Stereoselective Cross-Coupling of Grignard Reagents and Conjugated Dienylbromides using Iron Salts with Magnesium Alkoxides

Article abstract of DOI:10.1002/ejoc.202100844

A convenient procedure allowing iron-catalyzed cross-coupling of alkyl or aryl Grignard reagents and conjugated dienyl bromides is reported, relying on the use of cheap and non-toxic magnesium alkoxides as sole additives. An excellent stereoselectivity is observed in the alkyl-dienyl series. This sequence has been applied to the synthesis of the sex pheromone of codling moth, illustrating its applicability for obtaining targets of industrial interest. Preliminary mechanistic studies carried out on the aryl-dienyl cross-coupling suggest that in situ generated ate homoleptic organoiron(II) species act as catalytically relevant intermediates. A modified preparative method for the realization of THF solutions of dienyl bromides as “ready-to-use” coupling partners is also discussed, circumventing the thermal instability of those derivatives.

Full text of DOI:10.1002/ejoc.202100844

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Combination of iron salts with magnesium alkoxides: an efficient
strategy for stereoselective cross-coupling of Grignard reagents
and conjugated dienyl bromides.
Authors: Pablo Chourreu, Olivier Guerret, Loïc Guillonneau, Eric
Gayon, and Guillaume Lefèvre
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100844
Link to VoR: https://doi.org/10.1002/ejoc.202100844
01/2020

10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
Combination of iron salts with magnesium alkoxides: an efficient
strategy for stereoselective cross-coupling of Grignard reagents
and conjugated dienyl bromides.
Pablo Chourreu,[a,b] Olivier Guerret,[b] Loïc Guillonneau,[b] Eric Gayon[b] and Guillaume Lefèvre*[a]
[a]
[b]
Dr. G. Lefèvre, P. Chourreu
i-CLeHS, UMR 8060, CNRS Chimie ParisTech
11, rue Pierre et Marie Curie, 75005 Paris - FR
https://lefevreresearchgroup.com/
E-mail: guillaume.lefevre@chimieparistech.psl.eu
P. Chourreu, Dr. O. Guerret, Dr. L. Guillonneau, Dr. E. Gayon
M2i Development, Bꢀtiment ChemStart’Up, 64170 Lacq – FR
Supporting information for this article is given via a link at the end of the document.
Abstract: A convenient procedure allowing iron-catalyzed cross-
coupling of alkyl or aryl Grignard reagents and conjugated dienyl
bromides is reported, relying on the use of cheap and non-toxic
magnesium alkoxides as sole additives. An excellent stereoselectivity
is observed in the alkyl-dienyl series. This sequence has been applied
to the synthesis of the sex pheromone of codling moth, illustrating its
applicability to the obtention of targets of industrial interest.
Preliminary mechanistic studies carried out on the aryl-dienyl cross-
coupling suggest that in situ generated ate homoleptic organoiron(II)
species act as catalytically relevant intermediates. A modified
preparative method for the realization of THF solutions of dienyl
bromides as "ready-to-use" coupling partners is also discussed,
circumventing the thermal instability of those derivatives.
circumvented the drawbacks related to dienyl halides, the former
being bench-stable. Moreover, such electrophiles can also lead to
excellent coupling yields even in the absence of NMP, probably
thanks to the ability of the phosphate leaving group to act as a
stabilizing ligand to on-cycle iron intermediates.5
However, coupling strategies relying either on the use of NMP as
a co-solvent or involving diethyl phosphate as a leaving group
suffer from strong limitations for high-scale synthesis. On one
hand, NMP was recently categorized as a reprotoxic reagent6 and,
on the other hand, the use of a dienol phosphate as a leaving
group leads to overall sequences with a poor atom economy and
also brings eco-toxicity issues.7 Stereoselective synthesis of
dienol phosphates moreover requires cryogenic temperatures (-
78°C) as well as NMP-based methodologies,5d making difficult
their preparation at high industrial scales (Scheme 1).
Fe-catalyzed cross-coupling reactions have been intensely
developed in the last decades.1 Use of this cheap and abundant
metal indeed led to a significant breakthrough in transition-metal
catalysis owing to its ecologic and economic advantages.1b In this
regard, efficient Kochi-type cross-couplings between Grignard
reagents and organic halides in the absence of well-defined
exogenous ligands were described at a preparative scale by
Cahiez. Cross-coupling involving alkyl Grignard reagents and
alkenyl halides can indeed be mediated using simple ferric salts
such as FeCl3 in the presence of N-methylpyrrolidinone (NMP) as
a co-solvent.1c This method has moreover been broadly adapted
to a great variety of Fe-catalyzed coupling patterns ever since,
allowing the use of aliphatic halides, heteroaryl and aryl halides
as electrophilic partners.2 The state of the art however remains
scarce regarding iron-mediated coupling methodologies involving
dienyl halides as electrophilic partners. Yet, such substrates are
particularly useful synthons in retrosynthetic analysis, a large
variety of pharmaceutical or biological molecules featuring
conjugated dienes. This statement is particularly true in the field
of pheromone synthesis, such molecules often exhibiting
conjugated dienes with controlled stereochemistry. However,
dienyl halides display a strong tendency to polymerize, and
require special storage and handling conditions.3 Consequently,
coupling methodologies involving dienyl halides as electrophiles
are extremely rare.4 Cahiez demonstrated that the use of dienol
phosphates as electrophiles in alkyl-dienyl cross-coupling
Scheme 1. Synthesis of dienyl electrophiles and their use as coupling partners
in Fe-catalyzed cross-couplings.
In a recent work, we reported that the use of magnesium
alkoxides as cheap and non-toxic additives led to high cross-
coupling yields in alkyl-alkenyl and alkyl-aryl Kochi-type couplings
involving organic halides as electrophiles.8 This method thus
appears as an appealing alternative to the use of the
abovementioned coupling strategies involving either NMP or
1
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10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
dienol phosphates (Scheme 1). Encouraged by those results, we
developed a new efficient alkyl-dienyl and aryl-dienyl iron-
mediated coupling method between Grignard reagents and dienyl
bromides, which is reported herein. This transformation also relies
on the use of a magnesium ethoxide as additive, and can be
achieved with good to excellent retention of stereochemistry in the
alkyl-dienyl series (Scheme 1). Moreover, we also describe a
convenient modified procedure allowing an easy synthesis and
handling of sensitive dienyl bromides, hampering their
degradation and thus facilitating their use as coupling partners. A
short convenient synthesis of codling moth sex pheromone has
been performed to illustrate the synthetic potential of this strategy
in terms of future industrial applications. Synthesis of this
pheromone is of high industrial interest in the context of biocontrol
products development targeting codling moth, since this insect is
considered as a major pest to agricultural crops, mainly fruits such
as apples and pears.9
In order to access stereocontrolled dienic halides scaffolds, a
Hunsdiecker-Borodin decarboxylation of α,β,γ,δ-unsaturated
aliphatic acids was performed, adopting the recent conditions
developed by Rajanna et al. for the synthesis of alkenyl halides
starting from α,β-unsaturated acids.10 This transformation
requires the halodecarboxylation of an unsaturated acid using
association of N-bromosuccinimide (NBS) with a micellar medium
(cetyl trimethyl ammonium bromide (CTAB) is used as surfactant);
sorbic acid has been used as a benchmark substrate, affording 1-
bromopenta-1,3-diene 1 (Table 1).
containing mostly polybrominated and polymeric byproducts
being obtained. The separation of 1 by distillation from 1,2-
dichlorobenzene (Entry 3) was unsuccessful for the same
reasons. We then explored the possibility to carry out this
transformation in solvents which would be compatible with further
cross-coupling conditions, such as THF (Entry 4) or tBuOMe
(MTBE, Entry 5). Our idea was to obtain directly THF or MTBE
solutions of 1 after workup, with no need to further concentrate
the latter. Those solutions would then be used directly under
cross-coupling conditions, unlike their analogs involving
chlorinated solvents used in Entries 1-3, which do not tolerate
Grignard reagents. A high 95% conversion of sorbic acid was
obtained in THF (Entry 4), comparable with those obtained in
chlorinated solvents; however, an isomerization towards a 50/50
1E,3E/1Z,3E mixture was observed. A comparable isomerization
has been observed using tBuOMe (50/50 1E,3E/1Z,3E, Entry 5)
or DMF (32/68 1E,3E/1Z,3E, Entry 6) as solvents, with a much
smaller 50% conversion for the former, and an almost quantitative
conversion for the latter.
Therefore, the sole acceptable conditions which mostly retain the
stereochemistry of the starting dienic acid require the use of
chlorinated solvents (Entries 1-3). It was found that dilution of the
dichloromethane reaction mixture obtained at the end of reaction
(Entry 2) in THF (THF:DCM = 1:5) prior to concentration under
vacuo and separation of the byproducts on alumina column
inhibited the degradation of 1, which was obtained as a DCM-free
THF solution with a 0.45 M concentration. This solution was
stored at -30°C away from light, and no further isomerization of 1
was observed after a few days; storage at -4°C resulted in
isomerization towards a 85/15 1E,3E/1Z,3E mixture after 48h.
Following the same experimental procedure, a 0.72 M THF
solution of 1-bromonona-1,3-diene 2 (83/13/4 1E,3E/1Z,3E/1E,3Z
mixture) could also be prepared from the corresponding α,β,γ,δ-
unsaturated acid, and this substrate was used as a benchmark
reactant in iron-catalyzed couplings (Table 2). 2 was preferred to
1 for this benchmark work due to its better thermal stability,
allowing a more reproducible preparation of standard solutions.
Table 1. Solvent screening for the bromodecarboxylation reaction of sorbic
acid.[a]
Reaction
time
(h)
Acid
conversion
(%)[b]
GC ratio
(1)
(E,E)/(Z,E)
Entry
Solvent
1
2
3
4
5
6
Dichloroethane
Dichloromethane
1,2-Dichlorobenzene
THF
2
1
> 95
> 95
> 95
> 95
50
90/10
91/09
90/10
50/50
50/50
32/68
Table 2. Optimization of alkyl-dienyl cross-coupling conditions.[a]
4
1
tBuOMe (MTBE)
DMF
> 48
2
Fe(acac)3
(mol%)
Additive
(mol%)
GC yield[b]
(%)
GC ratio
A/B/C
Entry
> 95
1
2
3
4
5
6
7
5
5
-
75
91
87
78
87
79
80
81/13/6
82/14/4
82/14/4
81/13/6
82/14/4
82/13/5
82/13/5
[a] Reaction scale: 10 mmol of sorbic acid, 10 mmol of NBS in solvent (10 mL).
[b] Followed by GC-MS.
NMP (900)
Excellent conversions with a 90% retention of stereochemistry of
the starting dienic acid were obtained in dichloroethane and
dichloromethane (DCM) (Entries 1-2), with a faster reaction time
in dichloromethane (1h). A high 95% conversion was also
observed using 1,2-dichlorobenzene (Entry 3).
However, further purification of compound 1 could not be carried
out successfully due to its high thermal instability. For example,
evaporation of dichloromethane (Entry 2) proved to be
problematic since a complete degradation of 1 was observed
upon concentration under vacuo after 30 min at 40°C, a dark oil
5
EtOMgBr (200)
nOctOMgBr (200)
EtOMgBr (100)
EtOMgBr (40)
EtOMgBr (50)
5
2.5
1
2.5
[a] Reaction scale: 0.5 mmol of 2, 0.65 mmol of nBuMgCl in THF (1.0 mL).
[b] Measured in the crude using benzaldehyde as internal standard.
2
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10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
Cross-coupling with aliphatic Grignard reagents was first
investigated, and nBuMgCl was used as a benchmark nucleophile
in this alkyl-dienyl coupling series (see Table 2). Cross-coupling
between 2 and nBuMgCl mediated by 5% Fe(acac)3 in the
absence of any additive led to formation of 3a with a 75% yield
after 1h at 0°C (Entry 1). Use of NMP as a co-solvent in the classic
conditions described by Cahiez1c afforded 91% of coupling
product (Entry 2). Those results are in line with what is reported
in similar conditions for the coupling of alkyl Grignard reagents
and alkenyl bromides. The same reaction was then carried out
using magnesium alkoxides as additives. A high 87% yield (GC
yield, 82% isolated yield) was obtained using 5% Fe(acac)3 in
combination with 200% EtOMgBr (which corresponds to a
EtOMgBr:Fe = 40 ratio, Entry 3).This yield is comparable to what
is obtained using NMP as co-solvent (Entry 2). Supplanting
EtOMgBr by an aliphatic magnesium alkoxide bearing a longer
chain (n-C8H17OMgBr) was slightly detrimental to the coupling
efficiency (78% yield, Entry 4). To our delight, the catalytic load
could be decreased to a low 2.5% Fe(acac)3 quantity, associated
with 100% EtOMgBr (EtOMgBr:Fe = 40), with an unchanged 87%
coupling yield (Entry 5). Decreasing the iron catalytic load to 1%
and maintaining a EtOMgBr:Fe ratio of 40 led to a weaker 79%
yield (Entry 6). A similar decrease was observed when a 2.5%
3, Entry 3). A higher catalytic load (8 mol% Fe(acac)3 associated
with 25 equiv. EtOMgBr with respect to Fe, Entry 5) was required
to achieve a modest 60% yield. In all cases, an isomerization of
the diene moiety was observed, leading to a 67/25/8 mixture of
1E,3E/1Z,3E,1E,3Z isomers of the coupling product 4a. This loss
of stereochemistry mostly originates from the aryl-dienyl
conjugation in the latter.
Significant quantities of biphenyle PhPh (aryl Grignard
homocoupling product) were also obtained, inhibiting the
efficiency of the cross-coupling path (26% of PhMgBr was
converted into PhPh in the absence of additive, Entry 1).
Competition with homocoupling makes more challenging the aryl-
dienyl cross-coupling, as attested by the low 4a yield obtained in
the absence of additive (31%, Table 3, Entry 1, to be compared
with the analog alkyl-dienyl yield: 3a was obtained with a 75%
yield in the absence of additive, Table 2, Entry 1).
Table 4. Cross-coupling scope of alkyl and aryl Grignard reagents.[a]
iron catalytic load was used associated with
a smaller
EtOMgBr:Fe = 20 ratio (Entry 7). It is remarkable that the
stereochemistry of the starting mixture (83/13/4 mixture of
1E,3E/1Z,3E/1E,3Z isomers of 2) is maintained in the distribution
3 and 4
(% isolated
yield)[c]
GC ratio[d]
A/B/C
Entry
Method[b]
RMgX
of coupling products (3a1 /3a1 /3a1 )
,3
E Z
in conditions
,3
E
,3
E
Z
E
described in Table 2, regardless of the nature of the additive
(NMP, n-C8H17OMgBr, or EtOMgBr).
In a second time, we sought for optimal conditions allowing the
coupling between 2 and aryl Grignard reagents. PhMgBr was
used as a benchmark nucleophile (Table 3).
1
2
a
a
nBuMgCl
3a (82)
3b (85)
82/14/4
81/14/5
3
4
b
c
c
c
c
c
c
c
ClMgO-(CH2)6-MgCl
3c (92)
4a (56)
4b (67)
4c (54)
4d (traces)
4e (71)
4f (73)
82/14/4
67/25/8
74/19/7
71/21/8
-
Table 3. Optimization of aryl-dienyl cross-coupling conditions.[a]
5
6
GC yield[b]
(%)
GC ratio
A/B/C
7
Fe(acac)3
(mol%)
Additive
(mol%)
Entry
8
76/19/5
82/13/5
79/14/7
1
2
3
4
5
6
5
5
-
31
50
41
32
60
54
66/26/8
67/25/8
67/25/8
66/26/8
67/25/8
67/25/8
EtOMgBr (200)
EtOMgBr (100)
EtOMgBr (40)
EtOMgBr (200)
EtOMgBr (100)
9
2.5
1
10
4g (72)
8
[a] Reaction scale: 0.5 mmol of 2, 0.65 mmol of RMgX in THF (1.0 mL). [b]
Method a : 2.5 mol% Fe(acac)3, 100 mol% EtOMgBr; Method b : 2.5 mol%
Fe(acac)3; Method c : 8 mol% Fe(acac)3, 200 mol% EtOMgBr [c] After silica gel
column chromatography. [d] Just after reaction quench and before
chromatography purification.
8
[a] Reaction scale: 0.5 mmol of 2, 0.65 mmol of PhMgBr in THF (1.0 mL).
[b] Measured in the crude using benzaldehyde as internal standard.
The addition of EtOMgBr allowed to partly inhibit the
homocoupling process, since the amount of PhPh obtained in the
presence of 200 equiv. EtOMgBr (Entry 2) dropped to 20% of the
starting PhMgBr quantity. Optimized conditions (Entry 5) allowed
to reduce the homocoupling to 16% of the starting Grignard.
A EtOMgBr:Fe = 40 ratio was used, similarly to what was
optimized for the alkyl-dienyl coupling. Product 4a was obtained
with a small 41% yield under the conditions optimized using
nBuMgCl as nucleophile (that is : 2.5 mol% Fe(acac)3, see Table
3
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10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
Those results in hands, the scope of the aliphatic and aromatic
Grignard reagents suitable for such coupling conditions has been
examined using 2 as electrophile (Table 4). Reaction of n-BuMgCl
and of γ-substituted aliphatic Grignard acetal with 2 afforded 3a
and 3b with similar 82% and 85% yields (Entries 1-2). Cross-
coupling product 3c was obtained in a high 92% yield when an
aliphatic Grignard ω-substituted by a magnesium alkoxide moiety
(Entry 3) was used. In that case, owing to a magnesium alkoxide
moiety borne by the nucleophile, it is of note that no additional
alkoxide additive was required, making this coupling sequence
particularly efficient. In the aryl-dienyl series, modest to good
yields were obtained using aryl nucleophiles substituted by
electron-donating groups such as p-MeOC6H4MgBr (formation of
4b, 67% yield, Entry 5) or p-MeC6H4MgBr (4c, 54% yield, Entry
6). Bulky aryl nucleophiles such as MesMgBr only afforded traces
of coupling product (4d, Entry 7). Higher yields were obtained for
aryl Grignards bearing electron-withdrawing halides substituents.
The use of p-FC6H4MgBr as a nucleophile afforded the expected
coupling product 4e with a 71% isolated yield (Entry 8). Similarly,
disubstituted (m-Cl,p-F)-C6H3MgBr led to formation of 4f with a
73% yield (Entry 9). In both latter cases, no substitution of the
halide borne by the aryl ring was observed, thus opening
possibility of late-stage functionalization of those positions by
another coupling process. Finally, heteroaryl-dienyl coupling
involving 2-thienylMgBr as a nucleophile also led to a good 72%
coupling yield (formation of 4g, Entry 10). The lower yields
obtained for electron-rich aryl nucleophiles (involving p-OMe or p-
Me substituents, Entries 5, 6) are due to the competition of the
cross-coupling process with the homocoupling of the Grignard
reagent, leading to high quantities of bisaryls. Formation of
electron-rich symmetric bisaryls under transition-metal catalysis
has already been described as a process which is significantly
much faster than the formation of unsymmetrical analogs; a
thorough study of the involved stereoelectronic effects has for
example been reported by Hartwig regarding the reactivity trends
of (P,P)PtII(Ar)2 compounds in reductive elimination processes.11
In order to illustrate the potential of this methodology in terms of
future industrial applications, we applied it to a new efficient and
convergent synthesis of the codling moth (Cydia pomonella) sex
pheromone, (8E,10E)-dodecadien-1-ol (7) (Scheme 2).
methodology described by Samain12f is based on the introduction
of the C6-C7 bond via a copper-catalyzed cross-coupling between
sorbic alcohol derivatives, such as acetoxy derivative, and the
Grignard reagent from 6-chlorohexan-1-ol where the hydroxyl
group has been protected. This reaction affords, after
deprotection, the expected pheromone with an excellent 98%
isomeric ratio of (E,E) isomer. However, this methodology faces
efficiency issues since the cross-coupling product is obtained with
a modest 60% yield in the key step.
Encouraged by the results of the cross-coupling scope discussed
in Table 4, we propose an alternative methodology for the
synthesis of 7 relying on the introduction of the C7-C8 linkage by
a key alkyl-dienyl coupling (Scheme 2). The global synthesis is a
five-step convergent procedure leading to the sex pheromone 7
with an overall 38% yield with a diastereomeric purity of 90%. To
prepare
the
C1-C7
synthon
6,
diethyl
pimelate
(EtOOC(CH2)5COOEt) was chosen as starting material and
converted into 7-chloroheptan-1-ol (5) in two steps (85% yield)
following the procedure described in our previous work.5c
Preparation of the α,ω-magnesium alkoxide salt of Grignard
reagent 6 was then performed by addition of 5 to a THF mixture
containing in situ-synthesized nBuMgCl (1.0 equiv) and Mg (1.1
equiv) at -10 °C. Progressive heating at 70 °C allowed formation
of the corresponding Grignard reagent 6 in an overall yield of 90%.
6 was then directly subjected to the reaction with 1 (1E,3E/1Z,3E
= 91/09) in a one-pot strategy. The cross-coupling between the
two synthons previously prepared was performed using Fe(acac)3
and with a low 2.5 mol% catalytic loading. The reaction proceeded
very quickly with a full consumption of 1 in one hour and the cross-
coupling product 7 was then obtained in a high isolated 94% yield.
Moreover, this coupling was highly stereoselective since the
expected (8E,10E) isomer was obtained with 90% diastereomeric
purity. It is also worth noting that the alkyl−dienyl Fe-catalyzed
Kumada cross coupling between 6 and 1 remarkably proceeds
without requiring additional ligands or any toxic additive, akin to
the similar result reported in Table 4 (Entry 3).
We were then interested in delineating the nature of the
organometallic species active in the coupling process. The
question of the active oxidation state in iron-mediated couplings
still remains a challenging issue, due to the short lifetime of the
related species. A variety of couplings with aliphatic electrophiles
was shown to involve a key single electronic transfer step
featuring in situ generated organoiron(II) species.13
The majority of known and still currently used methods for the
synthesis of 7 date back to the late 1970s and all rely on the
introduction of the C6-C7 linkage as the key step.12 The general
Scheme 2. Synthetic route to pheromone 7 described in this work.
4
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10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
However, the question is much less discussed in the case of sp2-
hybridized electrophiles. In this regard, some of us recently
demonstrated that ate-FeII complexes such as [(PhCH2)3FeII]─
could be active in cross-coupling between benzylmanganese
reagents and alkenyl bromides.14 In the present case, low-
temperature 1H NMR monitoring performed at -40°C showed that
the homoleptic complex [Ph3FeII]─ was formed when Fe(acac)3
was treated with a slight excess of PhMgBr (4.5 equiv.). [Ph3FeII]─
was characterized by its paramagnetic signals at 126.6 and -
42.7 ppm (Section S3).15 This complex usually decomposes by
reductive elimination to afford mixtures of Fe0 and FeI species15,16
above -20°C. However, it remains stable at -40°C for several
hours. When an excess of 2 (10 equiv. per mole of iron) was
added at -40°C onto [Ph3FeII]─, the signals of the latter fully
disappeared after 3 minutes, and no other paramagnetic species
could be observed. GC-MS analysis revealed that 40% of the
coupling product 4a were obtained after acidic quench at -40°C.
This demonstrates that [Ph3FeII]─ can act as an on-cycle species
in the coupling process, and that no reduction towards lower
oxidation states is required (Scheme 3). This result is in line with
the recently reported reactivity of the [Me3FeII]─ anion towards
bromostyrene in Kochi-Kumada cross-coupling between the latter
and MeMgBr.17 Further mechanistic studies need to be performed
regarding the alkyl-dienyl coupling mechanism; ate-alkyliron(II)
species bearing β-hydrogens can indeed evolve towards
polynuclear reduced species after β-elimination, making much
more complex the related mechanistic studies.18
Research Program “PheroChem”. The IRP “IrMaCAR” (CNRS
program) is thanked for financial support. The NMR facilities from
ChimieParisTech (supported by SESAME project, region Île de
France) are acknowledged for technical support.
Keywords: iron • cross-coupling • pheromones • natural products
• reaction mechanisms
[1]
a) For a complete review on Fe-catalyzed cross-couplings, see I. Bauer,
H.-J. Knölker, Chem. Rev. 2015, 115, 3170–3387, section 2.4.1.; b) R.
B. Bedford, P. B. Brenner, The development of iron catalysts for cross-
coupling reactions. Iron Catalysis II; Bauer, E., Ed.; Springer Intl., 2015;
c) G. Cahiez, H. Avedissian, Synthesis 1998, 1199-1205.
[2]
a) A. Fꢁrstner, A. Leitner, Angew. Chem., Int. Ed. 2002, 41, 609-612; b)
A. Fꢁrstner, A. Leitner, M. Mꢂndez, H. Krause, J. Am. Chem. Soc. 2002,
124, 13856-13863; c) A. Fꢁrstner, A. Leitner, Angew. Chem., Int. Ed.
2003, 42, 308-311; d) B. Scheiper, M. Bonnekessel, H. Krause, A.
Fꢁrstner, J. Org. Chem. 2004, 69, 3943-3949; e) T. M. Gogsig, A. T.
Lindhardt, T. Skrydstrup, Org. Lett. 2009, 11, 4886-4888; f) S. Gulak, T.
N. Gieshoff, A. Jacobi von Wangelin, Adv. Synth. Catal. 2013, 355, 2197-
2202; g) W.-J. Guo, Z.-X. Wang, Tetrahedron 2013, 69, 9580; h) D.
Gartner, A. L. Stein, S. Grupe, J. Arp, A. Jacobi von Wangelin, Angew.
Chem., Int. Ed. 2015, 54, 10545-10549; i) A. C. P. Rivera, R. Still, D. E.
Frantz, Angew. Chem., Int. Ed. 2016, 55, 6689-6693; j) A. Piontek, M.
Szostak, Eur. J. Org. Chem. 2017, 48, 7271-7276; k) E. Bisz, M. Szostak,
ChemSusChem 2018, 11, 1290-1294.
[3]
[4]
Ullmann's Encyclopedia of Industrial Chemistry, 6th ed. Wiley-VCH,
2003, vol. 8, p. 89.
a) K. Tamao, K. Sumitani, M. Zembayashi, A. Fujioka, S.-i. Kodama, I.
Nakajima, A. Minato, M. Kumada, Bull. Chem. Jpn. Soc. 1976, 49, 1958-
1969; b) H. Sakurai, A. Hosomi, M. Saito, K. Sasaki, H. Iguchi, J.-i.
Sasaki, Y. Araki, Tetrahedron 1983, 39, 883-894.
[5]
a) G. Cahiez, V. Habiak, O. Gager, Org. Lett. 2008, 10, 2389-2392 ; b)
G. Cahiez, O. Guerret, A. Moyeux, S. Dufour, N. Lefèvre, Org. Process
Res. Dev. 2017, 21, 10, 1542–1546 ; c) P. Chourreu, O. Guerret, L.
Guillonneau, E. Gayon, G. Lefèvre, Org. Process Res. Dev. 2020, 24, 7,
1335–1340; d) for an example of stereoselective synthetic procedure for
dienol phosphates, see G. Cahiez, V. Habiak, O. Gager, J. Org. Chem.
2008, 73, 6871–6872.
Scheme 3. Relevance of in situ generated ate species [Ph3FeII]─ as an on-cycle
intermediate in cross-coupling with 2.
An in-depth investigation of the exact role played by magnesium
alkoxide additives in the efficiency of this coupling is currently in
progress. It can reasonably be hypothesized that those salts
contribute to a stabilization of the FeII oxidation state during the
catalytic cycle, inhibiting its evolution towards lower oxidation
states, thus contributing to limit the occurrence of off-cycle,
reactant-consuming pathways.
[6]
[7]
Reprotoxic Category 2, R61, Official Journal of the European Union,
December 31, 2008, European regulation No. 1272/2008.
a) F. Yang, J. Li, G. Pang, F. Ren, B. Fang, Molecules 2019, 24, 10,
2003-2014 ; b) diethyl chlorophosphate (DCP), broadly used as a dienol
phosphate precursor, is also registered under REACH regulation, see
https://echa.europa.eu/fr/.
In conclusion, we reported a convenient procedure for the
synthesis and purification of thermally sensitive aliphatic dienyl
bromides, obtained as stabilized THF solutions. Those mixtures
can be used as an efficient electrophile source in Fe-catalyzed
Kumada cross-couplings with a variety of aliphatic and aromatic
Grignard reagents. The coupling yields can moreover be
improved thanks to the use of magnesium alkoxides as additives,
and a complete stereochemistry retention is observed in alkyl-
dienyl couplings. This makes this sequence particularly useful for
the synthesis of insect pheromones, as illustrated by the codling
moth sex pheromone synthesis. In the aryl-dienyl coupling
sequence, preliminary mechanistic studies suggest the
implication of organoiron(II) species as key intermediates,
showing that no reduction of the iron precursor at lower oxidation
states is required to ensure catalytic activity.
[8]
[9]
G. Cahiez, G. Lefèvre, A. Moyeux, O. Guerret, E. Gayon, L. Guillonneau,
N. Lefèvre, Q. Gu, E. Zhou, Org. Lett. 2019, 21, 2679-2683.
D. M. Jackson, Ann. Entomol. Soc. Am. 1982, 75, 284-289.
[10] K. C. Rajanna, N. Maasi Reddy, M. Rajender Reddy, P. K. Saiprakash,
J. Dispersion Sci. Technol. 2007, 28, 613.
[11] Hartwig : S. Shekhar, J. F. Hartwig, J. Am. Chem. Soc. 2004,126, 13016-
13027.
[12] a) R. Rossi, Synthesis 1977, 817; b) C. A. Henrick, Tetrahedron 1977,
33, 1845; c) D. Samain, C. Descoins, A. Commerson, Synthesis 1978,
388; d) H. J. Bestman, J. SUss, O. Vostrowsky, Tetrahedron Lett. 1978,
3329; e) G. Decodts, G. Dressaire, J. Langlois, Synthesis 1979. f) D.
Samain, C. Descoins, G. Kunesch. U.S. Patent 4,189,614, 1980.
[13] S. H. Kyne, G. Lefèvre, C. Ollivier, M. Petit, V.-A. Ramis-Cladera, L.
Fensterbank, Chem. Soc. Rev., 2020, 49, 8501-8542.
[14] A. Desaintjean, S. Belrhomari, L. Rousseau, G. Lefèvre, P. Knochel, Org.
Lett. 2019, 21, 8684-8688.
[15] L. Rousseau, C. Herrero, M. Clémancey, A. Imberdis, G. Blondin, G.
Lefèvre, Chem. Eur. J. 2020, 26, 2417-2428.
[16] M. Clémancey, T. Cantat, G. Blondin, J.-M. Latour, P. Dorlet, G. Lefèvre,
Inorg. Chem. 2017, 56, 7, 3834–3848.
Acknowledgements
|17] S. B. Muꢃoz III, S. L. Daifuku, J. D. Sears, T. M. Baker, S. H. Carpenter,
W. W. Brennessel, M. L. Neidig, Angew. Chem., Int. Ed. 2018, 57, 6496-
6500.
The M2i Company is thanked for its financial support (CIFRE
Grant Program for P.C.) in the frame of the M2i−CNRS Joint
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10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
[18] J. D. Sears, S. B. Muñoz III, S. L. Daifuku, A. A. Shaps, S. H. Carpenter,
W. W. Brennessel, M. L. Neidig, Angew. Chem. Int. Ed. 2019, 58, 2769-
2773.
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10.1002/ejoc.202100844
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Insert graphic for Table of Contents here.
Synthesis of dienic scaffolds by Fe-mediated coupling between Grignard reagents and dienyl bromides is reported. This methodology
involves the use of magnesium alkoxides as additives, and can be applied to targets of industrial interest, such as insect pheromones.
Mechanistic studies suggest that the active species is an organoiron(II) complex, showing that no reduction of the precursor to low
oxidation states is required.
Institute and/or researcher Twitter usernames: @GuillaumeLefvr1, @m2ilifesciences
7
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