Iron-Catalyzed Cross-Coupling of Functionalized Benzylmanganese Halides with Alkenyl Iodides, Bromides, and Triflates

Article abstract of DOI:10.1021/acs.orglett.9b03292

Various substituted benzylic manganese chlorides were prepared by insertion of magnesium turnings in the presence of MnCl₂·2LiCl in THF at -5 °C within 2 h. These benzylic manganese reagents underwent smooth cross-couplings with various functionalized alkenyl iodides, bromides, and triflates or iodoacrylates in the presence of 10 mol % FeCl₂ at 25 °C for 1-12 h. Mechanistic studies showed that benzylic manganese halides produced, in the presence of FeCl₂, a very reactive iron ate complex.

Full text of DOI:10.1021/acs.orglett.9b03292

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Cross-Coupling of Functionalized Benzylmanganese
Halides with Alkenyl Iodides, Bromides, and Triflates
,‡
Alexandre Desaintjean,† Sophia Belrhomari,† Lidie Rousseau,‡,§ Guillaume Lefevre,*
̀
and Paul Knochel*,†
†
̈
̈
Department of Chemistry, Ludwig-Maximilians-Universitat Munchen, Butenandstr. 5-13, Haus F, 81377 Munich, Germany
‡Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, CSB2D, 75005 Paris, France
§NIMBE, CEA, CNRS, Univ. Paris-Saclay, 91191 Gif-sur-Yvette, France
S
* Supporting Information
ABSTRACT: Various substituted benzylic manganese chlor-
ides were prepared by insertion of magnesium turnings in the
presence of MnCl2·2LiCl in THF at −5 °C within 2 h. These
benzylic manganese reagents underwent smooth cross-couplings
with various functionalized alkenyl iodides, bromides, and
triflates or iodoacrylates in the presence of 10 mol % FeCl2 at 25
°C for 1−12 h. Mechanistic studies showed that benzylic
manganese halides produced, in the presence of FeCl2, a very
reactive iron ate complex.
Table 1. Catalyst Screening of the Reaction between the
Benzylic Manganese Chloride 1a and (E)-1-Iodooctene
(3a)
ransition-metal catalyzed cross-couplings are essential for
a
1
Tforming C−C bonds with unsaturated electrophiles.
a
Scheme 1. Preparation of Benzylic Manganese Reagents by
in Situ Transmetalation Followed by Iron-Catalyzed Cross-
Couplings with Alkenyl Iodides, Bromides, and Triflates
b
entry
catalyst (10 mol %)
none
FeBr2
Fe(acac)2
Fe(acac)3
yield (%)
1
2
3
4
5
6
7
8
65
63
75
74
80
96
97
FeBr3
FeCl3
FeCl2 (99.5% purity)
FeCl2 (99.99% purity)
98
a
b
For clarity, the magnesium salt has been omitted. Yield of
analytically pure product.
reaction partners, organomagnesium8 and organozinc9 re-
agents have mainly been used.10
a
For clarity, the magnesium salt has been omitted. Yields were
Organomanganese reagents pioneered by Cahiez have
proven to be excellent nucleophiles in various cross-coupling
reactions, including those catalyzed by iron salts.11 However,
these reactions required the use of N-methylpyrrolidinone
(NMP)12,13 and displayed limited functional group tolerance.
determined by titration against iodine in THF.
Although palladium- and nickel-catalyzed cross-couplings2 are
the most versatile, tolerating various functionalities on both
electrophiles and nucleophiles, these metals have drawbacks
including acute toxicity for nickel3 and high prices in the case
of palladium.4 Alternative metal catalyses based on copper,5
iron6 and cobalt7 have been developed. As organometallic
Received: September 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03292
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Iron-Catalyzed Cross-Couplings of Benzylmanganese Reagents (1a−k) with Alkenyl Iodides, Bromides, and Triflates
b
(3a−k)
a
b
c
For clarity, the magnesium salt has been omitted. Reaction time: 1 h for iodides, 12 h for bromides and triflates. Yield of analytically pure
d
e
product. In parentheses, yield obtained without catalyst. For this reaction, 1.0 equiv of 1e was used.
Because of the low price and low toxicity of these metals, such
cross-couplings are attractive alternatives especially compared
to organo-boronic esters which may have genotoxic proper-
ties.14
Recently, we have developed an effective preparation of
functionalized benzylic manganese reagents of type 1 starting
from benzylic chlorides of type 2.15 Herein, we report an iron-
catalyzed cross-coupling of functionalized benzylic manganese
reagents (1) with alkenyl iodides, bromides, and triflates of
type 3 providing a range of polyfunctionalized alkenes of type
4 (Scheme 1).
In preliminary experiments, we have prepared various
benzylic organometallics derived from 3-methoxybenzyl
chloride (2a). Thus, the benzylic manganese reagent 1a was
conveniently prepared by treating 2a (1.0 equiv) in THF at −5
°C with magnesium turnings (2.4 equiv) and MnCl2·2LiCl
(1.3 equiv) for 1 h. Titration16 with iodine led to a yield for 1a
of 78%. We also prepared the corresponding benzylic
magnesium (5; 48% yield) and zinc (6; 42% yield) chlorides.17
In the absence of any iron catalyst, the cross-coupling of 1a
with (E)-1-iodooctene (3a; 25 °C, 1 h) produced the desired
cross-coupling product 4a in 65% yield (Table 1, entry 1).
Under these conditions, 5 and 6 gave lower yields
B
DOI: 10.1021/acs.orglett.9b03292
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Table 3. Iron-Catalyzed Cross-Couplings of Benzylmanganese Reagents (1a−b, d−j) with Iodoacrylates (3l−n)
Letter
a
a
b
c
For clarity reasons, the magnesium salt has been omitted. Yield of analytically pure product. In parentheses, yield obtained without catalyst.
(respectively, 47% and 14%). Although the cross-coupling
performed with FeBr2 gave a moderate yield of 63%, the use of
Fe(acac)2, Fe(acac)3, or FeBr3 afforded 4a in 74−80% yield
(entries 2−5). Using FeCl3 proved to be even more effective,
as the yield increased to 96% (entry 6). Our best result was
obtained with FeCl2 as catalyst, producing 4a in 97% yield.
Moreover, the use of 99.99% pure FeCl2 similarly gave 4a in
98% yield, showing that it is unlikely that metal impurities are
responsible for this catalysis (entries 7−8).
Furthermore, the cross-coupling of 1a with (2-bromovinyl)-
trimethylsilane (3b; Z/E = 10:90) gave the olefin 4b in 92%
yield with retention of stereochemistry (Z/E = 6:94) whereas
the yield without iron salt was 0% (Table 2, entry 1). When the
electron-rich 4-(methylthio)benzylmanganese chloride (1b)
was mixed with (1-bromovinyl)trimethylsilane (3c), alkenylsi-
lane 4c was generated in 92% yield and no product was
observed without iron catalyst (entry 2). Benzylmanganese
chloride (1c) underwent smooth cross-couplings with 3a and
(E)-1-bromo-2-(2-iodovinyl)benzene (3d) to afford E-alkenes
4d and 4e in 77% and 87% yield. In comparison, 7% and 52%
were obtained without catalyst (entries 3−4). Also, 4-(tert-
butyl)benzylmanganese chloride (1d) reacted with 2,2-
diphenylvinyl trifluoromethanesulfonate (3e) to give 4f in
95% yield (entry 5). Very interestingly, 4-isopropylbenzyl-
manganese chloride (1e) reacted with the acid-sensitive (E)-1-
We noticed that the reprotoxic cosolvent NMP12,13 did not
positively influence the reaction.17 However, the amount of
FeCl2 could be reduced to 2.5 mol % without any significant
yield decrease.17 We also observed that the benzylic
magnesium and zinc species (5 and 6) were less efficient
reagents and reacted with 3a in the presence of 10 mol %
FeCl2 (25 °C, 1 h) to give 4a in 66−68% yield.
C
DOI: 10.1021/acs.orglett.9b03292
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Organic Letters
Letter
(1c) and (2-bromovinyl)trimethylsilane (3b; Z/E = 10:90)
were conducted in order to identify the catalytically active
species in this benzyl-alkenyl cross-coupling reaction.17 It was
first shown that a Mn-to-Fe transmetalation of three benzyl
groups per mole of iron takes place rapidly, affording the high-
spin species (S = 2) [Bn3FeII]−, which has already been
characterized by Bedford (Figure S1).19 It was then shown that
[Bn3FeII]− quickly reacted with 3b at 0 °C (with full
consumption of the former in less than 10 min), whereas the
reaction of BnMnCl with the electrophile proved to be much
slower (Figure S2). This study then demonstrates that no
reduction at a lower iron oxidation state is required to ensure a
catalytic activity for this benzyl-alkenyl coupling system.
Therefore, we suggest the following catalytic cycle that echoes
the recent result reported by Neidig,13 who demonstrated that
the ate [Me3FeII]− anion proved to be reactive in cross-
coupling conditions with bromostyrene derivatives (Figure 1).
From a mechanistic standpoint, the nature of the activation
of the C−Br bond of the electrophile remains so far unknown,
as several scenarios could take place. One-electron reduction
processes could occur between [Bn3FeII]− and 3b, leading to a
coupling step relying on a FeII/FeIII cycle with in-cage
recombination of radical species, as it was suggested for the
cross-coupling between various Grignard reagents and alkyl
Figure 1. (a) Fast transmetalation equilibrium between BnMnCl and
[Bn3FeII]−. (b) Proposed catalytic cycle for the benzyl-vinyl cross-
coupling between BnMnCl and an aleknyl bromide under Fe-catalytic
conditions.
bromo-3,3-diethoxyprop-1-ene (3f) and 1,2-dibromocyclo-
pent-1-ene (3g, 1.0 equiv of 1e) to provide the acetal 4g
(Z/E = 1:99) and the bromopentene derivative 4h in 79% and
57% yield. The reaction without FeCl2 gave almost no product
(0−8%, entries 6−7). Electron-deficient fluorine-containing
benzylmanganese reagents (1f−1h) also reacted with various
cross-coupling partners (3a,h−i) producing 4i−k in 84−94%
yield (0−7% were obtained without FeCl2, entries 8−10). The
analogous chlorine-containing benzylmanganese species (1i−j)
reacted with the functionalized alkenyl halides (Z)-4-(2-
bromovinyl)benzonitrile (3j) and (Z)-1-(2-iodovinyl)-4-
(trifluoromethyl)benzene (3k) to yield 98% of 4l and 4m
(21% and 58% were obtained without any catalyst, entries 11−
12). Finally, 4-bromobenzylmanganese chloride (1k) reacted
with the alkenyl triflate 3e and iodostyrene 3k, producing the
expected alkenes 4n and 4o in 43−53% yield (12−20% were
obtained without FeCl2, entries 13−14). Generally, we have
observed that alkenyl bromides and electron-poor benzyl-
manganese reagents only gave traces of product in the absence
of FeCl2.
electrophiles.20 On the other hand, formation of alkenyl Csp
2
radicals is energetically more demanding than formation of
alkyl radicals. This can open up the possibility of a cross-
coupling mechanism relying on a two-electron oxidative
addition of the electrophile onto the FeII species, leading to
the formation of FeIV intermediates as suggested by Nakamura
for the formation of biaryl systems.21
In summary, various electron-rich and electron-poor
functionalized benzylic manganese species have been readily
prepared from the corresponding benzylic chlorides by
insertion of magnesium turnings in the presence of MnCl2·
2LiCl in THF at −5 °C within 2 h. These benzylic manganese
reagents underwent smooth cross-couplings with various
functionalized alkenyl iodides, bromides, and triflates or
iodoacrylates in the presence of 10 mol % FeCl2 at 25 °C
for 1−12 h. Moreover, the reaction conditions enabled a good
functional group tolerance. In particular, aryl halides are
tolerated and can serve as a handle for further functionaliza-
tion. Mechanistic studies showed that benzylic manganese
halides produced, in the presence of FeCl2, a very reactive
iron(II) ate complex which promptly reacted with alkenyl
halides. Further extensions and in-depth mechanistic studies of
this activation step are currently in progress in our laboratories
and will be reported in due course.
These benzylic manganese species also undergo cross-
couplings with iodoacrylate derivatives (3l−n). Thus, the
benzylic manganese chloride 1a reacted with ethyl (Z)-3-
iodoacrylate (3l) to provide the Z-acrylate 4p in 98% yield
(73% was obtained without catalysis). Under the same
conditions, 4-(methylthio)benzylmanganese chloride (1b)
afforded the acrylate 4q in 78% yield (Table 3, entries 1−2).
Moreover, 4-alkylated benzylic manganese chlorides 1d−e
respectively reacted with (E)-3-iodoacrylate (3m) and ethyl
(Z)-3-iodobut-2-enoate (3n) to give the acrylates 4r and 4s in
55% and 78% yield, whereas the reactions without FeCl2 gave a
44% and 60% yield (Z/E = 44:56, entries 3−4). Also, 2-
fluorobenzylmanganese chloride (1f) reacted with both Z and
E isomers of ethyl-3-iodoacrylate (3l−m) to yield the
corresponding Z and E acrylates 4t in 97% yield and 4u in
66% yield (41% was obtained without catalysis, entries 5−6).
The two other fluorine-containing benzylic manganese species
1g−h also underwent smooth cross-couplings with 3l,n to
yield 50−71% of 4v−x (4w: 83%, Z/E = 67:33 were obtained
without FeCl2; entries 7−9). The chloro-substituted benzylic
manganese species 1i−j were treated with 3l and 10 mol %
FeCl2 to give the Z-acrylates 4y−z in 50−73% yield (entries
10−11).18
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03292.
Full experimental details and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
1
Mechanistic investigations relying on low-temperature H
*E-mail: guillaume.lefevre@chimieparistech.psl.eu.
*E-mail: paul.knochel@cup.uni-muenchen.de.
NMR monitoring of the reaction of benzylmanganese chloride
D
DOI: 10.1021/acs.orglett.9b03292
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(c) Quinio, P.; Benischke, A. D.; Moyeux, A.; Cahiez, G.; Knochel, P.
Synlett 2015, 26, 514.
(16) Krasovskiy, A.; Knochel, P. Synthesis 2006, 2006, 890.
(17) For more details, see the Supporting Information.
(18) Interestingly, partial isomerization of the double bond was
observed when reactions of unsymmetrically substituted substrates
were carried out without FeCl2.
̀
Guillaume Lefevre: 0000-0001-9409-5861
Paul Knochel: 0000-0001-7913-4332
Notes
The authors declare no competing financial interest.
(19) Bedford, R. B.; Brenner, P. B.; Carter, E.; Cogswell, P. M.;
Haddow, M. F.; Harvey, J. N.; Murphy, D. M.; Nunn, J.; Woodall, C.
H. Angew. Chem., Int. Ed. 2014, 53, 1804.
(20) Przyojski, J. A.; Veggeberg, K. P.; Arman, H. D.; Tonzetich, Z.
ACS Catal. 2015, 5, 5938.
(21) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J.
Am. Chem. Soc. 2009, 131, 11949.
ACKNOWLEDGMENTS
■
This work was supported by the CNRS, Chimie ParisTech
(Paris) and LMU (Munich) in the framework of the
International Associated Laboratory IrMaCar. We thank the
DFG (SFB749) for financial support and Albemarle
(Germany) and BASF (Ludwigshafen, Germany) for the
generous gift of chemicals. G.L. also thanks the ANR research
program (Project JCJC SIROCCO).
DEDICATION
■
́
This work is dedicated to the memory of Prof. Gerard Cahiez.
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DOI: 10.1021/acs.orglett.9b03292
Org. Lett. XXXX, XXX, XXX−XXX