Angewandte
Communications
Chemie
developed by the group of Olofsson was identified as the most
convenient strategy to produce a diverse set of diaryliodo-
nium salts.[14b] A 0.1 mL PFA reactor coil (750 mm I.D.) was
constructed and reagents were introduced by three separate
feed streams (i.e., reagent feed, oxidant feed, and acid feed;
see Figure S4 in the Supporting Information). To prevent
microreactor clogging and to ensure excellent heat dissipa-
tion, the reactor assembly was submerged in an ultrasonic
bath kept at room temperature. After initial optimization (see
Table S1), it was found that the target di-p-tolyliodonium
triflate (4a) could be obtained, after only a two-seconds
residence time, in excellent yield (89%) after crystallization
(Table 1). Notably, our flow protocol was highly reproducible
(80%) and 3i (85%) were obtained in significantly higher
yields than previously reported.[7,16] Moreover, the unsym-
metrical diaryliodonium triflates bearing electron-rich sub-
stituents (3c and 3l) were synthesized for the first time by this
one-step procedure. We believe that this module provides
a useful tool to enable the large-scale preparation of valuable
and costly diaryliodonium salts in a safe and time-efficient
fashion.
We next addressed the development of module 2, which
À
involves the continuous-flow meta-selective C H arylation of
anilines. It is generally accepted that the reported meta-
À
selective C H arylation reaction operates by a homogeneous
mechanism, thus making the use of heterogeneous catalysts
superfluous. Nevertheless, the use of heterogeneous precursor
materials, which can serve as cheap and convenient reservoirs
for the release of homogeneous catalytically active species,
can be of highly added value.[17] We hypothesized that the
catalytically active species could be readily formed from Cu0
in the presence of highly electrophilic diaryliodonium salts.[18]
Preliminary batch investigations revealed that inexpensive
copper powder enabled the meta-arylation of N-(o-tolyl)pi-
valamide (5a) with di-p-tolyliodonium triflate (4a; see
Table S2). Moreover, these experiments revealed that
copper powder was more active than the benchmark Cu-
(OTf)2 catalyst source reported by Gaunt, thus reducing the
batch reaction time from 24 to 2 hours (see Figure S1). In
addition, reactions with surface-treated copper turnings
revealed that both Cu0 and CuI can be used as catalyst
source (see Figure S1b).[19] Translating this concept to con-
tinuous manufacturing, we speculated that the meta-selective
Table 1: Scope for the synthesis of (un)symmetrical diaryliodonium salts
in flow.[a]
À
C H arylation could highly benefit from the use of copper
tube flow reactors (CTFRs),[20] which would allow for
À
a significant breakthrough in operational simplicity for C H
activation chemistry.[21] To test this hypothesis, a 20 mL CTFR
(1.65 mm I.D.) was constructed from cheap and commercially
available copper tubing (see Figure S5). After initial optimi-
zation of the reaction parameters, full conversion was
obtained within only 20 minutes residence time, thus yielding
88% of 6a (see Table 2 and Tables S3 and S4). Next, various
pivanilides with 4a as the coupling partner were subjected to
our flow protocol (Table 2). Pivanilides bearing either ortho-
alkyl, ortho-aryl, or ortho-methoxy substituents were well
tolerated and yielded the monoarylated compounds 6b, 6c,
and 6d respectively, in excellent yields (86–91%). In the
absence of ortho substituents, both meta positions became
highly accessible, thus resulting in a high-yielding mixture of
both mono- and diarylated products 6e/6e’ (80% yield,
mono/di 1:2.3). Also, the heterocyclic substrate indoline was
readily converted into 6 f in our flow reactor, thus yielding the
pure compound in 80% yield upon isolation. Generally, meta-
substituted substrates are perceived as more challenging
substrates but could nevertheless be acquired in flow within
20 minutes (6g,h). More complex ortho,para-disubstituted
pivanilides were also compatible (6i–l), thus obtaining 6i and
a 6j/6j’ mixture in high yields (85–86%). Modest yields (30–
42%) were obtained for 6k and 6l because of incomplete
conversion.
[a] Reaction conditions: Syringe 1: 5.0 mmol of aryl iodide (1) and
5.5 mmol of arene (2) in 25 mL DCE at 0.75 mLminÀ1; syringe 2:
5.5 mmol of m-CBPA in 25 mL of DCE at 0.75 mLminÀ1; syringe 3:
10.0 mmol TfOH in 50 mL DCE at 1.5 mLminÀ1. Added to the reactor by
syringe pump. [b] Mesityl iodide was used. [c] 3 mL reactor volume with
tr =60 s, 6.5 mmol m-CBPA, and 15 mmol TfOH. Note: The 3 series
refers to unsymmetrical diaryliodonium salts with mesitylene as arene,
and the 4 series to symmetrical diaryliodonium salts. m-CPBA=m-
chloroperbenzoic acid, Tf=trifluoromethanesulfonyl.
and the yields were typically higher than those obtained with
conventional batch labware (52–67%).[14b,15] The procedure
can be readily scaled and, as an example, we obtained
2.04 grams of 4a (5 mmol scale, 89%). Next, a small library of
symmetrical and unsymmetrical diaryliodonium salts was
established in flow (Table 1). Awide variety of unsymmetrical
diaryliodonium triflates bearing diverse substituents and
mesitylene as the counterligand were successfully synthesized
on a gram scale (3a–l). In particular, the compounds 3d
Next, a diverse set of diaryliodonium salts, all prepared on
a gram scale in flow by module 1, were evaluated as coupling
2
ꢀ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!
Gemoets, Hannes P. L.
