New preparation of benzylic manganese chlorides by the direct insertion of magnesium into benzylic chlorides in the presence of MnCl2·2LiCl

Article abstract of DOI:10.1055/s-0034-1379944

Functionalized benzylic manganese chlorides were smoothly prepared by the direct insertion of magnesium into benzylic chlorides in the presence of MnCl₂·2LiCl. Reactions with acid chlorides, aldehydes, an allyl bromide, and an enone proceed without any additional transition metal.

Full text of DOI:10.1055/s-0034-1379944

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 514–518
letter
514
P. Quinio et al.
Letter
Synlett
New Preparation of Benzylic Manganese Chlorides by the Direct
Insertion of Magnesium into Benzylic Chlorides in the Presence of
MnCl2·2LiCl
Pauline Quinioa
O
Andreas D. Benischkea
Alban Moyeuxb,c
Gérard Cahiezb
Paul Knochel*a
O
MnCl
(0.9 equiv)
THF, –40 °C to 25 °C, 12 h
F
F
a Department Chemie, Ludwig-Maximilians-Universität,
Butenandtstr. 5-13, 81377 München, Germany
Paul.Knochel@cup.uni-muenchen.de
79%
b Institut de Recherche de Chimie Paris, CNRS - Chimie ParisTech,
11 rue Pierre et Marie Curie, 75005 Paris, France
gerard.cahiez@chimie-paristech.fr
c Université Paris 13, Sorbonne Paris Cité, 74 rue Marcel Cachin,
93017 Bobigny, France
Dedicated to Dr. Klaus Römer on the occasion of his 75th birthday
Received: 31.10.2014
Accepted after revision: 26.11.2014
Published online: 12.01.2015
Cl
MnCl•MgCl2•2LiCl
Mg turnings (2.4 equiv)
MnCl2•2LiCl (1.25 equiv)
DOI: 10.1055/s-0034-1379944; Art ID: st-2014-b0911-l
FG
FG
0 °C, 1–1.5 h
2a–f
1a–f (52–85%)
Abstract Functionalized benzylic manganese chlorides were smoothly
prepared by the direct insertion of magnesium into benzylic chlorides
in the presence of MnCl2·2LiCl. Reactions with acid chlorides, aldehydes,
an allyl bromide, and an enone proceed without any additional transi-
tion metal.
FG = OMe, SMe, Cl, F, CF3
Scheme 1 Magnesium insertion into functionalized benzylic chlorides
in the presence of MnCl2·2LiCl
Key words manganese, magnesium, insertion, addition, cross-cou-
pling
Thus, the treatment of benzyl chloride (2a) with Mg
turnings (2.4 equiv) and MnCl2·2LiCl (1.25 equiv; prepared
as a 1 M solution in THF) at 0 °C produces benzyl manga-
nese chloride (1a) within one hour reaction time with a
yield of 85% as determined by iodolysis (Table 1, entry 1). As
a general procedure, various substituted benzylic chlorides
were converted into the corresponding manganese organo-
metallics 1a–f in 52–85% (Table 1). However, in some cases,
like 2-chlorobenzyl chloride (2b) and 3-trifluoromethyl-
benzyl chloride (2c), extensive amounts of homocoupling
products were obtained in pure THF. Interestingly, the use
of a 2:1 mixture of THF and methyl tert-butyl ether (MTBE)
reduces the amount of homocoupling to less than 10% af-
fording the corresponding manganese reagents (1b,c) in
62–65% yield (Table 1, entries 2 and 3). The presence of a
sulfur substituent, like in 1f, does not disturb the insertion
and produces the benzylic manganese reagent 2f in 54%
yield (Table 1, entry 6), showing the tolerance of such meta-
lation process.
The direct insertion of a metal into an organic halide
(Grignard synthesis) constitutes the most established
method for forming organometallic reagents.1 Since this
synthesis requires the use of a metal powder, the metal ac-
tivation is often required for the success of the insertion re-
action. Rieke showed in a pioneer work that in situ reduc-
tion of magnesium chloride with lithium produces highly
active magnesium allowing insertions under extremely
mild conditions.2 Recently, we have developed an alterna-
tive approach involving the use of commercial magnesium
powder or turnings in the presence of lithium chloride.3
This method can be readily extended to other metals such
as indium,4 aluminum,5 and zinc.6 More recently we have
shown that manganese7 can be similarly activated by lithi-
um chloride allowing the production of aryl reagents. Here-
in, we wish to report the formation of benzylic manganese
organometallics of type 1 using magnesium turnings in the
presence of MnCl2·2LiCl8 with various benzylic chlorides
(Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 514–518

515
P. Quinio et al.
Letter
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2, eq. 1). Also, the benzylic manganese reagent 1d under-
goes a smooth 1,4-addition to cyclohexenone leading to the
ketone 5 in 79% yield (Scheme 2, eq. 2). In the presence of
10% CuI, trans-β-nitrostyrene11 undergoes a conjugated ad-
dition providing the nitroalkene 6 in 74% yield (Scheme 2,
eq. 3).
Table 1 Magnesium Insertion into Benzylic Chlorides in the Presence
of MnCl2·2LiCl
Entry Benzylic manganese
chloride
1
Time (
h)
Temp
(°C)
Iodolysis
yield (%)a
MnCl
1
1a
1b
1
0
0
85
Br
MnCl
2
1.5
62b
(0.9 equiv)
MnCl
(1)
(2)
(3)
Cl
THF
–40 °C to 25 °C
12 h
MeO
MeO
MnCl
1e
4, 92%
3
1c
1.5
1
0
0
65b
64
O
CF3
O
MnCl
MnCl
(0.9 equiv)
4
1d
THF, 0–25 °C, 12 h
F
F
F
1d
5, 79%
MnCl
MnCl
5
1e
1f
1
0
0
52
54
NO2
Ph
(0.9 equiv)
MeO
MnCl
NO2
CuI (10 mol%), THF
Ph
6
1.5
–78 °C to 25 °C, 12 h
F
F
MeS
a The formation of benzylic manganese chlorides is characterized by iodoly-
1d
6, 74%
sis.
Scheme 2 Further transformations of benzylic manganese reagents
b A 2:1 mixture of THF and MTBE is used.
In summary, we have reported a new convenient prepa-
ration of benzylic manganese reagents and have demon-
strated their versatility in the presence of various electro-
philes such as an allylic bromide, an enone, aldehydes, and
acid chlorides in the absence of any additional transition
metal.12
Organomanganese are important organometallic inter-
mediates9 reacting readily with a number of electrophiles
(E+) furnishing products of type 3. The benzylic manganese
reagents obtained by our method react with carbonyl
groups, in the absence of any additional catalyst (Table 2).
Thus, benzyl manganese chloride (1a) adds to benzalde-
hyde overnight at 25 °C affording the desired alcohol 3a in
94% yield (Table 2, entry 1). Similarly, the functionalized
benzylic manganese reagents 1b,c,e,f react with aromatic
and heterocyclic aldehydes leading to the products 3b–e in
76–95% yield (Table 2, entries 1–5). As expected, the reac-
tion of manganese reagents of type 1 with acid chlorides
furnished the desired ketones 3f–i without any transition-
metal catalyst in 72–93% (Table 2, entries 6–9). Smooth pal-
ladium-catalyzed cross-couplings with aryl bromides or io-
dides take place by treating the benzylic manganese re-
agent 1 with 2% Pd(OAc)2, 4% S-Phos10 at 25 °C overnight
affording the diaryl methane derivatives 3j–o in 50–96%
(Table 2, entries 10–15).
Acknowledgment
This work was supported by the CNRS and Chimie ParisTech (Paris,
France) as well as by the Ludwig Maximilian University (Munich, Ger-
many) in the frame work of the International Associated Laboratory
IrMaCaR between the research groups of Professors P. Knochel and G.
Cahiez. We also thank BASF SE (Ludwigshafen, Germany) and Rock-
wood Lithium GmbH (Hoechst, Germany) for the generous gift of
chemicals.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379944.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Interestingly, the reaction of benzylic manganese re-
agents such as 1e with 3-bromocyclohexene at 25 °C over-
night provides the allylated product 4 in 92% yield (Scheme
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 514–518

516
P. Quinio et al.
Letter
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Table 2 Synthesis of 15 Examples 3a–o
Mg turnings
(2.4 equiv)
E+
Cl
E
MnCl
25 °C
MnCl2•2LiCl
(1.25 equiv)
FG
2a–f
FG = OMe, SMe, Cl, F, CF3
FG
3a–o (50–96%)
FG
1a–f
Entry
1
Benzylic manganese chloride
1
Electrophilea
Product
3
Yield (%)b
94
O
MnCl
1a
1b
3a
3b
H
H
OH
CN
O
MnCl
Cl
2
3
95
76
OH
CN
Cl
O
MnCl
1c
1e
3c
H
OH Br
CF3
Br
CF3
O
MnCl
S
H
H
4
3d
94
S
MeO
OH
MeO
MeS
O
MnCl
O
5
6
1f
3e
3f
94
78
O
MeS
OH
Cl
O
MnCl
Cl
1b
Cl
O
O
Cl
Cl
Cl
Cl
Cl
O
O
MnCl
7
8
1c
3g
3h
76
72
Cl
Cl
CF3
CF3
MnCl
1d
O
F
Cl
F
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 514–518

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P. Quinio et al.
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Table 2 (continued)
Entry
Benzylic manganese chloride
1
Electrophilea
Product
3
Yield (%)b
OMe
O
MnCl
9
1f
3i
93
Cl
MeS
O
OMe
MeS
I
I
MnCl
MnCl
MnCl
10
11
1a
1b
3jc
96
94
OMe
OMe
3kc
Cl
OMe
O
Cl
OMe
Br
Br
O
O
12
1c
3lc
71
O
CF3
CF3
MnCl
13
14
1d
1e
3mc
3nc
69
88
CN
CN
F
F
Br
Br
MnCl
MnCl
MeO
CO2Et
MeO
CO2Et
OMe
OMe
OMe
OMe
15
1f
3oc
50
MeS
MeS
OMe
OMe
a Reacion conditions: 1.1 equiv of the benzylic manganese chloride are used for 1.0 equiv of electrophile.
b Isolated yield of pure product.
c 2% Pd(OAc)2 and 4% S-Phos are used.
References and Notes
(9) Cahiez, G.; Duplais, C.; Buendia, J. Chem. Rev. 2009, 109, 1434.
(10) (a) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7,
3965. (b) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2006, 45, 6523. (c) Barder,
T. E.; Buchwald, S. L. Org. Lett. 2004, 6, 2649.
(11) (a) Bresser, T.; Knochel, P. Angew. Chem. Int. Ed. 2011, 50, 1914.
(b) Prasad, A. S. B.; Eick, H.; Knochel, P. J. Organomet. Chem.
1998, 562, 133. (c) Juber, C.; Knochel, P. J. Org. Chem. 1992, 57,
5431.
(1) (a) Klatt, T.; Markiewicz, J.; Sämann, C.; Knochel, P. J. Org. Chem.
2014, 79, 4253. (b) Grignard, V. C. R. Acad. Sci. 1900, 130, 1322.
(2) (a) Rieke, R. D. Science 1989, 246, 1260. (b) Rieke, R. D.; Hanson,
M. V. Tetrahedron 1997, 53, 1925.
(3) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
(4) Chen, Y.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 7648.
(5) Blümke, T.; Chen, Y.; Peng, Z.; Knochel, P. Nat. Chem. 2010, 2,
313.
(6) (a) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem. Int. Ed. 2006, 45, 6040. (b) Metzger, A.; Schade, M.
A.; Knochel, P. Org. Lett. 2008, 10, 1107. (c) Metzger, A.; Piller, F.
M.; Knochel, P. Chem. Commun. 2008, 5824.
(7) (a) Peng, Z.; Knochel, P. Org. Lett. 2011, 13, 3198. (b) Peng, Z.; Li,
N.; Sun, X.; Wang, F.; Xu, L.; Jiang, C.; Song, L.; Yan, Z. Org.
Biomol. Chem. 2014, 12, 7800.
(8) Cahiez, G. Manganese(II) Chloride in Encyclopedia of Reagents for
Organic Synthesis; Vol. 5; Paquette, L., Ed.; Wiley: Chichester,
1995, 3227.
(12) Procedures
All reactions were carried out under an argon atmosphere in
flame-dried glassware. Syringes which were used to transfer
anhydrous solvents or reagents were purged with argon prior to
use. THF was continuously refluxed and freshly distilled from
sodium benzophenone ketyl under nitrogen. Methyl tert-butyl
ether (MTBE) was freshly distilled from sodium benzophenone
ketyl under nitrogen. Yields refer to isolated yields of com-
pounds estimated to be >95% pure as determined by 1H NMR
(25 °C) and capillary GC analysis.
Solution of MnCl2·2LiCl (1.0 M in THF)
A dry and argon-flushed 250 mL Schlenk flask, equipped with a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 514–518

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P. Quinio et al.
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Synlett
magnetic stirring bar and a glass stopper, was charged with LiCl
(6.8 g, 160 mmol) and heated up to 150 °C under high vacuum
for 3 h. After cooling to r.t. under argon, MnCl2 (10.1 g, 80 mmol,
99% pure) was added under inert atmosphere. The Schlenk flask
was further heated to 130 °C for 3 h under high vacuum, cooled
to r.t. and charged with freshly distilled THF (80 mL) under
argon with vigorous stirring. The mixture was stirred for at
least 24 h at 25 °C. The reagent MnCl2·2LiCl (1.0 M in THF)
appears as a yellow solution.
2340, 2225, 1946, 1700, 1606, 1573, 1504, 1471, 1444, 1412,
1374, 1355, 1318, 1308, 1270, 1173, 1048 cm–1. MS (70 eV, EI):
m/z (%) = 77 (15), 89 (13), 91 (30), 102 (10), 104 (49), 125 (28),
126 (84), 127 (17), 128 (27), 132 (100), 239 (2). HRMS (EI): m/z
[M+] calcd for C15H12NOCl: 257.0607; found: 239.0486 (– H2O).
5-[3-(Trifluoromethyl)benzyl]benzo[d][1,3]dioxole (3l)
To a solution of 5-bromo-1,3-benzodioxole (101 mg, 0.06 mL,
0.5 mmol) in THF (0.5 mL) was added 2% Pd(OAc)2 (2.3 mg) and
4% S-Phos (8.2 mg). The benzyl manganese chloride solution 1c
(0.44 M, 1.25 mL, 1.1 equiv) was added dropwise at 0 °C, and
the reaction mixture was slowly warmed up to 25 °C and
stirred overnight. Purification by flash chromatography (SiO2;
i-hexane–EtOAc, 98:2) afforded the desired product 3l (100 mg,
Preparation of Benzyl Manganese Chlorides 1a–f
A dry and argon flushed Schlenk flask, equipped with a mag-
netic stirring bar and a rubber septum, was charged with mag-
nesium (175 mg, 2.40 equiv), followed by dry THF (1 mL) or
MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.75 mL, 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 the reac-
tion was maintained at 0 °C still complete conversion of the
starting material was observed (reaction of aliquots with iodine
followed by GC analysis).
When the insertion reaction was complete, the solution of
benzyl manganese chloride was separated from the resulting
salts via a syringe equipped with a filter and transferred to
another Schlenk flask, dry and argon flushed, before being
titrated against iodine.
1
71%) as a colorless liquid. H NMR (300 MHz, CDCl3): δ = 7.51–
7.33 (m, J = 23.50, 3.87 Hz, 4 H), 6.80–6.73 (dd, J = 0.83 Hz, 2 H),
6.67 (dd, J = 1.11, 0.55 Hz, 2 H), 5.94 (s, 3 H), 3.96 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 147.9, 146.2, 142.2, 133.8, 132.1,
132.1, 130.8 [q, 2J(C,F) = 32 Hz], 128.9, 125.4 [q, 3J(C,F) = 4 Hz],
124.2 [q, 1J(C,F) = 272 Hz], 123.0 [q, 3J(C,F) = 4 Hz], 109.3, 108.3,
101.0, 41.3 ppm. 19F NMR (282 MHz, CDCl3): δ = –62.6 ppm. IR
(diamond ATR, neat): ν = 3017, 2896, 2778, 2361, 1846, 1714,
1610, 1597, 1503, 1488, 1442, 1360, 1329, 1244, 1160, 1120,
1092, 1072, 1038 cm–1. MS (70 eV, EI): m/z (%) = 135 (33), 152
(18), 153 (11), 159 (11), 181 (26), 201 (10), 242 (24), 249 (11),
261 (11), 279 (23), 280 (100), 281 (15). HRMS (EI): m/z [M+]
calcd for C15H11O2F3: 280.0711; found: 280.0704.
Reaction of Benzyl Manganese Chlorides with Electrophiles;
Typical Procedure
A dry and argon flushed Schlenk flask, equipped with a mag-
netic stirring bar and a rubber septum, was charged with the
electrophile (1.0 equiv), followed by dry THF. The benzyl man-
ganese chloride solution (1.05–1.10 equiv) was added dropwise
at 0 °C, and the reaction mixture was slowly warmed up to
25 °C and stirred overnight. Sat. aq NH4Cl (4 mL) and H2O (2 mL)
were added and the aqueous layer was extracted with EtOAc (3
× 20 mL). The combined organic layers were dried over Na2SO4
and filtered. Evaporation of the solvents in vacuo and purifica-
tion by flash column chromatography afforded the expected
products.
3-(3-Fluorobenzyl)cyclohexanone (5)
To a solution of cyclohexenone (96 mg, 0.10 mL,1.0 mmol) in
THF (1 mL) was added dropwise the benzyl manganese chloride
solution 1d (0.44 M, 2.5 mL, 1.1 equiv) at –40 °C. The reaction
mixture was slowly warmed up to 25 °C and stirred overnight.
Sat. aq NH4Cl (4 mL) and H2O (2 mL) were added, and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were dried over Na2SO4 and filtered. Evap-
oration of the solvents in vacuo and purification by flash
column chromatography (SiO2; i-hexane–EtOAc, 9:1 + Et3N 1%)
afforded the desired product 5 (163 mg, 79%) as a yellowish oil.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.17 (m, J = 7.43, 1.37 Hz, 1
H), 6.90–6.83 (m, J = 5.87, 2.93 Hz, 2 H), 6.80 (dd, J = 9.98, 1.57
Hz, 1 H), 2.66–2.51 (m, J = 6.65 Hz, 2 H), 2.38–2.17 (m, 3 H),
2.07–1.95 (m, 3 H), 1.89–1.79 (m, 1 H), 1.66–1.55 (m, 1 H),
1.41–1.28 (m, 1 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 211.2,
162.8 [d, 1J(C,F) = 246 Hz], 141.9 [d, 3J(C,F) = 7 Hz], 129.7 [d,
3J(C,F) = 8 Hz], 124.7 [d, 4J(C,F) = 3 Hz], 115.8 [d, 2J(C,F) = 21 Hz],
113.1 [d, 2J(C,F) = 21 Hz], 47.6, 42.6 [d, 4J(C,F) = 2 Hz], 41.3, 40.6,
30.8, 25.0 ppm. 19F NMR (282 MHz, CDCl3): δ = –113.6 ppm. IR
(diamond ATR, neat): ν = 2933, 2866, 1708, 1614, 1587, 1486,
1448, 1346, 1311, 1249, 1225, 1139, 1056 cm–1. MS (70 eV, EI):
m/z (%) = 41 (54), 42 (10), 55 (41), 69 (38), 83 (33), 97 (42), 109
(100), 133 (19), 135 (20), 147 (33), 148 (94), 206 (9), 207 (5).
HRMS (EI): m/z [M+] calcd for C13H15FO: 206.1107; found:
206.1102.
4-[2-(2-Chlorophenyl)-1-hydroxyethyl]benzonitrile (3b)
To a solution of 4-cyanobenzaldehyde (66 mg, 0.5 mmol) in THF
(1 mL) was added dropwise a solution of benzyl manganese
chloride 1b (0.37 M, 1.49 mL, 1.1 equiv) at 0 °C. The reaction
mixture was slowly warmed up to 25 °C and stirred overnight.
Purification by flash chromatography (SiO2; i-hexane–EtOAc,
7:3 + Et3N 1%) afforded the desired product 3b (122 mg, 95%) as
a white solid; mp 90–92 °C.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.00 Hz, 2 H), 7.49 (d,
J = 8.20 Hz, 2 H), 7.40 (d, J = 7.22 Hz, 1 H), 7.26–7.12 (m, J = 7.22,
1.76 Hz, 3 H), 5.09 (dd, J = 8.49, 4.59, 3.90 Hz, 1 H), 3.23–3.00
(ddd, J = 13.66, 8.68, 4.49 Hz, 2 H), 2.18 (br s., 1 H, OH) ppm. 13
C
NMR (101 MHz, CDCl3): δ = 149.3, 135.2, 134.6, 132.5 (2C),
132.3, 130.0, 128.8, 127.2, 126.7 (2 C), 119.1, 111.6, 73.0, 44.1
ppm. IR (diamond ATR, neat): ν = 3556, 3064, 2953, 2925, 2360,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 514–518

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