.25): The above general procedure was followed using 3-phenylpropanal (2.94 mL, 21.9 mmol) and (2- methoxymethyl)triphenylphosphonium chloride (10.2 g, 29.7 mmol, 1.35 equiv) with potassium tert-butoxide

(3.33 g, 29.7 mmol, 1.35 equiv). The crude oil was purified by Kugelrohr distillation

50 under reduced pressure to give (4-methoxybut-3-en-1-yl)benzene (2.96 g, 18.2 mmol,

83%) as a clear, colorless oil.

Spectral data of the product matched reported literature values.52

OMe TBSO 3

tert-Butyl((6-methoxyhex-5-en-1-yl)oxy)dimethylsilane (1.27): The above general procedure was followed using 5-((tert-butyldimethylsilyl)oxy)pentanal54 (5.45 g, 25.2 mmol) and (2-methoxyethyl)triphenylphosphonium chloride (11.2 g, 32.7 mmol, 1.3 equiv) with potassium tert-butoxide (3.68 g, 32.8 mmol, 1.3 equiv). tert-Butyl((6- methoxyhex-5-en-1-yl)oxy)dimethylsilane (4.41 g, 18.1 mmol, 72%) was isolated by

Kugelrohr distillation to give a clear, colorless oil. The product was isolated as a 1.7:1

(E:Z) mixture isomers. FTIR (film, cm-1): 2929, 2856, 1654, 1462, 1255, 1209, 1101; 1H

NMR (CDCl3, 400 MHz): ! 6.27 (d, J = 12.4 Hz, 1H), 5.86 (d, J = 6.4 Hz, 0.6H), 4.72

(dt, J = 12.4, 7.2Hz, 1H), 4.33 (q, J = 7.2 Hz, 0.6H), 3.60 (t, J = 6.4 Hz, 3.2H), 3.57 (s,

1.7H), 3.49 (s, 3H), 2.07 (qd, J = 7.6, 1.2 Hz, 1.2H), 1.93 (q, J = 7.2 Hz, 2H), 1.57-1.49

13 (m, 3.2H), 1.41-1.34 (m, 3.2H), 0.90 (s, 14.4H), 0.46 (s, 9.5H); C NMR (CDCl3, 100

MHz): ! 147.3, 146.3, 107.1, 103.2, 63.4, 63.3, 59.6, 56.1, 32.7, 32.4, 27.7, 27.2, 26.2,

+ 23.8, 18.6, -5.1; HRMS (ESI) calcd for [C13H28O2Si + Na] calcd 267.1751, found

267.1761.

OMe AcO 3

6-Methoxyhex-5-en-1-yl acetate (1.29): To a stirring solution of 6-methoxyhex-5-en-1-

50 ol (0.825 g, 6.34 mmol) and pyridine (1.60 mL, 19.8 mmol, 3 equiv) in CH2Cl2 (11 mL) was added acetic anhydride (1.20 mL, 12.7 mmol, 2 equiv) and 4-

(dimethylamino)pyridine (79.5 mg, 0.651 mmol, 0.1 equiv) at 0 °C. The reaction was allowed to stir for 30 min at 0 °C and an additional 15 h at 23 °C. The mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and freed of solvent under reduced pressure to afford a yellow oil, which was purified by flash chromatography on silica gel (15% EtOAc/hexanes) to give 6-methoxyhex-5-en-1-yl acetate (0.994 g, 5.77 mmol, 91%) as a clear, colorless oil. The product was isolated as a

2:1 (E:Z) mixture isomers. FTIR (film, cm-1): 2940, 1713, 1434, 1402, 1208, 1142; 1H

NMR (CDCl3, 400 MHz): ! 6.29 (d, J = 12.4 Hz, 0.5H), 5.89 (dt, J = 6.0, 1.2 Hz, 0.5H),

4.70 (dt, J = 12.4, 7.2 Hz, 1H), 4.33-4.29 (m, 0.5H), 4.06 (t, J = 6.8 Hz, 3.1H), 3.57 (s,

1.4H), 3.50 (s, 3H), 2.12-2.06 (m, 5.6 H), 1.99-1.93 (m, 2H), 1.67-1.60 (m, 3.1H), 1.44-

13 1.37 (m, 3.1H); C NMR (CDCl3, 100 MHz): ! 171.3, 147.6, 146.7, 106.4, 102.6, 64.7,

64.6, 59.6, 56.1, 28.3, 28.1, 27.5, 27.2, 26.2, 23.6, 21.2; HRMS (ESI) calcd for

+ [C9H16O3+ Na] calcd 195.0992, found 195.0996.

SiEt3 OMe 2

Triethyl((1Z)-7-methoxyhepta-1,6-dien-1-yl)silane (1.31): The above general procedure was followed using (Z)-6-(triethylsilyl)hex-5-enal11 (2.00 g, 11.5 mmol) and

(2-methoxyethyl)triphenylphosphonium chloride (4.62 g, 13.7 mmol, 1.5 equiv) with potassium tert-butoxide (1.54 g, 13.7 mmol, 1.5 equiv). The resulting oil was purified by flash chromatography on silica gel (hexanes) to give triethyl((1-Z)-7-methoxyhepta-1,6- dien-1-yl)silane (1.15 g, 4.78 mmol, 51%) as a clear, colorless oil. The product was isolated as a 2:1 (E:Z) mixture of isomers. FTIR (film, cm-1): 2952, 2873, 1728, 1605,

1 1461, 1016; H NMR (CDCl3, 400 MHz): ! 6.36 (m, 3.4H), 6.29 (d, J = 12.4 Hz, 2H),

5.88 (dd, J = 6.4, 1.2 Hz, 1H), 5.43-5.37 (m, 3.4H), 4.72 (dt, J = 12.4, 7.2 Hz, 2H), 4.34-

4.30 (m, 1H), 3.57 (s, 3H), 3.50 (s, 6H), 2.14-2.07 (m, 9.3H), 1.94 (q, J = 7.2 Hz, 4H),

13 1.46-1.39 (m, 6.6H), 0.94 (s, 32H), 0.61 (q, J = 8.0 Hz, 21H); C NMR (CDCl3, 100

MHz): ! 150.4, 150.1, 147.5, 146.5, 125.5, 125.3, 106.8, 102.9, 59.6, 56.0, 33.9, 33.7,

+ 31.1, 30.2, 27.7, 23.9, 7.7, 4.9; HRMS (ESI) calcd for [C14H28OSi + Na] calcd

263.1802, found 263.1815.

OMe O O

8-(Methoxymethylene)-1,4-dioxaspiro[4.5]decane (1.33): The above general procedure was followed using 1,4-dioxaspiro[4.5]decan-8-one (2.04 g, 13.0 mmol) and (2- methoxyethyl)triphenylphosphonium chloride (5.81 g, 16.9 mmol, 1.30 equiv) with potassium tert-butoxide (1.90 g, 16.9 mmol, 1.30 equiv). The resulting oil was purified by flash chromatography on silica gel (10% EtOAc/hexanes) to give 8-

(methoxymethylene)-1,4-dioxaspiro[4.5]decane (1.65 g, 8.96 mmol, 69%) as a clear

-1 1 colorless oil. FTIR (film, cm ): 2952, 2885, 1718, 1127, 1099; H NMR (CDCl3, 400

MHz): ! 5.78 (s, 1H), 3.94 (s, 4H), 3.53 (s, 3H), 2.31 (t, J = 6.8 Hz, 2H), 2.09 (t, J = 6.8

13 Hz, 4H), 1.64-1.59 (m, 4H); C NMR (CDCl3, 100 MHz): ! 139.4, 114.9, 108.9, 64.0,

+ 58.9, 35.9, 34.6, 27.1, 21.9. HRMS (ESI) calcd for [C11H16O3 + Na] calcd 207.0992, found 2.0993.

OMe t-Bu

1-(tert-Butyl)-4-(methoxymethylene)cyclohexane (1.35): The above general procedure was followed using 4-(tert-butyl)cyclohexanone (2.07 g, 13.4 mmol) and (2- methoxyethyl)triphenylphosphonium chloride (5.97 g, 17.4 mmol, 1.3 equiv) with potassium tert-butoxide (1.95 g, 17.4 mmol, 1.3 equiv). The resulting oil was purified by

Kugelrohr distillation under reduced pressure to give 1-(tert-butyl)-4-

(methoxymethylene)cyclohexane (2.11 g, 11.6 mmol, 87%) as a clear, colorless oil.

Spectral data of the product matched reported literature values.54

O OMe N O 3

2-(6-Methoxyhex-5-en-1-yl)isoindoline-1,3-dione (1.37): To a stirring solution of 6-

50 methoxyhex-5-en-1-ol (1.30 g, 9.98 mmol), phthalimide (1.62 g, 11.0 mmol), and PPh3

(2.89 g, 11.0 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (2.25 g,

11.1 mmol) over 40 min at 23 °C. The reaction was allowed to stir for 48 h. The reaction was reduced under vacuum and diethyl ether added before filtering over Celite®. The filtrate was then reduced under vacuum and the yellow-orange oil purified by flash chromatography on silica gel (20% EtOAc/hexanes) to give 2-(6-methoxyhex-5-en-1- yl)isoindoline-1,3-dione (2.18 g, 8.41 mmol, 84%) as a yellow oil. The product was isolated as a 1.8:1 (E:Z) mixture isomers. FTIR (film, cm-1): 3032, 2936, 2856, 1770,

1 1713, 1395, 1208, 1106; H NMR (CDCl3, 400 MHz): ! 7.83-7.80 (m, 5.7H), 7.70-7.68

(m, 5.7H), 6.26 (d, J = 12.4 Hz, 1.8H), 5.85 (d, J = 6.0 Hz, 1H), 4.67 (m, 1.8H), 4.29 (q, J

= 7.2 Hz, 1H), 3.67 (t, J = 7.2 Hz, 5.9H), 3.54 (s, 3H), 3.47 (s, 5.4H) 2.08 (q, J = 7.2 Hz,

2H), 1.95 (q, J = 7.2 Hz, 3.8H), 1.72-1.63 (m, 5.8H), 1.42-1.34 (m, 5.8H); 13C NMR

(CDCl3, 100 MHz): ! 168.3, 147.3, 146.4, 133.8, 133.7, 123.0 (2C), 106.0, 102.2, 59.4,

+ 55.8, 37.9, 37.8, 28.0, 27.8, 27.1, 26.9, 23.2; HRMS (ESI) calcd for [C15H17NO3 + Na] calcd 282.1101, found 282.1088.

O OMe N O 3

1-(6-Methoxyhex-5-en-1-yl)pyrrolidine-2,5-dione (1.39): To a stirring solution of 6- methoxyhex-5-en-1-ol50 (497 mg, 3.82 mmol), succinimide (421 mg, 4.25 mmol, 1.1 equiv), and PPh3 (1.10 g, 4.20 mmol, 1.1 equiv) in THF (6.5 mL) was added diisopropyl

55 azodicarboxylate (0.90 mL, 4.6 mmol, 1.2 equiv) over 40 min at 23 °C. The reaction was allowed to stir for 5 h. The reaction was reduced under vacuum and the yellow-orange oil purified by flash chromatography on silica gel (40% EtOAc/hexanes) to give 1-(6- methoxyhex-5-en-1-yl)pyrrolidine-2,5-dione (753 mg, 3.56 mmol, 93%) as a yellow oil.

Isolated as a 2.6:1 (E:Z) mixture of isomers. FTIR (film, cm-1): 2936, 2856, 1740, 1654,

1 1241, 1038; H NMR (CDCl3, 400 MHz): ! 6.27 (dt, J = 12.4 Hz, 1H), 5.87 (dt, J = 6.0,

1.6 Hz, 0.4 H), 4.68 (dt, J = 12.8, 7.2 Hz, 1H), 4.29 (dt, J = 6.0Hz, 0.4H), 3.57 (s, 1.2 H),

3.50 (t, J = 7.2 Hz, 2.8H), 3.49 (s, 3 H), 2.70 (s, 4H), 2.69 (s, 1.6H), 2.07 (dq, J = 7.4, 1.2

Hz, 0.8H), 1.94 (dq, J = 7.2 Hz, 0.8 Hz, 2H), 1.62-1.53 (m, 2.8H), 1.38-130 (m, 2.8H);

13 C NMR (CDCl3, 100 MHz): ! 177.4, 147.6, 146.7, 106.2, 102.5, 59.7, 56.1, 39.0, 38.9,

+ 28.4, 28.1, 27.4 (2 C), 27.2 (2 C), 23.5; HRMS (ESI) calcd for [C11H17NO3 + Na] calcd

234.1101, found 234.1108.

OMe

5-(Methoxymethylene)-6,7,8,9-tetrahydro-5H-benzo[7]annulene (1.41): The above general procedure was followed using 1-benzosuberone (3.20 mL, 21.4 mmol) and (2- methoxyethyl)triphenylphosphonium chloride (8.98 g, 26.2 mmol, 1.22 equiv) with potassium tert-butoxide (2.93 g, 26.1 mmol, 1.22 equiv). The resulting oil was purified by flash chromatography on silica gel (hexanes) to give (3.04 g, 16.1 mmol, 75%) as a clear, colorless oil. The product was isolated as a 1:1.8 (E:Z) mixture isomers. FTIR

-1 1 (film, cm ): 3057, 3012, 2927, 2849, 1658, 1443, 1221, 1130; H NMR (CDCl3, 400

MHz): ! 7.26-7.24 (m, 1H), 7.15-7.06 (m, 11H), 6.06 (s, 1H), 6.02 (s, 1.9H), 3.66 (s, 6H),

3.54 (s, 3H), 2.74-2.71 (m, 6H), 2.38 (s, 4H), 2.13-2.10 (m, 2H), 1.80-1.64 (m, 12H); 13C

NMR (CDCl3, 100 MHz): ! 144.7, 143.2, 141.8 (2), 141.4, 139.5, 130.3, 129.6, 129.2,

128.2, 126.8 (2 C), 126.3, 125.8, 122.1, 120.4, 60.0, 37.2, 35.8 (2 C), 32.8, 28.5, 27.9,

+ 27.8, 27.0; HRMS (ESI) calcd for [C13H16O + Na] calcd 211.1093, found 211.1088.

MeO

(1-Cyclohexyl-2-methoxyvinyl)benzene (1.43): The above general procedure was followed using cyclohexyl phenyl ketone (1.96 g, 10.4 mmol) and (2- methoxyethyl)triphenylphosphonium chloride (4.63 g, 13.5 mmol, 1.3 equiv) with potassium tert-butoxide (1.52 g, 13.5 mmol, 1.3 equiv). The resulting oil was purified by flash chromatography on silica gel (hexanes) to give (Z)-(1-cyclohexyl-2- methoxyvinyl)benzene (0.700 g, 3.25 mmol, 31%) and (E)-(1-cyclohexyl-2- methoxyvinyl)benzene (1.30 g, 6.01 mmol, 58%) as clear, colorless oils. (Z)-(1- cyclohexyl-2-methoxyvinyl)benzene: FTIR (film, cm-1): 3027, 2923, 2850, 1650, 1493,

1 1447, 1219, 1130, 1072; H NMR (CDCl3, 400 MHz): ! 7.28-7.24 (m, 2H), 7.22- 7.17

(m, 3H), 5.91 (s, 1H), 3.63 (s, 3H), 2.64 (tt, J = 12.4, 3.2 Hz, 1H), 1.75-1.61 (m, 5H),

1.45 (qd, J = 13.6, 5.6 Hz, 2H), 1.30 (qt, J = 12.8, 3.2 Hz, 2H), 1.18-1.06 (m, 1H); 13C

NMR (CDCl3, 100 MHz): ! 145.2, 140.5, 128.9, 127.9, 126.3, 126.0, 59.9, 39.5, 31.7,

27.2, 26.4. (E)-(1-cyclohexyl-2-methoxyvinyl)benzene: FTIR (film, cm-1): 3053, 3018,

1 2925, 2850, 1657, 1448, 1249, 1204, 1147; H NMR (CDCl3, 400 MHz): ! 7.32-7.24 (m,

4H), 7.21-7.17 (1H), 5.95 (d, J = 1.1 Hz, 1H), 3.55 (s, 3H), 2.24-2.17 (m, 1H), 1.79-1.71

13 (m, 4H), 1.68-1.63 (m, 1H), 1.32-1.21 (m, 2H), 1.17-1.06 (m, 3H); C NMR (CDCl3,

100 MHz): ! 143.0, 138.6, 129.0, 127.9, 126.2, 124.2, 59.8, 41.7, 33.2, 27.0, 26.5; HRMS

+ (ESI) calcd for [C15H20O + Na] calcd 239.1406, found 239.1410.

Boc OMe N

tert-Butyl 2-(6-methoxyhex-5-en-1-yl)-1H-indole-1-carboxylate (1.45): The above general procedure was followed using tert-butyl 2-(5-oxopentyl)-1H-indole-1- carboxylate51 (1.03 g, 3.42 mmol) and (2-methoxyethyl)triphenylphosphonium chloride

(3.51 g, 10.2 mmol, 3.0 equiv) with potassium tert-butoxide (1.15 g, 10.2 mmol, 3.0 equiv). The resulting oil was purified by flash chromatography on silica gel (20-40%

CH2Cl2/hexanes) to give (0.723 g, 2.20 mmol, 64%) as a clear, colorless oil. The product was isolated as a 1.2:1 (E:Z) mixture isomers. FTIR (film, cm-1): 3030, 2977, 2932, 2855,

1 1732, 1654, 1567, 1455, 1329, 1116, 747; H NMR (CDCl3, 400 MHz): ! 8.11-8.08 (m,

1H), 7.45-7.42 (m, 1H), 7.24-7.15 (m, 2H), 6.34 (m, 1H), 6.29 (dt, J = 12.6, 1.0 Hz,

0.55H), 5.87 (dt, J = 6.2, 1.4 Hz, 0.45H), 4.73 (dt, J = 12.6, 7.3 Hz, 0.55H), 4.34 (dt, J =

7.3, 6.2 Hz, 0.45H), 3.57 (s, 1.35H), 3.49 (s, 1.65H), 2.99 (m, 2H), 2.13 (m, 1H), 1.98 (m,

13 1H), 1.76-1.68 (m, 11H), 1.52-1.43 (m, 2H); C NMR (CDCl3, 100 MHz): ! 150.6,

147.2, 146.3, 142.5, 142.4, 136.7 (2 C), 129.4 (2 C), 123.2, 123.1, 122.6, 122.5, 119.6 (2

C), 115.6, 115.5, 107.1, 107.0, 106.6, 102.8, 83.6 (2 C), 59.5, 55.9, 30.5, 30.0 29.5, 28.5,

+ 28.3, 27.6, 23.7; HRMS (ESI) calcd for [C20H27NO3 + Na] calcd 352.1883, found

352.1902.

OMe

1-Methoxy-4,8-dimethylnona-1,7-diene (1.47): The above general procedure was followed using (±)-citronellal (1.80 mL, 1.54 g, 10.0 mmol) and (2- methoxyethyl)triphenylphosphonium chloride (4.56 g, 13.3 mmol, 1.3 equiv) with potassium tert-butoxide (1.46 g, 13.0 mmol, 1.3 equiv). The resulting oil was purified by

Kugelrohr distillation under reduced pressure to give 1-methoxy-4,8-dimethylnona-1,7- diene (1.64 g, 9.04 mmol, 90%) as a clear, colorless oil. Isolated as a 1.2:1 (E:Z) mixture of isomers. FTIR (film, cm-1): 3033, 2954, 2912, 2853, 1654, 1454, 1209, 1110, 934,

1 738; H NMR (CDCl3, 400 MHz): ! 6.25 (dt, J = 12.6, 1.1 Hz, 0.55H), 5.91 (dt, J = 6.3,

1.5 Hz, 0.45H), 5.12-5.08 (m, 1 H), 4.71 (dt, J = 12.6, 7.6 Hz, 0.55 H), 4.34 (dt, J = 7.4,

6.3 Hz, 0.45H), 3.57 (s, 1.35H), 3.51 (s, 1.65H), 2.09-1.89 (m, 3.45H), 1.79-1.72 (m,

0.55H), 1.68 (m, 3H), 1.60 (s, 3H), 1.46-1.30 (m, 2H), 1.19-1.09 (m, 1H), 0.89-0.85 (m,

13 3H); C NMR (CDCl3, 100 MHz): ! 147.6, 146.5, 130.9, 130.8, 125.1, 124.9, 105.3,

101.2, 59.3, 55.8, 36.6, 36.4, 34.9, 33.4, 32.9, 30.9, 25.7, 25.6 (2 C), 19.4, 19.2, 17.6,

17.5.

Pd(OAc)2 (1-5 mol %) BQ (1.2 equiv) R R 1 H2O (1.1 equiv), AcOH (4 equiv) 1 R2 O R2 O CH2Cl2, 23 °C, time

General Procedure for the Synthesis of !,"-Unsaturated Aldehydes: To 4 mL borosilicate glass vial containing the alkyl enol ether (1.00 mmol), 1,4-benzoquinone

(130 mg, 1.2 mmol, 1.20 equiv), water (20.0 µL, 1.11 mmol, 1.11 equiv), AcOH (240 µL,

4.19 mmol, 4.19 equiv) was added Pd(OAc)2 followed by CH2Cl2 (1.00 mL). The reaction was stirred at 23 °C until completion as indicated by GC analysis. The reaction mixture was then diluted with CH2Cl2 (50 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, reduced under vacuum and the resulting oil purified by flash chromatography on silica gel.

O Ph

1,2,3,6-Tetrahydro-[1,1’-biphenyl]-4-carbaldehyde (1.22): The above general procedure was followed using (4-(methoxymethylene)cyclohexyl)benzene (206 mg, 1.02 mmol) and 2 mol % Pd(OAc)2 (4.4 mg, 0.020 mmol). The crude product was purified by flash chromatography on silica gel (5 % EtOAc/hexanes) to give 1,2,3,6-tetrahydro-[1,1’- biphenyl]-4-carbaldehyde (160 mg, 0.84 mmol, 84%) as a clear, colorless oil.

Spectral data of the product matched reported literature values.58

O 9

(E)-Tridec-2-enal (1.24): The above general procedure was followed using 1- methoxytridec-1-ene (212 mg, 1.00 mmol) and 2 mol % Pd(OAc)2 (4.6 mg, 0.020 mmol).

The crude product was purified by flash chromatography on silica gel (2%

EtOAc/hexanes) to give (E)-tridec-1-enal (131 mg, 0.670 mmol, 67%) as a clear, colorless oil.

Spectral data of the product matched reported literature values.55

(E)-4-Phenylbut-2-enal (1.26): The above general procedure was followed using (4- mehoxybut-3-en-1-yl)benzene (162 mg, 1.00 mmol) and 1 mol % Pd(OAc)2 (2.3 mg,

0.020 mmol). The crude product was purified by flash chromatography on silica gel (1:1

CH2Cl2/hexanes) to give (E)-4-phenylbut-2-enal (110 mg, 0.750 mmol, 75%) as a clear, colorless oil.

Spectral data of the product matched reported literature values.56

O TBSO 3

(E)-6-((tert-Butyldimethylsilyl)oxy)hex-2-enal (1.28): The above general procedure was followed using tert-butyl((6-methoxyhex-5-en-1-yl)oxy)dimethylsilane (244 mg,

1.00 mmol) and 2.5 mol % Pd(OAc)2 (5.6 mg, 0.020 mmol). The crude product was purified by flash chromatography on silica gel using a solvent gradient (0-4%

EtOAc/hexanes) to give (E)-6-((tert-butyldimethylsilyl)oxy)hex-2-enal (160 mg, 0.70 mmol, 70%) as a clear, colorless oil.

Spectral data of the product matched reported literature values.57

O AcO 3

(E)-6-Oxohex-4-en-1-yl acetate (1.30): The above general procedure was followed using 6-methoxyhex-5-en-1-yl acetate (172 mg, 1.00 mmol) and 1 mol % Pd(OAc)2 (2.4 mg, 0.020 mmol). The crude product was purified by flash chromatography on silica gel using a solvent gradient (10% EtOAc/hexanes) to give (E)-6-oxohex-4-en-1-yl acetate

(125 mg, 0.80 mmol, 80%) as a clear, colorless oil. FTIR (film, cm-1): 2955, 1734, 1686,

1 1367, 1242, 1045; H NMR (CDCl3, 400 MHz): ! 9.52 (d, J = 8.0 Hz, 1H), 6.87 (dt, J =

15.6, 6.8 Hz, 1H), (qt, J = 7.6, 1.6 Hz, 1H), 4.12 (t, J = 6.4 Hz, 2H), 2.47-2.41 (m, 2H),

13 2.06 (s, 1H), 1.87 (quin, J = 6.4 Hz, 2H); C NMR (CDCl3, 100 MHz): ! 193.7, 170.9,

+ 156.9, 133.3, 63.2, 29.1, 26.8, 20.8; HRMS (ESI) calcd for [C8H12O3 + Na] calcd

179.0679, found 179.0671.

SiEt3 O 2

(2E, 6Z)-7-(Triethylsilyl)hepta-2,6-dienal (1.32): The above general procedure was followed using triethyl((1Z)-7-methoxyhepta-1,6-dienal (246 mg, 1.03 mmol) and 4 mol

% Pd(OAc)2 (8.9 mg, 0.04 mmol). The crude product was purified by flash chromatography on silica gel (2 % EtOAc/hexanes) to give (2E, 6Z)-7-

(triethylsilyl)hepta-2,6-dienal (159 mg, 0.69 mmol, 69%) as a clear, colorless oil. FTIR

-1 1 (film, cm ): 2954, 2909, 2874, 2819, 1686, 1605, 1458, 1123, 1015; H NMR (CDCl3,

400 MHz): ! 9.51 (d, J = 7.6 Hz, 1H), 6.85 (dt, J = 15.6, 6.8 Hz, 1H), 6.38-6.31 (m, 1H),

6.17-6.11 (m, 1H), 5.52 (d, J = 14.4 Hz, 1H), 2.43 (q, J = 6.8 Hz, 2H), 2.33 (q, J = 7.2 Hz,

13 2H), 0.95 (t, J = 7.6 Hz, 9H), 0.62 (q, J = 8.0 Hz, 6H); C NMR (CDCl3, 100 MHz): !

193.7, 157.3, 147.2, 133.2, 127.4, 32.6, 32.0, 7.4, 4.6; HRMS (ESI) calcd for

+ [C13H24NOSi + Na] calcd 247.1489, found 247.1499.

O O O

1,4-Dioxaspiro[4.5]dec-7-ene-8-carbaldehyde (1.34): The above general procedure was followed using 8-(methoxymethylene)-1,4-dioxaspiro[4.5]decane (183 mg, 1.00 mmol) and 2.5 mol % Pd(OAc)2 (5.6 mg, 0.02 mmol). The crude product was purified by flash chromatography on silica gel (10% EtOAc/hexanes) to give 1,4-dioxaspiro[4.5]dec-7- ene-8-carbaldehyde (129 mg, 0.77 mmol, 77%) as a clear, colorless oil. FTIR (film, cm-

1 1 ): 2958, 2887, 2821, 1683, 1117, 1061; H NMR (CDCl3, 400 MHz): ! 9.39 (s, 1H), 6.63

(t, J = 2.0 Hz), 3.94 (s, 4H), 2.52 (t, J = 0.8 Hz, 2H), 2.38 (td, J = 5.2, 2.8 Hz, 2H), 1.73

13 (t, J = 6.4 Hz, 2H); C NMR (CDCl3, 100 MHz): ! 193.2, 147.4, 140.8, 107.6, 64.7,

+ 37.0, 30.2, 20.5; HRMS (ESI) calcd for [C9H12O3 + Na] calcd 191.0679, found

191.0675.

O t-Bu

4-(tert-Butyl)cyclohex-1-enecarbaldehyde (1.36): The above general procedure was followed using 1-(tert-butyl)-4-(methoxymethylene)cyclohexane (182 mg, 1.00 mmol) and 2 mol % Pd(OAc)2 (4.5 mg, 0.02 mmol). The crude product was purified by flash chromatography on silica gel using a solvent gradient (5% EtOAc/hexanes) to give 4-

(tert-butyl)cyclohex-1-enecarbaldehyde (153 mg, 0.92 mmol, 92%) as a clear, colorless oil. Spectral data of the product matched reported literature values.59

N O 3 O

(E)-6-(1,3-Dioxoisoindolin-2-yl)hex-2-enal (1.38): The above general procedure was followed using 2-(6-methoxyhex-5-en-1-yl)isoindoline-1,3-dione (262 mg, 1.01 mmol) and 2.5 mol % Pd(OAc)2 (5.6 mg, 0.025 mmol). The crude product was purified by flash

64 chromatography on silica gel (25 % EtOAc/hexanes) to give (E)-6-(1,3-dioxoisoindolin-

2-yl)hex-2-enal (180 mg, 0.73 mmol, 73%) as a white solid. FTIR (film, cm-1): 3032,

1 2936, 2856, 1770, 1713, 1395, 1208, 1106; H NMR (CDCl3, 400 MHz): ! 9.48 (d, J =

7.6 Hz, 1H), 7.88-7.83 (m, 2H), 7.76-7.71 (m, 2H), 6.85 (dt, J = 16.0, 6.4 Hz, 1H), 6.18-

6.12 (m, 1H), 3.76 (t, J = 7.2 Hz, 2H), 2.45-2.39 (m, 2H), 1.97-1.89 (m, 2H); 13C NMR

(CDCl3, 100 MHz): ! 193.6, 168.2, 156.5, 134.0, 133.4, 131.9, 123.2, 37.1, 29.9, 26.7;

+ HRMS (ESI) calcd for [C14H13NO3 + Na] calcd 266.0788, found 266.0790.

N O 3 O

6-(2,5-Dioxopyrrolidin-1-yl)hexanal (1.40): The above general procedure was followed using 1-(6-methoxyhex-5-en-1-yl)pyrrolidine-2,5-dione (210 mg, 1.00 mmol) and 2.5 mol % Pd(OAc)2 (5.6 mg, 0.025 mmol). The crude product was purified by flash chromatography on silica gel (30-40% EtOAc/hexanes) to give (E)-6-(2,5- dioxopyrrolidin-1-yl)hex-2-enal (145 mg, 0.74 mmol, 74%) as a pale yellow oil. FTIR

-1 1 (film, cm ): 2944, 2829, 1693, 1440, 1402, 1163, 1137; H NMR (CDCl3, 400 MHz): !

9.51-9.48 (m, 1H), 6.88-6.79 (m, 1H), 6.17-6.09 (m, 1H), 3.58-3.53 (m, 2H), 2.73-2.71

13 (m, 4H), 2.39-2.34 (m, 2H), 1.85-1.77 (m, 2H); C NMR (CDCl3, 100 MHz): ! 193.8,

+ 177.3, 156.6, 133.4, 38.0, 29.9, 28.2, 25.9; HRMS (ESI) calcd for [C10H13NO3 + Na] calcd 218.0788, found 218.0781.

OMe

6,7-Dihydro-5H-benzo[7]annulene-9-carbaldehyde (1.42): A slight modification to the above general procedure was followed. To 4 mL borosilicate glass vial containing the 5-

(methoxymethylene)-6,7,8,9-tetrahydro-5H-benzo[7]annulene (188 mg, 1.00 mmol), 1,4- benzoquinone (129 mg, 1.20 mmol, 1.2 equiv), and water (20.0 µL, 1.11 mmol, 1.11 equiv) was added 5 mol % Pd(OAc)2 (11.2 mg, 0.05 mmol) followed by AcOH (1.00 mL). The reaction was stirred at 40 °C until completion as indicated by GC analysis. The reaction mixture was then diluted with CH2Cl2 (50 mL) and washed with water (50 mL).

The organic layer was dried over Na2SO4, reduced under vacuum and the crude product purified by flash chromatography on silica gel (5% EtOAc/hexanes) to give (E)-6-

(benzyloxy)hex-2-enal (85 mg, 0.42 mmol, 42%) as a clear, pale orange oil. FTIR (film,

-1 1 cm ): 3055, 2932, 2857, 1690, 1448, 1226, 1120, 1075; H NMR (CDCl3, 400 MHz): !

13 9.66 (s, 1H), 7.44-7.14 (m, 5H), 2.55-2.52 (m, 2H), 2.23-2.22 (m, 4H); C NMR (CDCl3,

100 MHz): ! 192.6, 154.9, 143.6, 141.2, 132.7, 129.2, 129.1, 128.3, 126.1, 33.9, 32.1,

+ 26.3; HRMS (ESI) calcd for [C12H12O + Na] calcd 195.0780, found 195.0779.

2-Cyclohexylidene-2-phenylacetaldehyde (1.44): A slight modification to the above general procedure was followed. To 4 mL borosilicate glass vial containing (1- cyclohexyl-2-methoxyvinyl)benzene (216 mg, 1.00 mmol), 1,4-benzoquinone (130 mg,

1.20 mmol, 1.2 equiv), and water (20.0 µL, 1.11 mmol, 1.11 equiv) was added 10 mol %

Pd(OAc)2 (22.4 mg, 0.10 mmol, 0.10 equiv) followed by AcOH (1.00 mL). The reaction was stirred at 23 °C for 4 d. The reaction mixture was then diluted with CH2Cl2 (50 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, reduced under vacuum and the crude product purified by flash chromatography on silica gel (1%

EtOAc/hexanes) to give 2-cyclohexylidene-2-phenylacetaldehyde (115 mg, 0.58 mmol,

58%) as a light brown oil. FTIR (film, cm-1): 2935, 2857, 1683, 1448, 1274, 1149; 1H

NMR (CDCl3, 400 MHz): ! 10.3 (s, 1H), 7.38-7.26 (m, 3H), 7.05-7.03 (m, 2H), 2.90-

2.87 (m, 2H), 2.21-2.18 (m, 2H), 1.84-1.81 (m, 2H), 1.84-1.62 (m, 4H); 13C NMR

(CDCl3, 100 MHz): ! 189.7, 164.1, 136.6, 135.9, 129.9, 128.2, 127.2 34.6, 29.6, 28.9,

+ 28.6, 26.4; HRMS (ESI) calcd for [C14H16O + Na] calcd 223.1093, found 223.1092.

Boc O N

(E)-tert-Butyl 2-(6-oxohex-4-en-1-yl)-1H-indole-1-carboxylate (1.46): The above general procedure was followed using tert-butyl 2-(6-methoxyhex-5-en-1-yl)-1H-indole-

1-carboxylate (330 mg, 1.00 mmol) and 5 mol % Pd(OAc)2 (11.2 mg, 0.050 mmol). The crude product was purified by flash chromatography on silica gel (3% EtOAc/hexanes) to

67 give (E)-tert-butyl 2-(6-oxohex-4-en-1-yl)-1H-indole-1-carboxylate (143 mg, 0.45 mmol,

45%) as a pale yellow oil.

Spectral data of the product matched reported literature values.60

(E)-4,8-Dimethylnona-2,7-dienal (1.48): The above general procedure was followed using 1-methoxy-4,8-dimethylnona-1,7-diene (183 mg, 1.00 mmol) and 5 mol %

Pd(OAc)2 (11.2 mg, 0.050 mmol). The crude product was purified by flash chromatography on silica gel (3-5 % EtOAc/hexanes) to give (E)-4,8-dimethylnona-2,7- dienal (123 mg, 0.74 mmol, 74%) as a colorless oil.

Spectral data of the product matched reported literature values.16

General Procedure for Enal Formation with O2 as Reoxidant: To a 4-mL vial equipped with a stir bar was added hydroquinone (0.1 equiv), copper (II) acetate (0.05 equiv), and palladium (II) acetate (0.05 equiv). The vial was fitted with a septa cap and pump-filled with oxygen (x3). To the vial was added methyl enol ether (1 equiv) in

CH2Cl2 (1 M), acetic acid (4.2 equiv), and water (1.1 equiv). The reaction mixture was stirred until complete by GC, diluted with CH2Cl2, washed with water, and the organic layer was dried over Na2SO4. The solution was filtered, concentrated, and subjected to flash chromatography.

4.3 Chapter 2 Experimental Details

O MeO HO

(Z)-3-(3-Methoxyallyl)tetrahydro-2H-pyran-3-ol (2.26): Following a slightly modified procedure,41 a chunk of samarium was broken into pieces (0.98 g, 6.5 mmol, 2.5 equiv) and added to a 25 mL round bottom flask along with 1,2-diiodoethane (1.61 g, 5.7 mmol,

2.2 equiv). The flask was pump filled with nitrogen and THF (10 mL) was added. The solution was stirred for 3 h as it turned yellow, green, and finally dark blue. To the dark blue solution was added HMPA (8.2 mL, 47 mmol, 18 equiv). The solution turned purple upon the addition of HMPA. Then was added dihydro-2H-pyran-3(4H)-one (0.261 g,

2.60 mmol), tert-butanol (0.50 mL), and methoxyallene (0.45 mL, 5.3 mmol, 2 equiv) in

THF (40 mL). The solution turned yellow and was stirred for 18 h. The reaction was quenched with sat. aq. NaHCO3 and water, the aqueous layer was extracted with Et2O.

The combined organic layers were washed with water and dried over Na2SO4 and concentrated. The crude product was purified by was purified by column chromatography

(silica gel, 3-5% EtOAc/hexanes) to give 34% of the product (0.152 g, 0.883 mmol) as a colorless oil. FTIR (film, cm-1): 3442, 3041, 2942, 2850, 1665, 1449, 1390, 1264, 1215,

1 1108, 944; H NMR (CDCl3, 400 MHz): ! 6.04 (dt, J = 6.2, 1.3 Hz, 1H), 4.45 (dt, J = 7.8,

6.3, Hz, 1H), 3.76 (m, 1H), 3.59 (s, 3H), 2.70 (br s, 1H), 2.29-2.17 (m, 2H), 1.88-1.79 (m,

13 1H), 1.71-1.50 (m, 3H); C NMR (CDCl3, 100 MHz): ! 148.4, 100.1, 75.6, 69.3, 68.0,

+ 59.4, 34.0, 32.5, 22.5; HRMS (ESI) calcd for [C9H16O3 + Na] calcd 195.0992, found

195.0988.

3-Isopropoxyprop-1-ene: To a solution of sodium hydroxide (24.3 g, 607 mmol, 5 equiv) and benzyltriethylammonium chloride (1.40 g, 6.15 mmol, 0.05 equiv) in water

(40 mL) was slowly added a solution of allyl alcohol (8.25 mL, 121.3 mmol, 1 equiv) and

2-bromopropane (23.0 mL, 245 mmol, 2 equiv). The solution was heated at reflux for 24 h, allowed to cool, and diluted with water (15 mL). The organic layer was separated and washed with water (15 mL x 6) and brine (15 mL). The organic layer was dried over

Na2SO4 and filtered to afford pure 3-isopropoxyprop-1-ene (3.75 g, 37.4 mmol, 31%) as a colorless oil. FTIR (film, cm-1): 3036, 3026, 2968, 2933, 2798, 1454, 1384, 1260, 1076,

1 804, 731; H NMR (CDCl3, 400 MHz): ! 5.92 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H), .30-5.24

(m, 1H), 5.16-5.12 (m, 1H), 3.97 (dt, J = 5.6, 1.4 Hz, 1H), 3.62 (sep, J = 6.1 Hz, 1H),

13 1.17 (d, J = 6.1 Hz, 6H); C NMR (CDCl3, 100 MHz): ! 135.5, 116.2, 70.8, 69.0, 22.0.

2-(Allyloxy)-2-methylbutane: A solution of allyl alcohol (4.00 mL, 3.42 g; 58.8 mmol,

1 equiv) and 2-methyl-2-butene (15.0 mL, 9.93 g, 142 mmol, 2.4 equiv) was heated to 45

!C and through a reflux condenser was slowly added conc. H2SO4 (0.30 mL, 5.6 mmol,

0.096 equiv) over 20 min. The reaction was allowed to stir an additional 4 h at 45 !C. The reaction was allowed to cool to ambient temperature, the bottom dark layer was discarded, and the top organic layer was washed with water (10 mL), sat. NaHCO3(aq)

(10 mL), and dried over Na2SO4. The light yellow oil was purified by Kugelrohr distillation under reduced pressure to give 2-(allyloxy)-2-methylbutane (4.89 g, 38.1 mmol, 65%) as a clear, colorless oil. FTIR (film, cm-1): 3080, 2969, 2879, 1464, 1364,

1 1179, 1077, 918; H NMR (CDCl3, 400 MHz): ! 5.97-5.88 (m, 1H), 5.30-5.24 (m, 1H),

5.12-5.09 (m, 1H), 3.88-3.86 (m, 2H), 1.52 (q, J = 7.5 Hz, 2H), 1.16 (s, 6H), 0.88(t, J =

13 7.5 Hz, 3H); C NMR (CDCl3, 100 MHz): ! 136.2, 115.5, 75.1, 62.6, 32.6, 25.1, 8.2.

sBuLi (1.3 equiv) R R O -78 °C, THF 1 2 OMe + HO R1 R2 (1.3 equiv) OMe

General procedure for the preparation of 4-hydroxy enol ethers: To a solution of sBuLi (1.4 M in cyclohexane, 1.3 equiv) in THF cooled to -78 !C was added allyl alkyl ether (1.3 equiv). The yellow solution was allowed to stir for 15 min then aldehyde or ketone (1 equiv) was added and allowed to stir at -78 !C for 0.5 h and 2 h at 24 !C. The reaction was quenched with sat. NH4Cl(aq), the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3x), the combined organic layers were dried over Na2SO4, decanted, concentrated under reduced pressure, and purified by column chromatography on silica gel (EtOAc/hexane) to afford pure 4-hydroxy enol ether.

OMe Ph OH

(Z)-6-Methoxy-1-phenylhex-5-en-3-ol (2.32): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 3-phenylpropionaldehyde (2.64 mL, 2.69 g, 20.0 mmol, 1 equiv), allyl methyl ether46 (1.3 equiv), and THF (20 mL). The crude product was purified by column chromatography (silica gel, 3 - 5%

EtOAc/hexanes) to give 37% of the product (1.54 g, 7.48 mmol) as a colorless oil. FTIR

-1 1 (film, cm ): 3386, 3025, 2932, 1664, 1453, 1258, 1108, 699; H NMR (CDCl3, 400

MHz): ! 7.29-7.15 (m, 5H), 6.02 (dt, J = 6.3, 1.2 Hz, 1H), 4.40 (dt, J = 7.6, 6.3 Hz, 1H),

3.68-3.62 (m, 1H), 3.58 (s, 3H), 2.83-2.63 (m, 2H), 2.28-2.24 (m, 2H), 2.03 (br s, 1H),

13 1.80-1.74 (m, 2H); C NMR (CDCl3, 100 MHz): ! 148.4, 142.4, 128.5, 128.4, 125.7,

+ 101.8, 71.0, 59.6, 38.6, 32.1 (2 C); HRMS (ESI) calcd for [C13H18O2 + Na] calcd

229.1199, found 257.1198

OEt Ph OH

(Z)-6-Ethoxy-1-phenylhex-5-en-3-ol (2.40.1): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 3-phenylpropionaldehyde (0.66 mL, 0.53 g, 5.0 mmol, 1 equiv), allyl ethyl ether (1.3 equiv), and THF (5 mL). The crude

72 product was purified by column chromatography (silica gel, 3 - 5% EtOAc/hexanes) to give 36% of the product (0.393 g, 1.78 mmol) as a colorless oil. FTIR (film, cm-1): 3386,

1 3026, 2977, 2930, 1664, 1381, 1110, 746 699; H NMR (CDCl3, 400 MHz): ! 7.30-7.16

(m, 5H), 6.11 (dt, J = 6.3, 1.2 Hz, 1H), 4.41 (dt, J = 7.5, 6.3 Hz, 1H), 3.81 (q, J = 7.0 Hz,

2H), 3.70-3.63 (m, 1H), 2.85-2.64 (m, 2H), 2.30-2.26 (m, 2H), 1.98 (d, J = 4.4 Hz, 1H),

13 1.82-1.76 (m, 2H), 1.25 (t, J = 7.0 Hz, 3H); C NMR (CDCl3, 100 MHz): ! 147.0, 142.4,

128.5, 128.3, 125.7, 101.7, 71.1, 67.8, 38.5, 32.2, 32.1, 15.3; HRMS (ESI) calcd for

+ [C14H20O2 + Na] calcd 243.1356, found 243.1353.

OiPr Ph OH

(Z)-6-Isopropoxy-1-phenylhex-5-en-3-ol (2.42): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 3- phenylpropionaldehyde (2.10 mL, 2.14 g, 15.9 mmol, 1 equiv), allyl isopropyl ether (2.10 mL, 2.14 g, 15.9 mmol, 1 equiv), and THF (50 mL). The crude product was purified by column chromatography

(silica gel, 3 - 5% EtOAc/hexanes) to give 28% of the product (1.04 g, 4.46 mmol) as a colorless oil. FTIR (film, cm-1): 3381, 3027, 2974, 2931, 1662, 1602, 1453, 1337, 1109,

1 1054, 699; H NMR (CDCl3, 400 MHz): ! 7.92-7.15 (m, 5H), 6.13 (dt, J = 6.4, 1.2 Hz,

1H), 4.41 (dt, J = 7.5, 6.4 Hz, 1H), 3.92 (sep, J = 6.2 Hz, 1H), 3.70-3.63 (m, 1H), 2.84-

2.64 (m, 2H), 2.29-2.25 (m, 2H), 2.05 (d, J = 4.2 Hz, 1H), 1.81-1.75 (m, 2H), 1.22 (d, J =

13 6.2 Hz, 6H); C NMR (CDCl3, 100 MHz): ! 145.9, 142.4, 128.5, 128.3, 125.7, 101.8,

+ 74.3, 71.2, 38.5, 32.3, 32.1, 22.4; HRMS (ESI) calcd for [C15H22O2 + Na] calcd

257.1512, found 257.1508.

O Ph OH

(Z)-6-(tert-Pentyloxy)-1-phenylhex-5-en-3-ol (2.40.2): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 3- phenylpropionaldehyde (0.80 mL, 0.82 g, 6.0 mmol, 1 equiv), 2-(allyloxy)-2- methylbutane (1.3 equiv), and THF (15 mL). The crude product was purified by column chromatography (silica gel, 3 - 5% EtOAc/hexanes) to give 15% of the product (0.242 g,

0.923 mmol) as a colorless oil. FTIR (film, cm-1): 3395, 3026, 2973, 2932, 1658, 1454,

1 1368, 1246, 1172, 1059, 699; H NMR (CDCl3, 400 MHz): ! 7.28-7.14 (m, 5H), 6.30 (dt,

J = 6.4, 1.1 Hz, 1H), 4.45 (dt, J = 7.5, 6.4 Hz, 1H), 3.69-3.63 (m, 1H), 2.84-2.63 (m, 2H),

2.38 (br s, 1H), 2.29-2.26 (m, 2H), 1.81-1.74 (m, 2H), 1.55 (q, J = 7.5 Hz, 2H), 1.21 (s,

13 6H), 0.88 (t, J = 7.5 Hz, 3H); C NMR (CDCl3, 100 MHz): ! 142.5, 141.0, 128.5, 128.4,

128.3, 125.7, 102.6, 78.4, 71.3, 38.6, 33.5, 32.3, 32.2, 25.5, 8.2; HRMS (ESI) calcd for

+ [C17H26O2 + Na] calcd 285.1825, found 285.1828.

OPh Ph OH

(Z)-6-Phenoxy-1-phenylhex-5-en-3-ol (2.40.3): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 3-phenylpropionaldehyde (0.80 mL, 0.82 g, 6.0 mmol, 1 equiv), allyl phenyl ether130 (1.3 equiv), and THF (15 mL).

The crude product was purified by column chromatography (silica gel, 3 - 5%

EtOAc/hexanes) to give 30% of the product (0.486 g, 1.81 mmol) as a colorless oil. FTIR

(film, cm-1): 3372, 3026, 2921, 1667, 1595, 1493, 1226, 1047, 754, 692; 1H NMR

(CDCl3, 400 MHz): ! 7.33-7.26 (m, 4H), 7.21-7.18 (m, 3H), 7.08-7.03 (m, 1H), 7.01-6.98

(m, 2H), 6.52 (dt, J = 6.2, 1.3 Hz, 1H), 4.89 (dt, J = 7.6, 6.2 Hz, 1H), 3.78-3.71 (m, 1H),

2.86-2.67 (m, 2H), 2.46-2.42 (m, 2H), 1.86-1.80 (m, 2H), 1.63 (d, J = 4.7 Hz, 1H); 13C

NMR (CDCl3, 100 MHz): ! 157.3, 142.5, 142.2, 129.7, 128.5, 128.4, 125.8, 122.8, 116.4,

+ 108.0, 77.5, 77.1, 76.8, 70.9, 38.6, 32.2, 32.1; HRMS (ESI) calcd for [C18H20O2 + Na] calcd 291.1356, found 291.1356.

SMe Ph OH

6-(Methylthio)-1-phenylhex-5-en-3-ol (2.40.4): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 3-phenylpropionaldehyde (0.66 mL, 5.0 mmol, 1 equiv), allyl methyl sulfide (1.2 equiv), and THF (2.5 mL). The crude product was purified by column chromatography (silica gel, 5 - 10% EtOAc/hexanes) to give 47% of the product (0.522 g, 2.35 mmol) as a yellow oil in a 7:3 (Z:E) mixture of

-1 1 isomers. FTIR (film, cm ): 3391, 3024, 2919, 1603, 1454, 1052, 700; H NMR (CDCl3,

400 MHz): ! 7.29-7.25 (m, 2H), 7.21-7.15 (m, 3H), 6.10 (dt, J = 15.0, 1.2 Hz, 0.3H), 6.04

(dt, J = 9.5, 1.2 Hz, 0.7H), 5.58 (dt, J = 9.5, 7.4 Hz, 0.7H), 5.39 (m, 0.3H), 3.75-3.59 (m,

1H), 2.83-2.63 (m, 2.3H), 2.35-2.31 (m, 1.7H), 2.26 (s, 2H), 2.22 (s, 1H), 1.82-1.72 (m,

13 2H); C NMR (CDCl3, 100 MHz): ! 142.1, 142.0, 130.0, 128.5, 128.4 (2C), 127.7,

125.9, 125.8, 124.1, 122.0, 70.7, 70.4, 41.4, 38.6, 37.2, 32.1, 17.1, 14.9.

i O Pr

(Z)-4-Isopropoxy-1-phenylbut-3-en-1-ol (2.45): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using benzaldehyde (2.00 mL, 2.09 g,

19.7 mmol, 1 equiv), allyl isopropyl ether (1.3 equiv), and THF (55 mL). The crude product was purified by column chromatography (silica gel, 3 - 5% EtOAc/hexanes) to give 43% of the product (1.76 g, 8.53 mmol) as a colorless oil. FTIR (film, cm-1): 3398,

3030, 2973, 2930, 2877, 1662, 1493, 1383, 1338, 1104, 1049, 912, 743, 700; 1H NMR

(CDCl3, 400 MHz): ! 7.39-7.31 (m, 4H), 7.27-7.23 (m, 1H), 6.13 (dt, J = 6.3, 1.2 Hz,

1H), 4.74 (m, 1H), 4.39 (dt, J = 7.4, 6.4 Hz, 1H), 3.92 (sep, J = 6.2 Hz, 1H), 2.65-2.47

13 (m, 3H), 1.22 (m, 6H); C NMR (CDCl3, 100 MHz): ! 146.0, 144.5, 128.2, 127.2, 101.7,

+ 74.3, 74.1, 34.4, 22.4 (2 C); HRMS (ESI) calcd for [C13H18O2 + Na] calcd 229.1199, found 229.1209.

OH MeO

OiPr OMe

(Z)-1-(2,5-Dimethoxyphenyl)-4-isopropoxybut-3-en-1-ol (2.46): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 2,5- dimethoxybenzaldehyde (2.64 g, 15.9 mmol, 1 equiv), allyl isopropyl ether (1.3 equiv), and THF (50 mL). The crude product was purified by column chromatography (silica gel,

5 - 10% EtOAc/hexanes) to give 35% of the product (1.47 g, 5.53 mmol) as a pale yellow oil. FTIR (film, cm-1): 3448, 3039, 2972, 2936, 2833, 1662, 1590, 1497, 1216, 1048; 1H

NMR (CDCl3, 400 MHz): ! 7.00 (d, J = 3.0 Hz, 1H), 6.80-7.72 (m, 2H), 6.11 (dt, J = 6.3,

1.2 Hz, 1H), 4.92 (dt, J = 7.4, 5.4 Hz, 1H), 4.42 (m, 1H), 3.91 (sep, J = 6.2 Hz, 1H), 3.80

(s, 3H), 3.79 (s, 3 H), 2.89 (d, J = 5.5 Hz, 1 H), 2.62-2.49 (m, 2 H), 1.21 (m, 6H); 13C

NMR (CDCl3, 100 MHz): ! 153.6, 150.6, 145.6, 133.6, 102.4, 74.1, 70.1, 55.8, 55.7,

+ 32.2, 22.4 (2 C); HRMS (ESI) calcd for [C15H22O4 + Na] calcd 289.1409, found

289.1410.

S OiPr

(Z)-4-Isopropoxy-1-(thiophen-2-yl)but-3-en-1-ol (2.48): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 2- thiophenecarboxaldehyde (1.00 mL, 1.20 g, 10.7 mmol, 1 equiv), allyl isopropyl ether

(1.3 equiv), and THF (50 mL). The crude product was purified by column chromatography (silica gel, 10 - 15% EtOAc/hexanes) to give 36% of the product (0.813 g, 3.83 mmol) as a pale yellow oil. FTIR (film, cm-1): 3414, 3041, 2973, 2930, 1662,

1 1452, 1384, 1372, 1339, 1249, 1103, 1041, 698; H NMR (CDCl3, 400 MHz): ! 7.22 (dd,

J = 4.9, 1.4 Hz, 1H), 6.99-6.95 (m, 2H), 6.15 (dt, J = 6.4, 1.3 Hz, 1H), 5.01-4.97 (m, 1H),

4.43 (dt, J = 7.4, 6.4 Hz, 1H), 3.94 (sep, J = 6.2 Hz, 1H), 1.24-1.22 (m, 6H); 13C NMR

(CDCl3, 100 MHz): ! 148.6, 146.2, 126.5, 124.2, 123.3, 101.1, 74.4, 70.3, 34.4, 22.4;

+ HRMS (ESI) calcd for [C11H16O2S + Na] calcd 235.0763, found 235.0771.

TBSO OiPr

(Z)-8-((tert-Butyldimethylsilyl)oxy)-1-isopropoxyoct-1-en-4-ol (2.50): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using 5-

((tert-butyldimethylsilyl)oxy)pentanal54 (1.50 g, 6.90 mmol, 1 equiv), allyl isopropyl ether (1.3 equiv), and THF (20 mL). The crude product was purified by column chromatography (silica gel, 3 - 5% EtOAc/hexanes) to give 33% of the product (0.721 g,

2.27 mmol) as a colorless oil. FTIR (film, cm-1): 3409, 3037, 2930, 2858, 1662, 1482,

1 1384, 1337, 1254, 1101, 835, 775; H NMR (CDCl3, 400 MHz): ! 6.12 (dt, J = 6.3, 1.2

Hz, 1H), 4.43 (dt, J = 7.6, 6.4 Hz, 1H), 3.92 (sep, J = 6.2 Hz, 1H), 3.63-3.60 (m, 3H),

2.25-2.21 (m, 2H), 2.01 (d, J = 4.1 Hz, 1H), 1.22 (d, J = 6.2 Hz, 6H), 0.89 (s, 9H), 0.04

13 (s, 6H); C NMR (CDCl3, 100 MHz): ! 145.6, 102.1, 74.1, 71.7, 63.2, 36.5, 32.8, 32.1,

+ 25.9, 22.3, 22.0, 18.3, -5.3; HRMS (ESI) calcd for [C17H36O3Si + Na] calcd 339.2326, found 339.2334.

OH OiPr O

(Z)-3-(3-Isopropoxallyl)-2,2,5,5-tetramethyltetrahydrofuran-3-ol (2.55): This reaction was performed according to the general procedure for 4-hydroxy enol ethers using dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (3.10 mL, 2.87 g, 20.2 mmol, 1 equiv), allyl isopropyl ether (1.3 equiv), and THF (75 mL). The crude product was purified by column chromatography (silica gel, 10 - 20% EtOAc/hexanes) to give 23% of the product (1.13 g, 4.66 mmol) as a colorless oil which solidified to a white solid upon storage in freezer.

FTIR (KBr, cm-1): 3402, 2974, 1657, 1377, 1233, 1110, 1041, 982, 760; 1H NMR

(CDCl3, 400 MHz): ! 6.16 (dt, J = 6.4, 1.2 Hz, 1H), 4.46 (dt, J = 7.7, 6.4 Hz, 1H), 3.94

(sep, J = 6.2 Hz, 1H), 2.36-2.26 (m, 2H), 2.18 (br s, 1H), 2.01 (m, 2H), 1.35 (s, 3H), 1.29

13 (s, 3H), 1.25 (s, 3H), 1.23 (d, J = 6.2 Hz, 6H), 1.20 (s, 3H); C NMR (CDCl3, 100 MHz):

! 146.1, 100.8, 85.4, 84.2, 77.6, 50.4, 31.6, 31.0, 30.8, 26.9, 23.3, 22.4; HRMS (ESI)

+ calcd for [C14H26O3 + Na] calcd 265.1773, found 265.1774.

OH Pd(OAc)2 (2.5 mol %) PPh3 (10 mol %), BQ (1.1 equiv) R O R AcOH (1 equiv) OiPr CH2Cl2, 23 °C, 2-6 h then 2 M HCl

General procedure for the preparation of furans: To a stirred solution of Pd(OAc)2

(5.6 mg, 0.025 mmol, 0.025 equiv), PPh3 (26.3 mg, 0.10 mmol, 0.10 equiv), p- benzoquinone (119 mg; 1.10 mmol, 1.1 equiv), and AcOH (60 µL, 1.0 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added 4-hydroxy enol ether (1.0 mmol, 1.0 equiv). The solution was stirred at 24 !C for 2 – 6 h. The reaction mixture was then diluted with CH2Cl2 (15 mL) and vigorously stirred with 2 M HCl (aq) (10 mL) for 10 min – 2 h. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL x 3), the combined organic layers were dried over Na2SO4, decanted, concentrated under reduced pressure, and purified by column chromatography on silica gel (EtOAc/hexane) to afford pure furan.

OH Pd(OAc)2 (2.5 mol %) PPh3 (10 mol %), BQ (1.1 equiv) R O R AcOH (1 equiv) OiPr CH2Cl2, 23 °C, 2-6 h then 2 M HCl

2-Phenylfuran (2.39): This reaction was performed according to the general procedure for furans using (Z)-4-isopropoxy-1-phenylbut-3-en-1-ol (207 mg, 1.00 mmol), and stirring for 2 h, then stirred with 2 M HCl (aq) for 0.5 h. The crude product was purified by column chromatography (silica gel, 1% EtOAc/hexanes) to give 76% of the product

(109 mg, 0.756 mmol) as a colorless oil.

This product spectroscopically matched that of the known compound.61

OMe

O MeO

2-(2,5-Dimethoxyphenyl)furan (2.47): This reaction was performed according to the general procedure for furans using (Z)-1-(2,5-dimethoxyphenyl)-4-isopropoxybut-3-en-1- ol (267 mg, 1.00 mmol), and stirring for 2 h, then stirred with 2 M HCl (aq) for 0.5 h. The crude product was purified by column chromatography (silica gel, 3% EtOAc/hexanes) to give 91% of the product (186 mg, 0.911 mmol) as a colorless oil. FTIR (film, cm-1):

3145, 3117, 2998, 2906, 2833, 2067, 1611, 1573, 1499, 1221, 1051, 739; 1H NMR

(CDCl3, 400 MHz): ! 7.48 (dd, J = 1.8, 0.8 Hz, 1H), 7.45 (d, J = 3.1 Hz, 1H), 7.00 (dd, J

= 3.3, 0.8 Hz, 1H), 6.91-6.88 (m, 1H), 6.82-6.79 (m, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H,

13 3.89 (s, 3H), 3.84 (s, 3H); C NMR (CDCl3, 100 MHz): ! 153.8, 150.1, 149.8, 141.2,

120.6, 113.4, 112.4, 111.8, 111.1, 110.2, 55.9, 55.8; HRMS (ES) calcd for [C12H12O3 +

Na]+ calcd 227.0679, found 227.0684.

S O

2-(2-Thienyl)furan (2.49): This reaction was performed according to the general procedure for furans using (Z)-4-isopropoxy-1-(thiophen-2-yl)but-3-en-1-ol (212 mg,

1.00 mmol), and stirring for 2 h, then stirred with 2 M HCl (aq) for 2 h. The crude

81 product was purified by column chromatography (silica gel, 1% EtOAc/hexanes) to give

72% of the product (108 mg, 0.719 mmol) as a pale yellow oil.

This product spectroscopically matched that of the known compound.61

2-Phenethylfuran (2.41): This reaction was performed according to the general procedure for furans using (Z)-6-isopropoxy-1-phenylhex-5-en-3-ol (235 mg, 1.00 mmol), and stirring for 2 h, then stirred with 2 M HCl (aq) for 10 min. The crude product was purified by column chromatography (silica gel, 1% EtOAc/hexanes) to give 82% of the product (142 mg, 0.825 mmol) as a colorless oil.

This product spectroscopically matched that of the known compound.62

TBSO O

tert-Butyl(4-(furan-2-yl)butoxy)dimethylsilane (2.51): This reaction was performed according to the general procedure for furans using (Z)-8-((tert-butyldimethylsilyl)oxy)-

1-isopropoxyoct-1-en-4-ol (317 mg, 1.00 mmol), and stirring for 6 h, then stirred with 2

M HCl (aq) for 1 h. The crude product was purified by column chromatography (silica

82 gel, 3% EtOAc/hexanes) to give 78% of the product (199 mg, 0.785 mmol) as a colorless oil. This product spectroscopically matched that of the known compound.62

Pd(OAc)2 (2.5 mol %) R2 R1 PPh3 (10 mol %), BQ (1.1 equiv) R1 O HO R2 AcOH (1 equiv) OiPr OiPr CH2Cl2, 23 °C

General procedure for the preparation of 2,5-dihydrofurans: To a stirred solution of

Pd(OAc)2 (5.6 mg, 0.025 mmol, 0.025 equiv), PPh3 (26.3 mg, 0.10 mmol, 0.10 equiv), p- benzoquinone (119 mg; 1.10 mmol, 1.1 equiv), and AcOH (60 µL, 1.0 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added 4-hydroxy enol ether (1.0 mmol, 1.0 equiv). The solution was stirred at 24 ! C for 1 - 17 h. The reaction mixture was then diluted with CH2Cl2 (15 mL) and washed with sat. NaHSO3(aq) (10 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (10 mL x 3), the combined organic layers were dried over Na2SO4, decanted, concentrated under reduced pressure, and purified by column chromatography on silica gel (EtOAc/hexane) to afford pure 2,5-dihydrofuran.

OMe

O OiPr MeO

2-(2,5-Dimethoxyphenyl)-5-isopropoxy-2,5-dihydrofuran (2.53): This reaction was performed according to the general procedure for 2,5-dihydrofurans using (Z)-1-(2,5-

83 dimethoxyphenyl)-4-isopropoxybut-3-en-1-ol (0.266 g, 1.00 mmol), and stirring for 1 h.

The crude product was purified by column chromatography (silica gel, 3%

EtOAc/hexanes) to give 85% of the product (225 mg, 0.852 mmol) as a pale yellow oil.

The product was isolated as a 1:1 mixture of diastereomers. FTIR (film, cm-1): 2969,

1 2833, 1496, 1466, 1216, 1041, 805; H NMR (CDCl3, 400 MHz): ! 7.17 (d, J = 2.6 Hz,

1H), 6.91 (d, J = 2.9 Hz, 1H), 6.81-6.73 (m, 2H), 6.29 (dt, J = 5.9, 1.2 Hz, 0.5H), 6.25 (dt,

J = 5.9, 1.4 Hz, 0.5H), 6.23 -6.21 (m, 0.5H), 6.16-6.15 (m, 0.5H), 6.06 (m, 0.5H), 6.02

(m, 0.5H), 5.82-5.80 (m, 0.5H), 5.76-5.74 (m, 0.5H), 4.12 (sep, J = 6.2 Hz, 0.5H), 4.04

(sep, J = 6.2 Hz, 0.5H), 3.80 (m, 3H), 3.76 (m, 3H), 1.34 (d, J = 6.2, 1.5 Hz, 1.5H), 1.27

13 (d, J = 6.2, 1.5 Hz, 1.5H), 1.24 (m, 3H); C NMR (CDCl3, 100 MHz): ! 154.0, 153.9,

150.6, 149.9, 135.5, 134.9, 130.6, 130.0, 125.9, 125.2, 113.7, 112.9, 112.6, 112.4, 111.4,

111.2, 107.6, 107.5, 82.2, 81.2, 70.9, 70.0, 56.0, 55.9, 55.7 (2 C), 24.0, 23.8, 22.6, 22.4;

+ HRMS (ESI) calcd for [C15H20O4 + Na] calcd 287.1254, found 287.1272.

S O OiPr

2-Isopropoxy-5-(thiophen-2-yl)-2,5-dihydrofuran (2.54): This reaction was performed according to the general procedure for 2,5-dihydrofurans using (Z)-4-isopropoxy-1-

(thiophen-2-yl)but-3-en-1-ol (0.212 g, 1.00 mmol), and stirring for 1.5 h. The crude product was purified by column chromatography (silica gel, 3% EtOAc/hexanes) to give

91% of the product (191 mg, 0.907 mmol) as a pale yellow oil. The product was isolated

84 as a 1:1 mixture of diastereomers. FTIR (film, cm-1): 3087, 2971, 2891, 2244, 1624,

1 1465, 1438, 1378, 1343, 1310; H NMR (CDCl3, 400 MHz): ! 7.24 (m, 1H), 7.00 (m,

1H), 6.93 (m, 1H), 6.21 (dt, J = 5.9, 1.2 Hz, 0.5H), 6.18 (m, 0.5H), 6.12(m, 0.5H), 6.07

(m, 0.5H), 5.93 (m, 1H), 5.89(m, 1H), 4.00 (m, 1H), 1.26 (d, J = 6.2 Hz, 1.5H), 1.20 (m,

13 4.5H); C NMR (CDCl3, 100 MHz): ! 145.0, 144.1, 134.8, 134.3, 127.8, 127.2, 126.8,

126.5, 125.9, 125.7, 125.3, 125.1, 107.1, 106.7, 82.1, 81.7, 70.5, 70.2, 23.8, 23.7, 22.4,

+ 22.1; HRMS (ESI) calcd for [C11H14O2S + Na] calcd 233.0607, found 233.0605.

O O OiPr

2-Isopropoxy-6,6,8,8-tetramethyl-1,7-dioxaspiro[4.4]non-3-ene (2.56): This reaction was performed according to the general procedure for 2,5-dihydrofurans using (Z)-3-(3- isopropoxallyl)-2,2,5,5-tetramethyltetrahydrofuran-3-ol (0.242 g, 1.00 mmol), and stirring for 17 h. The crude product was purified by column chromatography (silica gel,

4% EtOAc/hexanes) to give 77% of the product (185 mg, 0.770 mmol) as a colorless oil.

The product was isolated as a 3:1 mixture of diastereomers, the assignment of diastereomers was not clear from NOESY experiment. FTIR (film, cm-1): 2971, 2931,

1 1465, 1378, 1066, 1025, 1006, 742; H NMR (CDCl3, 400 MHz): ! 6.03-6.00 (m, 1H),

5.86 (m, 1H), 5.84 (dd, J = 6.0, 1.0 Hz, 0.35H), 5.77 (dd, J = 5.9, 1.2 Hz, 0.65H), 4.07-

3.95 (m, 1H), 2.33 (d, J = 13.4 Hz, 0.35H), 2.23 (d, J = 13.3 Hz, 0.65H), 2.03 (d, J = 13.4

Hz, 0.35H), 1.93 (d, J = 13.3 Hz, 0.65H), 1.38 (m, 3H), 1.32 (m, 3H), 1.31 (m, 2H), 1.25

(m, 1.65H), 1.24 (m, 3.35H), 1.20 (m, 1.35H), 1.18-1.17 (m, 4.65H), 1.13 (m, 1H); 13C

NMR (CDCl3, 100 MHz): ! 134.3, 134.0, 128.2, 127.5, 106.7, 105.9, 100.4, 100.2, 85.3,

85.0, 79.2, 78.6, 70.3, 70.1, 50.2, 49.9, 31.4, 31.3, 30.3, 29.9, 28.0, 27.6, 24.5, 23.8, 23.5,

+ 22.9, 22.5, 21.9; HRMS (ESI) calcd for [C14H24O3 + Na] calcd 263.1618, found

263.1609.

4.4 Chapter 3 Experimental Details

TsHN

Ph O

(E)-N-(4-Isopropoxy-1-phenylbut-3-en-1-yl)-4-methylbenzenesulfonamide (3.12):

This reaction was performed according to the general procedure for 4-hydroxy enol ethers using N-benzylidene-4-methylbenzenesulfonamide (1.29 g, 5.00 mmol, 1 equiv), allyl isopropyl ether (0.89 mL, 6.5 mmol, 1.3 equiv), and THF (35 mL). The crude product was purified by column chromatography (silica gel, 15% EtOAc/hexanes) to give

14% of the product (0.328 g, 0.91 mmol) as a colorless oil. FTIR (film, cm-1): 3278,

3030, 2974, 2928, 1659, 1599, 1495, 1454, 1384, 1329, 1250, 1160, 1106, 1061, 947,

1 920, 813, 743, 700, 668; H NMR (CDCl3, 400 MHz): ! 7.58 (m, 2H), 7.17 (m, 7H), 6.06

(d, J=6.28 Hz, 1H), 5.33 (d, J= 5.2 Hz, 1H), 4.31 (m, 1H), 4.14 (m, 1H), 3.94 (sep, J=6.16

Hz, 1H), 2.51-2.32 (m, 2H), 2.37 (s, 3H), 1.26 (dd, J = 13.28, 6.20 Hz, 6H); 13C NMR

(CDCl3, 100 MHz): ! 146.6, 142.8, 141.4, 137.6, 129.2, 128.1, 127.2, 127.0, 126.6,

+ 100.4, 74.7, 58.2, 32.1, 22.4, 21.5; HRMS (ESI) calcd for [C20H25NO3S + Na] calcd,

382.1147 found 382.1138.

Ts Ph N

2-Phenyl-1-tosyl-1H-pyrrole (3.13): A clean, dry 4 mL vial equipped with a stir bar was charged with (E)-N-(4-isopropoxy-1-phenylbut-3-en-1-yl)-4-methylbenzenesulfonamide

(0.449 g, 1.25 mmol, 1 equiv), Pd(TFA)2 (20 mg, 5 mol %), PPh3 (49 mg, 15 mol %) and toluene (15 mL). The reaction was purged with O2 and run under 1 atm of oxygen

(balloon) for 16 hours at 40 °C. The reaction was quenched with water (15 mL), diluted with CH2Cl2 (15 mL), and the layers were separated. The aqueous layer was extracted with CH2Cl2 (3 x 15 mL) and the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silca gel, 1% EtOAc/Hexanes) to give the pyrrole in 38 % yield (0.14 g,

0.47 mmol).

Spectroscopic data matched that of the known compound.68

References and Notes

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2173

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5311.

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(9) A large portion of the work in this section was performed by Dr. William H.

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Appendix A: 1H NMR and 13C NMR Spectra for Selected Compounds

1.27

1.29

1.30

1.31

100

1.31

101

1.32

102

1.32

103

1.33

104

1.33

105

1.34

106

1.34

107

1.41

108

1.41

109

1.42

110

1.42

111

1.43

112

1.43

113

1.43

114

1.43

115

1.44

116

1.44

117

1.37

118

1.37

119

1.38

120

1.38

121

1.39

122

1.39

123

1.40

124

1.40

125

1.45

126

1.45

127

1.47

128

1.47

129

2.22

130

6 2.2

131

132

133

134

135

2.32

136

2.22

137

2.40.1

138

2.40.1

139

2.42

140

2.42

141

2.40.2

142

2.40.2

143

2.40.3

144

2.40.3

145

2.40.4

146

2.40.4

147

2.45

148

2.45

149

2.46

150

2.46

151

2.47

152

2.47

153

2.48

154

2.48

155

2.50

156

2.50

157

2.53

158

2.53

159

2.54

160

2.54

161

2.55

162

2.55

163

2.56

164

2.56

165

OiPr 2 1 . Ph 3 NHTs

166

OiPr 2 1 . Ph 3 NHTs

167