High temperature metalation of functionalized aromatics and heteroaromatics using (tmp)2Zn·2MgCl2·2LiCl and microwave irradiation

Article abstract of DOI:10.1021/ol802118e

(Chemical Equation Presented) A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF via direct zincation using (tmp)₂Zn·2MgCl₂·2LiCl and microwave irradiation. Ester and cyano functions as well as ketones are compatible with the high temperatures of the zincation. The resulting bis-organo zinc species undergo a number of subsequent reactions leading to highly functionalized aromatics and heteroaromatics in good to excellent yields.

Full text of DOI:10.1021/ol802118e

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4705-4707
High Temperature Metalation of
Functionalized Aromatics and
Heteroaromatics using
(tmp)2Zn·2MgCl2·2LiCl and Microwave
Irradiation
Stefan Wunderlich and Paul Knochel*
Department Chemie and Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
Received September 10, 2008
ABSTRACT
A wide range of polyfunctional aryl and heteroaryl zinc reagents were efficiently prepared in THF via direct zincation using (tmp)2Zn·2MgCl2·2LiCl
and microwave irradiation. Ester and cyano functions as well as ketones are compatible with the high temperatures of the zincation. The
resulting bis-organo zinc species undergo a number of subsequent reactions leading to highly functionalized aromatics and heteroaromatics
in good to excellent yields.
The metalation of aromatic and heteroaromatic rings is of
central importance for pharmaceutical, agrochemical, and
material research. A number of new selective bases for
achieving chemoselective and regioselective metalations have
been reported.1 Especially ate-bases have found useful
applications.2 Recently, we reported that magnesium bases
such as tmpMgCl·LiCl and (tmp)2Mg·2LiCl (tmp ) 2,2,6,6-
tetramethylpiperidyl) proved to be highly active and selective
magnesium bases.3 Additionally, for the tolerance of very
sensitive functionalities like aldehydes or nitro groups, we
have prepared the neutral mixed-metal complex base
(tmp)2Zn·2MgCl2·2LiCl (1).4 LiCl leads to a high base
solubility,5 and MgCl2 is responsible for the high base reac-
tivity.6 The combination of these Lewis-acids7 with
(1) (a) Snieckus, V. Chem. ReV. 1990, 90, 879. (b) Leroux, F.; Jeschke,
P.; Schlosser, M. Chem. ReV. 2005, 105, 827. (c) Hodgson, D. M.; Miles,
S. M. Angew. Chem., Int. Ed. 2006, 45, 93. (d) Yus, M.; Foubelo, F.
Handbook of Functionalized Organometallics; Knochel, P., Ed.; Wiley-
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Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673. (c) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew.
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Uchiyama, M. J. Am. Chem. Soc. 2007, 129, 15102.
(5) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int.
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10.1021/ol802118e CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

(tmp)2Zn8 allows highly chemoselective zincations. Over the
last decades, microwave irradiation has been used to ac-
celerate numerous organic reactions9 including organome-
tallic reactions.10 Because organozinc reagents of the type
RZnX feature a good thermal stability and tolerate functional
groups even at elevated temperature,11 we have envisioned
to force (tmp)2Zn-mediated zincations using microwave
irradiation. Thus, the direct zincation of ethyl 4-chloroben-
zoate or ethyl 4-bromobenzoate with (tmp)2Zn·2MgCl2·2LiCl
(1) at 25 °C requires 110 h for a complete reaction. By
applying microwave irradiation, a complete zincation was
achieved within 2 h (80 °C) leading to the expected bis-
arylzinc species 3a and 3b in >90% yield (Scheme 1).
after 5 h of reaction time. The zincated species 3a-d could
either undergo a copper-mediated acylation12 or Pd-catalyzed
cross-coupling reactions.13 The desired biphenyls 4a-d were
isolated in 82-86% yield (Table 1, entries 1-4).
This procedure proved to be quite general (see Table 1).
Thus, the zincation of terephthalic acid diethyl ester (2e)
proceeded after 4 h of (90 °C) and a Pd-catalyzed cross-
coupling reaction13 afforded the desired biphenyl 4e in 74%
yield (entry 5). In contrast, ethyl 4-cyanobenzoate (2f) was
regioselectively zincated within only 1 h (80 °C) at 2-position
(entry 6).14 Quenching of the metalated intermediate with
ethyl 2-(bromomethyl)acrylate15 in the presence of CuCN·
2LiCl (25 mol %)12 furnished the allylated product 4f in 76%
yield. Interestingly, ethyl 2-fluorobenzoate (2g) and phthalic
acid diethyl ester (2h) required a longer metalation time (3-4
h at 90-95 °C). After Pd-catalyzed cross-coupling reac-
tions,13 the functionalized esters 4g and 4h were obtained
in 71-74% yield (entries 7 and 8). Also the more sensible
benzoic acid methyl ester derivatives like isophthalic acid
dimethyl ester (2i) and methyl 4-chlorobenzoate (2j) under-
went a smooth zincations within 2 h and Pd-catalyzed cross-
coupling reactions13 led to the diesters 4i and 4j in 73-79%
yield (entries 9 and 10). Furthermore, 2-fluorobenzonitrile
(2k) and 4-fluorobenzonitrile (2l) were reacted with the base
1 leading to the zincated species within 3 h at 80 °C (entries
11 and 12). Pd-catalyzed cross-coupling reactions13 gave the
biaryls 4k and 4l in 88-89% yield. Finally 4-fluoroben-
zophenone (2m) provided a zinc reagent bearing a keto group
within 5 h (80 °C). After a Pd-catalyzed cross-coupling
reaction13 the functionalized benzophenone 4m was isolated
in 70% (entry 13).
Scheme 1
.
Zincation of 2a-d Using 1 With and Without
Microwave Irradiation
We have extended this zincation procedure to heterocyclic
systems. Ethyl 2-chloronicotinate (5a) could be smoothly
zincated within 1 h and a copper-mediated acylation12 gave
the ketone 6a in 80% yield (entry 14). 4-Cyanopyridine (5b)
underwent a zincation in 2-position (entry 15). The reaction
with ethyl 2-(bromomethyl)acrylate15 in the presence of
CuCN·2LiCl (25 mol %)12 led to the acrylate derivate 6b in
68% yield. Substrates such as benzothiophene (5c), benzo-
furan (5d) and could hardly be zincated with the base 1 at
25 °C. However, microwave irradiation allowed a smooth
zincation at 120 °C. Trapping of the resulting zincated
heterocycles with various aryl iodides in the presence of a
Pd-catalyst13 afforded the heterocycles 6c-d in 95% yield
(entries 16 and 17).
In conclusion, we have reported that in contrast to well-
known low temperature lithiations1 and magnesiations,2b,3
a high temperature zincation of various functionalized
aromatics and heteroaromatics using the complex base
(tmp)2Zn·2MgCl2·2LiCl (1) and microwave irradiation is
feasible. This mode of heating proved to be essential since
an alternative heating with an oil bath at the same temper-
Additionally, ethyl benzoate (2c) or N,N-diethyl benza-
mide, which could not be metalated at 25 °C, reacted with
(tmp)2Zn·2MgCl2·2LiCl (1) under microwave irradiation (120
°C, 5 h) leading to the corresponding zinc reagents 3c-d in
>90% yield (Scheme 1). The microwave irradiation is
essential since heating of 2c or 2d by using an oil bath at
120 °C provides only 10-20% of the zinc reagents 3c-d
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Org. Lett., Vol. 10, No. 20, 2008

Table 1. Products of Type 4 and Type 6 Obtained by Zincation Using (tmp)2Zn·2MgCl2·2LiCl (1) and Microwave Irradiation and
Subsequent Reactions with Electrophiles
a Numbers in parentheses refer to the metalation conditions. b Yields of pure and isolated material. c A transmetalation with CuCN·2LiCl (1.1 equiv) was
performed. d Obtained by palladium-catalyzed cross-coupling using Pd(dba)2 (5 mol %) and (o-furyl)3P (10 mol %). e CuCN·2LiCl (25 mol %) was used.
atures leads only to low metalation rates (see discussion about
Scheme 1). Remarkably, functionalities such as an ester, a
cyano group or a ketone group are tolerated at these high
temperatures (60-120 °C). The scope and further applica-
tions of this method are investigated in our laboratories.
Chemetall GmbH (Frankfurt), BASF AG (Ludwigshafen),
and W. C. Heraeus GmbH (Hanau) for financial support.
Supporting Information Available: Procedures and
characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the DFG, Merck Research Laboratories (MSD),
OL802118E
Org. Lett., Vol. 10, No. 20, 2008
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