Polyfunctional benzylic zinc chlorides by the direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl2

Article abstract of DOI:10.1039/b812396a

Benzylic zinc chlorides bearing various functional groups are smoothly prepared by the direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl₂. The Royal Society of Chemistry.

Full text of DOI:10.1039/b812396a

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Polyfunctional benzylic zinc chlorides by the direct insertion of
magnesium into benzylic chlorides in the presence of LiCl and ZnCl2w
Albrecht Metzger, Fabian M. Piller and Paul Knochel*
Received (in Cambridge, UK) 18th July 2008, Accepted 26th August 2008
First published as an Advance Article on the web 1st October 2008
DOI: 10.1039/b812396a
Benzylic zinc chlorides bearing various functional groups are
smoothly prepared by the direct insertion of magnesium into
benzylic chlorides in the presence of LiCl and ZnCl2.
Polyfunctional organometallics are key intermediates for syn-
thetic organic chemistry.1 Organozinc compounds play an
Scheme 1
especially important role since they combine high reactivity
with excellent functional group tolerance.2 Benzylic zinc re-
agents are of particular interest since, in contrast to benzylic
lithium3 and magnesium4 reagents, they tolerate numerous
functional groups.5 Recently, we have reported that LiCl
Scheme 2
considerably facilitates the insertion of metals (zinc,6 magne-
sium,7 indium8) into organic halides. Herein, we report the
converted to the organozinc compound 1b within 2 h at 0 1C.
After subsequent reactions with benzaldehyde 3c or
preparation of polyfunctional benzylic zinc chlorides of type 1
by the direct insertion of magnesium turnings into benzylic
Cu(I)-mediated 1,4-addition to 3-iodocyclohex-2-enone (3d)
the expected products 4c and 4d are isolated in 77–83% yield
chlorides of type 2 in the presence of LiCl and ZnCl2 under
mild and convenient conditions,9 and their subsequent reac-
(entries 3 and 4). Also, electron-rich benzylic chlorides are
tions with various electrophiles (Scheme 1). In contrast to the
previously reported zinc insertion,5,6 magnesium insertion in
the formation of homo-coupling products. The methoxy-
converted to the corresponding zinc reagents without
the presence of zinc chloride is much faster and proceeds at a
lower temperature (see below and Scheme 2). Also, by using
substituted benzylzinc chlorides 1c and 1d are obtained after
1 h of stirring at 25 1C. After Cu(I)-mediated treatment with
3,3-dimethylbutanoyl chloride (3e) or reaction with 3-chloro-
0.5 equivalents of ZnCl2, this method allows the preparation of
dibenzylic zinc reagents such as (PhCH2)2Zn.
In a typical experiment, the addition of 3-ethoxycarbonyl-
benzaldehyde (3f) the products 4e and 4f are isolated in
82–92% yield (entries 5 and 6). Similarly, the thio-substituted
benzyl chloride (2a) to magnesium turnings (2.5 equiv.), LiCl
benzylic zinc chloride 1e is obtained after 1.5 h reaction time at
(1.25 equiv.) and ZnCl2 (1.1 equiv.) in THF leads to the
25 1C. Its addition to 4-bromobenzaldehyde, provides the
benzylic zinc chloride 1a within 2 h at 25 1C as indicated by
iodometric titration. Prior activation of the magnesium turn-
ings is not required.10 The intermediate benzylic magnesium
reagent is transmetalated in situ to the corresponding zinc
organometallic. In the absence of ZnCl2 the resulting magne-
sium reagent decomposes rapidly and a considerable amount
of homo-coupling product is observed. Interestingly, in the
presence of ZnCl2 the amount of homo-coupling formed is
below 5%. The benzylic zinc reagent 1a is transmetalated
using CuCNÁ2LiCl11 (1.0 equiv.) and reacted with 4-chloro-
benzoyl chloride (3a) giving the ketone 4a in 82% yield.
(Table 1, entry 1). Additionally, the zinc reagent 1a also
smoothly reacts with the thiosulfonate 3b yielding the benzylic
thio-derivative 4b in 67% yield (entry 2). Analogously, a cyano
function is tolerated as well. 3-Cyanobenzyl chloride (2b) is
alcohol 4g in 82% yield (entry 7). Other halogen atoms on
the aromatic ring are readily tolerated. The chloro-substituted
benzylic chlorides 2f and 2g react smoothly with magnesium
turnings in the presence of LiCl and ZnCl2 (15–45 min, 25 1C)
and the resulting zinc reagents are treated with various electro-
philes giving the products 4h–j in 76–89% yield (entries 8–10).
As mentioned above, the formation of the benzylic zinc
reagent 1h by the Mg/ZnCl2/LiCl-method is much faster.
Thus, using Mg (2.5 equiv.), ZnCl2 (1.1 equiv.) and LiCl (1.25
equiv.) the insertion proceeds in 45 min at 25 1C (Scheme 2 and
Table 1, entry 11), whereas with Zn (2.0 equiv.) and LiCl
(2.0 equiv.) the formation of 1h requires 24 h at 25 1C.
A Negishi-catalyzed cross-coupling reaction12 of 4-fluoro-
benzylzinc chloride (1h) with 4-bromobenzonitrile (3k) using
Pd(OAc)2Á(1 mol%) and S-Phos13 (2 mol%) as the catalytic
system gives the diarylmethane 4k in 75% yield (entry 11).
3-Trifluoromethylbenzyl chloride (2i) is converted to the
benzylic zinc organometallic 1i within 30 min at 25 1C. Reac-
tion with 4-chlorobenzoyl chloride (3a) (after transmetalation
with CuCNÁ2LiCl) or 2-chlorobenzaldehyde (3l) gives the
desired products 4l and 4m in 85–91% yield (entries 12 and 13).
Department Chemie und Biochemie, Ludwig-Maximilians-Universitat,
¨
Munchen Butenandtstr. 5-13, D-81377 Munchen, Germany.
¨
¨
E-mail: knoch@cup.uni-muenchen.de; Fax: +49-89-2180-77680;
Tel: +49-89-2180-77681
w Electronic supplementary information (ESI) available: Experimental
procedures and NMR spectra. See DOI: 10.1039/b812396a
ꢀc
This journal is The Royal Society of Chemistry 2008
5824 | Chem. Commun., 2008, 5824–5826

View Online
Table 1 Direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl2 and subsequent reactions with various
electrophiles
Time/h (insertion/reaction
with electrophile)
Entry
1
Benzylic zinc chloride (1)
Electrophile (3)a
Product (4)
Yield (%)b
4ac 82
1a
1a
1b
1b
1c
3a
3b
3c
3d
3e
4 (2/2)
4 (2/2)
4 (2/2)
20 (2/18)
2 (1/1)
2
3
4
5
4b
4c
67
83
4dc 77
4ec
82
6
7
1d
1e
3f
5 (1/4)
4f
92
82
3g
3.5 (1.5 /2)
4g
8
9
1f
1f
3h
3i
1.5 (0.75/0.75)
16.75 (0.75/16)
4hd 77
4i
89
76
10
11
12
1g
1h
1i
3j
3.25 (0.25/3)
1.75 (0.75/1)
1.5 (0.5/1)
4jc
3k
3a
4ke 75
4lc
91
85
13
14
1i
1j
3l
1.5 (0.5/1)
4m
3m
3 (2/1)
4n
4o
98
70
14
15
1k
1l
3g
3e
3 (1/2)
1.5 (0.5/1)
4pc 81
a
b
c
0.7 equiv. of electrophile is used. Isolated yield of analytically pure product. Stoichiometric amount of CuCNÁ2LiCl (1.0 M in THF) is
d
e
used. 0.5 mol% of CuCNÁ2LiCl (1.0 M in THF) is used. Pd(OAc)2 (1 mol%) and S-Phos (2 mol%) are used.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5824–5826 | 5825

View Online
and BASF AG (Ludwigshafen) for generous gifts of
chemicals.
Notes and references
1 P. Knochel, H. Leuser, L.-Z. Gong, S. Perrone and F. F. Kneisel,
in Handbook of Functionalized Organometallics, ed. P. Knochel,
Wiley-VCH, Weinheim, 2005.
Scheme 3
2 P. Knochel, N. Millot, A. Rodriguez and C. E. Tucker, in Organic
Reactions, ed. L. E. Overman, Wiley & Sons Inc., New York, 2001;
P. Knochel and R. D. Singer, Chem. Rev., 1993, 93, 2117.
3 J. N. Reed, Sci. Synth., 2006, 8a, 329.
4 A. H. Stoll, A. Krasovskiy and P. Knochel, Angew. Chem., Int.
Ed., 2006, 45, 606.
5 A. Metzger, M. A. Schade and P. Knochel, Org. Lett., 2008, 10,
1107; M. A. Schade, A. Metzger, S. Hug and P. Knochel, Chem.
Commun., 2008, 3046; G. Manolikakes, M. A. Schade, C. Munoz
Hernandez, H. Mayr and P. Knochel, Org. Lett., 2008, 10, 2765;
M. M. Yugushi, M. Tokuda and K. Orito, J. Org. Chem., 2004, 69,
908; C. Piazza, N. Millot and P. Knochel, J. Organomet. Chem.,
2001, 624, 88; J. X. Wang, Y. Fu and Y. L. Hu, Chin. Chem. Lett.,
2002, 5, 405; S. C. Berk, M. C. P. Yeh, N. Jeong and P. Knochel,
Organometallics, 1990, 9, 3053; T. Harada, T. Kaneko, T. Fujiwara
and A. Oku, J. Org. Chem., 1997, 62, 8966; M. Gaudemar, Bull.
Soc. Chim. Fr., 1962, 5, 974.
6 A. Krasovskiy, V. Malakhov, A. Gavryushin and P. Knochel,
Angew. Chem., Int. Ed., 2006, 45, 6040; N. Boudet, S. Sase, P.
Sinha, C.-Y. Liu, A. Krasovskiy and P. Knochel, J. Am. Chem.
Soc., 2007, 129, 12358.
7 F. M. Piller, P. Appukkuttan, A. Gavryushin, M. Helm and P.
Knochel, Angew. Chem., Int. Ed., 2008, 47, 6802.
8 Y.-H. Chen and P. Knochel, Angew. Chem., Int. Ed., 2008, 47,
7648.
9 For the preparation of benzylic boron compounds see also: H. C.
Brown and U. S. Racherla, J. Org. Chem., 1986, 51, 427.
10 R. D. Rieke, Science, 1989, 246, 1260; R. D. Rieke and M. V.
Hanson, Tetrahedron, 1997, 53, 1925.
Benzyl chloride (2j) itself is converted to the corresponding zinc
reagent 1j within 2 h. Reaction with 4-(dimethylamino)benzal-
dehyde (3m) furnishes 4n in 98% yield (Scheme 3, Table 1,
entry 14). In contrast, the reaction of benzylic zinc chloride
prepared by the Zn/LiCl-method with the electron-rich ben-
zaldehyde 3m does not provide the expected product 4n in any
appreciable amount (Scheme 3).
Secondary benzylic chlorides react as well. Thus, 1-phenylethyl
chloride14 (2k) or 1,1-diphenylchloromethane (2l) are smoothly
converted to the corresponding secondary benzylic zinc reagents
within 30 min to 1 h at 0–25 1C. Subsequent reaction with
4-bromobenzaldehyde (3g) or Cu(I)-mediated acylation with
3,3-dimethylbutanoyl chloride (3e) yields the adducts 4o and 4p
in 70–81% yield (entries 15 and 16).
In summary, we have reported a new and convenient
method for the preparation of functionalized benzylic zinc
chlorides by the direct insertion of magnesium into benzylic
chlorides in the presence of LiCl and ZnCl2. These benzylic
zinc organometallics react with a variety of electrophiles, such
as aldehydes, acid chlorides and enones or undergo
Pd-catalyzed cross-coupling reactions. Additionally, these
new benzylic zinc reagents display an exceptional reactivity
compared to benzylic zinc compounds prepared by the Zn/
LiCl-method. Further extensions of the new method are
currently underway in our laboratories.
11 P. Knochel, M. C. P. Yeh, S. C. Berk and J. Talbert, J. Org. Chem.,
1988, 53, 2390.
12 E. Negishi, Acc. Chem. Res., 1982, 15, 340.
13 T. E. Barder, S. D. Walker, J. R. Martinelli and S. L. Buchwald,
J. Am. Chem. Soc., 2005, 127, 468.
14 In contrast, by using the direct zinc insertion (Zn (1.5 equiv.), LiCl
(1.5 equiv.)) a reaction time of 11 h at 25 1C is observed.
We thank the DFG for financial support. We thank
Chemetall GmbH (Frankfurt), Evonik Industries AG (Hanau)
ꢀc
This journal is The Royal Society of Chemistry 2008
5826 | Chem. Commun., 2008, 5824–5826