Facile construction of benzylic quaternary centers via palladium catalysis

Transcription

1 Facile construction of benzylic quaternary centers via palladium catalysis This chapter details our study to develop a straightforward, practical and scalable protocol for the palladium catalyzed conjugate addition of arylboronic acids to, - disubstituted enones, leading to the formation of benzylic quaternary centers. Compared to existing literature, this procedure avoids the synthesis of preformed catalysts, or forcing conditions. Further, the role of KSbF 6 as an additive to obtain increased yields in case of acyclic enones is studied. Parts of this chapter will be submitted for publication: Gottumukkala, A.L., Suljagic, J., Matcha, K., de Vries, J. G., Minnaard, A. J., Manuscript in preparation.

2 5.1 Introduction ccurrence and non-catalytic synthesis The benzylic quaternary center 1-5 is a widely prevalent motif in a variety of natural products, 5,6 drug candidates 7 and fragrances. A few examples of molecules containing this motif are presented in Figure 1. Figure 1: Examples of natural products bearing a benzylic quaternary center The synthesis of this architectural element has remained a challenge and continues to be an actively studied area over the past decade. 1,2 The convenience rendered by a selective and mild approach to install these units is so significant that it can shorten synthesis routes considerably and greatly increase yields. A clear example of this is the synthesis of (-)-α-cuparenone, in which this seemingly simple target, by non-catalytic approach, required a linear sequence of 16 steps to synthesize the molecule. 8 A straightforward conjugate addition, on the other hand, allowed the synthesis of the same compound in merely 2 steps (Section 4.5, Chapter 4). Conjugate addition to enones is a particularly facile approach for building molecular diversity as it offers several convenient handles for functionalization. Upon conjugate addition, the molecule is left with two α positions that are regiochemically distinct, in addition to the ketone moiety; all of which can be targeted selectively for further chemical transformations (Scheme 1). Scheme 1: Handles for selective functionalization following conjugate addition. 126

3 Facile Construction of Benzylic Quaternary Centers via Pd catalysis Commonly, the synthesis of these motifs via conjugate addition, under uncatalyzed conditions is achieved by Gilman reagents 9 (Scheme 2). Scheme 2: Gilman reagents applied in uncatalyzed conjugate addition reactions. Transition metal catalysis offers a convenient alternative to the above. Conjugate addition reactions catalyzed by copper and rhodium have been well studied in recent years, and are the subject of a recent review. 26 The application of these metals in catalysis is often considered to be complementary: whilst copper catalysis is particularly successful for the conjugate addition of alkyl substituents, rhodium catalysis allows facile addition of alkenyl and aryl groups. 26 A qualitative comparison of the two approaches has been presented in Section 4.1 (Chapter 4) Palladium in conjugate addition For many years, while it was possible to obtain tertiary and quaternary centers via conjugate addition with Cu 27,28 and Rh 29,30 catalysis, it was thought that Pd catalysis 29,31 was limited to the formation of tertiary centers. The first report to dispel this notion came in 2010, when the group of Lu disclosed 32 that cationic Pd complex C1 was able to catalyze the formation of 8 (Scheme 3) via the conjugate addition of phenylboronic acid to 3-methylcyclohexenone (1). Scheme 3: The first Pd-catalyzed benzylic quaternary center formation via conjugate addition. The reported synthesis of C1 was via the dehalogenation of 9 using AgBF 4. It was however, found to proceed with a rather low yield (27 %). Scheme 4: Synthesis of catalyst C1. 127

4 Recently, Lee and coworkers reported 33 good diastereoselectivities for the Pdcatalyzed conjugate addition of arylboroxines, using Pd(MeCN) 4 (Tf) 2 or alternatively a combination of Pd(Ac) 2 and TfH, as catalysts (Scheme 5). The authors found that the addition of 1 equiv of NaN 3 was helpful to minimize the formation of biphenyl, though they failed to comment whether NaN 3 functioned as an oxidant of Pd. While the conditions of the reactions are indeed mild, and the diastereoselectivities impressive; the reaction requires 5 mol% of Pd, in addition to prior synthesis of the arylboroxines (via dehydration of the corresponding boronic acids), and the addition of 1 equiv of NaN 3. Further, the catalyst, Pd(MeCN) 4 (Tf) 2 is not readily available and moisture sensitive (it decomposes within 2 min upon exposure to ambient atmospheric conditions). Scheme 5: Diastereoselective conjugate addition of arylboroxines. The groups of Li and Duan recently reported 34 a desulfitative conjugate addition of arylsulfinic acids with enones (Scheme 6). The authors probed the reaction mechanism via ESI-MS/MS. The intermediates identified were largely consistent with the mechanism put forth by Lu. 32 Despite the relevance of this procedure to synthesis, a catalyst loading of 5 mol% was necessary for success of the reaction, in addition to high temperatures (90 o C). Further, the acidic conditions of the reaction limit the functional groups that could be used in this reaction. Scheme 6: Desulfitative conjugate addition of arylsulfinic acids to enones. Computational studies disclosed by Houk et al. 35, verified the mechanism advanced by Lu. 32 DFT calculations explain several empirical observations such as the catalytic activity of hydroxo-palladium species (Scheme 4), the regioselectivity of the addition and the necessity for a cationic Pd species. In addition, the authors rationalized why conjugate addition does not take place when there is an aryl substituent in the -position, as this gives rise to a steep energy barrier of 37 kcal/mol, going to the transition state. Further, the formation of the substitution 128

5 Facile Construction of Benzylic Quaternary Centers via Pd catalysis product observed when an alkoxy function is present in the -position, was rationalized on the account of energetically favorable -alkoxy elimination. 5.2 Goal The goal of this study was to develop a straightforward and easily scalable procedure for Pd catalyzed conjugate addition reactions leading to the formation of benzylic quaternary centers, using low catalytic loadings. We chose to develop a procedure based on arylboronic acids, as these are easily accessible commercially, available with a variety of functional groups, and can be stored and manipulated at ambient conditions. Such a procedure would preferably avoid the dehydration of the arylboronic acids to the corresponding boroxines, and also the combination of acid and high temperature that is required to extrude S 2 in the reported desulfitation reaction. 5.3 Results and discussion ur initial focus was to study the role of BIAN as a ligand for Pd in the formation of quaternary centers, following its success in the oxidative Heck reaction (Chapter 3). We chose the reaction of 3-methylcyclohexenone with phenylboronic acid to optimize the reaction ptimization of reaction parameters for conjugate addition With the optimized catalyst system of the oxidative Heck reaction but without the oxygen balloon; ie Pd(Ac) 2 (5 mol%), BIAN (7 mol%), MeH : H 2 (9:1), rt, 12 h (Table 1, entry 1) no product formation was observed. Performing the same reaction at 40 o C did not have any beneficial influence (entry 2). Subsequently, we assayed cationic sources of Pd, along with the use of dry methanol, as described by Lu (Scheme 3). 32 Using Pd(CH 3 CN) 4 (BF 4 ) 2, 14% conversion was obtained (entry 3). Switching to Pd( 2 CCF 3 ) 2 gave an improved conversion of 33%. Performing the reaction in a solution of MeH : H 2 (9:1) improved the conversion, though it was still below 50% (entry 5). Interestingly, performing the reaction at higher temperature (60 o C) gave full conversion (entry 6). However, when the catalyst loading was lowered to 1 mol%, conversion was found to drop significantly (entry 7). 129

6 Table 1: Reaction of 3- methylcyclohexenone with phenylboronic acid a Entry Pd (mol%) Ligand (mol%) Solvent Temp. ( o C) Conv. (%) b Pd(Ac) 2 (5 ) BIAN (7) MeH:H 2 (9:1) rt 0 2 Pd(Ac) 2 (5 ) BIAN (7) MeH:H 2 (9:1) Pd(CH 3CN) 4(BF 4) 2 (5) BIAN (7) MeH rt 14 4 Pd( 2CCF 3) 2 (5) BIAN (7) MeH rt 33 5 Pd( 2CCF 3) 2 (5) BIAN (7) MeH:H 2 (9:1) rt 43 6 Pd( 2CCF 3) 2 (5) BIAN (7) MeH:H 2 (9:1) 60 full 7 Pd( 2CCF 3) 2 (1) BIAN (1.5) MeH:H 2 (9:1) Pd( 2CCF 3) 2 (5) Phen (7) MeH:H 2 (9:1) Pd( 2CCF 3) 2 (5) Bipy (7) MeH:H 2 (9:1) 60 full 10 Pd( 2CCF 3) 2 (1) Bipy (1.5) MeH:H 2 (9:1) 60 full 11 Pd( 2CCF 3) 2 (1) Bipy (1.5) MeH:H 2 (9:1) rt Pd( 2CCF 3) 2 (1) Bipy (1.5) MeH:H 2 (4:1) c Pd( 2CCF 3) 2 (1) Bipy (1.5) MeH:H 2 (9:1) d Pd( 2CCF 3) 2 (1) Bipy (1.5) MeH:H 2 (9:1) e Pd( 2CCF 3) 2 (1) Bipy (1.5) MeH:H 2 (9:1) 60 0 a 3-methylcyclohexenone (0.5 mmol), phenylboronic acid (1mmol), Pd precursor, ligand, solvent (1 ml), 12 h. b Conversion determined by GC analysis. c 9 used instead of 7. d 10 used instead of 7. e 11 used instead of 7.

7 Facile Construction of Benzylic Quaternary Centers via Pd catalysis At this stage, we assayed other nitrogen based ligands. 2,9- Dimethylphenanthroline proved to be a poor ligand (entry 8). n the other hand, 2,2 -bipyridine gave full conversion even with 5 mol% Pd(Ac) 2 (entry 9), and the conversion remained the same when the Pd loading was lowered to 1 mol% (entry 10). Trying the reaction at room temperature resulted in poor conversion (entry 11), and increasing the proportion of water in the solvent was not beneficial (entry 12). Substituting phenylboronic acid by potassium trihydroxyphenylborate 36 (entry 13), potassium phenyltetrafluoroborate 37 (entry 14) or phenyl MIDA boronate 38 (entry 15) did not lead to product formation. Comparing to the system developed by Lu, 32 our protocol avoids the need to synthesize the catalyst, C1, a synthesis which is low yielding. Both the protocols require only 1 mol% Pd, while a higher reaction temperature (60 o C) was found to be necessary in our case Conjugate addition to cyclic enones With the optimized conditions [1 mol% Pd( 2 CCF 3 ) 2, 1.5 mol% 2,2-bipyridine, 60 o C, MeH:H 2 (9:1)] at hand, we went on to explore the scope and limitations of the reaction (Figure 2). In general, the reaction proceeded well for a series of 3- substituted 5, 6 and 7 membered cyclic enones with variety of arylboronic acids, affording yields higher than 90% in many cases. The reactions proceeded cleanly affording only the product. Reactions of 3-methylcyclohexenone (1) afforded 3b and 3c in yields over 90% with 4- and 3-tolylboronic acid. 4-Fluorophenylboronic acid gave 3d in a reduced yield of 70%. Alkoxy substituted arylboronic acids afforded 3e and 3f in 72% and 85%, respectively. Whilst 3-chlorophenyl boronic acid afforded 3h in 90% yield, 3- chloro-4-methoxyphenyl boronic acid gave 3g in 95% yield. As observed earlier, (Chapter 4, Table 3, entry 4), 3-phenylcyclohexenone 12 was found to be unreactive, and 3-cyclopentyl-cyclohexenone (13) formed the product only in trace amounts. The failure of these substrates (12,13) in the reaction has been explained more recently by the work of Houk et al. as described earlier Methyl-cyclopentenone proved to be an excellent substrate for the conjugate addition of arylboronic acids. Yields for the conjugate addition products of 4- and 3- tolylboronic acids were found to be 96% (14b) and 93% (14c) respectively. 4- fluorophenylboronic gave 14d in 88% yield. Alkoxy substituted phenylboronic acids afforded 14e and 14f in 90% and 93% yield respectively. 14g Could be isolated in 90% yield, indicating that the benzyl protecting group remained intact during the reaction. 3-Methylcycloheptenone afforded 15a, in a respectable 80% yield 131

8 Figure 2: Conjugate addition of arylboronic acids to cyclic enones. a,b a Enone (1 mmol), arylboronic acid (2 mmol) Pd( 2CCF 3) 2 (1 mol%), 2,2 -Bipyridine (1.5 mol%), MeH : H 2 (9:1) 2 ml, 12 h. b Isolated yields. Reactions with 3-methylcyclopentenone gave higher yields and often exhibited shorter reaction times (6-8 h), as compared to 3-methylcyclohexenone (12-18 h) with the same arylboronic acid. This may be explained by a release in ring strain of the enone, following conjugate addition. Both electron rich and electron deficient arylboronic acids were amenable to the reaction, though best yields were usually 132

9 Facile Construction of Benzylic Quaternary Centers via Pd catalysis obtained with electron rich boronic acids. The applicability of halogenated arylboronic acids for the reaction allows further functionalization via Pd-catalyzed cross coupling reactions. Despite the impressive yields obtained with a variety of arylboronic acids, certain classes of boronic acids did not result in any product formation. These include heteroaromatic boronic acids, alkenylboronic acids, phenylboronic acids bearing an ortho-substituent or phenylboronic acids substituted with a nitro- or trifluoromethyl substituent and are listed in Figure 3. Figure 3: Boronic acids that failed to undergo conjugate addition reactions. Further we were interested to test the scope of our reaction on acyclic systems Conjugate addition to acyclic enones Acyclic substrates have been particularly challenging substrates for conjugate addition reactions. This is often the case because the lack of structural rigidity, which, permits an easy s-cis to s-trans isomerization of the substrate. As a result, most often, the conditions that are successful for cyclic enones are not the same for acyclic enones, 39 which was also found to be true in our case. For our study, we chose the reaction of 26 with phenylboronic acid to optimize the reaction conditions (Table 2). In general, the reactivity of linear substrates was lower than that of cyclic substrates, (reaction times ranging between h to attain full conversion, while cyclic substrates required 8-12 h). A higher temperature (80 o C) was also found to be necessary. The use of the optimized conditions for cyclic substrates (Table 2, entry 1) only led to 20% conversion after 36 h. Increasing the catalyst loading to 5 mol% led to an improved conversion, though it remained incomplete, even at higher temperature. At this point, we considered the use of additives to improve the conversion. We found that adding 20 mol% of potassium hexafluoroantimonate (KSbF 6 ) to the reaction afforded full 133

10 conversion (entry 4). The choice of KSbF 6 was based on our previous studies on the enantioselective conjugate addition to cyclic enones (Chapter 4, Section 4.3.1), in which the use of SbF 6 as a counter ion for the cationic Pd complex resulted in improved yield and selectivity. Therefore, we surmised that adding KSbF 6 to the current reaction system could have a similar influence, and this was indeed found to be the case. The improved activity upon the addition of SbF 6 may be attributed to a salt metathesis between the trifluoroacetate (CF 3 C 2 ) ion and SbF 6 leading to catalytically more active species. However, lowering the catalyst loading to 1 mol% in the presence of the additive, gave diminished conversions (entry 5), though still higher than in the case where no additive was present (entry 5 vs. entry 1). Hence it was decided to use 5 mol% of Pd for subsequent experimentation. Table 2: Conjugate addition of cyclic enones. Entry Pd (mol%) Ligand (mol%) Additive Temp. ( o C) Conv. (%) 1 Pd( 2CCF 3) 2 (1) BIAN (1.5) Pd( 2CCF 3) 2 (3) dmphen (5) Pd( 2CCF 3) 2 (5) Bipy (7) Pd( 2CCF 3) 2 (5) Bipy (7) KSbF 6 (20 mol%) 80 full 5 Pd( 2CCF 3) 2 (1) Bipy (1.5) KSbF 6 (5 mol%) a 26 (0.25 mmol), phenylboronic acid (0.5 mmol) Pd( 2CCF 3) 2, 2,2 -bipyridine, MeH : H 2 (9:1) 1 ml, 12 h. b Conversion determined by GC analysis. Bipy = 2,2 -Bipyridine. dmphen = 2,9- dimethylphenanthroline. To test the scope and limitations of the reaction on acyclic enones, we assayed several classes of linear substrates for the reaction. The results are summarized in Table 3. We started our study with 28, a substrate found to be suitable for the conjugate addition of boronates by rhodium catalysis. However, the product was formed only in trace quantities. 29, bearing a bulkier tert-butyl group was found to 134

11 Facile Construction of Benzylic Quaternary Centers via Pd catalysis Table 3: Substrate scope for conjugate addition of acyclic enones. a Entry Substrate Boronic acid Product Yield (%) b 1 28 trace (27) 5 75 (27b) (27c) 7 72 (27d) 135

12 Entry Substrate Boronic Acid Product Yield (%) b 8 70 (27e) 9 78 (27f) (27g) 11 73(27h) (32) 13 E (32b) 14 Z (32) a Enone (0.5 mmol, 1 equiv), phenylboronic acid (1 mmol, 2 equiv) Pd( 2CCF 3) 2 (5 mol%), 2,2 - Bipyridine (7 mol%), MeH : H 2 (9:1) 2 ml, KSbF 6 (20 mol%), h, 80 o C. b Isolated yields 136

13 Facile Construction of Benzylic Quaternary Centers via Pd catalysis be completely inactive towards conjugate addition. Substrate 30, a derivative of Meldrum s acid could be recovered unreacted as well. 26 Was found to be a successful substrate for conjugate addition. A variety of boronic acids were found to be amenable to the reaction. Phenylboronic acid afforded 27 in 72% yield, while m-tolylboronic acid gave 27b in 75% yield. p-fluorophenylboronic acid gave 27c in 70% yield, and 27d could be obtained from p-methoxyphenylboronic acid in 72% yield. In general, boronic acids bearing alkoxy functionalities performed well in the reaction. Compounds 27e, 27f, 27g and 27h were all obtained in yields between 72-78% (entries 8-11). Substrate E-31, bearing a benzyl moiety was also found to be applicable in conjugate addition under the optimized reaction conditions. Phenylboronic acid and m-tolylboronic acid afforded 32 and 32b in 74% and 90% yield respectively. Substrate Z-31 also afforded 32, albeit in a slightly reduced yield of 68%. In order to ascertain whether the observed success of substrates 26 and 31 was due to the coordination of the allylic oxygen atom to the metal center during the catalysis, we designed substrate 33. Substrate 34 was designed additionally to test the amenability of a nitrogen-containing substituent in the reaction. However, both these substrates were found to be unreactive under the reaction conditions. Thus it remains unclear whether the observed influence of allylic oxygen atom for the reaction is due to a coordination of the substrate to the metal center or due to an electronic influence. It is noted that in most of the successful cases, the isolated yields were in the range of 70-80%, though, in all cases complete consumption of the substrate in the reaction had been indicated by GC. Further, TLC of the worked up reaction mixture, showed only a single spot. The cause of the lower yield was not apparent at the time of the investigation. It was found later (See section for details), that a side reaction leading to the decomposition of the starting material was occurring. The decomposition products could be identified, when using a substrate bearing a larger substituent on the -position of the carbonyl, such as a n-butyl (35) or phenyl (38). Ketoaldehydes, 37 and 40 were obtained from 35 and 38 respectively (Scheme 7), and their formation accounts for the gap between the conversion of the starting material and isolated yield of the product. The boronic acids described in Figure 3 were also found to be inapplicable for the reaction with linear substrates. 137

14 Scheme 7: Side products due to decomposition of starting material. 5.4 Summary and conclusions This study has resulted in the development of a simple catalyst system for the Pdcatalyzed conjugate addition of arylboronic acids to β,β-disubstituted enones resulting in the formation of quaternary centers. This procedure avoids the synthesis of preformed catalysts, arylboroxines or forcing conditions necessary for the extrusion of S 2. nly 1 mol% of Pd( 2 CCF 3 ) 2 along with 1.5 mol% of inexpensive 2,2 -bipyridine is necessary to achieve full conversion and good yields in the case of cyclic enones. 5, 6 and 7-membered rings were found to be amenable to the reaction, though 5-membered rings usually exhibited higher yields and shorter reaction times. Linear substrates bearing an allylic oxygen function were found to be good substrates for the reaction. A higher catalyst loading (5 mol%) of Pd( 2 CCF 3 ) 2, along with 20 mol% of KSbF 6 as an additive was needed in that case to obtain full conversion. Isolated yields for the products were mostly in the range of 70-80%, and the missing yield could be attributed to the formation of 138

15 Facile Construction of Benzylic Quaternary Centers via Pd catalysis a ketoaldehyde side product. The study also established limitations on the scope of arylboronic acids that currently can be employed in the reaction. Future research in this direction could focus on expanding the scope of linear substrates for conjugate addition, and suppression of side product formation. 139

16 5.5 Experimental General All experiments were carried out in flame dried or oven dried (150 o C) glassware, in an atmosphere of dinitrogen, unless specified otherwise, by standard Schlenk techniques. Schlenk tubes with screw caps, and equipped with a teflon-coated magnetic stir bar were flame dried under vacuum and allowed to return to rt prior to being charged with reactants. A manifold permitting switching between dinitrogen atmosphere and vacuum was used to control the atmosphere in the reaction vessel. Reaction temperature refers to the temperature of the oil bath. Flash chromatography was performed using Merck silica gel type 9385 ( mesh), using the indicated solvents. All solvents used for filtration and chromatography were of commercial grade, and used without further purification. Anhydrous methanol, and acetonitrile were sourced from Sigma-Aldrich or Acros and stored under dinitrogen. TLC was performed on Merck silica gel 60, 0.25 mm plates and visualization was done by UV and staining with Seebach s reagent (a mixture of phosphomolybdic acid (25 g), cerium (IV) sulfate (7.5 g), H 2 (500 ml) and H 2 S 4 (25 ml)) or Vanillin stain (a mixture of vanillin (6g), conc. sulphuric acid (1.5 ml) and ethanol (95 ml)) or KMn 4 stain. 1 H- and 13 C-NMR were recorded on a Varian AMX400 (400, MHz, respectively) using CDCl 3 as solvent, unless specified otherwise. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl 3 : 7.27 for 1 H, 77.1 for 13 C). Data are reported as follows: chemical shifts (), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants J (Hz), and integration. GC-MS measurements were made using a HP 6890 Series Gas Chromatograph system equipped with a HP 5973 Mass Sensitive Detector. GC measurements were made using a Shimadzu GC 2014 gas chromatograph system bearing a AT5 column (Grace Alltech) and FID detection. Whenever GC conversion is reported, the quantification was done using cyclo-octane as internal standard. High 140

17 Facile Construction of Benzylic Quaternary Centers via Pd catalysis Resolution Mass Spectrometry was performed using a ThermoScientific LTQ ribitrap XL spectrometer. Synthesis of starting materials: The synthesis of 26 and 31 has been described in Chapter 3 (Section 3.5). The substrates 12, 40 28, 41 and were synthesized according to literature procedures General procedure for the conjugate addition of arylboronic acids to β,β-disubstituted enones Method A: Conjugate addition to cyclic enones To a Schlenk tube equipped with a magnetic stirring bar and a septum was added palladium trifluoroacetate (3.3 mg, 1 mol%, 0.01 mmol), and 2,2 -bipyridine (2.34 mg, 1.5 mol%, mmol). The Schlenk tube was capped and alternated through 3 cycles of vacuum and dinitrogen. The mixture was dissolved in 2 ml of a solution of MeH : H 2 (9:1) and the tube was placed in a pre-heated oil bath at 60 o C and allowed to stir for 15 min. The tube was removed from the oil bath, cooled to room temperature, followed by the addition of the enone (1 mmol, 1.0 equiv) via syringe or pipette and the boronic acid (2 mmol, 2 equiv), in one portion. The septum was replaced with a screw cap. Upon complete consumption of the enone (monitored by TLC / GC), the reaction mixture was allowed to cool to rt and filtered through a pad of silica. The filtrate was dried over MgS 4, concentrated in vacuo and adsorbed onto silica before being loaded on a silica-gel column. Elution with a mixture of n-pentane: ether afforded the corresponding product. Method B: Conjugate addition to acyclic (linear) enones To a Schlenk tube equipped with a magnetic stirring bar and a septum was added palladium trifluoroacetate (8.3 mg, 5 mol%, 0.05 mmol), 2,2 -bipyridine (11 mg, 7 mol%,) and KSbF 6 (27.5 mg, 20 mol%, 0.2 equiv). The Schlenk tube was capped and alternated through 3 cycles of vacuum and dinitrogen. The mixture was dissolved in 2 ml of a solution of MeH : H 2 (9:1). The Schlenk was placed in a pre-heated oil bath at 80 o C and allowed to stir for 15 min. The tube was removed from the oil bath, cooled to room temperature, followed by the addition of the enone (0.5 mmol, 1.0 equiv) via syringe or pipette and the boronic acid (1 mmol, 2 141

18 equiv), in one portion. The septum was replaced with a screw cap. Upon complete consumption of the enone (monitored by TLC / GC), the reaction mixture was allowed to cool to rt and filtered through a pad of silica. The filtrate was dried over MgS 4, concentrated in vacuo and adsorbed onto silica before being loaded on a silica-gel column. Elution with a mixture of n-pentane: ether afforded the corresponding product Characterization of synthesized compounds 3-Methyl-3-phenylcyclohexanone (3): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and phenylboronic acid (243 mg, 2.0 mmol.), and purified by flash chromatography (n-pentane : Et 2 = 4:1) to afford 3 (174 mg, 92%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 5H) 2.84 (d, J = 14.2 Hz, 1H), 2.39 (d, J = 14.2 Hz, 1H), 2.27 (t, J = 6.8 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), 1.28 (s, 3H). 13 C- NMR (101 MHz, CDCl 3 ) 211.4, 147.4, 128.5, 126.2, 125.6,, 53.1, 42.8, 40.8, 37.9, 29.8, HRMS (ESI+): Calculated for C 13 H 17 [M+H] + : , found [M+H] + : Characterization matches literature. 32,43 3-Methyl-3-(4-tolyl)cyclohexanone (3b): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and p-tolylboronic acid (272 mg, 2.0 mmol,), and purified by flash chromatography (n-pentane : Et 2 = 4:1) to afford 3b (190 mg, 94%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.23 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 2.88 (d, J = 14.1 Hz, 1H), 2.43 (d, J = 14.1 Hz, 1H), 2.33 (s, 3H), (m, 2H), (m, 2H), (m, 2H), 1.32 (s, 3H); 13 C-NMR (101 MHz, CDCl 3 ) 211.5, 147.5, 128.6, 126.2, 125.6, 53.1, 42.9, 40.8, 38.0, 29.8, 22.0, 20.8., HRMS (ESI+): Calculated for C 14 H 19 [M+H] + : , found: Characterization matches literature Methyl-3-(3-tolyl)cyclohexanone(3c): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and m-tolylboronic acid (272 mg, 2.0 mmol), and purified by flash chromatography (n- 142

19 Facile Construction of Benzylic Quaternary Centers via Pd catalysis pentane : Et 2 = 4:1) to afford 3c (182 mg, 90%), as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.22 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 2.88 (d, J = 14.2 Hz, 1H), 2.43 (d, J = 14.2 Hz, 1H), 2.36 (s, 3H), 2.32 (t, J = 6.8 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), 1.32 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 211.5, 147.5, 137.9, 128.4, 126.9, 126.3, 122.6, 53.1, 42.7, 40.8, 37.9, 29.7, 22.0, HRMS (ESI+): Calculated for C 14 H 19 [M+H] + : , found: Characterization matches literature (4-Fluorophenyl)-3-methylcyclohexanone (3d): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and 4-fluorophenylboronic acid (280 mg, 2.0 mmol), and purified by flash chromatography (n-pentane : Et 2 = 4:1) to afford 3d (145 mg, 70%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 2H), (m, 2H), 2.85 (d, J = 14.2, 1H), 2.44 (d, J = 14.2 Hz, 1H), 2.32 (t, J = 6.7 Hz, 2H) (m, 1H), (m, 2H), (m, 1H), 1.32 (s, 3H). HRMS (ESI+): Calculated for C 13 H 15 FNa [M+Na] + : , found: Characterization matches literature. 32,43 3-(4-Methoxyphenyl)-3-methylcyclohexanone (3e): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and 4-methoxyphenylboronic acid (304 mg, 2.0 mmol), and purified by flash chromatography (n-pentane: Et 2 = 5:1) to afford 3e (157mg, 72%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 7.24 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 2.85 (d, J = 14.2 Hz, 1H), 2.42 (d, J = 14.2 Hz, 1H), 2.30 (t, J = 6.7 Hz, 2H), (m, 1H), (m, 2H), (m,1h), 1.30 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 211.7, 157.7, 139.4, 126.7, 113.8, 55.2, 53.3, 42.3, 40.8, 38.1, 30.1, HRMS (ESI+): calculated for C 14 H 18 2 Na [M+Na]: , found: Characterization matches literature (3-Ethoxyphenyl)-3-methylcyclohexanone (3f): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, F

20 mmol) and 3-ethoxyphenylboronic acid (332 mg, 2.0 mmol), and purified by flash chromatography (n-pentane : Et 2 = 6:1) to afford 3f (198 mg, 85%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 7.21 (t, J = 8.1 Hz, 1H), 6.87 (d, J = 7.7 Hz, 2H), 7.03 (d, J = 8.1 Hz, 1H), 4.0 (q, J = 6.9 Hz, 2H), 2.85 (d, J = 14.2 Hz, 1H), 2.41 (d, J = 14.2 Hz, 1H), 2.30 (t, J = 10.6 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), 1.40 (t, J = 6.7 Hz, 3H) 1.38 (s, 3H), 13 C-NMR (101 MHz, CDCl 3 ) 211.5, 159.1, 149.3, 129.5, 118.0, 112.8, 111.5, 63.4, 53.2, 42.9, 40.9, 38.0, HRMS (ESI+): Calculated for C 15 H 21 2 [M+H] + : , found: (3-Chloro-4-methoxyphenyl)-3-methylcyclohexanone (3g): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and 3-chloro-4-methoxyphenylboronic acid (373 mg, 2.0 mmol) and purified by flash chromatography (n-pentane : Et 2 = 6:1) to afford 3g (240 mg, 95%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.35 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 2.5, 8.6 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H), 2.83 (d, J = 14.1 Hz, 1H), 2.43 (d, J = 14.1 Hz, 1H), 2.33 (t, J = 6.7 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), 1.31 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 13 C-NMR (101 MHz, CDCl 3 ) 210.9, 153.1, 140.6, 127.6, 124.9, 122.3, 111.8, 56.1, 52.9, 42.2, 40.6, 37.8, 29.8, HRMS (ESI+): Calculated for C 14 H 18 Cl + 2 [M+H] + : , found: (3-Chlorophenyl)-3-methylcyclohexanone (3h): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclohexen-1-one (110 μl, 1.0 mmol) and 3-chlorophenylboronic acid (313 mg, 2.0 mmol), and purified by flash chromatography (n-pentane: Et 2 = 6:1) to afford 3h (200 mg, 90%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 8.61 (s, 1H), (m, 1H), (m, J = 7.4 Hz, 2H), 4.14 (d, J = 14.1 Hz, 1H), 3.75 (d, J = 14.3 Hz, 1H), 3.63 (t, J = 6.6 Hz, 2H), Cl Cl (m, 1H), (m, 2H), (m, 1H), 2.62 (s, 3H). 13 C- NMR (101 MHz, CDCl 3 ) 210.7, 149.6, 129.8, 126.4, 125.9, 123.8, 52.9, 42.8, 144

21 Facile Construction of Benzylic Quaternary Centers via Pd catalysis 40.7, 37.7, 29.5, 21.9, HRMS (ESI+): Calculated for C 13 H 16 Cl [M+H] + : , found: Methyl-3-phenylcyclopentanone (14a): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclopenten-1-one (107 μl, 1.0 mmol) and phenylboronic acid (243 mg, 2.0 mmol), and purified by flash chromatography (n-pentane: Et 2 = 6:1) to afford 14a (165 mg, 95%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 5H), 2.61 (d, J = 17.6 Hz, 1H), 2.43 (d, J = 17.6 Hz, 1H), (m, 2H), (m, 2H),1.34 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 218.5, 148.5, 128.5, 126.3, 125.4, 52.2, 43.8, 36.7, 35.8, HRMS (ESI+): Calculated mass for C 12 H 14 Na [M+Na]: , found: Characterization matches literature. 32,43 3-Methyl-3-(4-tolyl)cyclopentanone (14b): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclopenten-1-one (107 μl, 1.0 mmol) and p-tolylboronic acid (272 mg, 2.0 mmol), and purified by flash chromatography (n-pentane : Et 2 = 6:1) to afford 14b (180 mg, 96%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 7.19 (dd, apparent q, J = 8.7 Hz, 4H), 2.66 (d, J = 17.8 Hz, 1H), 2.47 (d, J = 17.8 Hz, 1H) (m, 2H), 2.36 (s, 3H), (m, 2H), 1.40 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 218.4, 145.4, 135.7, 129.1, 125.3, 52.3, 43.4, 36.7, 35.8, 29.3, HRMS (ESI+): calculated mass C 13 H 16 Na [M+Na] + : , found: Methyl-3-(4-tolyl)cyclopentanone (14c): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclopenten-1-one (107 μl, 1.0 mmol)and m-tolylboronic acid (272 mg, 2.0 mmol). The reaction mixture was purified by flash column chromatography (pentane : ether 6:1) to yield product 14c (174 mg, 93%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 1H), 7.02 (d, J = 6.5 Hz, 2H), 6.98 (d, J = 7.5 Hz, 1H), 2.58 (d, J = 17.6 Hz, 1H), 2.38 (d, J = 17.6 Hz, 1H), (m, 1H), 2.29 (s, 3H), (m, 3H), 1.30 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 218.7, 148.4, 138.1, 128.4, 127.0, 126.2, 122.4, 52.3, 43.7, 36.7, 145

22 35.8, 29.4, HRMS (ESI+): calculated mass C 13 H 17 [M+H] + : , found: Methyl-3-(4-fluorophenyl)cyclopentanone (14d): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclopenten-1-one (107 μl, 1.0 mmol) and p-fluorophenylboronic acid (280 mg, 2.0 mmol). The reaction mixture was purified by flash column chromatography (n-pentane : ether 6:1) to yield product 14d (170 mg, 88%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) 7.18 (dd, J = 7.8 Hz, 2H), 6.95 (t, J = 8.5 Hz, 2H), 2.54 (d, J = 17.6 Hz, 1H), 2.40 (d, J = 17.6 Hz, 1H), (m, 2H), (m, 2H), 1.30 (s, 3H). HRMS (ESI+): calculated mass C 12 H 14 F [M+H] + : , found: Methyl-3-(4-methoxyphenyl)cyclopentanone (14e): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclopenten-1-one (107 μl, 1.0 mmol), and 4-methoxyphenylboronic acid (304 mg, 2.0 mmol). The reaction mixture was purified by flash column chromatography (n-pentane : ether 6:1) to yield product 14e (170 mg, 88%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.14 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.73 (s, 3H), 2.56 (d, J = 17.6 Hz, 1H), 2.37 (d, J = 17.6 Hz, 1H), (m, 2H) (m, 2H),1.30 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 218.8, 157.9, 140.5, 126.4, 113.8, 55.3, 52.5, 43.2, 36.8, 36.0, HRMS (ESI+): calculated mass C 13 H 17 2 [M+H] + : , found: Methyl-3-(3-ethoxyphenyl)cyclopentanone (14f): Synthesized according to the general procedure (Method A) from 3-methyl-2-cyclopenten-1- one (107 μl, 1.0 mmol), and 3-ethoxyphenylboronic acid (332 mg, 2.0 mmol). The reaction mixture was purified by flash chromatography (n-pentane : ether 6:1) to yield product 14f (203 mg, 93%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.18 (t, J = 9.8 Hz, 1H), 6.79 (d, J = 7.7 Hz, 1H), 6.76 (t, J = 2.1 Hz, 1H), 6.69 (dd, J = 8.1, 2.2 Hz, 1H), 3.97 (q, J = 7.0 Hz, 2H), 2.57 (d, J = 17.7 Hz, 1H), 2.39 (d, J = 17.7 Hz, 1H,), (m, 2H), (m, 2H), 1.35 (t, J = 6.9 Hz, 3H), 1.30 (s, 3 H). 13 C-NMR 146 F

23 Facile Construction of Benzylic Quaternary Centers via Pd catalysis (101 MHz, CDCl 3 ) 218.5, 159.0, 150.2, 129.5, 117.7, 112.8, 111.3, 63.4, 52.2, 43.8, 36.7, 35.7, 29.3, 14.8 HRMS (ESI+): calculated mass C 14 H 19 2 [M+H] + : , found: Methyl-3-(4-benzyloxyphenyl)cyclopentanone (14g): Synthesized according to the general procedure (Method A) from 3-methyl-2- cyclopenten-1-one (107 μl, 1.0 mmol) and 4- (benzyloxy)phenylboronic acid (456 mg, 2.0 mmol), and purified by flash chromatography (n-pentane: Et 2 = 6:1) to afford 14g (252 mg, 90%), as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 5H), 7.22 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.07 (s, 2H), 2.64 (d, J = 18.0 Hz, 1H), 2.45 (d, J = 18.0 Hz, 1H), (m, 1H), (m, 2H), 2.19 (d, J = 1.0 Hz, 1H), 1.38 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 218.7, 157.2, 140.8, 137.0, 128.6, 127.9, 127.4, 126.5, 114.8, 70.0, 52.5, 43.2, 36.8, 36.0, HRMS (ESI+): Calculated mass C 19 H 21 2 [M+H] + : , found: Methyl-3-phenylcycloheptanone (15a): Synthesized according to the general procedure (Method A) from 3-methyl-2-cycloheptenone-1-one (1.0 mmol, 1.0 eq) and phenylboronic acid (243 mg, 2.0 mmol, 2.0 eq.) and purified by flash chromatography (n-pentane: Et 2 = 6:1) to afford 15a (162 mg, 80%). 1 H-NMR (400 MHz, CDCl 3 ) 7.32 (d, J = 4.3 Hz, 4H), (m, 1H), 3.20 (d, J = 14.4 Hz, 1H), 2.71 (d, J = 14.4 Hz, 1H), (m, 2H), (m, 1H), (m, 5H), 1.27 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) 213.8, 147.9, 128.6, 126.0, 125.6, 55.7, 44.2, 43.5, 39.8, 31.9, 25.8, 23.9.; HRMS (ESI+): calculated mass [M+Na] , found: Characterization matches literature. 18,43 5-(Tert-butoxy)-4-methyl-4-phenylpentan-2-one (27): Synthesized according to the general procedure (Method B) from (E)-5-(tert-butoxy)-4- methylpent-3-en-2-one (0.5 mmol,85 mg) and phenylboronic acid (1 mmol, 122 mg), and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 27 (90 mg, 72%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 2H), (m, 147

24 2H), (m, 1H), 3.52 (d, J = 8.5 Hz, 1H), 3.36 (d, J = 8.5 Hz, 1H), 2.92 (d, J = 15.5 Hz, 1H), 2.87 (d, J = 15.5 Hz, 1H), 1.92 (s, 3H), 1.44 (s, 3H), 1.15 (s, 9H). 13 C-NMR (101 MHz, CDCl 3 ) 208.3, 146.0, , , 126.3, 126.1, 72.7, 69.6, 51.6, 41.3, 31.8, 27.4, HRMS (ESI+): Calculated Mass for C 16 H 25 2 [M+H] + : , found: 249: (Tert-butoxy)-4-methyl-4-(m-tolyl)pentan-2-one (27b): Synthesized according to the general procedure (Method B) from (E)-5-(tert-butoxy)-4-methylpent-3-en-2- one (0.5 mmol, 85 mg) and m-tolylboronic acid (1 mmol, 136 mg), and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 27b (98 mg, 75%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 3H), (m, 1H), 3.43 (d, J = 8.5 Hz, 2H), 3.25 (d, J = 8.5 Hz, 2H), 2.28 (s, 3H),1.84 (s, 3H), 1.35 (s, 3H),1.07 (s, 9H). 13 C-NMR (101 MHz, CDCl 3 ) 208.4, 145.9, 137.4, 127.9, 127.0, 126.8, 123.2, 72.6, 69.6, 51.6, 41.2, 31.8, 27.4, 23.4, HRMS (ESI+): Calculated Mass for C 13 H 17 [M-tBu] + : , found: (Tert-butoxy)-4-(4-methoxyphenyl)-4-methylpentan-2-one (27d): Synthesized according to the general procedure (Method B) from (E)-5- (tert-butoxy)-4-methylpent-3-en-2-one (0.5 mmol, 85 mg) and 4-methoxyphenylboronic acid (1 mmol, 152 mg) and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 27d (101 mg, 72%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.30 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H), 3.46 (d, J = 8.5 Hz, 1H), 3.30 (d, J = 8.5 Hz, 1H), 2.84 (q, J = 15.3 Hz, 2H), 1.90 (s, 3H), 1.40 (s, 3H), 1.13 (s, 9H). 13 C-NMR (101 MHz, CDCl 3 ) 208.5, 157.7, 137.9, 127.3, 113.4, 72.6, 69.8, 55.1, 51.8, 40.7, 31.8, 27.4, HRMS (ESI+): Calculated Mass for C 13 H 17 2 [M-tBu] + : , found: (Benzo[d][1,3]dioxol-5-yl)-5-(tert-butoxy)-4-methylpentan-2-one (27e): Synthesized according to the general procedure (Method B) from (E)-5-(tertbutoxy)-4-methylpent-3-en-2-one (0.5 mmol, 85 mg) and 3,4- (methylenedioxy)phenylboronic acid (1 mmol, 166 mg) and purified by flash 148

25 Facile Construction of Benzylic Quaternary Centers via Pd catalysis chromatography (n-pentane: Et 2 = 20:1) to afford 27e (101 mg, 70%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 6.92 (s, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 5.93 (s, 2H), 3.42 (d, J = 8.5 Hz, 1H), 3.29 (d, J = 8.5 Hz, 1H), 2.82 (q, J = 15.6 Hz, 2H), 1.93 (s, 3H), 1.38 (s, 3H), 1.13 (s, 9H). 13 C-NMR (101 MHz, CDCl 3 ) 208.1, 147.4, , 140.0, 119.2, 107.7, 107.2, 100.8, 72.7, 69.8, 51.8, 41.1, 31.8, 27.4, HRMS (ESI+): Calculated Mass for C 13 H 15 3 [M-tBu] + : , found: (Tert-butoxy)-4-(3-chloro-4-isopropoxyphenyl)-4-methylpentan-2-one (27f): Synthesized according to the general procedure (Method B) from (E)-5-(tert-butoxy)-4-methylpent-3-en-2-one (0.5 mmol, 85 mg) and 3-chloro-4-isopropoxyphenylboronic acid (1 mmol, 166 mg) and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 27f (133 mg, 78%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) = 7.38 (s, 1H), 7.18 (d, J = 8.7 Hz,1H), 6.87 (d, J = 8.7 Hz, 1H), (m, 1H), 3.40 (d, J = 8.5 Hz, 1H), 3.31 (d, J = 8.5 Hz, 1H), 2.83 (q, J = 15.7 Hz, 2H), 1.95 (s, 3H), 1.38 (s, 3H), 1.36 (d, J = 6.1 Hz, 6H), 1.13 (s, 9H). 13 C-NMR (101 MHz, CDCl 3 ) 207.9, 151.7, 139.5, 128.5, 125.4, 123.7, 115.5, 72.7, 72.1, 69.5, 51.4, 40.6, 31.8, 27.4, 23.3, 22.1, HRMS (ESI+): Calculated Mass for C 15 H 20 2 Cl [M-tBu] + : , found: (Tert-butoxy)-4-(3-ethoxyphenyl)-4-methylpentan-2-one (27g): Synthesized according to the general procedure (Method B) from (E)-5-(tert-butoxy)-4- methylpent-3-en-2-one (0.5 mmol, 85 mg) and 3- ethoxyphenylboronic acid (1 mmol, 166 mg) and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 27g (62 mg, 75%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 7.23 (t, J = 9.3 Hz, 1H), 6.97 (d, J = 6.8 Hz,1H), 6.95 (s, 1H), Cl 6.74 (d, J = 7.7 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.49 (d, J = 8.6 Hz, 1H), 3.33 (d, J = 8.5 Hz, 1H), 2.86 (s, 2H), 1.92 (s, 3H), (m, 6H), 1.14 (s, 9H). 13 C- NMR (101 MHz, CDCl 3 ) , 147.7, 128.9, 118.6, 113.6, 111.3, 72.6, 149

26 , , 23.4, HRMS (ESI+) Calculated Mass for C 14 H 19 2 [M-tBu] + : found: (Tert-butoxy)-4-(4-methoxy-3,5-dimethylphenyl)-4-methylpentan-2-one (27h): Synthesized according to the general procedure (Method B) from (E)-5-(tert-butoxy)-4-methylpent-3-en-2-one (0.5 mmol, 85 mg) and 3,5-dimethyl-4-methoxyphenylboronic acid (1 mmol, 180 mg) and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 27h (112 mg, 73%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) 6.99 (s, 2H), 3.70 (s, 3H), 3.46 (d, J = 8.6 Hz, 1H), 3.28 (d, J = 8.6 Hz, 1H), 2.83 (s, 2H), 2.27 (s, 6H), 1.92 (s, 3H), 1.38 (s, 3H), 1.14 (s, 9H). 13 C-NMR (101 MHz, CDCl 3 ) 208.5, 155.1, 141.1, 130.0, 126.6, 72.6, 69.61, 59.6, 51.6, 40. 8, 31.9, 27.4, 23.5, (Benzyloxy)-4-methyl-4-phenylpentan-2-one (32): Synthesized according to the general procedure (Method B) from (E) or (Z) 5-(benzyloxy)-4-methylpent-3- en-2-one (0.5 mmol, 102 mg) and phenylboronic acid (1 mmol, 122 mg) and purified by flash chromatography (npentane: ether = 20:1) to afford 32b (105 mg, 74%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) (m, 10H), 4.53 (s, 2H), 3.69 (d, J = 8.9 Hz, 1H), 3.61 (d, J = 8.9 Hz, 1H), 2.94 (q, J = 15.5 Hz, 2H), 1.93 (s, 3H), 1.52 (s, 3H). 13 C-NMR (101 MHz, CDCl 3 ) 207.7, 145.3, 138.4, 128.3, 128.2, 127.5, 127.4, 126.3, 126.1, 78.0, 73.2, 51.5, 41.7, 31.8, HRMS (ESI+): calculated mass [M+Na] + : , found: (Benzyloxy)-4-methyl-4-(m-tolyl)pentan-2-one (32b): Synthesized according to the general procedure (Method B) from (E)-5- (benzyloxy)-4-methylpent-3-en-2-one(0.5 mmol,102 mg) and m-tolylboronic acid (1 mmol, 136 mg) and purified by flash chromatography (n-pentane: Et 2 = 20:1) to afford 32b (127 mg, 90%) as a colorless oil. 1 H-NMR (400 MHz, CDCl 3 ) = (m, 9H), 4.42 (s, 2H), 3.57 (d, J = 8.9 Hz, 1H), 3.48 (d, J = 8.9 Hz, 1H), 2.82 (q, J = 15.4 Hz, 2H), 2.26 (s, 3H), 1.82 (s, 3H), 1.39 (s, 3H). 13 C-NMR (50 MHz, CDCl 3 ) : 208.0, 145.3, 138.5, 137.7, 128.4, 128.2, 127.6, 127.5, 127.1, 126.9, 123.2, 78.1, 150

27 Facile Construction of Benzylic Quaternary Centers via Pd catalysis 73.3, 51.7, 41.7, 31.9, 23.6, HRMS (ESI+): calculated mass [M+H] + : , found: Characterization data for compounds is found in the experimental section of Chapter

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