Gram-Scale, Cheap, and Eco-Friendly Iron-Catalyzed Cross-Coupling between Alkyl Grignard Reagents and Alkenyl or Aryl Halides

Article abstract of DOI:10.1021/acs.orglett.9b00665

A new robust methodology for gram-scale iron-catalyzed cross-coupling between alkyl Grignard reagents and alkenyl or aryl halides is developed. This method does not require toxic additives such as NMP or expensive ligands. Its efficiency relies on the use of simple alkoxide magnesium salts as additives. On the basis of these results, a new procedure for one-pot synthesis of substituted benzamides from chloroesters is also proposed.

Full text of DOI:10.1021/acs.orglett.9b00665

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gram-Scale, Cheap, and Eco-Friendly Iron-Catalyzed Cross-Coupling
between Alkyl Grignard Reagents and Alkenyl or Aryl Halides
,†
,‡
Gerard Cahiez,* Guillaume Lefevre,* Alban Moyeux,§ Olivier Guerret,⊥ Eric Gayon,⊥
́
̀
Loïc Guillonneau, Nicolas Lefevre, Qinzhuo Gu,† and Edouard Zhou†,‡,⊥
†Institut de Recherche de Chimie Paris, CNRS (UMR 8247) and CNRS, Institute of Chemistry for Life and Health Sciences,
⊥
†,¶
̀
‡
CSB2D, Chimie ParisTech, PSL Research University, 75005 Paris, France
§
́
Laboratoire CSPBAT, UMR 7244, Universite Paris 13, 1 rue de Chablis, 93017 Bobigny Cedex, France
⊥
̂
́
M2i Development, Batiment ChemStart’Up, Allee Le Corbusier, 64170 Lacq, France
S
* Supporting Information
ABSTRACT: A new robust methodology for gram-scale iron-catalyzed
cross-coupling between alkyl Grignard reagents and alkenyl or aryl halides is
developed. This method does not require toxic additives such as NMP or
expensive ligands. Its efficiency relies on the use of simple alkoxide
magnesium salts as additives. On the basis of these results, a new procedure
for one-pot synthesis of substituted benzamides from chloroesters is also
proposed.
ransition-metal-catalyzed-based methodologies applied to
the formation of CC bonds by cross-coupling brought
reactants and afforded cross-coupling products in good to
T
excellent yields. Importantly, all the reactions reported in this
work could be performed at a gram scale (up to 50 mmol for
alkyl-alkenyl couplings, up to 10 mmol for alkyl-aryl
couplings).
an incredible breakthrough in synthetic chemistry.1 This field
is however so far mostly dominated by palladium catalysis. The
high cost of palladium coupled with its toxicity1b raises the
issue of the development of alternative solutions based on the
use of non-noble, cheap catalysts with a low toxicity.2 In this
context, iron appears as one of the best candidates since it is
cheap, eco-friendly, and abundant.3 However, the sustainability
and the toxicity features of the additives or ligands required by
new developed methodologies is also a critical issue. Very
representative is the example of the coupling method reported
by our group in 1998, demonstrating that the use of N-
methylpyrrolidinone (NMP) as a cosolvent in iron catalysis led
to excellent cross-coupling yields between Grignard reagents
and alkenyl halides.4 This methodology requires the use of
simple iron salts (e.g., FeCl3, Fe(acac)3) and thus has the
advantage of not requiring any exogenous expensive ligand.
This NMP-based strategy has been extensively applied to a
large scope of cross-coupling targets ever since.5 However, a
major drawback of this method is the reprotoxicity of NMP,
which has been demonstrated a decade ago,6 and which thus
hampers the use of NMP-based procedures at large scales.
Numerous powerful methodologies involving well-defined iron
complexes with suitable ligands were then reported,7 and
allowed for some of them to circumvent the drawbacks of
coligand-free methodologies, such as the homocoupling of the
Grignard reagent.7i
The positive effect of alkoxide salts (RO[M]) on the
conversion of the reactants and on the cross-coupling yield was
observed using n-butylmagnesium chloride and (1,Z)-bromo-
hexene (1a) as coupling partners in the presence of an in situ-
generated alkoxide magnesium salt (ROMgCl, Table 1). The
latter is prepared by metalation of the corresponding alcohol
with nBuMgCl prior to addition of the reactants, unless
specified otherwise. A first coupling attempt between 1a and
nBuMgCl in the presence of FeCl3 (5 mol %) and EtOMgCl
(250 mol %) was performed. To our delight, a total conversion
of the starting material 1a was observed, and (5,Z)-decene
(2a) was obtained with a 85% yield (Table 1, entry 1). In the
absence of EtOMgCl, 2a is obtained with a lower 75% yield
(Table 1, entry 2). The benefic role of alkoxide salts on the
efficiency of this alkyl-alkenyl cross-coupling is similar to what
is observed using NMP as additive in Fe-catalyzed method-
ologies since it also improves cross-coupling product yield.4 In
our case, the use of NMP as a cosolvent in cross-coupling
between 1a and nBuMgCl afforded olefin 2a with an excellent
97% yield (Table 1, entry 3). Optimization of the catalyst load
and EtOMgCl/Fe ratio (Table 1, entries 4−9) allowed us to
obtain 2a with an excellent 93% yield (2.5 mol % FeCl3, 100
mol % EtOMgCl − EtOMgCl/Fe = 40, Table 1, entry 6), close
to that obtained using 900 mol % NMP. Moreover, this
method is highly stereoselective since the stereochemistry of
In the course of our investigations on the development of
new, eco-friendly, and easily scalable iron-catalyzed cross-
coupling methodologies between alkyl Grignard reagents and
Csp2 (alkenyl or aryl) organic halides, we observed that the
combination of a catalytic charge of FeCl3 with alkoxide
magnesium salts in THF led to a complete conversion of the
Received: February 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00665
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Organic Letters
Letter
magnesium salt (Table 2). This choice has been made to
demonstrate the versatility of this method and show that the
Grignard reagent used for the magnesiation step can differ
from the cross-coupling partner introduced in the coupling
step. Supplanting nBuMgCl by iPrMgCl did not have a
significant impact on the cross-coupling yield determined
earlier between 1a and nBuMgCl (Table 1, entry 6) since 2a
Table 1. Optimization of Nature of RO[M] Additive and of
ROM/FeCl3 Ratio
FeCl3
% conversion
a
entry
(mol %)
RO[M] (mol %)
EtOMgCl (250)
(GC yield)
1
2
3
4
5
6
7
8
5
5
5
5
100 (85)
100 (75)
100 (97)
100 (92)
100 (83)
100 (93)
100 (83)
100 (83)
100 (80)
100 (82)
100 (81)
100 (67)
Table 2. Cross-Coupling Scope of Alkyl Grignard Reagents
a
with Various Alkenyl Halides
0 (900 mol % NMP)
EtOMgCl (200)
EtOMgCl (100)
EtOMgCl (100)
EtOMgCl (40)
EtOMgCl (90)
EtOMgCl (80)
MeOMgCl (100)
nOctOMgCl (100)
iPrOMgCl (100)
tBuOMgCl (100)
5
2.5
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
9
10
11
12
13
14
b
100 (67 )
ClMgOCH2CH2OMgCl
(50)
100 (76)
15
16
17
18
19
20
21
22
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
PhOMgCl (100)
CF3CH2OMgCl (100)
AcOMgCl (100)
Et2NMgCl (100)
100 (80)
100 (67)
100 (77)
100 (70)
100 (95)
100 (72)
80 (56)
c
EtOLi (100)
d
EtONa (100)
d
EtOK (100)
d
EtOMgOEt (100)
100 (70)
a
b
Using dodecane as internal standard. Yield after 1 h reaction.
c
d
Prepared by metalation of EtOH with nBuLi. Commercial salt.
the starting alkenyl halide is conserved in all cases (obtention
of 2a with a stereoisomeric purity Z > 99%).
Encouraged by these results, we investigated the effect of
different alkoxide salts on the cross-coupling of 1a and
nBuMgCl. Various in situ-generated magnesium alkoxide
chloride salts were used in the optimized conditions (2.5
mol % FeCl3, and RO[M]/Fe = 40). The use of MeOMgCl
and n-octylOMgCl, respectively, afforded 82 and 81% of 2a
(Table 1, entries 10−11), whereas the use of iPrOMgCl and of
the bulkier tBuOMgCl led to yields lower than in the absence
of alkoxide additives (67% and 67%, entries 12−13).
Interestingly, the use of bidentate glycoxide salts such as
ClMgOCH2CH2OMgCl did not have a significant effect on the
global yield (76%, entry 14). Alkoxide salts with a lower
Brønsted basicity led to yields similar to that obtained in the
absence of additive (entries 15−16). The effect of alkali salts
(entries 19−21) was also investigated. Use of EtOLi (entry 19)
allowed the formation of 2a with an excellent 95% yield. The
use of the magnesium diethoxide salt only led to 70% of cross-
coupling product (entry 22), probably due to the poor
solubility of this salt in THF. In all examples displayed in Table
1, the steroisomeric purity was excellent since the Z isomer of
2a was selectively obtained (Z:E > 99:1).
The scope of this methodology was determined using
EtOMgCl as additive associated to FeCl3 (2.5 mol % FeCl3,
EtOMgCl/FeCl3 = 40) since the magnesium salt is more
convenient to prepare in situ compared to its lithium analogue.
Moreover, this scope has been investigated using iPrMgCl as a
metalation reagent for the preparation of the alkoxide
a
EtOMgCl was preliminary prepared by metalation of EtOH with
b
iPrMgCl (0.95 equiv) in THF. Only traces of coupling products are
detected by GC−MS when E-dichloroethene is used as starting
material.
B
DOI: 10.1021/acs.orglett.9b00665
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Organic Letters
Letter
could also be obtained with an excellent 91% GC yield upon
use of iPrMgCl as a metalation reagent (Table 2, entry 1).
Olefin 2a was then isolated by distillation under reduced
pressure with a good 82% yield. Reaction of 1a with various
alkyl Grignard reagents afforded the corresponding olefins with
good yields (Table 2, entries 2−4), ranking between 65% (use
of iPrMgCl, entry 3) and 81% (use of C6H11MgCl, entry 4).
Alkenyl bromides MeCH=CHBr (1b) and PhCH=CHBr (1c),
respectively, afforded cross-coupling products 2e (reaction
with nC10H21MgCl) and 2f (reaction with nBuMgCl) with
good (74%) and excellent (94%) yields (entries 5−6).
Unfortunately, bulky disubstituted vicinal alkenyl halides
were poorly converted to the corresponding cross-coupling
products: nBu2C=CHX (1d, X = Br; 1e, X = Cl) reacted with
nBuMgCl to afford nBu2C=CHnBu (2g) with a low 37% (X =
Br) or 20% (X = Cl) yield (Table 2, entry 7). Less hindered
Me2C=CHX (1f, X = Br; 1g, X = Cl) could however react with
nC10H21MgCl to afford Me2C=CHnBu (2h) with a moderate
66% (X = Br) yield (Table 2, entry 8). Similarly, alkenyl
bromides 1h and 1i reacted with nC10H21MgCl to afford 2i
and 2j in, respectively, 81% and 63% yield (entries 9−10).
Again, the stereoselectivity of this method was excellent since
we observed a retention of the C=C bond configuration in all
cases. α,β-Unsaturated ketones were moreover tolerated since
substrate 1k could efficiently react with nBuMgCl to afford 2l
with an excellent 87% yield (entry 12).
bromobenzoate (3ac) and ethyl 4-iodobenzoate (3ad),
respectively, gave poor 22% and 17% yields (Table 3, entries
4−5), along with a significant amount (ca. 40% in each case)
of the arene reduction product C6H5COOEt. This side
reaction explains why the efficiency of the cross-coupling
pathway is hampered for these substrates. Ethyl 4-fluoroben-
zoate (3ae) did not lead to the expected coupling product, and
side addition of nBuMgCl onto the ester was observed (entry
6).
The excellent alkyl−aryl cross-coupling yield displayed
thereabove using activated aryl chloroesters prompted us to
investigate the scope of the (hetero)aryl electrophiles, which
can be efficiently converted thanks to this methodology.
Methyl 4-chlorobenzoate (3b) and menthyl 4-chlorobenzoate
(3c) could be quantitatively converted into the cross-coupling
products 4b and 4c by reaction with nC6H13MgCl and
nBuMgCl (Table 4, entries 2−3). Moreover, it is of note that
quantitative formation of esters 4b and 4c demonstrates that
no transesterification occurs between the ethoxide additive and
the starting material. α and β-Chloronaphtalene mixtures also
reacted with nBuMgCl to afford the mixture 4d in a good 85%
yield (entry 4). Unfortunately, this methodology was
inefficient for electrophiles substituted in ortho and non-
activated meta positions since ethyl 2-chlorobenzoate (3e) and
its meta isomer (3f) poorly reacted with nBuMgCl (entries 5−
6). Similarly, no reaction was observed using nonactivated
substrates such as chlorobenzene (3g, entry 7).
In a second time, we sought to investigate the extensibility of
our methodology to alkyl−aryl cross-coupling systems. The
reaction conditions (catalyst load and alkoxide/iron ratio)
were thus reoptimized using nBuMgCl and ethyl 4-
chlorobenzoate (3a) as coupling partners (see Supporting
Information) since the latter is known to easily react under
iron-catalyzed coupling conditions with Grignard reagents.5 To
our delight, 4-nBuC6H4COOEt (4a) could be quantitatively
obtained using a low 1 mol % catalyst load, and 15 mol %
EtOMgCl (EtOMgCl/Fe ratio = 15, Table 3, entry 1). It is
As outlined above, the reaction is compatible with the
presence of esters (Table 4, entries 1−3) and also tolerated
nitriles (entry 10). Chloroaryl ketones are however not
tolerated (Table 4, entry 11). Heteroaryl chlorides such as 2-
chloroquinoline (3l) and 2-chloropyrimidine (3m) were also
successfully used as cross-coupling partners with nBuMgCl in,
respectively, 97% and 88% yield (4k and 4l, Table 3, entries
12−13). Interestingly, when aryl dihalide 4-ClC6H4Br (3n) is
used, the chloride atom acts more like an activating electron-
withdrawing group than a leaving group since the cross-
coupling occurs on the brominated carbon with no displace-
ment of the chloride. The coupling product 4m is however
obtained in a low 17% yield (Table 4, entry 14), along with
reduction product of the CBr into CH bond.
Table 3. Effect of Leaving Group in Alkyl−Aryl Cross-
Coupling
These results are comparable with other NMP-free method-
ologies reported by some of us using Fe(S-2-naphthyl)2 as
catalyst,7b or by Fox, who used a catalytic amount of Fe(acac)3
associated with N,N-tetramethylethylenediamine as a stoichio-
metric additive.7f In both cases, excellent yields were also
obtained using activated para-substituted aryl chloroesters.
The methodology reported herein demonstrates that very
simple and cheap alkoxide salts can efficiently supplant such
additives. These salts can moreover be used at catalytically
loads for alkyl−aryl couplings.
entry
leaving group (X)
4a (% isolated yield)
1
2
3
4
5
6
Cl (3a)
99
70
CF3SO3 (3aa)
PhSO3 (3ab)
Br (3ac)
I (3ad)
F (3ae)
a
57
ab
,
22
17
ab
,
ac
,
0
a
b
GC yield. Reduction product C6H5COOEt was obtained as a major
c
We then transposed these results to the one-pot synthesis of
alkylbenzamides starting from 4-chloroester 3a, amide salts and
nBuMgCl (Table 5). In a first step, amidification of 3a is
performed by addition of an amide magnesium salt, generating
in situ one equivalent of EtOMgCl. In a second time, the cross-
coupling step is performed by successive additions of FeCl3
and nBuMgCl. Alkyl benzamides 5a−d could be obtained in
excellent yields (90−99%, Table 5). It is noteworthy to state
that this method could be applied to both alkyl (entries 1−3)
and aryl (entry 4) amide salts.
product. Addition product 4-FC6H4C(nBu)2(OH) was obtained as a
major product.
noticeable that these conditions require both a lower catalyst
load and a lower EtOMgCl/Fe ratio than the alkyl−alkenyl
coupling conditions reported above. Moreover, we also
investigated the effect of the leaving group, and chloroarenes
proved to be the most reactive. In cross-coupling reaction with
nBuMgCl, triflate 4-TfOC6H4COOEt (3aa) led to 70% of the
cross-coupling product 4a; benzenesulfonate 4-PhSO3−
C6H4COOEt (3ab) led to a modest 57% yield. Ethyl 4-
In summary, we developed a new efficient iron-catalyzed
alkyl−alkenyl and alkyl−aryl coupling methodology between
C
DOI: 10.1021/acs.orglett.9b00665
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Organic Letters
Letter
Table 4. Cross-Coupling Scope of Alkyl Grignard Reagents
with Various (Hetero)aryl Halides
Table 5. One-Pot Alkylbenzamide (5) Synthesis from
Chloroester 3a
toxicity problems of NMP-based strategies. Moreover, this
method proceeds without the need of expensive functionalized
ligands. The performances of this system are comparable to the
current procedures for similar Fe-mediated cross-coupling
between Grignard reagents and organic halides. An intriguing
point is the lack of reactivity of bromo- and iodoarenes in this
cross-coupling procedures, which undergo preferentially one-
electron reduction of the Chalide bond, echoing previous
mechanistic studies that were performed on similar Fe(acac)3-
catalyzed Kumada cross-coupling systems.8a From a mecha-
nistic standpoint, the nature of the catalytically active iron
species is so far unknown. For similar systems using NMP as
additive, the group of Neidig recently demonstrated that
tricoordinated ate iron(II) species could react with sp2
electrophiles at catalytically relevant rates and that NMP
actually acted as a ligand to the magnesium and not to the
iron.8b On the other hand, some of us also demonstrated that
in situ-generated iron(0) species could efficiently promote the
activation of sp2 electron-poor organic halides.8c The exact
role of the alkoxide salts in the overall catalytic process as well
as the nature of the catalytically active oxidation state and the
redox elementary steps governing this cross-coupling system
are currently investigated, and results will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00665.
Standard experimental procedures and spectral data for
all compounds (PDF)
a
b
c
d
Reaction run at 25 °C. α/β = 85:15. GC yield. 5 mol % FeCl3 and
75 mol % EtOMgCl were used.
AUTHOR INFORMATION
Corresponding Authors
■
Grignard reagents and organic halides. This method involves
alkoxide magnesium salts as additives, which circumvent the
*E-mail: guillaume.lefevre@chimieparistech.psl.eu
*E-mail: gerard.cahiez@chimieparistech.psl.eu
D
DOI: 10.1021/acs.orglett.9b00665
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
́
Gerard Cahiez: 0000-0003-2107-4132
̀
Guillaume Lefevre: 0000-0001-9409-5861
Present Address
¶N.L., M2i Salin, 36 Route d’Arles RD 36, 13129 Salin de
Giraud, France.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by PHEROCHEM, a joint
laboratory CNRS/Chimie ParisTech/M2i. We thank the
Fondation de la Maison de la Chimie for a postdoctoral grant
to N.L. and the company M2i for a grant to E.Z. (bourse
CIFRE). We gratefully acknowledge PSL Research University
(NIMCOS project) and M2i for financial support. G.L. thanks
the ANR research program (project JCJC SIROCCO).
DEDICATION
■
́
This work is dedicated to the memory of Prof. Gerard Cahiez.
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