Bromonium salts: diaryl-λ3-bromanes as halogen-bonding organocatalysts

Article abstract of DOI:10.1039/d0cc07733j

Bromonium salts have been typically but infrequently used in various reactions as good leaving groups or as aryl or vinyl transfer reagents owing to their extremely high nucleofugality. Herein, we report the synthesis of novel, stable bromonium salts and

Full text of DOI:10.1039/d0cc07733j

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Bromonium salts: diaryl-k3-bromanes as
halogen-bonding organocatalysts†
Cite this: Chem. Commun., 2021,
57, 2519
Yasushi Yoshida, * Seitaro Ishikawa, Takashi Mino
and Masami Sakamoto
Received 25th November 2020,
Accepted 1st February 2021
DOI: 10.1039/d0cc07733j
rsc.li/chemcomm
Bromonium salts have been typically but infrequently used in containing heterocycles (Fig. 1).5b Subsequently, drawing on their
various reactions as good leaving groups or as aryl or vinyl transfer extremely high nucleofugality, these compounds have been applied
reagents owing to their extremely high nucleofugality. Herein, we in fascinating reactions such as the metal-free amination of unac-
report the synthesis of novel, stable bromonium salts and their first tivated alkanes,5f thermal solvolysis,5d and the amination of ethers.5g
catalytic application to the Michael reaction, with excellent product Despite their unique structures and reactivities, only limited
yield (up to 96%).
examples demonstrating the utility of bromonium salts have
been reported due to their instability.
Because of their high and unique reactivities, hypervalent halogen
Halogen bonding7 has been a focus in organic chemistry as a
compounds have been widely investigated in organic chemistry.1 versatile interaction that is complementary to hydrogen bonding,
The most familiar examples of this class are the hypervalent iodine which is employed as a major substrate-activation motif in
reagents, which have been developed over the last few decades for organocatalysis.8 Halogen-bonding organocatalysts have been
many reactions, including chiral transformations.2,3 These com- developed as non-covalent Lewis-acidic activators.9,10 In recent
pounds have mainly been employed in the asymmetric oxidation years, halonium salts have been utilized as catalysts by Wan et al.
of phenol derivatives,2a,c,d,3c,e,i oxidative functionalization of C–C (bromine-containing cationic catalysts),10a Han, Liu, and Zhang
multiple bonds,2b,3b,j and the construction of quaternary carbon (Lewis-acidic iodonium salt catalysts, Fig. 1),10b and Weiss, Huber
centres.3a Iodonium salts, which comprise one species of hyperva- and colleagues (halogen-bonding cyclic iodonium salt catalysts,
lent iodine reagents, have been widely used as strong arylating Fig. 1).10c In 2020, Mayer, Legault, and co-workers constructed a
reagents due to their extremely high electron-withdrawing ability Lewis acidity scale for diaryliodonium salts, which revealed that
and nucleofugality.4 In 2009, Gaunt and co-workers reported the
copper-catalysed meta-selective C–H arylation of pivanilides with
diaryliodonium salts, which provided the corresponding products in
up to 93% yield (Fig. 1).4e In contrast to the iodonium salt motif, the
research on bromonium salts, i.e., hypervalent bromine reagents, is
limited.1a,5 In 1952, Sandin and Hay reported the first preparation of
a bromonium salt through intramolecular nucleophilic bromine
attack on an aryldiazonium salt.1a A bromonium salt possesses
greater leaving group ability than an iodonium salt because of its
higher electron-withdrawing ability and ionization potential.6 There-
fore, several elegant synthetic transformations employing bromo-
nium salts have been described. In 2006, Ochiai and co-workers
reported the first synthesis of bromonium ylides and demonstrated
their applications as aryl or vinyl transfer reagents to nitrogen-
Molecular Chirality Research Center, Graduate School of Engineering, Chiba
University, 1-33, Yayoi-cho, Inage-ku, Chiba-Shi, Chiba 263-8522, Japan.
E-mail: yoshiday@chiba-u.jp
† Electronic supplementary information (ESI) available. CCDC 2013305. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Fig. 1 Selected applications of halonium salts.
d0cc07733j
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Table 1 Optimisation of conditions for the Michael reaction of indole (5a)
with trans-crotonophenone (6a)a
Entry
Cat.
Solvent
Conv.b (%)
1
2
3
4
5
6
7
8
2b
2b
2b
2b
2b
2a
2c
3a
3b
3c
4a
4b
4c
—
CHCl3
tAmylOH
MeCN
THF
Toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
12
0
0
0
0
36
26
499
499
499
499
499
499
0
Scheme 1 Synthesis of l3-bromanes.
9
10
11
12
13
14
cyclic diaryliodonium salts possess higher acidities than acyclic
ones.10d Herein, we report the synthesis and structure determina-
tion of novel, stable cyclic diarylbromonium salts and their first
halogen-bonding-driven catalytic applications to the Michael reac-
tion, which provided the corresponding products in up to
96% yield.
a
Unless noted, reactions were performed with 5a (1.0 equiv.), 6a
(1.0 equiv.), and Cat. (20 mol%) in appropriate solvent (0.2 M) at 60 1C.
b
All conversions were determined by 1H NMR analysis.
First, haloarenes 1 and bromonium salts 2 were synthesized
using the reported procedure5h with slight modification
(Scheme 1). Functionalised substrates 1, obtained through
palladium-catalysed coupling reactions, were successfully
cyclised via the corresponding diazonium salts to afford novel
bromonium salts 2. To check the effect of counteranion on
catalytic activity, bromonium salts 3 and 4 were prepared in
good yields by the respective treatment of 2 with silver triflate
and NaB(3,5-CF3C6H3)4 (NaBArF4). Because 2a could be isolated
as a fine single crystal, X-ray crystallographic analysis was
carried out. From the ORTEP diagram, 2a exists in an ion pair
rather than covalently bonded form.11
Table 2 Catalyst optimisation for the Michael reaction of indole (5a) with
trans-crotonophenone (6a)a
Entry
Cat.
X
Time (h)
Conv.b (%)
1
2
3
4
3a
3a
3a0
3b
3b
3b
3b
3c
4a
4b
4c
10
10
10
10
10
5
0.5
1.5
1.5
0.5
1.5
4
8
1.5
6
58
499
Trace
59
Next, the conditions for the Michael reaction of indole 5a
with trans-crotonophenone 6a were optimised (Table 1).9i Solvent
screening with 2b revealed that the reaction in chloroform
provided 7a, whereas other polar or non-polar solvents gave no
reaction (Table 1, entries 1–5). With this promising result in
hand, catalyst screening was conducted (Table 1, entries 6–14).
Although l3-bromanes 2 provided Michael adduct 7a in moderate
conversion, the bromonium salts with the triflate anion (3) and
5
499
499 (92)
27
6
7c
8
5
10
20
20
10
76
60
21
84
9
10
11
6
1.5
BArF anion (4) gave 7a in 499% conversion (Table 1, entries
4
6–13). Finally, the reaction without a l3-bromane additive failed to
afford the desired product (Table 1, entry 14), which confirmed
the effective and high catalytic activity of bromonium salts 2–4 for
the present transformation.
To determine the best catalyst, further reaction optimizations
were performed (Table 2). When the reactions were conducted reaction with 3b was conducted at 25 1C, the conversion of 5a
for 1.5 h with 10 mol% catalyst loading of 3a and 3b, the desired was only 27% even after prolonged reaction (Table 2, entry 7).
Remarkably, the l3-iodane analogue 3a0 exhibited significantly
product was obtained with 499% conversion; the other catalysts
provided inferior results, even with higher catalyst loads or lower catalytic activity than the l3-bromane (Table 2, entry 3).
extended reaction times (Table 2, entries 2, 5, and 8–11). When
Next, the scope and limitations of the present reaction were
the reactions were stopped after 0.5 h, 7a was obtained in 58% explored (Scheme 2). Screening of the indole reactant revealed
conversion with 3a and 59% conversion with 3b, which revealed that, in every case, the corresponding products 7a–7i could be
that the best catalyst was 3b (Table 2, entries 1 and 4). When the isolated in high yields irrespective of their steric or electronic
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Scheme 3 Mechanistic studies.
2-bromobiphenyl as a catalyst in place of 3b (Scheme 3(2)).5g
These results eliminate the possibility of catalytically active
species of Br2 or a bromoarene derived from decomposition of
the l3-bromane. Additionally, the reaction in the presence of
TEMPO proceeded smoothly, which excludes a radical-mediated
mechanism (Scheme 3(3)).14 Finally, the present reaction was
conducted in the presence of water to accelerate the formation
of TfOH through the decomposition of 3b. The production of 7a
in only 8% yield indicates that in situ-generated TfOH is not the
catalytically active species (Scheme 3(4)).9i
A plausible reaction mechanism is shown in Fig. 2. trans-
Crotonophenone coordinates to 3b, and the nucleophilic addi-
tion of indole to II takes place to form III. Then, intramolecular
proton transfer provides IV, after which product 7a is elimi-
nated together with the regeneration of catalyst 3b. Under this
catalytic cycle, the triflate counteranion on 3b is beneficial for
the activation of 6 by increasing the halogen bonding strength,
depending on the non-coordinating nature of the anion.10c
Based on this effect and the substrate scope of the reaction, the
indole addition step appears to be the rate-determining step.
Scheme 2 Scope and limitations for Michael reactions catalysed by
l3-bromane 3b.a a Unless noted, reactions were performed with
5 (1.0 equiv.), 6 (1.0 equiv.), and 3b (5 mol%) in CHCl3 (0.2 M) at 60 1C
for 4 h. Yields of isolated products are shown. b Reactions were conducted
for 6 h. c Reaction was conducted for 8 h. d Reactions were conducted for
12 h. e Reactions were conducted for 24 h.
nature, although strongly electron-withdrawing 5-cyano-substituted
7h was not obtained, and only the substrate was recovered.
The investigation of substituted trans-crotonophenones showed
that electron-rich and -deficient aromatic substituents were well
tolerated, giving products 7j and 7k in good yields. In the case of
chalcone derivatives as Michael acceptors, 7m was not obtained,
even after 12 h, although products 7l, 7n, and 7o were isolated in
moderate yields. Finally, N-methyl indole and 2-phenyl indole were
found to be well tolerated in the present reaction.12
To gain more insight into the reaction mechanism, control
experiments were carried out (Scheme 3). Conducting the
reaction in the presence of 2.5 mol% cyclohexene provided 7a
in almost the same yield as that under the standard conditions
(Scheme 3(1)).13 The reaction did not proceed when employing Fig. 2 Plausible reaction mechanism.
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In conclusion, the first halogen-bonding l3-bromane
catalyst was developed and characterised by X-ray crystallo-
graphic analysis. Its performance in the catalysis of the Michael
reaction was evaluated, and its wide substrate scope suggests
broad applicability. Mechanistic studies disclosed that the
intact l3-bromane, rather than the decomposition products,
functioned as the active catalyst in the reaction. Further inves-
tigations to develop chiral versions of these catalysts are
ongoing.
We are grateful for financial support from a Grant-in-Aid for
Early-Career Scientists (No. 20K15271) from the JSPS, and the
Leading Research Promotion Program ‘Soft Molecular Activa-
tion’ of Chiba University, Japan.
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Conflicts of interest
There are no conflicts to declare.
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