Functionalized benzylic magnesium reagents through a sulfur-magnesium exchange

Article abstract of DOI:10.1002/anie.200501882

(Chemical Equation Presented) Switch it: lodobiphenyl thioethers readily undergo an iodine-magnesium exchange followed by, after the addition of tBuOLi, an intramolecular sulfur-magnesium exchange, which provides benzylic magnesium reagents in excellent yield through a fragmentation reaction.

Full text of DOI:10.1002/anie.200501882

Communications
Exchange Reactions
DOI: 10.1002/anie.200501882
Functionalized Benzylic Magnesium Reagents
through a Sulfur–Magnesium Exchange**
Armin H. Stoll, Arkady Krasovskiy, and Paul Knochel*
The preparation of benzylic magnesium compounds has been
studied extensively because of the high reactivity and
synthetic utility of these reagents.[1] Although the direct
insertion of magnesium into benzylic bromides is possible, the
formation of Wurtz homocoupling products complicates this
approach, especially when electron-rich benzylic halides are
used as substrates. Herein, we report the preparation of
functionalized benzylic magnesium reagents by using a new
sulfur–magnesium exchange reaction.[2,3] We prepared o-(o-
[*] Dipl.-Chem. A. H. Stoll, Dr. A. Krasovskiy, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the Deutsche
Forschungsgemeinschaft (DFG), and the Merck Research Labora-
tories (MSD) for financial support. We also thank Chemetall GmbH
(Frankfurt) and BASF AG (Ludwigshafen) for generous gift of
chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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iodophenyl)phenylthio derivatives[4] of type 1 because a range
of functionalized benzylic derivatives are readily available
through the reaction of thiosulfonates 2 with the monomag-
nesium derivative 3 of 2,2’-diiodobiphenyl (4) (Scheme 1).[5,6]
tBuOLi improves the yields by avoiding alkylation side
reactions.
The role of tBuOLi may be explained tentatively through
the assumption of the formation of a magnesiate intermediate
(ArMg(OtBu)ClꢀLi+), which has a
more reactive carbon–magnesium
bond and initiates the sulfur–mag-
nesium exchange. Thus, the reaction
of o-(o-iodophenyl)phenyl benzyl
thioether (1a) with iPrMgCl
(1.1 equiv; ꢀ50!ꢀ208C, 1.5 h) fol-
lowed by evaporation of the solvent
(10ꢀ1 mmHg, 258C, 2 h), redissolu-
tion in THF, and addition of tBuOLi
(1.0 equiv; ꢀ208C, 20 h) provide
the benzylic magnesium derivative
8a. Subsequent reaction with vari-
ous electrophiles such as benzalde-
hyde,
entries 1 and 2), 6-bromo-1-
methoxycyclohexene (Table 1,
entry 3), benzoyl chloride, and
pivaldehyde
(Table 1,
Scheme 1. Preparation of benzylic o-(o-iodophenyl)phenylthio derivatives 1 with thiosulfonates 2, or
through chloromethyl thioether 5 and aryl copper derivatives. NCS=N-chlorosuccinimide
The required thiosulfonates 2 were prepared either by the
reaction of PhSO2Na with disulfides[7] or by the reaction of
PhSO2SNa with various benzylic halides in N,N-dimethylfor-
mamide[8] (see Supporting Information). Alternatively, the
benzylic o-(o-iodophenyl)phenylthio derivatives 1 can also be
synthesized from 4 through the two-step preparation of the
chloromethyl thioether 5, which was obtained in 72% overall
yield.[9] Treatment of 5 with various aryl copper derivatives
(ArCu, 1.5 equiv; ꢀ408C!RT, 20 h), in the presence of
Bu4NI (1.0 equiv), directly produces the benzylic thioethers 1
in satisfactory yields.
The reaction of the aryl iodide 1 with iPrMgCl (1.1 equiv)
at ꢀ50!ꢀ158C affords the expected I/Mg exchange product
6. Remarkably, the treatment of the aryl magnesium deriv-
ative 6 with tBuOLi (0.1–1.0 equiv)[10] triggers a new intra-
molecular sulfur–magnesium exchange reaction that leads to
the stable heterocycle 7 and to the benzylic magnesium
reagents 8 after approximately 20 h at ꢀ208C (Scheme 2).
Evaporation of the solvent and iPrI before the addition of
cyclohexanecarbonyl chloride (Table 1, entries 4 and 5) lead
to the expected products 9a (75%), 9b (85%), 9c (82%), 9d
(90%), and 9e (78%), respectively, in excellent yields.
The reaction with acid chlorides requires successive
transmetalation of the benzylic magnesium reagent 8a with
ZnCl2 and CuCN·2LiCl[11] to avoid homocoupling of the
sensitive benzylic copper intermediate that is obtained by
direct transmetalation from 8a. Interestingly, the sulfur–
magnesium exchange reactions of substrates 1 in which the
benzylic moiety bears electron-withdrawing substituents such
as bromine, chlorine, or trifluoromethyl groups (Table 1,
entries 6–13, 8b–f) do not need the addition of tBuOLi and
are complete within a few hours. Electron-donating groups,
such as the methoxy group, are compatible with the S–Mg
exchange reaction and lead to benzylic magnesium species
such as 8g (Table 1, entries 14 and 15). The reaction with
electrophiles such as pivaldehyde and benzoyl chloride lead
to the expected products 9n (95%) and 9o (81%). Interest-
ingly, the benzylic magnesium reagent can also be generated
in the presence of an electrophile (Barbier conditions). Thus,
treatment of the biphenyl derivative 1h with iPrMgCl
(1.05 equiv, -50!108C) in the presence of an electrophile (a
nitrile such as 4-bromobenzonitrile (0.9 equiv) or an alkyl
iodide such as butyl iodide (2.0 equiv)) leads to the desired
products 9p (79%) and 9q (90%), respectively (Scheme 3).
In summary, we have developed a new synthesis of
functionalized benzylic magnesium compounds by using a
novel sulfur–magnesium exchange reaction. Extensions of
this method to the preparation of other magnesium reagents
are currently underway in our laboratory.
Experimental Section
Typical procedure (9n): A dry and argon-flushed 50-mL Schlenk
flask, equipped with a magnetic stirring bar and a septum, was
charged with 2’-iodo-2-(2-methoxybenzylsulfanyl)biphenyl (1g)
(216 mg, 0.50 mmol) and THF (1 mL). The solution was cooled to
Scheme 2. Preparation of functionalized benzylic magnesium deriva-
tives by using an intramolecular S/Mg exchange reaction.
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Communications
Table 1: Products of type 9 obtained by the reaction of benzylic magnesium derivatives through a S/Mg exchange.
Entry
Benzylic
Electrophile
Product 9
Yield [%][b]
Mg reagent[a]
1
2
8a
8a
PhCHO
9a
9b
75
85
tBuCHO
3
8a
9c
82
4
5
6
8a
8a
8b
PhCOCl
9d
9e
9 f
90[c]
78[c]
89
c-HexCOCl
PhCHO
7
8
8b
8b
PhCOCl
9g
9h
82[c]
80[c]
c-HexCOCl
9
8c
tBuCHO
9i
81
10
11
8d
8d
c-HexCOCl
9j
81[c]
86[c]
PhCOCl
9k
12
13
8e
8 f
tBuCHO
9l
70
PhCOCl
9m
89[c]
14
15
8g
8g
tBuCHO
9n
9o
95
PhCOCl
81[c]
[a] X=Cl or OtBu. [b] Yield of isolated analytically pure compound. [c] Reaction performed after the successive addition of ZnCl2 (1 equiv) and
CuCN·2 LiCl (1 equiv).
was dissolved in THF (2 mL) and concentrated again as described
above. THF (1.5 mL) was used to dissolve the residue a second time,
and completion of the I–Mg exchange was checked by GC analysis
with tetradecane as an internal standard. A solution of tBuOLi
(0.50 mL. 0.50 mmol, 1.0m in THF) was then added at ꢀ158C, and the
mixture was stirred for 18 h at ꢀ58C to give the benzylic magnesium
reagent 8g. The reaction mixture was cooled to ꢀ208C and
pivaldehyde (35 mg, 0.40 mmol) was added. After additional stirring
40 min at this temperature the reaction mixture was quenched with
water (100 mL), extracted with Et2O (3 ” 150 mL), and dried over
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography (pentane/Et2O = 5:1) yielded
9n (79 mg, 95%) as a colorless oil.
Scheme 3. Reaction of benzylic o-(o-iodophenyl)phenylthio derivative
1h with iPrMgCl under Barbier conditions.
ꢀ508C, and iPrMgCl (0.58 mL, 0.55 mmol, 0.95m in THF) was added
slowly through a syringe. The reaction mixture was then immediately
concentrated (10ꢀ1 mmHg, 258C, 1 h). The resultant white precipitate
Received: May 31, 2005
Revised: August 25, 2005
Published online: December 15, 2005
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Keywords: benzylic organometallic compounds ·
.
cross-coupling · fragmentation · Grignard reaction ·
organocopper compounds
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