Iodine(III)-Mediated, Controlled Di- or Monoiodination of Phenols

Article abstract of DOI:10.1021/acs.joc.9b00161

An oxidative procedure for the electrophilic iodination of phenols was developed by using iodosylbenzene as a nontoxic iodine(III)-based oxidant and ammonium iodide as a cheap iodine atom source. A totally controlled monoiodination was achieved by buffering the reaction medium with K₃PO₄. This protocol proceeds with short reaction times, at mild temperatures, in an open flask, and generally with high yields. Gram-scale reactions, as well as the scope of this protocol, were explored with electron-rich and electron-poor phenols as well as heterocycles. Quantum chemistry calculations revealed PhII(OH)·NH₃ to be the most plausible iodinating active species as a reactive "I⁺" synthon. In light of the relevance of the iodoarene moiety, we present herein a practical, efficient, and simple procedure with a broad functional group scope that allows access to the iodoarene core unit.

Full text of DOI:10.1021/acs.joc.9b00161

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Article
Iodine(III)-Mediated, Controlled Di- or Monoiodination of Phenols
Yuvraj Satkar, Luisa F Yera-Ledesma, Narendra Mali, Dipak Patil, Pedro Navarro-
Santos, Luis A Segura-Quezada, Perla I Ramírez-Morales, and César R. Solorio-Alvarado
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00161 • Publication Date (Web): 12 Mar 2019
Downloaded from http://pubs.acs.org on March 12, 2019
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Page 1 of 18
The Journal of Organic Chemistry
Iodine(III)-Mediated, Controlled Di- or Monoiodination of Phenols
1
2
3
4
Yuvraj Satkar,a‡ Luisa F. Yera-Ledesma,a Narendra Mali,a Dipak Patil,a Pedro Navarro-Santos,b Luis A.
Segura-Quezada,a Perla I. Ramírez-Morales,a and César R. Solorio-Alvaradoa*
5
6
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8
aUniversidad de Guanajuato, Campus Guanajuato, División de Ciencias Naturales y Exactas, Departamento de Química, Noria
Alta S/N, 36050, Guanajuato, Guanajuato. México.
bUniversidad Michoacana de San Nicolás de Hidalgo, Instituto de Ciencias Químico Biológicas, Av. Universidad S/N, 58000,
Morelia, Michoacán, México.
9
OH
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(PhIO)n / NH4I
K3PO4
"
"
synthon
I
I
Controlled
Mono-iodination
R
H
MeOH, 0 ºC
5 min
H3N
H
O
OH
OH
R
I
I
I
OH
(PhIO)n / NH4I
R1
R
or
I
MeOH, 23 ºC
plausible
iodinating species
20 min
I
Mono-iodination
Diiodination
• Broad scope •High yielding •Fast reaction •Open flask •Mild conditions
• Electron-donating •Electron-withdrawing toleration •Cheap Iodine source
ABSTRACT: An oxidative procedure for the electrophilic iodination of phenols was developed by using iodosylbenzene as a non-
toxic iodine(III)-based oxidant and ammonium iodide as a cheap iodine atom source. A totally controlled mono-iodination was
achieved by buffering the reaction medium with K3PO4. This protocol proceeds with short reaction times, at mild temperatures, in an
open flask and generally with high yields. Gram scale reactions, as well as the scope of this protocol, were explored with electron-
rich and electron-poor phenols as well as heterocycles. Quantum chemistry calculations revealed PhII(OH)·NH3 to be the most plau-
sible iodinating active species as a reactive “ I+ ” synthon. In light of the relevance of the iodoarene moiety, we present herein a
practical, efficient and simple procedure with a broad functional group scope that allows access to the iodoarene core unit.
INTRODUCTION
odisulfate,20 DMSO,21 HIO3,22 urea-H2O2,23 or NO2.24 An addi-
tional strategy consists of the oxidation of iodide salts using the
systems NH4I/H2O2,25 NaI/NaClO226 or NaClO2/NaI/HCl.27 On
the other hand, iodination reactions based on the use of (I+)
synthons are frequently carried out with ICl,28 N-iodosaccha-
Iodinated arenes and heteroarenes including indophenols are
an important class of organic structures.1 They are ubiquitous in
marine natural products such as the terpenes or prostanoids iso-
lated from sponges Topsentia sp.2 or from corals of genus
Clavularia viridis.3 In the field of medical research, iodoarenes
are found in pharmacologically active drugs,4 in non-steroidal
hormones L-thyroxine (T4) and Liothyronine (T3)5 or in antifun-
gal6 or bactericidal compounds.7 In chemistry, iodoarenes are
found as starting materials in the synthesis of hypervalent I(V)8
or iodine(III)9 derivatives. They have also been found to be the
best electrophiles in the Suzuki and Stille cross-coupling reac-
tions, as well as the Sonogashira alkynylation and the Mizoroki-
Heck olefination (Figure 1).10
30
rin,29 IPy2BF4 and NIS in harsh acidic media such as TFA,31
TfOH,32 and HFIP.33 Additionally, radical iodination using
I2/TBHP34 has recently been developed. Finally, a much less
well exploited strategy for the oxidative iodination of arenes
and phenols involves the use of hypervalent iodine(V)35 or io-
dine(III) reagents. The few procedures using iodine(III)36 have
a common strategy involving the synthesis of a diaryliodonium
salt as an intermediate, which then reacts with a metallic iodide,
typically NaI. This intermediate undergoes a thermally-pro-
moted reductive elimination, allowing the formation of two dif-
ferent aryl iodides37 from the iodonium salt at high temperatures
(Scheme 1).
Me
O
H
Me
O
I
Me
COOMe
Me
Me
I
O
O3SO
O3SO
I
OEt
Me
HO
OH
Scheme 1. Hypervalent iodine strategies for the iodination
of arenes and phenols.
Topsentiasterol sulfate
Iodovulone-I
antifungal activity
OH
I
Me
N
I
Kumar [Iodine (V)]35
OH
O
I
O
HN
Se
OH
IBX-I2
HO
I
MeO
Se
OH
N
NH
NH2
Me
R
2 I
O
O
O
DiMagno [Iodine (III)]36c
R= I, L-Thyroxine (T4
)
anti-thyroid drug
I
I
R=H, Liothyronine (T3
)
bactericide activity
TfO
R
I
EDG
AcO
I
OAc
TMS-OTf
NaI
Figure 1. Relevance of the iodoarene moiety.
Due to the high relevance of the iodophenol moiety, several
120 ºC
R= -CO2Me
EDG
R
R
R
EDG
EDG = electron-donating groups
ONLY EDG
procedures have been developed to date for its synthesis.
Among the most significant iodination strategies are those in-
volving transition metals such as Ru,11 In,12 Pd,13 Mo,14 Hg,15
Fe,16 Ce,17 Yb18 or Ag.19 A number of transition-metal-free io-
dination procedures have also been described using I2 in com-
bination with 1,4-bis(triphenylphosphonium)-2-butene perox-
this work
without K3PO4
with K3PO4
OH
I
H
(PhIO)n / NH4I
K3PO4
I
OH
OH
or
R
R
R
MeOH, 0 -23 ºC
5 - 20 min
Monoiodination (naphthols)
Diiodination (phenols)
Controlled
Monoiodination
♦ Broad scope EDG and EWG ♦Mild conditions 0 ºC or 23 ºC
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In general, iodination methods of phenols require expensive The starting conditions were based on our previous chlorina-
tion38 and bromination39 procedures. Thus, 1.2 equivalents of
PIDA or PIFA were used, along with 2.4 equivalents of AlI3 in
acetonitrile at room temperature (entries 1 and 2). Unfortu-
nately, only molecular iodine was obtained as product in this
trial. Different conditions were explored by changing the io-
dine(III) reagent from PIDA / PIFA to iodosylbenzene (PhIO).
Iodide salts were also considered as the iodine atom source. In
line with the results of Kita and coworkers, both PIFA and
PIDA are prone to generate radicals when mixed with halogen
salts having cations different to ammonium.40 The topic about
radical generation is outside of this work scope, hence PhIO was
chosen as the iodine(III) reagent. Initial trials used potassium
iodide in methanol to solubilize both PhIO and KI. In this way,
1 was isolated in a 17% yield (entry 3). The reaction in water as
solvent showed poor conversion (<5%) and large quantities of
unreacted starting material (entry 4). The use of 5 mol% of sul-
furic acid as additive significantly increased the yield to 86% in
methanol (entry 5) and 25% in water (entry 6). The (1:1) solvent
combination of methanol and water did not improve the yield
(entry 7), however it demonstrated that the reaction is water tol-
erant. As acidic media gave considerably better yields, another
protic iodide salt was explored. Surprisingly, use of 1.2 equiva-
lents of PhIO and 2.4 equivalents of ammonium iodide in meth-
anol at 23 ºC provided 1-iodo-2-naphthol in nearly quantitative
yield (98%) within 20 minutes (entry 8). This result highlighted
several aspects of the process, such as the fast and high-yield
reactions as well as its economical iodine atom source. Addi-
tionally, we avoid the possibility of the radical generation in the
process since is used the ammonium cation. Changing the sol-
vent to acetonitrile lowered the yield to 70% (entry 9). Decreas-
ing the amount of PhIO (to 1.0 and 0.5 equivalents) provided
yields of only 80% and 40%, respectively (entries 10 and 11).
On the other hand, the yield was not improved by decreasing
the ammonium iodide loading to 1.5 equivalents (entry 12). At
this point the possibility of the iodide anion oxidation generat-
ing molecular iodine was considered, which could be the io-
dinating active species in the process. To test this mechanistic
hypothesis, experiments using molecular iodine in absence of
an iodine(III) reagent were carried out, using the conditions
found to be best in the initial optimizations (entry 8). Thus, the
reaction was tested with 1.0, 1.5 and 2.0 equivalents of molec-
ular iodine at 23 ºC in methanol (entries 13-15) or trifluoroeth-
anol (entry 16). Interestingly, the desired iodination was
achieved with yields of 58%, 52%, 46% and 57% respectively.
However, the yields remain far below that obtained in entry 8,
thus molecular iodine was ruled out as the iodinating species.
Control experiments were then carried out in order to complete
the optimization. The use of PhIO in the absence of ammonium
salt led to no reaction (entry 17). Similarly, the use of ammo-
nium iodide without the iodine(III) reagent failed to produce 1.
1
2
3
4
5
6
7
8
transition metals or are based on oxidative procedures using
strong oxidants, leading to poor functional group compatibility.
To overcome this problem, hypervalent reagents appear to be
an excellent alternative. With respect to the known hypervalent-
based iodination procedures of phenols, the very few of them
that available are synthetically restricted in several ways, the
most significant being low selectivity,35 polyhalogenation, ex-
pensive starting materials,36 more than one preparation step,
limitation to electron-rich arenes, very narrow scope, and the
requirement for high temperatures, strong Lewis acids and/or
long reaction times. All of the aforementioned aspects make an
efficient iodine(III)-based iodination procedure elusive. There-
fore, we were interested in developing a new and systematic al-
ternative iodination of phenols by using the hypervalent io-
dine(III) reagent iodosylbenzene (PhIO) in combination with
NH4I, an inexpensive source of iodine atoms. The scope and
advantages of our new method are detailed herein, and theoret-
ical calculations supporting the plausible operation of
PhII(OH)·NH3 as the iodinating species are provided.
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RESULTS
Our initial optimization of the iodination reaction used 2-
naphthol as a model system, the results of which are tabulated
in Table 1.
Table 1. Optimization of the iodine(III)-mediated electro-
philic iodination of 2-naphthol.a
I
H
PIDA= Ph-I(OAc)2
PIFA= Ph-I(OTFA)2
OH
OH iodine(III) /I source
O
I
solvent, 23 ºC
n
PhIO=
1
Ph
I Source
(equiv)
iodine(III)
(equiv)
Yield
(%)b
Entry
Solvent
1
2
PIDA (1.2) AlI3 (2.4)
MeCN
MeCN
MeOH
H2O
-- c
-- c
17
PIFA (1.2)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
PhIO (1.2)
AlI3 (2.4)
KI (2.4)
KI (2.4)
KI (2.4)
KI (2.4)
KI (2.4)
3
4
< 5
86d
25 d
38
5
MeOH
H2O
6
7
MeOH / H2O
MeOH
MeCN
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TFE
8
PhIO (1.2) NH4I (2.4)
PhIO (1.2) NH4I (2.4)
PhIO (1.0) NH4I (2.4)
PhIO (0.5) NH4I (2.4)
PhIO (1.2) NH4I (1.5)
98e
70
9
10
11
12
13
14
15
16
17
18
80
40
68
This set of experiments allowed reliable determination of the
optimal iodination conditions, thus we proceeded to explore the
scope of the new procedure with respect to changes in the aryl
unit (Scheme 2).
-
I2 (1.0)
I2 (1.5)
I2 (2.0)
I2 (1.0)
-
58
-
52
-
46
-
PhIO (1.2)
--
57
MeOH
MeOH
n.r.
n.r.
NH4I (2.4)
a
Reaction conditions: 2-naphthol (0.5 mmol), solvent (0.15
M), open flask. b Yields as average of two runs. c I2 was obtained.
d 5 mol% of H2SO4 used as additive. e Yields as average of three
runs. n.r. = no reaction observed.
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The Journal of Organic Chemistry
Scheme 2. Phenol ring scope in the PhIO/NH4I-mediated io-
dination of phenols.a
ing methyl, methoxyl and phenyl groups (18-22) were diio-
1
2
3
4
5
6
7
8
dinated in moderate to good yields (46-72%). Although it was
expected to obtain the monoiodination products, the synthe-
sized derivatives 15-22 are also important building blocks in
synthetic chemistry.8-10 On the other hand, the reactivity of our
system was compared against the commonly used reagent NIS.
Different phenols containing strong electron-withdrawing
groups (5- 7 and 16) which usually show great difficulties to
react, undergo iodination reaction with moderate (52%) to ex-
cellent yields (86-90%) by using our system.
I
OH
PhIO (1.2 equiv)
NH4I (2.4 equiv)
H
R
I
I
OH
R
OH
or
R
Methanol, 23 ºC
20 min
R= -OMe, -Me, -Ph, -Cl, -Br, -F.
naphthols
I
I
I
I
OH
OH
OH
Br
OH
Br
9
From this initial scope exploration, it is possible to conclude
that the optimized conditions allow the controlled monoio-
dination of naphthols, while phenols are diiodinated. Inspired
by these results, we were interested in developing controlled
monoiodination reactions, thus a new optimization was initiated
using 4-iodophenol as the model system (Table 2).
1 (98%)
(92%) gram scale
2 (93%)
(90%) gram scale
3 (92%)
4 (88%)
Cl
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
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49
50
51
52
53
54
55
56
57
58
59
60
I
I
I
OH
OH
OH
Cl
F
F
5 (86%)
NIS= 0%e
6 (88%)
NIS= 0%e
7 (90%)
NIS= 0%e
F
F
I
I
I
Table 2. Optimization of the PhIO/NH4I-mediated, con-
trolled monoiodination of phenols.a
OH
OH
OH
NC
9 (96%)
10 (93%)
8 (86%)
OH
OH
OH
Me
PhIO /NH4I
Additive
I
I
I
I
I
I
OH
OH
+
OH
solvent, T (ºC)
MeO
MeO
O
I
I
I
11 (98%)
12 (96%)
13 (94%)
H
CH3
MeO
34
15
NOE
NOE
PhIO
(equiv) (equiv)
NH4I
Additive
(equiv)
T
(ºC)
Yield (%)
34 / 15
CH3
H
I
OH
OH
OH
Entry
Solvent
OH
O
OH
I
I
I
I
I
I
I
I
phenols b
1
2
1.2
1.2
1
2.4
2.0
1.5
2.4
2.4
2.4
2.4
2.4
2.4
2.4
--
--
--
--
--
--
MeOH 23
MeOH 23
MeOH 23
-- / 64
-- /56
-- / 60
n.r.
14 (96%)
(94%) gram scale
F
I
I
Br
16 (52%)
NIS= 0%e
15a (46%)c
17 (60%)
15b (64%)d
3
OH
OH
OH
OH
OH
I
I
I
I
I
I
I
I
I
4
1.2
1.2
1.2
1.2
1.2
1.2
1.2
MeCN
H2O
23
23
0
MeO
OMe
OMe
OMe
5
n.r.
Me
Br
19 (70%)
I
OMe
18 (67%)
20 (58%)
21 (72%)
22 (70%)
6
MeOH
25 / 36
80 / 5
88 / --
-- / 55
10 / 28
7
K3PO4 (1.5) MeOH
0
a Reaction conditions: 2-naphthol (0.5 mmol), methanol (0.15
8
K3PO4 (1.0) MeOH
0
M), open flask. b PhIO (2.4 equiv) / NH4I (4.8 equiv) were used.
c
Synthesized from phenol. d Synthesized from 4-iodophenol.
9b
10b
H2SO4
H2SO4
MeOH 23
e Reaction conditions: phenol (0.5 mmol), NIS (1.2 equiv), TFA
0
MeOH
(10 mol%), MeCN (0.15 M) at 23 ºC by 12 h.
a
Reaction conditions: 4-iodophenol (0.5 mmol), solvent
(0.15 M), open flask. b 5 mol% of additive was used. n.r. = no
reaction observed.
Several mono-annular phenols and naphthols were submitted
to our optimized iodination conditions. We observed that the
reaction shows great tolerance towards naphthols containing the
electron-withdrawing groups bromine (2 and 3), chlorine (4 and
5), fluorine (6 and 7) or nitrile (8); as well as the electron-do-
nating groups phenyl (9), tolyl (10), and methoxyl (11 and 12).
The reaction took place regioselectively at the ortho position
with respect to the hydroxyl group, in no more than 20 minutes
and with good yields ranging from 86% to 98%. The NOESY
correlation of methoxyl protons in 13 and 14 with the ortho pro-
tons at C4 and C8 demonstrated the observed regiochemistry
(Scheme 2). Moreover, the scalability was illustrated by the
gram-scale preparation of 1, 2 and 14 in excellent yields (93-
98%). On the other hand, when the procedure was applied to the
iodination of mono-annular phenols, a mixture of unreacted
starting material, mono- and diiodinated derivatives was ob-
tained, in which case an additional amount of PhIO/NH4I was
necessary to complete the reaction. Under these conditions a
range of phenols bearing electron-attracting fluorine, bromine
or iodine groups (15-17), as well as electron-rich phenols bear-
The optimal previous conditions afforded the diiodinated
phenol 15 in 64% yield at 23 ºC (entry 1). By reducing the NH4I
loading to 2.0 or 1.5 equivalents, and the PhIO loading to 1.0
equivalent, 15 was systematically obtained in lower yields (en-
tries 2 and 3). Changing the solvent to acetonitrile or water did
not yield any product (entries 4 and 5). However, when the re-
action was carried at 0 ºC in methanol, a mixture of mono- and
diiodinated phenols was observed, but the starting material was
not fully consumed (entry 6). This result highlights the im-
portant role of the temperature in controlling the reaction. At
this point we hypothesized that a slightly acidic media could be
influencing the outcome due to the inherently acidic nature of
NH4I, as well as the release of H+ after the aromatization pro-
cess. This could be eroding the control over the monoiodination
process, since it is well known that acidic media accelerates the
iodination process, leading to unwanted polyhalogena-
tion.22,27,31-33 In consequence, we decided to buffer the reaction
pH by using tribasic potassium phosphate as an additive.41 To
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our delight, the use of 1.5 equivalents of K3PO4 at 0 ºC gave rise methyl groups (25 and 26) or an isopropyl (27) were success-
1
2
3
4
5
6
7
8
to the monoiodination product 34 in 80% yield in only five
minutes of reaction, in addition to a small amount (5%) of the
diiodination product 15 (entry 7). Upon decreasing the phos-
phate salt loading to 1.0 equivalents, the yield of 34 increased
to 88% and the diiodination derivative 15 was not observed.
These reaction conditions finally facilitated the totally con-
trolled mono-iodination of the 4-iodophenol. To validate if the
acidic medium is responsible for the observed diiodination in
the reaction we performed the reaction with 5 mol% of sulfuric
acid as additive. Under these conditions (at 23 ºC) the complete
consumption of the starting material was observed, but with
only a 55% yield to the diiodination product 15, in a complex
reaction mixture (entry 9). When the reaction was carried at 0
ºC, a mixture of 34 and 35 was obtained (entry 10). These re-
sults strongly point towards the diiodination being promoted by
acidic medium.
fully obtained in good yields ranging from 80 to 90%. Phenols
containing electron-rich groups such as phenyl or methoxyl (28
and 29) afforded excellent monoiodination yields (88 and 78%).
Additional examples involving phenols with the electron-at-
tracting fluoride (30), chloride (31 and 32), bromide (33 and 35)
or iodide (34 and 36) groups were tolerated very well, leading
to the totally controlled introduction of a single iodine atom in
high to excellent yields (86-92%). Even the strongly deac-
tivated 2-chloro-4,5-difluorophenol led to the monoiodinated
37 in 88% yield. This starting phenol as well as the 4-chloro-
phenol did not react under the typically iodination conditions
with NIS.
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
This set of monoiodinated phenols obtained demonstrated the
scope and the excellent applicability of this methodology, al-
lowing the use of both electron-rich and -poor monoannular
phenols. The short reaction times (ca. 5 min.), good yields, and
mild and open-flask reaction conditions are important aspects
to be highlighted. To the best of our knowledge this is the first
report describing a totally controlled monoiodination of phenols
using a buffered system.
After this analysis and determination of the optimal condi-
tions, we explored the scope of the controlled monoiodination
of phenols (Scheme 3).
Scheme 3. Scope of the PhIO/NH4I-mediated, controlled
monoiodination of phenolsa
The following set of trials was devised to determine the tol-
erance of our procedure in the presence of: 1) different func-
tional groups at the phenolic oxygen, 2) functionalized phenols
with more than one functional group, 3) functionalities other
than phenol present in the aryl moiety, and 4) heterocycles
(Scheme 4).
PhIO (1.2 equiv)
NH4I (2.4 equiv)
OH
OH
OH
I
H
K3PO4 (1 equiv)
or
R
R
R
Methanol, 0 ºC
5 min
I
H
R= -Me, -OMe, -iPr, -Ph, -F, -Cl -Br, -I
Scheme 4. Functional group scope in the PhIO/NH4I-
mediated iodination of arenes and heteroarenes.a
OH
OH
OH
OH
I
I
Me
Me
H
I
I
H
PhIO (1.2 equiv)
NH4I (2.4 equiv)
R
R
Me
OR
OR
or
I
Me
Me
I
Het
Het
or
Methanol, 75 ºC
23 (56%)
24 (82%)
25 (80%)
OH
26 (88%)
R= -Me, -Bn, -OMe, -OAc, -CHO, -COOMe
OH
OH
O
I
38, R= Me (57%)
39, R= Bn (38%)
40, R= Ac ( 0%)
41, R= Piv ( 0%)
I
I
MeO
I
MeO
OR
O
I
MeO
I
OMe
MeO
I
Br
Br
42 (37%)
43 (20%)
Me
Me
I
I
27 (90%)
28 (88%)
29 (78%)
MeO
MeO
O
OMe
OH
OH
OH
OH
I
Cl
Cl
I
I
O
N
I
O
H
46 (16%)b,e
47 (96%)b,c
44 (36%)
45 (28%)
I
OH
OH
Cl
I
F
Br
NH
31 (88%)
NIS= 0%b
OH
32 (74 %)
30 (90%)
33 (92%)
N
OH
N
NH
OH
OH
Cl
NO2
no reaction
H
complex reaction
mixture
OH
c,d
I
Br
I
NO2
48 (47%)c
49 (92%)
I
a Reaction conditions: arene (0.5 mmol), methanol (0.15 M),
open flask. b One equivalent of NH4I was used. c Reaction car-
ried out at 23 ºC. d o-phenylenediamine was the starting mate-
rial. e Combined yield of the mono- and diiodination at the 2,8
positions in a (1.5:1) ratio.
F
I
I
I
F
37 (88%)
34 (86%)
35 (92%)
36 (92%)
NIS= 0%b
a Reaction conditions: phenol (0.5 mmol), methanol (0.15 M),
open flask. b Reaction conditions: phenol (0.5 mmol), NIS (1.2
equiv), TFA (10 mol%), MeCN (0.15 M) at 23 ºC by 12 h.
The first attempts to carry out the iodination reaction were
evaluated using 2-methoxynaphthalene as the model system.
However, no reaction was observed when the standard condi-
tions (PhIO 1.2 equiv / NH4I 2.4 equiv, 23 ºC) were applied,
suggesting the importance of the hydroxyl group. By heating
this reaction to 75 ºC, using the same stoichiometry, the io-
dination provided a 57% yield of 38. By increasing the size of
A number of monoannular phenols bearing groups with dif-
ferent electronic nature were tested in the controlled monoio-
dination reaction. The exploration started with the simplest phe-
nol (hydroxybenzene), leading to the monoiodinated product 23
in 56% yield in only five minutes. Neither the ortho regioisomer
nor the diiodinated product were observed. Other monoio-
dinated phenols bearing alkyl groups, such as one (24) or two
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The Journal of Organic Chemistry
The chlorination and bromination of 2-naphthol, 6-bromo-2-
the alkyl group through the use of a benzyl-substituted sub-
1
2
3
4
5
6
7
8
strate, iodide 39 was obtained in only 38% yield. When the ac-
etyl 40 and pivaloyl 41 derivatives were submitted to the same
reaction conditions, no product was formed. Functionalities at
the aryl moiety other than phenol, such as phenol-ether (42),
aldehyde (43) or ester (44) could only be iodinated in moderate
to low yields (20-37%). Moreover, oxy-heterocycles as well as
nitrogenated heterocycles were tested. In these cases, the io-
dination of a 1,3-benzodioxole, dibenzofuran, as well as free N-
H indoles and carbazoles (45-48) were achieved in low to ex-
cellent yields (16-96%) by using only one equivalent of NH4I.
Is important to mention that dibenzofuran gave rise to a (1.5:1)
ratio of mono- and diiodinated products. Finally, o-phenylene-
diamine gave rise to the 1,2-diimine oxidation product 51 in
91% yield rather than the expected iodination product. Other
substrates such as pyridine-2-ol, as well as 3-nitro- and 4-ni-
trophneol showed complex reaction mixtures or did not react
even by heating at 75 ºC for a period of 24 h.
naphthol, 7-methoxy-2-naphthol and 6-(p-tolyl)-2-naphthol
also produced their corresponding chlorinated and brominated
derivatives 51 and 52, 54-57, 60 and 61, respectively, in 80-
96% yields. A number of additional brominated phenols con-
taining electron-withdrawing (53, 62-65) and electron-donating
groups (58 and 59) were isolated in high yields (90-95%), which
demonstrated the excellent efficiency of our protocol. In fact,
these described conditions resulted in a general improvement of
our previous iodine(III)-mediated chlorination38 and bromina-
tion39 procedures. It is also important to mention that a very
complex reaction mixture was observed when NH4F was used,
presumably due to formation of a strongly oxidizing reagent
that degraded the starting material. To conclude the exploration
of the scope of the halide salt, a one-pot two-halogenation-re-
action sequence was attempted. Thus, starting from 2-naphthol,
the one-pot chlorination-bromination sequence afforded 54 in
an 84% overall yield. Similarly, tandem bromination-bromina-
tion and iodination-bromination sequences gave rise to 55 and
2 in 91% and 78% yields, respectively.
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
A complementary scope exploration was considered in order
to determine if different halogens can be introduced by chang-
ing the anion in the ammonium salt, thereby a range of phenols
were examined (Scheme 5).
In addition to its broad scope, these tests demonstrated the
exciting and varied possibilities of this reaction method, includ-
ing high-yielding bis-iodination, fully controlled monoio-
dination, and chlorination or bromination of phenols possessing
a free hydroxyl group.
Scheme 5. Scope of the NH4X salt in the PhIO/NH4X-
mediated chlorination and bromination of phenols.a
Cl/ Br
OH
PhIO (1.2 equiv)
NH4X (2.4 equiv)
X= Cl, Br
H
OH
To conclude the experimental part of this study, a series of
reactions were devised to showcase the synthetic utility of the
reaction (Scheme 6).
R
R
Methanol, 23 ºC
R= -OMe, -Me, -Ph, -Br, -F
20 min
Cl/ Br
Br
OH
Cl/ Br
OH
OH
OH
Scheme 6. Synthetic utility of the synthesized halogenated
derivatives.a
Br
Br
Ph-B(OH)2 (1 equiv),
Pd(PPh3)4 (10 mol%),
K2CO3 (2 equiv)
Br
51, X= Cl (80%)
52, X= Br (94%)
I
54, X= Cl (90%)
55, X= Br (92%)
53 (95%)
50 (86%)
OH
OH
Br
Br
Cl/ Br
OH
1,4-dioxane-H2O (8:2)
80 ºC, 8 h
OH
Br
OH
Br
MeO
2
66 (86%)
4-Me-Ph-B(OH)2 (1 equiv),
Pd(PPh3)4 (10 mol%),
K2CO3 (2 equiv)
Me2SO4 (2 equiv),
K2CO3 (2 equiv),
acetone, 23 ºC
56, X= Cl (92%)
57, X= Br (96%)
58 (93%)
59 (94%)
Br
Br
Cl/ Br
OH
1,4-dioxane-H2O (8:2)
80 ºC, 8 h
OH
OH
I
OMe
OH
63 (92%)
60, X= Cl (90%)
61, X= Br (92%)
62 (94%)
F
MeO
Br
Me
Br
Br
68 (94%)
67 (82%)
OH
OH
Me
−≡ (1.2 equiv),
Ph
F
F
Cl
Pd(PPh3)2Cl2
(3 mol%),
CuI (1 mol%),
64 (90%)
65 (90%)
F
Et3N, 23 ºC, 2 h
one-pot dihaologenationb
Ph
Ph
reaction secuence
1st 2nd
OH
Cl
Br
I
3-Cl-4-F-Ph(OH)2 (1.2 equiv)
Pd(PPh3)4 (5 mol%),
K2CO3 (2.4 equiv)
OH
OH
Br
Cl
Br
I
Br
Br
Br
OMe
OMe
Br
Br
toluene-ethanol (8:2),
80 ºC, 12 h
Cl
54 (84%)
55 (91%)
2 (78%)
Br
69 (88%)
70 (68%)
a Reaction conditions: phenol (0.5 mmol), methanol (0.15 M),
open flask. b overall yield for the one-pot dihalogenation reac-
tion using 2-naphthol as starting material.
F
The synthetic applicability of the derivatives obtained
through our procedure was illustrated with the compound 6-
bromo-1-iodo-2-naphthol (2) which possesses two halide
groups with different reactivities. We considered the synthesis
of 2 as an excellent opportunity to carry out two distinct orthog-
onal reaction sequences: sequential double Suzuki cross-cou-
pling, and Sonogashira alkynylation / Suzuki cross-coupling. In
The ammonium chloride and bromide were mainly employed
under the optimized standard conditions (scheme 5) in order to
introduce these halides into a range of phenols. In this way, 2-
phenylphenol was brominated in 86% yield, giving rise to 50.
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the first sequence, regioselective Suzuki cross-coupling at the performing harmonic frequency calculations at 298 K and 1 atm
1
2
3
4
5
6
7
8
C1 atom of 2 with phenyl boronic acid led to the formation of
the 6-bromo-1-phenyl-2-naphthol 66 in 86% yield. The second
Suzuki cross-coupling with 4-methylboronic acid introduced
the p-tolyl fragment exclusively at the C6 position, affording
the diarylated naphthol 67 in 82% yield. The second sequence
started with the O-methylation of 2, producing 68 in 94% yield.
This compound was submitted to Sonogashira alkynylation
conditions, giving rise to 69 in 88% yield with regioselective
functionalization at the C1 position. The methylated alkynyl
naphthol underwent subsequent Suzuki cross-coupling with (3-
chloro-4-fluorophenyl)boronic acid leading to the formation of
70 in 68% yield with the regioselective functionalization at C6
of the naphthol.
(selected bond lengths and angles are included, see SI).
On the other hand, the electrophilic nature of the plausible
iodinating species was analyzed by using the Fukui functions as
the covalent descriptor45-46 (Figure 2).
A)
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
Finally, in order to gain more insight into the reaction mech-
anism, we decided to carry out the iodination of 2-naphthol in
the presence of the radical scavengers TEMPO42 (tetramethylpi-
peridine N-oxide) and DPPH (2,2-diphenyl-1-picrylhydrazyl)
in order to determine if a radical or cationic pathway was oper-
ating (Eq. 1).
B)
PhIO (1.2 equiv)
NH4I (2.4 equiv)
radical scavenger
I
H
OH
OH
( 1 )
Methanol, 23 ºC
TEMPO = 96%
DPPH = 89%
1
radical scavenger
NNPh2
Me
Me
Me
Me
O2N
NO2
N
O
TEMPO
Figure 2. (a) The Fukui function for electrophilic attack of the plau-
sible iodinating active species and (b) its 2D projection. Color code
for atoms in brackets: C (Brown), O (red), I (purple), (N) light blue
and H (pink).
DPPH
NO2
The presence of 1 equivalent of TEMPO or DPPH did not
affect the reaction, and 1 was isolated in 96% and 89% yield
respectively. This experiment ruled out a radical mechanism in
the process, suggesting a cationic iodination as the more feasi-
ble pathway.
The highest values of the calculated Fukui function (Figure
2a) showed the most electrophilic site47 at the terminal iodine
atom as an electrophilic center48 which is identified with the
isosurface in yellow color. It is clearly observed that the termi-
nal iodine is the most electrophilic atom of the adduct
PhII(OH)·NH3, which is in agreement with our proposed cati-
onic iodination mechanism. A 2D projection of the electrophilic
form of the Fukui function (Figure 2b) is illustrated to evaluate
the reactivity and susceptibility of the iodinating adduct towards
electrophilic attacks. The full results of this mechanic study will
be published separately.
To provide a preliminary determination of the iodinating ac-
tive species involved in this process, a DFT computational
study was performed at the B3LYP/DGDZVP level43 (Ec. 2).
plausible
iodinating species
H3N
H
O
O
H3N
H
O
I
I
NH4I
I
( 2 )
I
isomerization
I
CONCLUSIONS
cis-adduct
trans-adduct
ΔHoR= -23.9 kcal·mol-1
ΔGoR= -19.4 kcal·mol-1
ΔHoR = -36.5 kcal·mol-1
ΔGoR = -28.2 kcal·mol-1
In summary, we have developed a new hypervalent io-
dine(III)-based iodination procedure of phenols by using iodo-
sylbenzene (PhIO) and ammonium iodide (NH4I) as an inex-
pensive source of iodine atoms. This protocol was applied to a
wide range of different arenes including aromatic and heteroar-
omatic derivatives. The best yields were obtained with phenols
having at least one free hydroxyl group, and total control over
the di- or monoiodination was achieved by buffering the reac-
tion with tribasic potassium phosphate (K3PO4). This novel pro-
cedure takes place under mild, open-flask, one-step and opera-
tionally simple reaction conditions with short reaction times (5
to 20 min) and high yields. Initial mechanistic investigations
showed PhII(OH)·NH3 to be the most plausible iodinating spe-
cies in the process.
The enthalpy and Gibbs free energy of the reaction between
PhIO and NH4I were calculated to evaluate the energetic stabil-
ity of the obtained product. The resulting values strongly sug-
gested the formation of the trans-adduct PhII(OH)·NH3 as the
most plausible active iodinating species. This hypervalent io-
dine(III) derivative is obtained after the isomerization of its cor-
responding cis-adduct which is formed initially as the kinetic
product; while the aforementioned trans-PhII(OH)·NH3 is the
thermodynamic compound (see SI for full details).44 We veri-
fied that the optimized geometry of the iodinating active species
corresponds to a minimum on the potential energy surface by
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General Procedure B. A 25 mL oven-dried round-bottom flask
EXPERIMENTAL SECTION
1
2
equipped with a magnetic stirrer bar was charged with the cor-
responding phenol (0.5 mmol, 1 equiv) and methanol (0.15 M)
at 0°C. After dissolving and obtaining homogeneous mixture,
NH4I (1.2 mmol, 2.4 equiv) was added and stirred for 2 min.
Then K3PO4 (1 equiv) and iodosylbenzene (0.6 mmol, 1.2
equiv) was added and stirred at 25 °C until fully consumption
of the starting material (usually 5 min). To quench the reaction,
AcOEt (5 mL) was added and concentrated to vacuo. Purifica-
tion was carried out by column chromatography with EtOAc-
Hexanes system to give the desired product.
Organic synthesis.
General Information. All moisture- and oxygen-sensitive re-
actions were carried out in flame-dried round-bottom flasks un-
der an inert atmosphere of nitrogen. Unless otherwise specified,
all commercial materials were used as received without further
purification. Anhydrous solvents were purchased from Sigma-
Aldrich in SureSeal bottles. Column chromatography was per-
formed using silica gel of sizes 100−200 and 230−400 mesh
(Sigma-Aldrich). Thinlayer chromatography was performed
with TLC silica gel 60 F256 plates, and visualization was ef-
fected with short wavelength UV light (254 nm). Compounds
were characterized using 1H NMR and 13C NMR. (Copies of 1H
NMR and 13C NMR spectra are provided for all the compounds
in the SI.) Data of known compounds were compared with ex-
isting literature characterization data, and the references are
3
4
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
Suzuki-Miyaura Cross-Coupling procedure. The starting
materials of the examples 4-1268, 69, 70 and 58-6568, 69, 70 were syn-
thesized by Suzuki-Miyaura Cross-Coupling according to the
following procedure. A 50 mL round bottom flask with a stir
bar was fitted with a rubber septum and flame dried under high
vacuum. The flask was purged with argon and charged with
Pd(PPh3)4 (155.5 mg, 0.1 mmol), K2CO3 (580.5 mg, 4.2 mmol),
6-bromonaphthalen-2-ol (443.9 mg, 2.0 mmol), boronic acid
(4.0 mmol), 10.0 mL 1,4-dioxane and 2 mL distilled water. The
following boronic acids were purchased from Sigma Aldrich
and used as such without additional purification: 4-chloro-
phenylbronic acid for compound 4; 3-chloro-4-fluorophenyl-
boronic acid for compounds 5 and 64; 4-fluorophenylboronic
acid for compounds 6 and 63; 3,4-difluorofenilboronic acid for
compounds 7 and 65; 4-cyanophenylboronic acid for compound
8; phenylboronic acid for compounds 9 and 58; 4-methyl-
boronic acid for compounds 10, 60 and 61; 4-methoxyphenyl
boronic acid for compounds 11 and 62; 3,4-dimethoxy-
phneylboronic acid for compound 12 and 2-naphthylboronic
acid for compound 59. The reaction mixture was then heated at
80 °C for 8 h. After the reaction was cooled down to room tem-
perature, the organic layer was separated, and the aqueous layer
was extracted with ethyl acetate (3 × 10 mL), and the combined
organic layer was dried over Na2SO4 and concentrated. The
crude products were purified by flash chromatography on silica
gel.
given. H and 13C NMR spectra were recorded with 500 MHz
1
and Bruker advance 400 MHz instruments using deuterated sol-
1
vents purchased from Sigma-Aldrich like CDCl3. H spectra
were referenced with tetramethyl silane (TMS, 0.0 ppm) or
chloroform (CDCl3, 7.26 ppm) and are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constant (Hz), and integra-
tion. Chemical shifts of the 13C NMR spectra were measured
relative to CDCl3 (δ = 77.16 ppm). All the starting materials
were synthesized according to reported procedures in the liter-
ature. High-resolution masses (HRMS) analyses were obtained
under the following procedure: Samples were introduced by di-
rect infusion at 3 μL min−1 to the electrospray ionization (ESI)
source of a quadrupole time-of-flight mass spectrometer
(Bruker Daltonics ESI-QTOF-MS maXis impact), equipped
with Data Analysis 4.1. ESI was operated in positive mode with
ion spray voltage 4 500 V, nitrogen dry gas 4 L min−1, drying
temperature 180 °C, and gas pressure 0.4 bar. Mass calibration
was accomplished based on sodium formate clusters. Chemical
nomenclature was generated using Chemdraw. Infrared (IR)
spectra were recorded using PerkinElmer system 2000 FT-IR
spectrometer. Melting points of solids were measured using a
Fisher-Johns melting point apparatus.
Examples in Scheme 2. 1-iodonaphthalen-2-ol (1).21 The fol-
lowing compound was obtained according to the general proce-
dure A, by using 2-naphthol as starting material and NH4I. The
crude material was purified by flash column chromatography
over silica gel with the system (3% EtOAc/Hexane) to afford
the product 1 (92 mg, 98%); gram scale (1.72 g, 92%) as a white
solid. m.p.= 89-91 °C. Rf= 0.5 (5% EtOAc/Hexane). 1H NMR
(500 MHz, CDCl3) δ 7.94 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.4,
3.3 Hz, 2H), 7.58 (t, 1H), 7.42 (t, 1H), 7.28 (d, J = 2.1 Hz, 1H),
5.79 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.9, 134.9,
130.7, 130.4, 129.8, 128.4, 128.4, 124.3, 116.9, 86.7. HRMS
(ESI+): m/z calculated for C10H8IO [M+H]+=270.9620, found
270.9616.
Synthesis of iodosylbenzene (PhIO)n. In a 250 mL round-bot-
tom flask was suspended bis(acetoxy)iodobenzene (PIDA) (10
g, 31.04 mmol, 1 equiv) in 150 mL of a 3 M NaOH solution.
The reaction was strongly stirred to room temperature during
12 h. Then, a precipitate was formed which was filtered-off and
washed with cold water until pH of water was neutral. Then the
solid was washed (3x10 mL) with CHCl3 to remove impurities
of PIDA. The obtained solid was dried at high vacuum without
heating to yield (PhIO)n (6.2 g, 91%) as yellowish solid. Cau-
tion: (PhIO)n is explosive upon drying at 110 ºC in vacuum con-
ditions.
6-bromo-1-iodonaphthalen-2-ol (2).49 The following com-
pound was obtained according to the general procedure A, by
using 6-bromonaphthalen-2-ol as starting material and NH4I.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (5% EtOAc/Hexane) to
afford the product 2 (73 mg, 93%), gram scale (1.41 g, 90%).
as a white solid. m.p.= 85-87 °C Rf = 0.2 (8% EtOAc/Hexane).
IR (neat) ν/cm−1 = 3439, 3228, 2921, 1589. 1H NMR (500 MHz,
CDCl3) δ 7.96 (d, J = 9.9 Hz, 1H), 7.82 (dd, J = 8.9, 5.2 Hz,
1H), 7.56 (dd, J = 8.7, 5.4 Hz, 2H), 7.27 (dd, J = 2.6 Hz, 1H),
5.81 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 154.1, 133.4,
132.1, 131.3, 130.4, 130.0, 129.6, 118.6, 117.5, 85.9. HRMS
(ESI+): m/z calculated for C10H7BrIO [M+H]+= 348.8725,
found 348.8705.
General Procedure A. A 25 mL oven-dried round-bottom
flask equipped with a magnetic stirrer bar was charged with the
corresponding phenol (0.5 mmol, 1 equiv) and methanol (0.15
M) at 25 °C. After dissolving and obtaining homogeneous mix-
ture, NH4X (1.2 mmol, 2.4 equiv) (X= Cl, Br or I) was added
and stirred for 2 min. Then iodosylbenzene (0.6 mmol, 1.2
equiv) was added and stirred at 25 °C until fully consumption
of the starting material (usually 5 to 20 min). To quench the
reaction, AcOEt (5 mL) was added and concentrated to vacuo.
Purification was carried out by column chromatography with
EtOAc-Hexanes system to give the desired product.
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3-bromo-1-iodonaphthalen-2-ol (3). The following compound MHz, CDCl3) δ 7.92 (d, J = 8.7 Hz, 1H), 7.88 (s, 1H), 7.77 (t, J
1
2
3
4
5
6
7
8
was obtained according to the general procedure A, by using 3-
bromonaphthalen-2-ol as starting material and NH4I. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (5% EtOAc/Hexane) to afford the prod-
uct 3 (72 mg, 92%) as a white solid. m.p.= 67-69°C. Rf = 0.14
(10% EtOAc/Hexane). IR (neat) ν/cm−1= 3390, 3023, 1560,
1429. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.97 (d, J =
8.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H),
7.39 (t, J = 7.4 Hz, 1H), 6.22 (s, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 149.7, 134.7, 132.5, 130.8, 129.9, 128.6, 127.4,
125.1, 109.6, 84.7. HRMS (EI): m/z calculated for C10H6BrIO
[M]+= 347.8647, found 347.8639.
= 8.2 Hz, 2H), 7.56 (d, J = 7.7 Hz, 2H), 7.24 (d, J = 4.1 Hz, 1H),
7.21 (s, 1H), 5.74 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ
153.8, 137.6, 137.4, 137.2, 134.0, 130.9, 130.9, 129.8, 127.8,
127.3, 125.8, 116.9, 86.8, 21.9. HRMS (EI): m/z calculated for
C17H13IO [M]+= 360.0011, found 360.0006.
1-iodo-6-(4-methoxyphenyl)naphthalen-2-ol (8). The following
compound was obtained according to the general procedure A,
by using 6-(4-methoxyphenyl) naphthalen-2-ol as starting ma-
terial and NH4I. The crude material was purified by flash col-
umn chromatography over silica gel with the system (8%
EtOAc/Hexane) to afford the product 8 (74 mg, 98%) as a white
solid. m.p.= 140-142 °C. Rf = 0.12 (15% EtOAc/Hexane). IR
(neat) ν/cm−1= 3398, 3040, 1598, 1498, 1440. 1H NMR (400
MHz, CDCl3) δ 7.95 (d, J = 8.7 Hz, 1H), 7.88 (s, 1H), 7.75 (d,
J = 8.9 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 3.7 Hz,
1H), 7.01 (d, J = 8.3 Hz, 2H), 5.79 (s, 1H), 3.86 (s, 3H).13C{1H}
NMR (101 MHz, CDCl3) δ 159.8, 153.7, 136.8, 133.8, 132.9,
130.8, 130.8, 130.4, 128.4, 127.8, 125.6, 116.9, 114.5, 86.8,
55.5. HRMS (EI): m/z calculated for C17H13IO2 [M]+=
375.9960, found 375.9955.
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
1-iodo-3-methoxynaphthalen-2-ol (4). The following com-
pound was obtained according to the general procedure A, by
using 3-methoxynaphthalen-2-ol as starting material and NH4I.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (5% EtOAc/Hexane) to
afford the product 4 (81 mg, 94%), as a white solid. m.p.= 73-
75 °C. Rf = 0.5 (10% EtOAc/Hexane). IR (neat) ν/cm−1 = 3328,
3012, 1620, 1478, 1439. 1H NMR (500 MHz, CDCl3) δ 8.01
(d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 7.5
Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.12 (s, 1H), 6.58 (s, 1H),
4.04 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 146.6, 146.9,
130.8, 129.6, 127.7, 126.1, 126.3, 124.8, 106.6, 82.7, 56.9.
HRMS (EI): m/z calculated for C11H9IO2 [M]+= 299.9647,
found 299.9641.
6-(3,4-dimethoxyphenyl)-1-iodonaphthalen-2-ol (9). The fol-
lowing compound was obtained according to the general proce-
dure A, by using 6-(3,4-dimethoxyphenyl)naphthalen-2-ol as
starting material and NH4I. The crude material was purified by
flash column chromatography over silica gel with the system
(10% EtOAc/Hexane) to afford the product 9 (70 mg, 96%) as
a white solid. m.p.= 132-134 °C. Rf = 0.15 (15% EtOAc/Hex-
1-iodo-7-methoxynaphthalen-2-ol (5). The following com-
pound was obtained according to the general procedure A, by
using 7-methoxynaphthalen-2-ol as starting material and NH4I.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (6% EtOAc/Hexane) to
afford the product 5 (83 mg, 96%), gram scale (1.62 g, 94%).
as a white solid m.p.= 79-81°C. Rf = 0.15 (10% EtOAc/Hex-
ane). IR (neat) ν/cm−1 = 3428, 3018, 1630, 1380, 1409. 1H NMR
(500 MHz, CDCl3) δ 7.66 (dd, J = 8.7, 5.7 Hz, 2H), 7.28 (s, 1H),
7.13 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.84 (s, 1H),
4.00 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.9, 154.4,
136.5, 130.6, 130.2, 124.9, 116.5, 114.3, 109.8, 85.6, 55.6.
HRMS (ESI+): m/z calculated for C11H10IO2 [M+H]+=
300.9725, found 300.9715.
1
ane). IR (neat) ν/cm−1= 3330, 3020, 1610, 1491, 1425. H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 9.6
Hz, 1H), 7.80 – 7.75 (m, 2H), 7.27 (d, J = 9.2 Hz, 2H), 7.21 (d,
J = 1.7 Hz, 1H), 6.99 (d, J = 8.1, 4.2 Hz, 1H), 5.79 (s, 1H), 3.99
(s, 3H), 3.95 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.7,
149.4, 148.8, 136.8, 133.9, 133.9, 130.8, 130.7, 129.8, 127.6,
125.5, 119.6, 116.8, 111.6, 110.5, 85.9, 56.0. HRMS (EI): m/z
calculated for C18H15IO3 [M]+= 406.0066, found 406.0063.
6-(4-chlorophenyl)-1-iodonaphthalen-2-ol (10). The following
compound was obtained according to the general procedure A,
by using 6-(4-chlorophenyl) naphthalen-2-ol as starting mate-
rial and NH4I. The crude material was purified by flash column
chromatography over silica gel with the system (8%
EtOAc/Hexane) to afford the product 10 (65 mg, 88%) as a
white solid. m.p.= 160-162 °C. Rf= 0.20 (8% EtOAc/Hexane).
IR (neat) ν/cm−1= 3330, 3045, 1580, 1486, 1460. 1H NMR (500
MHz, CDCl3) δ 7.96 (d, J = 8.7 Hz, 1H), 7.88 (d, J = 1.5 Hz,
1H), 7.75 (d, J = 8.8 Hz, 1H), 7.72 (dd, J = 8.7, 1.8 Hz, 1H),
7.59 (d, J = 8.4 Hz, 2H), 7.44 – 7.40 (m, 2H), 7.24 (d, J = 6.7
Hz, 1H), 5.79 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
154.4, 138.8, 135.7, 134.9, 133.7, 131.2, 130.8, 129.8, 129.9,
128.8, 127.6, 126.2, 117.5, 85.8. HRMS (EI): m/z calculated for
C16H10ClIO [M]+ = 379.9465, found 379.9460.
1-iodo-6-phenylnaphthalen-2-ol (6).50 The following com-
pound was obtained according to the general procedure A, by
using 6-phenylnaphthalen-2-ol as starting material and NH4I.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (4% EtOAc/Hexane) to
afford the product 6 (66 mg, 96%) as a white solid. m.p.= 138-
140 °C. Rf = 0.42 (8% EtOAc/Hexane). IR (neat) ν/cm−1= 3410,
3020, 1585, 1472, 1430. 1H NMR (400 MHz, CDCl3) δ 7.96 (d,
J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.77 (t, J = 8.2 Hz, 2H), 7.68 (d,
J = 7.6 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.4 Hz,
1H), 7.23 (d, J = 3.3 Hz, 1H), 5.79 (s, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 153.8, 140.4, 136.9, 134.5, 130.8, 130.8, 129.8,
128.9, 127.7, 127.4, 127.8, 126.1, 116.8, 85.9. HRMS (EI): m/z
calculated for C16H11IO [M]+= 345.9855, found 345.9847.
6-(4-fluorophenyl)-1-iodonaphthalen-2-ol (11). The following
compound was obtained according to the general procedure A,
by using 6-(4-fluorophenyl) naphthalen-2-ol as starting material
and NH4I. The crude material was purified by flash column
chromatography over silica gel with the system (12%
EtOAc/Hexane) to afford the product 11 (67 mg, 88%) as a light
yellowish solid. m.p.= 136-138 °C. Rf = 0.14 (20% EtOAc/Hex-
ane). IR (neat) ν/cm−1= 3400, 3035, 1580, 1485, 1454. 1H NMR
(500 MHz, CDCl3) δ 7.98 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 1.4
Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.75 (dd, J = 8.7, 1.7 Hz, 1H),
7.67 – 7.63 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 8.7
Hz, 2H), 5.80 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
1-iodo-6-(p-tolyl)naphthalen-2-ol (7).50 The following com-
pound was obtained according to the general procedure A, by
using 6-(p-tolyl) naphthalen-2-ol as starting material and NH4I.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (6% EtOAc/Hexane) to
afford the product 7 (62 mg, 93%) as a white solid. m.p.=132-
134 °C. Rf = 0.55 (15% EtOAc/Hexane). IR (neat) ν/cm−1=
3210, 3040, 1680, 1600, 1530, 1482, 1454. 1H NMR (400
ACS Paragon Plus Environment

Page 9 of 18
The Journal of Organic Chemistry
fluorophenol as starting material and NH4I. The crude material
162.74 (d, J = 247.0 Hz), 154.8, 136.7 (d, J = 3.3 Hz), 136.9,
1
2
3
4
5
6
7
8
134.8 (d, J = 3.1 Hz), 131.2 (d, J = 17.9 Hz), 130.1, 128.9 (d, J
= 8.0 Hz), 127.7, 126.1, 117.1, 115.9 (d, J = 21.5 Hz), 86.4.
HRMS (EI): m/z calculated for C16H10FIO [M]+= 363.9760,
found 363.9753.
was purified by flash column chromatography over silica gel
with the system (4% EtOAc/Hexane) to afford the product 16
(65 mg, 52%) as a white solid. m.p.= 64-66 °C. Rf= 0.15 (6%
EtOAc/Hexane). IR (neat) ν/cm−1= 3400, 290, 1580, 1498,
1465. 1H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 7.3 Hz, 2H),
5.49 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 155.9 (d, J =
248.5 Hz), 150.8 (d, J = 3.0 Hz), 125.9 (d, J = 24.6 Hz), 80.6
(d, J = 8.5 Hz). HRMS (ESI-): m/z calculated for C6H2FI2O [M-
H]- = 362.8179, found 362.8175.
6-(4-chloro-3-fluorophenyl)-1-iodonaphthalen-2-ol (12). The
following compound was obtained according to the general pro-
cedure A, by using 6-(4-chloro-3-fluorophenyl)-naphthalen-2-
ol as starting material and NH4I. The crude material was puri-
fied by flash column chromatography over silica gel with the
system (10% EtOAc/Hexane) to afford the product 12 (63 mg,
86%) as a light yellowish solid. m.p.= 142-144 °C. Rf= 0.55
(15% EtOAc/Hexane). IR (neat) ν/cm−1= 3440, 3140, 1680,
1498, 1420. 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.7 Hz,
1H), 7.84 (s, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.67 (t, J = 7.2 Hz,
2H), 7.53 – 7.47 (m, 1H), 7.22 (dd, J = 16.8, 9.0 Hz, 2H), 5.80
(s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 157.9 (d, J = 249.5
Hz), 154.3, 137.8 (d, J = 4.1 Hz), 134.8, 134.4, 131.8, 130.9,
129.8, 129.7, 127.4, 127.2 (d, J = 7.1 Hz), 126.7, 121.6 (d, J =
18.0 Hz), 117.7 (d, J = 13.7 Hz), 117.5, 86.1. HRMS (ESI-):
m/z calculated for C16H8ClFIO [M-H]- = 396.9298, found
396.9290.
9
4-bromo-2,6-diiodophenol (17).51 The following compound
was obtained according to the general procedure A, by using 4-
bromophenol as starting material and NH4I. The crude material
was puri-fied by flash column chromatography over silica gel
with the system (2% EtOAc/Hexane) to afford the product 17
(85 mg, 60%) as a white solid. m.p.= 115-117 °C. Rf= 0.4 (4%
EtOAc/Hexane).1H NMR (500 MHz, CDCl3) δ 7.71 (s, 2H),
5.65 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.7, 140.9,
113.6, 82.6.
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
2,6-diiodo-4-methylphenol (18).51 The following compound
was obtained according to the general procedure A, by using 4-
methylphenol as starting material and NH4I. The crude material
was pu-rified by flash column chromatography over silica gel
with the system (2% EtOAc/Hexane) to afford the product 18
(100 mg, 67%) as a white solid. m.p.= 49-51°C. Rf= 0.55 (6%
6-(3,4-difluorophenyl)-1-iodonaphthalen-2-ol (13). The fol-
lowing compound was obtained according to the general proce-
dure A, by using 6-(3,4-difluorophenyl) naphthalen-2-ol as
starting material and NH4I. The crude material was purified by
flash column chromatography over silica gel with the system
(15% EtOAc/Hexane) to afford the product 13 (67 mg, 90%) as
a light yellowish solid. m.p.= 122-124 °C. Rf = 0.55 (20%
EtOAc/Hexane). IR (neat) ν/cm−1= 3400, 3040, 1600, 1498,
1445. 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.7 Hz, 1H),
7.83 (s, 1H), 7.74 (dd, J = 8.8, 1.7 Hz, 1H), 7.69 – 7.65 (m, 1H),
7.49 – 7.42 (m, 1H), 7.39 – 7.33 (m, 1H), 7.26 – 7.19 (m, 2H),
5.80 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 154.9 , 151.9
– 150.9 (m), 150.6 – 148.8 (m), 137.7 (dd, J = 5.6, 3.9 Hz),
135.0, 134.4, 131.2, 130.9, 129.8, 127.2, 126.4, 123.7 (dd, J =
6.0, 3.3 Hz), 117.8 (d, J = 17.3 Hz), 117.3, 116.5 (d, J = 17.7
Hz), 86.0. HRMS (EI): m/z calculated for C16H9F2IO [M]+=
381.9666, found 381.9662.
1
EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.50 (s, 2H),
5.59 (s, 1H), 2.24 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
151.4, 139.6, 133.8, 82.5, 19.7. HRMS (ESI+): m/z calculated
for C7H7I2O [M+H]+= 360.8586, found 360.8577.
4-bromo-2,6-diiodo-3-methoxyphenol (19). The following
compound was obtained according to the general procedure A,
by using 4-bromo-3-methoxyphenol as starting material and
NH4I. The crude material was purified by flash column chroma-
tography over silica gel with the system (5% EtOAc/Hexane) to
afford the product 19 (79 mg, 70%) as a white solid. m.p.= 64-
68°C. IR (neat) ν/cm−1= 3382, 3060, 1613, 1485, 1454. Rf = 0.2
1
(10% EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.88 (s,
1H), 5.84 (s, 1H), 3.86 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 157.8, 154.6, 141.5, 107.4, 82.3, 76.4, 60.8. HRMS
(EI): m/z calculated for C7H5BrI2O2 [M]+= 453.7562, found
453.7559.
6-hydroxy-5-iodo-2-naphthonitrile (14).50 The following com-
pound was obtained according to the general procedure A, by
using phenol as starting material and NH4I. The crude material
was purified by flash column chromatography over silica gel
with the system (10% EtOAc/Hexane) to afford the product 14
(75 mg, 86%) as a yellow solid. From 6-hydroxy-2-naphthoni-
trile. Rf=0.55(15% EtOAc/Hexane). 1H NMR (500 MHz,
DMSO) δ 8.43 (d, J = 1.1 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H),
7.94 (d, J = 8.9 Hz, 1H), 7.78 (dd, J = 8.8, 1.6 Hz, 1H), 7.35 (d,
J = 8.8 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO) δ 158.9,
137.6, 135.6, 131.6, 131.8, 128.9, 127.9, 119.6, 119.6, 105.9,
84.7.
3,5-diiodo-[1,1'-biphenyl]-2-ol (20). The following compound
was obtained according to the general procedure A, by using
[1,1'-biphenyl]-2-ol as starting material and NH4I. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (4% EtOAc/Hexane) to afford the prod-
uct 20 (81 mg, 58%) as a colorless oil. Rf= 0.14 (10%
EtOAc/Hexane). IR (neat) ν/cm−1= 3480, 3010, 1485, 1470,
1430. 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 1.7 Hz, 1H),
7.53 (d, J = 1.7 Hz, 1H), 7.51 – 7.37 (m, 5H), 5.58 (s, 1H).
13C{1H} NMR (126 MHz, CDCl3) δ 151.9, 145.2, 139.5, 135.9,
130.7, 129.2, 128.6, 87.1, 83.7. HRMS (ESI-): m/z calculated
for C12H7I2O [M-H]- = 420.8292, found 420.8263.
2,4,6-triiodophenol (15).35 The following compound was ob-
tained according to the general procedure A, by using phenol as
starting material and NH4I. The crude material was purified by
flash column chromatography over silica gel with the system
(2% EtOAc/Hexane) to afford the product 15a (116 mg, 46%)
as a white solid. From 4-iodophenol, 15b (160 mg, 64%). m.p.=
2,6-diiodo-3,5-dimethoxyphenol (21).52 The following com-
pound was obtained according to the general procedure A, by
using 3,5-dimethoxyphenol as starting material and NH4I. The
crude material was purified by flash column chromatography
over silica gel with the system (5% EtOAc/Hexane) to afford
the product 21 (190 mg, 72%) as a white solid. m.p.= 149-
141°C. Rf = 0.55 (15% EtOAc/Hexane). IR (neat) ν/cm−1=
3430, 2920, 1810, 1488, 1428. 1H NMR (500 MHz, CDCl3) δ
6.01 (s, 1H), 5.92 (s, 1H), 3.83 (s, 6H). 13C{1H} NMR (126
MHz, CDCl3) δ 160.4, 154.9, 88.4, 64.5, 56.8. HRMS (ESI+):
1
137-139 °C. Rf= 0.46 (4% EtOAc/Hexane). H NMR (500
MHz, CDCl3) δ 7.87 (s, 2H), 5.69 (s, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 153.8, 146.4, 83.9, 83.5. HRMS (ESI+): m/z
calculated for C6H4I3O [M+H]+= 472.7396, found 472.7391.
4-fluoro-2,6-diiodophenol (16). The following compound was
obtained according to the general procedure A, by using 4-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 18
m/z calculated for C8H9I2O3 [M+H]+= 406.8641, found
406.8638.
5-bromo-3-iodo-[1,1'-biphenyl]-2-ol (28). The following com-
1
2
3
4
5
6
7
8
pound was obtained according to the general procedure B, by
using 5-bromo-[1,1'-biphenyl]-2-ol as starting material and
NH4I. The crude material was purified by flash column chroma-
tography over silica gel with the system (5% EtOAc/Hexane) to
afford the product 28 (66 mg, 88%) as a yellowish liquid. Rf =
0.55 (10% EtOAc/Hexane). IR (neat) ν/cm−1= 3360, 3080,
1540, 1486, 1480. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H),
7.51 – 7.36 (m, 6H), 5.57 (s, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 151.4, 139.5, 135.9, 133.5, 129.9, 128.9, 128.9, 128.5,
113.3, 86.6. HRMS (ESI-): m/z calculated for C12H7BrIO [M-
H]- = 372.8730, found 372.8727.
2,6-diiodo-3,4-dimethoxyphenol (22). The following compound
was obtained according to the general procedure A, by using
3,4-dimethoxyphenol as starting material and NH4I. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (6% EtOAc/Hexane) to afford the prod-
uct 22 (186 mg, 70%) as a white solid. m.p.= 150-152 °C. Rf=
0.5 (10% EtOAc/Hexane). IR (neat) ν/cm−1= 3400, 3030, 1595,
1492, 1430. 1H NMR (500 MHz, CDCl3) δ 6.01 (s, 1H), 5.92
(s, 1H), 3.83 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 160.3,
154.9, 130.8, 128.8, 88.4, 68.7, 64.5, 56.8. HRMS (EI): m/z cal-
culated for C8H8I2O3 [M]+= 405.8563, found 405.8558.
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
4-bromo-2-iodo-5-methoxyphenol (29).55 The following com-
pound was obtained according to the general procedure B, by
using 4-bromo-5-methoxyphenol as starting material and NH4I.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (5% EtOAc/Hexane) to
afford the product 29 (66 mg, 78%) as a yellow liquid. Rf = 0.55
Examples in Scheme 3. 4-iodophenol (23).21 The following
compound was obtained according to the general procedure B,
by using phenol as starting material and NH4I. The crude mate-
rial was purified by flash column chromatography over silica
gel with the system (2% EtOAc/Hexane) to afford the product
23 (133 mg, 56%) as a white solid. m.p.= 80-82 °C. Rf = 0.5
(6% EtOAc/Hexane). 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J
= 7.7 Hz, 2H), 6.55 (d, J = 7.6 Hz, 2H), 4.91 (s, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 155.8, 138.9, 117.9, 82.8.
1
(10% EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.73 (s,
1H), 6.62 (s, 1H), 5.26 (s, 1H), 3.86 (s, 3H).13C{1H} NMR (126
MHz, CDCl3) δ 157.6, 155.4, 139.9, 103.9, 99.4, 73.8, 56.6.
HRMS (ESI+): m/z calculated for C7H7BrIO2 [M+H]+=
328.8674, found 328.8661.
2-iodo-4-methylphenol (24).21 The following compound was
obtained according to the general procedure B, by using 4-
methylphenol as starting material and NH4I. The crude material
was purified by flash column chromatography over silica gel
with the system (5% EtOAc/Hexane) to afford the product 24
(178 mg, 82%) as a white solid. m.p.= 96-98 °C. Rf = 0.55 (10%
EtOAc/Hexane). 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 1.4
Hz, 1H), 7.04 (dd, J = 8.2, 1.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H),
5.15 (s, 1H), 2.25 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
152.9, 138.4, 132.1, 130.9, 114.8, 85.5 20.8.
4-fluoro-2-iodophenol (30).56 The following compound was ob-
tained according to the general procedure B, by using 4-fluoro-
phenol as starting material and NH4I. The crude material was
purified by flash column chromatography over silica gel with
the system (5% EtOAc/Hexane) to afford the product 30 (96
mg, 90%) as a white solid. m.p.= 118-120 °C Rf = 0.55 (10%
1
EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.38 (dd, J =
7.6, 2.9 Hz, 1H), 7.02 – 6.96 (m, 1H), 6.93 (dd, J = 9.0, 4.9 Hz,
1H), 5.11 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 156.6 (d,
J = 243.4 Hz), 151.6 (d, J = 2.5 Hz), 124.5 (d, J = 25.4 Hz),
117.1 (d, J = 23.1 Hz), 115.5 (d, J = 7.8 Hz), 84.6.
2-iodo-4,5-dimethylphenol (25).53 The following compound
was obtained according to the general procedure B, by using
4,5-dimethylphenol as starting material and NH4I. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (4% EtOAc/Hexane) to afford the prod-
uct 25 (176 mg, 80%) as a white solid. m.p.= 50-52 °C. Rf= 0.12
4-chloro-2-iodophenol (31).17 The following compound was
obtained according to the general procedure B, by using 4-chlo-
rophenol as starting material and NH4I. The crude material was
purified by flash column chromatography over silica gel with
the system (5% EtOAc/Hexane) to afford the product 31 (87
mg, 88%) as a white solid. m.p.=76-78 °C. Rf = 0.4 (10%
EtOAc/Hexane). 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J = 2.4
Hz, 1H), 7.24 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H),
5.29 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 153.9, 137.3,
130.9, 126.5, 115.8, 85.6.
1
(8% EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.39 (s,
1H), 6.79 (s, 1H), 5.04 (s, 1H), 2.18 (s, 3H), 2.15 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 152.80, 139.6, 138.6,
130.9, 116.4, 81.7, 19.9, 18.9.
4-iodo-2,6-dimethylphenol (26).51 The following compound
was obtained according to the general procedure B, by using
2,6-dimethylphenol as starting material and NH4I. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (6% EtOAc/Hexane) to afford the prod-
uct 26 (178 mg, 88%) as a white solid. m.p.= 96-98°C. Rf= 0.2
2,6-dicholoro-4-iodophenol (32).71 The following compound
was obtained according to the general procedure B, by using
2,6-dichlorophenol as starting material and NH4I. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (2% EtOAc/Hexane) to afford the prod-
uct 32 (65 mg, 74%) as a white solid. Rf = 0.22 (5%
1
(10% EtOAc/Hexane). H NMR (400 MHz, CDCl3) δ 7.29 (s,
2H), 4.62 (s, 1H), 2.19 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 152.8, 137.1, 125.7, 82.3, 15.5.
1
EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.57 (s, 1H),
5.83 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 148.7, 136.6,
122.5, 80.5.
2-iodo-4-isopropylphenol (27).54 The following compound was
obtained according to the general procedure B, by using 4-iso-
propylphenol as starting material and NH4I. The crude material
was purified by flash column chromatography over silica gel
with the system (3% EtOAc/Hexane) to afford the product 27
(174 mg, 90%) as a colorless liquid. Rf = 0.55 (8% EtOAc/Hex-
ane). 1H NMR (500 MHz, CDCl3) δ 7.44 – 7.41 (m, 1H), 7.02
(dd, J = 8.3, 2.0 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 5.05 (s, 1H),
2.72 (hept, J = 13.7, 6.9 Hz, 1H), 1.13 (d, J = 6.0 Hz, 6H).
13C{1H} NMR (126 MHz, CDCl3) δ 152.8, 143.3, 135.8, 128.3,
114.8, 85.6, 32.9, 24.6.
4-bromo-2-iodophenol (33).17 The following compound was
obtained according to the general procedure B, by using 4-Bro-
mophenol as starting material and NH4I. The crude material was
purified by flash column chromatography over silica gel with
the system (4% EtOAc/Hexane) to afford the product 33 (79
mg, 92%) as a white solid. m.p.= 70-72 °C. Rf = 0.22 (8%
1
EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 2.3
Hz, 1H), 7.35 (dd, J = 8.7, 2.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H),
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The Journal of Organic Chemistry
solution (2 M) of Na2CO3. After dissolving in 8 mL of acetoni-
5.28 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 154.3, 139.8,
1
2
3
4
5
6
7
8
133.7, 116.3, 113.6, 86.1.
trile the mixture was stirred at 25 ºC overnight. After this period
the starting material was fully consumed judging by TLC. To
quench the reaction, AcOEt (5 mL) was added and concentrated
to vacuo. Purification was carried out by column chromatog-
raphy with EtOAc-Hexanes system to give the desired product.
2,4-diiodophenol (34).51 The following compound was obtained
according to the general procedure B, by using 4-iodophenol as
starting material and NH4I. The crude material was purified by
flash column chromatography over silica gel with the system
(3% EtOAc/Hexane) to afford the product 34 (68 mg, 86%) as
a colorless needle. m.p.= 72-74 °C. Rf = 0.5 (5% EtOAc/Hex-
2-acetylnaphthalene.39,67 A 25 mL oven-dried round-bottom
flask equipped with a magnetic stirrer bar was charged with 2-
naphthol (2 mmol), acetyl chloride (2 mmol) and triethylamine
(2mmol). After dissolving in 8 mL of dichloromethane the mix-
ture was stirred at 25 ºC overnight. After this period the starting
material was fully consumed judging by TLC. To quench the
reaction, AcOEt (5 mL) was added and concentrated to vacuo.
Purification was carried out by column chromatography with
EtOAc-Hexanes system to give the desired product.
1
ane). H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 2.3 Hz, 1H),
7.51 (dd, J = 8.5, 2.3 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 5.32 (s,
1H). 13C{1H} NMR (126 MHz, CDCl3) δ 155.3, 145.7, 139.4,
117.9, 87.9, 82.9.
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
2-bromo-4-iodophenol (35).57 The following compound was
obtained according to the general procedure B, by using 2-Bro-
mophenol as starting material and NH4I. The crude material was
purified by flash column chromatography over silica gel with
the system (4% EtOAc/Hexane) to afford the product 35 (79
mg, 92%) as a white solid. m.p.= 52-54 °C. Rf = 0.14 (8%
Naphthalene-2-yl pivalate.39,67 A 25 mL oven-dried round-bot-
tom flask equipped with a magnetic stirrer bar was charged with
2-naphthol (2 mmol), pivaloyl chloride (2 mmol) and triethyla-
mine (2mmol). After dissolving in 8 mL of dichloromethane the
mixture was stirred at 25 ºC overnight. After this period the
starting material was fully consumed judging by TLC. To
quench the reaction, AcOEt (5 mL) was added and concentrated
to vacuo. Purification was carried out by column chromatog-
raphy with EtOAc-Hexanes system to give the desired product.
1
EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.76 (d, J =1.5
Hz, 1H), 7.51 (dd, J = 8.4, 2.3 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H),
5.52 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 152.5, 139.7,
138.7, 118.3, 111.6, 82.6.
2,5-diiodophenol (36). The following compound was obtained
according to the general procedure B, by using 3-iodophenol as
starting material and NH4I. The crude material was purified by
flash column chromatography over silica gel with the system
(2% EtOAc/Hexane) to afford the product 36 (73 mg, 92%) as
a white solid. m.p.= 68-70 °C. Rf = 0.14 (5% EtOAc/Hexane).
IR (neat) ν/cm−1= 3390, 3023, 1580, 1450, 1429. 1H NMR (500
MHz, CDCl3) δ 7.34 (dd, J = 4.8, 3.4 Hz, 2H), 7.00 (dd, J = 8.3,
1.3 Hz, 1H), 5.29 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
155.0, 139.2, 131.0, 124.5, 94.4, 85.3. HRMS (ESI-): m/z
calculated for C6H4I2O [M-H]- =345.8352, found 345.8350.
1-iodo-2-methoxynaphthalene (38).21 The following compound
was obtained according to a modified general procedure A, by
using 2-methoxynaphthalene as starting material and NH4I (re-
action was in reflux overnight). The crude material was purified
by flash column chromatography over silica gel with the system
(3% EtOAc/Hexane) to afford the product 38 (52 mg, 57%) as
a white solid. m.p.= 86-88 °C. Rf = 0.5 (5% EtOAc/Hexane). 1H
NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.6 Hz, 1H), 7.83 (d, J
= 8.9 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H),
7.38 (t, J = 7.4 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 4.03 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 156.6, 135.6, 131.2, 130.7,
129.9, 128.9, 128.2, 124.6, 112.9, 87.7, 57.4.
6-chloro-3,4-difluoro-2-iodophenol (37). The following com-
pound was obtained according to the general procedure B, by
using 6-chloro-3,4-difluorophenol as starting material and
NH4I. The crude material was purified by flash column chroma-
tography over silica gel with the system (3% EtOAc/Hexane) to
afford the product 37 (92 mg, 98%) as a white solid. m.p.= 80-
82 °C. Rf = 0.5 (5% EtOAc/Hexane). IR (neat) ν/cm−1= 3385,
3080, 1590, 1486, 1427. 1H NMR (500 MHz, CDCl3) δ 7.41 (t,
J = 8.5 Hz, 1H), 5.86 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3)
δ 151.6 (d, J = 14.5 Hz), 149.8 – 149.1 (m), 144.1 (dd, J = 249.2,
15.8 Hz), 120.1 (d, J = 21.0 Hz), 101.8 (dd, J = 7.7, 4.2 Hz),
73.3 (d, J = 25.7 Hz). HRMS (EI): m/z calculated for
C6H2ClF2IO [M]+= 289.8807, found 289.8803.
2-(benzyloxy)-1-iodonaphthalene (39).58 The following com-
pound was obtained according to a modified general procedure
A, by using 2-(benzyloxy)naphthalene as starting material and
NH4I (reaction was in reflux overnight). The crude material was
purified by flash column chromatography over silica gel with
the system (3% EtOAc/Hexane) to afford the product 39 (30
mg, 38%) as a white solid. m.p.= 84-86 °C. Rf = 0.5 (5%
EtOAc/Hexane). 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.6
Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.56
(t, J = 10.2 Hz, 3H), 7.40 (q, J = 7.5 Hz, 3H), 7.33 (t, J = 7.3
Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 5.32 (s, 2H). 13C{1H} NMR
(126 MHz, CDCl3) δ 155.8, 136.6, 135.7, 131.6, 130.3, 130.1,
128.6, 128.9, 128.9, 127.9, 127.4, 124.6, 114.7, 89.5, 71.9.
Examples in Scheme 4. The starting materials for the examples
38-4139,67 were synthesized according to the previously de-
scribed procedures.
4-iodo-1,2-dimethoxybenzene (42).54 The following compound
was obtained according to a modified general procedure A, by
using 1,2-dimethoxybenzene as starting material and NH4I
(reaction was in reflux overnight). The crude material was
purified by flash column chromatography over silica gel with
the system (2% EtOAc/Hexane) to afford the product 42 (71mg,
2-methoxynaphthalene.39,67 A 25 mL oven-dried round-bottom
flask equipped with a magnetic stirrer bar was charged with 2-
naphthol (2 mmol), dimethyl sulfate (2 mmol) and 3 mL of a
solution (2 M) of Na2CO3. After dissolving in 8 mL of acetoni-
trile the mixture was stirred at 25 ºC overnight. After this period
the starting material was fully consumed judging by TLC. To
quench the reaction, AcOEt (5 mL) was added and concentrated
to vacuo. Purification was carried out by column chromatog-
raphy with EtOAc-Hexanes system to give the desired product.
1
37%) as a yellow liquid. Rf = 0.5 (5% EtOAc/Hexane). H
NMR (500 MHz, CDCl3) δ 7.37 (dd, J = 11.1, 4.6 Hz, 1H),
7.09 (s, 1H), 6.77 (d, J = 9.8, 4.9 Hz, 1H), 4.01 (s, 3H), 4.00
(s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 149.8, 149.2,
129.7, 120.8, 113.8, 111.3, 82.3, 55.9, 55.8.
2-benzyloxynaphthalene.39,67 A 25 mL oven-dried round-bot-
tom flask equipped with a magnetic stirrer bar was charged with
2-naphthol (2 mmol), benzyl bromide (2 mmol) and 3 mL of a
2-iodo-4,5-dimethoxybenzaldehyde (43).33 The following com-
pound was obtained according to a modified general procedure
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A, by using 4,5-dimethoxybenzaldehyde as starting material NMR (126 MHz, CDCl3) δ 139.6, 138.9, 134.2, 129.9, 126.7,
1
2
3
4
5
6
7
8
and NH4I (reaction was in reflux overnight). The crude material
was purified by flash column chromatography over silica gel
with the system (5% EtOAc/Hexane) to afford the product 43
(36 mg, 20%) as a white solid. Rf = 0.5 (10% EtOAc/Hexane).
1H NMR (500 MHz, CDCl3) δ 9.82 (s, 1H), 7.37 (s, 1H), 7.21
(s, 2H), 3.91 (s, 3H), 3.87 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 194.9, 154.5, 149.9, 128.4, 121.8, 111.2, 92.7, 56.9,
56.8.
126.7, 122.5, 120.6, 120.1, 112.7, 110.8, 82.3.
cyclohexa-3,5-diene-1,2-diimine (49).62 The following com-
pound was obtained according to the general procedure A, by
using o-phenylendiamine as starting material and NH4I. The
crude material was purified by flash column chromatography
over silica gel with the system (4% EtOAc/Hexane) to afford
the product 49 (56 mg, 38%) as a white solid. m.p.= 64-66°C.
Rf = 0.4 (6% EtOAc/Hexane). IR (neat) ν/cm−1 = 3400, 3045,
1600, 1495, 1450, 1265. 1H NMR (400 MHz, CDCl3) δ 7.33 –
7.29 (m, 1H), 5.74 – 5.70 (m, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 142.6, 114.6, 106.2. HRMS (ESI+): m/z calculated
for C6H7N2 [M+H]+= 107.0609, found 107.0602.
Methyl 2-iodo-4,5-dimethoxybenzoate (44).59 The following
compound was obtained according to a modified general proce-
dure A, by using methyl 3,4-dimethoxybenzoate as starting ma-
terial and NH4I (reaction was in reflux overnight). The crude
material was purified by flash column chromatography over sil-
ica gel with the system (3% EtOAc/Hexane) to afford the prod-
uct 44 (59 mg, 36%) as a white solid. Rf = 0.5 (5% EtOAc/Hex-
ane). 1H NMR (500 MHz, CDCl3) δ 7.44 (s, 1H), 7.39 (s, 1H),
3.91 (s, 6H), 3.90 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
166.5, 152.7, 148.8, 126.9, 123.8, 113.9, 84.8, 56.4, 56.8, 52.4.
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
Examples in Scheme 5.
5-bromo-[1,1'-biphenyl]-2-ol (50).39 The following compound
was obtained according to the general procedure A, by using
[1,1'-biphenyl]-2-ol as starting material and NH4Br. The crude
material was purified by flash column chromatography over sil-
ica gel with the system (5% EtOAc/Hexane) to afford the prod-
uct 50 (63 mg, 86%) as a yellow oil. Rf = 0.12 (8% EtOAc/Hex-
5-iodobenzo[d][1,3]dioxole (45).54 The following compound
was obtained according to a modified general procedure A, by
using benzo[d][1,3]dioxole as starting material and NH4I (reac-
tion was in reflux overnight). The crude material was purified
by flash column chromatography over silica gel with the system
(3% EtOAc/Hexane) to afford the product 45 (58 mg, 28%) as
1
ane). H NMR (500 MHz, CDCl3) δ 7.50 (t, J = 8.0 Hz, 2H),
7.43 (d, J = 8.1 Hz, 3H), 7.37-7.34 (m, 2H), 6.88 (d, J = 8.4 Hz,
1H), 5.22 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 151.7,
135.8, 132.7, 131.9, 130.2, 129.6, 129.0, 128.5, 117.7, 112.9.
1
1-chloronaphthalen-2-ol (51).38 The following compound was
obtained according to the general procedure A, by using 2-
napthol as starting material and NH4Cl. The crude material was
purified by flash column chromatography over silica gel with
the system (5% EtOAc/Hexane) to afford the product 51 (49
mg, 80%) as a white solid. Rf = 0.2 (10% EtOAc/Hexane). 1H
NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.6 Hz, 1H), 7.81 (d, J
= 8.1 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.59 (t, J = 8.8 Hz ,1H),
7.42 (t, J = 7.9 Hz, 1H), 7.27 (s, 1H), 5.90 (s, 1H). 13C{1H}
NMR (126 MHz, CDCl3): δ 149.3, 131.0, 129.4, 128.4, 128.1,
127.5, 124.1, 122.7, 117.2, 113.3.
a liquid. Rf = 0.5 (5% EtOAc/Hexane). H NMR (500 MHz,
CDCl3) δ 7.24 (d, J = 5.3 Hz, 2H), 6.71 (d, J = 8.0 Hz, 1H), 6.07
(s, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 148.8, 147.9,
130.7, 117.9, 110.6, 101.5, 82.5.
2-iododibenzo[b,d]furan (46).72 The following compound was
obtained according to a modified general procedure A, by using
dibenzo[b,d]furanas starting material and NH4I (reaction was in
reflux overnight). The crude material was purified by flash col-
umn chromatography over silica gel with the system (2%
EtOAc/Hexane) to afford the product 46 (58 mg, 16%) as a
white solid in a 1.5:1 mixture with its corresponding 2,8-diio-
dodibenzo[b,d]furane. Rf = 0.15 (4% EtOAc/Hexane). Signals
1-bromonaphthalen-2-ol (52).39 The following compound was
obtained according to the general procedure A, by using 2-
naphthol as starting material and NH4Br. The crude material
was purified by flash column chromatography over silica gel
with the system (5% EtOAc/Hexane) to afford the product 52
(69 g, 94%) as a white solid. Rf = 0.55 (10% EtOAc/Hexane).
1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.5 Hz, 1H), 7.63 (d,
J = 8.1 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 7.6 Hz,
1H), 7.26 (t, J = 7.4 Hz, 1H), 7.14 (s, 1H), 5.83 (s, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 150.6, 132.4, 129.8, 129.4, 128.3,
127.9, 125.4, 124.2, 117.2, 106.2.
1
for monoiodinated derivative. H NMR (500 MHz, CDCl3) δ
8.28 (s, 1H), 7.74 (t, J = 12.0, 8.6, 1.8 Hz, 2H), 7.57 (d, J = 8.3
Hz, 1H), 7.51 – 7.46 (m, 1H), 7.36 (dt, J = 8.6, 3.0 Hz, 2H).
13C{1H} NMR (126 MHz, CDCl3) δ 156.3, 155.6, 136.4, 135.6,
129.8, 129.6, 127.9, 123.1, 120.8, 113.8, 113.7, 111.8, 85.7.
3-iodo-1H-indole (47).60 The following compound was ob-
tained according to a modified general procedure A, by using
1H-indole as starting material and NH4I (iodosylbenzene and
ammonium iodide were used in 1 equiv each). The crude mate-
rial was purified by flash column chromatography over silica
gel with the system (2% EtOAc/Hexane) to afford the product
47 (99.5 mg, 96%) as a white solid. Rf = 0.54 (5% EtOAc/Hex-
1,3-dibromonaphthalen-2-ol (53).39 The following compound
was obtained according to the general procedure A, by using 3-
bromonaphthalen-2-ol as starting material and NH4Br. The
crude material was purified by flash column chromatography
over silica gel with the system (5% EtOAc/Hexane) to afford
the product 53 (65 mg, 95%) as a white solid. Rf = 0.10 (15%
1
ane). H NMR (500 MHz, CDCl3) δ 8.24 (s, 1H), 7.39 (d, J =
7.5 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.22 – 7.10 (m, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 135.6, 129.8, 128.4, 123.2,
121.3, 120.8, 111.7, 57.6.
1
3-iodo-9H-carbazole (48).61 The following compound was
obtained according to a modified general procedure A, by using
9H-carbazole as starting material and NH4I (reaction was in
reflux overnight). The crude material was purified by flash
column chromatography over silica gel with the system (3%
EtOAc/Hexane) to afford the product 48 (58 mg, 47%) as a
EtOAc/Hexane). H NMR (500 MHz) δ 8.04 (d, J = 7.2 Hz,
2H), 7.70 (s, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 8.1 Hz,
1H), 6.21 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 147.3,
131.9, 131.6, 129.9, 128.3, 127.4, 125.9, 125.2, 110.8. 106.5.
6-bromo-1-chloronaphthalen-2-ol (54).38 The following com-
pound was obtained according to the general procedure A, by
using 6-bromonaphthalen-2-ol as starting material and NH4Cl.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (10% EtOAc/Hexane) to
afford the product 54 (65 mg, 90%) as a white solid. Rf = 0.2
1
liquid. Rf = 0.5 (5% EtOAc/Hexane). H NMR (500 MHz,
CDCl3) δ 8.39 (d, J = 1.5 Hz, 1H), 8.08 (s, 1H), 8.02 (d, J = 7.8
Hz, 1H), 7.66 (dd, J = 8.5, 1.7 Hz, 1H), 7.47 – 7.41 (m, 2H),
7.26 – 7.24 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H). 13C{1H}
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(15% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ 7.81 (d,
J = 9.9 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 7.4 Hz,
1H), 5.84 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.7,
130.9, 130.5, 130.2, 129.7, 127.6, 124.7, 118.5, 118.1, 113.6.
127.6, 126.4, 126.5, 126.9, 126.6, 125.9, 125.2, 117.7, 106.9.
HRMS (EI): m/z calculated for C20H13BrO [M]+=348.0150,
found 348.0145.
1
2
3
4
5
6
7
8
1-chloro-6-(p-tolyl)naphthalen-2-ol (60). The following com-
pound was obtained according to the general procedure A, by
using 6-(p-tolyl)naphthalen-2-ol as starting material and
NH4Cl. The crude material was purified by flash column chro-
matography over silica gel with the system (10% EtOAc/Hex-
ane) to afford the product 60 (52 mg, 90%) as a white solid.
m.p.=146-148 °C Rf = 0.22 (15% EtOAc/Hexane). IR (neat)
ν/cm−1= 3398, 3032, 1600, 1498, 1429. 1H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J = 8.7
Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.51 (t, J = 13.2 Hz, 2H), 7.21
(dd, J = 14.3, 5.6 Hz, 3H), 5.82 (s, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 149.9, 137.6, 137.8, 136.9, 130.1, 129.9, 129.7,
128.6, 127.9, 127.1, 125.7, 123.6, 117.6, 113.3, 21.6. HRMS
(EI): m/z calculated for C17H13ClO [M]+= 268.0655, found
268.0649.
1,6-dibromonaphthalen-2-ol (55).39 The following compound
was obtained according to the general procedure A, by using 6-
bromonaphthalen-2-ol as starting material and NH4Br. The
crude material was purified by flash column chromatography
over silica gel with the system (5% EtOAc/Hexane) to afford
the product 55 (63 mg, 92%) as a white solid. Rf = 0.49 (10%
9
1
EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ 7.85 (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
7.81 (d, J = 9.0 Hz, 1H), 7.58-7.51 (m, 2H), 7.19 (d, J = 8.7 Hz,
1H), 5.85 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 151.0,
131.8, 131.1, 130.7, 130.2, 128.5, 127.3, 118.4, 118.1, 106.2.
1-chloro-7-methoxynaphthalen-2-ol (56).38 The following com-
pound was obtained according to the general procedure A, by
using 1-chloro-7-methoxynaphthalen-2-ol as starting material.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (10% EtOAc/Hexane) to
afford the product 56 (55 mg, 92%) as a white solid. Rf = 0.55
(15% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3) δ 7.67 (d,
J = 8.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.33 (s, 1H), 7.11 (d,
J = 8.7 Hz, 1H), 7.05 (d, J = 8.9 Hz, 1H), 5.90 (s, 1H), 3.97 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.4, 150.0, 132.6,
130.0, 128.2, 124.8, 116.7, 114.6, 112.6, 101.7, 55.5.
1-bromo-6-(p-tolyl) naphthalen-2-ol (61). The following com-
pound was obtained according to the general procedure A, by
using 6-(p-tolyl) naphthalen-2-ol as starting material and
NH4Br. The crude material was purified by flash column chro-
matography over silica gel with the system (8% EtOAc/Hex-
ane) to afford the product 61 (62 mg, 92%) as a white solid.
m.p.=150-152 °C Rf = 0.46 (15% EtOAc/Hexane). IR (neat)
ν/cm−1= 3400, 3043, 1603, 1490, 1450, 1260. 1H NMR (400
MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 1H), 7.88 (s, 1H), 7.79 –
7.68 (m, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 14.5, 5.9
Hz, 4H), 5.84 (s, 1H), 2.35 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 150.8, 137.7, 137.4, 137.7, 131.5, 130.5, 129.8, 129.8,
127.6, 127.4, 126.3, 125.8, 117.8, 106.8, 21.8. HRMS (EI): m/z
calculated for C17H13BrO [M]+= 312.0150, found 312.0148.
1-Bromo-7-methoxynaphthalen-2-ol (57).39 The following
compound was obtained according to the general procedure A,
by using 7-methoxynaphthalen-2-ol as starting material and
NH4Br. The crude material was purified by flash column chro-
matography over silica gel with the system (8% EtOAc/Hex-
ane) to afford the product 57 (66 mg, 96%) as a white solid. Rf
1
= 0.55 (15% EtOAc/Hexane). H NMR (500 MHz, CDCl3) δ
1-bromo-6-(4-methoxyphenyl) naphthalen-2-ol (62).65 The fol-
lowing compound was obtained according to the general proce-
dure A, by using 6-(4-methoxyphenyl) naphthalen-2-ol as start-
ing material and NH4Br. The crude material was purified by
flash column chromatography over silica gel with the system
(10 % EtOAc/Hexane) to afford the product 62 (62 mg, 94%)
as a white solid. m.p.=156-158 °C Rf = 0.28 (15% EtOAc/Hex-
7.60 (dd, J = 9.2 Hz, 2H), 7.26 (d, J = 2.5 Hz, 1H), 7.06 (d, J =
8.7 Hz, 1H), 6.98 (dd, J = 8.9, 2.5 Hz, 1H), 5.89 (s, 1H), 3.91
(s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 159.6, 150.9,
133.8, 129.9, 129.1, 124.9, 116.4, 114.5, 105.3, 104.4, 55.4.
1-bromo-6-phenylnaphthalen-2-ol (58).63 The following com-
pound was obtained according to the general procedure A, by
using 2-naphthol as starting material and NH4Br. The crude ma-
terial was purified by flash column chromatography over silica
gel with the system (5% EtOAc/Hexane) to afford the product
58 (73 mg, 93%) as a white solid. m.p.=138-140 °C Rf = 0.12
(10% EtOAc/Hexane). IR (neat) ν/cm−1= 3390, 3026, 1598,
1485, 1415. 1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.7 Hz,
1H), 7.99 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.7, 1.8 Hz, 1H),
7.80 (d, J = 8.8 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.49 (t, J = 7.7
Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 5.93
(s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 150.8, 140.9,
137.1, 131.5, 129.9, 129.9, 128.9, 127.5, 127.3, 127.7, 126.5,
125.9, 117.6, 106.3. HRMS (EI): m/z calculated for C16H11BrO
[M]+ = 297.9993, found 297.9988.
1
ane). IR (neat) ν/cm−1= 3400, 3033, 1590, 1495, 1429. H NMR
(500 MHz, CDCl3) δ 7.99 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 1.6
Hz, 1H), 7.75 – 7.68 (m, 2H), 7.59 – 7.53 (m, 2H), 7.19 (d, J =
3.6 Hz, 1H), 6.97 – 6.91 (m, 2H), 5.83 (s, 1H), 3.80 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 159.3, 150.5, 136.6, 132.9,
131.8, 130.5, 129.4, 128.8, 127.9, 125.8, 125.3, 117.5, 114.4,
106.4, 55.9. HRMS (EI): m/z calculated for C17H13BrO2 [M]+=
328.0099, found 328.0091.
1-bromo-6-(4-fluorophenyl) naphthalen-2-ol (63). The follow-
ing compound was obtained according to the general procedure
A, by using 6-(4-fluorophenyl) naphthalen-2-ol and NH4Br.
The crude material was purified by flash column chromatog-
raphy over silica gel with the system (10% EtOAc/Hexane) to
afford the product 63 (61 mg, 92%) as a white solid. m.p.=124-
126°C Rf = 0.45 (15% EtOAc/Hexane). IR (neat) ν/cm−1= 3400,
3045, 2225, 1600, 1485, 1450. 1H NMR (400 MHz, CDCl3) δ
8.09 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H), 7.85 – 7.70 (m, 2H), 7.68
– 7.62 (m, 2H), 7.29 (d, J = 8.8 Hz, 1H), 7.17 (t, J = 8.7 Hz,
2H), 5.95 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.6 (d,
J = 246.7 Hz), 150.7, 136.8, 136.0, 131.4, 129.9, 129.54, 128.8
(d, J = 8.1 Hz), 127.7, 126.07, 125.9, 117.7, 115.8 (d, J = 21.5
Hz), 106.3. HRMS (EI): m/z calculated for C16H10BrFO [M]+=
315.9899, found 315.9895.
5-bromo-[2,2'-binaphthalen]-6-ol (59). The following com-
pound was obtained according to the general procedure A, by
using 5-bromo-[2,2'-binaphthalen]-6-ol as starting material and
NH4Br. The crude material was purified by flash column chro-
matography over silica gel with the system (10% EtOAc/Hex-
ane) to afford the product 59 (69 mg, 94%) as a white solid.
m.p.=144-146 °C Rf = 0.55 (15% EtOAc/Hexane) IR (neat)
1
ν/cm−1= 3386, 1717, 1600, 1450, 1258. H NMR (400 MHz,
CDCl3) δ 8.15 (s, 1H), 8.12 (d, J = 5.7 Hz, 1H), 7.90 (ddd, J =
28.0, 19.6, 9.1 Hz, 5H), 7.57 – 7.48 (m, 2H), 7.31 (d, J = 8.8
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 150.7, 137.7,
136.8, 133.7, 132.8, 131.6, 130.2, 129.6, 128.6, 128.2, 127.7,
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1-bromo-6-(3-chloro-4-fluorophenyl)naphthalen-2-ol
(64).
The following compound was obtained according to the general
procedure A, by using 6-(3-chloro-4-fluorophenyl)naphthalen-
2-ol as starting material and NH4Br. The crude material was pu-
rified by flash column chromatography over silica gel with the
system (10% EtOAc/Hexane) to afford the product 64 (61 mg,
90%) as a white solid. m.p.=136-138 °C Rf = 0.45 (15%
EtOAc/Hexane). IR (neat) ν/cm−1= 3395, 3060, 1660, 1540,
1427. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.87 (s, 1H),
7.80 – 7.63 (m, 3H), 7.49 (s, 1H), 7.22 (d, J = 13.2 Hz, 2H),
5.92 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 157.9 (d, J =
254 HZ), 151.1, 137.9, 134.8, 131.9, 130.0, 129.7, 129.5, 127.1,
127.0, 126.4, 126.2, 121.6 (d, J = 60 Hz), 118.1, 117.1 (d, J =
85 Hz), 106.2. HRMS (ESI+): m/z calculated for C16H10BrClFO
[M+H]+= 350.9588, found 350.9580.
match perfectly with the previous obtained compound. Then,
without purification this grey solid was submitted to the second
halogenation reaction using the general procedure A and NH4I
1
2
3
4
5
6
7
8
to yield the compound 2 (89 mg, 78%) after column chroma-
1
tography as a withe solid. The H and 13C of this compound
match perfectly with the previously obtained.
Sequences followed in scheme 6.
6-bromo-1-phenylnaphthalen-2-ol (66).66 The following sub-
strate was prepared by Suzuki-Miyaura cross-coupling reac-
tions between 6-bromo-1-iodonaphthalen-2-ol and phenyl-
boronic acid. A 50 mL round bottom flask with a stir bar was
fitted with a rubber septum and flame dried under high vacuum.
The flask was purged with argon and charged with Pd(PPh3)4
(173.1 mg, 0.1 mmol), K2CO3 (445.2 mg, 4.2 mmol), 6-bromo-
1-iodonaphthalen-2-ol (667.9 mg, 2.0 mmol), phenylboronic
acid (4.0 mmol), 10.0 mL 1,4-dioxene, and 2 mL distiled water.
The reaction mixture was then heated at 80 °C for 12 h. After-
wards the reaction was cooled down to room temperature, the
organic layer was separated, and the aqueous layer was ex-
tracted with ethyl acetate (3 × 10 mL), and the combined or-
ganic layer was dried over Na2SO4 and concentrated. The crude
products were purified by flash chromatography on silica gel
(5% EtOAc/Hexane) to afford the product 6-Bromo-1-phe-
nylnaphthalen-2-ol (420.1 mg, 86%) as a white solid. m.p.= 96-
98°C. Rf = 0.2 (10% EtOAc/Hexane). IR (neat) ν/cm−1= 3386,
3034, 1720, 1600, 1450, 1260. 1H NMR (500 MHz, CDCl3) δ
8.09 (d, J = 8.7 Hz, 1H), 7.94 (s, 1H), 7.83 – 7.75 (m, 2H), 7.62
(d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 8.8
Hz, 1H), 5.95 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ
150.8, 138.9, 135.7, 133.8, 131.6, 129.8, 129.9, 129.8, 128.8,
127.8, 126.5, 125.9, 117.8, 106.4. HRMS (EI): m/z calculated
for C16H11BrO [M]+= 297.9993, found 297.9985.
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
1-bromo-6-(3,4-difluorophenyl) naphthalen-2-ol (65). The fol-
lowing compound was obtained according to the general proce-
dure A, by using 6-(3,4-difluorophenyl) naphthalen-2-ol and
NH4Br. The crude material was purified by flash column chro-
matography over silica gel with the system (10% EtOAc/Hex-
ane) to afford the product 67 (88 mg, 90%) as a white solid.
m.p.=124-126 °C. Rf = 0.14 (20% EtOAc/Hexane). IR (neat)
1
ν/cm−1= 3395, 3032, 1600, 1496, 1427. H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.9
Hz, 1H), 7.66 (dd, J = 8.8, 1.6 Hz, 1H), 7.42 (ddd, J = 11.3, 7.6,
2.1 Hz, 1H), 7.35 – 7.30 (m, 1H), 7.25 – 7.17 (m, 2H), 5.91 (d,
J = 4.6 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.5 (dd,
J=256 Hz), 151.0, 149.1 (dd, J = 256 Hz), 137.6 (dd, J = 24 Hz),
134.9, 131.7, 129.8, 129.6, 126.9, 126.3, 126.1, 123.1 (dd, J =
24 Hz), 117.9, 117.7 (d, J = 68 Hz), 116.1 (d, J = 68 Hz), 106.0.
HRMS (EI): m/z calculated for C16H9BrF2O [M]+= 333.9805,
found 333.9801.
One-pot dihalogenations.
1-phenyl-6-(p-tolyl)naphthalen-2-ol (67). The following sub-
strate were prepared by Suzuki-Miyaura cross-coupling reac-
tions between 6-bromo-1-phenylnaphthalen-2-ol (66) obtained
in the previous reaction and p-tolylboronic acid. A 50 mL round
bottom flask with a stir bar was fitted with a rubber septum and
flame dried under high vacuum. The flask was purged with ar-
gon and charged with Pd(PPh3)4 (106.24 mg, 0.1 mmol), K2CO3
(445.2 mg, 4.2 mmol), 6-bromo-1-phenylnaphthalen-2-ol (66)
(410 mg, 2.0 mmol), p-tolylboronic acid (4.0 mmol), 10.0 mL
1,4-dioxene, and 2 mL distiled water. The reaction mixture was
then heated at 80 °C for 12 h. After the reaction was cooled
down to room temperature, the organic layer was separated, and
the aqueous layer was extracted with ethyl acetate (3 × 10 mL),
and the combined organic layer was dried over Na2SO4 and con-
centrated. The crude products were purified by flash chroma-
tography on silica gel (10% EtOAc/Hexane) to afford the prod-
uct 1-phenyl-6-(p-tolyl)naphthalen-2-ol (67) (349 mg, 82%) as
a yellowish solid. m.p.=138-140°C. Rf = 0.2 (10% EtOAc/Hex-
ane). m.p. = 92-94 °C. Rf = 0.2 (15% EtOAc/Hexane). IR (neat)
one-pot synthesis of 54. This compound was synthesized by two
consecutive halogenations (chlorination-bromination) which
were carried out in the same flask with only single purification
after the second reaction. Starting from 2-naphthol and NH4Cl
the general procedure A was used to obtain 1-chloro-2-naphthol
51 (58 mg) as a dark solid. The 1H and 13C{1H} of this deriva-
tive match perfectly with the previous obtained compound.
Then, without purification this dark solid was submitted to the
second halogenation reaction using the general procedure A and
NH4Br to yield the compound 56 (71 mg, 84%) after column
1
chromatography as a withe solid. The H and 13C{1H} of this
compound match perfectly with the previously obtained.
one-pot synthesis of 55. This compound was synthesized by two
consecutive halogenations (bromination-bromination) which
were carried out in the same flask with only single purification
after the second reaction. Starting from 2-naphthol and NH4Br
the general procedure A was used to obtain 1-bromo-2-naphthol
52 (72 mg) as a dark-yellow solid. The 1H and 13C{1H} of this
derivative match perfectly with the previous obtained com-
pound. Then, without purification this dark-yellow solid was
submitted to the second halogenation reaction using the general
procedure A and NH4Br to yield the compound 57 (89 mg, 91%)
1
ν/cm−1= 3400, 3040, 2222, 1600, 1482, 1454. H NMR (500
MHz, CDCl3) δ 8.03 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.63 (dd,
J = 14.4, 6.8 Hz, 5H), 7.56 (t, J = 7.4 Hz, 1H), 7.49 (d, J = 6.2
Hz, 3H), 7.31 (dd, J = 13.6, 7.0 Hz, 3H), 5.20 (s, 1H), 2.44 (s,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 150.8, 138.4, 136.9,
136.5, 134.3, 132.2, 131.8, 129.7, 129.7, 129.7, 129.2, 128.6,
127.6, 126.1, 125.6, 125.4, 120.9, 117.8, 21.2. HRMS (EI): m/z
calculated for C23H18O [M]+ = 310.1358, found 310.1355.
after column chromatography as a withe solid. The 1H and 13
of this compound match perfectly with the previously obtained.
C
one-pot synthesis of 2. This compound was synthesized by two
consecutive halogenations (iodination-bromination) which
were carried out in the same flask with only single purification
in after the second reaction. Starting from 2-naphthol and NH4I
the general procedure A was used to obtain 1-iodo-2-naphthol
1 (88 mg) as a grey solid. The 1H and13C{1H} of this derivative
6-bromo-1-iodo-2-methoxynaphthalene (68).50 To a solution of
2 (0.434 mg, 1.25 mmol) in acetone (5 mL) was added K2CO3
(0.345 mg, 10.0 mmol), dimethyl sulfate (0.2 mL, 10.0 mmol).
The solution was heated to reflux for 4 h at which time TLC
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The Journal of Organic Chemistry
CDCl3) δ 159.4, 158.6, 156.6 (d, J = 1.1 Hz), 138.2 (d, J = 5.1
indicated complete consumption of the naphthol. The reaction
1
2
3
4
5
6
7
8
mixture was cooled to room temperature Et3N (5.0 mL) was
added and the reaction was stirred for 1 h. The layers were sep-
arated, and the aqueous layer was extracted with DCM (3 × 10
mL). The combined organic layers were dried over Na2SO4 and
concentrated under reduced pressure to give crude material,
which was purified by flash column chromatography over silica
gel with the system (5% EtOAc/Hexane) to afford the product
6-bromo-1-iodo-2-methoxynaphthalene 68 (0.413 mg, 94%) as
a yellowish solid. Rf = 0.15 (8% EtOAc/Hexane). 1H NMR (500
MHz, CDCl3) δ 8.02 (d, J = 9.1 Hz, 1H), 7.91 (s, 1H), 7.73 (d,
J = 8.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 9.0 Hz,
1H), 4.02 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 156.9,
134.3, 133.2, 131.8, 130.6, 129.9, 129.4, 118.2, 113.7, 87.7,
57.2.
Hz), 134.9, 133.9, 131.9, 130.4, 129.3, 128.6, 128.3 (d, J = 11.6
Hz), 126.8 (d, J = 6.9 Hz), 126.5 – 125.9 (m), 123.6, 121.46,
121.3 (d, J = 1.3 Hz), 117.02, 116.85, 113.4, 106.3, 99.1, 83.6,
56.7. HRMS (EI): m/z calculated for C25H16ClFO [M]+=
386.0874, found 386.0866.
Computational Details.
The enthalpy and Gibbs free energy calculations for the adduct
PhII(OH)·NH3 were computed as the energy difference between
the adduct and the sum of the energies of the optimized PhiIO
and the NH4I at the gas phase employing the Gaussian 16 soft-
ware package.
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
Fukui function calculations for PhII(OH)·NH3. The reactivity
of the iodinating species was analyzed by exploring a very use-
ful covalent reactivity descriptor: the Fukui or frontier function,
which is usually a reliable predictor of the regioselectivity of
soft molecules.44-46 Fukui functions are defined as the response
of the electron density when the number of electrons (N) suffers
an infinitesimal change, providing us information about the re-
active sites of a molecular system.47 Particularly to indicate how
the electron density is redistributed when molecules react, thus,
molecular regions suffering more charge rearrangements are the
most reactive sites. The Fukui functions are obtained calculat-
ing the electron density of the PhII(OH)·NH3 with N, N-1 and
N+1 electrons respectively at the ground state. The positive
(ꢀꢁ(ꢂ)) and negative (ꢀꢃ(ꢂ)) forms of the Fukui functions are
useful descriptors to evaluate nucleophilic or electrophilic at-
tacks respectively.48
6-bromo-2-methoxy-1-(phenylethynyl)naphthalene (69). A 50
mL round bottom flask with a stir bar was fitted with a rubber
septum was flame dried under high vacuum. The flask was
purged with nitrogen and sequentially charged with 6-bromo-1-
iodo-2-methoxynaphthalene (68) (361.8 mg, 1.00 mmol) added
Et3N (2 mL), phenylacetylene (1.1 mmol), PdCl2(PPh3)2 (0.1
mmol) and CuI (0.25 mmol). The mixture was stirred at 60 ℃
for 6 h until fully consumption of 68 by judging on TLC devel-
opment. Then the mixture was filtered through a pad of CeliteÒ.
The solvent was removed under reduced pressure to afford the
crude material which was purified by flash column chromatog-
raphy over silica gel with the system (2% EtOAc/Hexane) giv-
ing rise to the product 6-bromo-2-methoxy-1-(phenylethynyl)-
naphthalene (69) (0.296 mg, 88%) as a yellow liquid. Rf = 0.44
(5% EtOAc/Hexane). IR (neat) ν/cm−1= 3400, 3360,3033, 1590,
The transition state search for the PhII(OH)·NH3 adduct was
obtained by using the DL-FIND library73 implemented in Tera-
chem 1.9.374,75 employing the nudged elastic band method.
1
1495, 1460. H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 8.9 Hz,
1H), 7.93 (s, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 6.8 Hz,
2H), 7.60 (d, J = 8.9 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.27 (d, J =
9.4 Hz, 1H), 4.04 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
159.1, 133.9, 131.9, 130.6, 130.0, 129.9, 129.1, 128.9, 128.7,
127.2, 123.7, 117.9, 113.7, 106.8, 99.4, 83.5, 56.7. HRMS
(ESI+): m/z calculated for C19H13BrO [M+H]+= 337.0228,
found 337.0237.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
6-(3-chloro-4-fluorophenyl)-2-methoxy-1-(phenylethynyl)nap-
hthalene (70). The following substrate was prepared by Suzuki-
Miyaura cross-coupling reactions between 6-bromo-2-
methoxy-1-(phenylethynyl)naphthalene (69) obtained in the
previous reaction and (3-choloro-4-fluorophenyl)boronic acid.
A 50 mL round bottom flask with a stir bar was fitted with a
rubber septum and flame dried under high vacuum. The flask
was purged with argon and charged with Pd(PPh3)4 (0.1 mmol),
1
Copies of H and 13C NMR spectra of compounds 1-70
as well as computational details related to the energetic
profile formation, MEP and general details regarding
PhII(OH)·NH3.
AUTHOR INFORMATION
K2CO3
(4.2
mmol),
6-bromo-2-methoxy-1-
(phenylethynyl)naphthalene (69) (56 mg, 2.0 mmol), (3-
choloro-4-fluorophenyl)boronic acid (4 mmol), 1,4-
dioxene(10.0 mL), and distilled water (2 mL). The reaction
mixture was then heated at 80 °C for 12 h. Afterwards the
reaction was cooled down to room temperature, the organic
layer was separated, and the aqueous layer was extracted with
ethyl acetate (3 × 10 mL), and the combined organic layer was
dried over Na2SO4 and concentrated. The crude products were
purified by flash chromatography on silica gel (5%
EtOAc/Hexane) to afford the product 6-(3-chloro-4-
fluorophenyl)-2-methoxy-1-(phenylethynyl)naphthalene (70)
(45 mg, 68%) as a white solid. m.p.= 96-98 °C. Rf = 0.55 (8 %
EtOAc/Hexane). IR (neat) ν/cm−1=3460, 3320,2933, 1560,
1510, 1440. 1H NMR (500 MHz, CDCl3) δ 8.41 (d, J = 8.7 Hz,
1H), 7.93 (s, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.74 (s, 1H), 7.73 (t,
J = 2.4 Hz, 1H), 7.69 (dt, J = 3.4, 1.9 Hz, 2H), 7.56 (t, J = 8.5,
4.5, 2.3 Hz, 1H), 7.43 – 7.35 (m, 3H), 7.33 (d, J = 9.1 Hz, 1H),
7.24 (d, J = 8.7 Hz, 1H), 4.09 (s, 3H). 13C{1H} NMR (126 MHz,
Corresponding Author
* E-mail: csolorio@ugto.mx
ORCID
Yuvraj Satkar: 0000-0002-7545-6884
Luisa F. Yera Ledesma: 0000-0002-1992-2828
Narendra Mali: 0000-0003-4976-7600
Dipak Bathu: 0000-0003-2010-5822
Pedro Navarro-Santos: 0000-0001-8370-1651
Luis A. Segura Quezada: 0000-0003-2179-9678
Perla I. Ramírez-Morales: 0000-0001-7096-9683
César R. Solorio-Alvarado: 0000-0001-6082-988X
Notes
The authors declare no competing financial interest.
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(17) Das, B.; Krishnaiah, M.; Venkateswarlu, K.; Reddy, V. S. A
ACKNOWLEDGMENT
mild and simple regioselective iodination of activated aromat-
ics with iodine and catalytic ceric ammonium nitrate. Tetrahe-
dron Lett, 2007, 48, 81-83.
1
2
3
4
This work was supported by CONACyT (CB-2013/220836). We
acknowledge the facilities of the DCNyE, the Chemistry Depart-
ment, and the National Laboratory UG-CONACyT (LACAPFEM)
at the University of Guanajuato, for full characterization. We thank
CONACyT for PhD fellowships to Y.S., N.M. and D.B. We also
thank M.C. Kevin Juárez for preliminary optimization assays.
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Dedicated to Professor Keiji Maruoka in occasion of his
66th birthday.
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