Synthesis of Functionalized Allylic, Propargylic and Allenylic Compounds

Synthesis of functionalized allylic, propargylic and allenylic compounds

Selective formation of CB, CC, CCF3 and CSi bonds

Tony Zhao

ISBN 978-91-7649-189-8

Printed in Sweden by E-print AB 2015 Distributor: Department of Organic Chemistry, Stockholm University ii iii iv Abstract

This thesis is focused on the development of new palladium and copper- mediated reactions for functionalization of alkenes and propargylic alcohol derivatives. The synthetic utility of the 1,2-diborylated butadienes synthesized in one of these processes has also been demonstrated. We have developed an efficient procedure for the synthesis of allenyl boronates from propargylic carbonates and acetates. This was achieved by using a bimetallic system of palladium and copper or silver as co-catalyst. The reactions were performed under mild conditions for the synthesis of a variety of allenyl boronates. Furthermore, the synthesis of 1,2-diborylated butadienes was achieved with high diastereoselectivity from propargylic epoxides. The reactivity of the 1,2-diborylated butadienes with aldehydes was studied. It was found that the initial allylboration reaction proceeds via an allenylboronate intermediate. The allenylboronate reacts readily with an additional aldehyde to construct 2-ethynylbutane-1,4-diols with moderate to high diastereoselectivity. We have also studied the copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates. It was also shown that a transfer of chirality occurred when an enantioenriched starting material was used. In the last part of the thesis, we have described a method for palladium- catalyzed functionalization of allylic CH bonds for the selective synthesis of allylic silanes. The protocol only works under highly oxidative conditions which suggest a mechanism involving high oxidation state palladium intermediates.

v vi List of Publications

This thesis is based on the following papers, which will be referred to by Roman numerals IIV. Reprints were made with the kind permission from the publishers.

I. Borylation of Propargylic Substrates by Bimetallic Catalysis. Syn- thesis of Allenyl, Propargylic and Butadiene Bpin Derivatives Tony S. N. Zhao, Yuzhu Yang, Timo Lessing, Kálmán, J. Szabó Journal of American Chemical Society, 2014, 136, 7563-7566 II. Stereoselective Synthesis of 1,4-Diols by a Tandem Allylboration- Allenylboration Sequence Tony S. N. Zhao, Jian Zhao, Kálmán, J. Szabó Organic Letters, 2015, 17, 2290-2293 III. Trifluoromethylation of Propargylic Halides and Trifluoroace- tates Using (Ph3P)3Cu(CF3) Reagent Tony S. N. Zhao, Kálmán, J. Szabó Organic Letters, 2012, 14, 3966–3969 IV. Palladium-Catalyzed Oxidative Allylic C−H Silylation Johanna, M. Larsson, Tony S. N. Zhao, Kálmán, J. Szabó Organic Letters, 2011, 13, 1888–1891

vii Contents

Abstract ...... v List of Publications ...... vii Contents ...... viii Abbreviations ...... x 1. Introduction ...... 1 1.1 Transition metal-catalyzed allylic substitution ...... 1 1.2 Transition metal-catalyzed propargylic substitution ...... 2 1.3 Reactions of allyl and allenyl boronates with aldehydes...... 3 1.4 Trifluoromethylation of organic compounds ...... 4 1.5 Objectives of the thesis ...... 4 2. Borylation of propargylic alcohol derivatives (Paper I) ...... 5 2.1 Method development for synthesis of α,γ-substituted allenyl boronates ...... 7 2.2 Synthesis of α,γ-substituted and α-substituted allenyl boronates ...... 11 2.3 Method development for synthesis of γ-substituted allenyl boronates 13 2.4 Stereochemistry of the formation of allenyl boronate ...... 16 2.5 Borylative opening of propargylic epoxides; synthesis of 1,2-diborylated butadienes...... 17 2.6 Proposed catalytic cycle ...... 21 2.6.1 Proposed catalytic cycle for the borylation of propargylic carbonates ...... 21 2.6.3 Proposed catalytic cycle for the borylation of propargylic epoxides 22 2.7 Summary and conclusions for borylation of alcohol derivatives...... 24 3. Sequential addition of 1,2-diborylated butadienes to aldehydes (Paper II) ...... 25 3.1 Method development for the synthesis of 2-ethynylbutane-1,4-diols from (mono)aldehydes ...... 26 3.2 Synthesis of 2-ethynylbutane-1,4-diols from aldehydes ...... 27 3.3 Synthesis of 1,4-dihydroxytetralin derivatives from dialdehydes and 1,2,-diborylated butadienes ...... 29 3.4 Determination of relative stereochemistry of the 1,4-diol products ..... 32 3.5 Mechanism of the sequential allylboration-allenylboration reaction ... 33 3.6 Summary and conclusion for addition of 1,2-diborylated butadienes to aldehydes ...... 35

viii 4. Cu-mediated trifluoromethylation of propargylic alcohol derivatives (Paper II) ...... 36 4.1 Initial experiments ...... 37 4.2 Synthesis of trifluoromethylated allenylic and propargylic compounds ...... 38 4.3 Stereochemistry of the trifluoromethylation reaction ...... 42 4.4 Investigation of a possible radical mechanism ...... 42 4.5 Study of the thermal rearrangement of 20b ...... 43 4.6 Proposed mechanism ...... 44 4.7 Recent publications for the synthesis of trifluoromethylated propargylic and allenylic compounds ...... 44 4.8 Summary and conclusions for trifluoromethylation of propargylic substrates...... 45 5. Palladium-catalyzed oxidative CH silylation (Paper III) ...... 46 5.1 Background ...... 46 5.1.1 Previous palladium-catalyzed methods for the synthesis of allylic silanes ...... 46 5.1.2 Previous allylic CH functionalization developed in the group ...... 47 5.2 Development of palladium-catalyzed CH silylation ...... 48 5.3 Synthesis of allylic silanes – scope and limitations ...... 48 5.4 Mechanistic investigation and proposed catalytic cycle for the silylation of alkenes ...... 50 5.5 Conclusions and summary for CH functionalized silylation of alkenes ...... 52 6. Concluding remarks and outlook ...... 53 X. Acknowledgements ...... 54 Y. Vetenskaplig sammanfattning ...... 56 Z. References ...... 57

ix Abbreviations

Abbreviations and acronyms are used in agreement with standards of the subject.† Only nonstandard and unconventional ones that appear in the thesis are listed here.

BQ 1,4-benzoquinone bpy 2,2’-bipyridine CMD concerted metallation-deprotonation DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DPEPhos bis(2-diphenylphosphinophenyl)ether dppb 1,4-bis(diphenylphosphino)butane dr diastereomeric ratio HSQC heteronuclear single quantum correlation IPr 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene L.A. Lewis acid LG leaving group M.S. molecular sieves Nu nucleophile Piv pivaloyl pin pinacolato PTS polyoxyethanyl α-tocophery sebacate TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy Tf trifluoromethanesulfonyl TRIP 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-bi-2-naphthol cyclic monophosphate TS transition state rt room temperature X- anionic ligand

† The ACS Style Guide; 3rd ed.; Oxford University Press: New York, 2006.

x 1. Introduction

Transition-metal catalysis is one of the most important tools in modern organic synthesis.1 Transition metal-catalyzed reactions have been widely utilized for a range of transformations, such as, cross-coupling,2 substitution3 and CH functionalization reactions.4

1.1 Transition metal-catalyzed allylic substitution One of the most utilized and studied reactions are transition metal- catalyzed substitution of allylic compounds.1b, 5 The most well-known is the Tsuji-Trost reaction,6 where palladium is used to catalyze the reaction (Fig- ure 1).5a, 7

Figure 1. General mechanism of the palladium-catalyzed Tsuji-Trost reaction

These reactions generally start with an oxidative addition of a pre- functionalized allylic substrate to Pd0 which forms a cationic η3-allyl PdII- complex. The oxidative addition of allylic substrates to Pd0 commonly occurs with inversion of stereochemistry.7c, 7d, 8 However, it has been shown that syn addition is also possible using appropriate ligands and solvents.7e, 8-9 The resulting cationic η3-allyl palladium-complex then undergoes a nucleophilic attack. The overall stereochemistry of the reaction is also affected by the type of nucleophile used. Stabilized or so-called “soft” nucleophiles attack the carbon center directly and thus yields a net retention of the configu-

1 ration with regards to the leaving group.7c, 7d, 10 On the other hand, non- stabilized or “hard” nucleophiles attack the metal-center. After a reductive elimination, the reaction results in a net inversion of the configuration with regard to the leaving group.7c, 7d, 11 Depending on the reaction conditions, the regioselectivity of the nucleophilic attack can differ to give substitution at the least or most substituted position.3a, 7b, 7d, 12

1.2 Transition metal-catalyzed propargylic substitution Similar to the allylic substitution, the substitution of a leaving group on a propargylic substrate can either occur at the α- or γ-positions (Scheme 1). Depending on the regioselectivity of the displacement, the outcome can either yield the propadienyl (allene) or acetylene (propargyl) metal intermediates.13 After transmetalation and subsequent reductive elimination, the reaction yields the corresponding allene or propargylic product. This is in contrast to the allylic substitution, which only affords different alkenes (Figure 1). In many transition metal-catalyzed propargylic substitution reactions, high levels of selectivity can be achieved for the synthesis of propargylic or allenylic structures.3b, 12, 13b, 13c, 14

Scheme 1. Possible reaction pathways for metal-mediated propargylic substitution reactions

The allene moiety is built up by orthogonal, cumulative π-systems which gives it a unique reactivity compared to alkenes and alkynes.15 Unlike substituted alkenes, allenes may possess axial chirality, which gives a new dimen- sion to their synthetic utility.16 In recent years, allenes have become useful and important intermediates in organic synthesis.17 Novel reactions have been developed where allenes are used as precursors.18 Allenes has also been shown to be able to transfer chirality to the newly formed stereocenters.16b, 17b, 19 The allene structural motifs have also been discovered in many natural products and started to attract an increased attention in pharmaceutical research.14b, 17b

2 1.3 Reactions of allyl and allenyl boronates with aldehydes

The stereoselective allylation and propargylation of carbonyl compounds are important transformations in modern organic synthesis.20 The allylation of aldehydes can be performed with allylsilanes and allylboronates affording homoallylic alcohols in high diastereoselectivity.21 Similarly, the addition of allenyl boronates to aldehydes provides the synthesis of homopropargylic alcohol.21d, 22 The high diastereoselectivity of the allylboration reaction is attributed to an internal Lewis acid activation of the aldehyde by the empty p-orbital of boron. The addition proceeds via a six-membered (Zimmerman-Traxler type) transition state (Scheme 2a).23 Compared to allylboration, allenylboration usually proceeds with lower diastereoselectivity (Scheme 2c).21d, 23a In contrast, the addition of allylic silanes and allylic stannanes to aldehydes requires activation from an external Lewis acid and proceeds via an “open” transition state (Scheme 2b).12b, 20, 23a, 24

Scheme 2. (a) Allylboration of aldehydes via Zimmerman-Traxler TS (b) Type II allylation mechanism via an open TS. (c) Allylboration of aldehydes, synthesis of homopropargylic alcohols

The addition of Lewis or Brønsted acids may accelerate the allylation and allenylation of aldehydes.21b, 21d, 23a It has been proposed that the Lewis acid interacts with the lone pair of the boronate oxygen which renders the boron atom more electron deficient and thus more reactive (Figure 2).21c, 21d, 23a, 25 A similar mode of activation has been proposed for chiral Brønsted acids which have been shown to give rise to high levels of enantioselectivity in the allylation and propargylation of aldehydes.21b, 22a, 23a, 26

Figure 2. Possible modes of Lewis acid activation for the allylation of aldehydes

1.4 Trifluoromethylation of organic compounds

During recent years several new methods for fluorination (CF) and tri- 27 fluoromethylation (CCF3) reactions have been developed. This is mainly due to the unique properties of the fluorine atom. The introduction of fluorine into organic compounds can make them more lipophilic and metaboli- cally stable.28 Fluorinated compounds can also show increased affinity to proteins, most likely due to increased polar interactions.28a, 28b, 29 The incor- poration of fluorine into drug candidates can therefore be highly desirable and is demonstrated by the fact that about 20% of all pharmaceuticals con- tains fluorine, e.g. Efavirenz, Fluoxetine and Celecoxib shown in Figure 3.27f

Figure 3. Examples of pharmaceuticals including a trifluoromethyl group

1.5 Objectives of the thesis This thesis is mainly centered on the development of novel and efficient methods for the synthesis of functionalized alkenes and allenes, based on copper- and palladium-mediated reactions. The focus has been on develop- ing new methods for forming CB and CSi bonds, as well as investigating the possibility of introducing trifluoromethyl groups by metal-mediated propargylic substitution. We also aimed to study the synthetic utility of the newly prepared 1,2-diborylated butadienes via sequential addition to aldehydes.

4 2. Borylation of propargylic alcohol derivatives (Paper I)

The Szabó group has previously developed efficient methods for palladium pincer complex-catalyzed stannylation and silylation of propargylic alcohol derivatives (Scheme 3a).30 When propargylic epoxides were used, the opening of the epoxides resulted in stannylated homoallenylic alcohols (Scheme 3b).30b

Scheme 3. Palladium pincer-catalyzed synthesis of allenylic and propargylic silanes/stannanes

Furthermore, the group has developed efficient protocols for palladium- catalyzed borylation of allylic alcohols (Scheme 4).31 An analogous metal- catalyzed borylation of propargylic alcohols and their derivatives (similarly to the Pd-catalyzed stannylation, Scheme 3a) was attempted, but these efforts remained unsuccessful. However, considering the more recent developed protocols31c and mechanistic investigation11c by the Szabó group, it was appealing to resume the studies for finding new methodologies for borylation of propargyl alcohol derivatives.

Scheme 4. Various methods for the formation of allylic boronates and boronic acids

The group of Sawamura and Ito have presented a novel and useful procedure for the synthesis of allenyl boronates (3) from propargylic carbonates (2) using a catalytic system of CuOtBu and Xantphos (Scheme 5).22b The authors were able to selectively synthesize various allenyl boronates (3) via a formal SN2′-type displacement. This procedure was shown to be highly stereoselective yielding a chiral allenyl boronate with high enantiomeric purity from an enantiomerically enriched propargylic carbonate.

Scheme 5. Synthesis of allenyl boronates using CuOtBu and Xantphos

The reaction requires the use of CuOtBu which is air-sensitive and unsta- ble. Therefore, sublimation of CuOtBu is required to ensure reproducibility of the catalytic reaction. The above protocol22b (Scheme 5) is ineffective for borylation of terminal alkynes (when R1 = H). This is most likely due to the basicity of the reaction which may lead to formation of metal-acetylide intermediates. We therefore sought to develop an alternative methodology for the synthesis of allenyl boronates, to circumvent the use of a basic and air- sensitive catalyst such as CuOtBu.

6 2.1 Method development for synthesis of α,γ-substituted allenyl boronates The initial experiments were focused on the development of palladium- catalyzed borylation of propargylic alcohols using the previously developed reaction conditions with allylic alcohols (Scheme 4).31 The initial screening revealed that the previous methods suitable for borylation of allylic alcohols31 (Table 1, cf. entries 1-6 and Scheme 4) did not afford the desired allenyl boronate 3a. Instead, a mixture of the unreact- ed starting material 4a (entries 1 and 3) as well as side products from the corresponding elimination (5a) and Meyer-Schuster rearrangement (6a) were obtained (entries 2 and 4-6). The formation of 5a and 6a are probably facilitated by the Lewis and Brønsted acids. However, without the Lewis acidic ligands the reaction does not proceed under the applied reaction conditions (entries 7-8).

Table 1. Selected experiments with propargylic alcohols[a]

Temp Yield 5a Entry Pdcat (1) (°C) Solvent and 6a[b]

1 Pd(BF4)2(MeCN)4 50 DMSO-d6:MeOD-d4 (1:1) n/r

5a: 22% 2 50 DMSO-d :MeOD-d (1:1) 6 4 6a: 25%

3 22 DMSO-d6:MeOD-d4 (1:1) n/r

[c] Pd2(dba)3 4 50 DMSO-d6:MeOD-d4 (1:1) 6a: 65% + 2 equiv. BF3·OEt2 5a: 55% 5 H2PdCl4 in H2O 50 DMSO-d6 6a: 40%

6 H2PdCl4 in H2O 50 MeOD-d4 6a: 75%

7 Pd(PPh3)4 50 MeOD-d4 n/r [c] 8 Pd2(dba)3 50 MeOD-d4 n/r

[a] Reaction conditions: 4a (0.100 mmol), Pdcat (1) (0.010 mmol), B2pin2 (0.120 mmol), solvent (0.4 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at the [b] [c] indicated temperature for 16 h Isolated yields, n/r = no reaction 5 mol% Pd2(dba)3 was used

7 We sought to improve our methodology by using a propargylic alcohol derivative that may be more reactive, and trying to find a way to activate the B2pin2. Using carbonate 2a and 5 mol% Pd2(dba)3, enyne 5a was obtained (cf. Table 1, entry 8 and Table 2, entry 1). We hypothesized that the formation of 5a occurred due to β-hydride elimination of the organopalladium intermediate which is formed. This could be a consequence of a slow transmetalation of B2pin2. We examined different possibilities to accelerate the transmetalation of B2pin2 to Pd. It was proposed that Cu-complexes readily react with B2pin2 via σ-bond metathesis to form CuBpin.32 We decided to use IPr-CuOtBu, an air-stable analog of CuOtBu.33 However, the reaction with IPr-CuOtBu was ineffective (Table 2, entry 2). Using the protocol by Ito, Sawamura and co- workers (Scheme 5), allenyl boronate 3a could be isolated in 65% yield.22b We also carried out the reaction using an IPr-CuOtBu and Pd2(dba)3 bimetallic catalyst system (entry 4). Although applying these conditions resulted in the formation of side products from elimination and rearrangement, we were able to isolate the allenyl boronate 3a in 16% yield. Subsequently, we found that replacing IPr-CuOtBu with CuI suppressed the formation of side products 5a and 6a and product 3a could be isolated in 55% yield (entry 5).

Table 2. Selected experiments with propargylic carbonates[a]

[b] Entry Mcat Solvent Yield

1 Pd2(dba)3 MeOD-d4 5a: 45% 2 IPr-CuOtBu THF n/r

[d] CuOtBu +10 mol% 3 THF 3a: 65% Xantphos IPr-CuOtBu + 4 [c] THF 3a: 16% 5a: 40%, 6a: 32% Pd2(dba)3 [c] 5 CuI + Pd2(dba)3 THF 3a: 55% 5a: 20% 6a: 20%

[a] Reaction conditions: propargylic alcohol (0.100 mmol), Mcat (0.010 mmol), B2pin2 (0. 200 mmol), solvent (0.4 mL) were weighed inside an Ar-filled glovebox and then taken out and [b] [c] stirred at 50 °C for 16 h Isolated yields, n/r = no reaction, 5 mol% Pd2(dba)3 was used [d]Reaction conditions reported by Sawamura and Ito22b

As a model reaction for the optimization of the experimental conditions we chose the borylation of a secondary propargylic carbonate 2b and its analogs (Table 3). A practical advantage of using this substrate is that product 3b and the byproducts give characteristic peaks in the 1H NMR spectrum

8 allowing easy assessment of the reaction conditions. First the effects of various leaving groups were studied. As shown in Table 3, the best results were obtained with carbonate as leaving group, as it gave high yields and also the highest conversion of the starting material (Table 3, entry 1). It was possible to obtain similar results using propargylic phosphate esters (entry 2) where the reaction gave a relatively high yield and high conversion. The side reaction was the formation of enyne 5b from the elimination reaction. Further experiments were conducted to optimize the yield of the reaction with phosphate esters, but we were never able to fully suppress the formation of 5b. Neither the use of acetate (entry 3) or trifluoroacetate (entry 4) leaving groups was efficient as the desired allenyl product 3b was not obtained from the corresponding reactions.

Table 3. Screening of various leaving groups[a]

Entry Leaving Group Yield 3b (%)[b]

1 -OCO2Me (2b) 55 (90)

2 -OPO(OEt)2 43 (80)

3 -OCOCH3 n/r

4 -OCOCF3 n/r

[a] Reaction conditions: propargylic alcohol derivative (0.100 mmol), Pd2(dba)3 (0.005 mmol), CuI (0.010 mmol), B2pin2 (0.200 mmol), THF (0.4 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at the indicated temperature for 16 h [b]Isolated yields, n/r = no reaction (in parenthesis, conversion of starting material determined by 1H NMR spectroscopy of the crude reaction mixture)

Considering the above results, we decided to continue the method development using propargylic carbonates (such as 2b) as it gave the highest conversion rate and was selective in the formation of allenyl boronate. We have briefly studied the effects of different solvents on the reaction (Table 4). The highest conversion to the desired allenyl product 3b was observed using THF (entry 1). The reaction in CDCl3 and C6D6 resulted only in formation of enyne 5b (entries 2 and 3), while the reaction in MeOD-d4 only resulted in the formation of 6b (entry 4). Although, using 1,2- dimethoxyethane as solvent yielded the allenyl product 3b, a substantial amount of undesired products 5b and 6b was formed. Considering the above results, we concluded that THF was the best solvent for the borylation reaction.

9 Table 4. Solvent screening[a]

Entry Solvent Yield 3b (%)[b] 1 THF 55[c] (~90)

2 CDCl3 <5 (~45) [c] 3 C6D6 15 (~95)

4 MeOD-d4 <5 (~95) 5 1,2-dimethoxyethane 37[c] (>95)

[a] Reaction conditions: 2b (0.100 mmol), Pd2(dba)3 (0.005 mmol), CuI (0.010 mmol), B2pin2 (0.200 mmol), solvent (0.4 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at 50 °C for 16 h [b]In parenthesis, conversion of starting material determined by 1H NMR spectroscopy of the crude reaction mixture [c]Isolated yields

Several metal catalysts were evaluated for their ability to promote the borylation of propargylic carbonates (Table 5). The best results were obtained with Pd(PPh3)4 and CuI (Table 5, entry 2), where the combination of the two metal catalysts gave a high conversion and the formation of 5b and 6b was suppressed.

Table 5. Selected examples of metal catalysts screened[a]

[b] Entry Pdcat Mcat Yield (%) [c] 1 Pd2(dba)3 CuI 55 (90)

2 Pd(PPh3)4 CuI 92 (>95)

3 Pd(PPh3)4 Cu(BF4)(MeCN)4 38 (>95)

4 Pd(PPh3)4 Ag2O 32 (>95)

5 Pd(PPh3)4 - n/r 6 - CuI n/r

7 5 mol% Pd(PPh3)4 10 mol% CuI 40 (55)

8 10 mol% Pd(PPh3)4 30 mol% CuI 74 (89)

9 5 mol% (Pd(PPh3)4 5 mol% CuI 92 (>95) [a] Reaction conditions: 2b (0.100 mmol), Pdcat (0.010 mmol), Mcat (0.010 mmol), B2pin2 (0.200 mmol), solvent (0.4 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at 50 °C for 16 h [b]Isolated yields, n/r = no reaction (In parenthesis, conversion of starting material determined by 1H NMR spectroscopy of the crude reaction mixture)

10 Furthermore, it was found that Ag2O could be used as a co-catalyst instead of a copper-species (entry 4). Without the Pd-source or the second metal additive (Table 5, entries 5 and 6) formation of 3b was not observed. Inter- estingly, changing the Pd:Cu ratio from 1:1 to 1:2 (Table 5, entry 7) and 1:3 (Table 5, entry 8) led to a decreased conversion of 2b. Further tuning of the reaction conditions involved decreasing the catalyst loading to 5 mol% for both Pd(PPh3)4 and CuI which did not decrease the conversion and yield of the reaction (entry 9). Further attempts to optimize the reaction conditions by lowering the temperature, reducing the reaction time, and decreasing the B2pin2 loading led to a drop in conversion of the starting material to product. Increasing the temperature above 50 °C increased the formation of enyne 5b.

2.2 Synthesis of α,γ-substituted and α-substituted allenyl boronates After studying the reactivity of propargylic carbonate 2b under various conditions we decided to explore the scope of the reaction. Using the above described method we successfully synthesized various allenyl boronates from different propargylic carbonates (Table 6). A broad variety of allenyl boronates could be isolated from primary (Ta- ble 6, entries 6, 7 and 10), secondary (entries 2-5 and 11) and tertiary propargylic carbonates (entries 1, 8 and 9). Compared to 2a and 2b the reactivity was decreased when 2c was used as substrate (entry 3). This could be due to the steric bulk at the α-position. Similarly, when 2j and 2k was used, the conversion to the desired allenyl boronate 3j was low (entries 10 and 11). Although the reaction gave full conversion to the desired allenyl boronate, the isolation via column chromatography had to be performed quickly; oth- erwise decomposition of the product occurred.

11 Table 6. Palladium and copper-catalyzed borylation of propargylic carbonates[a]

Entry Substrate Product Yield (%)[b]

1 2a 3a 65

2 2b 3b 92

3 2c 3c 55

4 2d 3d 76

5 2e 3e 85

6 2f 3f 56

7 2g 3g 97

8 2h 3h 88

9 2i 3i 61

10 2j 3j 14

11 2k 3k <5

[a] Reaction conditions: propargylic carbonate 2 (0.300 mmol), Pd(PPh3)4 (0.015 mmol), CuI (0.015 mmol), B2pin2 (0.600 mmol), THF (1.2 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at 50 °C for 16 h [b]Isolated yields

12 2.3 Method development for synthesis of γ-substituted allenyl boronates As mentioned above, copper-catalyzed borylation of terminal alkynes is difficult due to the possible formation of metal-acetylide intermediates. Thus, we investigated alternative reaction conditions to include terminal alkynes as substrates for the borylation of propargylic carbonates. First the same reaction conditions for the borylation of propargylic carbonates 2a-j (Table 5, entry 9) were applied to terminal propargylic carbonate 2l (Scheme 7). However, the 1H NMR spectrum of the crude mixture did not show any formation of allenyl boronate (3l). Instead formation of compound 7 was observed, which arises from the competing homocoupling reaction.34

Scheme 6. Initial attempt for Pd-catalyzed borylation of terminal alkynes

We sought out ways to suppress the competing homocoupling reaction. Fairlamb and co-workers reported that propargylic carbonates, such as 2l readily give homocoupling product in the presence of a Cu-catalyst.35 In contrast, it was shown that the use of propargylic acetate analogs, such as 8a did not undergo the same homocoupling process. Accordingly, homocoupling product 7 was not formed when using propargylic acetate 8a as substrate (Scheme 8). However, formation of the desired allenyl boronate 3m was not observed.

Scheme 7. Attempts for borylation of propargylic acetates using our developed reaction conditions

Crudden and co-workers reported that Ag2O facilitates the transmetalation of organoboronates.36 Furthermore, we have previously shown that Pd(PPh3)4 and Ag2O is able to catalyze the borylation of propargylic carbonates (Table 5, entry 4). Thus, we envisioned that using silver instead of copper as co-catalyst would prevent the formation of the metalacetylide intermediate that is involved in the formation of the homocoupling product 7. By replacing CuI with Ag2O and using acetate 8a as precursor we were

13 able to successfully suppress the formation of the homocoupling product and isolate the desired allenyl boronate 3m in 18% yield (Scheme 9).

Scheme 8. Palladium and silver-catalyzed borylation of propargylic acetate

To improve the yield of the desired product we screened different solvents, temperatures and silver-sources. We found that replacing Ag2O with AgOAc or AgOPiv increased the selective formation of 3m. Next we investigated the role of the solvent. We found that using toluene suppressed the formation of side products more efficiently than the other screened solvents. Further tuning of the reaction parameters by decreasing the temperature and decreasing the amount of solvent reduced the formation of side products even more, and we were able to isolate the desired product 3m in 32% yield (Scheme 10).

Scheme 9. Results from initial screening

After the initial screening, the remaining major side product was identi- fied as the protodeborylated compound 9 which is probably formed from the allenyl boronate 3m. Therefore we investigated the possibilities to suppress the formation of the protodeborylated product 9 (Table 7). We first directed our efforts to reduce the formation of protodeborylated product 9 by removal of potential proton sources, such as residual water. This was attempted by adding molecular sieves (Table 7, entry 2) and anhy- drous MgSO4 (entry 3). However, the addition of molecular sieves or anhy- drous MgSO4 decreased the yield of 3m without significantly suppressing the formation of 9 (Table 7, entries 2 and 3). We have also studied the ligand effects on the formation of protodeborylated product 9. Interestingly, addition of PPh3 reduced the conversion of 8a (entry 4). We therefore decided to investigate the effects of the phosphine ligand to palladium ratio (entries 5- 7). The highest conversion rate was obtained when using 20 mol% of PPh3, which also reduced the formation of 9 (entry 6). The ligand screening (entries 8-13) indicated that using more electron-supplying (such as in entries 8

14 and 11) or more electron-withdrawing ligands than PPh3 (such as in entries 9 and 10) gave lower yields. Using bidentate phosphine ligands (such as in entries 12 and 13) did not improve the yield of 3m either.

Table 7. Further investigation of the reaction conditions to suppress the formation of the protodeborylated product[a]

Entry Pdcat Additives Conversion Yield 3m (%)[b] (%)[c]

1 Pd(PPh3)4 - 82 32

2 Pd(PPh3)4 4 Å M.S. 80 12

3 Pd(PPh3)4 MgSO4 anhyd. >95 <5

4 Pd(PPh3)4 10 mol% PPh3 22 17 [d] 5 Pd2(dba)3 10 mol% PPh3 72 40 [d] 6 Pd2(dba)3 20 mol% PPh3 78 42 [d] 7 Pd2(dba)3 30 mol% PPh3 65 38 [d] 8 Pd2(dba)3 20 mol% (4-MeOPh)3P 53 37 [d] 9 Pd2(dba)3 20 mol% (4-ClPh)3P 60 40 [d] 10 Pd2(dba)3 20 mol% (OPh)3P 0 <5 [d] 11 Pd2(dba)3 20 mol% PCy3 95 <5 [d] 12 Pd2(dba)3 20 mol% Xantphos 20 <5 [d] 13 Pd2(dba)3 20 mol% dppb 33 28

[a] Reaction conditions: 8a (0.100 mmol), Pdcat 1 (0.010 mmol), AgOPiv (0.010 mmol), B2pin2 (0.200 mmol), toluene (0.1 mL), weighed inside an Ar-filled glovebox and then taken out and stirred at 35 °C for 16h [b]Conversion of 8a was determined by 1H NMR spectroscopy of the [c] [d] crude reaction mixture Isolated yields. 5mol% Pd2(dba)3 was used

To summarize the above findings, the best conditions for the borylation of terminal propargylic acetates involved using 2 equivalents of B2pin2, 10 mol% AgOPiv, 5 mol% Pd2(dba)3 and 20 mol% PPh3 (Table 7, entry 6). The reaction time and temperature was varied to decrease the amount of protodeborylated byproducts. Using these optimized conditions allenylboronates 3m-o could be synthesized from propargylic acetates 8a-c. Secondary (Table 8, entries 1 and 2) and tertiary (entry 3) propargylic acetates were converted to the corresponding allenyl boronates.

15 Table 8. Palladium and silver-catalyzed synthesis of allenyl boronates[a]

Temp Time Yield Entry Substrate Product (°C) (h) (%)[b]

1 8a 40 12 3m 45

2 8b 45 8 3n 36

3[c] 8c 35 16 3o 31

[a] Reaction conditions: propargylic acetate 8 (0.300 mmol), Pd2(dba)3 (0.015 mmol), AgOPiv (0.030 mmol), B2pin2 (0.600 mmol), PPh3 (0.060 mmol), toluene (0.1 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at the indicated temperature for the indicated time [b]Isolated yield [c] 0.2 mL toluene was used instead

2.4 Stereochemistry of the formation of allenyl boronate

As mentioned in the introduction, the procedure developed by the group of Sawamura and Ito occurs with chirality transfer (section 2).22b Therefore, we investigated whether the same chirality transfer may occur when using the Pd/Cu bimetallic system as well. We synthesized the enantiomerically enriched propargylic carbonate (S)-2d and subjected it to our standard reaction conditions (Table 9).

Table 9. Investigation of the enantiospecificity of the reaction[a]

Temp Yield ee Entry [b] [c] (°C) (%) (%) 1 50 95 12 2 22 98 >90

[a] Reaction conditions: (S)-2d (0.300 mmol), Pd(PPh3)4 (0.030 mmol), CuI (0.030 mmol), B2pin2 (0.600 mmol), THF (1.2 mL), weighed inside an Ar-filled glovebox and then taken out and stirred at the indicated temperature for 16 h [b]Isolated yields [c]Measured by GC and optical rotation

16 At 50 °C, the reaction gave low enantiospecificity (entry 1). However, lowering the temperature to room temperature led to full conversion and a high level of chirality transfer was observed (entry 2). The absolute stereochemistry of the enantiomeric allenyl boronate was determined on the basis of optical rotation data. The sign and value of optical rotation of product (S)- 3d was in agreement with the data reported by Sawamura and co-workers for the same compound.22b

2.5 Borylative opening of propargylic epoxides; synthesis of 1,2-diborylated butadienes

As mentioned above (section 2, Scheme 2), our group has previously demonstrated that the palladium-catalyzed stannylation can be performed using propargylic epoxides as substrates.30b This reaction involved an epoxide opening to form the stannylated homoallenylic alcohol. Therefore, we decided to examine if the borylation reaction follows the same reactivity pattern with propargylic epoxides.

Scheme 10. Initial experiments of borylation of propargylic epoxides

According to the 1H NMR spectrum of the crude reaction mixture, the starting material 10a was fully converted. Upon isolating the product by column chromatography we found that the borylated product was the 1,2- diborylated butadiene derivative 11a instead of the expected allenyl boronate 3p (Scheme 10). Although the yield was acceptable, the main product was the enyne 5c. By increasing the amount of B2pin2 to 3 equivalents and reducing the temperature, formation of the enyne byproduct 5c could be reduced. Without a copper-source full conversion of the starting material to the enyne 5c was observed, which demonstrates that copper is needed in the borylation reaction, perhaps to activate B2pin2. Recently, Tsuji and co-workers presented a related study on the Cu- catalyzed borylation of α-alkoxy allenes (Scheme 11a).37 Considering the results of this study, the formation of the 1,2-diborylated butadiene 11a can be explained by an additional borylation of 3p under the applied reaction conditions (Scheme 11b).

Scheme 11. (a) Copper-catalyzed borylation of α-alkoxy allenes with B2pin2 presented by Tsuji and co-workers37 (b) Formation of 1,2-diborylated butadiene 11a from expected intermediate 3p

The previously developed methodology using a bimetallic system of Pd/Cu gave 11a-b (Table 10, entries 1 and 2) and 11d (entry 4) in moderate yields.

Table 10. Palladium and copper-catalyzed diborylation of propargylic epoxides[a]

Yield [c] Entry Substrate Product [b] E/Z (%)

1 10a 11a 59 8:1

2 10b 11b 42 4:1

3 10c 11c <5 -

4[d] 10d 11d 70 >95:5

5[d] 10e 11e 19 >95:5

[a] Reaction conditions: propargylic epoxide 10 (0.300 mmol), Pd(PPh3)4 (0.030 mmol), CuI (0.030 mmol), B2pin2 (0.900 mmol), THF (1.2 mL) were weighed inside an Ar-filled glovebox and then taken out and stirred at 22 °C for 16 h [b]Isolated yields [c]E/Z ratio determined by 1H NMR spectroscopy of the crude reaction mixture [d]Reactions performed in MeOH (1.2 mL) instead of THF

18 The reaction generally proceeds with good diastereoselectivity (entries 1- 2), whereas cyclic structures provided only one diastereomer (entries 4 and 5). Compounds 10e-d (entries 4 and 5) gave a higher yield in MeOH than in THF. However substrate 10c gave no conversion to the corresponding 1,2- diborylated butadiene 11d. The major side product was the formation of the corresponding enyne. As mentioned above, Ito and Sawamura demonstrated that CuOtBu is able to catalyze the borylation of propargylic carbonates (Scheme 5).22b Thus, we hypothesized that epoxide 10 can undergo borylative epoxide opening with an in situ generated catalyst from CuCl and KOtBu. The intermediate product is then able to undergo an additional borylation to give the 1,2-diborylated butadiene 11 (see Scheme 11b).

Table 11. Copper and base-catalyzed diborylation of propargylic epoxides[a]

Yield [c] Entry Substrate Product (%)[b] E/Z

1 10a 11a 94 12:1

2 10b 11b 83 10:1

3 10c 11c 62 8:1

4 10d 11d 97 >95:5

5 10e 11e 91 >95:5

[a] Reaction conditions: propargylic epoxide 10 (0.300 mmol), CuCl (0.030 mmol), PCy3 (0.090 mmol), KOtBu (0.090 mmol), B2pin2 (0.900 mmol), THF (1.2 mL) were weighed inside an Ar-filled glovebox and stirred for 16 h at 22 °C [b]Isolated yields of both diastereomers [c]E/Z ratio determined by 1H NMR spectroscopy from the crude reaction mixture

19 Indeed, when 10a-e reacted with B2pin2 (3 equiv.) in the presence of CuCl (10 mol%), KOtBu (30 mol%) and PCy3 (30 mol%), 1,2-diborylated butadienes 11a-e could be synthesized selectively and isolated in high yields. Grat- ifyingly, the formation of the enyne was completely suppressed. In addition, the diastereoselectivity was also improved compared to the corresponding reactions using the bimetallic catalyst system (cf. Table 10, entries 1 and 2 and Table 11, entries 1 and 2). The stereochemistry of the major diastereomer 11a was determined by X- ray crystallography. According to the X-ray structure, the Bpin moieties are in the (E)-configuration (Figure 4).

Figure 4. ORTEP representation of 11a

20 2.6 Proposed catalytic cycle The exact mechanism for the palladium-catalyzed borylation of propargylic alcohol derivatives is not fully understood. However, we are able to propose a catalytic cycle based on the above experiments.

2.6.1 Proposed catalytic cycle for the borylation of propargylic carbonates

Figure 5. Proposed catalytic cycle for the borylation of propargylic carbonates, X = -Cl, -I

The catalytic cycle is proposed to start with oxidative addition of propargylic carbonate 2 to the Pd0 complex 1 to form 12a (Figure 5). It has previously been reported that palladium-catalyzed reactions of propargylic alcohol derivatives give high anti-selectivity.14c, 38 The high stereoselectivity of the palladium-catalyzed borylation (shown above in section 2.5, Table 9) can be explained by a stereoselective displacement of the leaving group from the substrate. We propose that the πCC* of the alkyne and σCLG* of the leaving group MOs interact with the filled d-orbital of palladium in an anti-fashion during oxidative addition (Figure 6).

Figure 6. Orbital interaction for stereoselective addition by anti-SN2′-type displacement

This MO interaction ensures that the oxidative addition of palladium to the propargylic substrate occurs with anti-selectivity. Corey and co-workers proposed a similar model for the copper-catalyzed enantioselective SN2′- displacement of the leaving group from allylic halides.38a, 39 In the subsequent step, Pd-complex 12a transmetalates with CuI to generate complex 12b and CuOMe. The CuOMe complex can then facilitate the activation of B2pin2 to generate a CuBpin complex. The CuBpin undergoes transmetalation with 12b to form 12c and CuI.32b, 32c Upon reductive elimination of 12c the allenyl boronate 3 is formed.

2.6.3 Proposed catalytic cycle for the borylation of propargylic epoxides

As mentioned in section 2.5, two reaction conditions can be used for the diborylation of epoxides: a palladium/copper-bimetallic system (Table 10) and a copper/base-catalyzed system (Table 11).

2.6.3.1 Proposed mechanism for bimetallic catalyzed diborylation of epoxides

The Pd-catalyzed borylation of propargylic epoxides is proposed to proceed similarly to the borylation of propargylic carbonates (Figure 7, Cycle I and Cycle II). However, unlike the carbonate which is removed from the substrate after the initial oxidative addition, the epoxide ring opens. The opening of the epoxide 10 may be facilitated by the copper catalyst which forms complex 13a. Opening of 13a with 1 generates a bimetallic complex 40 13b. The copper-alkoxide complex is then able to activate B2pin2 to form CuBpin and complex 13c.32b, 41 Transmetalation of 13c with CuBpin provides 13d. This is followed by a reductive elimination providing complex 13e. As discussed above (section 2.6, Scheme 11b) 13e reacts further with an additional CuBpin complex to provide the diborylated species 11 (Cycle II).

Figure 7. Proposed catalytic cycle for the Pd- and Cu-catalyzed borylation of propargylic epoxides, X = -OBpin, -I

The formation of 11 from 13e may occur via a two-step mechanism with a borylcupration to form complex 13f followed by an elimination to yield 11.32a, 32c, 37, 41-42 An intermediate similar to 13f has been isolated and characterized via X-ray crystallography.41, 43 We could not observe formation of 13e by 1H NMR spectroscopy which indicates that the reaction from 13e to the 1,2-diborylated diene 11 is faster than the formation of 13e.

23 2.6.3.2 Proposed mechanism for copper- and base-catalyzed diborylation of epoxides

For the copper- and base-catalyzed process (section 2.5, Table 11), the reaction is proposed to start with activation of the catalyst with base. The copper tert-butoxide complex facilitates the transmetalation with B2pin2 to generate the active CuBpin catalyst 14a (Figure 8).22, 32a, 32b, 37, 41 Complex 14a 39b, reacts with the propargylic epoxide 10 via a formal SN2′-type mechanism. 44 The copper-complex 14b transmetalates with B2pin2 to regenerate the CuBpin catalyst 14a and intermediate 13e.45 Intermediate 13e reacts subsequently with 14a to form the diborylated product 11.

Figure 8. Copper- and base-catalyzed diborylation of propargylic epoxides

2.7 Summary and conclusions for borylation of alcohol derivatives We have developed a general and convenient method for the borylation of non-terminal propargylic carbonates which is catalyzed by Pd(PPh3)4 and CuI. The procedure is highly efficient for non-terminal propargylic carbonates and provides a broad spectrum of allenyl boronate derivatives. We have also developed a protocol for the synthesis of allenyl boronates from terminal propargylic acetates using AgOPiv instead of CuI. The transformation into allenyl boronate is highly stereospecific at 22 °C and occurs with a high level of chirality transfer. We have also developed an efficient protocol for the synthesis of 1,2-diborylated butadienes with high diastereoselectivity by ring-opening of epoxides. This new methodology provides access to synthetically important building blocks such as allenyl boronates and 1,2-diborylated butadienes that can be prepared under relatively mild conditions. This methodology may con- tribute to a broader application of allenyl boronates in organic synthesis.46

24 3. Sequential addition of 1,2-diborylated butadienes to aldehydes (Paper II)

Stereoselective reactions that convert simple building blocks into complex structures with contiguous stereocenters is very useful in organic synthesis.20c Organoboronates are recognized as versatile building blocks in organic synthesis since these compounds enable CC bond formations and functionalization at the CB bonds.12b, 21c, 47 The 1,2-diborylated butadienes presented in section 2.5 can be considered as potentially useful synthetic precursors for the synthesis of complex organic molecules. This has been demonstrated via sequential addition of allylboration to aldehydes.48 The usefulness of di- and multiple-borylated species in organic synthesis has been demonstrated by several studies.47 For example, the group of Shimizu reported a sequential triple addition of 1,2,3,4-tetraborylated butene to aldehyde (Scheme 12).48d The 1,5-diol was formed in high diastereoselectivity as only one single isomer was observed.

Scheme 12. Triple cascade addition of aldehyde presented by Shimizu, the last step is a syn elimination of (Bpin)2O

A similar sequential allylboration reaction was presented by Morken and co-workers (Scheme 13).48e The enantioselective 1,2-diborylation of butadienes provided chiral allylboron reagents. Two consecutive allylboration reactions with a dialdehyde reagent provided the synthesis of 1,4-diols with four contiguous stereocenters in high selectivity.

Scheme 13. Synthesis of 1,4-diols presented by Morken and co-workers

25 3.1 Method development for the synthesis of 2- ethynylbutane-1,4-diols from (mono)aldehydes As mentioned above (section 2.5, table 11), 1,2-diborylated butadienes could be easily prepared by copper- and base-catalyzed borylation of propargylic epoxides. These compounds incorporate an allylboronate unit which can react to carbonyl electrophiles, such as aldehydes. As a model reaction for the optimization we chose the addition of 11a to 4-nitrobenzaldehyde (15a) (Table 12).

Table 12. Selected initial experiments for the allylboration and allenylboration of 11a using 4-nitrobenzaldehyde 15a[a]

Entry Additives Solvent Temp Time (h) Conversion dr (°C) (%)[b] (16a) 1 - THF 20 24 10% 70:30 2 - Toluene 20 24 18% 75:25 3 - DMF 20 24 8% 75:25 4 - Toluene 20 120 80% (65%) 75:25 5 TsOH Toluene 20 24 decomp -

6 Toluene 25 32 92% (86%) 78:22

7 Toluene 20 24 56% 70:30

8 BF3·OEt2 Toluene 20 24 decomp. - 9 - Toluene 50 24 56% 75:25 10 - Toluene 80 24 >95% (84%) 75:25 [a]Reaction conditions: 11a (0.100 mmol), 15a (0.300 mmol), additives (0.020 mmol), solvent (0.5 mL) were weighed and stirred at the indicated temperature for the indicated time [b]Conversion were determined by 1H NMR spectroscopy of the crude reaction mixture using the (slow-reacting) (Z)-11a isomer as internal standard (In parenthesis, isolated yields)

The initial screening of different solvents showed that toluene (Table 12, entry 2) gave a higher conversion rate than THF (entry 1) and DMF (entry 3). However, the reaction was slow and showed low conversion to the desired diol product 16a after 24 hours. A nearly full conversion could be achieved in 5 days at 20 °C (entry 4).

26 As mentioned in section 1.3, Brønsted and Lewis acids are known to accelerate the allylboration reactions.21b-d, 26d, 49 Different Brønsted and Lewis acids were evaluated for the allylboration reactions (entries 5-10). The use of strong Brønsted acids such as TsOH (entry 5) led to decomposition of 11a. The same problem occurred when using Lewis acids such as BF3 · OEt2 (entry 8). Applying weaker Brønsted acids (entries 6-7) increased the conversion rate compared to the reaction without the addition of Brønsted acid (entry 4). Increasing the temperature also led to an increased conversion rate (cf. entries 9-10 and 4) without leading to a decrease in diastereoselectivity. The reaction at 80 °C gave the highest conversion with fair diastereoselectivity (entry 10). The reaction creates three new stereocenters. Gratifyingly, only two diastereomers were observed in the reaction mixture. The reaction proceeds only with the (E)-isomer of 11a as (Z)-11a was shown to be less reactive. When the reaction with aldehyde was carried out using a mixture of the (E)- and (Z)-isomer of 11a, the (Z)-isomer could be isolated in quantitative yields after the reaction was complete. The intermediary product, allenylboronate 17a could be isolated from the reaction using diphenyl phosphate (entry 7). Further attempts were made to improve the selective formation of 17a. However, the second addition of aldehyde could not be stopped, as a mixture of 16a and 17a was formed.

3.2 Synthesis of 2-ethynylbutane-1,4-diols from aldehydes After studying the reactivity of 11a with 15a under various conditions, we decided to explore the scope of the reaction (Table 13 and 14). Using the above described reaction condition we successfully synthesized various 1,4- diols (16a-d) from different aldehydes (15a-d) and 1,2-diborylated butadienes (11a, 11d-e). The reactions proceeded smoothly with aldehydes bearing either electron withdrawing (entries 1, 2), or electron-supplying (entry 4) substituents in the aromatic ring. The bromides of substrate 16b can be utilized in further transformations, such as Suzuki-Miyaura cross-coupling. The sequential addition could also be carried out with aliphatic aldehydes (entry 3). The products could be isolated in high yields and with moderate diastereoselectivity.

27 Table 13. Sequential allylboration and allenylboration of aldehydes using 11a[a]

Time Yield [c] Entry Aldehyde (h) Product (%)[b] dr

1 18 94 75:25

15a

16a

2 24 82 74:26

15b

16b

3 79 70:30 24

15c 16c

4 18 65 81:19

15d

16d

[a]Reaction conditions: 11a (0.300 mmol), aldehyde 15 (0.620 mmol), toluene (1.5 mL) were weighed and stirred at 80 °C for the indicated time [b]Isolated yields of both the minor and major diastereomer [c]Determined by 1H NMR spectroscopy of the crude reaction mixture

The same methodology was also applied for cyclic 1,2-diborylated butadienes 11d and 11e (Table 14). The cyclic 1,2-diborylated butadienes 11d-e reacted with 4-nitrobenzaldehyde (15a) to afford 16e and 16f with four contiguous stereocenters in high yields and good selectivity (Table 14, entries 1 and 4). Aldehyde precursors 15e (entry 2) and 15f (entry 3) could also be used as substrates. The reaction of 11d and 15f may only provide two diastereomers, but it proceeds with high diastereoselectivity; only one diastereomer was observed and could be isolated in high yield. Acrolein precursor 15e reacted with 11d smoothly to form 16f in good yield and diastereoselectivity. The alkene functionalities can be treated as valuable synthetic handles for subsequent transformations as well.

28 Table 14. Sequential allylboration and allenylboration of aldehydes using 11d-e[a]

Time Yield [c] Entry Diboronate Aldehyde (h) Product (%)[b] dr

1 22 81 70:30

11d 15a

16e

2 22 55 75:25

11d 15e

16f

3 22 89 >95:5

15f 11d 16g

4 22 77 80:20

11e 15a

16h

3.3 Synthesis of 1,4-dihydroxytetralin derivatives from dialdehydes and 1,2,-diborylated butadienes

Next we investigated the possibility to utilize dialdehydes as electrophiles. Initial reactions using the above described conditions (section 3.2) showed that phthalaldehyde (15g) reacted with 11a and provided 16i in high yields and good diastereoselectivity (Table 15, entry 1). The selectivity was improved when the reaction was performed at room temperature, but at a decreased conversion rate (entry 2). The use of Lewis acids (entries 3, 4) or a strong Brønsted acid (entry 5) led to decomposition of 11a. Gratifyingly, the

29 addition of pentafluorobenzoic acid (18) increased the conversion rate and improved the selectivity (cf. entry 1 and 7). Further decreasing the reaction temperature did not improve the selectivity (entries 8-9).

Table 15. Selected initial experiments for the allylboration and allenylboration of 11a using phthalaldehyde[a]

Entry Additives Temp Time Conversion dr[c] (°C) (h) (%)[b] - 1 80 24 88 80:20 - 2 25 96 60 91:9 3 Sc(OTf)3 25 24 decomp - 4 Yb(OTf)3 25 24 decomp - 5 TsOH 25 24 decomp -

6 25 24 50 91:9

7 25 24 >90 (84) ~95:5

8 0 80 72 ~95:5

9 -20 40 40 ~95:5

[a]Reaction conditions: 11a (0.100 mmol), 15g (0.120 mmol), additives (0.020 mmol), toluene (0.5 mL) were weighed and stirred at the temperature for the indicated time [b]Conversion was determined by 1H NMR spectroscopy of the crude reaction mixture by integrating the difference between the major and minor isomer of 11a (In parenthesis, isolated yields) [c]Determined by 1H NMR spectroscopy of the crude reaction mixture

Using the above developed conditions we extended the scope of synthesis to additional 1,4-dihydroxytetralin derivatives (Table 16). Substrate 11a reacted with different dialdehydes (15g-15j) affording various 1,4- dihydroxytetralin derivatives (Table 16, entries 1-4) in high yields and good to high diastereoselectivity. The reaction worked well using heteroaromatic dialdehydes 15i and 15j but required prolonged reaction time to proceed to

30 full conversion (entries 3 and 4). Compounds 15i and 15j afforded the corresponding 1,4-dihydroxytetralin-derivatives in high yields, but with lower diastereoselectivity. No allenyl boronate intermediate 17 could be observed in the crude reaction mixture which indicates that the second, allenylboration step is faster. Substrates 11d and 11e did not react with 15g-15j to form their corresponding 1,4-dihydroxytetralin derivatives as only starting material could be observed from their crude reaction mixtures. Several attempts to promote the allylboration, including prolonged reaction time, increased reaction temperature and addition of acid were unsuccessful.

Table 16. Sequential allylboration and allenylboration of dialdehydes using 11a[a]

Yield [c] Entry Dialdehyde Product Time (%)[b] dr

1 28 83 95:5

16i 15g

2 24 95 95:5

16j 15h

3 72 81 75:25

15i 16k

4 72 91 84:16

15j 16l

[a]Reaction conditions: 11a (0.300 mmol), 15 (0.350 mmol), 18 (0.06 mmol), toluene (1.5 mL) were weighed and stirred at 25 °C for the indicated time [b]Isolated yields of both the minor and major diastereomer [c]Determined by 1H NMR spectroscopy of the crude reaction mixture

31 3.4 Determination of relative stereochemistry of the 1,4- diol products The relative configuration for the major diastereomer of cyclic 1,4-diol 16i was determined from NMR experiments. After assigning the peaks by COSY and HSQC NMR experiments, the relative configuration of the diols and methyl substituent was determined by dNOE experiments (Figure 9 and 10).

Figure 9. Observed NOE when irradiating proton H1a. a = axial, e = equatorial

Irradiation of H1a showed a NOE effect (2.3%) to the methyl protons (at C3) as well as OH4e (2.3%) (Figure 9). This shows that H1a, the methyl group (at C3) and OH4e are on the same side of the cyclohexane ring. Consequent- ly, the relative configuration of the OH1e is anti to both the methyl group (at C3) and the OH4e.

Figure 10. Observed NOE when irradiating proton H4a. a = axial, e = equatorial

This relative configuration can be confirmed by additional dNOE experiments. Irradiation of H4a (Figure 10) generates a NOE effect of 2.3% and 1.1% at H2a and OH1e respectively. As a consequence, the relative configuration of OH4e and OH1e is anti; which is in agreement with the above assign- ment (Figure 9). Considering the similarities of the chemical shifts and coupling patterns of 16i with the other products we conclude that the structure of the major isomer of 16i-16l has the same relative stereochemistry. The major diastereomers of 16a-h obtained from the reactions with monoaldehydes are oils, which could not be crystallized. The only isolated diastereomer which gave crystals suitable for X-ray analysis was obtained from the minor diastereomer of 16a. Therefore, the relative stereochemistry of the

32 minor diastereomer of 16a was determined by X-ray crystallography (Figure 11). From the relative configuration of the minor diastereomer, the major diastereomer of 16a could be derived from our proposed model (see below).

Figure 11. Ball- and stick model of the minor diastereomer of 16a

3.5 Mechanism of the sequential allylboration- allenylboration reaction To explain the relative stereochemistry of 16i we rationalized the different stereochemical outcomes on the basis of different steric and electronic interactions (Scheme 14).

Scheme 14. Plausible mechanism and explanation for the relative stereochemistry of the major diastereomer, X = H or Bpin

33 We propose that the initial allylboration proceeds via a six-membered Zimmerman-Traxler-type TS (Scheme 14, TSI). In TSI the aromatic group of dialdehyde 15g is in the equatorial position in order to reduce the 1,3- diaxial strain. The Bpin groups of 11 are in (E)-configuration, which deter- mines the relative stereochemistry of the allenyl unit in intermediate 17. This step is presumed to follow with high diastereoselecitivity. Intermediate 17 has two chiral elements, an axis of chirality and a stereogenic center. The allenylboration of the second aldehyde moiety may proceed via transition states TSII and TSIII. TSII is considered to be unfavored since the πC=O and πAr orbitals are not conjugated, which is energetically unfavored. However, TSIII leaves the πC=O and πAr orbitals conjugated which could stabilize the TS. A plausible secondary interaction may be of a formyl CH hydrogen bond involving a 6-membered ring with the OH or OBpin.50 A similar model can be given for the stereoselectivity of the reactions with monoaldehydes (Scheme 15).

Scheme 15. Plausible mechanism and explanation for the relative stereochemistry of the major diastereomer, X = Bpin or H, Ar = 4-nitrophenyl

The initial allylboration is believed to proceed in the same way as with the monoaldehydes as for dialdehydes (cf. Scheme 14, TSI and Scheme 15, TSI). A similar intermediate 17′ is formed. The subsequent allenylboration of 17′ proceeds with a second aldehyde, which may proceed via TSII or TSIII. The steric clash between the aryl group on the aldehyde and methyl substituent (TSIII) is favored over the steric clash between the aryl group

34 and CH2CH(OX)Ar (TSII). The steric effects between these two groups are similar which could explain the low diastereoselectivities.

3.6 Summary and conclusion for addition of 1,2- diborylated butadienes to aldehydes In conclusion, the sequential addition of 1,2-diborylated butadienes to aldehydes has been investigated. Through the developed protocol, a number of functionalized 1,4-diols could be synthesized. The reaction creates three to four stereocenters with moderate to high diastereoselectivity. The relative stereochemistry was determined by 1H NMR experiments as well as X-ray crystallography. The relative stereochemistry of the products are rationalized on the basis of steric and electronic effects.

35 4. Cu-mediated trifluoromethylation of propargylic alcohol derivatives (Paper II)

As mentioned in section 1.4, there is a high demand in pharmaceutical in- dustries for organofluorine compounds.27f This has led to development of new methodologies for introducing fluorine and trifluoromethyl group into organic molecules.27e, 51 Although many recent studies have been focused on the synthesis of aryl,27a allyl52 and vinyl27b trifluoromethylated compounds, very few methods have been reported on the formation of trifluoromethylated allenes and corresponding propargylic species. Most of the methods reported are based on the transformation of prefunctionalized alkynylCF3 compounds to the trifluoromethylated allene.53 Burton and co-workers reported that perfluoroalkylated copper reagents could react with propargylic halides and tosylates to generate perfluoroalkylated allenes in moderate to good yields (Scheme 16).54

Scheme 16. Trifluoromethylation of propargylic halides using in-situ generated Cu- CF3 reported by Burton and co-workers

A limitation of this method is the use of ligandless CuCF3 which may undergo α-fluoroelimination and form CF2carbene which then is able to insert to CF bonds leading to perfluoroalkylated CuCnF2n+1 intermediates. This leads to complex mixtures of perfluoroalkylated compounds. We therefore sought to find a new protocol to synthesize trifluoromethylated allenylic and propargylic compounds by metal-mediated substitution of propargylic substrates. We envisioned that we could use stable ligated CuCF3 reagents and to use (PPh3)3CuCF3 (19) which was first synthesized and characterized by Komiya and co-workers.55 The synthesis of 19 was further developed by Grushin and co-workers which was used in the synthesis of trifluoromethylated aryls from aryl halides (Scheme 17).56

Scheme 17. Trifluoromethylation of aryl halides using (Ph3P)3CuCF3

4.1 Initial experiments

As a model reaction we studied the trifluoromethylation of a commercial- ly available internal propargylic chloride, 20a. Initially, 20a was subjected to the same reaction conditions that Grushin and co-workers applied for the trifluoromethylation of aryl iodides using 19.56 Gratifyingly the formation of the corresponding trifluoromethylated allene (21a) and propargylic (22a) species in a 1:2 ratio could be observed in the crude 19F NMR spectrum (Scheme 18).

Scheme 18. Initial experiment for trifluoromethylation of propargylic chlorides

Next we evaluated the effects of solvents and reaction temperature (Table 17). As shown in Table 17, the reaction temperature affects the selectivity of the reaction. At 22 °C the selectivity was towards the formation of trifluoromethylated allene product 21a (entry 2 and 4). However, at increased reaction temperature mainly the corresponding trifluoromethylated propargylic product 22a was obtained (entries 1 and 3). The highest selectivity for the formation of 22a was obtained using THF at 50 °C (Table 17, entry 3), while selective formation of 21a occurred using THF at 22 °C (entry 4). Inspection of the 19F NMR spectrum indicated that perfluoroalkylated products and HCF3 were not formed. According to Grush- in and co-workers these side products were predominant in their reaction with arylhalides and 19 at 80 °C (Scheme 17).56 However, these side reactions could be avoided at a lower reaction temperature.

37 Table 17. Screening of solvents and temperature[a]

Entry Solvent Temp (°C) Conversion[b] 21a:22a[c]

1 C6D6 50 >95% 1:2

2 C6D6 22 45% 3:1

3 THF 50 >95% 1:3

4 THF 22 >95% 5:1

5 DMF 22 >95% 4:1

[a] Reaction conditions: 20a (0.100 mmol), 19 (0.105 mmol), solvent (0.4 mL), weighed inside Ar-filled glovebox and then taken out and stirred at the indicated temperature for 16 h [b]Conversions were determined by 1H NMR spectroscopy of the crude reaction mixture [c]Ratio determined by 19F NMR spectroscopy of the crude reaction mixture

4.2 Synthesis of trifluoromethylated allenylic and propargylic compounds

Using the above results (section 4.1 Table 17) the scope and limitations of the method were studied (Tables 18 and 19). In general, the copper-mediated trifluoromethylation of propargylic halides provided the corresponding trifluoromethylated allenes (21) and corresponding propargylic compounds (22) in good yields and regioselectivity. The reactions gave good regioselectivity towards the trifluoromethylated allene (21) at room temperatures and the corresponding trifluoromethylated propargylic compound (22) at 50 °C. When the steric bulk is increased at the γ-position of the propargylic halide (Table 18, entries 5 and 6), the propargylic product is obtained, even at room temperature. Tertiary halides gave exclusively the allenyl product (Table 18, entries 8 and 9). Surprisingly, when substrate 20b reacted at 50 °C a rearrangement to propargylic compound 22b occurred. The thermal rearrangement is investigated in section 4.5.

38 Table 18. Copper-mediated trifluoromethylation of propargylic alcohol derivatives[a]

Temp Yield Entry Substrate (°C) Product (%)[b]

1 20a 22 21a 67

2 20a 50 22a 63

3 20b 22 21b 68

4 20b 50 22b 82

5 20c 22 22b 74

6 20d 22 22c 86

7 20e 22 21c 65

8 20f 50 21d 88[c]

9 20g 22 21e 87

[a] Reaction conditions: propargylic halide 20 (0.100 mmol), 19 (0.100 mmol), THF (0.4 mL) was weighed inside Ar-filled glovebox and then taken out and stirred at the indicated temperature for 16h [b]Isolated yield [c]Volatile product, NMR-yield is given using α,α,α- trifluorotoluene as internal standard

The reaction proceeds smoothly with propargylic halides as substrates. However, the selective synthesis of functionalized propargylic halides 20 from the corresponding propargylic alcohols is troublesome. The halogena- tion reaction gives a mixture of propargylic and allenyl halides. The allenyl halides are difficult to separate from the propargylic halides and are unreactive toward trifluoromethylation. We therefore looked for other substrates, in which the leaving group can be formed without cleavage of the CO bond of the propargylic alcohol precursors.

39 Propargylic carbonates gave a complex mixture of unidentified side products, even at lower temperature and shorter reaction times (Scheme 19a). Propargylic acetates were completely unreactive, even using a large excess of 22, at elevated temperatures and prolonged reaction times (Scheme 19b). However, the propargylic trifluoroacetate 23a reacted according to the previously developed protocol for trifluoromethylation of propargylic halides (Scheme 19c). Interestingly, substrate 23a showed the same thermal rearrangement as utilizing propargylic chloride 20b (see Table 19, entry 2).

Scheme 19. Trifluoromethylation using other alcohol derivatives

A broad variety of electron-supplying and electron-withdrawing aryl substituents was tolerated in the trifluoromethylation reaction (Table 19, entries 1-8). Notably, halogen-containing 4-bromoaryl functionalized propargylic trifluoroacetate, 23c, was found to be compatible with the reaction conditions (entry 4 and 5). The same thermal rearrangement was observed for all substrates at elevated reaction temperatures.

40 Table 19. Copper-mediated trifluoromethylation of propargylic alcohol derivatives[a]

Temp Yield Entry Substrate (°C) Product (%)[b]

1 23a 22 21b 85

2 23a 50 22b 74

3 23b 22 21f 86

4 23c 22 21g 63

5 23c 50 22d 87

6 23d 22 21h 58

7 23d 50 22e 73

8[c] 24 22 21i 52

[a]Reaction conditions: propargylic trifluoroacetate 23 (0.100 mmol), 19 (0.100 mmol), THF (0.4 mL) was weighed inside Ar-filled glovebox and then taken out to be stirred at the indicated temperature for 16h [b]Isolated yield [c]The trifluoroacetate was generated in situ (see scheme 24)

The synthesis of 4-methoxyaryl substituted propargylic trifluoroacetate (23e) was difficult, as the trifluoroacetate group easily eliminates and hydro- lyzes. However, synthesis of 23e and its trifluoromethylation could be performed in a one-pot sequence from the corresponding alcohol 24 (Scheme 20).

Scheme 20. One-pot reaction for the synthesis of 21i

4.3 Stereochemistry of the trifluoromethylation reaction

To investigate the stereochemistry of the reaction, enantiomerically enriched propargylic trifluoroacetate (R)-23a was prepared and treated with 19 under the standard reaction conditions. At 22 °C the reaction proceeds in moderate stereospecificity (56% ee). However, at 4 °C the corresponding trifluoromethylated allene 21b was formed in 70% isolated yield and with 89% ee (Scheme 21). The high stereospecificity indicates that the nucleophilic displacement of the leaving group occurs in a formal SN2′-type mechanism.

Scheme 21. Stereoselective formation of allenylic trifluoromethyl from enantioenriched propargylic trifluoroacetate

4.4 Investigation of a possible radical mechanism

To exclude a radical pathway, 3 equivalents of TEMPO was added, in the presence of (PPh3)3CuCF3 (19) and propargylic trifluoroacetate 23a (Scheme 22). The addition of TEMPO did not have any significant effect on the yield of the reaction (85% yield in the absence and 72% yield in the presence of TEMPO). This result, together with the results from section 4.3, supports the hypothesis that this reaction occurs via an ionic mechanism.

Scheme 22. Reaction with an excess of TEMPO

42 4.5 Study of the thermal rearrangement of 20b

We have also examined the thermal rearrangement of 20b (Scheme 23). According to the original findings at 22 °C, substrate 20b reacted with 19 to form the trifluoromethylated allene 22b (Table 18, entry 3). When the temperature was increased to 50 °C the rearranged trifluoromethylated product 22b was selectively formed (Table 18, entry 4). One possibility is the rearrangement of the propargylic chloride 20b to allenyl chloride (25) in the presence of CuI (Scheme 23). The allenyl chloride 25 would then rearrange under thermal conditions to propargylic chloride 20c which subsequently may react with 19 to form the propargylic trifluoromethylated product.

Scheme 23. Investigation into whether the thermal rearrangement is due to rearrangement of 20b

However, allenyl chloride 25 did not react with 19 under the standard reaction conditions. Even at elevated temperature and increased reaction time 25 remained unreactive. This shows that 25 is not an intermediate in the formation of 22b from propargyl chloride 20b.

Scheme 24. Investigation of thermal rearrangement of the product

We also investigated whether the trifluoromethylated allene rearranged under the reaction conditions. Isolated 21b was heated at elevated temperatures and prolonged reaction times (Scheme 24a) in the presence of copper salts and 19. The 19F NMR spectrum of the crude reaction mixture showed that rearrangement did not take place and only peaks corresponding to 21b could be observed. In a separate experiment we subjected propargylic chlo-

43 ride 20b with 19 at 22 °C (Scheme 24b). The recorded 19F NMR on the crude mixture indicated that 20b was converted to 21b. Subsequently, the same crude mixture was heated to 50 °C for 16 hours. According to 19F NMR spectrum of the crude reaction mixture, a full conversion to 22b had occurred. We concluded that the trifluoromethylated allene rearranges to the propargylic product at higher temperature, but only under the reaction conditions of the trifluoromethylation and in the presence of 22.

4.6 Proposed mechanism Based on the results from the mechanistic investigation and the stereoselectivity of the reaction (section 4.3-4.5) we propose that the reaction starts with ligand dissociation from 19 to form 26a followed by coordination of the propargylic alcohol derivative (26b) (Figure 12). The coordination is followed by a formal nucleophilic displacement. The displacement can occur at the γ- (pathway a) or α-position (pathway b) depending on the steric bulk at the α- and γ-position of the propargylic moiety. This is supported by the fact that reactions with bulky propargylic alcohol derivatives at the γ-position afforded only the corresponding trifluoromethylated propargylic products (Table 18, entries 5 and 6). Further evidence shows that sterically hindered, tertiary halides exclusively provide the allenyl product (Table 18, entries 8 and 9). It has also been shown that allene 21 may undergo a formal 1,3- hydride shift to propargylic trifluoromethylated product 22′ (Scheme 24b).

Figure 12. Proposed mechanism for the regioselective formation of trifluoromethylated propargylic and allenylic compounds

4.7 Recent publications for the synthesis of trifluoromethylated propargylic and allenylic compounds Since our study there have been several new methodologies for synthesiz- ing trifluoromethylated allenes and corresponding propargylic species.57 Cu-

44 mediated52, 58 and -catalyzed59 nucleophilic trifluoromethylation of propargylic alcohol derivatives has become a popular strategy for accessing CF3- based compounds (Scheme 25). The regioselectivity often depends on the degree of substitution at the leaving group.

Scheme 25. Cu-catalyzed trifluoromethylation of propargylic chlorides presented by Nishibayashi and co-workers59a

In addition, the group of Song and Lee,60 as well as Xu61 have reported Pd-catalyzed, regioselective synthesis of trifluoromethylated propargylic species (Scheme 26). In these studies, 1,1,1-trifluoro-2-iodoethane was used to introduce the trifluoromethyl group and both are proposed to proceed via an alkynyl-palladium intermediate.60-61

Scheme 26. Pd-catalyzed trifluoromethylation resulting in the selective synthesis of propargylic trifluoromethyls

4.8 Summary and conclusions for trifluoromethylation of propargylic substrates We have developed a novel, general method for efficient synthesis of allenylic and propargylic trifluoromethylated compounds. The proposed mechanism proceeds via a Cu-mediated SN2′-type displacement of the propargylic alcohol derivatives. The transformation to trifluoromethylated allenes is stereospecific and occurs with transfer of chirality from the propargylic substrate. This new protocol expands the methods available for trifluoromethylation via substitution.

45 5. Palladium-catalyzed oxidative CH silylation (Paper III)

Similar to allylic boronates, allylic silanes are important synthetic intermediates that are widely applied in stereoselective electrophilic substitution reactions.24 The increased reactivity in electrophilic addition is due to the hyperconjugation between the SiC σ-bond and the π-orbital of the alkene (Figure 13).20b The electrophiles react at the γ-position generating a so called β-silyl carbocation which in turn is stabilized by the SiC σ-bonding orbital that can donate electron density into the empty p-orbital of the carbocation.62 As mentioned in section 1.3, the stereochemistry of the allylation of aldehydes with allylic boronates (Type I), and allylic silanes are different (Type II). Therefore, the allylation by allylic silanes and allylic boronates can be complementary.

Figure 13. General mechanism for electrophilic addition to allylic silanes

5.1 Background

5.1.1 Previous palladium-catalyzed methods for the synthesis of allylic silanes Several methods have been published for the synthesis of allylsilanes based on palladium-catalyzed allylic substitution. Most of these methods utilizes pre-functionalized alcohol derivatives, allylic acetates63 (Scheme 27a) and allylic ethers64 (Scheme 27b). The Szabó group has published a Pd- catalyzed silylation of allylic alcohols (Scheme 27c).31c The efficiency of these traditional methods is limited by the need of pre-functionalized allylic substrates.

Scheme 27. Synthethis of allylic silanes through allylic substitution

In recent years the concept of step economical synthesis has emerged.65 One of the most efficient ways to reduce the number of steps of a synthesis is to avoid the functional group manipulations to obtain preoxidized substrates that are able to undergo the desired bond formations.66 However, CH bonds possess high kinetic barriers to react and are ubiquitous in organic molecules. As a consequence, much effort has been devoted to the design and synthesis of new catalytic systems for CH functionalization that are regio-, chemo-, and stereoselective.4b, 65a, 65c, 67

5.1.2 Previous allylic CH functionalization developed in the group

The Szabó group has previously developed an allylic CH acetoxylation 68 reaction using PhI(OAc)2 as oxidant (Scheme 28).

Scheme 28. Allylic CH acetoxylation

The results from the deuterium labeling experiments indicated that the reaction proceeds via an η3-allyl palladium intermediate. Stoichiometric reac- II IV tions with 1a have shown that PhI(OAc)2 is able to oxidize the Pd to Pd . We were therefore interested in investigating if it would be possible to per- form a CH silylation by using the above mentioned conditions. It was hypothesized that the silyl moiety would be transmetalated to the suggested allyl-PdIV intermediate and after reductive elimination, result in the formation of the allylic silane.

47 5.2 Development of palladium-catalyzed CH silylation

Scheme 29. Model reaction used when optimizing the reaction conditions

In the initial experiments we used the reaction conditions of the previously developed CH acetoxylation (Scheme 29) in the presence of (SiMe3)2. However, in the presence of PhI(OAc)2 which was used for the acetoxylation reaction the desired allylic silane product 28a was not formed. Detailed studies were conducted to find the appropriate reaction condition for C-H silylation. This involved variation of oxidant, Pd-source, solvent and temperature. It was found that the CH silylation can be carried out using benzoic acid based hypervalent iodines 29a-b. The reaction also resulted in the formation of 30a and 31a. Further optimization led to the reaction conditions given in Scheme 30 which was suitable for the synthesis of allylic silane 28a in high yields. It was shown that no reaction occurred in the absence of oxidant.

Scheme 30. Reaction conditions for the silylation of 27a

5.3 Synthesis of allylic silanes – scope and limitations Using the above developed reaction conditions for alkene 27a (Scheme 30), the substrate scope was evaluated using a variety of substrates (27). The developed methodology can be used to efficiently silylate allylic esters 27a- 27c and amide 27d with high E/Z selectivity (Table 20, entries 1-4). Howev- er, when allylic amide 27e and allylic phenyl derivative 27f were subjected

48 to the developed conditions the reaction gave low yields and chemoselectivi- ty. In the case of 27f the main byproduct was the Heck-type coupling product. The Heck coupling may proceed between 27f and the aryl iodide which is left from 29b after reduction.

Table 20. Oxidative CH silylation of alkenes (Method A)[a]

Yield [c] Entry Substrate Pdcat Product (%)[b] E/Z

1[d] 27a 1g 28a 70 80:20

2 27b 1g 28b 69 83:17

3 27c 1g 28c 58 83:17

4[e] 27d 1g 28d 60 90:10

5 27e 1h 28e 52 >95:5

6[f] 27f 1i 28f 59 >95:5

7 27g 1g-1i 28g <5 -

8 27h 1g-1i 28h <5 -

9 27i 1g-1i 28i <5 -

[a] Reaction conditions: 27 (0.200 mmol), (SiMe3)2 (0.400 mmol), 29b (0.400 mmol) and the Pd-catalyst 1 (0.01 mmol) was stirred for 18 h at 80 °C in monoglyme (0.50 mL) [b]Isolated yield of both isomers [c]E/Z ratio determined by 1H NMR spectroscopy of the crude reaction mixture [d]THF was used as solvent [e]4-Nitrobenzoic acid (0.10 mmol) was added [f]Reaction was performed at 60 °C

In order to improve the yield of the silylated product 28e and 28f, a second catalyst screening was made. Palladacycle 1h were able to efficiently silylate 27e (Table 20, entry 5). The formation of the byproduct could be

49 reduced further by lowering the temperature to 60 °C. The silylation of 27f proceeded smoothly with 1i (Table 20, entry 6). Silylation of other analogous substrates was also attempted using 1g-i, such as ketone 27g (entry 7), nitrile 27h (entry 8) and 4-fluoroaryl 27i (entry 9). However, none of these substrates gave any silylated products. The main products of these reactions arose from rearrangement of the double bond (as for ketone 27g and allylic nitrile 27h), and the Heck-type coupling product (as for aryl fluoride 27i).

Table 21. Oxidative C-H silylation of terminal alkenes (Method B)[a]

Yield [c] Entry Substrate Product [b] E/Z (%)

1 27b 28b 77 88:12

2 27j 28j 45 14:86

3 27k 28k 52 25:75

[a]Reaction conditions: allylic substrate 27 (0.200 mmol), (SiMe3)2, 29c (0.400 mmol), BQ (0.200 mmol) and the Pd-catalyst (0.01 mmol) was stirred for 18 h at 80 °C [b]Isolated yield of both isomers [c]E/Z ratio determined by 1H NMR spectroscopy of the crude reaction mixture

Using 27b as oxidant the silylation of sulfone 27b and sulfonamide 27k occurred with low yield. Therefore the oxidant was changed to a benzoyl peroxide (29c)/benzoquinone (BQ) system in the presence of 4-nitrobenzoic acid (Table 21). This new system increased the yield of the reaction (entries 2-3). The process was also found to be suitable for silylation of 27b with good yield and improved diastereoselectivity (cf. Table 20, entry 2 and Table 21, entry 1).

5.4 Mechanistic investigation and proposed catalytic cycle for the silylation of alkenes As mentioned above, the Szabó group68 and others69 have shown that hypervalent iodine reagents are able to oxidize PdII to PdIV-complexes. Thus,

50 the catalytic cycle is proposed to be initiated by oxidative addition of 1 with 29b to generate PdIV-complex 32a (Figure 14). Alkene coordination to 32a leads to formation of complex 32b. In 32b, one of the allylic protons of the the substrate undergoes CH cleavage to form an η3-allyl Pd-complex 32c. The CH cleavage step is proposed to proceed via a concerted metalation deprotonation (CMD) mechanism,4e which has been suggested for CH functionalization of arenes70 and het- eroarenes71. Formation of 32c is followed by the transmetalation of disilane to give 32d which upon reductive elimination forms product 28 and regener- ates the catalyst. Transmetalation of hexamethyldisilane is facilitated by the high-oxidation state of PdIV. In addition, the rate of reductive elimination is increased if the metal is more electrophilic.1b, 1c The formation of benzoyloxylated and phenylated byproducts can also be explained by the proposed catalytic cycle (Figure 14). The benzoyloxylated byproduct (such as 30a) is formed by reductive elimination of the benzo- yloxy group to the η3-allyl group from complex 32c. The phenylated byproduct (such as 31a) is formed via a Pd0/PdII-catalyzed Heck-type coupling with phenyl iodide which is present in the reaction mixture. Isomerization of the double-bond geometry is probably caused by an η3 - η1 - η3 interconversion of the Pd-allyl complexes 32c and 32c′. This process has been studied extensively in the group72 and by others73.

Figure 14. Proposed catalytic cycle for allylic C-H functionalization

51 Considering the mechanism of the silylation using method B (Table 21), we propose that benzoyl peroxide is able to oxidize PdII to PdIV.74 BQ could have several roles in the catalytic cycle. BQ is known for being efficient at stabilizing Pd0 and oxidizing it to PdII.75 The reduction of BQ to hydroqui- none requires protic conditions. The role of 4-nitrobenzoic acid could be to serve as a proton source.75a, 76 Based on our experiments, a palladium-catalyzed, tandem CH acyloxylation – allylic substitution sequence reaction was ruled out (Scheme 31). Under the applied reaction conditions, the allylic ester 27b did not give the acyloxylated compound 30b in the absence of (SiMe3)2. Furthermore, we found that even if 30b was formed during the reaction, it would not be converted to allylic silane 28b under the applied reaction condition.

Scheme 31. A tandem sequence was ruled out as the acyloxylated product was not able to be silylated under the applied reaction conditions

5.5 Conclusions and summary for CH functionalized silylation of alkenes To the best of our knowledge, the above presented procedure has been the first, general method for metal-catalyzed CH silylation. The developed protocol is suitable for allylic CH silylation of terminal alkenes with an electron withdrawing substituent. The reaction is highly regioselective and yields only the linear allylic silanes. (E)-Substituted alkenes were usually formed but the selectivity was reversed when using sulfone or sulfonamide substrates. It was concluded that the reaction did not proceed via a sequential acyloxylation – allylic substitution reaction pathway. The catalytic cycle is proposed to proceed via a PdII/PdIV catalytic cycle.

52 6. Concluding remarks and outlook

The work described in this thesis has been aimed at finding new efficient methods to broaden the scope of copper- and palladium-mediated CX (X = Bpin, SiMe3, CF3) bond-forming reactions. The main efforts has been focused on development of new methods to form functionalized allylic, propargylic and allenyl products. We have successfully developed a method for the selective synthesis of allenyl boronates. High selectivity could be achieved using internal propargylic carbonates and terminal propargylic acetates. We have also developed a methodology for the synthesis of 1,2-diborylated butadienes from propargylic epoxides. These 1,2-diborylated butadienes have been used for the synthesis of functionalized 1,4-diols via sequential allylboration and allenylboration. Furthermore, we have developed a copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates. The applied trifluoromethylating reagent is easy to handle and readily accessible. The reaction has high regioselectivity and forms the allenyl or the propargylic product with high selectivity depending on the applied reaction conditions. We have shown that the reaction proceeds with a high degree of chirality transfer at low temperature. The first method for palladium-catalyzed allylic CH silylation of terminal alkenes has been developed. The reaction is completely regioselective giving only the linear allylic silane. Further challenges based on the work presented in this thesis involve mechanistic studies for detailed understanding of the bimetallic borylation reaction. These studies should be valuable for further improvement of the borylation reaction of terminal alkynes.

53 X. Acknowledgements

I would like to express my sincere gratitude to the following people:

My research advisor Prof. Kálmán Szabó for accepting me as a Ph. D. can- didate in his group. I would like to thank you for the inspiration, motivation and support throughout these years.

Prof. Pher G. Andersson for showing interest in this thesis.

Past and present members of the Szabó group for creating such a nice working atmosphere in the office and in the lab, a special thanks to my collabora- tors; Dr. Johanna Larsson, Dr. Yuzhu Yang, Dr. Jian Zhao, Timo Lessing. I truelly appreciate all the hard work and help in these projects. I would like to give a special thanks (+1) to Johanna for all the help, support and guidance at the start of my studies.

Dr. Antonio Bermejo Gómez, Rauful Alam, Anuja Nagendiran, Sara Moa and Dr. Nicklas Selander for help with proof-reading this thesis and for of- fering suggestions on improvements.

My past educators for showing me how interesting chemistry is.

Vetenskapsrådet, K & A Wallenbergs stiftelse, Kungliga Vetenskaps- akademien, Ångpanneföreningens Forskningsstiftelse, for funding and travel grants.

The TA Staff and Administration for keeping this department running and well organized.

Mikael, Maoping, Rauful, Nadia, Anuja, Tove, Alexey, Fredrik, Oscar, Mad- eleine, Karl, Tamás for memorable conference trips to Philadelphia, Sapporo and San Francisco.

Everyone at the department with whom I have interacted with, thank you for creating the most wonderful and awesome working atmosphere. It has been a true pleasure and fun to work alongside you all.

54 Kilian, Angela, the members of Malines Firefists, JazzPear and Finale for frequent and satisfying sanity checks (3d6). To Tommy (Muga), Magnus (Bakkefar), Kevin (Shiku), Daniel (Naylia), Sebastian (Rica), Giorgio (Za- nar), Sebastian (Ryu): Let us be filthy casuals forever!

To my Mom and Dad, for all your support throughout the years.

Till Ulf, tack för allt.

55 Y. Vetenskaplig sammanfattning

Denna text avhandlar utvecklingen av nya syntesmetoder via palladium- och kopparkatalys. Forskningen har fokuserats mot selektiva funktionaliseringar av alkener och propargyliska alkoholderivat, samt den syntetiska användbarheten av de nya produkterna. En effektiv metod för syntes av allenyliska boronater från propargyliska karbonater och acetater har utvecklats. Metoden bygger på användning av ett bimetalliskt system bestående av palladium, och koppar eller silver. Under milda reaktionsbetingelser kan därigenom en mängd substituerade allenylboronater syntetiseras med en hög kontroll av selektiviteten. Vid användning av propargyliska epoxider som reaktionssubstrat erhölls 1,2- diborylerade butadiener med hög diastereoselektivitet. De diborylerade butadienernas reaktivitet har studerats genom additionsreaktioner med aldehyder. En metod för syntes av allenyliska och propargyliska trifluorometylerade föreningar har också studerats. Med hjälp av ett kopparreagens och kontroll av reaktionstemperaturen kan selektiviteten i denna process styras. I den sista delen av avhandlingen beskrivs en syntesmetod för allylsilaner från alkener baserad på palladiumkatalys. Då transformationen endast är möjlig under oxidativa betingelser är palladiumintermediärer med högt oxidationstillstånd troligtvis involverade.

56 Z. References

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