Iron-catalyzed hydromagnesiation: Synthesis and characterization of benzylic grignard reagent intermediate and application in the synthesis of ibuprofen

Article abstract of DOI:10.1021/om500319h

Iron-catalyzed hydromagnesiation of styrene derivatives using ethylmagnesium bromide has been investigated for the synthesis of benzylic Grignard reagents. The benzylic Grignard reagent formed in the reaction was observed directly and its conformation in solution characterized by multinuclear and variable-temperature NMR spectroscopy. The Grignard reagent could be stored for at least 2 weeks without significant loss in activity. Hydromagnesiation of styrene in tetrahydrofuran gave a mixture of monoalkyl- and dialkylmagnesium species, (1-phenylethyl)magnesium bromide (2; RMgBr) and bis(1-phenylethyl)magnesium (3; R₂Mg), with the equilibrium between these species lying in favor of the dialkylmagnesium species. The thermodynamic parameters of alkyl exchange for the reaction MgBr₂ + R₂Mg (3) 2RMgBr (2) were quantified, with the enthalpy and entropy of formation of 2 from MgBr₂ and 3 calculated as 32 ± 7 and 0.10 ± 0.03 kJ mol^-1, respectively. This methodology was applied, on a 10 mmol scale, as the key step in the synthesis of ibuprofen, using sequential iron-catalyzed alkyl-aryl and aryl-vinyl cross-coupling reactions to give 4-isobutylstyrene, which following hydromagnesiation and reaction with CO₂ gave ibuprofen. Each step proceeded in excellent yield, at temperatures between 0 °C and room temperature, at atmospheric pressure. Inexpensive, nontoxic, and air- and moisture-stable iron(III) acetylacetonate was used as the precatalyst in each step in combination with inexpensive amine ligands.

Full text of DOI:10.1021/om500319h

Article
pubs.acs.org/Organometallics
Iron-Catalyzed Hydromagnesiation: Synthesis and Characterization
of Benzylic Grignard Reagent Intermediate and Application in the
Synthesis of Ibuprofen
Mark D. Greenhalgh, Adam Kolodziej, Fern Sinclair, and Stephen P. Thomas*
School of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, U.K.
S
* Supporting Information
ABSTRACT: Iron-catalyzed hydromagnesiation of styrene
derivatives using ethylmagnesium bromide has been investigated
for the synthesis of benzylic Grignard reagents. The benzylic
Grignard reagent formed in the reaction was observed directly
and its conformation in solution characterized by multinuclear
and variable-temperature NMR spectroscopy. The Grignard
reagent could be stored for at least 2 weeks without significant
loss in activity. Hydromagnesiation of styrene in tetrahydrofuran
gave a mixture of monoalkyl- and dialkylmagnesium species, (1-
phenylethyl)magnesium bromide (2; RMgBr) and bis(1-phenyl-
ethyl)magnesium (3; R2Mg), with the equilibrium between these
species lying in favor of the dialkylmagnesium species. The
thermodynamic parameters of alkyl exchange for the reaction
MgBr2 + R2Mg (3) ⇌ 2RMgBr (2) were quantified, with the enthalpy and entropy of formation of 2 from MgBr2 and 3
calculated as 32 7 and 0.10 0.03 kJ mol−1, respectively. This methodology was applied, on a 10 mmol scale, as the key step in
the synthesis of ibuprofen, using sequential iron-catalyzed alkyl−aryl and aryl−vinyl cross-coupling reactions to give 4-
isobutylstyrene, which following hydromagnesiation and reaction with CO2 gave ibuprofen. Each step proceeded in excellent
yield, at temperatures between 0 °C and room temperature, at atmospheric pressure. Inexpensive, nontoxic, and air- and
moisture-stable iron(III) acetylacetonate was used as the precatalyst in each step in combination with inexpensive amine ligands.
magnesiation of olefins can be used for the synthesis of
Grignard reagents and is complementary to the standard
preparation by the reaction of alkyl halides with magnesium.10
Hydromagnesiation is particularly attractive when the required
alkyl halides are not readily available or contain functional
groups incompatible with Grignard reagent formation. The
direct addition of MgH2 to alkenes is inefficient, requiring high
temperatures and pressures;11 however, titanium and zirconium
catalysts can be used to affect the reaction.12
A more common approach is to use a Grignard reagent
bearing β-hydrogens, in the presence of a transition-metal
catalyst, as a superficial source of “HMgX” for Grignard−alkene
exchange (Scheme 1). This reaction involves β-hydride transfer
from a Grignard reagent to an alkene, to produce a new
Grignard reagent and alkene. The reaction can be catalyzed by
a range of transition-metal salts, including titanium, nickel,
vanadium, zirconium, and iron.10,13 “Grignard−alkene ex-
change” has been proposed to occur by alkylation of the
transition-metal catalyst by the Grignard reagent and co-
INTRODUCTION
■
Iron-catalyzed processes for the construction of complex
molecular frameworks have received increased industrial and
academic interest due to the cost, environmental, and health
benefits of using iron in place of traditionally used transition-
metal catalysts.1 Since the seminal publications by Kharasch2
and Kochi,3 iron-catalyzed cross-coupling methodologies for
carbon−carbon bond formation have been developed to
accommodate many coupling partners, which tolerate a wide
range of functional groups.4 Synthetically useful iron-catalyzed
methodologies for olefin and carbonyl reduction5 and olefin6
and C−H functionalization7 have also been developed. Despite
these advances, there have been only limited examples of the
use of iron catalysis for the synthesis of high-value
pharmaceutical and agrochemical products. The synthesis of
cinacalcet hydrochloride is an exception, as an iron-catalyzed
Kumada cross-coupling was chosen for the key carbon−carbon
bond-forming step.8 The reaction was applied on the
multikilogram scale, demonstrating the potential applicability
of Grignard reagents and iron-catalyzed methodologies in
industry.
Special Issue: Catalytic and Organometallic Chemistry of Earth-
Abundant Metals
Grignard reagents are highly versatile organometallic species
that can be used for the formation of a range of carbon−carbon
and carbon−heteroatom bonds, through direct reaction with
electrophiles or via cross-coupling methodologies.9 Hydro-
Received: March 24, 2014
© XXXX American Chemical Society
A
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Scheme 1. Transition-Metal-Catalyzed Hydromagnesiation
of Alkenes
Scheme 2. Iron-Catalyzed Hydromagnesiation of Styrene
Derivatives
reaction and application of these studies to the development of
a simplified catalytic system for use on scale.
Initial studies were directed at gaining a greater under-
standing of the iron-catalyzed hydromagnesiation methodology,
with a focus on improving the industrial potential of the iron-
catalyzed process. In particular, a simplified catalytic system was
required, which could be applied on scale.
RESULTS AND DISCUSSION
■
ordination of the alkene substrate, followed either by a β-
hydride elimination−hydrometallation pathway involving a
transient metal hydride species13a−c,f−j or by direct β-hydride
exchange13d,e between alkyl and alkene ligands on the catalyst
(Scheme 1). The alkyl−metal complex formed may then
undergo transmetallation with another 1 equivalent of Grignard
reagent to close the catalytic cycle and release the new Grignard
reagent.14 The hydromagnesiation of terminal alkenes can give
either primary or secondary Grignard reagents. The regiose-
lectivity is thermodynamically driven, with aliphatic alkenes
giving primary Grignard reagents and aryl alkenes giving
secondary Grignard reagents. Conceptually, the forward
reaction can be favored by selecting a Grignard reagent that,
following β-hydride transfer, gives an alkene that cannot
reenter,13j or can be removed from, the catalytic cycle. The
development of an efficient olefin hydromagnesiation method-
ology relies on careful tuning of the catalytic system to ensure
hydride transfer to the olefin. An appropriate choice of
transition-metal catalyst (including ligand) in conjunction
with optimization of the reaction conditions is required in
order to favor hydrometallation over other potential reactions,
such as carbometallation (alkyl transfer), cross-coupling (alkyl
transfer), protodehalogenation (hydride transfer), and polymer-
ization, among others (Scheme 2).1,4,9,14,15
The formation and structure of alkyl Grignard reagents
synthesized from alkenes by transition-metal-catalyzed hydro-
magnesiation had previously been inferred on the basis of the
products formed following reaction with an electrophile.10,13
We sought to gain a greater understanding of the nature of the
Grignard reagent intermediate by direct observation by
multinuclear and 2D NMR spectroscopy. In tetrahydrofuran
the composition of organomagnesium species can be expressed
by a simplified Schlenk equilibrium, where only monomeric
magnesium species are present (eq 1).16 The observation and
MgBr2 + R2Mg ⇌ 2RMgBr
(1)
characterization of discrete monoalkylmagnesium (RMgBr) and
dialkylmagnesium (R2Mg) species by NMR spectroscopy can
often be challenging due to rapid exchange between the species
on the NMR time scale. The rate of exchange between
organomagnesium species is, however, highly dependent upon
the structure and sterics of the organic group. Ashby reported
that while the methyl Grignard reagent required cooling to
−100 °C for the observation of MeMgX and Me2Mg, the tert-
butyl Grignard reagent was observed as discrete mono- and
dialkylmagnesium species at room temperature.17
We recently reported an iron-catalyzed formal hydro-
carboxylation reaction for the synthesis of α-aryl carboxylic
acids from styrene derivatives and carbon dioxide, using
ethylmagnesium bromide (EtMgBr) as the hydride source
(Scheme 2).13k Using 1 mol% of iron chloride and bis(imino)-
pyridine ligand 1, good to excellent yields of α-aryl carboxylic
acid derivatives were isolated for styrene derivatives bearing
electron-donating groups, without the observation of compet-
ing carbometallation or polymerization. The reaction was
proposed to occur by iron-catalyzed hydromagnesiation of the
styrene derivative to give a benzylic Grignard reagent, and the
reaction was driven to completion by the loss of ethene (from
the β-hydride elimination of EtMgBr) from solution. Herein we
report initial mechanistic studies of the hydromagnesiation
Conducting the iron-catalyzed hydromagnesiation of styrene
in d8-tetrahydrofuran gave a mixture of (1-phenylethyl)-
magnesium bromide (2; RMgBr) and bis(1-phenylethyl)
magnesium (3; R2Mg), which could be observed at room
temperature (25 °C) in a ratio of 1:1.5, corresponding to an
equilibrium constant (Keq) of 0.44 (Scheme 3).18,19 Character-
ization was aided by perturbation of the Schlenk equilibrium to
favor either organomagnesium species. Addition of 1,4-dioxane
resulted in the precipitation of MgBr2·(dioxane) to give a
majority of 3,20 while addition of MgBr2 led to an increase in 2
(Figure 1). Two-dimensional NMR spectroscopy was used to
identify and fully characterize 2 and 3. As expected, 3 was
observed as a 1:1 mixture of diastereoisomers. COSY NMR
1
spectroscopy was used for identification of the H resonances
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2 (RMgBr) from MgBr2 and 3 (R2Mg) were calculated using
13C NMR spectroscopy. Integration of the equivalent carbons
of 2 and 3 were compared over five resonances to give an
average ratio of the species. From these data, the enthalpy and
entropy of formation of 2 from MgBr2 and 3 were calculated as
Scheme 3. Schlenk Equilibrium of Intermediate Grignard
Reagent
32
7 and 0.10
0.03 kJ mol−1, respectively (Figure 3,
Figure 3. van’t Hoff plot of ln Keq vs. 103/T for the reaction MgBr2 +
R2Mg (3) ⇌ 2RMgBr (2).
Scheme 3). A positive value for ΔH in tetrahydrofuran is
common and has been proposed to reflect the increased
solvation of MgBr2 in comparison to the organomagnesium
species.16a These data show that the benzylic Grignard reagent
intermediate formed in this reaction exhibits a particularly large
preference to exist as the dialkylmagnesium species 3 in
tetrahydrofuran solution. The values for enthalpy and entropy
of formation are comparable to those reported for the
formation of tert-butylmagnesium chloride from t-Bu2Mg and
MgCl2 in tetrahydrofuran.17 The Grignard reagent intermediate
was found to be relatively stable, even when left in the presence
of the iron catalyst, with 95% of the active Grignard reagent
remaining 2 weeks after synthesis.18
Having confirmed the identity of the Grignard reagent
intermediate, the progress of the hydromagnesiation of styrene
was monitored by periodically removing aliquots and
quenching with chlorotrimethylsilane. Using 1 mol% of FeCl2
and bis(imino)pyridine 1, over 60% yield was obtained within
the first 10 min, and full conversion was reached within 2 h
(Figure 4, ×).22 In comparison to iron chloride and
ethylmagnesium bromide, bis(imino)pyridine 1 is relatively
expensive and toxic, and thus an alternative catalyst system was
investigated. A combination of inexpensive and air- and
moisture-stable Fe(acac)3 (1 mol%) and N,N,N′,N′-tetrame-
thylethylenediamine (TMEDA) (1 mol%) gave results
comparable to those using iron chloride and bis(imino)pyridine
1, providing a much simpler catalytic system (Figure 4, −).
The catalyst loading was lowered to 0.1 mol% in order to
follow the initial reaction kinetics in detail (Figure 5).22 Using
0.1 mol% of Fe(acac)3, TMEDA loadings of 0.1−1 mol% gave
comparable results (Figure 5, × and −); however, less than 0.1
mol% of TMEDA (less than 1 equiv with respect to iron)
resulted in a decreased rate of reaction (Figure 5, ▲). When
the scale of the reaction was increased 10-fold from 0.7 to 7
mmol, a slightly reduced rate of reaction was observed in the
first 30 min, but significantly only 40% yield was obtained after
2 h (Figure 5, +). Increasing the catalyst loading back to 1 mol
% gave only 63% yield after 2 h (Figure 4, ▲). Considering the
1
Figure 1. H NMR spectra of 2 and 3 at room temperature.
of the α-aryl proton(s) of both 2 and 3 due to overlap with d8-
tetrahydrofuran.
Alkyl exchange between 2 and 3 was sufficiently slow that
equilibrium constants could be recorded by variable-temper-
ature NMR spectroscopy (5−55 °C).21 Upon an increase in the
temperature, a decrease in dialkylmagnesium species 3 and,
correspondingly, an increase in the monoalkyl species 2 was
observed (Figure 2). Equilibrium constants for the formation of
Figure 2. Variable-temperature 13C NMR spectra of methyl carbons of
2 and 3 (R = PhCHCH3).
C
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observed, with a slower initial rate of reaction and only 46%
yield after 2 h (Figure 5, ●). The difference in the rate of
ethene loss from the small- and large-scale reactions might be
attributed to the larger surface area of the solution and more
efficient stirring on the small scale. To aid the loss of ethene on
a large scale, the reaction was continuously sparged with
nitrogen. As predicted, high catalyst activity was recovered and
a yield of 92% was obtained within 2 h (Figure 4, +). These
results indicate that, for the large-scale synthesis of benzylic
Grignard reagents in high yields using this methodology,
efficient ethene loss from solution is of paramount importance.
Having simplified and optimized the reaction conditions for
the hydromagnesiation of styrene [Fe(acac)3 (1 mol%),
TMEDA (1 mol%)], the synthesis of ibuprofen (4) from a
simple disubstituted benzene derivative using only iron-
catalyzed reactions was investigated.
Ibuprofen is a commodity α-arylpropanoic acid nonsteroidal
anti-inflammatory drug (NSAID), primarily used as a pain killer
and for the treatment of inflammatory diseases.23 The original
Boots synthesis of ibuprofen, which converted isobutylbenzene
to ibuprofen in six steps,24 was improved by a joint venture of
Boots and Hoescht Company (BHC) to just three steps
(Scheme 4).25 The BHC synthesis was highly atom economical
Figure 4. Hydromagnesiation of styrene using 1 mol% iron catalyst.
Conditions: iron salt (1 mol%), ligand (1 mol%), styrene (0.7 or 7
mmol), EtMgBr (140 mol%, 0.96 or 9.6 mmol, 3 M in Et2O, 0.32 or
3.2 mL), tetrahydrofuran (0.2 M). Key: (×) FeCl2, bis(imino)pyridine
1, styrene (0.7 mmol); (−) Fe(acac)3, TMEDA, styrene (0.7 mmol);
Scheme 4. Synthesis of Ibuprofen by the BHC Process and
Proposed Retrosynthesis of Ibuprofen Using Sequential
Iron-Catalyzed Cross-Coupling and Hydromagnesiation
▲
(
) Fe(acac)3, TMEDA, styrene (7 mmol); (+) Fe(acac)3, TMEDA,
styrene (7 mmol), with N2 bubbling.
and used catalysts in each step, which could be recycled.
However, high temperatures and pressures and the use of toxic
and/or corrosive reagents (hydrogen fluoride, carbon mon-
oxide, nickel) are required, as well as a final step involving a
palladium-catalyzed CO insertion. There has been considerable
recent industrial26 and academic interest27 in improving the
established synthetic route to ibuprofen and the development
of new methodologies to α-aryl carboxylic acid derivatives in
general.
This synthesis of ibuprofen would use the hydromagnesiation
of 4-isobutylstyrene as the final key step, and it was expected
that 4-isobutylstyrene (5) could be synthesized by sequential
iron-catalyzed cross-coupling reactions from a simple disub-
stituted benzene derivative 6 (Scheme 5). This would
demonstrate the utility of iron catalysis in synthesis, high-
lighting the potential to tune catalyst selectivity for alkyl
transfer (cross-coupling) and hydride transfer (hydrometalla-
tion).
Figure 5. Hydromagnesiation of styrene using Fe(acac)3 (0.1 mol%)
and TMEDA (0.075−0.1 mol%). Conditions: Fe(acac)3 (0.1 mol%),
TMEDA (0.075−0.1 mol%), styrene (0.7 or 7 mmol), EtMgBr (140
mol%, 0.96 or 9.6 mmol, 3 M in Et2O, 0.32 or 3.2 mL),
tetrahydrofuran (0.2 M). Key: (×) TMEDA (0.1 mol%), styrene
▲
(0.7 mmol); (−) TMEDA (1 mol%), styrene (0.7 mmol); (
)
TMEDA (0.075 mol%), styrene (0.7 mmol); (+) TMEDA (0.1 mol
●
%), styrene (7 mmol); ( ) TMEDA (0.1 mol%), styrene (0.7 mmol),
cyclopentene (1.4 mmol, 0.124 mL).
proposed mechanism for hydromagnesiation, it was rationalized
that ethene production may inhibit the reaction, and inefficient
loss of ethene from solution could be responsible for the
observed retardation of reaction rate. To investigate this
proposal, an excess of cyclopentene (2 equiv) was added at the
beginning of the reaction as a less volatile surrogate for ethene.
On a small scale (0.7 mmol) inhibition of the reaction was
D
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Regioselectivity for the α-aryl carboxylic acid was over 40:1;
however, the α:β ratio was further increased to approximately
150:1 by recrystallization from hexane.
Scheme 5. Retrosynthetic Analysis of Ibuprofen, Using Only
Iron-Catalyzed Reactions
The synthesis of 4-isobutylstyrene (5) from a simple
disubstituted benzene derivative 6 by two sequential iron-
catalyzed cross-coupling reactions was then investigated
(Scheme 5). With an initial focus on route I, disconnection
a, iron-catalyzed cross-coupling of commerically available 4-
halo-substituted styrene derivatives 7 (X = Br, Cl) with isobutyl
Grignard reagents using Fe(acac)3 and N-methyl-2-pyrrolidi-
none (NMP) (100 mol%) was investigated (Scheme 6). The
Scheme 6. Cross-Coupling of iBuMgCl with 4-Halo-
a
Substituted Styrene Derivatives 7a,b
Iron-catalyzed alkyl−aryl cross-coupling is well developed
(Scheme 5, disconnection a), with numerous methodologies
described for the coupling of alkyl Grignard reagents with aryl
electrophiles or of aryl Grignard reagents with alkyl electro-
philes.1,4 There have only been limited reports of iron-catalyzed
aryl−alkenyl cross-coupling using arylmetal reagents, however
(Scheme 5, disconnection b), and most give either moderate
yields or only disclose limited substrate scope.28 In addition,
very few examples have been reported for the synthesis of
terminal, unsubstituted styrene derivatives. The iron-catalyzed
reductive cross-coupling of aryl bromide derivatives with
alkenyl bromides developed by Jacobi von Wangelin, however,
gives styrene derivatives in good to excellent yield.29
Significantly, a range of functionalities were tolerated, including
alkyl and halide groups, thus either route I or route II could be
possible for disconnection b using this methodology (Scheme
5).
a
Conditions: 7a or 7b (1 mmol), Fe(acac)3 (5 mol%), NMP (100 mol
%), THF (0.2 M). iBuMgCl (1.3 mmol) added at 0 °C over 20 min;
stirring for a further 50 min and warming to room temperature.
reaction using 4-bromostyrene (7a) was not selective for cross-
coupling and resulted in low mass recovery, with only
protodehalogenation30 and competitive polymerization ob-
served.15 Using 4-chlorostyrene (7b), small amounts (<5%)
1
of 4-isobutylstyrene were observed by H NMR and GC-MS
analysis; however, polymerization of the starting material
dominated. This result is in accordance with previous attempts
at iron-catalyzed cross-coupling using 4-chlorostyrene.31
Reversal of the coupling partners, i.e. the cross-coupling
reaction between (4-vinylphenyl)magnesium bromide and
isobutyl bromide, was therefore tested (Scheme 7). Exploratory
The developed hydromagnesiation reaction conditions
(Fe(acac)3 (1 mol%), TMEDA (1 mol%)) were therefore
applied to the synthesis of ibuprofen (4) from 4-isobutylstyrene
(5). On a 1 mmol scale, ibuprofen (4) was synthesized in 67%
yield (Table 1, entry 1); however, when the scale of the
Scheme 7. Cross-Coupling of ArMgBr with Isobutyl
Bromide
Table 1. Optimization of Iron-Catalyzed Hydrocarboxylation
of 4-Isobutylstyrene
a
a
b
yield (%)
a
Conditions: isobutyl bromide (3 mmol), Fe(acac)3 (5 mol%),
entry
scale (mmol)
4
4-β
5
TMEDA (20 mol%), hexamethylenetetramine (HMTA) (5 mol%),
1
2
1
10
10
67
1
1
2
23
47
1
THF (1.5 M), 0 °C; Grignard reagent (4 mmol) added over 40 min;
45
b
stirring for a further 50 min. Conditions: isobutyl bromide (3 mmol),
c
d
3
92
FeCl3 (5 mol%), THF (2 M), room temperature; Grignard reagent
(3.6 mmol) and TMEDA (3.6 mmol) added as a mixture over 40 min;
stirring for a further 20 min.
a
Conditions: (i) 5 (1−10 mmol), Fe(acac)3 (1 mol%), TMEDA (1
mol%), THF (0.5 M), EtMgBr (140 mol%), 2 h, room temperature;
b
(ii) CO2, 15 min. Yield determined by 1H NMR using 1,3,5-
c
trimethoxybenzene (20 mol%) as an internal standard. N2 bubbled
through reaction during step i. Isolated yield, 1.90 g.
d
experiments using tolylmagnesium bromide in place of (4-
vinylphenyl)magnesium bromide showed promising activity for
cross-coupling with isobutyl bromide using conditions
developed by either Cahiez32 or Nakamura (Scheme 7).33
The cross-coupling using (4-vinylphenyl)magnesium bromide,
however, gave only a modest yield of 4-isobutylstyrene (5;
52%), with significant loss of material, which once again may be
attributed to polymerization of the styrene.15 Although
selectivity for cross-coupling was greatly improved using this
approach, in comparison to the attempted alkyl−aryl cross-
reaction was increased to 10 mmol, just 45% yield was
obtained, along with recovered starting material (entry 2). In
keeping with the results using styrene, the 10 mmol scale
reaction could be driven to completion by sparging the reaction
with nitrogen during the hydromagnesiation step. Ibuprofen
was obtained in 96% yield (92% isolated yield, entry 3),
representing an improvement upon the previously reported
yield of 83% using FeCl2 and bis(imino)pyridine ligand 1.13k
E
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coupling reactions using 4-halo-substituted styrene derivatives,
the moderate yields obtained were still not satisfactory.
octylmagnesium bromide,28f 1,4-dichlorobenzene (6e) was
unreactive in the cross-coupling reaction with isobutylmagne-
sium chloride (Table 2, entry 5). Aryl triflate 6f was cross-
coupled chemoselectively at the triflate group, over the aryl
chloride, and without protodehalogenation, to give 4-isobutyl-
1-chlorobenzene (8b) in excellent yield (entry 6). Slow
addition of the Grignard reagent improved the yield of 8b to
87% (entry 7). Reducing the quantity of NMP to 20 mol% or
using 2-methyltetrahydrofuran as the reaction solvent had only
small negative effects on the reaction yield (entries 8 and 9).
Attempts to use N,N,N′,N′-tetramethylethylenediamine
(TMEDA) as a cosolvent/ligand, however, gave very low
yields of 8b and returned a majority of starting material (entry
10). Using optimized conditions (entry 7), the reaction scale
was increased to 8 mmol, giving 4-isobutyl-1-chlorobenzene
(8b) in 82% isolated yield (entry 11).
Conversion of 4-isobutyl-1-chlorobenzene (8b) to the
corresponding aryl Grignard reagent and subsequent aryl−
vinyl cross-coupling to give 4-isobutylstyrene (5) was finally
investigated. Due to cost, environmental, and health benefits,
vinyl acetate, rather than vinyl bromide, was chosen as the
coupling partner.37,38 The reaction was highly chemoselective
for cross-coupling, giving 4-isobutylstyrene (5) in good to
excellent yield, with only minimal side reactions occurring at
the acyl group (Table 3). Interestingly, if vinyl acetate was
Attention was therefore switched to focus on the cross-
coupling of disubstituted benzene derivatives 6 with isobutyl
Grignard reagents to selectively give monosubstituted cross-
coupled products 8 (Scheme 5, route II, disconnection a). 4-
Isobutyl-1-bromobenzene (8a) was initially targeted in
anticipation of its compatibility in the aryl−vinyl cross-coupling
methodology intended for disconnection b.29 Furstner reported
̈
that efficient cross-coupling occurred between alkyl Grignard
reagents and aryl chlorides, tosylates, and triflates; however,
cross-coupling reactions with aryl bromides and iodides were
inefficient.34 We hoped to exploit this difference in reactivity to
synthesize 8a, by selective cross-coupling at the 4-substitutent
of a 4-substituted aryl bromide in which the bromide group
remained intact. Cross-coupling reactions between isobutyl-
magnesium chloride and 4-substituted aryl bromides 6a−c,
bearing chloride, triflate, and tosylate groups, respectively, were
therefore investigated (Table 2, entries 1−3). The reaction
Table 2. Optimization of Iron-Catalyzed Alkyl−Aryl Cross-
a
Coupling Reaction
Table 3. Optimization of Iron-Catalyzed Aryl−Vinyl Cross-
a
b
yield (%)
Coupling Reaction
entry
substrate
X
Y
6
8
9
10
1
2
3
4
6a
6b
6c
6d
6e
6f
Cl
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
80
<10
<10
<10
<10
<10
<10
<5
OTf
OTs
Br
<10
30
83
c
5
Cl
<5
82
87
84
75
<5
b
yield (%)
6
OTf
OTf
OTf
OTf
OTf
OTf
c
7
6f
entry
ligand
solvent
THF
5
11
cd
,
8
ce
,
6f
c
1
TMEDA
TMEDA
NMP
68
92
90
87
52
90
8
1
1
1
3
1
9
6f
d
2
THF
cf
,
10
11
6f
>75
<5
d
3
THF
cg
,
h
6f
82
d
4
TMEDA
none
2-Me-THF
THF
a
d
Conditions: aryl halide 6a−f (0.7 mmol), Fe(acac)3 (5 mol%), THF
5
(0.25 M), NMP (100 mol%), iBuMgCl (130 mol%, 2 M in THF)
de
,
6
TMEDA
THF
added over 5 min at 0 °C, then warming to room temperature over 30
a
b
1
Conditions: Fe(acac)3 (5 mol%), THF (0.25 M), TMEDA (20 mol
min. Yield determined by H NMR using 1,3,5-trimethoxybenzene
c
%), p-iBuC6H4MgCl (130 mol%), vinyl acetate (0.7 mmol), 0 °C, 1 h.
(20 mol%) as an internal standard. iBuMgCl added over 30 min.
b
1
d
e
f
Yield determined by H NMR using 1,3,5-trimethoxybenzene (20
NMP (20 mol%). 2-Me-THF used in place of THF. TMEDA (20−
c
g
h
mol%) as an internal standard. Vinyl acetate added immediately after
100 mol%) used in place of NMP. 8 mmol scale. Isolated yield, 1.11
g.
d
Grignard reagent. Vinyl acetate added 2 min after Grignard reagent.
e
4 mmol scale.
using 6a gave mostly recovered starting material, and reactions
with 6b,c resulted in poor mass recovery. In each reaction,
protodebromination of the substrates occurred, potentially
arising from iron-catalyzed protodehalogenation,30 hydrogen
abstraction from tetrahydrofuran,35 or halogen-magnesium
exchange36 and subsequent protonation upon workup.
Surprisingly, reactions using 6a−c gave small quantities of
chemoselective cross-coupling at the aryl−bromide bond;
however, the reaction using 1,4-dibromobenzene (6d) also
gave poor mass recovery and protodebromination products
(entry 4).30
added immediately after the Grignard reagent, up to 10% of the
corresponding acetophenone product 11 was formed (Table 3,
entry 1); however, when 2−10 min was allowed between
addition of the Grignard reagent and vinyl acetate, the
unwanted acyl addition side product was limited to less than
2% (entry 2). Grignard addition to ketone 11 to give a tertiary
alcohol was not observed. The cross-coupling was equally
effective using NMP as ligand (20 mol%, entry 3) or using 2-
methyltetrahydrofuran as solvent (entry 4). In the absence of
an amine ligand the aryl−vinyl cross-coupling reaction gave
only a moderate yield of 52% (entry 5). The reaction scale was
increased with no effect upon the yield or selectivity of the
reaction (entry 6). The crude product, 4-isobutylstyrene (5),
Due to unwanted side reactions observed using aryl bromide
substrates, the synthesis of 4-isobutyl-1-chlorobenzene (8b)
was targeted. In contrast to Furstner’s work using n-
̈
F
dx.doi.org/10.1021/om500319h | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
chromatography, silica gel (40−63 μm) was used. Aqueous sulfate
buffer (pH 2) was prepared by dissolving Na2SO4 (1.5 mol) and
H2SO4 (0.5 mol) in deionized water to give a total volume of 2000
mL.
could be used in the subsequent hydromagnesiation step to give
ibuprofen without purification.
CONCLUSION
■
(1-Phenylethyl)magnesium Bromide (2) and Bis(1-
phenylethyl)magnesium (3). Styrene (57 μL, 0.5 mmol) was
added to a solution of [2,6-bis(1-(2,6-diisopropylphenylimino)ethyl)-
pyridine]iron(II) chloride39 (2.5 mg, 0.004 mmol) in anhydrous d8-
tetrahydrofuran (1.5 mL). Ethylmagnesium bromide (0.5 mL, 1 M in
THF, 0.5 mmol) was reduced in volume under vacuum to give a
colorless solid, which was dissolved in anhydrous d8-tetrahydrofuran (1
mL) and added to the reaction mixture, which was stirred for 2 h. A
sample (0.6 mL) was removed and added to an oven-dried J. Young
NMR tube under a nitrogen atmosphere. The mixture of (1-
phenylethyl)magnesium bromide (2) and bis(1-phenylethyl)magne-
sium (3) (present as a 1:1 mixture of diastereoisomers, denoted as 3a
and 3b) were characterized by NMR spectroscopy.
(1-Phenylethyl)magnesium bromide (2): δH (500 MHz, d8-THF)
6.89−6.84 (m, 2H, m-Ar-H), 6.79−6.76 (m, 2H, o-Ar-H), 6.40−6.36
(m, 1H, p-Ar-H), ∼1.75−1.68 (obscured by d8-THF signal, PhCHMg-
(CH3)) 1.52 (d, J = 7 Hz, 3H, CH3); δC (126 MHz, d8-THF). 161.2
(ipso-ArC), 128.3 (m-ArC), 122.6 (o-ArC), 116.5 (p-ArC), 30.1
(PhCHMg(CH3)), 17.6 (CH3).
Bis(1-phenylethyl)magnesium (3; 1:1 mixture of diastereoisomers,
3a and 3b): δH (500 MHz, d8-THF) 6.87−6.82 (m, 8H, 3a + 3b m-Ar-
H), 6.79−6.76 (m, 8H, 3a + 3b o-Ar-H), 6.40−6.36 (m, 4H, 3a + 3b
p-Ar-H), ∼1.80−1.73 (obscured by d8-THF signal, 3a + 3b
PhCHMg(CH3)), 1.54 (d, J = 7 Hz, 6H, 3a or 3b CH3), 1.53 (d, J
= 7 Hz, 6H, 3a or 3b CH3); δC (126 MHz, d8-THF). 161.38 (3a or 3b
ipso-ArC), 161.35 (3a or 3b ipso-ArC), 128.5 (3a + 3b m-ArC), 122.1
(3a + 3b o-ArC), 115.98 (3a or 3b p-ArC), 115.96 (3a or 3b p-ArC),
29.8 (3a or 3b PhCHMg(CH3)), 29.6 (3a or 3b PhCHMg(CH3)),
17.99 (3a or 3b CH3), 17.95 (3a or 3b CH3).
The iron-catalyzed reaction of styrene derivatives with
ethylmagnesium bromide has been shown to proceed by olefin
hydromagnesiation to give an intermediate benzylic Grignard
reagent. This intermediate, which had previously been inferred
by its reactivity, was observed and characterized by multinuclear
and variable-temperature NMR spectroscopy. The benzylic
Grignard reagent showed excellent stability and could be stored
for at least 2 weeks without significant loss in activity. In
tetrahydrofuran, the equilibrium between monoalkyl- and
dialkylmagnesium species lay in favor of the dialkylmagnesium
species, with an equilibrium constant of 0.44 at room
temperature for the reaction MgBr2 + R2Mg (3) ⇌ 2RMgBr
(2). The thermodynamic parameters of alkyl exchange between
(1-phenylethyl)magnesium bromide (2; RMgBr) and bis(1-
phenylethyl)magnesium (3; R2Mg) was measured, with the
enthalpy and entropy of formation of 2 from MgBr2 and 3
calculated as 32 7 and 0.10 0.03 kJ mol−1, respectively. A
simple catalytic system for the hydromagnesiation of styrene
derivatives was developed using the inexpensive and air- and
moisture-stable reagents Fe(acac)3 (1 mol%), and tetramethy-
lethylenediamine (TMEDA) (1 mol%). The methodology was
applied, on scale, to the three-step synthesis of ibuprofen (4)
using only iron-catalyzed reactions (Scheme 8). Each step
Scheme 8. Three-Step, Iron-Catalyzed Synthesis of
Ibuprofen
2-(4-Isobutylphenyl)propanoic Acid (4; Ibuprofen). 4-Iso-
butylstyrene (5; 1.60 g, 10 mmol) was added to a solution of iron(III)
acetylacetonate (35 mg, 0.1 mmol) and N,N,N′,N′-tetramethylethyle-
nediamine (15 μL, 0.1 mmol) in anhydrous tetrahydrofuran (20 mL)
at room temperature. The reaction vessel, with condenser attached,
was immersed in a water bath maintained at 20−25 °C. Ethyl-
magnesium bromide (4.3 mL, 3 M in Et2O, 13 mmol) was added over
2 min, and nitrogen was gently bubbled through the stirred reaction
via a needle for 2 h. The water bath was cooled to around 5−10 °C,
and carbon dioxide was bubbled through the reaction via a needle for
15 min. Ice, followed by aqueous sulfate buffer solution (20 mL), was
added slowly and the aqueous phase extracted with diethyl ether (3 ×
30 mL). The combined organic extracts were washed with water and
brine, dried (MgSO4), and concentrated in vacuo to give the crude
reaction product as a yellow solid. The solid was dissolved in hot
hexane and cooled to 0 °C to give a colorless solid, which was
collected by vacuum filtration, washed with ice-cold hexane, and dried
under high vacuum to give 2-(4-isobutylphenyl)propanoic acid (4) as
an amorphous colorless solid (1.90 g, 9.22 mmol, 92%): mp 76−77 °C
(hexane); δH (400 MHz, CDCl3) 11.72 (br s, 1H), 7.26−7.21 (m,
2H), 7.15−7.09 (m, 2H)), 3.73 (q, J = 7 Hz, 1H), 2.47 (d, J = 7 Hz,
2H), 1.87 (app non, J = 7 Hz, 1H), 1.52 (d, J = 7 Hz, 3H), 0.92 (d, J =
6.5 Hz, 6H); δC (151 MHz, CDCl3) 180.9, 140.8, 137.0, 129.4, 127.3,
45.04, 44.96, 30.1, 22.4, 18.1. Data were in accordance with those
reported previously.40
proceeded in excellent yield (82−92%), at temperatures
between 0 °C and room temperature, all at atmospheric
pressure. The inexpensive, nontoxic, and air- and moisture-
stable iron salt Fe(acac)3 was used as the precatalyst in each
step in combination with inexpensive amine ligands (NMP,
TMEDA). The key iron-catalyzed hydrocarboxylation reaction
used just 1 mol% of iron catalyst and gave ibuprofen in 92%
isolated yield and over 150:1 regioselectivity.
4-Isobutylstyrene (5). 4-Chloro-(2-methylpropyl)benzene (8b;
1.27 g, 10 mmol) was added to magnesium turnings (290 mg, 12
mmol) in anhydrous tetrahydrofuran (10 mL). A single crystal of
iodine was added, and the reaction mixture was heated at reflux for 16
h. The reaction mixture was cooled to room temperature, transferred
to an oven-dried Young tube, and made up to 15 mL with anhydrous
tetrahydrofuran. The concentration of the Grignard reagent (4-
isobutylphenyl)magnesium chloride was determined to be 0.65 M by
titration using 2-hydroxybenzaldehyde phenylhydrazone.
EXPERIMENTAL SECTION
■
All reactions were carried out under anhydrous, air-free conditions
under a nitrogen atmosphere. Solvents for air- and moisture-sensitive
reactions were obtained from an Anhydrous Engineering Solvent
Purification System. Anhydrous d8-tetrahydrofuran was distilled from
sodium/benzophenone. Iron(III) acetylacetonate ≥99.9% was pur-
chased from Sigma-Aldrich (lot no. MKBL6220 V). H, 13C, and 19F
1
NMR spectra were recorded on 400, 500, and 600 MHz
spectrometers. All spectra were obtained at ambient temperature.
NMR yields were determined by 1H NMR using 1,3,5-trimethox-
ybenzene (20 mol%) as an internal standard. For column
(4-Isobutylphenyl)magnesium chloride (8 mL, 0.65 M in
tetrahydrofuran, 5.2 mmol) was added to a solution of iron(III)
acetylacetonate (70 mg, 0.2 mmol) and N,N,N′,N′-tetramethylethyle-
G
dx.doi.org/10.1021/om500319h | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
nediamine (0.12 mL, 0.8 mmol) in anhydrous tetrahydrofuran (15
mL) at 0 °C over 2 min. The reaction mixture was stirred for 2 min,
vinyl acetate (0.37 mL, 4 mmol) was added in one portion, and this
reaction mixture was stirred at 0 °C for 1 h. Aqueous sulfate buffer
solution (10 mL) was added, and the aqueous phase was extracted
with diethyl ether (3 × 30 mL). The combined organic extracts were
washed with water and brine, dried (MgSO4), and concentrated in
vacuo to give the crude reaction product as a colorless oil, which could
be used without further purification. Purification by column
chromatography (hexanes) gave spectroscopically pure 4-isobutylstyr-
ene (5). Data were in accordance with those reported previously.13k,41
4-Bromophenyl Trifluoromethanesulfonate (6b) and 4-
Chlorophenyl Trifluoromethanesulfonate (6f). These com-
pounds were prepared according to a literature procedure.42 Data
were in accordance with those reported previously.43
4-Chloro(2-methylpropyl)benzene (8b). 4-Chlorophenyl tri-
fluoromethanesulfonate (6f; 2.08 g, 8 mmol) was added to a solution
of iron(III) acetylacetonate (141 mg, 0.4 mmol) and N-methyl-2-
pyrrolidinone (0.77 mL, 8 mmol) in anhydrous tetrahydrofuran (15
mL) at room temperature. The reaction mixture was cooled to 0 °C,
and isobutylmagnesium chloride (5.2 mL, 2 M in tetrahydrofuran, 10.4
mmol) was added over 30 min at 0 °C. The reaction mixture was
warmed to room temperature over 30 min. Aqueous sulfate buffer
solution (10 mL) was added and the aqueous phase extracted with
diethyl ether (3 × 30 mL). The combined organic extracts were
washed with water and brine, dried (MgSO4), and concentrated in
vacuo to give the crude reaction products, which were purified by
column chromatography (hexanes) to give 4-chloro-(2-methylpropyl)-
benzene (8b) as a colorless oil (1.11 g, 6.58 mmol, 82%): Rf = 0.72
(hexane); δH (500 MHz, CDCl3) 7.26−7.22 (m, 2H), 7.10−7.05 (m,
2H), 2.45 (d, J = 7 Hz, 2H), 1.84 (app non, J = 7 Hz, 1H), 0.90 (d, J =
6.5 Hz, 6H); δC (126 MHz, CDCl3) 140.1, 131.3, 130.4, 128.2, 44.7,
30.2, 22.2. Data were in accordance with those reported previously.44
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́
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, tables, and figures giving experimental details, NMR
spectra, and calculations of thermodynamic parameters from
variable-temperature NMR spectroscopy. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for S.P.T.: stephen.thomas@ed.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(15) (a) Hirao, A.; Loykulnant, S.; Ishizone, T. Prog. Polym. Sci. 2002,
27, 1399. For reviews on the use of bis(imino)pyridine iron
complexes for polymerization see: (b) Gibson, V. C.; Redshaw, C.;
Solan, G. A. Chem. Rev. 2007, 107, 1745. (c) Gibson, V. C.; Solan, G.
A. Top. Organomet. Chem. 2009, 26, 107.
■
M.D.G. thanks the University of Edinburgh for the provision of
a studentship. S.P.T. thanks the Royal Society for generous
funding (Research Grant).
(16) Dimeric magnesium species are only expected in tetrahydrofur-
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(21) Alkyl−halide exchange between RMgBr (2) and MgX2 may be
faster but cannot be observed in this experiment.
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dx.doi.org/10.1021/om500319h | Organometallics XXXX, XXX, XXX−XXX