University of Groningen Carbon-carbon bond formations using organolithium reagents Heijnen, Dorus

University of Groningen

Carbon-carbon bond formations using organolithium reagents

Heijnen, Dorus

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Chapter 7 : Oxygen Activated, Palladium

Nanoparticle Catalyzed, Ultrafast Cross-Coupling

of Organolithium Reagents and its Application in

Nuclear Medicine

Part of this chapter was published in : D. Heijnen, F. Tosi, C. Vila, M. C. A. Stuart,

P. H. Elsinga, W. Szymanski and B. L. Feringa. Angew.Chem. Int. Ed. 2017, 56,

3354-3359

Abstract : The discovery of an ultrafast cross-coupling of alkyl- and aryllithium reagents with a range of aryl bromides is described in this chapter. The essential role of molecular oxygen to form the active palladium catalyst was established; palladium nanoparticles that are highly active in cross-coupling reactions with reaction times ranging from 5 s to 5 min are thus generated in situ. High selectivities were observed for a range of heterocycles and functional groups as well as for an expanded scope of organolithium reagents. The applicability of this method was showcased by the synthesis of the [11C]-labeled PET tracer Celecoxib.

7.1 Introduction

Transition-metal-catalyzed cross-couplings of organometallic reagents have found

widespread application in the synthesis of pharmaceutical products and organic materials,

including the formation of important functionalized heterocycles.

Despite their prominent

role in the modern synthetic repertoire, it remains of considerable interest to shorten

reaction times, apply milder conditions, use less expensive starting materials, reduce catalyst

loadings and trace residual metals in the desired product, and to minimize the amount of

toxic waste. We have recently reported the direct cross-coupling of alkyl-, alkenyl-, and

aryllithium reagents with a wide range of (pseudo)halogenated aryl and alkenyl electrophiles

catalyzed by either palladium or nickel complexes.

These organolithium-based methods

typically show cross-coupling with enhanced speed (<1h), operate at mild temperatures (in

most cases room temperature), and produce lighter and less toxic stoichiometric waste (LiX).

Reactions with excellent chemoselectivity were initially achieved by slow addition of the

highly reactive lithium reagent.

Typically, commercially available unaltered complexes

were employed, including Pd/PEPPSI, Pd(PtBu

)

(C1), or Pd/dba/XPhos, which are also

prominent catalysts in closely related transformations, such as Negishi or Suzuki

cross-coupling reactions.

We envisioned that the exceptional reactivity and versatility of organolithium

reagents could be taken advantage of in developing a fast cross-coupling that proceeds

under ambient conditions, especially in light of the major current interest and important

advances in fast cross-coupling reactions under mild conditions.

To the best of our

knowledge, the very recently published procedure by the group of Schoenebeck, based on

the use of Grignard and organozinc reagents (Figure 7.1) stands out in terms of short

reaction times.

Figure 7.110 Recent fast cross-coupling reactions

Herein, we present the discovery of an ultrafast cross-coupling with organolithium reagents.

In stark contrast to the common practice of rigorously excluding oxygen when working with

such extremely reactive organometallic reagents, we have found that molecular oxygen is

essential to form the active catalyst. Under our conditions, rapid C-C bond formation occurs

within seconds to minutes at room temperature while catalyst speciation studies point to

the involvement of 2-3 nm large Pd nanoparticles. Using this new procedure, chemoselective

cross-coupling reactions with organolithium reagents now include an expanded range of

heterocycles, functional groups, and organolithium compounds. Furthermore, it provides a

versatile method for isotope labeling, that is, for introducing -CD

labels and short-lived

C

radioisotopes (t

(

C)=20.3min) for PET imaging.

7.2 Oxygen activation

In preliminary experiments, we used the cross-coupling of methyllithium and

1-bromonaphthalene in the presence of Pd(PtBu

)

(C1

,

5 mol %) at room temperature to test

whether very short reaction times with full conversion would be possible (Scheme 7.1)

Under presumably identical conditions, we were puzzled to observe greatly varying results.

Scheme 7.1 Optimization of fast cross-coupling

After eliminating many potential causes (variations in the concentration of the reagents,

light, temperature, the presence of salts, water, or trace metal impurities), we established

that minute traces of air were essential for catalyst activation. Samples briefly purged with

dry oxygen prior to MeLi addition always gave complete and chemoselective conversion into

1-methylnaphthalene. The lack of reactivity observed after adding degassed water or when

employing strictly oxygen-free conditions supported the notion that the presence of oxygen

greatly enhanced the catalytic activity of the system, leading to optimized reaction

conditions with catalyst C1 after short oxygen purging, and allowing for catalyst oxidation for

10 min.

7.3 Scope

Under the optimized conditions, an extended range of organolithium and aryl bromide

reagents, compared to our previously reported method,

underwent highly selective

coupling, providing excellent yields in 2-5 min at room temperature (Table 7.1). Substrates

from the naphthalene (2a-3f) and anthracene families (4a) gave good yields with

near-perfect selectivity when coupled with a variety of commercially available organolithium

reagents.

Gratifyingly, identical results were achieved with both electron-poor and electron-rich

substrates (5a-8a). Unwanted side reactions were suppressed with near-perfect selectivity

for C-Br over C-Cl in aromatic and aliphatic substrates with competitive coupling possibilities

(9a-11a), while aryl bromides 12a-15a, including CF

-substituted analogue 16a, gave

selectivities similar to those of the naphthalene substrates.

Remarkably, the fast coupling

of RLi can even be used when an epoxide functional group is present at a temperature as

low as -10°C, where the expected epoxide ring opening by the organolithium reagent is

effectively suppressed, to provide the desired coupling product 17a. Importantly, alcohols

18a-20a, including an unprotected phenol, provided the corresponding products in good

yields, albeit with a larger excess of organolithium reagent. Novel substrates were also found

amongst heterocycles 21a-26a.

The direct lithiation of inexpensive, commercially available ferrocene is well described in the

literature,

and the corresponding nucleophile provides an alternative to the less available

and costly boron or halide derivatives to yield 27a and 28a. Finally, aryllithium reagents

synthesized via lithium--halogen exchange (e.g., 3-anisyllithium) also proved to be suitable

coupling partners, providing biaryl 29a.

Table 7.1 Fast cross-coupling of (hetero)aryl bromides with organolithium reagents.

Reaction conditions: Substrate : 0.6 mmol in 4 ml toluene, 5 mol% catalyst, 4 ml oxygen, 1.5 eq (0.9 mmol) organolithium reagent. All reactions were carried out at rt. Yields refer to isolated yields after column chromatography unless noted otherwise. a) Reaction performed at 0 °C; b) Performed with 2.5 eq of organolithium at 40 °C; c) Conversion determined by GCMS analysis; d) Reaction performed with 1 eq of n-BuLi at -10 °C; e) Reaction performed with 2.5 eq of organolithium reagent.

The reaction time of the coupling between nBuLi and 1-bromonaphthalene could be reduced

to just 5s at room temperature with 5 mol% of the precatalyst, giving full conversion and a

turnover frequency of 14×10

h

(Table 7.2 entry 1), provided that an excess of oxygen was

present with respect to Pd complex C1. With a catalyst loading of 0.05 %, we were able to

fully convert 1 on gram scale in just 10 min. On the other hand, by reducing the rate of

addition of nBuLi, we were able to use a catalyst loading as low as 0.025 mol % (entry 2-5). A

slightly higher catalyst loading was necessary for the coupling of 4-bromoanisole (entry 6).

Table 7.2 Screening of catalyst loading

Entry C1 (mol%) Addition time Conv.

1 5 5 sec Full 2 0.5 2 min Full 3 0.05 10 min Full 4 0.025 10 min 40 5 0.025 30 min Full 6 0.05a 30 min Full

All experiments were conducted at rt in toluene (0.15 M initial concentration of the substrate), entries 1 and 2 were conducted on 0.3 mmol scale, entries 3-6 on a 12 mmol (2.5 g) scale. Conversions were determined by GCMS analysis. a) 4-Br-anisole was used as substrate.

7.4 Active catalyst investigation

Focusing on the crucial role of molecular oxygen, we observed that the catalyst solution

turned red upon purging with O

, suggesting that Pd(PtBu

)

(C1) was converted into the

active catalyst. Many d

metal complexes are known to rapidly interact with O

to form

stable η

-peroxo complexes; however, C1 has not been reported as one of them.

The

reason for its stability towards O

was attributed to the extreme bulkiness of the ligands,

which shield the Pd and hence hamper its oxidation. Therefore, the sterically hindered C1

complex needs prolonged oxygen exposure at room temperature to ensure complete

oxidation. To investigate whether known peroxo complexes could be excluded as possible

catalysts, we tested the η

-peroxo derivatives of Pd(PCy

)

and Pd(PPh

)

,

which did not

show any catalytic activity (see the experimental section). Extensive

H and

PNMR studies

with catalytically inactive C1 prior to and after exposure to oxygen revealed the formation of

free PtBu

(see Experimental Section), phosphine oxides, and (yet unidentified) oxidized Pd

The hypothesis that the monoligated [Pd(PtBu

)] complex, arising from dissociation of one

phosphine from the starting complex, acted as the active catalyst was excluded on the basis

of the lack of reactivity with aryl chlorides and inhibition experiments by adding an excess of

PtBu

(up to 10 equiv, see Experimental Section), which had no effect on the outcome of the

cross-coupling, suggesting a different active species.

We were able to isolate the oxidized form (C1

) of C1 by washing the residue of the

oxidation step with acetonitrile (see Experimental Section). Addition of 4-bromoanisole to

C1

at room temperature showed no change at all by NMR analysis, which led to the

conclusion that up until the addition of the organolithium reagent, no reaction is taking

place.

Given the fast cross-coupling and the lack of any reaction between C1 or C1

and

the electrophile, we next tested whether the organolithium reagent initiates the catalytic

cycle by generation of the active Pd species. Upon stoichiometric addition of nBuLi to a

[D

]toluene solution of C1

, some of the Pd species were reduced to form again catalytically

inactive C1, and stoichiometry indicates the formation of another Pd

species, presumably

the active catalyst (see below). Important information came from independent experiments

with the bridged dinuclear Pd

complex C2 (Scheme 7.1), which is also a catalyst precursor in

our cross-coupling. Oxidation of C2 occurs within seconds at room temperature, although we

found that the product C2

arising from this reaction was not consistent with the one

described in the literature (see the Supporting Information).

Both C2 and C2

gave full

conversion in cross-couplings with RLi reagents. The oxidation of C2 and subsequent

reduction of C2

by nBuLi was studied in detail by

P NMR spectroscopy (Figure 7.2),

showing, much to our surprise, partial formation of mononuclear complex C1, which we

knew to be catalytically inactive.

Figure 7.2 31P-NMR Spectra of C2 in tol-d8 (a), after O2 exposure (b,c), and n-BuLi addition (d)

The lithium reagent promotes reduction from Pd

to Pd

and the formation of both

Pd(PtBu

)

(C1) and Pd

, which becomes evident from the observed stoichiometry (NMR

Scheme 7.2 Reduction of C2 with R-Li

Following the cross-coupling reaction of 4-bromoanisole by NMR spectroscopy, we also

observed the in situ formation of the bridged complex C2 from C1

after RLi addition (in

accordance with previous observations by Schoenebeck using Grignard reagents),

for

which we suggest the stoichiometry shown in Scheme 7.3.

Scheme 7.3 Schematic in situ formation of C2 from C1ox

The combined results of the RLi addition experiments with C1

, C2, and C2

, which clearly

showed reduction in all cases, led to the hypothesis that a common active species, that is, Pd

nanoparticles (PdNPs), are formed in situ. TEM measurements were carried out to

investigate the presence of nanoparticles in samples of C1 and C1

prior to RLi addition, but

in neither case, any PdNPs were observed. Studying the effect of the addition of the lithium

reagent to C1

, we clearly observed PdNPs with dimensions of 2—3 nm (Figure 7.3).

Figure 7.3 TEM image and corresponding EDX spectrum of PdNPs

In a highly informative set of experiments, under optimized cross-coupling conditions and

with all previously mentioned precatalysts (C1

, C2, and C2

), samples were taken both

during and at the end of the reaction, and analyzed by TEM for the in situ formation of

nanoparticles (Figure 7.3). We were pleased to see the formation of nanoparticles in all

cases where product was formed. Energy-dispersive X-ray analysis (EDX)

revealed the

elemental compositions of the samples, and clearly showed an increase in the Pd/P ratio

with respect to catalytically inactive complexes, supporting the formation of PdNPs. Isolation

of these nanoparticles was successful by centrifugation and repeated washing with toluene,

and the absence of homogeneous Pd complexes was confirmed by

H and

P NMR

spectroscopy. Fast cross-coupling reactions of organolithium reagents with the isolated

nanoparticles were successful, strongly supporting the involvement of PdNPs as the active

catalyst.

Scheme 7.4 Proposed catalyst activation pathway

Based on the experimental data, the catalyst activation pathway shown in Scheme 7.4 is

proposed. PdNPs are known to be formed from Pd

sources under reductive conditions.

In

our system, O

reacts first with the Pd

complex, thereby oxidizing it to C1

(Scheme 7.4a)

organolithium reagent, either directly (b) or via C2/C2

. The striking difference of the novel

catalytic system presented here, compared to other PdNP-catalyzed cross-coupling

reactions,

is the ultrafast cross-coupling of organolithium reagents, which can be

explained by the in situ formation of numerous small (2-3 nm) Pd nanoparticles.

7.5 Application in the coupling of

C and the synthesis of Celecoxib

The benefits of the ultrafast coupling presented here can best be exploited in reactions

where time restrictions are crucial. Therefore, we focused on the cross-coupling of

[

C]methyllithium (t

(

C)=20 min) for PET labeling.

Such a method would be

complementary to the more often used electrophilic quenching of a nucleophilic drug

precursor with [

C]iodomethane. The presence of several nucleophilic sites in specific

precursors often results in undesired (overalkylated) side products. We selected the

synthesis of [

C]celecoxib to illustrate the usefulness of our method (Scheme 7.5).

Scheme 7.5 Synthesis of radiolabelled Celecoxib

Initially, we explored the reaction of commercially available MeLi and celecoxib precursor

30. Having isolated the target 31 in excellent yield (91 %), we used in situ generated MeLi,

prepared from MeI in both a stoichiometric and a substoichiometric (0.1 equiv) ratio with

respect to nBuLi.

Gratifyingly, we were able to isolate the corresponding product by

preparative HPLC in good yield (85 %) with respect to the MeI starting material.

With a representative result for the radiolabeling based on the use of substoichiometric MeI

in hand, the synthesis of [

C]celecoxib (31*; coupling time 2 min, total preparation time

including HPLC purification <15 min) was pursued. The final decay-corrected radiochemical

yield for 31* was found to be 65 % (average of three runs).

For further application in isotope labelling, we considered the direct incorporation of the

-CD

moiety in organic compounds. The use of deuterated MeI is desirable from a cost

perspective, and its use with a range of electrophiles has recently been shown by Hu et al.

Since the reported procedure requires a large excess of the costly CD

I (3.5 eq) we

anticipated that our method using in situ generated CD

Li could provide a viable alternative

(Scheme 7.6). As we had already converted unlabeled MeI into MeLi, as well as the [

C]-analogue using n-BuLi and successfully applied it in cross-coupling, an identical experimental

setup for CD

I was used. Much to our surprise, no CD

-incorporation could be observed in

either a cross-coupling reaction, or electrophilic quench with benzaldehyde.

Switching

to tBuLi gave the desired CD

Li, which coupled readily with 2-Br-naphthalene to provide

2a-d

in 65 % yield, establishing a new method for the incorporation of the -CD

moiety.

Scheme 7.6 Cross-coupling of MeLi-d3

7.6 Conclusions and outlook

In conclusion, a novel procedure for the rapid palladium-catalyzed coupling of alkyl-

and aryllithium reagents has been developed, with a crucial role for O

in generating the

active catalyst. Systematic studies towards the active catalyst species revealed the formation

of palladium nanoparticles for all three active precatalysts upon addition of the

organolithium reagent, which facilitates rapid cross-couplings with a range of aryl bromides

at room temperature. The application of this novel method was showcased in the coupling

of [

C]methyllithium in less than two minutes with a decay-corrected yield of 65 % as a key

step in the synthesis of the PET tracer celecoxib.

Acknowledgements

This work described in this chapter was carried out together with Filippo Tosi. Initial studies were peformed by Dr. Carlos Vila.

7.7 Experimental section

General methods:

All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques unless noted otherwise. THF and toluene were dried using an SPS-system. White colored Pd[P(tBu)3]2, was purchased from Strem chemicals and stored under nitrogen at -25 ºC. Pure [PdBrP(tBu)3]2 was purchased from Strem chemicals, used in a glovebox and stored at -35 ºC. All alkyllithium reagents and aryl bromides were purchased from Aldrich or TCI and used without further purification, unless noted otherwise.

Chromatography: Merck silica gel type 9385 230-400 mesh, TLC: Merck silica gel 60, 0.25 mm, or Grace-Reveleris purification system with Grace cartridges. Components were visualized by UV and cerium/molybdenum or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). PREP-HPLC was perfomed on a Grace-reveleris PREP with a 5 u Denali C-18 (15 cm, 10 mm id). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) or a 600 MHz (600 and 125 MHz, respectively) using CDCl3 as solvent, unless noted otherwise. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CHCl3:  7.26 for 1H,  77.0 for 13C) unless noted otherwise. Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration.

Samples for TEM and TEM were analized on graphene grids (Graphene Supermarket). For cryo-TEM analysis, the grids were vitrified in liquid nitrogen (Vitrobot, FEI, Eindhoven, The Netherlands) and transferred to a Tecnai T20 cryo-electron microscope operating at 200 kV. EDX analysis was performed with a EDX Oxford xmax instrument, and the elemental ratio was calculated via INCA software.

General Procedures for the oxygen activated cross-coupling of organolithium reagents with aryl bromides

Method A: General procedure for the cross-coupling with organolithium reagents.

In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of pure oxygen and stirred for 1 min, upon which the color changed from slightly yellow to dark orange. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 2.0 mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump After the addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was purified by column chromatography.

Method B: General procedure for the cross-coupling with organolithium reagents at lower temperature

In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of pure oxygen and stirred for 1 min at rt, upon which the color changed from slightly yellow to dark orange. Then, the reaction vessel was cooled to the corresponding temperature by means of an ice batch. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 2.0 mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump. After the addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to

the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was purified by column chromatography.

Method C: General procedure for the cross-coupling with alkyllithium reagents in the presence of acidic groups

In a dry Schlenk flask Pd(PtBu3)2 (5 mol%, 0.03 mmol, 15,3 mg) and the aryl bromide (0.6 mmol) were dissolved in 4 mL of dry toluene at room temperature. The mixture was slowly purged with 10 ml of pure oxygen and stirred for 1 min, upon which the color changed from slightly yellow to dark orange. The corresponding alkyl or aryllithium reagent (1.5 eq) was diluted with toluene to reach 4.0 mL; this solution was added over 2 min (alkyl) or 5 min (aryl) by the use of a syringe pump After the addition was completed, the reaction was quenched with 0.5 mL of MeOH, and Celite was added to the reaction mixture. The solvent was evaporated under reduced pressure to afford the crude product on Celite which was purified by column chromatography.

Method D: General procedure for the cross-coupling with alkyllithium reagents for large scale and low catalyst loading

In a dry Schlenk flask Pd(PtBu3)2 (0,025 - 5 mol%) and the aryl bromide (0.6 -12 mmol) were dissolved in dry toluene (4 – 80 ml) at room temperature. The mixture was slowly purged with 20 ml of pure oxygen and stirred overnight to ensure complete oxidation of the precatalyst, upon which the color changed from slightly yellow to (dark) orange. In view of safety, excess oxygen was removed from the headspace by 2-3 careful vacuum/nitrogen cycles for the large scale reactions. The corresponding commercial alkyllithium (1.5 eq.) reagent was diluted with toluene (2 - 25 ml); this solution was added by the use of a syringe pump (2 – 30 min). After the addition was completed, the reaction was quenched with MeOH, and conversion checked by GCMS analysis

Experimental data of compounds 2a-29a:

2-methylnaphthalene (2a): Synthesized according to Method A. [68 mg, 80% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.8 Hz, 1H), 7.80 (dd, J = 8.1, 4.1 Hz, 2H), 7.66 (s, 1H), 7.53-7.43 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H), 2.57 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 135.5, 133.7, 131.7, 128.1, 127.7, 127.6, 127.3, 126.9, 125.9, 124.5, 21.7 ppm. The physical data were identical in all respects to those previously reported. 1

2-phenylnaphthalene (2b): Synthesized according to Method A. [95 mg, 78% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 8.10 (s, 1H), 7.99 – 7.89 (m, 3H), 7.80 (td, J = 8.6, 8.1, 1.3 Hz, 3H), 7.59 – 7.50 (m, 4H), 7.47 – 7.40 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 141.25, 138.69, 133.82, 132.75, 128.98, 128.54, 128.33, 127.77, 127.56, 127.47, 126.41, 126.05, 125.93, 125.72. The physical data were identical in all respects to those previously reported. 2

2-butylnaphthalene (2c): Synthesized according to Method A. [101 mg, 91% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 7.97 – 7.83 (m, 3H), 7.71 (s, 1H), 7.61 – 7.47 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 2.88 (t, J = 7.7 Hz, 2H), 1.80 (p, J = 7.6 Hz, 2H), 1.61 – 1.37 (m, 2H), 1.07 (t, J = 8.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.15, 136.42, 134.70, 130.47, 130.34, 130.20, 130.15, 129.04, 128.54, 127.72, 38.57, 36.30, 25.17, 16.76. The physical data were identical in all respects to those previously reported. 1

2-(sec-butyl)naphthalene (2d): Synthesized according to Method A. [97 mg, 88% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 7.96 – 7.82 (m, 3H), 7.71 – 7.68 (m, 1H), 7.58 – 7.46 (m, 2H), 7.43 (dd, J = 8.5, 1.8 Hz, 1H), 2.85 (h, J = 7.0 Hz, 1H), 1.85 – 1.71 (m, 2H), 1.42 (d, J = 7.0 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 147.82, 134.92, 130.61, 130.56, 130.30, 130.27, 128.61, 128.49, 127.93, 127.74, 44.56, 33.79, 24.62, 15.04.The physical data were identical in all respects to those previously reported. 3

trimethyl(naphthalen-2-ylmethyl)silane (2e): Synthesized according to Method A. [120 mg, 93%

yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3)) δ 7.82 (dt, J = 7.7, 1.1 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.49 – 7.38 (m, 3H), 7.21 (dd, J = 8.3, 1.8 Hz, 1H), 2.30 (s, 2H), 0.07 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 140.95, 136.53, 133.69, 130.58, 130.26, 130.18, 129.67, 128.42, 127.82, 127.00, 30.06, 0.89. The physical data were identical in all respects to those previously reported. 4

2-(methyl-d3)naphthalene (2e-d3) Synthesized according to Method A. [57 mg, 65% yield].

Preparation of methyllithium-d3: MeI-d3 (1,5 eq. 0,9 mmol, 56 ul) was added dropwise to a stirred solution of tBuLi (2.2 eq. 2 mmol in Hexane) in THF (1 ml) at -78 °C. The reaction mixture was allowed to reach room temperature, diluted with toluene (up to 5 mL) and used as such. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.5 Hz, 1H), 7.73 (ddd, J = 54.1, 8.5, 4.4 Hz, 2H), 7.59 (s, 1H), 7.40 (d, J = 264.2 Hz, 2H), 7.29 (dd, J = 8.4, 1.7 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 135.45, 133.80, 131.85, 128.23, 128.02, 127.81, 127.73, 127.36, 126.98, 125.98, 125.07, 21.02 (d, J = 19.9 Hz). The physical data were identical in all respects to those previously reported.5

(1) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 1678.

(2) Heijnen, D.; Gualtierotti, J.; Hornillos, V.; Feringa, B. L. Chem. - A Eur. J. 2016, 22, 3991–3995. (3) Cabiddu, S.; Cancellu, D.; Floris, C.; Gelli, G.; Melis, S. Synthesis. 1988, 1988, 888–890. (4) Heijnen, D.; Hornillos, V.; Corbet, B. P.; Giannerini, M.; Feringa, B. L. Org. Lett., 2015, 17 (9), pp 2262–2265.

(5) Ka Young Lee, Jeong Eun Na, Mi Jung Lee Jae, Nyoung Kim, Tetrahedron Lett, 2004, 45, 5977– 5981

1-methylnaphthalene (3a): Synthesized according to Method A. [72 mg, 84% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.60-7.52 (m, 2H), 7.45 – 7.40 (m, 1H), 7.37 (d, J = 6.9 Hz, 1H), 2.75 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 134.3, 133.6, 132.6, 128.6, 126.6, 126.4, 125.7, 125.6, 125.6, 124.1, 19.4 ppm. The physical data were identical in all respects to those previously reported.1

1-phenylnaphthalene (3b): Synthesized according to Method A. [92 mg, 75% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 9.5 Hz, 2H), 7.88 (d, J = 7.5 Hz, 1H), 7.58 – 7.49 (m, 6H), 7.49 – 7.42 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 140.74, 140.24, 133.77, 131.60, 130.05, 128.23, 128.22, 127.60, 127.20, 126.89, 126.00, 125.98, 125.73, 125.34. The physical data were identical in all respects to those previously reported.2

1-butylnaphthalene (3c): Synthesized according to Method A. [98 mg, 89% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 8.17 (d, 1H), 8.00 – 7.92 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.66 – 7.53 (m, 2H), 7.50 (dd, J = 8.1, 7.0 Hz, 1H), 7.42 (d, J = 7.0, 1.2 Hz, 1H), 3.18 (t, 2H), 1.85 (tt, J = 7.8, 6.5 Hz, 2H), 1.57 (h, J = 7.4 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 139.07, 133.99, 132.02, 128.84, 127.98 (naphthalene), 126.49, 125.95, 125.91 (naphthalene), 125.70, 125.62, 125.44, 124.01, 33.13, 32.94, 23.01, 14.15. The product was obtained with traces of naphthalene.1

1-(sec-butyl)naphthalene (3d): Synthesized according to Method A. [67 mg, 61% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 8.5, 5.5 Hz, 2H (+ naphthalene)), 7.75 (d, J = 8.1 Hz, 1H), 7.59 – 7.40 (m, 4H (+ naphthalene)), 3.57 (h, J = 6.9 Hz, 1H), 1.91 (dq, J = 14.0, 7.4 Hz, 1H), 1.78 (dq, J = 13.6, 7.3 Hz, 1H), 1.43 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.75, 133.97, 131.83, 128.97, 126.22, 125.64, 125.62, 125.22, 123.30, 122.49, 35.34, 30.62, 21.27, 12.34.The physical data were identical in all respects to those previously reported.1

trimethyl(naphthalen-1-ylmethyl)silane (3e): Synthesized according to Method A. [125 mg, 98%

yield] Colorless oil obtained after column chromatography (SiO2, n-pentane) 1H NMR (400 MHz, CDCl3) δ 8.05 – 7.98 (m, 1H), 7.93 – 7.85 (m, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.47 – 7.38 (m, 1H), 7.23 (d, J = 7.1 Hz, 1H), 2.65 (s, 2H), 0.10 – 0.05 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 139.95, 136.69, 134.43, 131.32, 128.22, 128.08, 127.98, 127.70, 127.50, 127.38, 26.19, 1.56. The physical data were identical in all respects to those previously reported. 4

2-(naphthalen-1-yl)thiophene (3f) Synthesized according to Method A. [77 mg, 61% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane ) 1H NMR (400 MHz, CDCl3) δ 8.26 – 8.19 (m, 1H), 7.91 – 7.87 (m, 1H), 7.85 (dt, J = 8.2, 1.1 Hz, 1H), 7.57 (dd, J = 7.1, 1.3 Hz, 1H), 7.53 – 7.45 (m, 3H), 7.42 (dd, J = 5.1, 1.2 Hz, 1H), 7.24 (dd, J = 3.5, 1.2 Hz, 1H), 7.18 (dd, J = 5.1, 3.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 141.77, 133.85, 132.44, 131.87, 128.41, 128.34, 128.22, 127.40, 127.29, 126.46, 126.02, 125.77, 125.64, 125.26.2

9-methylanthracene (4a): Synthesized according to Method A. [112 mg, 97% yield] White solid

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.30 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.54-7.46 (m, 4H), 3.11 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 131.5, 130.1, 130.0, 129.1, 125.3, 125.2, 124.8, 124.7, 13.9 ppm. Data was consistent with commercially available product.

1-methoxy-4-methylbenzene (5a): Synthesized according to Method A. [50 mg, 67% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.1 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.4, 129.9, 129.8, 113.7, 55.3, 20.5 ppm. Data was consistent with commercially available product.

4-methoxy-1,1'-biphenyl (5b): Synthesized according to Method A. [105 mg, 95% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.59 (td, J = 8.7, 1.8 Hz, 4H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.16, 140.84, 133.78, 128.76, 128.18, 126.76, 126.69, 114.22, 55.35. The physical data were identical in all respects to those previously reported.1

1-butyl-4-methoxybenzene (5c): Synthesized according to Method A. [79 mg, 80% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H), 2.58 (t, J = 7.7 Hz, 2H), 1.66 – 1.53 (m, 2H), 1.38 (dq, J = 14.6, 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.54, 134.95, 129.21, 113.58, 55.18, 34.70, 33.91, 22.29, 13.95. The physical data were identical in all respects to those previously reported.1

1-secbutyl-4-methoxybenzene (5d): Synthesized according to Method A. [75 mg, 76% yield]

Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 3.82 (s, 3H), 2.58 (q, J = 7.0 Hz, 1H), 1.60 (p, J = 7.3 Hz, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 157.61, 139.74, 127.82, 113.56, 55.16, 40.80, 31.32, 22.03, 12.23. The physical data were identical in all respects to those previously reported.1

(4-methoxybenzyl)trimethylsilane (5e): Synthesized according to Method A. [114 mg, 98% yield]

Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 6.94 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 2.03 (s, 2H), 0.01 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 156.49, 132.31, 128.80, 113.64, 55.20, 25.70, -1.91. The physical data were identical in all respects to those previously reported 4

1-methoxy-3-methylbenzene (6a): Synthesized according to Method A. [51 mg, 69% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.75-6.70 (m, 2H), 3.80 (s, 3H), 2.35 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.5, 139.5, 129.2, 121.5, 114.7, 110.7, 55.1, 21.6 ppm. Data was consistent with commercially available product.

1-methoxy-3-methylbenzene (6b): Synthesized according to Method A. [79 mg, 72% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane/ether 100:1) 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.1 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.40 (td, J = 7.6, 3.2 Hz, 2H), 7.24 (d, J = 9.1 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.07, 142.88, 141.22, 129.86, 128.84, 127.52, 127.31, 119.79, 113.03, 112.79, 55.38.6

N,N,4-trimethylaniline (7a): Synthesized according to Method A. [71 mg, 88% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.2 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 2.94 (s, 6H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 148.8, 129.6, 126.2, 113.3, 41.1, 20.3 ppm. The physical data were identical in all respects to those previously reported.7

N,N-dimethyl-[1,1'-biphenyl]-4-amine (7b): Synthesized according to Method A. [102 mg, 86% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 6.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 3.05 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 150.01, 141.28, 129.27, 128.72, 127.76, 126.35, 126.05, 112.83, 40.64. The physical data were identical in all respects to those previously reported.2

4-butyl-N,N-dimethylaniline (7c): Synthesized according to Method A. [90 mg, 85% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane/ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 2.97 (s, 6H), 2.59 (t, J = 7.5 Hz, 2H), 1.67 – 1.57 (m, 2H), 1.42 (dq, J = 14.6, 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.95, 131.26, 129.00, 113.04, 41.02, 34.66, 34.07, 22.44, 14.08.The physical data were identical in all respects to those previously reported.1

(6)Jin Yang, Lei, Wang, Dalton Trans., 2012, 41, 12031-12037 (7) Chen, W.-X.; Shao, L.-X. J. Org. Chem., 2012, 77, 9236.

4-(sec-butyl)-N,N-dimethylaniline (7d): Synthesized according to Method A. [85 mg, 80% yield]

Colorless oil obtained after column chromatography (SiO2, n-pentane/Ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.6 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 2.95 (s, 6H), 2.55 (h, J = 7.0 Hz, 1H), 1.75 – 1.46 (m, 2H), 1.25 (d, J = 7.0 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.99, 135.98, 127.57, 112.90, 40.94, 40.64, 31.38, 22.04, 12.37. HRMS [M+H|: 178.1596 Found : 178.1589.

N,N-dimethyl-4-((trimethylsilyl)methyl)aniline (7e): Synthesized according to Method A. [119 mg, 96% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane/Ether 100:1). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.7 Hz, 2H), 2.94 (s, 6H), 2.03 (s, 2H), 0.04 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 147.92, 128.75 (2x), 113.43, 41.24, 25.49, -1.72. HRMS [M+H|: Exact Mass: 208,1522 Found 208,1516.

2-(p-tolyl)-1,3-dioxolane (8a): Synthesized according to Method A. [84 mg, 86% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane/Ether 100:1). 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.80 (s, 1H), 4.27-3.94 (m, 4H), 2.37 (s, 3H) ppm. 13C

NMR (100 MHz, CDCl3) δ 139.0, 135.0, 129.0, 126.4, 103.8, 65.2, 21.3 ppm. The physical data were identical in all respects to those previously reported.4

1,3-dichloro-5-methylbenzene (9a): Synthesized according to Method A. [62 mg, 64% yield]

Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 7.06 (s, 2H), 2.31 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 141.1, 134.6, 127.5, 125.7, 21.0 ppm. The physical data were identical in all respects to those previously reported.20

1-butyl-4-(chloromethyl)benzene (10a) Synthesized according to Method B at 0ºC. [88mg, 80%

yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.59 (s, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.66 – 1.55 (m, 2H), 1.37 (dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 145.99, 137.38, 131.45, 131.21, 48.98, 38.03, 36.20, 25.01, 16.60. The physical data were identical in all respects to those previously reported.8

4-(chloromethyl)-1,1'-biphenyl (10b) Synthesized according to to Method B at 0ºC [121 mg, 100%

yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.56 (m, 4H), 7.50 – 7.43 (m, 4H), 7.37 (d, J = 7.3 Hz, 1H), 4.65 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 141.37, 140.47, 136.42, 129.04, 128.80, 127.52, 127.48, 127.11, 46.05. Data was consistent with commercially available product.

(

1-chloro-4-(prop-1-en-2-yl)benzene (11a): Synthesized according to Method A. [66 mg, 72% yield]

Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 5.36 (s, 1H), 5.20-5.04 (m, 1H), 2.14 (d, J = 0.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 142.1, 139.6, 133.1, 128.3, 126.8, 113.0, 21.7 ppm. The physical data were identical in all respects to those previously reported.9

2-methyl-1,1'-biphenyl (12a): Synthesized according to Method A. [95 mg, 94% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.50-7.44 (m, 2H), 7.43-7.37 (m, 3H), 7.35-7.29 (m, 4H), 2.35 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 142.0, 141.9, 135.4, 130.3, 129.8, 129.2, 128.1, 127.3, 126.8, 125.8, 20.5 ppm. The physical data were identical in all respects to those previously reported.10

4,4'-dimethyl-1,1'-biphenyl (13a): Synthesized according to Method A with 2.5 eq organolithium at

40 °C. [90 mg, 83% yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 2.44 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 138.3, 136.7, 129.5, 126.8, 21.1 ppm. The physical data were identical in all respects to those previously reported.11

(E)-prop-1-en-1-ylbenzene (14a): Synthesized according to Method A. [39 mg, 55% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.1 Hz, 1H), 6.42 (dq, J = 15.8, 1.4 Hz, 1H), 6.25 (dq, J = 15.7, 6.5 Hz, 1H), 1.90 (dd, J = 6.5, 1.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 137.9, 131.0, 128.5, 126.7, 125.8, 125.7, 18.5 ppm. The physical data were identical in all respects to those previously reported.12

(E)-1,2-diphenylethene (14b) Synthesized according to Method A. [77 mg, 71% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.0 Hz, 4H), 7.40 (t, J = 8.4 Hz, 4H), 7.31 (t, J = 7.1 Hz, 2H), 7.16 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 137.34, 128.73, 128.71, 127.67, 126.55. Data was consistent with commercially available product.

(E)-2-styrylthiophene (14c) Synthesized according to Method A. [92 mg, 82% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 7.0 Hz, 2H), 7.33 – 7.26 (m, 2H), 7.24 (d, J = 5.1 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 7.06 (dd, J = 5.1, 3.6 Hz, 1H), 7.00 (d, J = 16.1 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 142.92, 136.99, 128.76, 128.36, 127.66, 126.36, 126.20, 124.40, 121.83. The physical data were identical in all respects to those previously reported 6

9)

Tripathi, C. B.; Mukherjee, S. Angew. Chem. Int. Ed., 2013, 52, 8450. 10)

Rajabi, F.; Thiel, W. R. Adv. Synth. Catal. 2014, 356, 1873 – 1877. 11)

Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew. Chem. Int. Ed., 2014, 53, 3475.

12) Gauthier, D.; Lindhardt, A. T.; Olsen, E. P. K.; Overgaard, J.; Skrydstrup, T. J. Am. Chem. Soc.,

2010, 132, 7998.

2-methyl-9H-fluorene (15a): Synthesized according to Method A. [102 mg, 95% yield] White solid

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.45-7.40 (m, 2H), 7.34 (td, J = 7.4 , 1.1 Hz, 1H), 7.25 (dd, J = 7.7, 0.6 Hz, 1H), 3.91 (s, 2H), 2.50 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 143.5, 143.1, 141.9, 139.1, 136.6, 127.6, 126.7, 126.3, 125.8, 125.0, 119.6, 119.6, 36.8, 21.7 ppm. The physical data were identical in all respects to those previously reported.1

2-(4-butylphenyl)oxirane (17a) Synthesized according to to Method B at -10ºC. [61 mg, 58% yield]

Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.22 – 7.13 (m, 4H), 3.84 (dd, J = 4.1, 2.6 Hz, 1H), 3.13 (dd, J = 5.5, 4.1 Hz, 1H), 2.82 (dd, J = 5.5, 2.6 Hz, 1H), 2.61 (t, J = 7.6 Hz, 2H), 1.66 – 1.51 (m, 2H), 1.35 (h, J = 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 145.72, 137.36, 131.22, 128.12, 55.02, 53.73, 38.02, 36.26, 24.97, 16.59.The physical data were identical in all respects to those previously reported.13

p-tolylmethanol (18a): Synthesized according to Method C. [65 mg, 88% yield] Colorless oil obtained

after column chromatography (SiO2, n-pentane/Ether 90:10). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 4.63 (s, 2H), 2.36 (s, 3H), 1.90 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 137.9, 137.3, 129.2, 127.1, 65.2, 21.1 ppm. The physical data were identical in all respects to those previously reported.14

(4-butylphenyl)methanol (18b): Synthesized according to Method C. [70 mg, 71% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane/Ether 90:10). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 2.69 – 2.57 (m, 2H), 2.12 (s, 1H), 1.71 – 1.53 (m, 2H), 1.38 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 142.47 , 138.24, 128.67, 127.19, 65.25, 35.44, 33.77, 22.44, 14.04. Data was consistent with commercially available product.

2-(4-butylphenyl)ethan-1-ol (19a) Synthesized according to Method C. [56 mg, 52% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.62 (s, 2H), 2.63 (t, J = 7.1 Hz, 2H), 2.12 (s, 1H), 1.70 – 1.54 (m, 2H), 1.38 (dq, J = 14.6, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 145.05, 140.82, 131.25, 129.77, 67.82, 38.02, 41.44, 36.35, 25.01, 16.62. Exact Mass [M+H|: 179,1436 Found : 179,1430.

[1,1'-biphenyl]-4-ol (20a) Synthesized according to Method C. [85 mg, 83% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane 1H NMR (400 MHz, CDCl3 + DMSO-d6) δ 8.99 (s, 1H), 7.49 – 7.42 (m, 2H), 7.40 – 7.28 (m, 4H), 7.23 – 7.15 (m, 1H), 6.89 – 6.78 (m, 2H). 13C NMR (101 MHz, CDCl3 + DMSO-d6) δ 157.03, 140.83, 131.85, 128.61, 127.84, 126.26, 117.40, 115.80. Data was consistent with commercially available product.

(13) Maryanoff, B. E.; Mccomsey, D. F.; Gardocki, J. F.; Shank, R. P.; Costanzo, M. J.; Nortey, S.; Schneider, C. R.; Setler, P. E. J. Med. Chem. 1987, 30, 1433–1454.

(14) Sutter, M.; Pehlivan, L.; Lafon, R.; Dayoub, W.; Raoul, Y.; Metay, E.; Lemaire, M. Green Chem.,

2013, 15, 3020

3-butylbenzo[b]thiophene (21b) Synthesized according to Method A. [96 mg, 84% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.48 – 7.35 (m, 2H), 7.11 (s, 1H), 2.90 (d, J = 6.7 Hz, 2H), 1.79 (ddd, J = 15.3, 8.2, 6.9 Hz, 2H), 1.49 (dt, J = 14.7, 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 140.63, 139.28, 137.32, 124.17, 123.84, 122.97, 121.85, 120.92, 31.45, 28.41, 22.79, 14.10. The physical data were identical in all respects to those previously reported. 15

4-butyldibenzo[b,d]furan (22a) Synthesized according to Method A. [116 mg, 86% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.00 (ddd, J = 7.7, 1.4, 0.7 Hz, 1H), 7.85 (dd, J = 5.4, 3.6 Hz, 1H), 7.66 (dt, J = 8.2, 0.8 Hz, 1H), 7.51 (ddd, J = 8.3, 7.3, 1.4 Hz, 1H), 7.39 (td, J = 7.5, 1.0 Hz, 1H), 7.35 – 7.30 (m, 2H), (3.06 (t, J = 7.5 Hz, 2H)), 1.99 – 1.75 (m, 2H), 1.52 (h, J = 7.4 Hz, 2H), 1.06 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 156.07, 154.85, 127.27, 127.16, 126.91, 124.72, 123.82, 122.72, 122.54, 120.70, 118.09, 111.71, 32.15, 29.70, 22.66, 14.07.

3-butylthiophene (23a) Synthesized according to Method A. [69 mg, 82% yield] Colorless oil

obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.26 (dd, J = 4.9, 2.9 Hz, 1H), 6.96 (dd, J = 8.1, 3.4 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H), 1.71 – 1.59 (m, 2H), 1.40 (h, J = 7.3 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 143.21, 128.30, 125.04, 119.78,

32.75, 30.00, 22.43, 13.96. The physical data were identical in all respects to those previously reported. 16

3-butyl-1-(triisopropylsilyl)-1H-pyrrole (24a) Synthesized according to Method A. [117 mg, 70%

yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 6.69 (t, J = 2.2 Hz, 1H), 6.52 (s, 1H), 6.15 (s, 1H), 2.49 (t, J = 7.7 Hz, 2H), 1.63 – 1.50 (m, 2H), 1.49 – 1.29 (m, 5H), 1.09 (d, J = 7.5 Hz, 18H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 126.37, 123.86, 120.98, 110.57, 33.24, 26.71, 22.53, 17.88, 14.02, 11.69. HRMS [M+H|: 280.2461 Found : 280.2455.

3-phenyl-1-(triisopropylsilyl)-1H-pyrrole (24b) Synthesized according to Method A. [151 mg, 84%

yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J = 8.2, 1.3 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.17 (t, J = 6.7 Hz, 1H), 7.08 (t, J = 1.8 Hz, 1H), 6.82 (t, J = 2.4 Hz, 1H), 6.63 (dd, J = 2.8, 1.5 Hz, 1H), 1.59 – 1.41 (m, 3H), 1.15 (d, J = 7.5 Hz, 18H). 13C NMR (101 MHz, Chloroform-d) δ 138.68, 131.19, 129.43, 127.93, 127.88, 127.82, 123.22, 111.27, 20.50, 14.35. HRMS [M+H|: 300.2148 Found : 300.2142.

(15) Cabiddu, S.; Cancellu, D.; Floris, C.; Gelli, G.; Melis, S. Synthesis. 1988, 1988, 888–890 (16) Tan, L.; Curtis, M. D.; Francis, A. H. Macromolecules 2002, 35, 4628–4635.

3-phenylfuran (25a) Synthesized according to Method A. [47 mg, 54% yield] Colorless oil obtained

after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.57 – 7.48 (m, 3H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 6.73 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 143.67, 138.48, 132.41, 128.82, 127.01, 126.46, 125.88, 108.86.The physical data were identical in all respects to those previously reported.17

1-methyl-5-phenyl-1H-indole (26a) Synthesized according to Method A. [50 mg, 40% yield] Colorless

oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.77 – 7.63 (m, 2H), 7.56 – 7.45 (m, 3H), 7.41 (d, J = 8.5 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 3.1 Hz, 1H), 6.58 (t, J = 2.5 Hz, 1H), 3.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 145.30, 132.17, 131.62, 131.32, 130.07, 128.92, 124.08, 122.09, 112.12, 103.99, 35.63. The physical data were identical in all respects to those previously reported.18

1-(3-methoxyphenyl)naphthalene (27a) Synthesized according to Method A.

[75 mg, 40 % yield] Ferrocenyl lithium prepared according to literature procedure.7 Dark red oil obtained after column chromatography (SiO2, n-pentane:DCM). 1H NMR (400 MHz, CDCl3) δ 8.59 – 8.53 (m, 1H), 7.89 (ddd, J = 8.2, 6.2, 2.5 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.54 – 7.45 (m, 3H), 4.68 (t, J = 1.8 Hz, 2H), 4.42 (t, J = 1.8 Hz, 2H), 4.21 (s, 5H). 13C NMR (101 MHz, CDCl3) δ 136.07, 133.78, 131.91, 128.44, 127.99, 126.94, 126.02, 125.51, 125.46, 125.22, 87.09, 70.52, 69.64, 68.15. HRMS [M+H|: 313.0680 found 313.0625.

1-(3-methoxyphenyl)naphthalene (28a) Synthesized according to Method A

[35 mg, 20 % yield] Ferrocenyl lithium prepared according to literature procedure.7 Dark red oil obtained after column chromatography (SiO2, n-pentane:DCM). 1H NMR (400 MHz, CDCl3 ) δ 7.41 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.57 (t, J = 1.9 Hz, 2H), 4.27 (t, J = 1.9 Hz, 2H), 4.04 (s, 5H), 3.83 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.66, 133.92, 129.83, 116.48, 88.53, 72.10, 71.12, 68.77, 57.93. 8 HRMS Mass : 293.0551 Found : 293.0545.

1-(3-methoxyphenyl)naphthalene (29a) Synthesized according to Method B.

[122 mg, 87 % yield] Colorless oil obtained after column chromatography (SiO2, n-pentane). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 17.5, 8.1 Hz, 2H), 7.67 – 7.41 (m, 5H), 7.18 (d,

J = 7.6 Hz, 1H), 7.14 (s, 1H), 7.06 (dd, J = 8.3, 2.1 Hz, 1H), 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.22, 144.91, 142.85, 136.51, 134.33, 131.97, 130.99, 130.43, 129.51, 128.79, 128.78, 128.51, 128.07, 125.32, 118.38, 115.61. The physical data were identical in all respects to those previously reported.19

(17) Yu, J.; Liu, J.; Shi, G.; Shao, C.; Zhang, Y. Angew. Chem. Int. Ed. Engl. 2015, 54, 4079–4082 (18) Mesganaw, T.; Fine Nathel, N. F.; Garg, N. K. Org. Lett. 2012, 14, 2918–2921.

Synthesis of Celecoxib

Figure 1 Two-step synthesis of celecoxib precursor20

1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione : Synthesized according to reported procedure.20

1-(4-bromophenyl)ethan-1-one (1.6 g, 8 mmol) was dissolved in 8 mL of DMF under N2 atmosphere and 60% NaH dispersion in oil (500 mg, 10 mmol) was added in three portions at 0°C. After stirring at this temperature for 30 min, ethyl trifluoroacetate (1.2 mL, 10 mmol) was added and the reaction mixture was stirred for 4 h. The reaction mixture was poured on to ice water, acidified with 2N aqueous HCl and extracted with EtOAc. The combined organic layers were washed with water, dried and the solvent evaporated under vacuum. The crude mixture was purified by column chromatography (SiO2, n-pentane:ether 98:2). [2.17 g, 92% yield]. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 6.54 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 184.9, 177.4 (q, JC-F = 36.4 Hz), 132.4, 131.7, 129.3, 128.9, 117.0 (q, JC-F = 283.4 Hz), 92.3 (q, JC-F = 2.0 Hz) ppm. 19F

NMR (376 MHz, CDCl3) δ -76.51 (s, 3F). The physical data were identical in all respects to those previously reported.21

4-(5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (30): Synthesized

according to reported procedure.22 1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (1.2 g, 4 mmol) and 4-hydrazinylbenzenesulfonamide hydrochloride (1.07 g, 4.8 mmol) were dissolved in 15 mL of EtOH and the mixture heated at reflux for 24 h. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (SiO2, n-pentane:EtOAc 65:35). [1.60 gram 90% yield]. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.77 (s, 1H), 5.33 (s, 2H) ppm. 13C NMR (100 MHz,

CDCl3) δ 144.2 (q, JC-F = 38.7 Hz), 144.0, 142.1, 141.8, 132.4, 130.3, 127.6, 127.4, 125.6, 124.1, 120.9

(q, JC-F = 269.3 Hz), 106.7 (q, JC-F = 1.6 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ -62.43 (s, 3F).

(20) S. K. Singh, P. G. Reddy, K. S. Rao, B. B. Lohray, P. Misra, S. A. Rajjak, Y. K. Rao, A. Venkateswarlu, Bioor. Med. Chem. Lett., 2004, 14, 499-504.

(21) S. Büttner, A. Riahi, I. Hussain, M. A. Yawer, M. Lubbe, A. Villiger, H. Reinke, C. Fischer, P. Langer, Tetrahedron, 2009, 65, 2124-2135.

(22) J. Prabhakaran, V. J. Majo, N. R. Simpson, R. L. Van Heertum, J. J. Mann, J. S. D. Kumar, J. Label Compd. Radiopharm., 2005, 48, 887-895.

4-(5-(p-tolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide (31): In a dry Schlenk flask

Pd(PtBu3)2 (5 mol%, 0.05 mmol, 5.1 mg), and the aryl bromide (0.1 mmol, 44.5 mg) were dissolved in 1 mL of dry toluene , and 5 ml of O2 was bubbled through the reaction mixture with a syringe, followed by stirring for 10 min. Methyllithium (0.19 mL, 3 eq, 1.6 M in diethyl ether) was diluted with toluene to reach 1 mL; this solution was added over 2 min by the use of a syringe pump. After the addition was completed, the reaction was quenched with 0.5 mL of MeOH. The solvent was evaporated under reduced pressure to afford the crude product that was purified by column chromatography. [35 mg, 91% yield]. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.73 (s, 1H), 5.25 (s, 2H), 2.37 (s, 3H) ppm. 13

C NMR (100 MHz, CDCl3) δ 145.3, 144.0 (q, JC-F = 38.8 Hz), 142.5, 141.4, 139.8, 129.7, 128.7, 127.5,

125.6, 125.5, 121.0 (q, JC-F = 269.1 Hz), 106.3 (q, JC-F = 1.7 Hz), 21.3 ppm. 19F NMR (376 MHz, CDCl3) δ -62.42 (s, 3F). The physical data were identical in all respects to those previously reported.23

(23) Ji, G.Wang, X.; Zhang, S.; Xu, Y.; Ye, Y.n; Li, M.; Zhang, Y.; Wang, J. Chem. Commun., 2014, 50, 4361-4363.

General scheme [11C]-labelling experiments with 2-Br-Naphthalene and Precursor 30

[11C]-methyl iodide was trapped in a solution of n-BuLi in THF at -78 °C, and subsequently diluted with toluene and allowed to reach rt. The solution was drawn back up in the syringe, and added to a previously oxygenated mixture of Pd complex and substrate. In the case of the Celecoxib synthesis (31*), the oxygenated mixture was first treated with 1.1 eq. of n-butyllithium to ensure complete deprotonation of the sulfonamide, which would otherwise consume the prepared [11C]-MeLi. After slow addition (2 min) of the organolithium reagents, the reaction was quenched with methanol, and an aliquot of the crude mixture concentrated, dissolved in acetonitrile, and directly loaded onto a RP-HPLC (eluent water:acetonitrile:trifluoroacetic acid 50:49:1). The total reaction time from the start of [11C]-MeI trapping, lithium halogen exchange, cross coupling and injection on HPLC was less than 15 min.

Figure 2 [11C]-labelling experiments

Figure 4 Schematic representation of [11C]-labelling experiments

Method for [11C]-labelling experiments

The substrate was transferred to a dry nitrogen purged 20 ml vial equipped with a septum and a stirring bar (vial A), and was further flushed with nitrogen through a septum for 5 min. In a separate, dry conical 4 ml vial (vial B), 0.25 ml dry THF was cooled down to -78 ºC under a nitrogen atmosphere. n-BuLi (0.9 eq. 0.18 ml) was added. The [11C]-MeI inlet needle was inserted in the THF-n-BuLi mixture, and a carbosphere vent added. During the trapping procedure of the [11C]-MeI in vial B, 3 ml of dry toluene was added to the substrate in vial A, and the mixture purged with oxygen (10 ml). n-BuLi (1.1 eq, 0.22 ml) was added to vial A prior to the coupling reaction to deprotonate the sulfonamide. The activity of the trapped and converted MeI of vial B was measured, the solution was diluted with 1 ml of toluene by means of a 2.5 ml syringe, and subsequently drawn up in the syringe. The addition of the MeLi solution to vial A was executed by means of a syringe pump, and was performed in 2 min. After the addition was complete, the reaction was quenched with 0.5 ml MeOH, and the total activity measured. A sample was taken, and dried at 50 ºC under a stream of nitrogen. The sample was taken up in 1.5 ml of eluent, its activity measured, and loaded onto a RP C-18 Denali HPLC column. Finally, residual activity in the used syringe was measured. Peaks from the HPLC-run were collected in vials, and their activity measured. The product was obtained by comparison with retention time of the previously prepared (isolated/injected) product.