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(2-Ethylhexyl)sodium: A Hexane-Soluble Reagent for Br/Na-
Exchanges and Directed Metalations in Continuous Flow
Johannes H. Harenberg, Niels Weidmann, Alexander J. Wiegand, Carla A. Hoefer,
Dedicated to Prof. Dr. Dieter Seebach in recognition to his seminal contributions in chemistry
Abstract: We report the on-demand generation of hexane-
soluble (2-ethylhexyl)sodium (1) from 3-(chloromethyl)hep-
tane (2) using a sodium-packed-bed reactor under continuous
flow conditions. Thus, the resulting solution of 1 is free of
elemental sodium and therefore suited for a range of synthetic
applications. This new procedure avoids the storage of an
alkylsodium and limits the handling of metallic sodium to
a minimum. (2-Ethylhexyl)sodium (1) proved to be a very
useful reagent and undergoes in-line Br/Na-exchanges as well
as directed sodiations. The resulting arylsodium intermediates
are subsequently trapped in batch with various electrophiles
such as ketones, aldehydes, Weinreb-amides, imines, allyl
bromides, disulfides and alkyl iodides. A reaction scale-up of
the Br/Na-exchange using an in-line electrophile quench was
also reported.
Scheme 1. a) Generation of neopentylsodium in batch and its use in
halogen/sodium-exchange reactions. b) On-demand continuous flow
generation of (2-ethylhexyl)sodium (1) and subsequent in-line Br/Na-
exchange and directed metalation.
O
rganosodium reagents are highly reactive organometallics
use of organosodium reagents remains underexploited in
continuous flow due to their poor solubility.[6] We have
reported the generation of organosodium and -potassium
derivatives in continuous flow using Na- and K-amide bases.[7]
In the course of this work, we envisioned a new procedure for
generating soluble alkylsodiums in continuous flow expand-
ing pioneering work of Alcꢀzar,[8] Ley,[9] McQuade[8a] and
others,[10] which established the use of metal-packed-bed
reactors for the direct preparation of Mg or Zn organo-
metallics in continuous flow. Herein, we report a new sodium-
packed-bed reactor for on-demand generation of the hexane-
soluble sodium reagent (2-ethylhexyl)sodium (1)[11] from
readily available 3-(chloromethyl)heptane (2), which was
used for performing in-line Br/Na-exchanges as well as
directed metalations (Scheme 1b) in continuous flow.
To prepare the packed-bed reactor, we charged a glass
column (7.5 mL) with sodium particles (3.4 mL, Ø ca.
1 mm).[12,13] The resulting mixed-bed reactor[14] was flushed
with dry hexane and was activated using a 0.1 m solution of i-
PrOH in hexane. Pumping alkyl chloride 2 (0.2 m in hexane,
2.0 mLminÀ1, 258C) through the reactor afforded a slightly
yellow solution of 1 in hexane (ca. 0.15 m).[15] This soluble
alkylsodium species[16] was free of metallic sodium and was
directly used for in-line Br/Na-exchanges as well as directed
sodiations. Collected aliquots of 1 prepared in continuous
flow showed moderate stability (Figure 1), demonstrating the
importance of the direct use of the sodium species. This on-
demand procedure avoids storage problems of instable 1 and
considerably limits hazards of working with metallic sodium.
Whereas preparation of 1 in batch led to a dark solution over
towards various electrophiles due to the very ionic character
of the C Na bond.[1] Despite the appealing chemical proper-
À
ties and the low price, high abundancy and low toxicity of
sodium, these compounds have seldomly found applications
in organic syntheses.[2] Dimethylethylamine soluble NaDA
(sodium diisopropylamide) was prepared by Collum and co-
workers as an alternative to the frequently used LDA (lithium
diisopropylamide).[3] Recently, Asako and Takai have
reported a new method for the preparation of arylsodiums
via a Br/Na-exchange using neopentylsodium, which was
prepared by the reaction of neopentyl chloride with sodium
dispersion (Scheme 1a). This procedure seems to limit the
trapping of the resulting arylsodium to R3SiCl, D2O and
transmetalation reactions.[4] The presence of residual sodium
dispersion may hamper the use of more complex electro-
philes. In contrast to well established lithium chemistry,[5] the
[*] J. H. Harenberg, Dr. N. Weidmann, A. J. Wiegand, C. A. Hoefer,
Dr. R. R. Annapureddy, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
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