Decarboxylative Bromination of Sterically Hindered Carboxylic Acids with Hypervalent Iodine(III) Reagents

Article abstract of DOI:10.1021/acs.oprd.0c00130

Sterically hindered three-dimensional (3D) alkyl halides are promising precursors for various reactions; however, they are difficult to synthesize via conventional reactions. We present an efficient and practical method for decarboxylative bromination of sterically hindered 3D aliphatic carboxylic acids using commercially available (diacetoxyiodo)benzene and potassium bromide, one of the most stable and cheapest bromine sources in nature. The present method features a metal-free/Br2-free system, mild reaction conditions, one-pot operation under air at room temperature, wide functional group compatibility, and gram-scale synthetic capability. This highly efficient reaction cleanly converts a broad range of carboxylic acids, the most inexpensive and readily available sources of highly strained/naturally occurring/drug-related scaffolds, into the corresponding alkyl bromides in good to high yields.

Full text of DOI:10.1021/acs.oprd.0c00130

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Communication
Decarboxylative Bromination of Sterically Hindered
Carboxylic Acids with Hypervalent Iodine(III) Reagents
Ayumi Watanabe, Kenta Koyamada, Kazunori Miyamoto, Junichiro Kanazawa, and Masanobu Uchiyama
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00130 • Publication Date (Web): 11 Jun 2020
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Decarboxylative Bromination of Sterically Hindered
Carboxylic Acids with Hypervalent Iodine(III)
Reagents
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Ayumi Watanabe,†,‡ Kenta Koyamada,†,‡ Kazunori Miyamoto,*,† Junichiro Kanazawa,† Masanobu
⊥
Uchiyama*,†, §,
† Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-
ku, Tokyo 113-0033, Japan.
§ Research Initiative for Supra-Materials (RISM), Shinshu University, Ueda, 386-8567, Japan.
⊥ Cluster of Pioneering Research (CPR), RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198,
Japan.
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Table of content
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ABSTRACT
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Sterically hindered three-dimensional (3D) alkyl halides are promising precursors for various
reactions; however, they are difficult to synthesize via conventional reactions. We present an
efficient and practical method for decarboxylative bromination of sterically hindered 3D aliphatic
carboxylic acids using commercially available (diacetoxyiodo)benzene and potassium bromide,
one of the most stable and cheapest bromine sources in nature. The present method features a
metal-free/Br2-free system, mild reaction conditions, one-pot operation under air at room
temperature, wide functional group compatibility, and gram-scale synthetic capability. This highly
efficient reaction cleanly converts a broad range of carboxylic acids, the most inexpensive and
readily available sources of highly strained/naturally occurring/drug-related scaffolds, into the
corresponding alkyl bromides in good to high yields.
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KEYWORDS Hypervalent iodine • decarboxylative bromination • 3D scaffold • Strained •
Radical
INTRODUCTION
Three-dimensional scaffolds with carbon frameworks (3D scaffolds), such as cyclopropanes,
cubanes and bicycloalkanes, are of great interest in the pharmaceutical and material sciences as
building blocks of drugs and as modular components in functional molecules.1 For instance, in
drug discovery, installation of 3D scaffolds to escape the “flatland” of aryl systems often provides
significant improvements of physicochemical parameters, such as passive permeability, aqueous
solubility, etc. (Figure 1A).1 In contrast, the synthetic chemistry of sterically hindered 3D
structures has not been well developed; organic halides are widely used in organic synthesis, and
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are the most promising precursors for carbon-carbon and carbon-heteroatom bond-forming
reactions, but the preparation of sterically hindered 3D halides is usually difficult (Figure 1B).2,3
A common preparative method for organic halides is transformation of the corresponding alcohols.
However, this method generally suffers from significant limitations in the accessible 3D-scaffold
architectures; for example, (1) SN1-type halogenation usually proceeds in poor yield due to the
instability of the intermediary non-planar carbocation, and (2) SN2-type halogenation does not
occur intrinsically on bulky carbon frameworks. Hydro-halogenation reaction at unsaturated bonds,
which is another effective method for the preparation of aliphatic halides, is also ineffective in
sterically hindered 3D structures. Here we present a practical, scalable, and chemoselective method
for decarboxylative bromination that exhibits broad scope across a range of sterically hindered 3D-
carboxylic acids (primary, secondary, tertiary, naturally occurring, and pharmaceutical) (Figure
1C).
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A Pharmaceuticals Containing 3D-Scaffolds
4
Cl
5
6
7
Br
N
O
O
N
H
N
O
S
N
O
8
9
N
N
N
O
N
N
CF3
N
O
O
O
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O
NH2
4 OH
BMS-433771
RSV Fusion Inhibitor
Nicorandil Derivative
γ-Secretase Inhibitor
B Decarboxylative Bromination
・Metalation
Decarboxylative
Bromination
・Cross-coupling
CO2H
R
Br
R
R
Borodin,
Hunsdiecker
C, O, N Bond
Formation
3D-bromides
3D-carboxylic
acids
3D-structures
Since 1861
Heavy metal reagents,
with Br2
×
×
SN2 … Steric Hindrance
SN1 … Instability of
Cationic Intermediates
e.g.) Precursors of Bromocyclopropane
CO2H OH
$0.9/g $28/g
• Hardly available
• Unstable
R
OH
R
• Expensive
3D-alcohols
3D-alkenes
Inaccessible
C This Work
I
O
R1
Br
R1
+
+
KBr
OH
R2 R3
Fluorescent light
rt, air
R2 R3
29 examples
3D-Alkyl
Carboxylic Acids
Hypervalent
Iodine
Up to 100% yield
ꢀꢁ
Mild Conditions
ꢀꢁHeavy Metal Free
ꢀꢁBroad Scope
ꢀꢁ
Very Convenient
Figure 1. (A) 3D scaffolds in pharmaceuticals. (B) Decarboxylative bromination of carboxylic
acids. (C) This work.
RESULTS AND DISCUSSION
Since the pioneering work in 1861 by Borodin, who was also a well-known composer,
decarboxylative halogenation (the so-called “Borodin-Hunsdiecker reaction”) has been widely
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used in organic synthesis.4 However, it traditionally requires a stoichiometric amount of precious
metal or toxic metal reagent, such as Ag, Hg, Tl, and Pb, as well as multiple equivalents of Br2,
which may present a waste disposal problem if the reaction is performed on a large scale.5,6 During
our studies on hypervalent iodine(III)-mediated oxidative transformations, we occasionally found
that unpolarized light facilitates the decomposition of (diacetoxyiodo)benzene (1) to afford
acetoxy radical at room temperature. The homolysis reaction of 1 traditionally requires high
temperature (≥127 °C),7,8 but on the basis of our finding, we envisaged that the preparation of
PhI(OCOR)–Br9 with a more “fragile” I(III)–Br bond10 might efficiently initiate/facilitate the
radical chain to give the RCOO radical. This idea led to the fortuitous discovery of a new
decarboxylative bromination reaction. We found that the reaction of 1.0 equiv of 1 and 1.1 equiv
of KBr in CH2Cl2 at room temperature under weak fluorescent light from a usual ceiling fitting
provided 42% conversion of cyclopropanecarboxylic acid (2) into cyclopropyl bromide (3) (Table
1, entry 1).11 The cyclopropane ring is an important 3D substituent for pharmaceuticals,
agrochemicals and materials, but it remains synthetically challenging due to the poor
availability/high cost of cyclopropyl halides (Figure 1B). Thus, we proceeded to optimize the
reaction conditions for the decarboxylative bromination of 2 (Table 1). No reaction occurred in the
absence of 1 (entry 2). The chemical yield of the desired 3 was drastically decreased (5%) when
we used Bu4NBr as a Br– source in order to avoid a heterogeneous system (entry 3). Examination
of several solvents showed CH2Cl2 or PhCF3 (entry 4)12 to be greatly superior to acetonitrile or
ethyl acetate. The use of small excess amounts of 1 and KBr resulted in higher conversion of 3,
probably due to the competitive generation of MeBr from PhI(OCOMe)2 (1). Notably, in the
competitive reaction between methyl and phenyl radicals, addition of benzoic acid instead of 2
under the same reaction conditions did not afford phenyl bromide at all, suggesting that the
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decarboxylation process depends upon the stability of the radical intermediate.13 Finally, the set of
conditions shown in entry 5 or 6 was found to be optimal. Under these reaction conditions, neither
cyclopropane ring-opening reaction14 nor H-trapping reduction occurred. While no decrease in the
yield of 3 was observed when the reactions were conducted under air in an open vessel, addition
of 1 equivalent of water almost shut down the reaction.15
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To acquire mechanistic insight into the current reaction, several control experiments were
performed. No product formation was observed in the dark (entry 7), while blue LED light (λmax
= 455 nm) irradiation promoted the reaction (entry 8).16 Addition of the radical scavenger 9,10-
dihydroanthracene shut down the reaction (entry 9), supporting the free radical mechanism. Thus,
a plausible mechanism for the present photo-induced decarboxylative bromination reaction would
be as illustrated in Scheme 1. First, sequential ligand exchange of PhI(OAc)2 with 2 and
subsequently KBr gives the putative intermediate 5 (Figure S1 and S2 in Supporting Information).9
Next, visible light-induced I–Br bond homolysis of 5 would occur, affording the Br radical and
the 9–I–2 type radical intermediate 6.17 This radical 6 would be very labile, undergoing rapid I–O
bond homolysis to give an acyloxy radical 7 and iodobenzene.10,18 Decarboxylation of radical 7
would then take place smoothly, releasing cyclopropyl radical 8 and CO2.10 Finally, 8 would react
with any Br source, such as 5 to give 3, concomitantly with the regeneration of 6.
Table 1. Screening of Conditions for Decarboxylative Brominationa
AcO
I
OAc
O
2
Br source (Y eq)
+
Br
OH
solvent
rt, 17 h, under air
fluorescent light
1 (X eq)
3
Entry Br– source
KBr
Solvent
CH2Cl2
X / Y
3 (%)b
1
1.0 / 1.1
42
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2
KBr
Bu4NBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
CH2Cl2
CH2Cl2
PhCF3
CH2Cl2
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
0 / 1.1
0
3
1.0 / 1.1
1.0 / 1.1
1.5 / 1.7
1.5 / 1.7
1.5 / 1.7
1.5 / 1.7
1.5 / 1.7
1.5 / 1.7
5
4
45
71
80
5
5
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6
7c
8d
9e
10f
0
65
0
a
Reactixons were performed at room temperature under air for 17 h in the presence of a usual
ceiling fluorescent light. The concentration of 1 was 0.5 M. b 1H NMR yields. c In the dark. d Under
a blue LED light (λ = 455 nm) instead of a fluorescent light. In the presence of 9,10-
dihydroanthracene (1.0 eq).
e
O
O
O
O
AcO
I
OAc
O
2
I
Br–
I
OAc
I
Br
+
OH
– AcO–
– AcO–
1
4
5
O
O
O
O
[Br]
hν
Br
Br
– PhI
–
– CO2
Br
6
7
8
3
Scheme 1. Proposed Mechanism
With the optimized conditions in hand, we next explored the scope of this methodology.19 A broad
range of sterically hindered secondary (3–21), and tertiary (22–27) carboxylic acids were found to
be viable substrates (Table 2A). Gratifyingly, primary carboxylic acids (28–33) can be also used
in the reaction, though the primary carbon radical is generally unstable. Scalability of the reaction
was demonstrated through the preparation of 3, 21, and 28 on a 10–50 mmol (~10 gram) scale. It
should be noted that ketoprofen, an anti-inflammatory drug, was selectively converted into 21
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without decrease in yield. We have not experienced any dangerous/inconvenient events (rapid
evolution of gas, rapid temperature rise, etc.) in these large-scale reactions. Use of
(difluoroiodo)benzene (35) instead of 1 improved the system dramatically in some cases, probably
due to its facile ligand exchange ability (Table 2B).20,21 We also successfully demonstrated one-
pot operation, wherein 33 was formed in situ from iodobenzene and XeF2 (Figure S3 in the
Supporting Information).22 For larger-scale reaction, we found that 33 separately synthesized by
means of the more cost-effective Gilmour method was applicable without a significant decrease in
yield.23 These examples encompass acyclic (12, 16, 20, 21, 28–33, 36, 38), cyclic (3, 9–11, 13–15,
17-19), caged (13, 22–27, 37), bridgehead (22–27, 37), naturally occurring (27, 33, 37, 38), and
pharmaceutical (20, 21, 36) carboxylic acids, which were all transformed to the corresponding
bromides smoothly without rearrangement or fragmentation. A variety of functionalities such as
nitro (16, 19), ester (22–25, 30, 38)/lactone (37), amide (17)/sulfonamide (18, 19)/nosyl (2-
nitrophenylsulfonyl) (19)/imide (31), ketone (21, 28, 33, 36), and bromide (26, 29)/fluoride (20)
were left unscathed under the mild reaction conditions. Even the highly radical-sensitive ether
group (15) was tolerated. Norbornane-2-carboxylic acid and trans-4-tert-butylcyclohexane
carboxylic acid were converted to 13 and 14, respectively, as a diastereomeric mixture, which is
again consistent with a free radical mechanism. Notably, strained cycloalkylacetic acids generating
cyclopropyl/cyclobutylcarbinyl radical, used as a fast radical clock, produced bromoalkanes
selectively (32, 33), suggesting that the bromination step (8 to 3 in Scheme 1) is much faster than
the ring cleavage process.24
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Table 2. Substrate Scopea
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• a metal-free/Br2-free system
A Decarboxylative Bromination with PhI(OAc)2 (1)
• 26 examples, up to 100% yield
O
• primary, secondary, and tertiary alkyl carboxylic acids
• broad functional group tolerance
1 (1.5 eq), KBr (1.7 eq)
Br
OH
3D-
Structure
3D-
Structure
PhCF3 (A) or CH2Cl2 (B)
• room temperature, under air, scalable
• natural products and pharmaceuticals
rt, 17–22 h, under air, fluorescent light
Tertially
Secondary
Br
MeO2C
MeO2C
MeO2C
Br
Br
10: (A) 100%b
Br
(A) (80%)
(B) 70%b
Br
Br
24: (B) 85%
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Br
9: (B) 86%b
11: (A) 60%b
22: (A) 34% (60%)
23: (B) 53%
3:
(A) 65% (10 mmol)
(72%)
Me
Me
(A) (60%) (20 mmol)
CO2Me
Br
n-Bu
O
t-Bu
Br
n-Hex
Br
Br
Br
Br
Br
Br
O
12: (B) 90%
13: (A) 80%b,c
14: (B) 64%d
15: (A) 87%b
25: (A) 90%
26: (A) 90%
27: (A) 45%
from Ketopinic acid
Primary
Me
Br
O
O
O
O
Br
S
Br
N
N
Br
MeO2C
6
3
Br
O2N
16: (A) 86%
Me
Br
Br
(B) 80%e
(B) 80%e (50 mmol)
17: (B) 55%
Me
Br
18: (B) 53%
29: (A) 76%
30: (A) 88%
28:
O
O
O
Br
O
Me
Br
Br
S
N
3
Br
N
Me
Me
Me
O
NO2
Br
O
F
(A) 83%
(A) 85% (10 mmol)
from Ketoprofen
19: (B) 75%
20: (A) 66%
21:
31: (B) 71%g
32: (B) 56%b
33: (A) 80%
from Pinonic acid
from Flurbiprofen
B Alternative One-pot Decarboxylative Bromination with in situ generation PhIF2 (35)
• improved yields
O
• one-pot operation
F
I
F
I
Br
XeF2 (1.5 eq)
KBr (1.7 eq)
• facile ligand exchange
• mild conditions
OH
+
3D-
3D-
CH2Cl2, rt, 17–22 h
CH2Cl2, rt, 4 h
Structure
Structure
• acyclic, cyclic, bridgehead
• natural products, drugs
under air, fluorescent light
34 (1.5 eq)
35 (not isolated)
Me
Me
Br
O
Me
Me
Me
Me
H
MeO2C
Br
Br
Me
H
Br
O
Br
H
H
Br
O
Me
O
AcO
H
3
22
PhI(OAc)2 34% (60%)
PhIF2 75% (90%)
27
PhI(OAc)2 45%
PhIF2 88%
from Ketopinic Acid
36
PhI(OAc)2 0%
PhIF2 96%
from Fenbufen
37
PhI(OAc)2 0%
PhIF2 60%
from Camphanic Acid
38
PhI(OAc)2 (22%)
PhIF2
86%g
from Lithochoic Acid
PhI(OAc)2 (71%)
PhIF2 (86%)
10 mmol (70%)f
a Conditions (A): in PhCF3. Conditions (B): in CH2Cl2. Isolated yields. Numbers in parentheses
1
b
c
d
are H NMR yields. GC yields. exo/endo = 66:34 (starting material: exo/endo = 18:82).
trans/cis = 48:52 (starting material: trans/cis = 100:0). e 1 (1.2 eq) and KBr (1.4 eq) were used. f
Separately synthesized 35 was used. g 34 (3.0 eq), XeF2 (3.0 eq) and KBr (3.4 eq) were used.
CONCLUSION
In conclusion, we present a new strategy for the preparation of sterically hindered 3D alkyl
bromides from the corresponding carboxylic acids. Without exception, the carboxylic acids used
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are the most inexpensive and readily available sources of these sterically hindered 3D-carbon
frameworks (most of them are commercially available). For the past sixteen decades since the
discovery of the decarboxylative bromination by Borodin, Br2 has routinely been used as the
bromine source; however, only half of the bromine atoms of Br2 can be utilized in this
transformation. However, KBr is one of the most stable and cheapest bromine sources in nature.
The present method features a metal-free/Br2-free system, mild reaction conditions, one-pot
operation under air at room temperature, wide functional group compatibility, and gram-scale
synthetic capability, and thus provides a highly efficient method for synthesizing a wide range of
3D alkyl bromides. We believe this technique will greatly expand planning options for the
synthesis of highly strained complex molecules. Work to extend the scope of this reaction and to
apply it for the synthesis of new functional molecules is in progress.
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EXPERIMENTAL SECTION
General Information
Instruments
1H-NMR and 13C-NMR spectra were obtained on a BRUKER AVANCE III HD 500
spectrometer. Samples were recorded in CDCl3 at room temperature. Chemical shifts are expressed
1
13
in δ (ppm) values. H- and C-NMR spectra were referenced to tetramethylsilane (δ: 0.00 ppm
for 1H- and 13C-NMR) and C(H/D)Cl3 (δ: 7.26 and 77.16 ppm for 1H- and 13C-NMR, respectively)
as internal standards. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q
= quartet, quint = quintet, m = multiplet, br = broad. IR spectra were recorded on a JASCO FT/IR-
4700 spectrometer. UV-Vis spectra were collected on a JASCO V-670 spectrometer. Melting
points were determined with a SRS MPA 100 OptiMelt automated melting point system and are
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uncorrected. ESI mass spectra were measured on a Bruker micrOTOF-II spectrometer. GC yields
were determined on a Bruker 436-GC spectrometer or a Shimadzu GC-2025 spectrometer. Gel
permeation chromatography (GPC) was performed by LaboACE LC-5060 (Japan Analytical
Industry Ltd., two in-line JAIGEL-2HR, CHCl3, 10 mL/min, UV-4ch 800 LA detector).
Fluorescent light irradiation experiments were performed with a Hitachi FHF32EX-N-K (32 W,
color temperature: 5000 K). Blue LED light irradiation experiment was performed with a Relyon
Twin LED Light (15W × 2, λmax = 455nm).
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Materials
Unless otherwise noted, materials were purchased from Sigma-Aldrich Co. LLC., Wako Pure
Chemical Industries, Ltd., FUJIFILM Wako Pure Chemical Co., Tokyo Kasei Industry Co. Ltd.,
and other commercial suppliers. All chemicals except KBr and acetonitrile were used as received.
Normal-phase column chromatography was performed with silica gel 60 (230–400 mesh) from
Merck. Xenon difluoride was purchased from Apollo Scientific. Acetonitrile was dried over
activated molecular sieves 3A for >12 h.
General Procedures for Decarboxylative Bromination with 1 and KBr
General Procedure A for Synthesis of Alkyl Bromide (GP-1-A)
To a stirred solution of (diacetoxyiodo)benzene (1, 242 mg, 0.75 mmol) and alkyl carboxylic acid
(0.50 mmol) in PhCF3 or CH2Cl2 (1 mL) was added finely ground KBr (101 mg, 0.85 mmol) at
room temperature (25 °C) under air and the mixture was vigorously stirred for 17–22 h (until all 1
was consumed) in the presence of usual laboratory illumination with a standard ceiling fluorescent
light fitting (the light source was ca. 1.5 meters above the reaction mixture). The chemical yield
was determined by GC analysis using capillary column Bruker BR-5MS (0.25 mm x 30 m, 60 °C
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to 200 °C) with dodecane as an internal standard. The spectral data and GC retention time of
products were consistent with those of authentic samples.
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General Procedure B for Synthesis of Alkyl Bromide (GP-1-B)
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To a stirred solution of (diacetoxyiodo)benzene (1, 242 mg, 0.75 mmol) and alkyl carboxylic acid
(0.50 mmol) in CH2Cl2 or PhCF3 (1 mL) was added finely ground KBr (101 mg, 0.85 mmol) at
room temperature (25 °C) under air and the mixture was vigorously stirred for 17–22 h (until all 1
was consumed) in the presence of usual laboratory illumination with a standard ceiling fluorescent
light fitting (the light source was ca. 1.5 meters above the reaction mixture). The resulting mixture
was filtered with CH2Cl2 and solvents were removed under reduced pressure to give the crude
product. Purification by column chromatography on silica gel or GPC furnished the corresponding
bromoalkane.
Bromocyclopropane (3)25
Following GP-1-A using cyclopropanecarboxylic acid (39.5 μL, 0.50 mmol) and CH2Cl2, the
chemical yield determined by GC analysis was 70%. 1H NMR (500 MHz, CDCl3): δ = 2.89–2.84
(m, 1H), 1.00–0.95 (m, 2H), 0.89–0.85 (m, 2H).
10 mmol Scale Synthesis of 3
To a stirred solution of (diacetoxyiodo)benzene (1, 4.8 g, 15 mmol) and alkyl carboxylic acid (0.86
g, 10 mmol) in PhCF3 (20 mL) was added finely ground KBr (2.1 g, 17 mmol) at room temperature
(25 °C) under air and the mixture was vigorously stirred for 22 h (until all 1 was consumed) in the
presence of usual laboratory illumination with a standard ceiling fluorescent light fitting (the light
source was ca. 1.5 meters above the reaction mixture; see illustration in the Supporting
Information). The resulting mixture was filtered with PhCF3 and product was obtained by
fractional distillation as transparent oil in 65% yield (0.79 g).
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50 mmol Scale Synthesis of 28 (without column chromatography)
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To a stirred solution of (diacetoxyiodo)benzene (1, 19.3 g, 60 mmol) and 5-benzoylpentanoic acid
(10.3 g, 50 mmol) in CH2Cl2 (100 mL) was added finely ground KBr (8.3 g, 70 mmol) at room
temperature (25 °C) under air and the mixture was vigorously stirred for 22 h (until all 1 was
consumed) in the presence of usual laboratory illumination with a standard ceiling fluorescent light
fitting (the light source was ca. 1.5 meters above the reaction mixture; see illustration in the
Supporting Information). The resulting mixture was filtered with the aid of CH2Cl2 and washed
with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with CH2Cl2 two times.
The combined organic layer was washed with brine and dried over anhydrous MgSO4. After
evaporation, hexane was added to the residue and heated. The hot solution was then filtered and
concentrated under reduced pressure to give the crude product, which was recrystallized from
hexane to give pure 28 (9.7 g, 80%) as colorless prisms.
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General Procedure for Decarboxylative Bromination with 35 and KBr (GP-2)
To a PFA test tube were added xenon difluoride (127 mg, 0.75 mmol), CH2Cl2 (0.50 mL) and
iodobenzene (34, 83.6 μL, 0.75 mmol). After stirred at room temperature (25 °C) under air for 4 h
1
(the formation of 35 was confirmed by H NMR, see Figure S3 in the Supporting Information),
alkyl carboxylic acid (0.50 mmol), CH2Cl2 (0.50 mL) and finely ground KBr (101 mg, 0.85 mmol)
were added to the solution and the mixture was vigorously stirred for 17–22 h (until all of the
iodine(III) compound was consumed) in the presence of usual laboratory illumination with a
standard ceiling fluorescent light fitting (the light source was ca. 1.5 meters above the reaction
mixture). The resulting mixture was filtered with CH2Cl2 and solvents were removed under
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reduced pressure to give the crude product. Purification by column chromatography on silica gel
or GPC furnished the corresponding bromoalkane.
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CAUTION: PhIF2 may etch glassware in the presence of moisture so large-scale operation should
be carried out in Teflon/PFA apparatus.
PhIF2 was prepared according to the Gilmour method.23 To a flame-dried (with a heat gun <200 °C)
PFA round-bottomed flask was added iodobenzene (5.1 g, 25 mmol), Selectfluor (35.3 g, 100
mmol), CsF (19.0 g, 100 mmol), and dry acetonitrile (50 mL). The reaction vessel was flushed
with argon three times, wrapped in aluminum foil to exclude light, and stirred at room temperature
for 20 h. The reaction mixture was then evaporated to dryness. To the resulting slurry was added
a mixture of CHCl3/n-hexane (1:3) to dissolve the product. The supernatant was transferred via a
syringe to a flame-dried PFA round-bottomed flask. This process was repeated 4 times. Finally,
the solvent was evaporated to dryness at 0 °C (ice bath) and the resulting solid was dissolved in
CH2Cl2 (10 mL) to afford a CH2Cl2 solution of PhIF2 (35) (1.7 M concentration, as determined by
1H NMR using 1,1,2,2-tetrachloroethane as an internal standard; see also Figure S3 in the
Supporting Information). The solution was used for the following decarboxylative bromiation.
To a 100 mL PFA round-bottomed flask was added the CH2Cl2 solution of 35 (15 mmol),
cyclopropanecarboxylic acid (0.86 g, 10 mmol), CH2Cl2 (20 mL in total) and finely ground KBr
(101 mg, 0.85 mmol), and the mixture was vigorously stirred for 17 h (until all of the iodine(III)
compound was consumed) in the presence of usual laboratory illumination with a standard ceiling
fluorescent light fitting (the light source was ca. 1.5 meters above the reaction mixture). The yield
determined by 1H NMR was 70% (1,1,2,2-tetrachloroethane was used as an internal standard).
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ASSOCIATED CONTENTS
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Supporting Information.
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The Supporting Information is available free of charge at https://pubs.acs.org.xxx
Experimental details, compounds spectral data, UV-vis spectra (Figure S1), ESI-MS spectrum
(Figure S2), and NMR spectra. This material is available free of charge via the Internet at
https://pubs.acs.org.
The following files are available free of charge.
brief description (file type, i.e., PDF)
brief description (file type, i.e., PDF)
AUTHOR INFORMATION
Corresponding Author
*kmiya@mol.f.u-tokyo.ac.jp
*uchiyama@mol.f.u-tokyo.ac.jp
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
This work was partly supported by JSPS KAKENHI (S) (No. 17H06173) (to M.U.), JST CREST
(No. JPMJCR19R2) (to M.U.). Foundation NAGASE Science Technology Development,
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Sumitomo Foundation (to M.U.), JSPS KAKENHI (B) (No. 17H03017) (to K.M.), and JSPS
KAKENHI (No. 19K23621) (to J.K.).
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17. For S0 -> T1 excitation of hypervalent iodine(III) reagents with visible light, see: Nakajima,
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Reagents Mediated by Selectfluor. Org. Lett. 2005, 7, 3961–3964. (b) Yoshimura, A.; Zhdankin,
V. V. Advances in Synthetic Applications of Hypervalent Iodine Compounds Chem. Rev. 2016,
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21. Zupan, M; Pollak, A. Fluorination with Xenon Difluoride. Preparation of
Aryliodine/III/Difluoride. J. Fluorine Chem. 1976, 7, 445–447.
22. For attempted decaboxylative bromination with other di(hetero)-λ3-iodanes, see, Table S2 in
Supporting Information.
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