Cobalt-Catalyzed Cross-Coupling of Grignards ... - ACS Publications

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The Journal of Organic Chemistry

Cobalt Catalyzed Cross-Coupling of Grignards with Allylic and Vinylic Bromides: the Use of Sarcosine as a Natural Ligand. Rok Frlan,† Matej Sova,† Stanislav Gobec,† Gaj Stavber,‡ Zdenko Časar*†‡§ †

Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia

‡

API Development, Organic Synthesis Department, Lek Pharmaceuticals, d.d., Sandoz Development Centre Slovenia, Kolodvorska 27, 1234 Mengeš, Slovenia

§

Global Portfolio Management API, Sandoz GmbH, Biochemiestrasse 10, 6250 Kundl, Austria,

ABSTRACT: Sarcosine was discovered as an excellent ligand for cobalt-catalyzed carbon-carbon cross-coupling of Grignard reagents with allylic and vinylic bromides. The Co(II)/sarcosine catalytic system is shown to perform efficiently when phenyl and benzyl Grignards are coupled with alkenyl bromides. Notably, previously unachievable Co-catalyzed coupling of allylic bromides with Grignards to linearly coupled α-products was also realized with Co(II)/sarcosine catalyst. This method was used for efficient preparation of the key intermediate in an alternative synthesis of the antihyperglycemic drug sitagliptin.

Over this last decade, there has been intensive interest in the development of more environmentally benign, broadly applicable, and cheaper catalytic systems for transition metal catalyzed carbon-

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carbon cross-coupling reactions.1-3 In this context, low-cost iron and cobalt salts (first reported by Kharasch and co-workers4) have provided an excellent alternative to toxic and expensive palladium and nickel catalysts. Although iron-based catalysis offers a multifaceted class of effective carbon– carbon and carbon–X bond-forming reactions with a wide substrate range and functional group tolerance,5 the use of cheap, toxicologically and environmentally acceptable cobalt6 catalysts can sometimes result in reactivity for various carbon-carbon bond-forming reactions that is generally unattainable with other catalysts, such as with palladium, nickel, copper, and iron. In addition, generally mild reaction conditions, high functional group tolerance, and broad availability of cobalt halides have contributed to the growing success of cobalt catalyst over the last decade.7 Cobaltbased catalysis usually requires the addition of ligands to obtain higher efficiency of the reaction system. However, in contrast to palladium catalytic systems where a pleiades of various phosphine ligands8 and precatalysts9 have been explored, only a few original ligand systems have been proposed in the case of cobalt catalysis. Indeed, most reactions reported to date have used amine-7e,10 or phosphine-11 based ligands that were mainly chosen by analogy with palladium, copper, nickel and iron chemistry. Recently, Cahiez12 noted that the discovery of specific new ligands for ironcatalyzed carbon–carbon coupling is a forthcoming challenge to improve these reactions and to widen their scope in organic synthesis. We believe that the same holds for cobalt catalyzed carbon– carbon coupling reactions. Based on these concepts and taking into account the potential of cobaltcatalyzed carbon–carbon coupling reactions, we envisioned that the discovery of a more economical, simple and efficient catalytic system with new bio-based ligands will be very beneficial for the art of carbon–carbon cross coupling catalytic reactions on the one hand, and for appropriate industrial applicability on the other. This led us to take the challenge of discovery and development of a new cobalt/ ligand catalytic system for efficient carbon–carbon coupling of previously rarely studied substrates such as various allylic13 and vinylic14 bromides (Scheme 1).


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SCHEME 1. Cross-coupling of Grignards with allylic and vinylic halides and the scope of the present study.

Our study started with the screening of a variety of ligands, as initially based upon a model reaction between phenylmagnesium bromide (PhMgBr, 1a) and the corresponding methyl 4-bromocrotonate (2a) (Table 1). CoBr2 was selected as a cheap and readily available source of cobalt. In our starting model reaction, equimolar quantities of Grignard reagent (1a) (1M solution in THF) and bromide (2a) were used, which resulted in lower initial yields in this non-optimized system. Initially, various ligands were screened with a special focus on ligands of natural origin, along with the reaction without a ligand, all with 5 mol% CoBr2 and 10 mol% ligand at -20 °C (Table 1). Other well-known cobalt chelating agents, such as TMEDA (Table 1, entry 8) and HMTA/TMEDA (Table 1, entry 9) were also used in comparison, which have been routinely used as ligands for various cobalt- and iron-catalyzed reactions.1b However, most of the ligands surveyed (glucose, ribose, ascorbic acid,



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citric acid, L-Phe, Boc-Phe, alaninol, pyroglutamic acid, 8-hydroxyquinoline, cyclohexane-1,2diamine, pycolilamine and 8-aminoquinoline) returned the starting bromide (2a) and large quantities of biphenyl side products that resulted from oxidative homo-coupling of PhMgBr (1a), and the yields were equal to, or even lower than, the reaction without a ligand (Table 1, entry 1). Even for the usual ligands such as TMEDA the yield of 3 was only 27%. However, particular promise was seen when sarcosine (Table 1, entry 4) and L-proline (Table 1, entry 6) were used as ligands, where the yields achieved were comparable to, or better than, for TMEDA and HMTA (Table 1, entries 78). It is well established that amino acids form complexes with a variety of heavy metal salts, including cobalt.15 However, to date, the use of sarcosine and L-proline as ligands has been limited mainly to copper-catalyzed reactions,16 or to being used as organocatalysts.17 To the best of our knowledge, neither of these has been used in carbon–carbon coupling reactions. TABLE 1. Initial screening of different ligands on a model reaction.

Yield of 3 [%]a,b Entry Ligand 1 Without ligand 11 (16)c 2 D-Glucosamine·HCl 19 (20)c 3 Nicotinamide 17 (26)c 4 Sarcosine 32 (55)c 5 N,N-Dimethylglycine 12 (32)c 6 L-Proline 23 (29)c 7 HMTA 34 (35)c 8 TMEDA10b, 10d-10e 27 (38)c 9 HMTA/TMEDA (2/1) 19 (21)c a HPLC yield using 2,6-dichlorobenzaldehyde and phthalimide as internal standards. b Reaction conditions: 2a (3.0 mmol), CoBr2 (0.15 mmol), ligand (0.30 mmol), 1a (3.0 mmol), THF (20 mL), -20 °C. When Co(acac)3/sarcosine and Co(acac)2/sarcosine catalysts were used, 5% and 30% of 3, respectively, were obtained. c Cobalt(II) bromide anhydrous, beads.


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We decided to use sarcosine, as it had the highest efficiency, also compared to L-proline. In addition, sarcosine is a cost-beneficial alternative compared to both TMEDA and L-proline, which is a significant factor in industrial processes. Following this identification of CoBr2 in combination with sarcosine as a promising bio-based catalytic system6b-c for carbon–carbon coupling, we continued with the investigation of optimal reaction conditions starting with the catalyst. The observed lower yields in the initial set of screening experiments could be explained due to high hygroscopicity of the powdered CoBr2. To partially eliminate any detrimental effects of moisture, anhydrous CoBr2 beads were used instead of powdered CoBr2. This then improved the yield of 3 to 55% (Table 1, entry 4). Anhydrous CoBr2 beads were therefore used in all of the further experiments. Further investigation of the conditions for the cross-coupling reaction included variations to the initial allylic bromide, catalyst and ligand concentrations, choice of optimal reaction temperature, as well as the quantity and the addition rate of the Grignard reagent. A controlled drop-wise addition (67 µL/min) of Grignard 1a (1.4 equiv.) to a solution of 5 mol% of CoBr2, 10 mol% of sarcosine and 1.0 equiv. of bromide 2a at -20 °C was found to be optimal for our catalytic system, thus proving that the conditions used for the first ligand screening, which were very close to the optimal ones, were adequately chosen (for further details see Supporting information). With the appropriate reaction conditions in hand, the next focus was on evaluation of the efficiency and applicability on various substrates of the catalytic system developed. Thus a variety of structurally diverse allylic and vinylic bromides were combined with PhMgBr (1a) and BnMgBr (1b) (Table 2). Here, our method proved to be relatively general with respect to functional group variability of structurally different organic bromides 2b-2h, which provided a diverse array of products 4-15. In particular, we were interested to explore the cross-coupling of the allylic bromide substrates 2be, to demonstrate the possibilities of this catalytic system on a broader range of this class of substrate after successful application to 2a. Namely, allylic substitution represents one of the most stud-



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ied transformations with broad applicability.18 Although the chemistry of allylic substitutions has been extensively explored within the framework of copper, palladium, and nickel catalysis, these fundamental transformations have been less frequently studied within the context of iron and cobalt catalysis.19 To the best of our knowledge, α-selective cobalt-catalyzed allylic substitutions with organometallic reagents have proven successful to date only with diarylzinc compounds on allylic chlorides,20 and when Grignard reagents were coupled with allylic ether substrates.13 This latter reaction demonstrated high dependency on the structure of the substrate, ligand, and Gignard reagent used. In addition, moderate regioselectivity was observed (competition of α-selectivity vs γselectivity19) as well as C=C bond migration on some substrates, to give mixtures of three different products. Moreover, when an allylic bromide (e.g., cinnamyl bromide) was subjected to cross coupling with a Grignard reagent, only traces of the desired cross-coupled product were detected, along with main reaction products, which constituted a mixture of undesired dimeric 1,5-hexadiene side products (Scheme 1).13 Therefore, cobalt-catalyzed cross-couplings of allylic halides with Grignard reagents have remained an unconquered hurdle to date. Remarkably, allyl bromides 2b-e reacted well with Grignard reagents 1a and 1b to give good to excellent yields of linearly coupled products 4-11 that ranged from 55% to 96% (Table 2).

TABLE 2. CoBr2/ sarcosine-catalyzed carbon–carbon cross-coupling of allyl and alkenyl, bromides 2 with phenyl or benzyl Grignard reagents 1.a,b


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a


Reaction conditions: 2a-h (3.0 mmol), CoBr2 (anhydrous, beads, 0.15 mmol), sarcosine (0.30

mmol), R1MgBr (4.2 mmol), THF (20 mL), -20 °C, 1h. bIsolated yields.



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Next, encouraged by these results, the reactivity of our catalytic system was tested also on vinyl bromides. In general, vinyl bromides 2f-h gave even slightly higher yields compared to the crosscoupling reactions with allyl bromides 2a-e described above. These data additionally increase the scope and usefulness of our method, as successful reports of cobalt-catalyzed cross-coupling of alkenyl halides and Grignard reagents are limited.14 Therefore, our method complements the benchmark Cahiez approach, where 3 mol% Co(acac)2/ N-methylpyrrolidinone (4-9 equivalents) were used for efficient alkenyl cross-coupling with RMgX14c The beneficial effect of our method is related to the replacement of these 4-9 equivalents of reprotoxic N-methylpyrrolidinone (NMP),21 with only 10 mol% of the lower molecular weight sarcosine. This significantly decreases the NMP waste-stream burden of our method, in exchange for an insignificant increase in lower molecular weight metallic catalyst loading (10 mol% CoBr2 vs 3 mol% Co(acac)2). It is also worth mentioning that in these cases, the catalytic methodology developed provides very simple, one-step economical synthesis of phenyl substituted alkenes, where the desired styrene (12) and stilbene derivatives (13, 14) were easily prepared. Classical approaches to (E)-stilbene derivatives, including bioactive compounds like resveratrol, pinosylvin and pterostilbene, are usually more chemically complicated, require more chemical steps and/or operations, and show variable diastereoselectivities.22-26 Importantly, it should also be noted that in all of reactions with allyl bromides high αregioselectivity was observed and only low levels of side products, which could result from γselective addition, dimerization, double bond migration or reaction with the carboxylic moieties (e.g. for 2a and 2d) were detected. The extent of γ-regioselectivity was higher than 95 % according to NMR analysis of crude reaction mixtures. Finally, we explored the applicability of this CoBr2/sarcosine catalytic system for the preparation of a target intermediate in an alternative synthesis of the oral antihyperglycemic drug sitagliptin phosphate (17).27-28 The starting material methyl 4-bromocrotonate (2a) was reacted in the


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CoBr2/sarcosine catalyzed reaction with freshly obtained 2,4,5-trifluorophenyl magnesium bromide (1c) prepared via a Grignard exchange reaction, and target product methyl-4-(2,4,5trifluorophenyl)but-2-enoate (16) was successfully obtained with excellent 97% isolated yield and exclusively in the (E)-geometrical form. Moreover, when the amount of the Grignard reagent (1c) was lowered to 1.1 equivalent to have an even more economical process, 93% yield of 16 was still obtained (Scheme 2). This represents a notable advantage over the previously known approaches27b,d,f,l to 16, where 3-5 steps sequences had to be applied from more advanced and expensive starting materials in order to assemble 16. Moreover, by application of our approach to 16 and previously reported aza-Michael addition strategy towards 17,27d,f,l an attractive 6 step overall synthesis of sitagliptin phosphate 17 can be constructed, which applies simple chemistry and uses commodity starting materials as well as cheap reagents. SCHEME 2. Straightforward synthesis of (E)-methyl-4-(2,4,5-trifluorophenyl)but-2-enoate (16) using the CoBr2/sarcosine catalytic system, and its use in an alternative synthesis of the antidiabetic drug sitagliptin phosphate (17).27-28

In conclusion, we have demonstrated that sarcosine can be used as a new, efficient, environmentally benign, and cost-beneficial ligand,29 in combination with CoBr2 for cross-coupling of a number of allylic and vinylic bromides. It is of note that for the first time, the catalytic system presented here allows cross-coupling19 that involves allylic bromides and Grignard reagents within the framework of cobalt catalysis. Of particular benefit, the direct allylic substitution proceeds with high α-



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regioselectivity, and allows good functional-group tolerance while giving generally high yields of linearly coupled products. In addition, the method presented particularly extends the present limited options for efficient cobalt-catalyzed cross-coupling involving alkenyl bromides and Grignard reagents. Furthermore, to the best of our knowledge, this is the first cobalt-catalyzed carbon–carbon coupling using Grignard reagents and a natural ligand such as sarcosine. Moreover, we have also demonstrated that the presented methodology is very efficient in an alternative formal synthesis of the antidiabetic drug sitagliptin, which thus increases the likelihood that this ligand can be adopted as an alternative to TMEDA in an industrial setting. The use of cobalt as a less toxic metal catalyst and sarcosine as a simple and biocompatible amino-acid-type ligand for carbon–carbon coupling reactions with various allylic and vinylic bromide substrates makes this methodology industrially attractive from both the economic and environmental points of view.

EXPERIMENTAL SECTION General Remarks (Chemicals and Instrumentation). Unless otherwise noted, all reactions were per-

formed in dry round bottom flasks under an argon atmosphere. Chemicals were used without further purification. Reactions were conducted in anhydrous THF, which were dried and purified by distillation over Na before use. Analytical thin-layer chromatography (TLC) was performed on silica gel (60F254) plates (0.25 mm). Column chromatography was performed on silica gel 60 (particle size 240-400 mesh). 1H NMR spectra were recorded at 400 MHz and 13C NMR spectra at 100 MHz on a 400 MHz spectrometer in CDCl3. 1H NMR chemical shifts are reported in parts per million (δ) relative to tetramethylsilane (TMS) with the TMS resonance employed as the internal standard (TMS, δ 0.00 ppm). When TMS was not present or clearly visible solvent resonance was employed as the internal standard (CDCl3, δ 7.24 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants


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(Hertz) and integration. 13C NMR chemical shifts are reported in ppm from the solvent resonance as the internal standard (CDCl3, δ 77.23 ppm). HPLC analysis was performed on C18 column, 150 × 4.6 mm, 1.0 mL/min, inj. volume 5 µL, 25 °C, absorbance measurement at 220 nm and 254 nm. Method: CH3CN/H2O = 4/6 to CH3CN/H2O = 9/1 in 15 min, then 2.5 min at CH3CN/H2O = 9/1, then back to CH3CN/H2O = 4/6 at 18 min, post time 6 min. General Experimental Procedure for Ligand Screening A flame-dried and argon-flushed flask, equipped with a magnetic stirrer and a rubber septum was charged with anhydrous CoBr2 (0.15 mmol, dried 16 h in vacuum at 50 °C), a ligand (0.30 mmol, dried 16 h in vacuum at 50 °C) and dry THF (20 mL) at room temperature. After one hour the reaction mixture was cooled to -20 °C and methyl 4-bromocrotonate (2a, 3.0 mmol) was then added. After 10 minutes Grignard reagent phenyl magnesium bromide (1a, 3.0 mmol) was added dropwise (addition rate: 67 µL/min) and the reaction mixture was stirred for additional hour at -20 °C. Afterwards, the reaction system was slowly warmed to room temperature and stirred overnight. The saturated aqueous NH4CI solution (40 mL) was added and extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with brine (1 × 30 mL), dried with Na2SO4, filtered and evaporated. The yield of product 3 was determined by HPLC. HPLC analysis: The residue was diluted with ethyl acetate to final volume of 5 mL. 10 µL of solution was removed and dissolved in 1 mL of the solution of phthalimide and 2,6-dichlorobenzaldehyde in acetonitrile. The sample was further diluted (1/20) with acetonitrile/water (1/1) and filtered to obtain final sample for HPLC analysis. Typical Procedure for the CoBr2-Catalyzed Reaction of Grignard Reagents with Organic Bromides. A flame-dried and nitrogen-flushed flask equipped with a stirring bar was charged with CoBr2 (anhydrous, beads, 0.15 mmol, dried 16 h under vacuum at 50 °C), sarcosine (0.3 mmol, dried 16 h



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under vacuum at 50 °C) under an argon atmosphere and dissolved in dry THF (20 mL). After 1 h, the reaction mixture was cooled to -20 °C and bromide 2a-2h (3 mmol) was added. After 10 min, Grignard reagent 1 (1.4 equiv, 4.2 mmol) was added drop-wise (67 µL/min), and the solution obtained was stirred for 1 h. Afterwards, the reaction mixture was slowly warmed to room temperature and quenched with methanol. Then 1 M HCl solution (20 mL) was added to the reaction mixture, which was washed with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (1 × 30 mL), dried with Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography using gradient elution (petroleum ether to diethyl ether/ petroleum ether, 1/10) to obtain the desired product. All of the synthesized compounds are known and have been previously characterized in the literature. The 1H and

13

C NMR spectra of these compounds were consistent with those previously re-

ported. Methyl 4-phenylbut-2-enoate (3).30 Colorless liquid (338 mg, 64% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 3.44 (dd, 2H, J = 6.8 Hz, 1.8 Hz), 3.63 (s, 3H), 5.74 (dt, 1H, J = 15.6 Hz, 1.7 Hz), 6.98-7.12 (m, 3H), 7.12-7.19 (m, 1H), 7.19-7.27 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 38.6, 51.6, 122.1, 126.8, 128.9, 129.0, 137.8, 147.8, 167.1. (3-Methylbut-2-en-1-yl)benzene (4).31 Colorless liquid (360 mg, 82% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.75 (s, 3H), 1.78 (s, 3H), 3.38 (d, J = 7.4 Hz, 2H), 5.34-5.39 (m 1H), 7.16-7.24 (m, 3H), 7.26-7.34 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 18.1, 26.0, 34.6, 123.4, 125.9, 128.5, 128.6, 132.7, 142.0. (4-Methylpent-3-en-1-yl)benzene (5).32 Colorless liquid (317 mg, 66% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.49 (s, 3H), 1.61 (s, 3H), 2.22 (dt, J = 8.0, 7.5 Hz, 2H), 2.51-2.60 (m, 2H), 5.075.14 (m, 1H), 7.07-7.15 (m, 3H), 7.17-7.24 (m, 2H).

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C NMR (100 MHz, CDCl3): δ (ppm) 17.9,

25.9, 30.3, 36.4, 123.9, 125.9, 128.4, 128.6, 132.3, 142.6.


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(E)-Prop-1-ene-1,3-diyldibenzene (6).33 Colorless liquid (from 2d and 1a: 501 mg, 86% yield; from 2g and 1b: 554 mg, 95% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 3.58 (d, J = 6.8 Hz, 2H), 6.40 (td, J = 15.6, 6.8 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 7.20-7.41 (m, 10H). 13C NMR (100 MHz, CDCl3): δ (ppm) 39.6, 126.3, 126.4, 127.3, 128.7 (2 overlapping signals), 128.9, 129.4, 131.3, 137.6, 140.3. (E)-But-1-ene-1,4-diyldibenzene (7).34 Colorless liquid (537 mg, 86% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 2.48-2.58 (m, 2H), 2.79 (t, J = 7.8 Hz, 2H), 6.26 (dt, J = 15.9, 6.8 Hz, 1H), 6.42 (dt, J = 15.9, 1.6 Hz, 1H), 7.13-7.25 (m, 4H), 7.25-7.36 (m, 6H). 13C NMR (100 MHz, CDCl3): δ (ppm) 35.1, 36.1, 126.1, 126.2, 127.1, 128.6, 128.7 (2 overlapping signals), 130.2, 130.6, 137.9, 142.0. Methyl 2-benzylacrylate (8).35 Colorless liquid (508 mg, 96% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 3.62 (s, 2H), 3.71 (s, 3H), 5.44 (dt, J = 1.5 Hz, 1.4 Hz, 1H), 6.22 (dt, J = 1.5, 0.7 Hz, 1H), 7.15-7.22 (m, 3H), 7.25-7.31 (m, 2H).

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C NMR (100 MHz, CDCl3): δ (ppm) 38.1, 51.9, 126.3,

126.4, 128.5, 129.1, 138.7, 140.2, 167.4. Methyl 2-methylene-4-phenylbutanoate (9).36 Colorless liquid (348 mg, 61% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 2.59 (d, J = 7.1 Hz, 1H), 2.62 (d, J = 5.5 Hz, 1H), 2.76 (d, J =5.5 Hz, 1H), 2.79 (d, J = 7.2 Hz, 1H), 3.72 (s, 3H), 5.48 (dd, J = 2.7, 1.3 Hz, 1H), 6.14 (d, J = 1.3 Hz, 1H), 7.13-7.20 (m, 3H), 7.22-7.29 (m, 2H).

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C NMR (100 MHz, CDCl3): δ (ppm) 33.9, 34.9, 51.8,

125.5, 126.0, 128.4, 128.5, 139.9, 141.4, 167.6. 1,2,3,4-Tetrahydro-1,1'-biphenyl (10).37 Colorless liquid (356 mg, 75% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.60-1.81 (m, 2H), 1.82-1.95 (m, 1H), 2.07-2.35 (m, 3H), 3.45-3.60 (m, 1H), 5.85 (ddd, J = 10.2 Hz, 4.5 Hz, 2.1 Hz, 1H), 6.01 (dddd, J = 10.2 Hz, 3.7 Hz, 3.6 Hz, 2.3 Hz, 1H), 7.10-7.55 (m, 5H). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.4, 25.2, 32.8, 42.1, 126,1, 127.9, 128.4, 128.5, 130.4, 146.8.



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(Cyclohex-2-en-1-ylmethyl)benzene (11).38 Colorless liquid (284 mg, 55% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.27-1.39 (m, 1H), 1.49-1.63 (m, 1H), 1.72-1.83 (m, 2H), 2.01-2.11 (m, 2H), 2.37-2.50 (m, 1H), 2.60 (dd, J = 8.3, 13.2 Hz, 1H), 2.70 (dd, J = 7.3, 13.2 Hz, 1H), 5.64 (ddd, J = 10.1, 4.8, 2.2 Hz, 1H), 5.75 (ddd, J = 10.1, 6.1, 3.4 Hz, 1H), 7.20-7.30 (m, 3H), 7.30-7.39 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 21.5, 25.6, 29.1, 37.4, 42.9, 126.0, 127.5, 128.3, 129.3, 131.5, 141.1 (2-Methylprop-1-en-1-yl)benzene (12).32b Colorless liquid (381 mg, 96% yield); 1H NMR (400 MHz, CDCl3): δ (ppm) 1.86 (s, 3H), 1.90 (s, 3H), 6.27 (s, 1H), 7.14-7.24 (m, 1H), 7.27-7.35 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 19.5, 27.0, 125.3, 125.9, 128.1, 128.9, 135.6, 138.9. (E)-1,2-Diphenylethene (13).39 White solid (465 mg, 86% yield); mp 123-125 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.11 (s, 2H), 7.22-7.30 (m, 2H), 7.32-7.40 (m, 4H), 7.48-7.55 (m, 4H). 13C NMR (100 MHz, CDCl3): δ (ppm) 126.7, 127.8, 128.8, 137.5. 2-Phenyl-1H-indene (14).40 White needles (548 mg, 95% yield); mp 169-170 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 3.70 (s, 2H), 7.10 (ddd, J = 7.4, 7.4, 1.2 Hz, 1H), 7.15 (s, 1H, ArH), 7.167.23 (m, 2H), 7.26-7.34 (m, 3H), 7.39 (ddd, J = 7.4, 1.7, 0.9 Hz, 1H), 7.52-7.58 (m, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 39.2, 121.2, 123.9, 125.0, 125.9, 126.7, 126.8, 127.7, 128.9, 136.2, 143.4, 145.6, 146.6. 2-Benzyl-1H-indene (15).41 White solid (477 mg, 77% yield); mp 42-44 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 3.33 (s, 2H), 3.86 (s, 2H), 6.56 (s, 1H), 7.12-718 (m, 1H), 7.21-7.43 (m, 8H). 13C NMR (100 MHz, CDCl3): δ (ppm) 38.2, 41.0, 120.4, 123.7, 124.1, 126.4, 126.5, 128.0, 128.7, 129.1, 140.2, 143.6, 145.5, 149.5. Methyl (E)-4-(2,4,5-trifluorophenyl)but-2-enoate (16).27e,28 A dry and nitrogen-flushed 200-mL two-necked flask equipped with a magnetic stirrer and a rubber septum was charged with anhydrous THF (20 mL) and cooled to -20 °C. Afterwards, 2,4,5-trifluorobenzene (65.2 mmol, 7.6 mL) was


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introduced through a septum, following by slow addition of iPrMgCl (65.2 mmol, 32.6 mL; 2.0M solution in THF). The reaction temperature was maintained near – 20 °C, and the reaction mixture was stirred for 1 h, when the Br/Mg exchange reaction was complete. The solution of 2,4,5trifluorophenyl magnesium bromide 1c obtained was immediately used further according to the general procedure described above to obtain product 16 (670 mg, 97% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 3.40 (d, J = 6.6 Hz, 2H), 3.64 (s, 3H), 5.73 (dt, J = 15.6 Hz, 1.8 Hz, 1H), 6.79-6.97 (m, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 30.9, 51.7, 105.7 (dd, J = 28.2, 20.9 Hz), 118.4 (dd, J = 19.4, 5.8 Hz), 121.2 (ddd, J = 18.4, 4.8, 4.7 Hz), 123.0, 144.7, 146.9 (ddd, J = 245.1, 12.6, 3.6 Hz), 149.1 (ddd, J = 250.3, 14.3, 12.7 Hz), 155.9 (ddd, J = 245.1, 9.2, 1.9 Hz), 166.6.

ASSOCIATED CONTENT

Supporting Information. 1

H NMR, 13C NMR spectra of all compounds and detailed information on ligand screening and op-

timization procedure are available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author *

E-mail: [email protected], Tel.: +386 1 580 2079, Fax: +386 1 568 3517

Notes The authors declare no competing financial interest.



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ACKNOWLEDGEMENTS This study was supported by the Slovenian Research Agency (Grant P1-0208). In addition, the authors thank Lek Pharmaceuticals d.d. for support of project SDCCROS/2011-351.

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(29) During the study presented here, an interesting catalytic system based on a CoCl2/ isoprene/ LiI catalytic system was reported for cobalt-catalyzed cross-coupling of alkyl halides with tertiary alkyl Grignard reagents: Iwasaki, T.; Takagawa, H.; Singh, S. P.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2013, 135, 9604. (30) Poeylaut-Palena, A. A.; Testero, S. A.; Mata, E. G. J. Org. Chem. 2008, 73, 2024. (31) Fristrup, P.; Jensen, G. H.; Andersen, M. L. N.; Tanner, D.; Norrby, P.-O. J. Organomet. Chem. 2006, 691, 2182. (32) (a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010, 132, 920. (b) Fristrup, P.; Tanner, D.; Norrby, P. O. Chirality 2003, 15, 360. (33) Baker, L.; Minehan, T. J. Org. Chem. 2004, 69, 3957. (34) Wang, Z.; Pitteloud, J.-P.; Montes, L.; Rapp, M.; Derane, D.; Wnuk, S. F. Tetrahedron 2008, 64, 5322. (35) Biju, A. T.; Padmanaban, M.; Wurz, N. E.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50, 8412. (36) Yajima, T.; Saito, C.; Nagano, H. Tetrahedron 2005, 61, 10203. (37) Kamigata, N.; Fukushima, T.; Satoh, A.; Kameyama, M. J. Chem. Soc. Perkin Trans. 1 1990, 549. (38) Boisvert, L.; Beaumier, F.; Spino, C. Can. J. Chem. 2006, 84, 1290. (39) Meic, Z.; Vikictopic, D.; Gusten, H. Org. Magn. Resonance 1984, 22, 237. (40) Deng, R.; Sun, L.; Li, Z. Org. Lett. 2007, 9, 5207. (41) Martínez, A.; Fernández, M.; Estévez, J. C.; Estévez, R. J.; Castedo, L. Tetrahedron 2005, 61, 485.


Cobalt-Catalyzed Cross-Coupling of Grignards ... - ACS Publications

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