Stepwise mechanism for the bromination of arenes by a hypervalent iodine reagent

Article abstract of DOI:10.1021/acs.joc.9b02784

A mild, metal-free bromination method of arenes has been developed using the combination of bis(trifluoroacetoxy)iodobencene and trimethylsilyl bromide. In situ-formed dibromo(phenyl)-λ3-iodane (PhIBr₂) is proposed as the reactive intermediate. This methodology using PIFA/TMSBr has been applied with success to a great number of substrates (25 examples). The treatment of mono-substituted activated arenes led to para-brominated products (2u-z) in excellent 83-96% yields. Density functional theory calculations indicate a stepwise mechanism involving a double bromine addition followed by a type II dyotropic reaction with concomitant re-aromatization of the six-membered ring.

Full text of DOI:10.1021/acs.joc.9b02784

Subscriber access provided by UNIV OF NEWCASTLE
Article
A stepwise mechanism for the bromination
of arenes by a hypervalent iodine reagent
Albert Granados, Alexandr Shafir, Ana Arrieta, Fernando P. Cossio, and Adelina Vallribera
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02784 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
A stepwise mechanism for the bromination of arenes by a
hypervalent iodine reagent
7
8
9
Albert Granados,† Alexandr Shafir,‡ Ana Arrieta,§ Fernando P. Cossío*,§ and Adelina Vallribera*,†
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Departament de Química and Centro de Innovación en Química Avanzada (ORFEO-CINQA),
Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193 Barcelona (Spain)
‡Department of Biological Chemistry IQAC-CSIC and Centro de Innovación en Química
Avanzada (ORFEO-CINQA), c/ Jordi Girona 18–26, 08034 Barcelona (Spain)
§Departamento de Química Orgánica I and Centro de Innovación en Química Avanzada
(ORFEO-CINQA), Universidad del País Vasco and Donostia International Physics Center (DIPC),
Pº Manuel Lardizabal, 3, 20018 Donostia -San Sebastián (Spain)
Dedicated to Prof. Dr. Antonio Otero on the occasion of his retirement
ABSTRACT: A mild, metal-free bromination method of arenes has been developed using the
combination of bis(trifluoroacetoxy)iodobencene and trimethylsilyl bromide. In situ formation
of dibromo(phenyl)-λ3-iodane (PhIBr2) is proposed as reactive intermediate. This methodology
using PIFA-TMSBr has been applied with success to a great number of substrates (25
examples). The treatment of mono-substituted activated arenes led to para brominated
products (2u-z) in excellent 83-96% yields. DFT calculations indicate a stepwise mechanism
involving a double bromine addition followed by a type II dyotropic reaction with concomitant
re-aromatization of the six-membered ring.
Introduction
Aryl bromides are useful intermediates in the production of pharmaceuticals, agrochemicals,
and organic semiconductors.1 Additionally, they have found widespread usefulness in metal-
catalyzed cross-coupling reactions, as well as classical precursors for organometallic
reagents.2,3 Although electrophilic aromatic bromination was discovered in the 19th century, it
is still the most common synthetic methodology for the preparation of aryl bromides.
Classically, it has been driven using Br2 and HOBr in presence or absence of catalyst.4 In 1997,
Majetich’s group showed that bromodimethylsulfonium bromide was a milder and more
selective reagent than Br2.5 Many reagents have been used including NBS,6 1,3-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
1
2
3
4
5
dibromomethylhydantoin,7 benzyltrimethylammonium tribromide,8 pyridinium bromide
perbromide,9 and NaBrO310 among others.
6
7
8
9
The use of hypervalent reagents for the aromatic bromination is of current interest. In a
seminal work, Evans and Brandt described the use of PhI(OAc)2 (PIDA)-TMSBr system at 0oC for
the bromination of a few 1,4-dimethoxynaphthalenes.11 In 1999, Togo and collaborators
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
obtained
the
monobromination
of
1,3,5-triisopropylbenzene
mixing
1-(p-
chlorobenzenesulfonyloxy)benziodoxolone with LiBr.12 Huang’s group described the use of
PIDA, CuBr2 and NH2SO3H for the bromination of quinolines.13 Rao’s group14 reported the
PIDA/NaBr-mediated bromination of indoles, and Solorio-Alvarado15 reported the electrophilic
bromination of phenols and phenol-ethers by the PIDA–AlBr3 system. Very recently, the use of
PIDA and strong HBr or bromide salts was described.16 Particularly, the use of PhIBr2, 1,
(Scheme 3) is scarcely reported. In 1985, it was used by Macdonald and Narasimhan17 for the
nucleophilic substitution of alkyl iodides via oxidative ligand transfer; and by Cui and
coworkers18 for the anti addition of bromine to a double bond in one step of the synthesis of
24-methylenecholest-4-en-3β,6α-diol. No references regarding its preparation could be found.
In our previous studies,19 the mixture of PhI(OTFA)2 (PIFA) and TMSCl resulted in an excellent
combination for the chlorination of a great variety of arenes in high yields, even when working
at a multigram scale. Moreover, we confirmed the in-situ formation of PhICl2 as reactive
species. These results suggested us that we should test the combination PIFA-TMSBr in the
bromination of arenes. To the best of our knowledge, the mixture PIFA-TMSBr has never been
explored before.
Results and discussion
1,3,5-Triisopropylbenzene was selected as a model. Using the mixture PIFA-TMSBr (1:1.5
equiv) in dry dichloromethane (Table 1, entry 1) compound 2a was isolated (78% yield). Better
yield (90%) was obtained with 2 equiv. of TMSBr (Table 1, entry 2), presumably due to the full
generation of PhIBr2. Further equivalents of TMSBr (Table 1, entry 3) did not enhance the yield.
We noticed worst results when the reaction was done in open air and/or with no dried solvent
(Table 1, entries 4-6), probably due slow degradation of reagents. The use of other solvents
such as DMF, toluene and THF did not improve the reaction yield (Table 1, entries 6 and 8). The
change of PIFA to PIDA gave lower yield (Table 1, entries 2 vs 9).
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
1
2
3
4
Table 1. Optimization of the reaction of 1,3,5-triisopropylbenzene and PIFA-TMSBr
5
6
7
Br
Br
PIFA-TMS
8
9
18 h
r.t.
2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
1
Solvent[a]
CH2Cl2
Equivalents TMSBr
1.5
Yield 2a (%)
78
2
3
CH2Cl2
CH2Cl2
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
90
89
[b]
4
CH2Cl2
n.d.
n.d.
86
[c]
5
CH2Cl2
6
DMF
PhMe
THF
7
64
8
77
9[d]
CH2Cl2
81
[a] Anhydrous solvent [b] Dry solvent and open-air reaction. [c] Wet solvent and open-air
reaction. [d] Using PIDA-TMSBr.
After screening the reaction conditions, we followed to examine the substrate scope (Scheme
1). We first performed the reaction with trisubstituted symmetrical arenes. Compounds 2a-c
were prepared in high yields (80-93%). The highest yield (93%) was obtained for the strongly
activated 2c. Otherwise, deactivated arenes, such as 1,3,5-tribromobenzene or 4-
trifluoromethylacetophenone did not react. Next, 1,4-disubstituted arenes were tested. As
expected, those aromatics which possess almost one strong electron-donating group (-OCH3, -
OH, -N(CH3)2), furnished the reaction in good to high yields (2d-2i: 67-92%). The bromination of
p-trifluorodimethylaniline and 2-nitrophenol was achieved in low yields, in agreement with the
presence of a strong electron-withdrawing group. Moreover, two salicyl derivatives afforded 2l
(87%) and 2m (82%) in excellent yields. Other phenols and phenolethers were assayed yielding
excellent results. Especially fast bromination reactions (less than 5 minutes) were obtained for
2c,d,o,q. Some nitrogen-based heterocycles such as pyrrole and indole, gave rise to complex
crude reactions. In turn, excellent performance was found for naphthalene, anthracene and 9-
bromoanthracene. The reaction conditions were tolerant with a large list of functional groups
including easily oxidable aldehydes.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
1
2
3
4
5
PIFA (1 eq.)
Br
Br
TMS (2 eq.)
6
7
8
9
CH2Cl2 anh.
Ar atm
r.t., overnight*
R
R
2a-t
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OMe
OMe
Br
Br
Br
Br
MeO
OMe
80%
2b
85%
90%
2a
93%
2c
OMe
OH
2d
N
OMe
OMe
N
Br
Br
Br
Br
Br
Br
O
O
OMe
67%
2f
Br
87%
2h
72%
2g
92%
2e
86%
2i
N
Br
Br
Br
Br
HO
HO
HO
NO2
OH
O
O
CF3
87%
2l
35%
82%
2m
20%
2j
2k
OH
OMe
Br
OH
Br
O
Br
Br
Br
S
MeO
86%
2q
OH
92%
2o
O
88%
2p
74%
2n
Br
Br
Br
83%
Br
77%
100%
2t
2r
2s
Scheme 1. Scope of the bromination of arenes using PIFA/TMSBr.*Especially fast bromination
reactions (less than 5 minutes) were obtained for 2c,d,o,q.
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Then, we addressed our efforts to the problem of regioselectivity, given that efficient
methodologies for the regioselective preparation of bromobenzenes are still required.
Recently, Xia’s group reported that the combination of Eosin Y with Selecfluor resulted in a
regioselective para-brominating agent.20 To our delight, we discovered that the treatment of
mono-substituted activated arenes with PIFA/TMSBr led to para brominated products (2u-z) in
excellent 83-96% yields (Scheme 2).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
R
PIFA (1 eq.)
Br
TMS (2 eq.)
CH2Cl2 anh.
Ar atm
r.t., overnight
Br
OH
NH2
OCH3
Br
96%
Br
2v
Br
2w
2u
93%
94%
O
N(CH3)2
NHCH3
HN
2x
2y
Br
Br
2z
Br
95%
88%
83%
Scheme 2. Regioselective para-bromination in monosubstituted phenyl compounds.
To get insights into the mechanism, we performed a control experiment mixing 1 equivalent of
1
PIFA and 2 equivalents of TMSBr (reaction conditions). H NMR analysis showed that after 5
minutes PIFA was consumed leading to the formation of 1 equiv. of PhI and 2 equiv. of
Me3SiOCOCF3 (TMSOTFA, see SI). The unique signal in 19F NMR was assigned to this salt by
comparison of with a commercial sample. The formation of two equivalents of TMSOTFA might
be explained by the exchange of both OTFA ligands from PIFA by two bromine atoms,
generating in-situ the PhIBr2 which quickly reacts with the corresponding arene (Scheme 3 (a)).
In its absence, 1 decomposes to PhI and Br2. As OTFA is a better leaving ligand than OAc a
more efficient formation of PhIBr2 is expected. Other authors using PIDA and several inorganic
halogen sources as AlBr3, ZnBr2 or HCl have proposed a non-symmetrical hypervalent iodine
species as intermediate (PhI(OAc)X).15,16 We have also proposed the formation of PhI(OTFA)Cl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
1
2
3
4
5
6
7
8
9
1
as reactive intermediate (detected by H NMR) in the chlorination of arenes using PIFA and
KCl.19 In contrast, in this work using PIFA-TMSBr we could never detect the non-symmetrical
hypervalent iodine PhI(OTFA)Br by spectroscopic techniques and we propose PhIBr2 as reactive
species. In the same way, when using PIFA-TMSCl, exchange of both OTFA ligands has been
previously demonstrated.19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Moreover, It has been described that the non-symmetrical hypervalent iodine intermediate
PhI(OTFA)Br, if formed, can evolve to give the CF3C(O)OBr (TFAOBr) salt (Scheme 3 (b)), a good
brominating agent.21 In our case TFAOBr could not be detected in 19F NMR analysis of the
mixture of 1 equivalent of PIFA and 2 equivalents of TMSBr (reaction conditions), which is an
indirect probe that PhI(OTFA)Br is not formed.
A possible reaction pathway could be the direct bromination by the Br2 generated from the
reductive elimination of 1 (Scheme 3 (a)) as previously proposed by Evans.11 Thus, we
compared the evolution of the reaction of 1,3,5-trimethoxybenzene using Br2 (1 equivalent) or
PIFA-TMSBr as reagents. Both reactions were stopped after 5 minutes, obtaining 2c in 45%
(50% of 1,3,5-trimethoxybenzene recovered) and 88% yield, respectively. These results
indicate that the proposed intermediate PhIBr2 is more reactive than Br2 under the same
conditions. When we analyzed the bromination of anisole we observed that using Br2 as
reagent, 2,4-dibromoanisole, 2g, was obtained in 46% yield in 4 hours. In contrast, using the
PIFA-TMSBr mixture the bromination of anisole exclusively gave the para substitution in 94%
yield (2w, Scheme 4). Thus, confirming that Br2 is not the halogenating agent in our process. As
mentioned before, Evans11 proposed that Br2 was responsible of the bromination of 1,4-
dimethoxynapthalene on the bases of its slow disappearance of the reaction media (followed
by UV-vis) when the arene was added. However, the same effect could be observed
considering 1 as the reactive intermediate, due to the displacement of the equilibrium
proposed in Scheme 3 (a). Finally, reagent PhIBr2 (1) could not be isolated by mixing PIFA (1
equiv) and TMSBr (2 equiv) following the conditions previously reported to prepare PhICl2.19
Although di-acetoxy or di-chloro derivatives are stable, this is not the case for
dibromoiodobenzene.22 In fact, to stabilize I-Br bonds,23 benziodoxoles were developed by C.
Martin22a and D. C. Braddock.22b
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
1
2
3
(a)
4
5
6
O
O
O
O
F3C
CF3
+
I
Br
Br
I
I
Br2
+
Br
2 TMS
7
8
9
-2 TMSOTFA
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(b)
Ph-I
O
O
O
CF3
F3C
CF3
+
TMSBr
O
I
O
Br
O
I
TFAOBr
Br2
Br
TMS
TMSOTFA
TMSOTFA
Scheme 3. Possible reaction intermediates.
O
O
PIFA
O
Br
2g
Br2
Br
TMS
CH2Cl2
4h
CH2Cl2
4h
2w
Br
Br
46%
94%
Scheme 4. Bromination in para or ortho/para positions.
In order to understand the main aspects that determine the regioselective bromination of
these arenes, we performed Density Functional Theory24 (DFT) based studies using the hybrid
B3LYP functional25 with the semiempirical D3 Grimme’s correction.26 Solvent effects were
tackled by means of the Polarization Continuum (PCM) model.27 All elements were computed
with the 6-31+G* split valence basis set28 including diffuse and polarization Gaussian functions,
except in the case of iodine atoms, for which the LANL2DZ Effective Core Potential (ECP) and
basis set were used.29 All the calculations were carried out by means of the Gaussian 09 suite
of programs.30
Interaction between methoxybenzene and PhI(Br)2 led to a loose van der Waals reactive
complex RC1 (Figure 1). The profile of the Nucleus Independent Chemical Shift31 (NICS) along
the axis perpendicular to the average molecular plane of RC1 shows a regular 2-aromatic
pattern,32 slightly lower than that associated with methoxybenzene. However, in the zone
between both reactants, the distortion of the NICS pattern indicates local diamagnetic
shielding associated with the lone pairs of the hypervalent iodine atom. At closer distances
between both
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
1
2
3
4
z (Å)
0.0
3.0
–3.0
5
6
7
–2.0
methoxybenzene
TS1
2.20
I
8
9
2.37
–6.0
3.35
Br
RC1
Br
3.16
2.20
3.36
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*
–10.0
1.45
1.37
TS1
1.42
+17.1
(+28.2)
Ph
NICS(0.5)=–7.198 ppm
Br
I
Br
1
+
+21.4
(+22.2)
OMe
–4.3
–6.1
(+5.2)
0.0
(0.0)
(+6.0)
anti-INT1
RC1
syn-INT1
–6.7
(+4.0)
Br
Ph
I
+
2.85
OMe
Ph
I
Br
+
2.14
Br
I
2.47
H
Br
Br
OMe
3.54
Br
H
3.50
*
NICS(0.5)=–9.814 ppm
Figure 1. DFT results (B3LYP-D3(PCM=CH2Cl2)/6-31+G*&LANL2DZ level of theory) of the para-
bromination of methoxybenzene. Nucleus Independent Chemical Shifts (NICS, in ppm) along
the z-axis perpendicular to reactants, reactive complex (RC1) and transition structure (TS1) are
shown. The NICS 0.5 Å below the molecular plane of methoxybenzene, denoted as NICS (0.5)
are also given for RC1 and TS1. The asterisk highlighted in blue indicates the local diamagnetic
interaction between both reactants. Relative energies, in kcal/mol, are indicated for each
stationary point. Numbers in parentheses correspond to the respective Gibbs energies,
computed at 298 K. Bond distances are given in Å.
reactants the bromination step progresses to reach saddle point TS1 (Figure 1). The new Br-C
bond is quite advanced in TS1 and the interaction between the remaining PhI and Br units with
the carbon ipso to the methoxy group ensures the para-regioselectivity of the bromination
with respect to the directing electron-releasing group. The reaction has an activation energy of
ca. 21-22 kcal/mol, which parallels the partial loss of aromaticity associated with the addition
process, as it is shown in the corresponding NICS profile (Figure 1). Formation of the C-Br bond
constitutes the rate-limiting step of the complete reaction. Assuming a second order kinetics
for this step, for normalized 1 M reactants and 298 K (the standard state in solution included in
our calculations) the half-life t1/2 of the reaction can be approximated as
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
―1
푘퐵·298
1
―∆퐺푎298
푅·298
1
푡1/2
=
≈
푒푥푝
= 3,146 푠
(
)
]
[
푘[퐴]0 [퐴]0
ℎ
which corresponds to ca. 0.83 h and is in acceptable agreement with the experimentally
9
observed reaction time of 4 h for complete conversion.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The next stationary point along the reaction coordinate is complex syn-INT1, in which there is
a weak MeO(Ar)C···Br– interaction. This intermediate evolves through a barrierless process
towards the slightly more stable intermediate anti-INT1. These intermediates are stabilized by
the presence of the phenyl iodide product resulting from the bromination step and by the
methoxy group.
Br
OMe
Br
Br
1.91
H
1.33
1.33
anti-INT2
3.33
Br
+
O
2.88
Si
CF3
OTMS
TS2
0.0
(0.0)
–6.1
(+6.3)
–2.2
(+12.9)
3.9
(6.5)
RC2
Br
OMe
Br
2w
Si
1.09
+
H
O
1.95
Br
–23.1
(–8.3)
2.11
Br
CF3 OTMS
INT3
Figure 2. DFT results of the formation of 4-bromomethoxybenzene 2w in the presence of
trimetylsilyl trifluoroacetate. See Figure 1 caption for further details.
Intermediate anti-INT1 can interact with one equivalent of TMSOTFA to yield cyclohexa-1,4-
dienyl dibromide anti-INT2, in which the formation of the second C-Br bond has been
completed (Figure 2). A fleeting van der Waals reactive complex RC2 was located on the
potential energy surface, from which concerted but asynchronous transition structure TS2 is
reached with an activation energy of only 4-6 kcal/mol. This cyclic saddle point corresponds to
a type II dyotropic reaction33 involving the concerted transfer of the H and Br atoms from anti-
INT2 to TMSOTFA. In this step, the aromaticity of the substrate is partially recovered in TS2,
thus resulting in a lower activation energy. Finally, 1-bromo-4-methoxybenzene 2w is formed
together with tetrahedral intermediate INT3 through an exothermic and exergonic step that
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
1
2
3
4
5
6
7
8
9
evolves to the formation of HBr and the recovery of one equivalent of TMSOTFA. This stepwise
mechanism provided by the DFT calculations is compatible with the main features of the
experimental results, namely the role of the electron releasing group and the para-orientation
of the bromination with respect to this director substituent. Of course, when para positions
are not available the ortho position with respect to the directing group would be the preferred
one (Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We also investigated the direct bromination of anisole with two equivalents of Br2 to yield 2,4-
dibromoanisole 2g (Scheme 4). The computed reaction profile at 298 K in dichloromethane
solution is gathered in Figure 3. These calculations show a quite complex stepwise mechanism
consisting in two consecutive addition-elimination processes on para and ortho positions of
anisole. From reactive complex RC3 addition of one bromine atom to the para position results
in the formation of zwitterionic intermediate INT4. All our attempts to locate the
corresponding transition structure met with no success. This can be related with the very
advanced saddle points found by Smith34a and Liljenberg et al.34b in their studies on the
bromination of benzene and anisole with Br2 to yield bromobenzene and 4-bromoanisole 2w,
respectively. These authors found that the transition structures associated with the formation
of the addition step showed C···Br distances of 2.04-2.13 Å, which correspond to an almost
completely formed C-Br bond. Intermediate INT4 can evolve towards an slightly more stable
analogue INT5, whose elimination of the C4-H bond via TS3 yields para-intermediate 2w
together with one equivalent of hydrobromic acid. This elimination step occurs with a
calculated activation free energy of 9.9 kcal/mol. Intermediate INT6 produces the formation of
the second C2-Br bond via loose saddle point TS4. Addition intermediate INT7 recovers its
aromaticity via a second elimination step mediated by transition structure TS5 to yield
dibrominated product 2g together with a second equivalent of hydrobromic acid. In summary,
this mechanistic profile shows a multistep process involving many weakly bound ionic pairs
that can evolve in other reaction pathways that can result in lower yields. In addition, our
results show that the second bromination step in the presence of these intermediates is less
kinetically demanding and therefore, the transformation of 2w into 2g is difficult to control.
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1
2
3
4
anisole + 2 Br2
OMe
OMe
0.0
(0.0)
Br
CH2Cl2
25 ºC
+ 2 Br2
+ 2 HBr
5
6
anisole
2g
Br
7
8
∆Erxn = −13.8 kcal/mol
∆Grxn = −11.5 kcal/mol
2.62
2.59
2.29
1.79
1.51
1.35
9
2.76
2.81
2.11
1.56
2.97
2w
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.98
1.56
1.95
3.98
2.71
1.47
1.66
3.00
RC3
1.98
2.59
1.09
2g + 2 HBr
2.59
−13.6
(+4.3)
1.95
2.12
2.64
−13.8
(−11.5)
TS3
TS5
−17.1
(+2.2)
−17.8
(+2.2)
−19.1
(−0.6)
INT7
−19.7
(−1-8)
2.76
2.73
3.88
−18.3
(+1.0)
TS4
3.73
2.08
2.08
INT6
(2w···HBr···Br2)
1.09
2.58
1.48
3.42
3.96
2.74
2.75
−23.3
(−5.3)
1.48
2.20
1.95
4.09
1.47
2.67
INT4
2.74
INT5
INT8
(2g···HBr···HBr)
2.95
−23.8
(−5.6)
2g
−26.6
(−7.7)
2.66
2.87
1.96
Figure 3. Computed reaction profile of the dibromination of anisole to yield 2,4-
dibromoanisole 2g. See Figure 1 caption for additional details.
In order to demonstrate the general applicability of this methodology, we have used our
conditions in the monobromination of two densely substituted intermediates (3 and 5, which
were prepared as previously described35,36) of the synthesis of high added valuable anticancer
molecules (Scheme 5). By one hand, the bromination of 335,36 gave 4 in a nicely 92% yield, a
key intermediate of the synthesis of (-)-renieramycin M. This reaction is competitive with the
previously described procedure33 (NBS, 0oC, 8h), which implied a column chromatography.
Secondly, the bromination of 536 afforded exclusively compound 6 (94%), which can be
transformed to (+)-puupehenone.37
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
1
2
3
1) POCl3, DMF, 110ºC
4
5
6
2) mCPBA, DCM, 
3) 10% KOH, then HCl
4) BnBr, K2CO3, ACN, 
Br
BnO
MeO
BnO
MeO
PIFA, TMSBr
MeO
OMe
7
8
OMe
OMe
CH2Cl2, r.t.
92%
78%
3
4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
OMe
O
O
MeO
(-)-renieramycin M
N
O
NMe
O
CN
O
1) BnBr, K2CO3, ACN, 
2) mCPBA, DCM, 
3) 10% KOH, then HCl
Br
BnO
BnO
HO
HO
PIFA, TMSBr
4) Et2NCOCl, NEt3, 
BnO
O
BnO
O
CH2Cl2, r.t.
94%
75%
5
6
O
Et2N
O
Et2N
O
OH
O
O
(+)-puupehenone
Scheme 5. Bromination key steps in the synthesis of valuable anticancer compounds.
As a synthetic application of PIFA combined with both TMSBr and TMSCl19 we performed the
synthesis shown in Scheme 6. 2,6-Dichloroaniline (9) is used in the preparation of the well-
known anti-inflammatory drug Diclofenac.38 Our proposal is based on the use of bromine as a
useful protective group.39 First, the PIFA-TMSBr system afforded 2w and 2x in 5 minutes (para
isomers were exclusively achieved). Next, 4 equiv. of TMSCl in combination with PIFA (2 equiv.)
were used for the dichlorination. Finally, debromination was performed in acid conditions
obtaining 9 and 1040 in three steps in 51 and 59% overall yields respectively.
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
R
R
R
R
R
R
N
R
R
N
N
PIFA
PIFA
HBr, AcOH
aniline
N
Cl
Cl
Br
Cl
TMS
TMS
Cl
Cl
7
8
9
Reflux
CH2Cl2
CH2Cl2
Br
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9
: R = H; 80%
10
2v
2x
7
: R = H; 68%
: R = H; 93%
: R = Me; 95%
: R = Me; 81%
8
: R = Me; 76%
Scheme 6. Synthesis of 9 and 10.
In summary, we have developed a mild, metal-free procedure for the bromination of arenes
based on the combination of PIFA and TMSBr. The protocol resulted to be para-selective upon
using activated aromatic substrates. To the best of our knowledge, no examples of para
selective brominations of activated aromatic compounds based on the use of PIFA and TMSBr
are reported. DFT calculations on the para-bromination of methoxybenzene as a model system
revealed a stepwise mechanism in which the limiting step is the formation of the C-Br bond in
the para position with respect to the methoxy substituent, which acts as the directing group
through an electrostatic stabilization with the second bromine atom. The trans-1,4-dibromo
intermediate yields 1-bromo-4-methoxybenzene by means of a type II dyotropic reaction with
concomitant recovery of aromaticity, which is the driving force of this second stage of the
reaction. The method proved to be useful in the synthesis of key intermediates of the
synthesis of densely substituted biologically valuable compounds.
Experimental section
General Information
The chemicals and solvents have been purchased from Sigma Aldrich or Fluorochem. Solvents
have been previously dried conveniently. GLC chromatography was performed on a capillary
column (5% biphenyl and 95% dimethylpolysiloxane) of 15 m × 0.25 mm with a stationary
phase diameter of 0.25 μm. Column chromatography was performed on silica gel (230−400
mesh). H NMR spectra were recorded operating at 250, 360, and 400 MHz. 13C NMR spectra
1
were registered at 63, 91, and 101 MHz.
General procedure for the bromination reaction using PIFA-TMSBr
In a multi-reaction tube 1.8 mmol of PIFA (720 mg, 1 equiv.) were dissolved in 12 mL of dry
CH2Cl2 under argon atmosphere. Next, 3.30 mmol of TMSBr (2.0 equiv.) were added to the
solution. The clear solution turned clear orange. Then, the corresponding arene was added in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
2
3
4
5
6
7
8
9
one portion (1.7 mmol) allowing the reaction to proceed at room temperature. When the
reaction was over, the solution was poured into water and extractions with CH2Cl2 were
performed. The organics were evaporated, and the crude was well dried under high vacuum
yielding the desired bromoarene.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-bromo-1,3,5-triisopropylbenzene (2a):41 Colourless oil. From the reported procedure, 280
1
mg (81% yield) were obtained from 250 mg (1.22 mmol) of 1a. H NMR (250 MHz, [D]CDCl3,
25ºC, TMS): δ = 1.28 (d, 3J(H,H) = 7.5 Hz, 18H), 2.94 (m, 1H), 3.52 (m, 2H), 7.02 (s, 2H).
2-bromo-1,3,5-trimethylbenzene (2b):42 Colourless oil. From the reported procedure, 662 mg
(80% yield) were obtained from 500 mg (4.16 mmol) of 1b. 1H NMR (250 MHz, [D]CDCl3, 25ºC,
TMS): δ = 2.31 (s, 3H), 2.44 (s, 6H), 6.95 (s, 2H). GC-MS: m/z 197.9 (M)+, 199.9 (M+2)+ and 119
(M-Br)+.
2-bromo-1,3,5-trimethoxylbenzene (2c):43 Yellowish solid. mp. 98-100ºC. From the reported
1
procedure, 2,58 g (88% yield) were obtained from 2,00 g (11.90 mmol) of 1c. H NMR (250
MHz, [D]CDCl3, 25ºC, TMS): δ = 3.83 (s, 3H), 3.90 (s, 6H), 6.20 (s, 2H).
2-bromo-1,4-dimethoxylbenzene (2d):44 Oil. From the reported procedure, 668 mg (85% yield)
1
were obtained from 500 mg (3.62 mmol) of 1d. H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ =
3.77 (s, 3H), 3.84 (s, 3H), 6.83 (bs, 2H), 7.14 (s, 1H). GC-MS: m/z 215.9 (M)+, 217.9 (M+2)+.
3-bromo-4-(dimethylamino)benzaldehyde (2e):45 Solid. m.p. 51-53ºC. From the reported
1
procedure, 492 mg (92% yield) were obtained from 350 mg (2.35 mmol) of 1e. H NMR (250
MHz, [D]CDCl3, 25ºC, TMS): δ = 2.89 (s, 6H), 7.02 (d, 3J(H,H) = 8.9 Hz, 1H), 7.66 (dd, 3J(H,H) = 8.9 Hz,
4J(H,H) = 1.8 Hz, 1H), 7.96 (d, 4J(H,H) = 1.8 Hz, 1H), 9.74 (s, 1H).
Methyl 3-bromo-4-methoxybenzoate (2f):46 Solid. m.p. 97-99ºC. From the reported procedure,
1
295 mg (67% yield) were obtained from 300 mg (1.80 mmol) of 1f. H NMR (250 MHz,
[D]CDCl3, 25ºC, TMS): δ = 3.91 (s, 3H), 3.98 (s, 3H), 6.95 (d, 3J(H,H) = 8.6 Hz, 1H), 7.98 (d, 3J(H,H)
8.6 Hz, 3J(H,H) = 2.0 Hz, 1H), 8.13 (d, 3J(H,H) = 2.0 Hz, 1H). GC-MS: m/z 243.9 (M)+, 245.9 (M+2)+.
=
2,4-dibromo-1-methoxybenzene (2g):47 Solid. m.p. 58-60ºC. From the reported procedure, 103
1
mg (72% yield) were obtained from 100 mg (0.53 mmol) of 1g. H NMR (250 MHz, [D]CDCl3,
25ºC, TMS): δ = 3.90 (s, 3H), 6.79 (d, 3J(H,H) = 8.8 Hz, 1H), 7.40 (dd, 3J(H,H) = 8.8 Hz, 4J(H,H) = 2.4 Hz,
1H), 7.69 (d, 4J(H,H) = 2.4 Hz, 1H).
2,4-dibromo-N,N-dimethylaniline (2h):48 Oil. From the reported procedure, 485 mg (87% yield)
1
were obtained from 400 mg (2.00 mmol) of 1h. H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ =
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
1
2
3
4
5
3
3
4
2.80 (s, 6H), 6.96 (d, J(H,H) = 8.8 Hz, 1H), 7.38 (dd, J(H,H) = 8.8 Hz, J(H,H) = 2.4 Hz, 1H), 7.71 (d,
4J(H,H) = 2.4 Hz, 1H).
6
7
8
9
2-bromo-4-(tert-butyl)phenol (2i):49 Solid. m.p. 49-51ºC. From the reported procedure, 262 mg
1
(86% yield) were obtained from 200 mg (1.33 mmol) of 1i. H NMR (250 MHz, [D]CDCl3, 25ºC,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TMS): δ = 1.32 (s, 9H), 5.45 (bs, 1H), 6.99 (d, 3J(H,H) = 8.7 Hz, 1H), 7.26 (dd, 3J(H,H) = 8.7 Hz, 4J(H,H)
2.5 Hz, 1H), 7.49 (d, 4J(H,H) = 2.5 Hz, 1H).
=
2-bromo-N,N-dimethyl-4-(trifluoromethyl)aniline (2j):50 Oil. From the reported procedure, 99
1
mg (35% yield) were obtained from 200 mg (1.06 mmol) of 1j. H NMR (250 MHz, [D]CDCl3,
25ºC, TMS): δ = 2.89 (s, 6H), 7.11 (d, 3J(H,H) = 8.4 Hz, 1H), 7.54 (d, 3J(H,H) = 8.4, 1H), 7.81 (bs, 1H).
4-bromo-2-nitrophenol (2k):51 Solid. m.p. 88-91ºC. From the reported procedure, 157 mg (20%
yield) were obtained from 500 mg (3.59 mmol) of 1k. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS):
δ = 7.09 (d, 3J(H,H) = 8.9 Hz, 1H), 7.68 (dd, 3J(H,H) = 8.9 Hz, 4J(H,H) = 2.4 Hz, 1H), 8.27 (d, 4J(H,H) = 2.4
Hz, 1H), 10.51 (s, 1H).
5-bromo-2-hydroxybenzaldehyde (2l):52 Solid. m.p. 50-52ºC. From the reported procedure,
7.16 g (87% yield) were obtained from 5.00 g (40.94 mmol) of 1l. 1H NMR (250 MHz, [D]CDCl3,
25ºC, TMS): δ = 6.93 (d, 3J(H,H) = 8.8 Hz, 1H), 7.62 (dd, 3J(H,H) = 8.8 Hz, 4J(H,H) = 2.4 Hz, 1H), 7.69 (d,
4J(H,H) = 2.4 Hz, 1H), 9.86 (s, 1H), 10.95 (s, 1H). GC-MS: m/z 199.9 (M)+, 201.9 (M+2)+.
5-bromo-2-hydroxybenzoic acid (2m):53 Solid. m.p. 205-207ºC. From the reported procedure,
1.29 g (82% yield) were obtained from 1.00 g (7.24 mmol) of 1m. 1H NMR (250 MHz, [D]CDCl3,
25ºC, TMS): δ = 6.95 (d, 3J(H,H) = 8.8 Hz, 1H), 7.62 (dd, 3J(H,H) = 8.8 Hz, 4J(H,H) = 2.4 Hz, 1H), 8.05 (d,
4J(H,H) = 2.4 Hz, 1H), 10.38 (s, 1H).
2,6-dibromo-4-methylphenol (2n):54 Solid. m.p. 47-49ºC. From the reported procedure, 265 mg
(74% yield) were obtained from 200 mg (1.07 mmol) of 1n. 1H NMR (250 MHz, [D]CDCl3, 25ºC,
TMS): δ = 2.28 (s, 3H), 5.73 (s, 2H).
5-bromo-2,4-dimethoxy-3-methylphenol (2o):55 Oil. From the reported procedure, 134 mg
(91% yield) were obtained from 100 mg (0.60 mmol) of 1o. 1H NMR (250 MHz, [D]CDCl3, 25ºC,
TMS): δ = 2.27 (s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 5.79 (s, 1H).
3-bromo-4-hydroxy-5-methoxybenzaldehyde (2p):56 Solid. m.p. 213-214ºC. From the reported
1
procedure, 267 mg (88% yield) were obtained from 200 mg (1.31 mmol) of 1p. H NMR (250
4
MHz, [D]CDCl3, 25ºC, TMS): δ = 4.01 (s, 3H), 6.57 (bs, 1H), 7.37 (d, J(H,H) = 1.6 Hz, 1H), 7.66 (d,
4J(H,H) = 1.6 Hz, 1H), 9.81 (s, 1H). GC-MS: m/z 231.9 (M)+, 233.9 (M+2)+.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
1
2
3
4
5
4-bromo-2-methylthiophene (2q):57 Oil. From the reported procedure, 766 mg (86% yield)
1
were obtained from 500 mg (5,00 mmol) of 1q. H NMR (400 MHz, [D]CDCl3, 25ºC, TMS): δ =
6
7
2.50 (s, 1H), 6.71 (m, 1H), 7.00 (d, 4J(H,H) = 3.6 Hz, 1H).
8
9
1-bromonaphthalene (2r):44 Oil. From the reported procedure, 249 mg (77% yield) were
obtained from 200 mg (1.56 mmol) of 1r. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 4.00 (s,
3H), 6.57 (bs, 1H), 7.38 (d, 4J(H,H) = 1.6 Hz, 1H), 7.66 (d, 4J(H,H) = 1.6 Hz, 1H), 9.81 (s, 1H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-bromoanthracene (2s):58 Solid. m.p. 98-99.5ºC. From the reported procedure, 288 mg (100%
yield) were obtained from 200 mg (7.24 mmol) of 1s. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS):
δ = 7.57 (m, 4H), 8.03 (m, 2H), 8.57 (m, 3H).
9,10-dibromoanthracene (2t):59 Solid. m.p. 224-226ºC. From the reported procedure, 217 mg
1
(83% yield) were obtained from 200 mg (0.78 mmol) of 1t. H NMR (250 MHz, [D]CDCl3, 25ºC,
TMS): δ = 7.66 (m, 4H), 8.61 (m, 4H). GC-MS: m/z 335.8 (M)+, 333.8 (M-2)+, 337.8 (M+2)+.
4-bromophenol (2u):60 Solid. m.p. 60-61ºC. From the reported procedure, 352 mg (96% yield)
1
were obtained from 200 mg (2.12 mmol) of 1u. H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ =
5.76 (s, 1H), 6.75 (d, 3J(H,H) = 8.9 Hz, 2H), 7.35 (d, 3J(H,H) = 8.9 Hz, 2H).
4-bromoaniline (2v):61 Solid. m.p. 58-60ºC. From the reported procedure, 343 mg (93% yield)
1
were obtained from 200 mg (2.14 mmol) of 1v. H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ =
3
3
3.67 (bs, 2H), 6.58 (d, J(H,H) = 9.0 Hz, 2H), 7.26 (d, J(H,H) = 9.0 Hz, 2H). GC-MS: m/z 170.9 (M)+,
172.9 (M+2)+ and 92 (M-Br)+.
4-bromoanisole (2w):62 Oil. From the reported procedure, 325 mg (94% yield) were obtained
from 200 mg (1.85 mmol) of 1w. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 3.80 (s, 3H), 6.81
(d, 3J(H,H) = 9.0 Hz, 2H), 7.40 (d, 3J(H,H) = 9.0 Hz, 2H). GC-MS: m/z 185.9 (M)+, 187.9 (M+2)+.
4-bromo-(N,N)-dimethylaniline (2x):63 Solid. m.p. 51-53ºC. From the reported procedure, 314
1
mg (95% yield) were obtained from 200 mg (1.65 mmol) of 1x. H NMR (250 MHz, [D]CDCl3,
25ºC, TMS): δ = 2.95 (s, 3H), 6.62 (d, 3J(H,H) = 8.9 Hz, 2H), 7.34 (d, 3J(H,H) = 8.9 Hz, 2H).
4-bromo-(N)-methylaniline (2y):64 Oil. From the reported procedure, 228 mg (88% yield) were
obtained from 150 mg (1.40 mmol) of 1y. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 2.84 (s,
3H), 3.69 (bs, H), 6.56 (d, 3J(H,H) = 9.0 Hz, 2H), 7.16 (d, 3J(H,H) = 9.0 Hz, 2H).
N-acetyl-4-bromoaniline (2z):65 Solid. m.p. 166-169ºC. From the reported procedure, 328 mg
(83% yield) were obtained from 250 mg (1.85 mmol) of 1z. 1H NMR (250 MHz, [D]CDCl3, 25ºC,
TMS): δ = 2.19 (s, 3H), 7.30 (d, 3J(H,H) = 8.8 Hz, 2H), 7.47 (d, 3J(H,H) = 8.8 Hz, 2H).
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1-(benzyloxy)-5-bromo-2,4-dimethoxy-3-methylbenzene (4):35 Oil. Following the general
procedure, 252 mg were obtained (92% yield) after column chromatography purification from
210 mg (0.81 mmol) of 3. Oil. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 2.29 (s, 3H), 3.79 (s,
3H), 3.86 (s, 3H), 5.08 (s, 2H), 7.04 (s, 1H), 7.43 (m, 5H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4,5-bis(benzyloxy)-2-bromophenyl diethylcarbamate (6):37 Oil. Following the general
1
procedure, 297 mg were obtained (94% yield) from 265 mg (0.65 mmol) of 5. H NMR (250
MHz, [D]CDCl3, 25ºC, TMS): δ = 1.28 (m, 6H), 3.47 (m, 4H), 5.12 (s, 2H), 5.14 (s, 3H), 6.93 (s,
1H), 7.16 (s, 1H), 7.44 (m, 10H).
Synthetic procedure for the preparation of 7, 8, 9 and 10:
4-bromo-2,6-dichloroaniline (7):66 Synthesized following the method previously reported in our
group,20 190 mg (68% yield) were obtained from 200 mg (1.16 mmol) of 4-bromoaniline (2v).
Solid, m.p. 82-85ºC. 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 4.48 (bs, 2H), 7.34 (s, 2H).
4-bromo-2,6-dichloro-N,N-dimethylaniline (8):67 Synthesized following the method previously
reported in our group,19 408 mg (76% yield) were obtained from 400 mg (2.00 mmol) of 4-
1
bromo-N,N-dimethylaniline(2x). Oil. H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 3.04 (s, 6H),
7.38 (s, 2H).
2,6-dichloroaniline (9):68 Prepared following the reported procedure.38 322 mg (80% yield)
1
were obtained from 600 mg (2.49 mmol) of 4-bromo-2,6-dichloroaniline (7). Oil, H NMR (250
MHz, [D]CDCl3, 25ºC, TMS): δ = 4.47 (bs, 2H), 6.64 (t, 3J(H,H) = 8.5 Hz, 1H) 7.19 (d, 3J(H,H) = 8.5 Hz,
2H).
2,6-dichloro-N,N-dimethylaniline (10):69 Prepared following the reported procedure.39 287 mg
(81% yield) were obtained from 500 mg (1.86 mmol) of 4-bromo-2,6-dichloro N,N-
dimethylaniline (8). Oil, 1H NMR (250 MHz, [D]CDCl3, 25ºC, TMS): δ = 2.92 (s, 6H), 6.98 (t, 3J(H,H)
= 8.4 Hz, 1H) 7.29 (d, 3J(H,H) = 8.4 Hz, 2H).
Associated content
1
The Supporting Information includes the H NMR spectra, the CG-MS chromatograms and the
details of the computational data.
Author Information
* E-mail: adelina.vallribera@uab.es
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
1
2
3
4
* Email: fp.cossio@ehu.es
5
6
ORCID
7
8
9
Albert Granados: 0000-0002-5362-5966
Alexandr Shafir: 0000-0002-8127-2299
Fernando P. Cossío: 0000-0002-4526-2122
Ana Arrieta: 0000-0002-0580-2545
Adelina Vallribera: 0000-0002-6452-4589
Acknowledgments
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We are thankful for financial support from Spain’s MICINN (Grants CTQ2017-86936-P,
CTQ2016-80375-P, RTI2018-097853-B-I00) and MEC (CTQ2016-81797-REDC and RED2018-
102387-T). Funding from DURSI-Generalitat de Catalunya (2017-SGR465) and Basque
Government / Eusko Jaurlaritza (Grant IT 1346-19) is also acknowledged. A.G. thanks UAB for
his postdoctoral contract.
References
(1)
(a) Sheppard, T. D. Metal-catalysed halogen exchange reactions of aryl halides. Org.
Biomol. Chem. 2009, 7, 1043-1052. (b) Tang, L. M.; Bao, Z. Halogenated Materials as Organic
Semiconductors. Chem. Mater. 2011, 23, 446-455.
(2)
(a) Molander, G. A.; Canturk, B. Organotrifluoroborates and Monocoordinated
Palladium Complexes as Catalysts—A Perfect Combination for Suzuki–Miyaura Coupling.
Angew. Chem. Int. Ed. 2009, 48, 9240-9261. (b) Chinchilla, R.; Nájera, C. Recent Advances in
Sonogashira Reactions. Chem. Soc. Rev. 2011, 40, 5084-5121. (c) McCartney, D.; Guiry, P. J. The
Asymmetric Heck and Related Reactions. Chem. Soc. Rev. 2011, 40, 5122-5150. (d) Phapale, V.
B.; Cárdenas, D. J. Nickel-catalysed Negishi Cross-coupling Reactions: Scope and Mechanisms.
Chem. Soc. Rev. 2009, 38, 1598-1607. (e) Lennox, A. J. J. G.; Lloyd-Jones, C. Transmetalation in
the Suzuki-Miyaura Coupling: the Fork in the Trail. Angew. Chem. Int. Ed. 2013, 52, 7362-7370.
(f)
Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. Copper(I)-Catalyzed Aryl Bromides To Form
Intermolecular and Intramolecular Carbon−Oxygen Bonds. J. Org. Chem. 2009, 74, 5075-5078.
(3)
Carey F. A. Sundberg, R. J. Advanced Organic Chemistry; Springer: New York, NY, USA,
2007.
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
(4)
(5)
Taylor, R. Electrophilic Aromatic Substitution, John Wiley & Sons, New York, 1990.
Majetich, G.; Hicks, R.; Reister, S. Electrophilic Aromatic Bromination Using
7
8
Bromodimethylsulfonium Bromide Generated in Situ. J. Org. Chem. 1997, 62, 4321-4326.
9
(6)
Pramanick, P. K.; Hou, Z.-L.; Yao, B. Mechanistic Study on Iodine-Catalyzed Aromatic
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bromination of Aryl Ethers by N-Bromosuccinimide. Tetrahedron 2017, 73, 7105-7114.
(7)
Auerbach, J.; Weissman, S. A.; Blacklock, T. J.; Angeles, M. R.; Hoogsteen, K. N-
Bromosuccinimide/Dibromodimethylhydantoin in Aqueous Base: A Practical Method for the
Bromination of Activated Benzoic Acids. Tetrahedron Lett. 1993, 34, 931-934.
(8)
Kajigaeshi, S.; Moriwaki, M.; Tanaka, T.; Fujisaki, S.; Takaaki Kakinami, T.; Okamoto T.
Halogenation using Quaternary Ammonium Polyhalides. Part 22. Selective Bromination of
Aromatic Ethers with Benzyltrimethylammonium Tribromide. J. Chem. Soc. Perkin Trans I 1990,
897-899.
(9)
Horning, E. C.; Parker, J. A. Polymethoxybromobenzenes. J. Am. Chem. Soc. 1952, 74,
2107-2108.
(10)
Groweiss, A. Use of Sodium Bromate for Aromatic Bromination:ꢀ Research and
Development. Org. Process Res. Dev. 2000, 4, 30-33.
(11)
Evans, P. A.; Brandt, T. A. Hypervalent Iodine Chemistry: Mechanistic Investigation of
the Novel Haloacetoxylation, Halogenation, and Acetoxylation Reactions of 1,4-
Dimethoxynaphthalenes. J. Org. Chem. 1997, 62, 5321-5326.
(12)
Muraki, T.; Togo, H.; Yokoyama, M. Reactivity and Synthetic Utility of 1-
(Arenesulfonyloxy)benziodoxolones. J. Org. Chem. 1999, 64, 2883-2889.
(13)
Liu, X.-X.; Wu, Z.-H.; Luo, X.-L.; He, Y.-Q.; Zhou, X.-Q. ; Fan, Y.-X.; Huang, G.-S. PhI(OAc)2
Oxidative C5 Halogenation of Quinolines Using Copper Halides Under Mild Conditions. RSC
Adv. 2016, 6, 71485-71488.
(14)
Himabindu, V.; Parvathaneni, S. P.; Rao, V. J. PhI(OAc)2/NaX-Mediated Halogenation
Providing Access to Valuable Synthons 3-Haloindole Derivatives. New J. Chem. 2018, 42,
18889-18893.
(15)
Satkar, Y.; Ramadoss, V.; Nahide, P. D.; García-Medina, E.; Juárez-Ornelas, K. A.;
Alonso-Castro, A. J.; Chávez-Rivera, R.; Oscar, J.; Jiménez-Halla, C.; Solorio-Alvarado, C. R.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
1
2
3
4
5
Practical, Mild and Efficient Electrophilic Bromination of Phenols by a New I(III)-Based Reagent:
the PIDA–AlBr3 System. RSC Adv. 2018, 8, 17806-17812.
6
7
8
9
(16)
Fosu, S. C.; Hambira, C. M.; Chen, A. D.; Fuchs, J. R.; Nagib, D. A. Site-Selective C-H
Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes. Chem. 2019, 5,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
417-428.
(17)
Macdonald, T. L.; Narasimhan, N. Nucleophilic Substitution of Alkyl Iodides via
Oxidative Ligand Transfer. J. Org. Chem. 1985, 50, 5000-5001.
(18)
Cui, J. G.; Lin, C. W.; Zeng, L. M.; Su, J. Y. Synthesis of Polyhydroxysterols (III): Synthesis
and Structural Elucidation of 24-methylenecholest-4-en-3β, 6α-diol. Steroids 2002, 67, 1015-
1019.
(19)
Granados, A.; Zhiyu, J.; del Olmo, M.; Vallribera, A. In situ Generation of Hypervalent
Iodine Reagents for the Electrophilic Chlorination of Arenes. Eur. J. Org. Chem. 2019, 2812-
2818.
(20)
Huang, B.; Zhao, Y.; Yang, C.; Gao, Y.; Xia, W. Combining Eosin Y with Selectfluor: A
Regioselective Brominating System for Para-Bromination of Aniline Derivatives. Org. Lett.
2017, 19, 3799-3802.
(21)
(a) Peilleron, L.; Grayfer, T. D.; Dubois, J.; Dodd R. H.; Cariou, K. Iodine(III)-mediated
Halogenations of Acyclic Monoterpenoids. Belstein J. Org. Chem. 2018, 14, 1103–1111. (b)
Barnett, R. L.; Andrews, J. ; Keefer R. M. Trifluoroacetyl Hypohalites as Aromatic Halogenating
Agents. J. Am Chem Soc. 1972, 94, 6129-6134.
(22)
(a) Amey, R. L.; Martin, J.C. Synthesis and Reaction of Substituted Arylalkoxyiodinanes:
Formation of Stable Bromoarylalcoxy and Aryldialcoxy Heterocyclic Derivatives of
Tricoordinate Organoiodine (III). J. Org. Chem. 1979, 1779-1784. (b) Braddock, D. C.; Cansell,
G.; Hermitage, S. A.; White, A. J. P. Bromoiodinanes with an I(III)-Br bond: Preparation, X-Ray
Crystallography and Reactivity as Electrophilic Brominating Agents. Chem. Commun. 2006,
1442-1444.
(23)
Arnold, A. M.; Ulmer, A. ; Gulder, T. Advances in Iodine(III)-Mediated Halogenations: A
Versatile Tool to Explore New Reactivities and Selectivities. Chem. Eur. J. 2016, 22, 8728-8739.
(24)
(a) Jones, R. O. Density Functional Theory: Its Origins, Rise to Prominence, and Future.
Rev. Mod. Phys. 2015, 87, 897-923. (b) Koch, W.; Holthausen, M. C. A Chemist’s Guide to
Density Functional Theory, 2nd Edition, Wiley-VCH, , Weinheim, 2001.
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
1
2
3
4
(25)
(a) Becke, A. D. Density functional thermochemistry. III. The role of exact exchange. J.
Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang, W.; Parr, R. G. Development of the Colle-
Salvetti Correlation-energy Formula into a Functional of the Electron Density. Phys. Rev. B:
Condens. Matter Mater. Phys. 1988, 37, 785-789.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(26)
(a) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, S. A Consistent and Accurate ab initio
Parametrization of Density Functional Dispersion Correction (DFT-D) for the 94 Elements H-Pu.
J. Chem. Phys. 2010, 132, 154104-154119. (b) Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the
Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011,
32, 1456-1465.
(27)
(a) Cammi, R.; Mennucci, B.; Tomasi, J. Fast Evaluation of Geometries and Properties of
Tamm-Dancoff Model with Application to 4-
Excited Molecules in Solution:
A
Dimethylaminobenzonitrile. J. Phys. Chem. A. 2000, 104, 5631-5637. (b) Tomasi, J.; Mennucci,
B.; Cammi, R. Quantum Mechanical Continuum Solvation Models. Chem. Rev. 2005, 105, 2999-
3094.
(28)
Jensen, F. Advanced Review Atomic Orbital Basis Sets. WIREs Comput. Mol. Sci. 2013,
3, 273-295.
(29)
Wadt, W. R.; Hay, P. J. Ab initio Effective Core Potentials for Molecular Calculations.
Potentials for K to Au Including the Outermost Core Orbitals. J. Chem. Phys. 1985, 82, 299-310.
(30)
Frisch, M. J. et al. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2009 (full
reference in the Supporting Information).
(31)
(a) Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Putcha, R.; Schleyer, P. v. R. Nucleus-
independent Chemical Shifts (NICS) as an Aromaticity Criterion. Chem. Rev. 2005, 105, 3842-
3888. (b) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes, N. J. r. V. E. Nucleus-
Independent Chemical Shifts: A Simple and Efficient Aromaticity Probe. J. Am. Chem. Soc. 1996,
118, 6317-6318.
(32)
(a) Schlayer, P. v. R.; Wu, J. I.; Cossío, F. P.; Fernández, I. Aromaticity in Transition
Structures. Chem. Soc. Rev. 2014, 43, 4909-4921. (b) Morao, I.; Cossío, F. P. A Simple Ring
Current Model for Describing in-plane Aromaticity in Pericyclic Reactions. J. Org. Chem. 1999,
64, 1868-1874. (c) de Lera, A. R.; Alvarez, R.; Lecea, B.; Torrado, A.; Cossío, F. P. On the
Aromatic Character of Electrocyclic and Pseudopericyclic Reactions: Thermal Cyclization of
(2Z)-Hexa-2,4-5-trienals and Their Schiff Bases. Angew. Chem. Int. Ed. 2001, 40, 557-561.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
(33)
(a) Reetz, M. T. Dyotropic Rearrangements, a New Class of Orbital-Symmetry
Controlled Reactions. Type I. Angew. Chem. Int. Ed. Engl. 1972, 11, 129-130. (b) Fernández, I.;
Bickelhaupt, M. F.; Cossío, F. P. Type-I Dyotropic Reactions: Understanding Trends in Barriers.
Chem. Eur. J. 2012, 18, 12395-12403. (c) Fernández, I.; Cossío, F. P.; Sierra, M. A. Dyotropic
Reactions: Mechanisms and Synthetic Applications. Chem. Rev. 2009, 109, 6687-6711.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(34)
(a) Smith, W. B. Ab initio studies of the bromination of benzene. J. Phys. Org. Chem.
2003, 16, 34-39. (b) Liljenberg, M.; Stenlid, J. H.; Brinck, T. Theoretical Investigation into the
Rate-Determining Factors in Electrophilic Aromatic Halogenation. J. Phys. Chem. A 2018, 122,
3270-3279.
(35) Wu, Y. C.; Zhu, J. P. Asymmetric Total Syntheses of (-)-Renieramycin M and G and (-)-
Jorumycin Using Aziridine as a Lynchpin. Org. Lett. 2009, 11, 5558-5561.
(36)
Vilsmeier, A.; Haack, A. Über die Einwirkung von Halogenphosphor auf
Alkyl-formanilide. Eine neue Methode zur Darstellung sekundärer und tertiärer
p-Alkylamino-benzaldehyde. Ber. Dtsch. Chem. Ges. 1927, 60B, 119-122.
(37)
Alvarez-Manzaneda, E. J.; Chahboun, R.; Perez, I. B.; Cabrera, E.; Alvarez, E.; Alvarez-
Manzaneda, R. First Enantiospecific Synthesis of the Antitumor Marine Sponge Metabolite (−)-
15-Oxopuupehenol from (−)-Sclareol. Org. Lett. 2005, 7, 1477-1480.
(38)
Sallmann A.; Pfister, R. Substituted Derivatives of 2-anilinophenylacetic acids and a
Process of preparation. US3558690A, 1971
(39)
Effenberger, F. How Attractive is Bromine as a Protecting Group in Aromatic
Chemistry? Angew. Chem. Int. Ed. 2002, 41, 1699-1700.
(40)
(a) Rosevear, J.; Wilshire, J. F. K. The chlorination of some N,N-Dimethylanilines with
1,3,5-Trichloro-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (Trichloroisocyanuric acid). Aust. J. Chem.
1980, 33, 843-852. (b) Hering, T.; Mühldorf, B.; Wolf, R.; König, B. Halogenase-Inspired
Oxidative Chlorination Using Flavin Photocatalysis. Angew. Chem. Int. Ed. 2016, 55, 5342-5345.
(41)
Muraki, T.; Togo, H.; Yokoyama, M. J. Reactivity and Synthetic Utility of 1-
(Arenesulfonyloxy)benziodoxolones. J. Org. Chem. 1999, 64, 2883-2889.
(42)
Mo, F. Y.; Yan, J. M.T.; Qiu, D.; Li,F.; Zhang, Y.; Wang, J. B. Gold-Catalyzed Halogenation
of Aromatics by N-Halosuccinimides. Angew. Chem. Int. Ed. 2010, 49, 2028-2032.
(43)
Steel, C. J.; Králik, A.; Hacker, M.; Frank, A.; König, B.; Gulder, T. Atom-Economic
Electron Donors for Photobiocatalytic Halogenations. ChemCatChem 2018, 10, 3960-3963.
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
4
5
(44)
Mo, F.; Yan, J. M.; Qui, D.; Li, F.; Zhang, Y.; Wang, J. Gold-Catalyzed Halogenation of
Aromatics by N-Halosuccinimides. Angew. Chem. Int. Ed. 2010, 49, 2028-2032.
6
7
8
9
(45)
Shi, Y.; Yeung, Y.-Y. Environmentally benign indole-catalyzed position-selective
halogenation of thioarenes and other aromatics. Green Chem. 2018, 20, 4448-4452.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(46)
Gao, H.-Y.; Ha, C.-Y. Total synthesis of aristogin C in aqueous systems. Synthetic
Commun. 2006, 36, 3283-3286.
(47)
Maibunkaew, T.; Thongsornkleeb, C.; Tummatorn, J.; Bunrit, A.; Ruchiwat, S. Practical
and Metal-Free Electrophilic Aromatic Halogenation by Interhalogen Compounds Generated In
Situ from N-Halosuccinimide and Catalytic TMSCl. Synlett 2014, 25, 1769-1775.
(48)
Jiang, P.-P.; Yang, X.-J. A quick, mild and efficient bromination using a CFBSA/KBr
system. RSC Adv. 2016, 6, 90031-90034.
(49)
Sweetman, B. A.; Guiry, P. J. Axially chiral tridentate isoquinoline derived ligands for
diethylzinc addition to aldehydes. Tetrahedron 2018, 74, 5567-5581.
(50)
Shishimi, T.; Hara, S. BrF3–KHF2: An air-stable fluorinating reagent. J. Fluorine Chem.
2014, 168, 55-60.
(51)
Khosravi, K.; Naserifar, S. 1, 1, 2, 2-Tetrahydroperoxy-1, 2-Diphenylethane: An efficient
and high oxygen content oxidant in various oxidative reactions. Tetrahedron 2018, 74, 6584-
6592.
(52)
Khatun, R.; Biswas, S.; Ghosh, S.; Islam, S. M. Polymer-anchored [Fe(III)Azo] complex:
An efficient reusable catalyst for oxidative bromination and multi-components reaction for the
synthesis of spiropiperidine derivatives. J. Organomet. Chem. 2018, 858, 37-46.
(53)
Oberhauser, T. A New Bromination Method for Phenols and Anisoles:ꢀ NBS/HBF4·Et2O
in CH3CN. J. Org. Chem. 1997, 62, 4504-4506.
(54)
Kulangiappar, K.; Anbukulandainathan, M.; Raju, T. Nuclear Versus Side-Chain
Bromination of 4-Methoxy Toluene by an Electrochemical Method. Synth. Commun. 2014, 44,
2494-2502.
(55)
Maruyama, K.; Nagao, N.; Naruta, Y. Lewis Acid Mediated Claisen-Type Rearrangement
of Aryl Dienyl Ethers. J. Org. Chem. 1986, 51, 5083-5092.
(56)
Cervi, A.; Aillard, P.; Hazeri,N.; Petit, L.; Chai,C. L. L.; Willis, A. C.; Banwell, M. G. Total
Syntheses of the Coumarin-Containing Natural Products Pimpinellin and Fraxetin Using Au(I)-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
5
Catalyzed Intramolecular Hydroarylation (IMHA) Chemistry. J. Org. Chem. 2013, 78,
9876−9882.
6
7
8
(57)
de Meijere, A.; Zhao, L.; Belov, V. N.; Bossi, M.; Noltemeyer, M.; Hell, S. W.
1,3-Bicyclo[1.1.1]pentanediyl: The Shortest Rigid Linear Connector of Phenylated
Photochromic Units and a 1,5-Dimethoxy-9,10-di(phenylethynyl)anthracene Fluorophore.
Chem. Eur. J. 2007, 13, 2503-2516.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(58)
Kong, L.; Han, X.; Jiao, P. Catalytic asymmetric Diels–Alder reactions involving aryl vinyl
ketones. Chem. Comm. 2014, 50, 14113-14116.
(59) Maddox, S. M.; Nalbandian, C. J.; Smith, D. E.; Gustafson, J. L. A practical Lewis base
catalyzed electrophilic chlorination of arenes and heterocycles. Org. Lett. 2015, 17, 1042-1045.
(60)
Morin, J.; Zhao, Y.; Snieckus, V. Reductive Cleavage of Aryl O-Carbamates to Phenols by
the Schwartz Reagent. Expedient Link to the Directed Ortho Metalation Strategy. Org. Lett.
2013, 15, 4102-4105.
(61)
Fountoulaki, S. Daikopoulou, V.; Gkizis, P. L.; Tamiolakis, I.; Armatas, G. S.; Lykakis, I. N.
Mechanistic Studies of the Reduction of Nitroarenes by NaBH4 or Hydrosilanes Catalyzed by
Supported Gold Nanoparticles. ACS Catal. 2014, 4, 3504-3511.
(62)
Prebil, R.; Laali, K. K.; Stavber, S. Metal and H2O2 Free Aerobic Oxidative Aromatic
+
–
Halogenation with [RNH3 ] [NO3 ]/HX and [BMIM(SO3H)][NO3)x(X)y] (X = Br, Cl) as
Multifunctional Ionic Liquids. Org. Lett. 2013, 15, 2108-2111.
(63)
Tajbakhsh, M.; Hosseinzadeh, R.; Alinezhad, H.; Ghahari, S.; Heydari, A.; Khaksar, S.
Catalyst-free one-pot reductive alkylation of primary and secondary amines and N,N-
dimethylation of amino acids using sodium borohydride in 2, 2, 2-trifluoroethanol. Synlett
2011, 3, 490-496.
(64)
Rueping, M.; Vila, C.; Szadkowska, A.; Koenigs, R. M.; Fronert, J. Photoredox Catalysis
as an Efficient Tool for the Aerobic Oxidation of Amines and Alcohols: Bioinspired
Demethylations and Condensations. ACS Catal. 2012, 2, 2810-2815.
(65)
Drillaud, N.; Banaszak, E.; Pezron, I.; Len, C. Synthesis and evaluation of a
photochromic surfactant for organic reactions in aqueous media. J. Org. Chem. 2012, 77, 9553-
9561.
(66)
Rogers, D. A.; Bensalah, A. T.; Espinosa, A. T.; Hoer, J. L.; Refai, F. H.; Pitzel, A. K.;
Alvarado, J. J.; Lamar, A. A. Amplification of Trichloroisocyanuric Acid (TCCA) Reactivity for
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
Chlorination of Arenes and Heteroarenes via Catalytic Organic Dye Activation. Org. Lett. 2019,
21, 4229-4233.
6
7
8
9
(67)
Schlosser, M.; Heiss, C.; Marzi, E.; Scopelliti, R. Proton Mobility in 2-Substituted
1,3-Dichlorobenzenes: “ortho” or “meta” Metalation?. Eur. J. Org. Chem. 2006, 4398-4404.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(68)
Choi, H. Y.; Chi, D. Y. A facile debromination reaction: Can bromide now be used as a
protective group in aromatic systems? J. Am. Chem. Soc. 2001, 123, 9202-9203.
(69)
Vogt, E.-J.; Zapol’skii, V. A.; Nutz, E.; Kaufmann, D. E. Chemistry of Polyhalogenated
Nitrobutadienes, Part 11: ipso-Formylation of 2-Chlorothiophenes under Vilsmeier-Haack
Conditions. Z. Naturforsch. B. 2012, 67, 285-294.
TOC
ERG=p-OMe
Ph
I
bromination
TFA
2 TMSBr
TFA
I
Br
Br
2 TMSTFA
Br
Ph
I
PhI + HBr
Br
ERG
ERG
R’
ERG
ERG
H
Br
Ri
Ri
Ri
Ri
R’
H
Br
ACS Paragon Plus Environment