Angewandte
Chemie
DOI: 10.1002/anie.201409595
Flow Chemistry Hot Paper
Rapid and Efficient Copper-Catalyzed Finkelstein Reaction of
Hetero)Aromatics under Continuous-Flow Conditions**
(
Mao Chen, Saki Ichikawa, and Stephen L. Buchwald*
Abstract: A general, rapid, and efficient method for the
copper-catalyzed Finkelstein reaction of (hetero)aromatics has
been developed using continuous flow to generate a variety of
aryl iodides. The described method can tolerate a broad
spectrum of functional groups, including N-H and O-H
groups. Additionally, in lieu of isolation, the aryl iodide
solutions were used in two distinct multistep continuous-flow
processes (amidation and Mg–I exchange/nucleophilic addi-
tion) to demonstrate the flexibility of this method.
elevated temperatures and pressures. Moreover, the exceed-
ingly low solubility of anhydrous sodium iodide in the
nonpolar solvents that we previously utilized could be an
[
10a]
advantage in flow.
This is because a sodium iodide packed-
bed reactor would provide efficient mixing and enhanced
mass and heat transfer to further improve the efficiency of the
proposed transformation. Herein, we describe the develop-
ment of a rapid and efficient copper-catalyzed Finkelstein
reaction of (hetero)aromatics in flow. The reaction was then
applied to two distinct, multistep continuous-flow processes,
including either a halogen exchange/CÀN bond-forming
A
ryl and heteroaryl iodides are valuable building blocks
widely used in organic synthesis. Their versatility stems, in
part, from their higher reactivity when compared to the
corresponding aryl chloride/bromide, particularly with
respect to transition-metal-catalyzed carbonÀcarbon and
sequence or a halogen exchange/Mg–I exchange/nucleophilic
addition sequence, thus further demonstrating the flexibility
of the methodology.
During our preliminary investigation using batch condi-
tions, we found that while reactivity improved by increasing
the reaction temperature from 908C to 1308C, increasing the
[
1]
carbonÀheteroatom bond-forming reactions. Aryl iodides
have also found applications in hypothyroidism and myxe-
[
2]
[3]
À
dema coma treatment, anticancer therapy, and X-ray
contrast imaging. Because of their importance in both
industrial and academic settings, several synthetic methods
loading of the “I ” source had no effect on the conversion of
[
4]
the electrophile (see the Supporting Information). An
increase of the reaction temperature beyond 1308C resulted
[
5,6]
[15]
have been developed to access (hetero)aryl iodides.
in inconsistent conversions and yields.
Considering the
However, these processes usually require the use of either
a stoichiometric amount of a transition-metal reagent, or
highly polar solvents; many others have a limited substrate
difficulties of handling superheated reaction mixtures, a flow
process would be a good alternative to mitigate potential
safety hazards, prevent the vaporization of volatile compo-
[
6]
[13,14]
scope. The use of these methods may also be hampered by
incomplete conversion, and/or generate side products that are
chromatographically inseparable from the desired product. In
addition, the preparation of functionalized (hetero)aromatic
nents, and maintain uniform heating.
Therefore, we
designed a sodium iodide packed-bed reactor for further
investigations under flow conditions (Figure 1). Although
[6]
iodides is usually not trivial.
In recent years, improvements in reactions to effect
[
7]
aromatic iodination have been made, particularly by Yu,
[
8]
[9]
[10]
Sanford, Hayashi, and others. These methods have the
advantage of being simple and high yielding, although the use
of directing groups, or long reaction times may be required.
Considering our previous work on the copper-catalyzed
[
10a]
halogen-exchange reaction of aryl halides
and continu-
we felt that the Finkelstein
[
11–14]
ous-flow manufacturing,
Figure 1. Experimental setup for the copper-catalyzed Finkelstein reac-
tion of aromatics in flow. See the Supporting Information for details.
reaction of aromatics could be effectively accelerated under
flow conditions by precise control over residence time at
sodium iodide is highly hygroscopic, the reactor and all
reagent solutions were easily prepared on the bench top and
the reagents were subsequently introduced to the reactor
using syringe pumps. As shown in Table 1, by using L1 as the
ligand, 68% conversion of 1a was achieved at 1608C with
a 30 min residence time (entry 4). A further increase of the
reaction temperature to 1808C afforded 95% conversion
(entry 5). After evaluating several diamine ligands, L1 proved
to be the most effective. By increasing the catalyst loading of
CuI to 7 mol%, more than 99% conversion was achieved
[
*] Dr. M. Chen, S. Ichikawa, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
[
**] We thank Novartis International AG, and thankfully acknowledge Dr.
Aaron C. Sather and Dr. Christine Nguyen for their assistance with
the preparation of this manuscript.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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