Iron-Catalyzed Cross-Coupling of Alkenyl Acetates

Article abstract of DOI:10.1002/anie.201504524

Stable C-O linkages are generally unreactive in cross-coupling reactions which mostly employ more electrophilic halides or activated esters (triflates, tosylates). Acetates are cheap and easily accessible electrophiles but have not been used in cross-couplings because the strong C-O bond and high propensity to engage in unwanted acetylation and deprotonation. Reported herein is a selective iron-catalyzed cross-coupling of diverse alkenyl acetates, and it operates under mild reaction conditions (0 C, 2 h) with a ligand-free catalyst (1-2 mol%). Iron clad: Acetates are underutilized electrophiles in metal-catalyzed cross-coupling reactions because of the strong alkenyl C-O bond and their propensity to engage in unwanted reactions. Combination of a ligand-free low-valent Fe catalyst with nucleophilic organomagnesium reagents, low temperature, and short reaction times results in highly selective cross-couplings with alkenyl acetates.

Full text of DOI:10.1002/anie.201504524

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504524
German Edition: DOI: 10.1002/ange.201504524
Cross-Coupling
Hot Paper
Iron-Catalyzed Cross-Coupling of Alkenyl Acetates
Dominik Gärtner, AndrØ Luiz Stein, Sabine Grupe, Johannes Arp, and
Axel Jacobi von Wangelin*
Dedicated to Professor Manfred Scheer on the occasion of his 60th birthday.
À
Abstract: Stable C O linkages are generally unreactive in
cross-coupling reactions which mostly employ more electro-
philic halides or activated esters (triflates, tosylates). Acetates
are cheap and easily accessible electrophiles but have not been
À
used in cross-couplings because the strong C O bond and high
propensity to engage in unwanted acetylation and deprotona-
tion. Reported herein is a selective iron-catalyzed cross-
coupling of diverse alkenyl acetates, and it operates under
mild reaction conditions (08C, 2 h) with a ligand-free catalyst
(1–2 mol%).
T
he recent developments of selective iron-catalyzed cross-
coupling reactions rival their conventional palladium- and
nickel-catalyzed counterparts in terms of reactivity and scope
while displaying higher sustainability and operational sim-
plicity.[1] However, the use of non-activated halide-free
electrophiles remains a true challenge for all cross-coupling
methods (Scheme 1).[2] Oxygen-based electrophiles are espe-
À
Scheme 2. Iron-catalyzed cross-coupling of non-activated C O electro-
philes. EWG=electron-withdrawing group.
shielding (tert-butyl) or electronic deactivation (OR, NR2).[4]
To the best of our knowledge, there are no reports of iron-
catalyzed cross-coupling reactions of simple unbiased esters.
Among them, organic acetates are an especially attractive
Scheme 1. Electrophiles in metal-catalyzed cross-coupling reactions.
Tf =trifluoromethanesulfonyl, Ts =4-toluenesulfonyl.
À
class of cheap, halide-free C O electrophiles bearing a small,
nonhazardous leaving group, and is easily accessible by
various acetylation protocols.[5] However, the considerable
electrophilicity and acidity (pKa 24), and low bond dissocia-
cially attractive starting materials because of their ubiquitous
occurrence in biomass-derived chemicals and facile prepara-
tion from alcohols or carbonyl compounds. However, the
À
tion energy of the acetyl O bond appear to prohibit, on
À
general stability of C O bonds has limited the scope of most
thermodynamic grounds, the use of acetates in coupling
reactions with highly basic/nucleophilic organometallic
reagents. Consistently, all known cross-coupling protocols
involve mild organoboron/zinc species.[3] Thus, iron-catalyzed
cross-couplings between organic acetates and Grignard
reagents requires an especially active catalyst which operates
under kinetic control where the competing deprotonation and
acetylation pathways are suppressed. We envisioned capital-
izing on the combination of a) a ligand-free, low-valent iron
catalyst which favors rapid oxidative addition of the non-
activated electrophile, b) Grignard reagents as good nucleo-
philes which exhibit rapid transmetalation, and c) low tem-
peratures/short reaction times to achieve selective cross-
coupling of alkenyl acetates. Similar reaction conditions have
been reported for the mechanistically different ring-opening
of 2-pyrones (Scheme 2).[6]
cross-coupling methods to activated esters (triflate, tosylate
or in benzyl/allyl position). There are very few nickel- or
rhodium-catalyzed protocols which employ non-activated
ester derivatives at elevated temperatures.[3]
Iron-catalyzed cross-coupling was reported with alkenyl
pivalates and aryl carbamates/sulfamates (Scheme 2) where
the undesired carbonyl/sulfonyl attack is suppressed by steric
[*] M.Sc. D. Gärtner, Dr. A. L. Stein, Dr. S. Grupe, Dr. J. Arp,
Prof. Dr. A. Jacobi von Wangelin
Institute of Organic Chemistry, University of Regensburg
Universitaetsstr. 31, 93040 Regensburg (Germany)
E-mail: axel.jacobi@ur.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504524.
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To provide reaction conditions which would strictly favor
kinetic control, we set out to study ligand-free iron catalysts
(prepared in situ by reduction of ferrous salts with strongly
nucleophilic alkyl Grignard reagents) in cross-coupling reac-
tions at 08C. We initially probed the feasibility of chemo-
selective cross-coupling of n-octyl magnesium bromide with
the alkenyl acetate 1, bearing a vicinal ester group, to give the
tetrasubstituted olefin 3 (Table 1).[7] To our delight, iron
Table 1: Selected optimization experiments.[a]
Figure 1. Comparison of O-based leaving groups (X=Tf, Ac, Piv,
CONMe2). Piv=pivaloyl.
Entry
Catalyst (mol%)
Additive (equiv)
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (10)
FeCl2 (2)
–
–
31[c]
62
57
62
82
91
98
2
LiCl (1)
Table 2: Cross-coupling of 1 with organomagnesium halides.[a]
SIMes·HCl (0.2)
IPr HCl (0.2)
TMEDA (0.2)
BDMAEE (0.2)
NMP (2)
NMP (2)
–
Entry
Grignard reagent
MeMgBr
Yield [%][b]
0 (0)[d,e]
99[d] (97)[f]
1
2
3
4
5
6
R’=H
R’=n-C10H21
R’=Ph
86[c]
94[c]
87[c]
85[c]
79[c]
83[c]
–
FeCl2 (2)
NMP (2)
[a] Reaction onditions: 0.25 mmol 1, 0.5 mmol 2 in 1 mL THF, 1 h, 08C.
[b] Quantitative GC versus internal n-C15H32. [c] 258C. [d] Addition of
1.25 equiv 2 over 5 min. [e] 6 h, 608C, 1 was recovered. [f] 1.1 equiv 2,
À308C. BDMAEE=bis(2-(N,N-dimethyl-amino)ethyl)ether, NMP=N-
methyl-2-pyrrolidinone, SIMes=1,3-bis(2,4,6-trimethylphenyl)-4,5-dihy-
droimidazol-2-ylidene, THF=tetrahydrofuran, TMEDA=N,N,N’,N’-tet-
ramethylethylendiamine.
n=1
n=2
7
74
8
R’=Cl
89[c]
68[c]
76
9
R’=F
10
11
R’=OMe
R’=SMe
75
precatalysts showed far superior activity to PdCl2, NiCl2, and
CuI (< 8% yield). Donor ligands (chloride, amine, phosphine,
N-heterocyclic carbene) enhanced the selectivity (entries 2–
7). As expected from thermodynamic control, catalyst-free
reaction conditions effected rapid acetyl deprotonation
(determined by D2O quench) and only minimal conversion
of 1 (< 10%, entry 9). The optimized reaction conditions
involved reaction of 1 with a slight excess of 2 (1.1–1.25 equiv,
slow addition) in the presence of 2 mol% FeCl2 in THF/NMP
(20:1) at 08C for 1 hour (entry 10). The reactivity of the
starting materials with different O-based leaving groups
12
71
[c]
13
14
15
TMSCH2MgCl
–
<5[c]
=
H2C CHMgBr
PhMgBr
16
[a] Reaction conditions: 0.5 mmol 1, 0.58 mmol (1.15 equiv) Grignard
reagent, 2 mol% FeCl2, 1 mmol NMP in 1.9 mLTHF, 08C, 1 h. [b] Yield of
isolated product. [c] 0.76 mmol (1.5 equiv) Grignard reagent. TMS=tri-
methylsilyl.
followed
the
order
OTf > OAc > OPiv > OCONMe2
Homogeneous and heterogeneous catalysis mechanisms
can be distinguished by kinetic experiments.[10] Quantitative
analyses of the model reaction between 1 and 2 documented
an extremely rapid onset of catalyst activity even between
À35 and 08C without induction periods or sigmoidal curves,
which could indicate nanocluster nucleations en route to
particle formation.[10,11] The reaction is complete (> 97%
yield) after 3 minutes at 08C (20 min at À358C) with turnover
frequencies (TOF) of 3000 hÀ1.
Kinetic poisoning studies were also in agreement with
a homogeneous catalysis. The addition of mercury (100 equiv
per Fe, at 45% conversion) resulted in no alteration of
catalyst activity (Scheme 3).[12] A similar experiment with the
p-acceptor ligand dibenzo[a,e]cyclo-octatetraene (dct;
2 equiv per Fe, at 35% conversion)[10,13] resulted in immediate
and complete inhibition.[7] We thus postulate the operation of
(Figure 1).[4] The substrate scope of this protocol was further
explored by variation of the Grignard reagents (Table 2).[7]
Primary and secondary alkylMgX were effective, and
tBuMgCl gave low conversion and some deacetylation.[8]
The reaction conditions also allowed clean methyl transfer
from MeMgCl (entry 4). Vinyl and phenyl magnesium
bromides gave very low conversion of 1. Halides (F, Cl),
amines, alcoholates, arylmethylethers, aryl sulfides, esters,
ketones, and nitriles were tolerated, with the latter two
proceeding at lower temperature (< À108C). A wide chem-
ical space was explored by use of various alkenyl acetates,
vinylogous carbonates and anhydrides, 1-styryl acetates, and
2-pyrones (Table 3). Thermodynamic migration to the higher-
substituted olefin products was not observed (entries 8–15, 18,
and 19).[9]
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Table 3: Cross-coupling of alkenyl acetates with alkylmagnesium hal-
studies, we discovered an assisting role of olefin substituents
ides.[a]
À
in cross-couplings at strong C X bonds within the electro-
phile.[15]
The significant secondary kinetic isotope effects (secon-
dary KIE)[14] observed with D-labelled alkenyl acetates are
consistent with
whereas catalyst–arene interactions are negligible (Sche-
me 4a). Accordingly, saturated and aromatic acetates and
a rate-determining olefin coordination,
Entry
Product
Yield [%][b]
1
2
n=1
n=2
83[c]
99
3
68[d]
4
5
6
R’=Et
R’=CH CH2
R’=(CH2)4O-(4-ClC6H4)
86[c]
76[c]
81[c]
=
c
7
84
8
9
R’=H
R’=Cl
66[d]
65
10
R’=OMe
91
11
Ar=4-anisyl
76
12
13
14
15
R’=OMe
R’=F
R’=CO2Me
R’=CN
92[e]
69[e]
48[e]
28[e]
Scheme 4. The assisting role of conjugated olefin substituents.
16
17
R’=n-C6H13
R’=c-C6H11
66[c,e,f]
substrates with distal olefin units did not undergo cross-
coupling (< 10%), possibly because of the lack of competent
coordination sites (Scheme 4b).[15,16] Alkylations of allyl
acetates were reported earlier.[17a] The reaction order 1!3,
with respect to [FeCl2], is about 1 at low concentrations
(< 10 mm, < 5 mol%), and about 0.9 with respect to [1] under
standard conditions.[7,18] Therefore, we postulate a mechanism
involving rate-determining olefin coordination to the cata-
lyst.[19] The formation of iron(I) catalysts under similar
reaction conditions was recently shown by various studies.[20]
The coordination of pentadienoates to iron catalysts
under similar reaction conditions was proposed, by Sun and
Fürstner, to operate in the ring-opening methylation of 2-
pyrones to (2Z)-hexadienoates.[6] Accordingly, we performed
sequential cross-couplings with 4-acetoxy-6-methyl-2-pyrone.
Clean acetate substitution occurred with subsequent methyl-
ative ring-opening with a vinylogous acetate acting as formal
leaving group to give the (2E,4E)-hexadienoate at room
temperature in excellent yield (Scheme 5).
69[f]
18
19
R’=Et
R’=OC6H4-OMe
82
75
20
21
R’=Me
R’=n-C8H17
78[d]
49
[a] Reaction conditions (see Table 2). [b] Yield of isolated product.
[c] 1.5 equiv Grignard reagent; [d] 1.05 equiv n-hexylMgBr. [e] Cyclohex-
ylmagnesium chloride. [f] E/Z (starting material) 3.2:1; E/Z (product)
5:1.
Arylations of alkenyl acetates were very sensitive to steric
bulk (entry 15, Table 2).[7] Good conversions were only
obtained with vinyl acetate and monosubstituted alkenyl
acetates (Table 4).[21] The addition of LiCl and NMP afforded
similar results.[22] The formation of arylmagnesium halides
Scheme 3. Poisoning studies with Hg (100 equiv/Fe) and dct (2 equiv/
Fe).
a homogeneous mechanism by soluble low-valent iron
catalysts. In the absence of strong ligands, such iron species
were reported to coordinate p-hydrocarbons.[14] In recent
Scheme 5. Cross-coupling of 2-pyrones according to Fürstner and
Sun.[6]
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Table 4: Cross-coupling of alkenyl acetates with arylmagnesium bromi-
Keywords: alkenes · cross-coupling · enols · Grignard reaction ·
iron catalysis
des.[a]
How to cite: Angew. Chem. Int. Ed. 2015, 54, 10545–10549
Angew. Chem. 2015, 127, 10691–10695
Entry
Product
R
Yield [%][b]
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[7] Further experimental details are given in the Supporting
Information.
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1
2
3
4
5
6
R=H
97
99
82
53
60
50
R=Me
R=OMe
R=F
R=Cl
R=CN
7
8
R=H
R=Me
95
96
9
96
10
11
12
R=Me
R=OMe
R=F
100
81
83
15
16
R=Ph, R’=H
R=H, R’=n-C8H17
75
69
17
18
R=H, n=1
R=OMe, n=2
40
15
[a] Reaction conditions: Mg (1.5 equiv), LiCl (1.5 equiv), THF (2 mL),
08C, ArBr (1.25 equiv), 0!208C over 2 h; then addition of FeCl3
(5 mol%) in THF (0.5 mL) at 08C, alkenyl acetate (1 mmol), 3 h. [b] Yield
of isolated product.
was effected by LiCl-assisted magnesium insertion to give
ArMgBr·LiCl reagents which were directly employed in the
subsequent cross-coupling.
In summary, we have developed a practical iron-catalyzed
cross-coupling of alkenyl acetates with Grignard reagents
which effectively suppresses the thermodynamically favored
acylation and deprotonation as well as post-synthesis olefin
migration. Kinetic studies support a homogeneous mecha-
nism. The observed secondary KIEs suggest rate-determining
coordination of the conjugated alkenyl acetate. This protocol
constitutes a significant extension of the scope of metal-
catalyzed cross-coupling methods which, thus far, mostly
employed organohalides or activated esters as electrophiles.
Experimental Section
General procedure: An oven-dried flask was charged with the alkenyl
acetate (0.50 mmol) under argon. Then, 2.0 mL of a solution of FeCl2
(19.0 mg, 0.15 mmol) in NMP (0.96 mL, 10 mmol) and THF (19 mL)
were added. The mixture was cooled (08C, ice bath) and the alkyl
magnesium bromide (1m in THF, 0.53 mmol) was added by syringe
pump over 10 min. After 1 h at 08C, the reaction was quenched (1 mL
sat. aqu. NH4Cl) and extracted (3 ” 1.5 mL ethyl acetate). The organic
phases were dried (Na2SO4), the solvents evaporated and the residues
purified by flash column chromatography (SiO2, n-pentane).
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Acknowledgements
This work was generously supported by the Deutsche
Forschungsgemeinschaft (DFG).
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and approaches 0 at higher concentrations (> 0.2m, > 1.2 equiv).
The reaction order in substrate 1 is about 0 at concentrations of
greater than 0.5m.
[19] We cannot exclude the operation of a radical mechanism. The
observation of inhibition by TEMPO does not imply the
presence of radical intermediates as TEMPO also reacts with
the Grignard reagent itself. For the discussion of radical
mechanisms, see: a) U. Jahn in Radicals in Synthesis III,
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Received: May 19, 2015
Published online: July 14, 2015
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