Communications
DOI: 10.1002/anie.201006641
Metalation of Alkenes
Selective Magnesiation or Zincation of Highly Functionalized Alkenes
and Cycloalkenes Using 2,2,6,6-Tetramethylpiperidyl Bases**
Tomke Bresser and Paul Knochel*
Dedicated to Professor Carmen Najera on the occasion of her 60th birthday
The preparation of substituted aromatic molecules and
heterocycles is of great importance because of the potential
biological activity of such structures, which are present in
many pharmaceuticals or agrochemicals.[1] The functionaliza-
tion of these compounds has often been achieved by directed
metalation using various bases.[2] Mg and Zn TMP bases
complexed with lithium chloride, such as TMPMgCl·LiCl (1,
TMP = 2,2,6,6-tetramethylpiperidyl),[3] TMP2Mg·2 LiCl (2),[4]
TMPZnCl·LiCl (3),[5] and TMP2Zn·2MgCl2·2 LiCl (4)[6] have
proven to be especially versatile metalating agents. In
contrast to aromatic and heteroaromatic systems, the directed
deprotonation of functionalized non-aromatic and olefinic
systems is more difficult and sensitive, as substituents such as
a nitro or a trifluoromethylcarbonyl group are usually not
tolerated. Furthermore, when the alkenes contain an ester or
a nitrile substituent, lithiation temperatures between À113
and À958C are required.[7] Herein, we report that the
kinetically very active TMP bases 1–4 allow the smooth
metalation of various substituted olefins of type 5 under
practical reaction conditions to give highly functionalized
unsaturated organometallic compounds of type 6 (Scheme 1).
Quenching of these compounds with various electrophi-
les E+ provides polyfunctional alkenes of type 7–9 with
high chemoselectivity. Remarkably, this method allows the
first reported preparation of a-zincated nitroolefins
(6: FG1=NO2; MetX = ZnCl) and b-zincated trifluoromethyl
ketones (6: FG2 = COCF3; FG1 = NMe2; MetX = ZnCl; see
Tables 1–3). Also, the zincation or magnesiation of various
unsaturated esters can now be carried out under practical
conditions (between À308C and 258C).
The reaction of ethyl (2E)-3-ethoxyacrylate ((E)-5a) with
TMPMgCl·LiCl (1; 1.2 equiv, THF, 258C, 0.5 h) led to a highly
regioselective magnesiation at the 2-position to afford the
magnesium reagent (E)-6a (> 90%, Scheme 2a). The stereo-
selective copper-mediated acylation[8] of (E)-6a with 2-furoyl
chloride (2 equiv) provided the E-ketoester ((E)-7a) in 80%
yield. Similarly, the functionalized magnesium reagent (E)-6a
was acylated with pivaloyl chloride and morpholine-4-car-
bonyl chloride to give the E-1,4-dicarbonyl compounds
(E)-7b and c in 58 and 84% yield, respectively (Table 1,
entries 1 and 2). The copper-catalyzed allylation[8] of (E)-6a
with 3-bromocyclohexene or its addition to CyCHO stereo-
selectively provided the ester (E)-7d (83%; Table 1, entry 3)
and the lactone 7e (85%; entry 4). The sensitive dihydrofuran
5b[9] was cleanly metalated with TMP2Zn·2 LiCl (4; 0.6 equiv,
258C, 0.5 h) to afford the diorganozinc compound 6b
(>90%). A copper-mediated acylation[8] with PhCOCl pro-
vides the ketoester 7 f in 80% yield (Scheme 2b). The zinc
reagent 6b was also allylated with ethyl 2-(bromomethyl)a-
crylate[10] or underwent a Negishi cross-coupling reaction[11]
with 1-chloro-4-iodobenzene (3% [Pd(dba)2], 6% P(2-
furyl)3, 258C, 3 h)[12] to give the expected dihydrofurans 7g
and h in 83 and 55% yield, respectively (Table 1, entries 5 and
6). The related tetrahydropyridine 5c[9] requires a stronger
Scheme 1. Chemoselective metalation of functionalized alkenes.
FG=functional group.
[*] MSc. T. Bresser, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank BASF AG
(Ludwigshafen) and Chemetall GmbH (Frankfurt) for the generous
gift of chemicals.
Supporting information for this article is available on the WWW
Scheme 2. b-Metalation of unsaturated esters using TMP bases 1, 2, and 4,
and subsequent functionalization with electrophiles.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1914 –1917