One-Pot Synthesis and Conformational Analysis of Six-Membered Cyclic Iodonium Salts

Article abstract of DOI:10.1021/acs.joc.0c01125

Two one-pot procedures for the construction of carbon-bridged diaryliodonium triflates and tetrafluoroborates are described. Strong Br?nsted acids enable the effective Friedel-Crafts alkylation with diversely substituted o-iodobenzyl alcohol derivatives, providing diphenylmethane scaffolds, which are subsequently oxidized and cyclized to the corresponding dibenzo[b,e]iodininium salts. Based on NMR investigations and density functional theory (DFT) calculations, we could verify the so-far-undescribed existence of two stable isomers in cyclic iodonium salts substituted with aliphatic side chains in the carbon bridge.

Full text of DOI:10.1021/acs.joc.0c01125

Subscriber access provided by Uppsala universitetsbibliotek
Article
One-Pot Synthesis and Conformational
Analysis of 6-Membered Cyclic Iodonium Salts
Lucien Caspers, Julian Spils, Mattis Damrath, Enno Lork, and Boris Johannes Nachtsheim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01125 • Publication Date (Web): 16 Jun 2020
Downloaded from pubs.acs.org on June 18, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
One-Pot Synthesis and Conformational Analysis of 6-
Membered Cyclic Iodonium Salts
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
a
a
b
Lucien D. Caspers , Julian Spils , Mattis Damrath , Enno Lork and Boris
J. Nachtsheima*
aAddress: Institute for Organic and Analytical Chemistry, University of Bremen,
Leobener Straße 7, 28359 Bremen, Germany, phone: +49 421 218-63113
bAddress: Institute for Inorganic Chemistry and Crystallography, University of Bremen,
28359 Bremen, Germany, phone: +49 421 218-63155
Prof. Dr. Boris J. Nachtsheim, nachtsheim@uni-bremen.de
Two steps in one pot!
R2
R2
Friedel-Crafts
Alkylation
R3
+
R1
R3
OR
R1
Oxidation
I+
I
X
up to 93 % yield
Conformational
Isomerism
Abstract
Two one-pot procedures for the construction of carbon-bridged diaryliodonium triflates
and tetrafluoroborates are described. Strong Brønsted acids enable the effective
Friedel-Crafts alkylation with diversely substituted o-iodobenzylalcohol derivatives,
providing diphenylmethane scaffolds which are subsequently oxidized and cyclized to
the corresponding dibenzo[b,e]iodininium salts. Based on NMR-investigations and
DFT-calculations we could verify a so far undescribed existence of two stable isomers
in cyclic iodonium salts substituted with aliphatic side chains in the carbon bridge.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Keywords
hypervalent iodine • iodonium salts • one-pot synthesis • Friedel-crafts synthesis •
I-heterocycles
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Introduction
The last decades have witnessed extensive developments in the chemistry of
1
2
hypervalent iodine compounds (HVIs). Even in the delicate field of total synthesis or
3
4
in organo- and photocatalysis, HVIs have found widespread applications. An
3
important subclass of HVIs are diaryl- -iodanes or diaryliodonium salts (DIS, 1, Figure
5
6
1
). Bearing iodobenzene as potent leaving group (hypernucleofug) they have
n
become frequently utilized reagents in a plethora of C(sp )-H and Het-H arylation
7
reactions. Despite their outstanding performance as electrophilic group transfer
reagents in transition metal-mediated and metal-free arylations their time-consuming
8
3
multi-step synthesis often impedes their application. Albeit various  -iodane
mediated reactions have been performed in a catalytic manner and diverse atom-
economic conversions have been described for different types of (recyclable) HVIs,
most DIS are utilized generating equimolar amounts of waste.
X-
Y
Ar/
Het
I+
R
R'
R
I+
X-
Ar/
Het
R'
1
2
(Y = Het, O, NR'', S(O) , Se)
n
-
3 (Y = 2e ), 4 (Y = CR )
2
X = Hal, BF4, OTf, OTs etc.
Figure 1: Schematic presentation of DIS 1 (left) and CDIS 2 – 4 (right).
A subclass of DIS are cyclic diaryliodonium salts (CDIS) where the aryl moieties are
9
directly connected or bridged with carbon- or heteroatoms (2 – 4, Figure 1). While
comprising a comparable reactivity towards carbon and heteroatom nucleophiles as
their acyclic counterparts, CDIS are promising candidates for the effective synthesis of
doubly functionalized diaryl-based systems. The aryl-moieties are chemically bound
and are, after an initial ring-opening reaction, readily available for a second inter- or
intramolecular coupling event. Various transformations have been described with
2
ACS Paragon Plus Environment

Page 3 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
these iodacycles providing numerous highly functionalized biaryls and polycyclic
(hetero)arenes (Scheme 1). Here, tricyclic dibenzo[b,d]iodol-5-ium salts 3 were widely
applied. They have been utilized in enantioselective ring opening reactions to give o,o’-
10
difunctionalized biaryls (Scheme 1, a) and in effective double functionalizations for
the efficient synthesis of carbazoles, fluorenes, dibenzothio- and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dibenzoselenophenes (b),11,12,13 giving a fast access to a wide range of
pharmacophores and functional materials. 6-Membered dibenzo[b,e]iodininium salts 4
were commonly utilized as well. Effective ring-opening reactions with high
14
12
enantioselectivities (c), and the synthesis of (oxidized) thioxanthenes (d), acridines
13
15
(
e) and xanthen(on)es (f) have been described, emphasizing their wide range of
applications.
O
O
R1
R2
Y
I
R1
R2
f
N
a
1
R R2
e
3
R R4
R1
n
R2
I+
X-
b
d
3
4
R R
3
4
(n = 0)
(n = 1)
R2
R1
R1
R2
c
Y
S
O
Y = NR3, S, Se,
2
Y
I
H R
CR etc.
2
Scheme 1: Synthetic applications of cyclic diaryliodonium salts.
Compared to their acyclic counterparts, CDIS are much less frequently utilized in
organic synthesis apart from their specialized need as substrates for the synthesis of
heteroatom- or carbon-bridged o,o’-disubstituted biaryl systems. One reason for this
issue may be the availability of efficient protocols for their synthesis. The synthesis of
iodolium salts 3 and their precursors is commonly achieved via cross-coupling
reactions of o-haloanilines followed by a Sandmeyer-type iodination (Scheme 2, A).13
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The preparation of homologues iodininium salts 4 is less standardized: A selective
mono-metalation of o-diiodobenzenes and 1,2-addition to aromatic aldehydes with a
subsequent dehydroxylation enables the synthesis of various diphenylmethanes
13
(
Scheme 2, B1). Different p-toluidine derivatives have been o-alkylated in order to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
obtain diversely aminated 2,2-diphenylpropanes which were transformed into
precursors for CDIS via Sandmeyer iodination (B2).12 Unsubstituted
diphenylmethanes can be modified with electron-withdrawing groups, thus enabling a
selective electrophilic iodination at the methylene o-position (B3).16
A) Common pathway for the synthesis of o-iodobiphenyls
Cross
Sandmeyer
I
Coupling
NH2
NH2
I
B) Conventional syntesis of dibenzo[b,e]iodinium precursors
Metalation
then
OH
I
I
Reduction
(1)
1,2-Addition
I
I
Friedel-
Crafts
Sandmeyer
Ph
Ph
(
2)
3)
NH2 alkylation
NH2
I
1) Nitration
(
2) Iodination
O N
2
I
NO2
C) Our approach: One-pot Friedel-Crafts/oxidation sequence
R2
R2
1) Friedel-Crafts
Alkylation
R3
+
R1
R3
OH
R1
2) [O], HX
I+
X-
I
7
8
(X = TfO)
(X = BF4)
5
6
Commercially available
starting materials
Iodonium salts obtained
in one-pot
Scheme 2: Common pathways for the precursor synthesis of cyclic diaryliodonium salts.
4
ACS Paragon Plus Environment

Page 5 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
All these routes need at least two independent steps to obtain the o-iodinated diphenyl-
compounds which then need to be further oxidized to the desired CDIS 3 or 4. Herein,
we describe the effective synthesis of dibenzo[b,e]iodininium salts 4 in a one-step
Friedel-Crafts/oxidation sequence to give iodininium triflates and tetrafluoroborates 7
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and 8 (Scheme 2, C).17
Results and Discussion
For the initial Friedel-Crafts alkylation with o-iodobenzyl alcohols 5 different procedures
in dipolar aprotic solvents were known under Brønsted or Lewis-acidic conditions.18
We decided to utilize a strong but weakly coordinating Brønsted acid that promotes the
coupling step to the diphenylmethane 9 (Table 1) and the concluding oxidation to the
final dibenzo[b,e]iodininium salt 4 to serve as the activator in both steps and as the
final counter anion in the CDIS. In preliminary optimizations with
trifluoromethanesulfonic acid (TfOH) and mCPBA as oxidant (see SI, Table S1) the
desired one-pot reaction was effectively performed. However, the utilization of mCPBA
gave undesired side products that complicated the work-up of the reaction. Therefore,
®
we decided to conduct a second optimization with Oxone as oxidant, that enabled an
easier, extraction-based work-up procedure.
From literature and our preliminary test reactions we recognized that for a successful
®
oxidation of iodoarenes with Oxone , combinations of TfOH and H SO are best in
2
4
terms of reactions times and yields (SI, Table 2) and therefore focused on this
19
combination. We started our investigation with o-iodobenzyl alcohol 5a (R = H, Table
1) as the model substrate. Coupling with TfOH and 3 eq. of benzene (6a) in DCM and
®
subsequent oxidation with Oxone and H SO after addition of MeCN yielded the
2
4
desired iodonium salt 7a in 36% (entry 1). While the yield was still moderate, the
product could be easily purified by extraction and washing. Utilizing 5 eq. of 6a
enhanced the yield to 77% (entry 2) while the use of 10 eq. improved the product purity
due to a lowered side product profile in the coupling step (entry 3). A dropwise addition
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of 5a to the acidic solution led to a more selective generation of 9a and could increase
the yield to 89% (entry 4). Performing the first step in a 1:1 mixture of benzene and
DCM did not show any significant improvement (entry 5). Further experiments
revealed, that MeCN was necessary in the second step to ensure a clean conversion
of the intermediate (entry 6) while the generation of 9a could not be achieved in pure
MeCN (entry 7). Addition of low amounts of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)
in the second reaction step slightly improved the reaction time (entry 8).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
When we then started to investigate our substrate scope, we observed a significant
drop in yield with brominated o-iodobenzylic alcohol 5b (entry 9). Addition of HFIP in
the second step could increase the oxidation rate and product 7b was obtained in 85%
(
entry 10). With NO -substituted alcohol 5c addition of HFIP was not sufficient to
2
completely convert the intermediate 9c (entry 11). Possibly due to diminished stability
of the oxidant under these strongly acidic conditions, the addition of further Oxone®
and H SO after an initial oxidation period was necessary which finally increased the
2
4
yield of 7c to 84% (entry 12).
®
Table 1: Optimization of the One-Pot Procedure with Oxone as Oxidant.
benzene 6a
Oxone® R
H2SO4
R
R
OH
TfOH
I+
solvent A
solvent B
0 °C - rt
time
TfO-
I
I
0
°C
5a-c
9a-c
7a-c
time
Entry[a]
R
Benzene
(eq.)
Solvent Solvent
Yield of 7[b]
t1 / t
2
A
B
[min] / [h]
5 / 1.5
5 / 1.5
5 / 1.5
5 / 2
[%]
1
2
H (5a)
3
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
DCM
DCM
MeCN
MeCN
MeCN
MeCN
MeCN
DCM
36
77
H
5
3
H
10
10
28
10
10
10
10
71[c]
89
4[d]
5[d]
6[d]
7[d]
8[d]
9
H
H
5 / 2
90
H
H
5 / 24
< 10
0
MeCN
MeCN[e]
MeCN
360 / ---
5 / 1
H
89
Br (5b)
120 / 16
57
6
ACS Paragon Plus Environment

Page 7 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
0
Br
10
DCM
DCM
DCM
MeCN[e] 120 / 16
85
40 – 50
84
11
NO (5c)
10
MeCN[e] 300 / 16
2
1
2[f]
NO2
10
MeCN[e] 300 / 40
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
a] Reaction conditions: Step 1: 5a (0.2 mmol), benzene, TfOH (5 eq.), solvent A (1 mL), 5 min,
®
0
0
°C; Step 2: solvent B (1 mL), H SO (5 eq.), Oxone (1 eq.), tightly closed screw cap vial,
2
4
°C – rt. [b] Purity > 97% [c] Fluctuation in yield comes from washing process. 10 eq. of arene
were kept as purity improved from > 95% to > 98%. [d] Dropwise addition of 5a to 6a in DCM
®
and TfOH. [e] HFIP (0.2 mL) was added. [f] Addition of Oxone (1 eq.) and H SO (5 eq.) after
2
4
1
6 h of step 2.
With optimized conditions for different benzylic alcohols 5 in hand, we started to further
investigate the scope and scalability of the reaction (Scheme 3). Performing the
reaction on a 5 mmol scale, gave 7a in slightly improved yield of 93%. We then
investigated other leaving groups than Y = OH. When utilizing o-iodobenzyl acetate
1
0, 7a was obtained in 87% yield, whereas with methyl ether 11 or ethyl carbonate 12
iodonium salt 7a was isolated in 79% and 89% yield. With chloride 13 a complex miture
was obtained during the oxidation step which drastically reduced the isolated yield of
7
a to less than 10%.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R2
R2
1) TfOH (5 eq.)
DCM, 0 °C, 0.1 - 5 h
R3
R1
R3
+
Y
R1
2
) Oxone® (1 eq.), H SO (5 eq.)
I+
2
4
MeCN, 0 °C - rt, 2 - 40 h
-OTf
I
6
7
5, 10 - 13
7b: Y = OH, R = Br, 85%I[
b]
Y = OH
Y = OH
89%I
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
93%[ R1
a]
[c]
7
7
c: Y = OH, R = NO2, 84% [
87%
79%
b]
c]
Y = OAc (10)
Y = OMe (11)
Y = OCOOEt (12)
Y = Cl (13)
d: Y = OH, R = F,
74%
I+
I+
7e: Y = OH, R = CF3, 69% [
-OTf
[b]
[c]
8
9%
-OTf
7f: Y = OH, R = Cl,
g: Y = OH, R = CN,
58%
46%
< 10%
7
7a
Cl
I+
Br
I+
I+
-OTf
-OTf
Br
-OTf
Cl
[b]
7
h: Y = OH, 81% [b]
7i: Y = OH, 55% [b]
7j: Y = OH, 45%
R
Me
F
Cl
I+
I+
I+
-
-OTf
OTf
Me
-OTf
7m: Y = OH, 59%
7
k:Y = OH, R = H, 79% [d]
[
e]
7n: Y = OH, 93%
7
l: Y = OH, R = 3,5-(CF ), 73%
3
Scheme 3: Substrate scope using the optimized conditions of Table 1: Step 1: 5 (0.2 mmol),
(10 eq.), TfOH (5 eq.), DCM (1 mL), 5 min, 0 °C; Step 2: MeCN (1 mL), H SO (5 eq.),
6
2
4
®
Oxone (1 eq.), tightly closed screw cap vial, 0 °C – rt. [a] Reaction was performed on a
.0 mmol scale. [b] HFIP (0.2 mL) was used in step 2. [c] 0.2 mL HFIP were used in step 2.
5
®
After 16 h additional Oxone (1 eq.) and H SO (5 eq.) were added. [d] Compound identity was
2
4
confirmed by X-ray crystallography. For details see SI chapter 5. [e] Only 5 eq. of 6 were used.
As already discussed in Table 1, 5-Br and 5-NO derivatives were viable as well,
2
although under slightly different reaction conditions. Under these conditions F- and
CF -substituted derivatives 7d and 7e could be obtained in up to 74%. Cl-substitution
3
led to a diminished yield of 58% for 7f. CN-substituted iodonium salt 7g was generated
in 46%, albeit the rate for both reaction steps was significantly reduced. A variation of
the substitution pattern was viable as 4- and 3-Br-substituted derivatives 7h and 7i
were isolated in 81% and 55% respectively, indicating that steric effects may be
relevant during the oxidation step. Thus, the lowered yield for the (Cl) -substituted salt
2
7
j (45%) in comparison to 7f might be due to electronic or steric effects. The utilization
of secondary aliphatic benzyl alcohols was difficult due to significant styrene formation
during the Friedel-Crafts step (see SI, Figure S1) while secondary diphenylmethanols
8
ACS Paragon Plus Environment

Page 9 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
were suitable. Here, the Ph-substituted salt 7k could be obtained in 79% yield. Even
substrates with electron withdrawing substituents such as bis-(CF )- and Cl,F-
3
disubstituted diphenylmethanols were viable for a selective cyclization and yielded 7l
and racemic 7m in up to 73% yield.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction of 5a with p-xylene successfully lead to the formation of 7n in 93% yield.
However, arenes with an unsymmetrical substitution pattern or more electron donating
groups were problematic due to inseparable isomer formation and decomposition
during the oxidation step. The coupling with electron deficient arenes 6 was not
possible without high excesses of the arene or selectivity problems. Substrates that
could not successfully be synthesized are found in the SI (Figure S1). Due to the high
-
-
acidity of triflic acid a full exchange of the triflate to different anions (BF , TsO etc.)
4
was not possible during the one-pot procedure without severe purifications problems
or uneconomical amounts of salt solutions.
While the selectivities in Friedel-Crafts alkylations and the decomposition of electron
rich substrates were intrinsic problems of our methodology, we tried to reoptimize our
one-pot procedure to enable the transformation of secondary, aliphatic benzyl
alcohols. In preexaminations we found, that 1-(2-iodophenyl)ethan-1-ol (5n, Table 2)
reacts in DCM with toluene in excellent para-selectivity under mild conditions (0 °C)
with 1 eq. of HBF ·OEt . When adding more acid after the addition of mCPBA as
4
2
oxidant, the desired alkyl substituted iodonium salt 8a could be obtained in 67% (Table
, entry 1). TLC-MS and GC-MS investigations indicated the formation of side products
2
during the oxidation step. Thus, a reduction of oxidant lead to a significant increase in
yield (83%, entry 2). However, the reaction mixtures still contained a significant amount
of dark-coloured impurities which made an unwanted filtration necessary during the
work-up. Hence, we tried to modify our oxidation conditions by addition of MeCN. First,
this resulted in a reduced yield (entry 3), but the addition of more HBF during the
4
oxidation step enabled at least a moderate yield of 70% (entry 4). Reducing the amount
of oxidant was also not successful (entry 5 and SI, Table S5). We then revaluated the
acid stoichiometry and recognized that addition of 3 eq. HBF at the beginning of the
4
reaction was beneficial for its total outcome, yielding 81% of 8a (entry 6). We now were
satisfied with the reaction performance and stopped our optimization at this point to
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
investigate a preliminary substrate scope. Here we decided to use DCM as sole solvent
due to its higher efficiency in terms of applied amount of HBF4.
Table 2: Re-optimization with 1-(2-iodophenyl)ethan-1-ol (5n) for the synthesis of iodonium
salt 8a.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
toluene
HBF4
mCPBA
HBF4
OH
I+
I
DCM
0 °C, 5 min
DCM
0 °C - rt
I
BF4-
5n
8
a
Entry[a] PhMe
(eq.)
HBF (eq.)
1 / 2 step
mCPBA
(eq.)
Solvent
2 step
Yield of 8a[b]
4
st
nd
nd
[%]
1
2
3
4
5
6
5
5
5
5
5
5
1 / 2
4
2
DCM
DCM
67
83
53
70
58
81
1 / 2
1 / 2
2[c]
2
MeCN
MeCN
MeCN
MeCN
1 / 5
1 / 5
1
3 / 2
2
[
a] Standard conditions: 5n (0.2 mmol) in DCM (1 mL ) with toluene (5 eq.). Addition of
HBF ·OEt at 0 °C, stirring till completion, addition of DCM (1 mL), mCPBA, stirring for 10 min,
4
2
addition of HBF ·OEt , stirring till completion at rt. [b] Purity > 97%. [c] mCPBA (2 eq.) was
4
2
nd
added, as the intermediate was not completely converted in the 2 step.
When the reaction of 5n was performed with toluene on a 5 mmol scale under the
optimized conditions, pure 8a was obtained in 35% (Scheme 4). When exchanging the
Me-substituent to Et- or iPr-moieties the corresponding products 8b and 8c were
isolated in yields of up to 59%. The reduced yields may be attributed to a more
stabilized, sterically demanding benzylic cation and a higher lability to oxidants due to
the increased electron density at the benzylic position. While diphenylmethanols are
well tolerated under the previously optimized conditions, the Ph-derivative 8d could
only be obtained in 37%. A reduction of the electron density of the secondary alcohol 5
was detrimental for the reaction outcome and substrate 8e was obtained in only 20%.
Due to the increased steric demand of secondary benzyl cations, the coupling with
o-xylene was moderately selective and yielded 56% of 8f. The same effect was
10
ACS Paragon Plus Environment

Page 11 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
disadvantageous for the reaction with p-xylene giving 8g in 20%. With benzene as
coupling partner the Friedel-Crafts step could not be performed. Also, with tertiary
alcohols no product was obtained due to major side reactions during the first reaction
step (see SI, Figure 1). However, despite the intrinsic limitations of our protocols they
offer a faster alternative to the available syntheses of a broad range of
dibenzo[d,e]iodininium salts.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R2
R2
R2
mCPBA
arene 6
4
HBF ·OEt2
HBF ·OEt
4
2
R1
R3
OH
R1
R3
R1
I+
DCM
°C, 5 min.
DCM, 0 °C - rt
I
BF4-
I
0
5
8
Et
I+
iPr
I+
I+
BF4-
BF4-
BF4-
8a: 83%
8b: 59%
8c: 44%
[
a]
35%
Ph
Br
I+
I+
+
I+
I
BF4-
BF4-
BF4-
BF4-
8e: 20%
8f: 56%
8g: 20%
8d: 37%
Scheme 4: Substrate scope for the optimized conditions of Table 2: Step 1: 5 (0.2 mmol), 6
(5 eq.), HBF ·OEt (1 eq.), DCM (1 mL), 5 min, 0 °C; Step 2: DCM (1 mL), HBF ·OEt (2 eq.),
4
2
4
2
mCPBA (2 eq.), tightly closed screw cap vial, 0 °C – rt. [a] Reaction was performed on a
.0 mmol scale.
5
1
During our method development we observed that the H-NMR-spectra of the newly
obtained iodonium salts showed interesting exchange effects (Figure 2). Compounds
8a and 8b showed an unusual signal broadening, of the benzylic proton and all other
protons in the benzylic aliphatic side chain. In contrast, the corresponding protons of
the iPr-group in 8c and the benzylic proton of 8d showed well-resolved signals. As
these effects were also visible in the corresponding 13C-spectra (see SI, Chapter 6)
14
and some previously published literature spectra, we were interested in the origin of
these observations. At this point two causes were taken into account: First, a
coordination or even deprotonation of the benzylic protons by the counter-anion of the
iodonium salt or traces of water in the NMR-solvent were considered. But the spectra
in Figure 2 showed no significant effect on the peak shape or chemical shift of the
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
aromatic methyl groups at 2.4 ppm (green area) and a computational study of
Hoffmann et al. suggested that a potential zwitterionic iodabenzene structure was very
20
unlikely for our structures under the examined conditions. Therefore, conformational
changes of our substrates were more likely to be the reason for the observed signal
broadening and we investigated potential conformers via DFT calculations.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Figure 2: 600 MHz H-NMR-spectra of compounds 8a-d. The signals of the benzylic- () as
well as alkyl-protons () are broadened in compounds 8a and 8b.
As the aromatic Me-groups were unlikely to have a severe effect on conformational
changes at the benzylic position, we performed our calculations on the simplified
tetrafluoroborates 8a’-d’ (Figure 3). When optimizing the structure of the Me-derivative
8a’ at RI-PBE0-D3BJ/SVP level of theory, we were able to minimize two
conformational isomers 8a’ and 8a’ in which the central 6-membered iodininium-
ax
eq
ring adopts a boat-like structure with the methyl group in an either axial or equatorial
position. When revaluating the energies of the conformers at CPCM(DMSO)/RI-DSD-
BLYP/TZVPP level of theory we found that 8a’ was only 0.6 kcal/mol lower in energy
ax
than the equatorial conformer 8a’ . This corresponds to an equilibrium constant of
eq
K ≈ 3 that would provide a significant amount of both conformers at room temperature.
12
ACS Paragon Plus Environment

Page 13 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
While the availability of a reasonable amount of > 1% of both species is a prerequisite
for the occurrence of dynamic effects in NMR-spectra (besides a significant chemical
shift difference for the observed protons Hax and Heq in both conformers) we were
furthermore interested in an approximate activation energy for the process.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
H R
20
20.8
18
16
14
12
10
I+
BF4-
8a'-TS
8
8
8
8
a' R = Me
b' R = Et
c' R = iPr
d' R = Ph
15.4
2.6
1
sharp
NMR
10.4
signals
8
6
4
2
8
a'-eq
8a'-ax
4
.1 (K = 1300)
broadened
NMR
3.8 (K = 660)
1
0
.8 (K = 20)
.6 (K = 3)
signals
0
kcal
ax
eq
Figure 3: Relative energies in kcal/mol for conformational isomers of dibenzo[b,e]iodininium
tetrafluoroborates 8a’-d’ (R = Me, Et, iPr, Ph). Energies were calculated on CPCM(DMSO)/RI-
DSD-BLYP/TZVPP//RI-PBE0-D3BJ/SVP level of theory. The corresponding structures for the
-
methyl derivative are shown, the BF anions were omitted for clarity. For the coordinates of all
4
optimized structures see SI.
An optimization and energy evaluation for a transition state 8a’TS implied a free
ǂ
activation energy G of 12.6 kcal/mol that is reasonable for the observed dynamic
process at room temperature. As we could not concludingly account either the free
ǂ
activation energy G or the free energy difference ∆G between the axial and equatorial
conformers for the availability of sharp NMR signals, we conducted similar calculations
with Et-, iPr- and Ph-substituted compounds 8b’-8d’. Since the calculated free
activation energy Gǂ of each compound was in a range between 10.4 and
20.8 kcal/mol, exchange processes should be reasonably fast. Our calculated free
energy values ∆G for the conformers are in good agreement with observed signal
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
broadenings in the spectra as the ethyl derivative 8b’ gives with a ∆G of ≈ 1.8 kcal/mol
rise to an equilibrium constant of K ≈ 20. Calculations for 8c’ and 8d’ result in values
of K ≈ 660 and K ≈ 1300. Thus, the most reasonable explanation for the observed
signal broadening was the availability or absence of both equilibrium conformers 8ax
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
and 8 . Interestingly, a transition state for a potential Bu-substituted derivative could
eq
not be found which may indicate a non-interconvertibility of both isomers.
1
Figure 4: Top: Temperature dependant 360 MHz H-NMR-spectra of 10-methyl-10H-dibenzo-
[
b,e]iodinin-5-ium trifluoromethanesulfonate 14 in MeOH-d (for synthesis see SI). Bottom:
4
Axial and equatorial conformer of the cation of 14 as optimized on RI-PBE0-D3BJ/SVP level
of theory.
To back up the results of our DFT calculations we synthesized the triflate 14 as it was
better soluble than the corresponding tetrafluoroborate and performed temperature
14
ACS Paragon Plus Environment

Page 15 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
dependant 360 MHz- H-NMR measurements in a range between -80 and +55 °C
(Figure 4). At elevated temperatures the benzylic proton and the methyl groups gave
a well separated single quartet at 4.31 ppm and a single doublet at 1.81 ppm. Both
signals showed coalescence at T ≈ 0 °C and became very distinct at -60 °C showing
two quartets in a 1:2.8 ratio at 4.78 and 3.94 ppm and two corresponding doublets at
2.02 and 1.54 ppm. The ratio changed to 1:3.6 at -80 °C what most likely originates
from a different solubility of the conformers at low temperatures.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The observed conformer ratios and the previously calculated equilibrium constant of
K ≈ 3 are in good agreement. An approximate determination of the free activation
ǂ
energy from the measured spectra resulted in a ∆G value of ≈ 12.5 kcal/mol, which is
in first approximation in excellent agreement with the calculated value for 8a’. However,
at this point we cannot clearly allocate the measured signals to their corresponding
conformers. All attempts to assign the structures via low temperature
NOE-measurements or to synthetically fix the conformation of the iodonium salt did not
give resilient results and are still under current investigation.
Summary
In summary, we developed two one-pot procedures for the synthesis of 6-membered
cyclic iodonium triflates and tetrafluoroborates. With a Friedel-Crafts alkylation
followed by an oxidative cyclization, primary o-iodobenzyl alcohols and secondary
o’-iododiphenylmethanols were successfully transformed into a variety of tricyclic
dibenzo[b,e]iodininium triflates in moderate to excellent yields. Delicate aliphatic 1-(2-
iodophenyl) alcohols could be utilized as starting materials using a modified procedure
with HBF as the Brønsted acid. Depending on the substitution of the bridging carbon
4
1
atom, we observed significant signal broadenings in the corresponding H-NMR and
13C-NMR spectra and verified via DFT-calculations and temperature-dependent NMR-
measurements that a fast and so far undescribed conformational switch between two
stable isomers bearing the aliphatic side chain either in an axial or equatorial position
are the rational for this behaviour.
Experimental Section
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General Experimental Information
Unless otherwise noted, all reactions were carried out under air. Reactions with
chemicals sensitive to moisture or oxygen were carried out under a nitrogen
atmosphere using standard Schlenk techniques. All chemicals were purchased from
commercial suppliers and either used as received or purified according to “Purification
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
21
of Laboratory Chemicals”. Anhydrous tetrahydrofuran (THF) was obtained from an
Inert PS-MD-6 solvent purification system. All other solvents were dried using standard
21
methods if necessary. Reactions that required heating were performed in an oil bath
and regulated with a thermostat.
Yields refer to isolated yields of compounds estimated to be > 95 % pure as determined
1
by H-NMR spectroscopy.
Thin layer chromatography was performed on fluorescence indicator marked
precoated silica gel 60 plates (Macherey-Nagel, ALUGRAM Xtra SIL G/UV254) and
visualized by UV light (254 nm/366 nm). Flash column chromatography was performed
on silica gel (0.040 – 0.063 mm) with the solvents given in the procedures.
NMR spectra were recorded on a Bruker Avance DPX-200, a Bruker Avance 360WB
spectrometer, a Bruker Avance Neo 600 MHz spectrometer with BBO probe head and
a Bruker Avance Neo 600 MHz spectrometer with TXI probe head at 23 °C. Chemical
1
shifts for H-NMR spectra are reported as δ (parts per million) relative to the residual
proton signal of CDCl at 7.26 ppm (s), DMSO-d at 2.50 ppm (quint) or MeOH-d at
3
6
4
3
.31 ppm (quint). Chemical shifts for 13C-NMR spectra are reported as δ (parts per
million) relative to the signal of CDCl at 77.0 ppm (t), DMSO-d at 39.5 ppm (sept) or
3
6
19
MeOH-d at 49.0 ppm (sept). Chemical shifts for F-NMR spectra are reported as δ
4
(
parts per million) relative to the signal of Si(CH ) at 0.0 ppm. The following
3 4
abbreviations are used to describe splitting patterns: br. = broad, s = singlet, d =
doublet, t = triplet, q = quartet, quint = quintet, sept = septet, m = multiplet. Coupling
constants J are given in Hz.
L
ESI and APCI mass spectra were recorded on an Advion Expression CMS via ASAP
probe or direct inlet. Low resolution EI mass spectra were recorded on an Agilent
5977A Series GC/MSD system. High resolution (HR) EI mass spectra were recorded
on a double focusing mass spectrometer ThermoQuest MAT 95 XL from Finnigan
16
ACS Paragon Plus Environment

Page 17 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MAT. HR-ESI and HR-APCI mass spectra were recorded on a Bruker Impact II. All
Signals are reported with the quotient from mass to charge m/z.
IR spectra were recorded on a Nicolet Thermo iS10 scientific spectrometer with a
-1
diamond ATR unit. The absorption bands 푣 are reported in cm .
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Melting points of solids were measured on a Büchi M-5600 Melting Point apparatus
and are uncorrected. The measurements were performed with a heating rate of
2
°C/min and the melting point temperatures T are reported in °C.
Intensity data of suitable single crystals were collected on a Bruker Venture D8
diffractometer at 100 K with Mo-K (0.71073 Å) radiation. All structures were solved by
α
direct methods and refined based on F2 by use of the SHELX program package as
implemented in Olex 2.2 All non-hydrogen atoms were refined using anisotropic
displacement parameters. Hydrogen atoms attached to carbon atoms were included
in geometrically calculated positions using a rigid model. Figures were created using
Olex2. Crystallographic data for the structural analyses have been deposited with the
Cambridge Crystallographic Data Centre. Copies of this information may be obtained
free of charge from The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax:
+44-1223-336033;
e-mail:
deposit@ccdc.cam.ac.uk
or
http://www.ccdc.cam.ac.uk/).
Preparation of Starting Materials (Scheme S1)
General Procedure for Sandmeyer-type Iodination of
Anthranilic Acids with pTsOH (GP1a)
22
In modification of a reported procedure, the anthranilic acid derivative (10.0 mmol,
.00 eq.) and TsOH·H O (5.71 g, 30.0 mmol, 3.00 eq.) were suspended in MeCN
1
2
(
80 mL). The mixture was cooled to 10 – 15 °C. A solution of NaNO (1.38 g,
2
20.0 mmol, 2.00 eq.) and KI (4.15 g, 25.0 mmol, 2.50 eq.) in H O (15 mL) was added
2
dropwise over 1 h. After complete addition, the resulting dark coloured mixture stirred
for another 1 h and then 1 N HCl (50 mL) and EtOAc (100 mL) were added. The
phases were separated and the aqueous phases was extracted with EtOAc (2 x
50 mL). The combined organic phases were washed with water (50 mL), Na S O
2
2
3
(
10 % w/w, 50 mL) and brine (20 mL), dried over Na SO and concentrated under
2 4
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reduced pressure. The residue was either purified by filtration over silica or by column
chromatography.
General Procedure for Sandmeyer-type Iodination of
Anthranilic Acids with H SO (GP1b)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
23
In modification of a reported procedure, the anthranilic acid derivative (10.0 mmol,
1
.00 eq.) was suspended in aqueous H SO (15 mL, 1:2 v/v) at 0 °C and MeOH (5 to
2 4
10 mL) was added until complete dissolution of the substrate. Then a solution of
NaNO (759 mg, 11.0 mmol, 1.10 eq.) in H O (2 mL) was added dropwise over 30 min.
2
2
while maintaining a temperature between 0 and 5 °C. After complete addition the
solution was stirred for further 60 min at 0 °C. Then the diazonium salt solution was
added to a solution of KI (8.30 g, 50.0 mmol, 5.00 eq.) in H O (10 mL) at 60 °C over a
2
period of 5 min. and stirred at that temperature for 1 h. Then 1 N HCl (50 mL) and
EtOAc (100 mL) were added. The phases were separated and the aqueous phases
was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed
with water (50 mL), Na S O (10 % w/w, 50 mL) and brine (20 mL), dried over Na SO
4
2
2
3
2
and concentrated under reduced pressure. The residue was either purified by filtration
over silica or by column chromatography.
General Procedure for Borane-mediated Reduction of
Carboxylic Acids (GP2)
In modification of a reported procedure,24 the o-iodobenzoic acid derivative (S1,
1
.00 eq.) was dissolved in dry THF (0.25M). After cooling to 0 °C, NaBH (2.90 eq.)
4
was added portion wise. To the resulting mixture I (0.75 eq.) in THF (0.25M) was
2
slowly added over 1 h. After the addition, the mixture was allowed to warm to rt and
stirred overnight. After completion of the reaction, the mixture was cooled to 0 °C and
water (1 mL/mmol) was carefully added. Afterwards, 3N HCl was slowly added until
the solution was at pH 2 – 3. The resulting mixture was diluted with water (5 mL/mmol)
and extracted with Et O (3 x 20 mL/mmol). The combined organic phases were
2
washed with 1M Na CO (2 x 20 mL/mmol) and brine (20 mL/mmol), dried over
2
3
18
ACS Paragon Plus Environment

Page 19 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Na SO and concentrated under reduced pressure to either give the desired product
2
4
that could be purified (if necessary) by recrystallisation from cyclohexane or via a
filtration column over silica in cyclohexane/ethyl acetate 4:1.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Primary Benzylic Alcohols (5)
The o-iodobenzoic acid derivatives S1a, S1d and S1e were commercially available
and have been used as received for the synthesis of the corresponding alcohols.
(2-Iodophenyl)methanol (5a)
Following GP2, the reaction of o-iodobenzoic acid (S1a, 9.6 g, 200 mmol) with NaBH4
(
21.9 g, 580 mmol) and I (38.1 g, 150 mmol) gave (2-iodophenyl)methanol (5a,
2
1
4
6.8 g, 200 mmol, quant.) as a colourless solid without further purification. H-NMR
(
601 MHz, CDCl ) δ = 7.83 (dd, J = 7.8, 1.2 Hz, 1H), 7.46 (dd, J = 7.6, 1.7 Hz, 1H),
3
7.37 (td, J = 7.5, 1.2 Hz, 1H), 7.00 (td, J = 7.6, 1.8 Hz, 1H), 4.68 (d, J = 6.3 Hz, 2H),
2.00 (t, J = 6.3 Hz, 1H). 13C{ H}-NMR (151 MHz, CDCl3) δ = 142.9, 139.5, 129.6,
1
128.8, 128.7, 97.7, 69.6. FTIR (ATR, neat) 푣 = 3262, 3061, 2887, 2843, 1434, 1321,
+
·.
1
195, 1033, 1009, 738. MS (EI, 70 eV) m/z: 234.0 [M] Mp T = 91. The analytical data
is in accordance with literature data.25
(5-Bromo-2-iodophenyl)methanol (5b)
o-Iodobenzoic acid (4.96 g, 20.0 mmol, 1.00 eq.) and N-bromosuccinmide (4.45 g,
2
5.0 mmol, 1.25 eq.) were suspended in H SO (50 mL) and stirred for 2 h. The
2 4
mixture was poured on ice (150 g). The resulting solid was collected by filtration and
recrystallized from EtOH/H O (1:1, v/v) to obtain 5-bromo-2-iodobenzoic acid (S1b,
2
1
5
.21 g, 15.9 mmol, 80 %) as a colourless solid. H-NMR (360 MHz, CDCl ) δ = 8.15
3
13
1
(
d, J = 2.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.4, 2.4 Hz, 1H). C{ H}-
NMR (91 MHz, CDCl ) δ = 169.9, 143.2, 136.6, 135.0, 134.5, 122.3, 92.8. FTIR (ATR,
3
neat) 푣 = 3079, 1702, 1668, 1459, 1294, 1248, 1096, 1015, 898, 816, 776. HRMS
-
-
-
(
ESI , MeOH) m/z: [M-H] Calcd for C H BrIO : 324.8367; Found: 324.8264. Mp T =
7 3 2
59 – 161. The analytical data is in accordance with literature data.26
1
Following GP2, the reaction of 5-bromo-2-iodobenzoic acid (S1b, 1.63 g, 5.00 mmol)
with NaBH (549 mg, 14.5 mmol) and I (952 mg, 3.75 mmol) gave after filtration over
4
2
silica (cyclohexane/ethyl acetate 7:1) (5-bromo-2-iodophenyl)methanol (5b, 1.53 g,
1
4
.87 mmol, 97 %) as a colourless solid. H-NMR (360 MHz, CDCl ) δ = 7.63 (d, J = 8.3
3
Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.3, 2.0 Hz, 1H), 4.61 (d, J = 6.0 Hz,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
H), 2.23 (t, J = 6.0, 6.0 Hz, 1H). 13C{ H}-NMR (91 MHz, CDCl ) δ = 144.5, 140.3,
3
132.1, 131.1, 123.0, 94.6, 68.6. FTIR (ATR, neat) 푣 = 3206, 3076, 2908, 1435, 1387,
+
·
+
1
190, 1089, 1005, 984, 878, 806. MS (EI, 70 eV) m/z: 311.9 [M] , 233.0 [M-Br] , 185.0
+
27
[
M-I] . Mp T = 107 – 109. The analytical data is in accordance with literature data.
2-Iodo-5-nitrophenyl)methanol (5c) and (2-Iodo-3-nitrophenyl)methanol (5c’)
In modification of a reported procedure,23 nitric acid (7.4 mL, 10.1 g, 160 mmol,
.00 eq.) was slowly added to H SO (22.4 mL, 41.2 g, 420 mmol, 21.0 eq.) while
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
8
2
4
maintaining a temperature between -10 and 0 °C. At this temperature, o-iodobenzoic
acid (4.96 g, 20.0 mmol, 1.00 eq.) was added portionwise. The resulting mixture was
stirred for 15 min, allowed to warm to rt and stirred for another 30 min and then heated
to 135 °C for 1 h. After cooling to rt, the mixture was poured on ice (50 g) and the
resulting solid was collected by filtration. The residue was dissolved in EtOAc (200 mL),
washed with H O (50 mL), Na S O (50 mL, w = 10 %), H O (50 mL), brine (50 mL),
2
2
2
3
2
dried over Na SO and concentrated under reduced pressure to give a 3:1 mixture of
2
4
2
-iodo-5-nitro- (S1c) and 2-iodo-3-nitro-benzoic acid (S1c’, 5.46 g, 18.6 mmol, 93 %)
1
as a yellow solid which was analysed via H-NMR and used without further purification.
1
H-NMR (200 MHz, DMSO-d ) δ = 8.40 (d, J = 2.7 Hz, 1H, A), 8.29 (d, J = 8.6 Hz, 1H,
6
A), 8.00 (dd, J = 8.6, 2.8 Hz, 1H, A), 7.92 (dd, J = 7.8, 1.7 Hz, 1H, B), 7.78 (dd, J = 7.7,
1
.7 Hz, 1H, B), 7.66 (dd, J = 7.7, 7.7 Hz, 1H, B). (3:1 mixture of A and B). The analytical
data is in accordance with literature data.28
Following GP2, the reaction of a 3:1 mixture of 2-iodo-5-nitrobenzoic acid (S1c) and
2
-iodo-3-nitrobenzoic acid (S1c’) (2.49 g, 8.50 mmol) with NaBH (933 mg, 24.7 mmol)
4
and I (1.62 g, 6.38 mmol) gave after separation of the isomers via column
2
chromatography (silica, cyclohexane/ethyl acetate 10:1  4:1) gave (2-iodo-5-
nitrophenyl)methanol (5c, 1.63 g, 5.85 mmol, 67 %) as a colourless solid and (2-iodo-
1
3
-nitrophenyl)methanol (5c’, 475 mg, 1.70 mmol, 20 %) as a yellow solid. 5c: H-NMR
(
200 MHz, DMSO-d ) δ = 8.18 (d, J = 2.7 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.81 (dd, J
6
13
1
= 8.5, 2.8 Hz, 1H), 5.85 (t, J = 5.4 Hz, 1H), 4.45 (d, J = 5.1 Hz, 2H). C{ H}-NMR (50
MHz, CDCl ) δ = 147.8, 146.3, 139.9, 122.7, 121.0, 105.5, 66.8. FTIR (ATR, neat) 푣 =
3
3
202, 3091, 2906, 1601, 1567, 1516, 1335, 1193, 1043, 1014, 907, 806, 736. MS (EI,
+
·
+
+
70 eV) m/z: 279.0 [M] , 232.9 [M-NO ] , 152.0 [M-I] Mp T = 120 – 122 °C. The
2
29
1
analytical data is in accordance with literature data. 5c’: H-NMR (200 MHz, CDCl )
3
δ = 7.72 – 7.64 (m, 1H), 7.55 (dd, J = 8.0, 2.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 4.73 (s,
20
ACS Paragon Plus Environment

Page 21 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1
2
H), 2.59 (s, 1H). C{ H}-NMR (50 MHz, CDCl ) δ = 154.5, 145.9, 130.5, 129.1, 123.4,
3
88.1, 69.7. FTIR (ATR, neat) 푣 =3277, 3075, 2926, 1586, 1523, 1418, 1345, 1048,
+
·
+
+
1
018, 789. MS (EI, 70 eV) m/z: 279.0 [M] , 262.0 [M-OH] , 231.9 [M-HNO ] . Mp T =
2
9
1 – 92 °C. The analytical data is in accordance with literature data.29
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
5-Fluoro-2-iodophenyl)methanol (5d)
Following GP2, the reaction of 5-fluoro-2-iodobenzoic acid (665 mg, 2.50 mmol) with
NaBH (274 mg, 7.25 mmol) and I (476 mg, 1.88 mmol) gave after filtration over silica
4
2
(
cyclohexane/ethyl acetate 4:1) (5-fluoro-2-iodophenyl)methanol (5d, 577 mg,
1
2.19 mmol, 87 %) as a colourless solid. H-NMR (601 MHz, CDCl ) δ = 7.74 (dd, J =
3
8
.6, 3.1 Hz, 1H), 7.25 (dd, J = 9.3, 3.1 Hz, 1H), 6.76 (td, J = 8.3, 3.1 Hz, 1H), 4.63 (d,
13
1
J = 6.1 Hz, 2H), 2.07 (t, J = 6.1 Hz, 1H). C{ H}-NMR (151 MHz, CDCl ) δ = 163.1 (d,
3
J = 247.8 Hz), 145.0 (d, J = 6.9 Hz), 140.1 (d, J = 7.6 Hz), 116.4 (d, J = 22.0 Hz), 115.5
19
(d, J = 23.4 Hz), 89.1 (d, J = 2.7 Hz), 68.8. F-NMR (565 MHz, CDCl ) δ = -113.4.
3
FTIR (ATR, neat) 푣 = 3286, 1578, 1458, 1437, 1356, 1263, 1149, 1058, 1013, 808.
+
·
+·
HRMS (EI, 70 eV) m/z: [M] Calcd for C H FIO : 251.9442; Found: 251.9443. Mp T =
7
6
11.5 – 113. The analytical data is in accordance with literature data.30
1
(2-Iodo-5-(trifluoromethyl)phenyl)methanol (5e)
Following GP2, the reaction of 2-iodo-(5-trifluoromethyl)benzoic acid (790 mg,
2
.50 mmol) with NaBH (274 mg, 7.25 mmol) and I (476 mg, 1.88 mmol) gave after
4
2
filtration
over
silica
(cyclohexane/ethyl
acetate
4:1)
(2-iodo-5-
(
trifluoromethyl)phenyl)methanol (5e, 682 mg, 2.25 mmol, 90 %) as a colourless solid.
1
H-NMR (601 MHz, CDCl ) δ = 7.94 (d, J = 8.2 Hz, 1H), 7.76 – 7.75 (m, 1H), 7.31 –
3
13
1
7
.21 (m, 1H), 4.72 (d, J = 6.0 Hz, 2H), 2.07 (t, J = 6.1 Hz, 1H). C{ H}-NMR (151 MHz,
CDCl ) δ = 143.7, 139.6, 131.0 (q, J = 32.7 Hz), 125.5 (q, J = 3.5 Hz), 124.5 (q, J =
3
19
3
.5 Hz), 122.1 (q, J = 272.8 Hz), 100.8, 68.8. F-NMR (565 MHz, CDCl ) δ = -62.9.
3
FTIR (ATR, neat) 푣 = 3289, 1600, 1465, 1324, 1256, 1175, 1118, 1044, 1009, 897,
+·
+·
8
29, 743. HRMS (EI, 70 eV) m/z: [M] Calcd for C H F IO : 301.9410; Found:
8 6 3
301.9411. Mp T = 80.5 – 81.5. The analytical data is in accordance with literature
data.31
(
5-Chloro-2-iodophenyl)methanol (5f)
Following GP1a, the reaction of 2-amino-5-chlorobenzoic acid (1.72 g) gave 5-chloro-
2
-iodobenzoic acid (S1f, 2.22 g, 7.87 mmol, 79 %) as a colourless solid which still
1
contained some impurities (≈ 5 %) but was used without further purification. H-NMR
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
600 MHz, DMSO-d ) δ = 13.61 (brs, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 2.6 Hz,
6
1H), 7.32 (dd, J = 8.4, 2.6 Hz, 1H). 13C{ H}-NMR (151 MHz, DMSO-d ) δ = 167.0,
1
6
1
42.1, 138.9, 133.2, 132.2, 129.5, 92.1. FTIR (ATR, neat) 푣 = 1694, 1673, 1574, 1400,
-
-
1
290, 1246, 1117, 1017, 780, 749. HRMS (ESI , MeOH) m/z: [M-H] . Calcd for
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-
C H ClIO : 280.8872; Found: 280.8869. Mp T = 154 – 157. The analytical data is in
7
3
2
accordance with literature data.32
Following GP2, the reaction of 5-chloro-2-iodobenzoic acid (S1f, 1.41 g, 5.00 mmol)
with NaBH (549 mg, 14.5 mmol) and I (952 mg, 3.75 mmol) gave after column
4
2
chromatography
(silica,
cyclohexane/ethyl
acetate
10:1)
(5-chloro-2-
1
iodophenyl)methanol (5f, 1.08 g, 4.01 mmol, 80 %) as a colourless solid. H-NMR (601
MHz, CDCl ) δ = 7.71 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 6.99 (dd, J = 8.3,
3
.6 Hz, 1H), 4.63 (s, 2H), 2.10 (s, 1H). 13C{ H}-NMR (151 MHz, CDCl ) δ = 144.3,
1
2
3
140.0, 135.0, 129.2, 128.2, 93.6, 68.7. FTIR (ATR, neat) 푣 = 3289, 3212, 1452, 1436,
+
·
1
391, 1193, 1101, 1055, 1007, 974, 808. MS (EI, 70 eV) m/z: 268.0 [M] , 233.9 [M-
+
+
Cl] , 141.0 [M-I] Mp T = 118 – 119.5. The analytical data is in accordance with
literature data.27
3-(Hydroxymethyl)-4-iodobenzonitrile (5g)
In modification of a reported procedure,23 2-Amino-5-bromobenzoic acid (5.40 g,
2
5.0 mmol, 1 eq.) was dissolved in MeOH (100 mL). After addition of H SO (6.00 mL,
2 4
5.00 mmol, 0.2 eq., 98 % v/v) the mixture was heated under reflux for 16 h. The mixture
was concentrated under reduced pressure and sat. Na CO (50 mL) and EtOAc
2
3
(50 mL) were added. The phases were separated, the aqueous phase was extracted
with EtOAc (3 x 50 mL) and the combined organic phases were dried over Na SO and
2
4
concentrated under reduced pressure. After purification of the residue by column
chromatography (silica, cyclohexane/ethyl acetate 7:1  4:1) methyl 2-amino-5-
1
bromobenzoate (3.80 g, 16.7 mmol, 66 %) was obtained as a colourless solid. H-NMR
(600 MHz, CDCl ) δ = 7.96 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 6.55 (d,
3
13
1
J = 8.8 Hz, 1H), 5.75 (s, 2H), 3.86 (s, 3H). C{ H}-NMR (151 MHz, CDCl ) δ = 167.4,
3
1
49.3, 136.7, 133.4, 118.3, 112.0, 107.3, 51.7. FTIR (ATR, neat) 푣 = 3454, 3355, 1948,
683, 1625, 1558, 1442, 1296, 1236, 1082, 967, 824, 786. MS (EI, 70 eV) m/z: 229.0
1
+
·
+
+
[M] , 197.0 [M-MeOH] , 170.0 [M-COOMe] Mp T = 72 – 73. The analytical data is in
accordance with literature data.33
22
ACS Paragon Plus Environment

Page 23 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In a pressure vial methyl 2-amino-5-bromobenzoate (1.15 g, 5.00 mmol, 1.00 eq.) and
CuCN (493 mg, 5.50 mmol, 1.10 eq.) were suspended in dry DMF (20 mL) and stirred
for 4 h at 160 °C. Et O (50 mL) and 2N Na CO (50 mL) were added and the phases
2
2
3
were separated. The aqueous phase was extracted with Et O (2 x 50 mL) and the
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
combined organic phases were washed with H O (6 x 10 mL), dried over Na SO and
2
2
4
concentrated under reduced pressure. The residue was purified via column
chromatography (silica, cyclohexane/ethyl acetate 5:1  3:1) to obtain methyl 2-
1
amino-5-cyanobenzoate (484 mg, 2.75 mmol, 55 %) as a slightly yellow solid. H-NMR
(600 MHz, CDCl ) δ = 8.19 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.7, 2.0 Hz, 1H), 6.67 (d,
3
13
1
J = 8.7 Hz, 1H), 6.29 (s, 2H), 3.90 (s, 3H). C{ H}-NMR (151 MHz, CDCl ) δ = 167.1,
3
1
53.0, 136.9, 136.3, 119.3, 117.0, 110.5, 98.7, 52.1. FTIR (ATR, neat) 푣 = 3465, 3359,
212, 1708, 1629, 1591, 1550, 1439, 1263, 1188, 1077, 821. MS (EI, 70 eV) m/z:
2
+
·
+
+
176.1 [M] , 144.1 [M-MeOH] , 117.0 [M-COOMe] Mp T = 129 – 131. The analytical
data is in accordance with literature data.34
Following GP1a, methyl 2-amino-5-cyanobenzoate (317 mg, 1.80 mmol, 1.00 eq.) and
TsOH·H O (1.03 g, 5.40 mmol, 3.00 eq.) were suspended in Acetonitrile (8 mL). The
2
mixture was cooled to 10 – 15 °C. A solution of NaNO (278 mg, 3.60 mmol, 2 eq.) and
2
KI (747 mg, 4.50 mmol, 2.50 eq.) in H O (1 mL) was added dropwise over 1 h. After
2
complete addition, the resulting dark coloured mixture was allowed to stir for another
1 h and then 1 N HCl (10 mL) and EtOAc (20 mL) were added. The phases were
separated and the aqueous phases was extracted with EtOAc (2 x 20 mL). The
combined organic phases were washed with water (50 mL), Na S O (10 % w/w,
2
2
3
5
0 mL) and brine (20 mL), dried over Na SO and concentrated under reduced
2 4
pressure. The residue was purified by filtration over silica (cyclohexane/ethyl acetate
4:1) to obtain methyl 5-cyano-2-iodobenzoate (401 mg, 1.39 mmol, 78 %) as a
1
colourless solid. H-NMR (600 MHz, CDCl ) δ = 8.15 (d, J = 8.2 Hz, 1H), 8.07 (d, J =
3
13
1
2
.0 Hz, 1H), 7.39 (dd, J = 8.2, 2.0 Hz, 1H), 3.97 (s, 3H). C{ H}-NMR (151 MHz, CDCl )
3
δ = 165.1, 142.6, 136.2, 134.7, 134.0, 117.3, 112.5, 100.4, 53.1. FTIR (ATR, neat) 푣 =
3057, 2233, 1729, 1584, 1431, 1298, 1245, 1195, 1104, 1020, 973, 828. HRMS (EI,
+·
+·
7
0 eV) m/z: [M] Calcd for C H INO : 286.9438; Found: 286.9433. Mp T = 119 – 121.
9
6
2
Methyl 5-cyano-2-iodobenzoate (345 mg, 1.20 mmol, 1.00 eq.) was dissolved in
MeOH/THF (2:1 v/v, 10 mL) and at 0 °C NaBH (454 mg, 12.0 mmol, 10 eq.) was
4
added portionwise over 2 h and the suspension was stirred for 1 h. Et O (50 mL), H O
2
2
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
10 mL) and 1N HCl (10 mL) were added, the phases were separated and the aqueous
phase was extracted with Et O (2 x 50 mL). The combined organic phases were dried
2
over Na SO , concentrated under reduced pressure and purified via column
2
4
chromatography (cyclohexane/ethyl acetate 10:1) to obtain 3-(hydroxymethyl)-4-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
iodobenzonitrile (5g, 127 mg, 0.490 mmol, 41 %). H-NMR (600 MHz, DMSO-d ) δ =
6
8.05 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.48 (dd, J = 8.0, 1.6 Hz, 1H), 5.70 (s, 1H), 4.42
s, 2H). 13C{ H}-NMR (151 MHz, DMSO-d ) δ = 145.8, 139.8, 131.6, 129.9, 118.6,
1
(
6
1
11.0, 103.6, 66.8. FTIR (ATR, neat) 푣 = 3460, 2234, 1583, 1427, 1394, 1299, 1221,
+
·
1055, 1010, 891, 821. MS (EI, 70 eV) m/z: 259.0 [M] . Mp T = 147 – 148.5.
4-Bromo-2-iodophenyl)methanol (5h)
(
Following GP1a, the reaction of 2-amino-4-bromobenzoic acid (2.16 g) gave 4-bromo-
1
2
-iodobenzoic acid (S1h, 2.21 g, 7.06 mmol, 71 %) as a colourless solid. H-NMR
(600 MHz, DMSO-d ) δ = 13.47 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.70 (dd, J = 8.3, 1.8
6
13
1
Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H). C{ H}-NMR (151 MHz, DMSO) δ = 167.4, 142.1,
1
36.0, 131.5, 131.2, 125.0, 95.7. FTIR (ATR, neat) 푣 = 3064, 1672, 1422, 1291, 1542,
-
-
-
1
291, 1249, 1023, 838, 771. HRMS (ESI , MeOH) m/z: [M-H] Calcd for C H BrIO :
7 3 2
324.8367; Found: 324.8364. Mp T = 175 – 177.
Following GP2, the reaction of 4-bromo-2-iodobenzoic acid (S1h, 1.63 g, 5.00 mmol)
with NaBH (549 mg, 14.5 mmol) and I (952 mg, 3.75 mmol) gave after filtration over
4
2
silica (cyclohexane/ethyl acetate 4:1) (4-bromo-2-iodophenyl)methanol (5h, 1.39 g,
1
4
1
2
.44 mmol, 87 %) as a colourless solid. H-NMR (600 MHz, CDCl ) δ = 7.96 (d, J =
3
.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.62 (d, J = 5.6 Hz,
13
1
H), 2.06 (t, J = 6.0 Hz, 1H). C{ H}-NMR (151 MHz, CDCl ) δ = 141.6, 140.9, 131.5,
3
129.3, 121.7, 97.3, 68.6. FTIR (ATR, neat) 푣 = 3315, 3226, 1572, 1550, 1467, 1377,
+
·
+·
1
056, 1008, 801, 705. HRMS (EI, 70 eV) m/z: [M] Calcd for C H BrIO : 311.8641;
7 6
Found: 311.8644. Mp T = 104 – 105.
(3-Bromo-2-iodophenyl)methanol (5i)
Following GP1a, the reaction of 2-amino-3-bromobenzoic acid (2.16 g) gave 3-bromo-
2
-iodobenzoic acid (S1i, 1.25 g, 3.83 mmol, 38 %) as a colourless solid which still
1
contained some impurities (≈ 5 %) but was used without further purification. H-NMR
(601 MHz, DMSO-d ) δ = 13.54 (brs, 1H), 7.82 (dd, J = 8.0, 1.5 Hz, 1H), 7.46 (dd, J =
6
13
1
7
.6, 1.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H). C{ H}-NMR (151 MHz, DMSO-d ) δ = 169.0,
6
24
ACS Paragon Plus Environment

Page 25 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
42.9, 133.9, 131.3, 129.9, 127.0, 100.8. FTIR (ATR, neat) 푣 = 2864, 1675, 1567,
-
-
1407, 1390, 1281, 1249, 1199, 967, 750. HRMS (ESI , MeOH) m/z: [M-H] Calcd for
-
C H BrIO : 324.8367; Found: 324.8364. The analytical data is in accordance with
7
3
2
literature data.35
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Following GP2, the reaction of 3-bromo-2-iodobenzoic acid (S1i, 817 mg, 2.50 mmol)
with NaBH (274 mg, 7.25 mmol) and I (476 mg, 1.88 mmol) gave after filtration over
4
2
silica (cyclohexane/ethyl acetate 4:1) (3-bromo-2-iodophenyl)methanol (5i, 611 mg,
1
1.95 mmol, 78 %) as a colourless solid. H-NMR (600 MHz, CDCl ) δ = 7.61 (d, J = 7.9
3
Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.73 (d, J = 6.3 Hz, 2H),
13
1
2.19 (t, J = 6.3 Hz, 1H). C{ H}-NMR (151 MHz, CDCl ) δ = 146.2, 131.7, 131.0, 129.5,
3
126.2, 104.1, 71.0. FTIR (ATR, neat) 푣 = 3295, 1428, 1397, 1345, 1215, 1172, 1133,
+·
+·
1048, 980, 769. HRMS (EI, 70 eV) m/z: [M] Calcd for C H BrIO : 311.8641; Found:
7 6
311.8644. Mp T = 110 – 112.
(3,5-Dichloro-2-iodophenyl)methanol (5j)
Following GP1a, the reaction of 2-amino-3,5-dichlorobenzoic acid (2.06 g) gave 3,5-
dichloro-2-iodobenzoic acid (S1j, 1.39 g, 4.39 mmol, 44 %) as a colourless solid which
still contained some impurities (≈ 5 %) but was used without further purification.
1
H-NMR (600 MHz, DMSO-d ) δ = 13.85 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.57 (d, J =
6
13
1
2.4 Hz, 1H). C{ H}-NMR (151 MHz, DMSO-d ) δ = 167.7, 143.8, 140.3, 134.0, 129.8,
6
126.6, 96.8. FTIR (ATR, neat) 푣 = 3070, 1693, 1547, 1418, 1367, 1281, 1242, 1156,
-
-
-
1019, 870, 819. HRMS (ESI , MeOH) m/z: [M-H] Calcd for C H Cl IO : 314,8482;
7 2 2 2
Found: 314.8479. Mp T = 177 – 179.
Following GP2, the reaction of 3,5-dichloro-2-iodobenzoic acid (S1j, 792 mg,
2.50 mmol) with NaBH (274 mg, 7.25 mmol) and I (476 mg, 1.88 mmol) gave after
4
2
filtration
over
silica
(cyclohexane/ethyl
acetate
4:1)
(3,5-dichloro-2-
1
iodophenyl)methanol (5j, 744 mg, 2.46 mmol, 98 %) as a colourless solid. H-NMR
(601 MHz, CDCl ) δ = 7.44 – 7.41 (m, 1H), 7.41 – 7.38 (m, 1H), 4.66 (d, J = 6.1 Hz,
3
13
1
2H), 2.15 (t, J = 6.1 Hz, 1H). C{ H}-NMR (151 MHz, CDCl ) δ = 146.9, 139.8, 135.3,
3
127.8, 125.9, 98.0, 69.8. FTIR (ATR, neat) 푣 = 3183, 2889, 1551, 1418, 1399, 1384,
216, 1171, 1094, 1058, 1008, 858. HRMS (EI, 70 eV) m/z: [M] +· Calcd for
1
+
·
C H Cl IO : 301.8757; Found: 301.8756. Mp T = 95.5 – 97.
7
5
2
Derivatives of Primary Benzyl Alcohols (10 – 13)
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-Iodobenzyl acetate (10)
o-Iodobenzylalcohol (5a, 585 mg, 2.50 mmol, 1.00 eq.) was dissolved in dry DCM
(12.5 mL), cooled to 0 °C and triethylamine (520 µL, 3.75 mmol, 1.5 eq.) and Ac O
2
(295 µL, 3.13 mmol, 1.25 eq.) were added. The solution was warmed up to rt overnight.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Water (10 mL) was added. The phases were separated and the aqueous phase was
extracted with DCM (2 x 15 mL). The combined organic phases were washed with
brine (15 mL), dried over Na SO and concentrated under reduced pressure. Column
2
4
chromatography of the crude product (silica, cyclohexane/ethyl acetate 5:1) afforded
1
the product (10, 636 mg, 2.30 mmol, 92 %) as a colourless liquid. H-NMR (600 MHz,
CDCl ) δ = 7.86 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 7.6, 1.9 Hz, 1H), 7.35 (td, J = 7.4,
3
.9 Hz, 1H), 7.03 (td, J = 7.6, 1.9 Hz, 1H), 5.13 (s, 2H), 2.15 (s, 3H). 13C{ H}-NMR
1
0
(151 MHz, CDCl ) δ = 170.6, 139.5, 138.3, 129.8, 129.5, 128.3, 98.4, 70.1, 20.9. FTIR
3
(ATR, neat) 푣 = 3056, 2953, 1732, 1566, 1437, 1378, 1360, 1218, 1012, 746. MS (EI,
+
·
+
7
0 eV) m/z: 276.0 [M] , 149.1 [M-I] . The analytical data is in accordance with literature
data.36
-Iodo-2-(methoxymethyl)benzene (11)
In modification of a reported procedure,37 o-iodobenzylalcohol (5a, 585 mg,
.50 mmol, 1.00 eq.) was dissolved in dry DMF (12.5 mL). After cooling to 0 °C, NaH
200 mg, 5.00 mmol, 60 % w/w in mineral oil, 2.00 eq.) was added and the resulting
suspension was stirred for 10 min. Iodomethane (311 µL, 710 mg, 5.00 mmol,
.00 eq.) was added and the cooling bath was removed. After stirring for 1 h at rt,
1
2
(
2
triethylamine (1 mL) was added and the suspension was stirred for another 30 min.
Water (15 mL) was added, the phases were separated and the aqueous phase was
extracted with DCM (2 x 15 mL). The combined organic phases were washed with
water (30 mL), dried over Na SO and concentrated under reduced pressure. The
2
4
residue was purified by filtration over silica (cyclohexane/ethyl acetate 10:1) to obtain
the product (11, 615 mg, 2.48 mmol, 99 %) as a colourless liquid that solidifies at 4 °C.
1
H-NMR (601 MHz, CDCl ) δ = 7.83 (dd, J = 7.9, 0.9 Hz, 1H), 7.43 – 7.39 (m, 1H), 7.35
3
13
1
(td, J = 7.6, 1.0 Hz, 1H), 7.01 – 6.96 (m, 1H), 4.45 (s, 2H), 3.47 (s, 3H). C{ H}-NMR
(151 MHz, CDCl ) δ = 140.4, 139.2, 129.1, 128.6, 128.2, 97.7, 78.3, 58.6. FTIR (ATR,
3
neat) 푣 = 2921, 1565, 1437, 1378, 1193, 1116, 1099, 1013, 973, 744. MS (EI, 70 eV)
+
·
+
+
m/z: 248.0 [M] , 217.0 [M-OMe] , 121.1 [M-I] . The analytical data is in accordance
with literature data.37
26
ACS Paragon Plus Environment

Page 27 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ethyl (2-iodobenzyl) carbonate (12)
o-Iodobenzylalcohol (5a, 585 mg, 2.50 mmol) was dissolved in dry DCM (12.5 mL) and
at 0 °C, dry pyridine (303 µL, 297 mg, 3.75 mmol, 1.5 eq.) and ClCOOEt (298 µL,
339 mg, 3.13 mmol, 1.25 eq.) were added. The cooling bath was removed and the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
solution was allowed to stir at rt overnight. After completion of the reaction, sat.
NaHCO (15 mL) was added. The phases were separated and the aqueous phase was
3
extracted with DCM (2 x 15 mL). The combined organic phases were washed with
water (30 mL), dried over Na SO , concentrated under reduced pressure and the
2
4
residue was purified by filtration over silica (cyclohexane) to obtain ethyl (2-iodobenzyl)
1
carbonate (12, 665 mg, 2.17 mmol, 87 %) as a colourless solid. H-NMR (600 MHz,
CDCl ) δ = 7.85 (dd, J = 7.9, 1.0 Hz, 1H), 7.42 (dd, J = 7.6, 1.5 Hz, 1H), 7.35 (td, J =
3
7.5, 1.1 Hz, 1H), 7.03 (td, J = 7.7, 1.6 Hz, 1H), 5.19 (s, 2H), 4.24 (q, J = 7.1 Hz, 2H),
13
1
1.33 (t, J = 7.1 Hz, 3H). C{ H}-NMR (151 MHz, CDCl ) δ = 154.8, 139.5, 137.8, 130.0,
3
129.3, 128.4, 98.0, 73.0, 64.3, 14.3. FTIR (ATR, neat) 푣 = 2994, 1734, 1438, 1381,
1
365, 1282, 1259, 1013, 976, 789, 744. HRMS (EI, 70 eV) m/z: [M] +· Calcd for
+·
[
C H O I] : 305.9747; Found: 305.9750. Mp T = 27 – 28.
10
11
3
1-(Chloromethyl)-2-iodobenzene (13)
38
In modification of a reported procedure, o-Iodobenzylalcohol (5a, 1.87 g, 8.00 mmol)
was dissolved in dry DCM (40 mL) and SOCl (0.73 mL, 1.19 g, 10.0 mmol, 1.25 eq.)
2
was added dropwise at 0 °C. After complete addition, the cooling bath was removed
and the mixture was allowed to warm to rt and stirred overnight. Sat. NaCl (50 mL) was
added, the phases were separated and the aqueous phase was extracted with DCM
(2 x 50 mL). The combined organic phases were concentrated under reduced pressure
and the residue was purified via column chromatography (silica, cyclohexane) to obtain
the product (13, 1.22 g, 4.83 mmol, 60 %) as a colourless liquid.
1
H-NMR (601 MHz, CDCl ) δ = 7.87 (dd, J = 7.9, 0.9 Hz, 1H), 7.49 (dd, J = 7.6, 1.4 Hz,
3
13
1
1H), 7.36 (td, J = 7.6, 1.0 Hz, 1H), 7.01 (td, J = 7.7, 1.6 Hz, 1H), 4.68 (s, 2H). C{ H}-
NMR (151 MHz, CDCl ) δ = 139.9, 139.8, 130.2, 130.1, 128.8, 99.5, 51.0. FTIR (ATR,
3
neat) 푣 = 3067, 2966, 1587, 1564, 1462, 1441, 1256, 1206, 1013, 759, 719. MS (EI,
+·
0 eV) m/z: 252.0 [M] . The analytical data is in accordance with literature data.38
7
Secondary Benzyl Alcohols (5k – q)
2-Iodobenzaldehyde
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
o-Iodobenzylalcohol (5a, 24.9 g, 106 mmol, 1 eq.) was dissolved in CHCl (265 mL),
3
activated MnO (92.4 g, 1.06 mol, 10 eq.) was added and the suspension was stirred
2
for 24 h at rt. The mixture was filtrated over Celite and the filter material was washed
with ethyl acetate (300 mL). After removal of the solvent under reduced pressure, 2-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
iodobenzaldehyde (21.9 g, 94.4 mmol, 89 %) was obtained as a colourless solid. H-
NMR (600 MHz, CDCl ) δ = 10.07 (d, J = 0.7 Hz, 1H), 7.96 (dd, J = 7.9, 1.1 Hz, 1H),
3
7.89 (dd, J = 7.7, 1.8 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.29 (ddd, J = 7.9, 7.4, 1.8 Hz,
1
1
H). 13C{ H}-NMR (151 MHz, CDCl ) δ = 196.0, 140.8, 135.7, 135.2, 130.4, 128.9,
3
100.9. FTIR (ATR, neat) 푣 = 2849, 2833, 2746, 1683, 1578, 1436, 1388, 1261, 1200,
+
·
+
1
015, 748. MS (EI, 70 eV) m/z: 232.0 [M] , 203.0 [M-CHO] . Mp T = 34 – 35. The
analytical data is in accordance with literature data.39
2-Iodophenyl)(phenyl)methanol (5k)
(
To a suspension of Mg turnings (115 mg, 4.73 mmol, 1.05 eq.) in dry Et O (1 mL)
2
iodobenzene (0.56 mL, 4.95 mmol, 1.1 eq.) was slowly added so that the reaction
starts and keeps refluxing mildly. After complete formation of the Grignard reagent, dry
Et O (5 mL) was added and the resulting solution was added to a solution of 2-
2
iodobenzaldehyde (1.04 g, 4.50 mmol, 1 eq.) in dry Et O (10 mL) at 0 °C over 15 min.
2
The ice bath was removed and after 30 min. of stirring sat. NH Cl (10 mL) and EtOAc
4
(10 mL) were added. The phases were separated and the aqueous phase was
extracted with Et O (3 x 10 mL). The combined organic phases were dried over
2
Na SO and the solvent was removed under reduced pressure. The residue was
2
4
purified via column chromatography (silica, cyclohexane/ethyl acetate 20:1) to obtain
2-iodophenyl)(phenyl)methanol (5k, 829 mg, 2.67 mmol, 59 %) as colourless liquid.
(
1
H-NMR (200 Mhz, CDCl ) δ = 7.84 (dd, J = 7.9, 1.2 Hz, 1H), 7.53 (dd, J = 7.8, 1.8 Hz,
3
1H), 7.49 – 7.24 (m, 6H), 7.00 (td, J = 7.7, 1.8 Hz, 1H), 6.06 (d, J = 3.6 Hz, 1H), 2.49
13
1
(
dd, J = 3.7, 1.1 Hz, 1H). C{ H}-NMR (50 MHz, CDCl ) δ = 145.4, 142.2, 139.6, 129.5,
3
128.7, 128.6, 128.5, 127.9, 127.3, 98.8, 79.1. FTIR (ATR, neat) 푣 = 3320, 3059, 3028,
1584, 1562, 1493, 1452, 1435, 1181, 1114, 1077, 1006, 916, 849, 918, 746, 697, 669.
+
·
MS (EI, 70 eV) m/z: 310.0 [M] . The analytical data is in accordance with literature
data.40
(3,5-Bis(trifluoromethyl)phenyl)(2-iodophenyl)methanol (5l)
3,5-Bis(trifluoromethyl)bromobenzene (806 mg, 2.75 mmol, 1.1 eq.) was dissolved in
dry THF (20 mL) and cooled to -78 °C. nBuLi (1.1 mL, 2.5M in hexanes, 2.75 mmol,
28
ACS Paragon Plus Environment

Page 29 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
.1 eq.) was added dropwise over 10 min and the solution was stirred for 10 min. 2-
Iodobenzaldehyde (580 mg, 2.50 mmol, 1.00 eq.) in dry THF (10 mL) was added
dropwise over 30 min. via syringe pump. After complete addition the mixture was
slowly warmed to rt. Sat. NH Cl (50 mL) and Et O (50 mL) were added, the phases
4
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
were separated and the aqueous phase was extracted with Et O (2 x 50 mL). The
2
combined organic phases were washed with brine (20 mL), dried over Na SO and
2
4
concentrated under reduced pressure. The residue was purified via column
chromatography (cyclohexane/ethyl acetate 30:1) to obtain (3,5-
(bis(trifluoromethyl)phenyl)(2-iodophenyl)methanol (5l, 640 mg, 1.44 mmol, 57 %) as
1
a yellow oil. H-NMR (600 MHz, CDCl ) δ = 7.91 (s, 2H), 7.89 (d, J = 8.0 Hz, 1H), 7.81
3
(s, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.22
13
1
(d, J = 3.1 Hz, 1H), 2.54 (d, J = 3.4 Hz, 1H). C{ H}-NMR (151 MHz, CDCl ) δ = 144.6,
3
144.2, 139.9, 131.7 (q, J = 33.3 Hz), 130.3, 129.2, 128.4, 127.5 – 126.4 (m), 123.3 (q,
J = 272.9 Hz), 121.7 – 121.6 (m), 98.6, 77.9. FTIR (ATR, neat) 푣 = 3289, 1374, 1274,
+
·
+
1165, 1123, 1010, 899, 844, 741, 705. MS (EI, 70 eV) m/z: 446.1 [M] , 427.0 [M-F] ,
+
41
377.0 [M-CF ] . The analytical data is in accordance with literature data.
3
(5-Chloro-2-iodophenyl)(2-fluorophenyl)methanol (5m)
Following GP1a, (2-amino-5-chlorophenyl)(2-fluorophenyl)methanone (1.25 g,
.00 mmol, 1.00 eq.) and TsOH·H O (2.85 g, 15.0 mmol, 3.00 eq.) were suspended in
5
2
Acetonitrile (40 mL). The mixture was cooled to 10 – 15 °C and a solution of NaNO2
690 mg, 10.0 mmol, 2.00 eq.) and KI (2.08 g, 12.5 mmol, 2.50 eq.) in H O (6 mL) was
(
2
added dropwise over 1 h. After complete addition, the resulting dark coloured mixture
was allowed to stir for another 1 h and then 1 N HCl (25 mL) and EtOAc (50 mL) were
added. The phases were separated and the aqueous phases was extracted with
EtOAc (2 x 50 mL). The combined organic phases were washed with water (25 mL),
Na S O (10 % w/w, 25 mL) and brine (20 mL), dried over Na SO and concentrated
2
2
3
2
4
under reduced pressure. The residue was purified by column chromatography
(cyclohexane/ethyl
acetate
50:1)
to
obtain
(5-chloro-2-iodophenyl)(2-
1
fluorophenyl)methanone (1.37 g, 3.81 mmol, 76 %). H-NMR (360 MHz, CDCl ) δ =
3
7.82 (d, J = 8.4 Hz, 1H), 7.77 (td, J = 7.6, 7.6, 1.7 Hz, 1H), 7.64 – 7.53 (m, 1H), 7.30
(d, J = 2.4 Hz, 1H), 7.27 (t, J = 7.6, 7.6 Hz, 1H), 7.15 (dd, J = 8.4, 2.5 Hz, 1H), 7.13 –
13
1
7.08 (m, 1H). C{ H}-NMR (91 MHz, CDCl ) δ = 192.6, 161.7 (d, J = 259 Hz), 146.3,
3
141.0, 135.6 (d, J = 9.0 Hz), 134.6, 131.9, 131.6, 128.5 (d, J = 1.1 Hz), 124.6 (d, J =
29
ACS Paragon Plus Environment