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Functionalized Benzylic Magnesium Reagents through a SulfurЦMagnesium Exchange.

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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-Universit0t M1nchen
Butenandtstrasse 5–13, Haus F, 81377 M1nchen (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 Laboratories (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.
606
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 606 –609
Angewandte
Chemie
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 monomagnesium 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)ClLi+), which has a
more reactive carbon–magnesium
bond and initiates the sulfur–magnesium exchange. Thus, the reaction
of o-(o-iodophenyl)phenyl benzyl
thioether (1 a) with iPrMgCl
(1.1 equiv; 50!20 8C, 1.5 h) followed by evaporation of the solvent
(101 mmHg, 25 8C, 2 h), redissolution in THF, and addition of tBuOLi
(1.0 equiv; 20 8C, 20 h) provide
the benzylic magnesium derivative
8 a. Subsequent reaction with various electrophiles such as benzaldehyde,
pivaldehyde
(Table 1,
Scheme 1. Preparation of benzylic o-(o-iodophenyl)phenylthio derivatives 1 with thiosulfonates 2, or
entries
1
and
2),
6-bromo-1through chloromethyl thioether 5 and aryl copper derivatives. NCS = N-chlorosuccinimide
methoxycyclohexene
(Table 1,
entry 3), benzoyl chloride, and
cyclohexanecarbonyl chloride (Table 1, entries 4 and 5) lead
The required thiosulfonates 2 were prepared either by the
to the expected products 9 a (75 %), 9 b (85 %), 9 c (82 %), 9 d
reaction of PhSO2Na with disulfides[7] or by the reaction of
(90 %), and 9 e (78 %), respectively, in excellent yields.
PhSO2SNa with various benzylic halides in N,N-dimethylforThe reaction with acid chlorides requires successive
mamide[8] (see Supporting Information). Alternatively, the
transmetalation of the benzylic magnesium reagent 8 a with
benzylic o-(o-iodophenyl)phenylthio derivatives 1 can also be
ZnCl2 and CuCN·2 LiCl[11] to avoid homocoupling of the
synthesized from 4 through the two-step preparation of the
chloromethyl thioether 5, which was obtained in 72 % overall
sensitive benzylic copper intermediate that is obtained by
yield.[9] Treatment of 5 with various aryl copper derivatives
direct transmetalation from 8 a. Interestingly, the sulfur–
magnesium exchange reactions of substrates 1 in which the
(ArCu, 1.5 equiv; 40 8C!RT, 20 h), in the presence of
benzylic moiety bears electron-withdrawing substituents such
Bu4NI (1.0 equiv), directly produces the benzylic thioethers 1
as bromine, chlorine, or trifluoromethyl groups (Table 1,
in satisfactory yields.
entries 6–13, 8 b–f) do not need the addition of tBuOLi and
The reaction of the aryl iodide 1 with iPrMgCl (1.1 equiv)
are complete within a few hours. Electron-donating groups,
at 50!15 8C affords the expected I/Mg exchange product
such as the methoxy group, are compatible with the S–Mg
6. Remarkably, the treatment of the aryl magnesium derivexchange reaction and lead to benzylic magnesium species
ative 6 with tBuOLi (0.1–1.0 equiv)[10] triggers a new intrasuch as 8 g (Table 1, entries 14 and 15). The reaction with
molecular sulfur–magnesium exchange reaction that leads to
electrophiles such as pivaldehyde and benzoyl chloride lead
the stable heterocycle 7 and to the benzylic magnesium
to the expected products 9 n (95 %) and 9 o (81 %). Interestreagents 8 after approximately 20 h at 20 8C (Scheme 2).
ingly, the benzylic magnesium reagent can also be generated
Evaporation of the solvent and iPrI before the addition of
in the presence of an electrophile (Barbier conditions). Thus,
treatment of the biphenyl derivative 1 h with iPrMgCl
(1.05 equiv, -50!10 8C) 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 9 p (79 %) and 9 q (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
Scheme 2. Preparation of functionalized benzylic magnesium derivatives by using an intramolecular S/Mg exchange reaction.
Angew. Chem. Int. Ed. 2006, 45, 606 –609
Typical procedure (9 n): 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 (1 g)
(216 mg, 0.50 mmol) and THF (1 mL). The solution was cooled to
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
607
Communications
Table 1: Products of type 9 obtained by the reaction of benzylic magnesium derivatives through a S/Mg exchange.
Entry
Benzylic
Mg reagent[a]
Electrophile
Yield [%][b]
Product 9
1
8a
PhCHO
9a
75
2
8a
tBuCHO
9b
85
3
8a
9c
82
4
8a
PhCOCl
9d
90[c]
5
8a
c-HexCOCl
9e
78[c]
6
8b
PhCHO
9f
89
7
8b
PhCOCl
9g
82[c]
8
8b
c-HexCOCl
9h
80[c]
9
8c
tBuCHO
9i
81
10
8d
c-HexCOCl
9j
81[c]
11
8d
PhCOCl
9k
86[c]
12
8e
tBuCHO
9l
70
13
8f
PhCOCl
9m
89[c]
14
8g
tBuCHO
9n
95
15
8g
PhCOCl
9o
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).
Scheme 3. Reaction of benzylic o-(o-iodophenyl)phenylthio derivative
1 h with iPrMgCl under Barbier conditions.
50 8C, and iPrMgCl (0.58 mL, 0.55 mmol, 0.95 m in THF) was added
slowly through a syringe. The reaction mixture was then immediately
concentrated (101 mmHg, 25 8C, 1 h). The resultant white precipitate
608
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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, 1.0 m in THF) was then added at 15 8C, and the
mixture was stirred for 18 h at 5 8C to give the benzylic magnesium
reagent 8 g. The reaction mixture was cooled to 20 8C 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 C 150 mL), and dried over
Na2SO4. After filtration, the solvent was evaporated in vacuo.
Purification by flash chromatography (pentane/Et2O = 5:1) yielded
9 n (79 mg, 95 %) as a colorless oil.
Received: May 31, 2005
Revised: August 25, 2005
Published online: December 15, 2005
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 606 –609
Angewandte
Chemie
.
Keywords: benzylic organometallic compounds ·
cross-coupling · fragmentation · Grignard reaction ·
organocopper compounds
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584; b) T. Alonso, S. Harvey, P. C. Junk, C. L. Raston, B. Skelton,
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[2] The sulfoxide–magnesium exchange reaction is well known and
especially useful for the preparation of new magnesium carbenoids; see: a) T. Satoh, K. Horiguchi, Tetrahedron Lett. 1995, 36,
8235; b) T. Satoh, T. Oohara, Y. Ueda, K. Yamakawa, J. Org.
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HKlzer, R. W. Hoffmann, Chem. Commun. 2003, 732.
[3] For a related reductive sulfur–magnesium exchange reaction
that generates allylic magnesium reagents, see: D. Cheng, S. Zhu,
Z. Yu, T. Cohen, J. Am. Chem. Soc. 2001, 123, 30.
[4] Related compounds of this class were used for the rapid and mild
generation of various carbon radicals: a) T. Ooi, M. Furuya, D.
Sakai, J. Hokke, K. Maruoka, Synlett 2001, 541; b) T. Ooi, D.
Sakai, M. Takada, N. Komatsu, K. Maruoka, Synlett 2001, 791;
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2001, 343, 166.
[5] W. Neugebauer, A. J. Kos, P. v. R. Schleyer, J. Organomet. Chem.
1982, 228, 107.
[6] The use of 2,2’-dibromobiphenyl instead of 4 is unfortunately not
possible, although the corresponding bromo derivatives 1 can be
prepared (see Supporting Information). The Br/Mg exchange
does not occur to a significant extent under the typical reaction
conditions.
[7] K. Fujiki, N. Tanifuji, Y. Sasaki, T. Yokoyama, Synthesis 2002,
343.
[8] D. Scholz, Liebigs Ann. Chem. 1984, 259.
[9] P. G. Theobald, W. H. Okamura, J. Org. Chem. 1990, 55, 741.
[10] Lithium chloride also promotes the sulfur–magnesium exchange
reaction. For the activation of magnesium derivatives with LiCl,
see: A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396;
Angew. Chem. Int. Ed. 2004, 43, 3333.
[11] P. Knochel, M. C. P. Yeh, S. C. Berk, J. Talbert, J. Org. Chem.
1988, 53, 2390.
Angew. Chem. Int. Ed. 2006, 45, 606 –609
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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