Cobalt-Catalyzed Cross-Coupling of Grignards with Allylic and Vinylic Bromides: Use of Sarcosine as a Natural Ligand

Article abstract of DOI:10.1021/acs.joc.5b01156

Sarcosine was discovered to be 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.

Full text of DOI:10.1021/acs.joc.5b01156

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Cobalt Catalyzed Cross-Coupling of Grignards with Allylic and Vinylic Bro-
mides: the Use of Sarcosine as a Natural Ligand.
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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 Developꢀ
ment 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 cobaltꢀcatalyzed carbonꢀcarbon
crossꢀcoupling of Grignard reagents with allylic and vinylic bromides. The Co(II)/sarcosine catalytꢀ
ic system is shown to perform efficiently when phenyl and benzyl Grignards are coupled with
alkenyl bromides. Notably, previously unachievable Coꢀcatalyzed coupling of allylic bromides with
Grignards to linearly coupled αꢀproducts 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 carbonꢀ
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carbon crossꢀcoupling reactions.1ꢀ3 In this context, lowꢀcost iron and cobalt salts (first reported by
Kharasch and coꢀworkers4) have provided an excellent alternative to toxic and expensive palladium
and nickel catalysts. Although ironꢀbased catalysis offers a multifaceted class of effective carbon–
carbon and carbon–X bondꢀforming reactions with a wide substrate range and functional group tolꢀ
erance,5 the use of cheap, toxicologically and environmentally acceptable cobalt6 catalysts can
sometimes result in reactivity for various carbonꢀcarbon bondꢀforming reactions that is generally
unattainable with other catalysts, such as with palladium, nickel, copper, and iron. In addition, genꢀ
erally 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 Cobaltꢀ
based 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 proꢀ
posed in the case of cobalt catalysis. Indeed, most reactions reported to date have used amineꢀ7e,10 or
phosphineꢀ11 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 ironꢀ
catalyzed 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 cobaltꢀ
catalyzed carbon–carbon coupling reactions, we envisioned that the discovery of a more economiꢀ
cal, simple and efficient catalytic system with new bioꢀbased ligands will be very beneficial for the
art of carbon–carbon cross coupling catalytic reactions on the one hand, and for appropriate indusꢀ
trial 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 studꢀ
ied substrates such as various allylic13 and vinylic14 bromides (Scheme 1).
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SCHEME 1. Crossꢀcoupling of Grignards with allylic and vinylic halides and the scope of the preꢀ
sent study.
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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 4ꢀbromocrotonate
(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 nonꢀoptimized 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 wellꢀknown
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 cobaltꢀ and
ironꢀcatalyzed reactions.1b However, most of the ligands surveyed (glucose, ribose, ascorbic acid,
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citric acid, LꢀPhe, BocꢀPhe, alaninol, pyroglutamic acid, 8ꢀhydroxyquinoline, cyclohexaneꢀ1,2ꢀ
diamine, pycolilamine and 8ꢀaminoquinoline) returned the starting bromide (2a) and large quantiꢀ
ties of biphenyl side products that resulted from oxidative homoꢀcoupling 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 Lꢀproline (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 7ꢀ
8). It is well established that amino acids form complexes with a variety of heavy metal salts, inꢀ
cluding cobalt.15 However, to date, the use of sarcosine and Lꢀproline as ligands has been limited
mainly to copperꢀcatalyzed 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.
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TABLE 1. Initial screening of different ligands on a model reaction.
Yield of 3 [%]a,b
Entry
Ligand
Without ligand
DꢀGlucosamineꢁHCl
Nicotinamide
Sarcosine
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11 (16)c
19 (20)c
17 (26)c
32 (55)c
12 (32)c
23 (29)c
34 (35)c
27 (38)c
N,NꢀDimethylglycine
LꢀProline
HMTA
TMEDA10b, 10dꢀ10e
9
HMTA/TMEDA (2/1) 19 (21)c
a HPLC yield using 2,6ꢀdichlorobenzaldehyde and phthalimide as internal standards.
bReaction 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, respecꢀ
tively, were obtained.
cCobalt(II) bromide anhydrous, beads.
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We decided to use sarcosine, as it had the highest efficiency, also compared to Lꢀproline. In addiꢀ
tion, sarcosine is a costꢀbeneficial alternative compared to both TMEDA and Lꢀproline, which is a
significant factor in industrial processes. Following this identification of CoBr2 in combination with
sarcosine as a promising bioꢀbased catalytic system6bꢀc 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 inꢀ
vestigation of the conditions for the crossꢀcoupling 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 dropꢀwise addition (67 ꢀL/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 conꢀ
ditions used for the first ligand screening, which were very close to the optimal ones, were adeꢀ
quately chosen (for further details see Supporting information).
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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 structurꢀ
ally diverse allylic and vinylic bromides were combined with PhMgBr (1a) and BnMgBr (1b) (Taꢀ
ble 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 4ꢀ15.
In particular, we were interested to explore the crossꢀcoupling of the allylic bromide substrates 2b-
e, to demonstrate the possibilities of this catalytic system on a broader range of this class of subꢀ
strate after successful application to 2a. Namely, allylic substitution represents one of the most studꢀ
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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, αꢀselective cobaltꢀcatalyzed 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 reaꢀ
gent used. In addition, moderate regioselectivity was observed (competition of αꢀselectivity vs γꢀ
selectivity19) 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 couꢀ
pling with a Grignard reagent, only traces of the desired crossꢀcoupled product were detected, along
with main reaction products, which constituted a mixture of undesired dimeric 1,5ꢀhexadiene side
products (Scheme 1).13 Therefore, cobaltꢀcatalyzed crossꢀcouplings 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
4ꢀ11 that ranged from 55% to 96% (Table 2).
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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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aReaction conditions: 2aꢀh (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 crossꢀ
coupling reactions with allyl bromides 2a-e described above. These data additionally increase the
scope and usefulness of our method, as successful reports of cobaltꢀcatalyzed crossꢀcoupling of
alkenyl halides and Grignard reagents are limited.14 Therefore, our method complements the
benchmark Cahiez approach, where 3 mol% Co(acac)2/ Nꢀmethylpyrrolidinone (4ꢀ9 equivalents)
were used for efficient alkenyl crossꢀcoupling with RMgX14c The beneficial effect of our method is
related to the replacement of these 4ꢀ9 equivalents of reprotoxic Nꢀmethylpyrrolidinone (NMP),21
with only 10 mol% of the lower molecular weight sarcosine. This significantly decreases the NMP
wasteꢀstream 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, oneꢀstep 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 comꢀ
pounds like resveratrol, pinosylvin and pterostilbene, are usually more chemically complicated,
require more chemical steps and/or operations, and show variable diastereoselectivities.22ꢀ26
Importantly, it should also be noted that in all of reactions with allyl bromides high αꢀ
regioselectivity was observed and only low levels of side products, which could result from γꢀ
selective addition, dimerization, double bond migration or reaction with the carboxylic moieties
(e.g. for 2a and 2d) were detected. The extent of γꢀregioselectivity was higher than 95 % according
to NMR analysis of crude reaction mixtures.
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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 phosꢀ
phate (17).27ꢀ28 The starting material methyl 4ꢀbromocrotonate (2a) was reacted in the
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CoBr2/sarcosine catalyzed reaction with freshly obtained 2,4,5ꢀtrifluorophenyl magnesium bromide
(1c) prepared via a Grignard exchange reaction, and target product methylꢀ4ꢀ(2,4,5ꢀ
trifluorophenyl)butꢀ2ꢀenoate (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 approachꢀ
es27b,d,f,l to 16, where 3ꢀ5 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 preꢀ
viously reported azaꢀMichael 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.
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SCHEME 2. Straightforward synthesis of (E)ꢀmethylꢀ4ꢀ(2,4,5ꢀtrifluorophenyl)butꢀ2ꢀenoate (16)
using the CoBr2/sarcosine catalytic system, and its use in an alternative synthesis of the antidiabetic
drug sitagliptin phosphate (17).27ꢀ28
In conclusion, we have demonstrated that sarcosine can be used as a new, efficient, environmentally
benign, and costꢀbeneficial ligand,29 in combination with CoBr2 for crossꢀcoupling of a number of
allylic and vinylic bromides. It is of note that for the first time, the catalytic system presented here
allows crossꢀcoupling19 that involves allylic bromides and Grignard reagents within the framework
of cobalt catalysis. Of particular benefit, the direct allylic substitution proceeds with high αꢀ
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regioselectivity, and allows good functionalꢀgroup tolerance while giving generally high yields of
linearly coupled products. In addition, the method presented particularly extends the present limited
options for efficient cobaltꢀcatalyzed crossꢀcoupling involving alkenyl bromides and Grignard reaꢀ
gents. Furthermore, to the best of our knowledge, this is the first cobaltꢀcatalyzed 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 aminoꢀacidꢀtype 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.
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EXPERIMENTAL SECTION
General Remarks (Chemicals and Instrumentation). Unless otherwise noted, all reactions were perꢀ
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 distilꢀ
lation over Na before use. Analytical thinꢀlayer chromatography (TLC) was performed on silica gel
(60F254) plates (0.25 mm). Column chromatography was performed on silica gel 60 (particle size
240ꢀ400 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) relaꢀ
tive 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 ꢂL, 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.
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General Experimental Procedure for Ligand Screening
A flameꢀdried and argonꢀflushed 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 reacꢀ
tion mixture was cooled to ꢀ20 °C and methyl 4ꢀbromocrotonate (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 ꢂL/min) and the reaction mixture was stirred for additional hour at ꢀ20 °C. Afterꢀ
wards, the reaction system was slowly warmed to room temperature and stirred overnight. The satuꢀ
rated 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 diꢀ
luted 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 2,6ꢀdichlorobenzaldehyde 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 flameꢀdried and nitrogenꢀflushed flask equipped with a stirring bar was charged with CoBr2 (anꢀ
hydrous, 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 2aꢀ2h (3 mmol) was added. After 10 min,
Grignard reagent 1 (1.4 equiv, 4.2 mmol) was added dropꢀwise (67 ꢂL/min), and the solution obꢀ
tained 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.
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All of the synthesized compounds are known and have been previously characterized in the literaꢀ
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ture. The H and C NMR spectra of these compounds were consistent with those previously reꢀ
ported.
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Methyl 4-phenylbut-2-enoate (3).30 Colorless liquid (338 mg, 64% yield); H 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),
6.98ꢀ7.12 (m, 3H), 7.12ꢀ7.19 (m, 1H), 7.19ꢀ7.27 (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.
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(3-Methylbut-2-en-1-yl)benzene (4).31 Colorless liquid (360 mg, 82% yield); H NMR (400 MHz,
CDCl3): δ (ppm) 1.75 (s, 3H), 1.78 (s, 3H), 3.38 (d, J = 7.4 Hz, 2H), 5.34ꢀ5.39 (m 1H), 7.16ꢀ7.24
(m, 3H), 7.26ꢀ7.34 (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), 2.51ꢀ2.60 (m, 2H), 5.07ꢀ
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5.14 (m, 1H), 7.07ꢀ7.15 (m, 3H), 7.17ꢀ7.24 (m, 2H). 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;
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from 2g and 1b: 554 mg, 95% yield); H NMR (400 MHz, CDCl3): δ (ppm) 3.58 (d, J = 6.8 Hz,
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2H), 6.40 (td, J = 15.6, 6.8 Hz, 1H), 6.49 (d, J = 15.6 Hz, 1H), 7.20ꢀ7.41 (m, 10H). C NMR (100
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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.
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(E)-But-1-ene-1,4-diyldibenzene (7).34 Colorless liquid (537 mg, 86% yield); H NMR (400 MHz,
CDCl3): δ (ppm) 2.48ꢀ2.58 (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), 7.13ꢀ7.25 (m, 4H), 7.25ꢀ7.36 (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),
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7.15ꢀ7.22 (m, 3H), 7.25ꢀ7.31 (m, 2H). 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.
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Methyl 2-methylene-4-phenylbutanoate (9).36 Colorless liquid (348 mg, 61% yield); H 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),
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7.13ꢀ7.20 (m, 3H), 7.22ꢀ7.29 (m, 2H). 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.
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1,2,3,4-Tetrahydro-1,1'-biphenyl (10).37 Colorless liquid (356 mg, 75% yield); H NMR (400
MHz, CDCl3): δ (ppm) 1.60ꢀ1.81 (m, 2H), 1.82ꢀ1.95 (m, 1H), 2.07ꢀ2.35 (m, 3H), 3.45ꢀ3.60 (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), 7.10ꢀ7.55 (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); H NMR (400
MHz, CDCl3): δ (ppm) 1.27ꢀ1.39 (m, 1H), 1.49ꢀ1.63 (m, 1H), 1.72ꢀ1.83 (m, 2H), 2.01ꢀ2.11 (m,
2H), 2.37ꢀ2.50 (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), 7.20ꢀ7.30 (m, 3H), 7.30ꢀ7.39 (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
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(2-Methylprop-1-en-1-yl)benzene (12).32b Colorless liquid (381 mg, 96% yield); H NMR (400
MHz, CDCl3): δ (ppm) 1.86 (s, 3H), 1.90 (s, 3H), 6.27 (s, 1H), 7.14ꢀ7.24 (m, 1H), 7.27ꢀ7.35 (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.
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(E)-1,2-Diphenylethene (13).39 White solid (465 mg, 86% yield); mp 123ꢀ125 °C; H NMR (400
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MHz, CDCl3): δ (ppm) 7.11 (s, 2H), 7.22ꢀ7.30 (m, 2H), 7.32ꢀ7.40 (m, 4H), 7.48ꢀ7.55 (m, 4H). C
NMR (100 MHz, CDCl3): δ (ppm) 126.7, 127.8, 128.8, 137.5.
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2-Phenyl-1H-indene (14).40 White needles (548 mg, 95% yield); mp 169ꢀ170 °C; H 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), 7.16ꢀ
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7.23 (m, 2H), 7.26ꢀ7.34 (m, 3H), 7.39 (ddd, J = 7.4, 1.7, 0.9 Hz, 1H), 7.52ꢀ7.58 (m, 2H). C 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 42ꢀ44 °C; H NMR (400 MHz,
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CDCl3): δ (ppm) 3.33 (s, 2H), 3.86 (s, 2H), 6.56 (s, 1H), 7.12ꢀ718 (m, 1H), 7.21ꢀ7.43 (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 nitrogenꢀflushed 200ꢀmL
twoꢀnecked flask equipped with a magnetic stirrer and a rubber septum was charged with anhydrous
THF (20 mL) and cooled to ꢀ20 °C. Afterwards, 2,4,5ꢀtrifluorobenzene (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 2,4,5ꢀ
trifluorophenyl magnesium bromide 1c obtained was immediately used further according to the
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general procedure described above to obtain product 16 (670 mg, 97% yield) as a colorless oil. H
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), 6.79ꢀ6.97 (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.
1H NMR, 13C NMR spectra of all compounds and detailed information on ligand screening and opꢀ
timization procedure are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: zdenko.casar@sandoz.com, Tel.: +386 1 580 2079, Fax: +386 1 568 3517
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGEMENTS
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This study was supported by the Slovenian Research Agency (Grant P1ꢀ0208). In addition, the auꢀ
thors thank Lek Pharmaceuticals d.d. for support of project SDCCROS/2011ꢀ351.
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