Iron-Catalyzed Cross-Coupling of Benzylic Manganese Chlorides with Aryl and Heteroaryl Halides

Article abstract of DOI:10.1055/s-0035-1560812

The use of FeCl₂ (10 mol%) allows a convenient iron-catalyzed cross-coupling reaction of benzylic manganese(II) chlorides with various aryl and heteroaryl chlorides, bromides and iodides leading to polyfunctionalized diaryl- and arylheteroarylmethane derivatives.

Full text of DOI:10.1055/s-0035-1560812

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 471–476
letter
471
A. D. Benischke et al.
Letter
Synlett
Iron-Catalyzed Cross-Coupling of Benzylic Manganese Chlorides
with Aryl and Heteroaryl Halides
Andreas D. Benischkea
O
Br
CO2Et
Antoine J. A. Breuillacb
Alban Moyeuxb,c
Gérard Cahiezb
O
MnCl
CO2Et
FeCl2 (10 mol%)
THF, 0–25 °C, 3 h
Paul Knochel*a
F
F
70%
13 other examples
(58–80% yield)
a Department of Chemistry, Ludwig-Maximilians-Universität
München, Butenandtstr. 5–13, 81377 Munich, Germany
Paul.Knochel@cup.uni-muenchen.de
b Institut de Recherche de Chimie Paris, CNRS, Chimie ParisTech,
11 Rue Pierre et Marie Curie, 75005 Paris, France
c Université Paris 13, Sorbonne Paris Cité, 74 Rue Marcel Cachin,
93017 Bobigny, France
Received: 30.07.2015
Accepted after revision: 02.10.2015
Published online: 22.10.2015
lyst.10,11 Since functionalized benzylic magnesium reagents
are difficult to prepare and that benzylic zinc reagents do
not readily transmetalate to iron, we envisioned that a met-
al with intermediate electronegativity, such as manganese,
would be well suited for iron-catalyzed cross-couplings.
Herein, we wish to report that these benzylic manganese(II)
compounds undergo smooth iron-catalyzed cross-cou-
plings with a variety of aryl and heteroaryl halides in good
yields. Preliminary cross-coupling experiments of benzyl-
manganese chloride (1a), prepared from benzyl chloride
(2a),10 with 4-iodoanisole (3a) show that neither an uncata-
lyzed nor a chromium(II) chloride12 catalyzed reaction lead
to a significant amount of coupling product 4 within 16
hours at 25 °C in THF (Table 1, entries 1 and 2).
DOI: 10.1055/s-0035-1560812; Art ID: st-2015-b0593-l
Abstract The use of FeCl2 (10 mol%) allows a convenient iron-cata-
lyzed cross-coupling reaction of benzylic manganese(II) chlorides with
various aryl and heteroaryl chlorides, bromides and iodides leading to
polyfunctionalized diaryl- and arylheteroarylmethane derivatives.
Key words manganese, iron, magnesium, benzylic organometallics,
cross-coupling
Iron-catalyzed cross-coupling reactions are an import-
ant method for the formation of carbon–carbon bonds, as it
allows to replace palladium or nickel catalysts by inexpen-
sive iron salts.1 The low toxicity and excellent catalytic ac-
tivity of various iron complexes has been extensively inves-
tigated.2,3 The cross-coupling of benzylic organometallics
with aryl and heteroaryl halides has attracted our attention
since the resulting diarylmethane derivatives are present in
many natural products and pharmacologically active com-
pounds.4 Benzylic organometallics of Mg,5 In,6 Al,7 and Zn8
are readily available. The corresponding zinc reagents are
especially attractive, since they are compatible with nu-
merous functionalities and can be prepared in high yields.8
However, their moderate reactivity in iron-catalyzed cross-
couplings led us to search for alternative benzylic organo-
metallics. We have reported that benzylic manganese re-
agents can be prepared by the direct insertion of manga-
nese metal into benzylic halides in the presence of InCl3 and
PbCl2 (2.5 mol%).9 Recently, we have shown that the use of
catalytic amounts of toxic lead salts can be avoided by
treating various benzylic chlorides with magnesium turn-
ings in the presence of MnCl2·2LiCl at 0 °C in THF.10 The re-
sulting benzylic manganese(II) chlorides react with various
electrophiles such as enones, acid chlorides and allylic ha-
lides in the absence of any additional transition metal cata-
The use of cobalt(II) salts,13 such as CoCl2 and Co(acac)2,
gave better but still moderate yields (Table 1, entries 3 and
4). However, iron(II) and iron(III) salts displayed the best
catalytic activity (Table 1, entries 5–10) and especially FeCl2
(10 mol%) proved to be the most efficient catalyst (Table 1,
entry 10).14
With these optimized conditions in hand, we studied
the reaction scope of the cross-coupling between various
benzylic manganese(II) chlorides (1a–f) with a broad range
of aryl and heteroaryl halides. Thus, the benzylic manga-
nese(II) reagent (1b) reacted with ethyl 5-bromofuran-2-
carboxylate (3b) at 0 °C within three hours leading to the
desired product 5 in 70% yield (Scheme 1, eq. 1). Also the
benzylic manganese(II) chloride (1c) underwent a smooth
iron-catalyzed cross-coupling with ethyl 2-chloronicotinate
(3c) affording the benzylated pyridine 6 within two hours
in 65% yield (Scheme 1, eq. 2). However, under our condi-
tions, standard aryl chlorides did not react.
The reaction conditions used for these cross-couplings
could be extended to various other functionalized unsatu-
rated halides. Thus, the cross-coupling of benzylmanga-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 471–476

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A. D. Benischke et al.
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Table 1 Screening of Catalysts for the Palladium-Free Cross-Coupling
of Benzylic Manganese(II) Chloride (1a) with 4-Iodoanisole (3a)
ganese(II) chloride (1a) yielding the ketone 8d in 66% yield
(Table 2, entry 4). Furthermore, 3-(trifluoromethyl)benzyl-
manganese(II) chloride (1c) reacted with 5-bromo-2-io-
dopyridine (7e) affording the substituted N-heterocycle 8e
in 70% yield (Table 2, entry 5). Similarly, the functionalized
benzylmanganese(II) reagents (1c and 1d) reacted with ke-
tone 7d leading to the desired diarylmethane derivatives 8f
and 8g in 75% and 80% yield, respectively (Table 2, entries 6
and 7). Additionally, the electron-rich 4-methoxybenzyl-
manganese(II) chloride (1d) cross-coupled with 1-iodo-4-
(trifluoromethoxy)benzene (7f) giving 8h in 61% yield (Ta-
ble 2, entry 8). The cross-couplings of the benzylmanga-
nese(II) chloride (1e) with 2-bromobenzophenone (7d) or
ethyl 3-iodobenzoate (7g) led to the desired products 8i
and 8j in 79% and 79% yield, respectively (Table 2, entries 9
and 10). Finally, the reactions of 2-chlorobenzylmanga-
nese(II) chloride (1f) with the ortho-substituted ester 7h
and the functionalized pyridine 7i proceeded within two
hours at 0 °C affording the functionalized arenes 8k and 8l
in 68% and 70% yield, respectively (Table 2, entries 11 and
12). These reactions display a remarkable functional group
tolerance, since esters, nitriles and ketones are compatible
with the mild reaction conditions of this Fe-catalyzed
cross-coupling. Furthermore, very little amounts of homo-
coupling (<15%) of the benzylic manganese reagents were
observed, allowing us to use almost stoichiometric ratios of
reagents (1.1 equiv of benzylic manganese reagent was suf-
ficient).
I
OMe
MnCl
3a
catalyst (10 mol%)
THF, 0–25 °C, 16 h
OMe
1a
4
Entry
Catalyst
Yield of 4 (%)a
1
2
no catalyst
CrCl2
0
0
3
Co(acac)2
CoCl2
32
4
36
5
Fe(OTf)3
FeBr3
50
6
53
7
Fe(acac)3
Fe(acac)2
FeBr2
69
8
72
9
77
10
FeCl2
84 (79)b
a Determined by GC analysis with tetradecane as an internal standard.
b Isolated yield of pure product.
nese(II) chloride (1a) with 4-bromobenzonitrile (7a) and
ethyl 4-iodobenzoate (7b) proceeded within three hours at
25 °C and furnished the corresponding products 8a and 8b
in 75% and 76% yield, respectively (Table 2, entries 1 and 2).
Using an aryl bromide bearing moderately electron-donat-
ing substituents, such as 5-bromo-1,2,3-trimethoxyben-
zene (7c), led to the arene 8c within 24 hours in 58% yield
(Table 2, entry 3).15 Also 2-bromobenzophenone (7d) un-
derwent the cross-coupling smoothly with the benzylman-
In summary, we have reported a convenient iron-cata-
lyzed cross-coupling procedure of benzylic manganese(II)
chlorides with a range of functionalized aryl and heteroaryl
chlorides, bromides and iodides, producing polyfunctional-
ized diaryl- or arylheteroarylmethane derivatives.16 This
method tolerates a range of functional groups, such as es-
ters, nitriles or ketones and proceeds smoothly at room
temperature within 2 to 24 hours. Further investigations to-
wards the synthesis and applications of various benzylic or-
ganometallics are currently under way in our laboratories.
O
Br
CO2Et
O
MnCl
3b
CO2Et
(1)
FeCl2 (10 mol%)
THF, 0–25 °C, 3 h
F
F
Acknowledgment
1b
5: 70%
This work was supported by the CNRS and Chimie ParisTech (Paris,
France), as well as by the Ludwig-Maximilians-University (Munich,
Germany) in the framework of the International Associated Laborato-
ry IrMaCaR between the research groups of P. Knochel and G. Cahiez.
We also thank BASF SE (Ludwigshafen, Germany) and Rockwood Lith-
ium GmbH (Hoechst, Germany) for the generous gift of chemicals.
CO2Et
CO2Et
N
Cl
MnCl
3c
(2)
N
FeCl2 (10 mol%)
THF, 0–25 °C, 2 h
CF3
6: 65%
CF3
1c
Supporting Information
Scheme 1 First examples for iron-catalyzed cross-coupling reactions
of the benzylic manganese(II) reagents 1b and 1c with heteroaryl ha-
lides 3b and 3c
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560812.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 471–476

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A. D. Benischke et al.
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Synlett
Table 2 Fe-Catalyzed Cross-Coupling Reaction of Several Benzylic Manganese Chlorides 1a–f with Functionalized Electrophiles
Mg turnings
(2.40 equiv)
E+
E
MnCl
Cl
FeCl2 (10 mol%)
THF, 0–25 °C
MnCl2⋅2LiCl
(1.25 equiv)
FG
FG
FG
2a–f
1a–f
8a–l
FG = 3-CF3, 4-OMe, 4-t-Bu, 2-Cl
Entry
1
Manganese Reagenta
Electrophile
Product, Yieldb,c
Br
MnCl
CN
CN
1a
8a: 75%, 3 h
7a
I
2
3
1a
1a
CO2Et
CO2Et
8b: 76%, 3 h
7b
Br
OMe
OMe
OMe
OMe
OMe
O
OMe
7c
8c: 58%, 24 h
O
Ph
Br
Ph
4
5
1a
7d
8d: 66%, 2 h
MnCl
Br
N
Br
N
I
CF3
CF3
8e: 70%, 12 h
7e
7d
1c
O
Ph
6
1c
CF3
8f: 80%, 2 h
MnCl
O
Ph
7
8
9
7d
MeO
8g: 75%, 2 h
OMe
1d
I
1d
MeO
OCF3
OCF3
7f
8h: 61%, 18 h
MnCl
O
Ph
7d
t-Bu
8i: 79%, 2 h
t-Bu
1e
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 471–476

474
A. D. Benischke et al.
Letter
Synlett
Table 2 (continued)
Entry
Manganese Reagenta
Electrophile
Product, Yieldb,c
I
10
1e
t-Bu
CO2Et
CO2Et
8j: 79%, 2 h
7g
CO2Et
Cl
CO2Et
MnCl
I
11
12
Cl
1f
1f
7h
8k: 68%, 2 h
Cl
CN
CN
N
Cl
N
7i
8l: 70%, 2 h
a Reaction conditions: 1.1 equiv of benzylic manganese reagent was used.
b Isolated yield of pure product.
c Less than 15% of homocoupling of the manganese reagent was observed.
References and Notes
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A. D. Benischke et al.
Letter
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oxidative insertion was complete, the solution of benzylic man-
ganese(II) chloride was separated from the resulting salts via a
syringe equipped with a filter and transferred to another pre-
dried and argon-flushed Schlenk tube, before being titrated
with iodine.
General Procedure for the Iron-Catalyzed Cross-Coupling of
Benzylic Manganese(II) Chlorides 1a–f with Electrophiles: A
dry and argon-flushed Schlenk flask, equipped with a magnetic
stirring bar and a rubber septum, was charged with FeCl2 (10
mol%, 99.5% pure), the corresponding electrophile (1.0 equiv)
and freshly distilled THF. Thereupon, the benzylic manga-
nese(II) chloride solution (1.05–1.10 equiv) was added drop-
wise at 0 °C. After the addition was complete, the reaction
mixture was stirred for a given time at the prior adjusted tem-
perature and then allowed to warm to r.t. The reaction comple-
tion was monitored by GC analysis of the quenched aliquots. A
saturated aqueous solution of NH4Cl was added and the
aqueous layer was extracted three times with Et2O or EtOAc (3 ×
50 mL). The combined organic layers were dried over MgSO4, fil-
tered and concentrated under reduced pressure. Purification of
the crude products by flash column chromatography afforded
the desired products.
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Ethyl 5-(3-Fluorobenzyl)furan-2-carboxylate (5): To a solu-
tion of FeCl2 (12.7 mg, 0.10 mmol, 0.10 equiv) and ethyl 5-bro-
mofuran-2-carboxylate (3b; 220 mg, 1.0 mmol, 1.0 equiv) in
THF (1.0 mL) the benzylic manganese(II) chloride solution (1b,
4.0 mL, 0.26 M, 1.05mmol, 1.05 equiv) was added dropwise at 0
°C. Then, the reaction mixture was stirred for 2 h at 0 °C and
allowed to warm to r.t. A saturated aqueous solution of NH4Cl
was added and the aqueous layer was extracted three times
with Et2O (3 × 50 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated under reduced pressure.
Finally the crude product was purified by flash column chroma-
tography (SiO2, i-hexane–Et2O, 99:1, Rf 0.11) leading to the
desired product 5 (174 mg, 0.70 mmol, 70%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.20–7.24 (m, 1 H), 7.05 (d, J =
3.4 Hz, 1 H), 6.98 (dd, J = 8.0, 1.3 Hz, 1 H), 6.90 (m, 2 H), 6.06 (dt,
J = 3.4, 0.8 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 3.99 (s, 2 H), 1.32 (t,
J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 163.0 (d, 1JC–F
=
3
245 Hz), 158.9, 158.6, 144.1, 139.3 (d, JC–F = 7.0 Hz), 130.2 (d,
3JC–F = 8.0 Hz), 124.6 (d, 4JC–F = 3.0 Hz), 119.0, 115.9 (d, 2JC–F = 22
Hz), 113.9 (d, 2JC–F = 20 Hz), 109.2, 60.9, 34.5, 14.5. 19F NMR (376
MHz, CDCl3): δ = –113.0. IR (ATR): 3128, 2983, 2361, 1713,
1616, 1591, 1519, 1488, 1448, 1383, 1368, 1297, 1251, 1205,
1173, 1126, 1075, 1016, 970, 944, 912, 866, 789, 760, 731, 681
cm–1. MS (EI, 70 eV): m/z (%) = 249 (10), 248 (67), 220 (10), 219
(23), 203 (42), 176 (17), 175 (100), 147 (16), 146 (40), 127 (10).
HRMS (EI, 70 eV): m/z calcd for C14H13FO3: 248.0849; found:
248.0845.
(14) Reducing the catalyst loading to 5.0 mol% led in some cases to
decreased reaction yields.
Ethyl 2-[3-(Trifluoromethyl)benzyl]nicotinate (6): To a solu-
tion of FeCl2 (12.7 mg, 0.10 mmol) and ethyl 2-chloronicotinate
(3c; 186 mg, 1.0 mmol, 1.0 equiv) in THF (1.0 mL) the benzylic
manganese(II) chloride solution (1c, 3.3 mL, 0.34 M, 1.1 mmol,
1.1 equiv) was added dropwise at 0 °C. The reaction mixture
was stirred for 2 h at 0 °C and allowed to warm to r.t. A satu-
rated aqueous solution of NH4Cl was added and the aqueous
layer was extracted three times with Et2O (3 × 50 mL). The com-
bined organic layers were dried over MgSO4, filtered and con-
centrated under reduced pressure. Purification of the crude
product by flash column chromatography (SiO2, i-hexane–Et2O,
8:2, Rf 0.17) afforded the desired product 6 (200 mg, 0.65 mmol,
65%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ = 8.62
(dd, J = 4.8, 1.8 Hz, 1 H), 8.13 (dd, J = 7.9, 1.8 Hz, 1 H), 7.49 (s, 1
(15) Hansch, C.; Leo, R.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(16) General Procedure for the Preparation of Benzylic Manga-
nese(II) Chlorides (1a–f): A dry and argon-flushed Schlenk
tube, equipped with a magnetic stirring bar and a rubber
septum, was charged with magnesium (0.18 g, 7.20 mmol, 2.40
equiv), followed by freshly distilled THF (3.0 mL) or MTBE (1.9
mL) and a solution of MnCl2·2LiCl (3.8 mL, 3.80 mmol, 1.25
equiv, 1.0 M in THF). The mixture was cooled to 0 °C, the benzyl
chloride (3.0 mmol, 1.0 equiv) was added at once and main-
tained at 0 °C until complete conversion of the starting material
was observed. The completion of the metalation was monitored
by GC analysis of hydrolyzed and iodolyzed aliquots. When the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 471–476

476
A. D. Benischke et al.
Letter
Synlett
H), 7.40–7.17 (m, 4 H), 4.56 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.26
(t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.4, 160.4,
1118, 1094, 1073, 1057, 1017, 917, 862, 822, 793, 782, 747, 734,
701, 676, 660 cm–1. MS (EI, 70 eV): m/z (%) = 310 (18), 309 (83),
308 (92), 290 (12), 281 (54), 264 (52), 263 (59), 262 (13), 237
(16), 236 (100), 235 (59), 234 (65), 216 (18), 167 (31), 139 (11).
HRMS (EI, 70 eV): m/z calcd for C16H14F3NO: 309.0977; found:
309.0966.
4
2
152.2, 140.7, 138.9, 132.6 (q, JC–F = 2.4 Hz), 130.6 (q, JC–F = 32
3
1
Hz), 128.7, 126.2, 125.9 (q, JC–F = 3.8 Hz), 124.4 (q, JC–F = 271
Hz), 123.1 (q, JC–F = 3.9 Hz), 121.7, 61.7, 42.2, 14.2. 19F NMR
3
(376 MHz, CDCl3): δ = –62.5. IR (ATR): 3049, 2985, 2363, 1720,
1583, 1570, 1448, 1438, 1368, 1328, 1300, 1259, 1190, 1161,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 471–476