Mild, Efficient, and Highly Regioselective Synthesis of 2,6-Diiodobenzaldehyde Derivatives

Article abstract of DOI:10.1055/s-0040-1708004

An efficient and versatile synthesis of 2,6-diiodobenzaldehydes via highly regioselective metal-iodine exchange (MIE) of 5-substituted 1,2,3-triiodobenzenes is reported. The nature of substituents (R) on the phenyl has a large influence on the reactivity of reaction but not on the regioselectivity. The regioselectivity of the MIE can be controlled by the use of ethyl formate as a formylating agent providing only the internal benzaldehyde derivatives in excellent site-selectivity. The best reactivity and the highest isolated yields were furnished with products bearing electron-rich substituents. Several chemical transformations of the target compound as a valuable precursor in synthesis were also demonstrated providing the desired derivatives in good isolated yields. This report discloses a protocol for the synthesis of 2,6-diiodobenzaldehyde derivatives that is scalable, general in scope, and indeed difficult to be made by other means.

Full text of DOI:10.1055/s-0040-1708004

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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, 953–958
letter
953
en
Synlett
R. M. Al-Zoubi et al.
Letter
Mild, Efficient, and Highly Regioselective Synthesis of 2,6-Diiodo-
benzaldehyde Derivatives
Raed M. Al-Zoubi*a
Khaled T. Jaradata
Walid K. Al-Jammala
Robert McDonaldb
Nucleophilic Addition
(Oxime and Hydrazone)
Crystalline & Bench
Stable Solids
Regioselective Formylation
R
X
Reduction
(Benzylalcohol)
O
H
H
I
i. iPrMgCl (2M),
THF, – 78 °C
Ar2
Ar1
I
I
I
I
a
Applications
Department of Chemistry, Jordan University of Science and
Technology, P.O.Box 3030, Irbid, 22110, Jordan
rmzoubi@just.edu.jo
Department of Chemistry, Gunning-Lemieux Chemistry Cen-
ii. EtOCHO, THF,
Suzuki–Miyaura Coupling
(mono and double)
–
78 °C to 25 °C
R
R
R
b
10 examples
5 examples
75–94%
R = F, Cl, Br, H, Me,
OMe, CO2Me, NO2
tre, University of Alberta, Edmonton, AB, T6G 2G2, Canada
45–80%
Highlights Highly regioselective
Scalable (Gram Scale) High yielding
Two X-ray crystal structures
Received: 04.01.2020
Accepted after revision: 02.03.2020
Published online: 20.03.2020
useful
for
the
treatment
of
tumors
by
2
embolotherapy. Furthermore, 2,3,5,6-tetraiodobenzalde-
DOI: 10.1055/s-0040-1708004; Art ID: st-2020-b0004-l
hyde 3 is a polyiodinated derivative that is reported as im-
ageable radiopaque hydrogel in drug delivery. Moreover,
3
Abstract An efficient and versatile synthesis of 2,6-diiodobenzalde-
hydes via highly regioselective metal–iodine exchange (MIE) of 5-sub-
stituted 1,2,3-triiodobenzenes is reported. The nature of substituents
3,5-difluoro-4′-[(4-methyl-1,4-diazocan-1-yl)methyl]-
(1,1′-biphenyl)-4-carbaldehyde (4, Figure 1) is a doubly or-
tho-fluorinated benzaldehyde derivative which is reported
to be an inhibitor of choline kinase, an enzyme that is con-
cerned with phospholipid synthesis and key roles with the
regulation of oncogenic transformation, cell proliferation,
(
R) on the phenyl has a large influence on the reactivity of reaction but
not on the regioselectivity. The regioselectivity of the MIE can be con-
trolled by the use of ethyl formate as a formylating agent providing only
the internal benzaldehyde derivatives in excellent site-selectivity. The
best reactivity and the highest isolated yields were furnished with prod-
ucts bearing electron-rich substituents. Several chemical transforma-
tions of the target compound as a valuable precursor in synthesis were
also demonstrated providing the desired derivatives in good isolated
yields. This report discloses a protocol for the synthesis of 2,6-diiodo-
benzaldehyde derivatives that is scalable, general in scope, and indeed
difficult to be made by other means.
4
and human carcinogenesis. Lastly, 3,5-dichloro-3′-fluoro-
4
′-hydroxy-(1,1′-biphenyl)-4-carbaldehyde (5, Figure 1) is a
doubly ortho-chlorinated benzaldehyde derivative that is
found to have potency and selectivity for estrogen-receptor
5

-ligands. The status quo of these compounds and other
6
halogenated benzaldehyde derivatives as well as the exces-
sive market price for some iodinated benzaldehydes have
7
Keywords 2,6-diiodobenzaldehydes, Grignard reactions, regioselec-
tivity, metal–iodine exchange, substituent effect, Suzuki–Miyaura
cross-coupling, nucleophilic addition
initiated great attention and enthusiasm for developing
synthetic approaches to these small molecules for their
novel applications in industry and medicine. Although
there are a number of published protocols for the synthesis
of dihalogenated benzaldehydes,8 a practical protocol to
access 2,6-diiodobenzaldehyde derivatives has not been re-
ported yet.
Halogenated benzaldehydes and mainly iodinated mo-
tifs are remarkable intermediates and largely utilized sub-
strates in medicinal and pharmaceutical chemistry. Due to
the unique chemical combination between two reactive
functional groups, numerous applications are found in the
literature. For instance, 2,6-diiodobenzaldehyde (1, Figure
,9
Herein, we report the first synthetic method for 2,6-
diiodobenzaldehyde derivatives via highly regioselective
metalation of 5-substituted 1,2,3-triiodonbenzene that is of
wide scope, is readily scalable, and provides good isolated
yields. A number of 5-substituted 1,2,3-triiodonbenzenes
bearing electron-rich, electron-poor, and neutral groups
were subjected to the optimized conditions affording the
desired diiodinated benzaldehyde products with excellent
site-selectivity and indeed are difficult to be made by other
means.
1) is a doubly ortho-iodinated benzaldehyde which is used
as a precursor to form (E)-2-(2,6-diiodobenzylidene)hydra-
zinecarboximidamide. Compound 1 is a therapeutic com-
pound reported for reducing endoplasmic reticulum stress
and for producing analgesia in animals. Additionally, 2,3,5-
triiodobenzaldehyde 2 that contains one ortho-iodo group
1
at C on the aryl ring is reported as useful emulsion compo-
nent for improved stability and coherence. Compound 2 is
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 953–958
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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Synlett
R. M. Al-Zoubi et al.
Letter
I
O
I
I
O
I
O
I
internal
I
terminal
I
I
H
O
H
I
H
H
H
I
metal-halogen exchange
reaction
I
I
I
O
+/or
1
2
I
3
I
R1
I followed by formylating agent R1
R1
precursor to therapeutic
cpd for reducing stress & embolotherapy
producing analgesia
cancer
radiopaque
hydrogels for drug
discovery
A
B
agent
R1 = EDG, EWG, neutral, H
2,6-diiodobenzaldehyde
derivative
2,3-diiodobenzaldehyde
derivative
F
O
Cl
O
H
H
Scheme 1 Possible diiodinated benzaldehyde regioisomers from met-
al–iodine exchange (MIE) of 5-substituted 1,2,3-triiodobenzene
F
F
Cl
N
N
4
5
HO
choline kinase inhibitor
estrogen b-receptor
Therefore, to examine this hypothesis, 1,2,3-triiodoben-
zene (6) was used as a model substrate as shown in Table 1.
The reaction of 1,2,3-triiodobenzene (6) and isopropylmag-
nesium chloride (2 M) in THF with different formylating re-
agents were examined. The use of triethyl orthoformate
and ethyl formate reagents provided the internal regioiso-
mer as a sole product in 23% and 52%, respectively (entries
1 and 2). Piperidine-1-carbaldehyde was found to be less
effective providing a mixture of products in 24% (entry 3).
Another formylating agent, DMF, was previously examined
and found to have some reproducibility issues. The use of
other bases like t-BuLi, s-BuLi, or n-BuLi at –78 °C in THF
Figure 1 Some biologically active halogenated benzaldehyde com-
pounds in medicine
Owing to the known biological and chemical activities
of dihalogenated benzaldehyde derivatives in literature, we
felt excited to examine metal–iodine exchange on 5-substi-
tuted 1,2,3-triiodobenzenes with the goal of making 2,6-
diiodinated benzaldehyde derivatives.
A handful of examples on regioselective functionaliza-
tion of 1,2-diiodo- and 1,2,3-triiodoarenes are reported in
the literature. Togni and co-workers reported the synthesis
of o-iodobenzyl alcohol derivatives with isopropylmagne-
sium chloride by metal–iodine exchange reaction of 1,2-
diiodobenzene via addition of o-iodophenyl Grignard re-
Table 1 Conditions for the Regioselective Metal–Iodine Exchange Re-
a
action of 1,2,3-Triiodobenzene (6) Followed by Formylating Agent
10
agent to aldehydes and ketones. We also reported three
regioselective metal–iodine exchange reactions of 1,2,3-
triiodobenzene derivatives with isopropylmagnesium chlo-
ride for the synthesis of diiodobenzyl alcohols, diiodophen-
H
O
I
I
O
1
. metal-iodine exchange
reaction conditions
I
I
I
I
I
+
H
2. formylationg agent
6
6A
6B
11
ylboronic acids, and iodinated benzoboroxoles. The de-
sired products were isolated in good yields where the
regioselectivity and reactivity of the reactions per se are
controlled by both the nature of the substituent at C-5 on
the aryl group and the type of electrophile favoring the dis-
placement to occur either at the terminal or internal posi-
tion. Other works on regioselective metal–bromine/iodine
Entry Conditions (equiv.) Formylating agent (equiv.) Yield of Yield of
b
b
6
A
(%)
6
B
(%)
1
2
3
i-PrMgCl (1.0), THF triethyl orthoformate (1.0) 23
0
0
i-PrMgCl (1.0), THF ethyl formate (1.0)
52
6
i-PrMgCl (1.0), THF piperidine-1-carbalde-
18
hyde (1.0)
12a–c
exchange reaction for the synthesis of benzoic acid,
4
5
6
7
t-BuLi (2.0), THF
s-BuLi (1.0), THF
n-BuLi (1.0), THF
ethyl formate (1.0)
ethyl formate (1.0)
ethyl formate (1.0)
ethyl formate (1.0)
0
0c
0c
9d
0
1
2d
12e
12f
benzyl alcohol, arylboronic acids, m-terphenyls, ar-
12g
12h
0
ylthiols, and arylamines are also reported.
The metal–iodine exchange/functionalization sequence
on 5-substituted 1,2,3-triiodobenzenes with two regio-
chemically different C–I positions provide no more than
two possible diiodinated benzaldehydes, the internal and
the terminal products (Scheme 1). Therefore, the use of
only 1.0 equivalent of an adequate base is theoretically suf-
ficient to exchange one of the iodo groups, making the aryl-
metal intermediate that is quenched with the formylating
reagent to yield the desired diiodinated benzaldehyde prod-
uct.
0
i-PrMgCl (1.0),
diethyl ether
45
8
i-PrMgCl (1.0),
toluene
ethyl formate (1.0)
38
0
9
i-PrMgCl (1.1), THF ethyl formate (1.2)
i-PrMgCl (1.2), THF ethyl formate (1.2)
i-PrMgCl (1.1), THF ethyl formate (1.5)
i-PrMgCl (1.1), THF ethyl formate (1.2)
63
56
71
65
0
0
0
0
10
11
1
2e
a
Conditions: All reactions were carried out using 1.0 mmol (1.0 equiv., 0.1
M) of 1,2,3-triiodobenzene (6) in 10 mL solvent at –78 °C.
b
Isolated yield.
Unknown mixture of products.
Impure isolated product.
c
d
e
1.0 gram scale (2.19 mmol).
©
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R. M. Al-Zoubi et al.
Letter
provided nonclean reactions (entries 4–6). Changing the re-
action conditions by using other solvents was found to be
unsuccessful providing lower isolated yields (entries 7 and
In contrast, electron-withdrawing groups gave low to mod-
erate isolated yields (7 , 9 , and 12 , Scheme 2). Further-
A
A
A
more, products bearing electron-rich groups had the best
8
1
). Raising the amount of isopropylmagnesium chloride to
.1 equivalents provided a higher isolated yield of the de-
reactivity and gave the highest isolated yields (11 , Scheme
2). No exchange reaction with bromo or chloro groups was
A
sired aldehyde 6A (entry 9). The highest isolated yield for
this transformation was achieved by using 1.1 equivalents
of isopropylmagnesium chloride and 1.5 equivalents of ethyl
formate at –78 °C in THF (entry 11). The reaction also
worked well on gram scale (entry 12).
observed (8 , 9 , 13 , and 14 , Scheme 2). Unfortunately, a
derivative bearing a nitro group at the C-5 was found to be
unsuccessful providing a mixture of unidentified products
A
A
A
A
(15 , Scheme 2).
A
The geometry of 2,6-diiodobenzaldehyde derivatives is
confirmed by X-ray crystallography of product, 2,6-diiodo-
The superb site-selectivity and promising isolated yield
(
entry 11) encouraged us to examine our previously syn-
4-methylbenzaldehyde (10 , Figure 2). It shows clearly the
A
thesized 5-substituted 1,2,3-triiodobenzenes under the op-
timized conditions aiming to expand the scope of 2,6-diio-
dinated benzaldehydes for their application in industry and
medicine. Consequently, a variety of 5-substituted 1,2,3-
triiodobenzenes were subjected to the optimized reaction
conditions and formed the desired aldehyde products with
superior regioselectivity after flash chromatography
position of both the iodo and the formyl groups.13
(Scheme 2).
internal
terminal
H
O
I
i
I
O
i) PrMgCl (2 M, 1.1 equiv.)
I
I
THF, –78 °C, 1 h
I
I
I
H
A
+
B
ii) EtOCHO (1.5 equiv.)
THF, –78 to 25 °C, 12 h
not formed
R1
R1
R1
Figure 2 ORTEP view of 2,6-diiodo-4-methylbenzaldehyde 10 . Ther-
A
mal Gaussian ellipsoids at 30% probability level.
O
H
O
H
O
H
O
H
O
H
I
I
I
I
I
I
I
I
I
I
A plausible mechanism for the regioselective formation
of 2,6-diiodobenzaldehydes is proposed in Scheme 3. Sev-
eral approaches for metal–iodine exchange of diiodo inter-
mediates using isopropylmagnesium chloride/bromide
F
Cl
Br
Me
6A, 71%
7A, 50%
8A, 78%
9A, 45%
10A, 76%
14
have been previously studied and reported, The treatment
of 5-substituted 1,2,3-triiodobenezne with isopropylmag-
nesium chloride at –78 °C in THF provided immediately the
yellow-colored ate complex C with the less hindered and
more accessible iodo group. It became an intense yellow
color within ca. 1 minute and faded within 1–2 hours based
on the nature of the R substituent. It is believed that the or-
tho-iodine atom conveyed much thermodynamic stability
of the ate complex by stabilizing the negative charge on the
ortho carbon. Electron-withdrawing groups (R) were found
to further increase the thermodynamic stability by preserv-
ing the intense yellow color for longer time (ca. 2 h). The
addition of ethyl formate reagent, which is known as a
slow-reacting electrophile,15 decolorized the mixture by
transforming the ate complex C to the new Grignard D. Hal-
ogen-dance (HD) rearrangement provided the internal
Grignard E, which is the more stable regioisomer (calculated
by using DFT), that quenched with ethyl formate reagent to
form the desired benzaldehyde derivative.
O
H
O
H
O
H
O
H
O
H
I
I
I
I
I
Cl
I
Br
I
I
OMe
NO2
O
OMe
15A, 0%a
1
1A, 80%
12A, 66%
13A, 77%
14A, 75%
Scheme 2 Internal diiodinated benzylaldehyde derivatives via regiose-
lective metal–iodine exchange of 5-substituted 1,2,3-triiodobenzenes
and ethyl formate. Yields are given for isolated compounds (reaction
a
scale: 1.00 mmol). Unidentified mixture of products.
We found that the nature of substituents on the 1,2,3-
1
triiodobenzene (R , Scheme 2) has a large influence on the
reactivity but not on the regioselectivity. The formation of
the terminal regioisomer (B, Scheme 2) was not observed
with ethyl formate in all examples. The scope is summa-
rized in Scheme 2. It is found that bearing neutral and elec-
tron-rich groups afforded the desired products in good to
high isolated yields (Scheme 2: 6 8 10 11 13 , and 14 ).
A, A,
A,
A,
A
A
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 953–958

9
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Synlett
R. M. Al-Zoubi et al.
Letter
ate complex
_
I
H
I
I
H
I
+
MgCl
I
I
OH
NH2OH⋅HCl (1.5 equiv)
O
N
I
I
I
Mg
THF, – 78 °C
fast step
1 min
THF, – 78 °C
+
Cl
Me
pyridine, EtOH, 25 °C
Me
slow step
8
h
R
R
I
10A
19, 94%
~
~1–2 h
C
less hindered & more
accessible site
R dependant
Scheme 6 Synthesis of 1-(2,6-diiodo-4-methylphenyl)-N-hydroxy
methanimine (19) from 2,6-diiodo-4-methylbenzaldehyde (10A)
yellow color
more stable by DFT
I
I
I
O
I
(
slow reacting E+)
EtOCHO
I
MgCl
HD
H
R
MgCl
R
I
R
THF, –78 °C
D
E
off-white color
Scheme 3 Plausible mechanism for the formation of 2,6-diiodobenzal-
dehydes
We then turn our thoughts to examine the reactivity of
the other two iodo groups under different reaction condi-
tions aiming to expand their applications in synthesis.
Therefore, mono and double Suzuki–Miyaura cross-cou-
pling reactions of 2,6-diiodo-4-methylbenzaldehyde (10A)
with phenylboronic acid were performed and provided the
coupling products 16 and 17 in good isolated yields
Figure 3 ORTEP view of methanimine 19; thermal Gaussian ellipsoids
at 30% probability level
Alternatively, a reduction reaction with NaBH was also
4
(
Scheme 4).
examined with 2,6-diiodo-4-methoxybenzaldehyde (11A).
Having a symmetrical molecule with one regiochemical
carbon occupied with iodine, it can be easily found if nucle-
ophilic reduction using sodium borohydride can affect io-
dine by displacement reaction. Supremely, the reaction was
The process to access functionalized and active mole-
cules from readily available starting materials is essential in
synthesis and biology. A quick screening in the literature
revealed that 2,6-dichloroarylcarbaldehyde oximes are bio-
logical active derivatives in medicine. We decided to ex-
amine them if we could use this chemistry and quickly ac-
cess oxime and hydrazone derivatives from our 2,6-diiodin-
ated benzaldehydes (vide supra). Gladly, the use of 4-
chloro-2,6-diiodobenzaldehye (8 ) with hydrazine carbox-
amide formed the desired condensation product as a mix-
ture of E/Z isomers in a 10:1 ratio and in 91% isolated yield
5b,c
achieved successfully with 1.5 equivalents of NaBH in THF
4
providing the desired benzyl alcohol 20 in 64% isolated
(Scheme 7)
I
H
I
I
A
O
NaBH4 (1.5 equiv.)
THF, 0 °C, 10 min
OH
MeO
MeO
I
11A
20, 64%
(Scheme 5). Whereas the reaction of 2,6-diiodo-4-methyl-
benzaldehyde (10 ) with hydroxylamine gave the oxime
Scheme 7 Synthesis of (2,6-diiodo-4-methoxyphenyl)methanol (20)
from 2,6-diiodo-4-methoxybenzaldehyde (11
A
product 19 in excellent isolated yield (Scheme 6). The struc-
ture of 1-(2,6-diiodo-4-methylphenyl)-N-hydroxy meth-
animine (19) is confirmed by X-ray crystallography as
shown in Figure 3.14
)
A
O
H
O
H
O
H
Ph3P)4Pd (12 mol%),
PhB(OH)2 (1.0 equiv.)
(Ph3P)4Pd (12 mol%),
PhB(OH)2 (2.2 equiv.)
I
I
I
K2CO3, EtOH, toluene,
K2CO3, EtOH, toluene,
100 °C, 12 h
100 °C, 12 h
Me
6, 80%
Me
Me
7, 75%
1
10A
1
Scheme 4 Mono and double Suzuki–Miyaura cross-coupling reactions of 2,6-diiodo-4-methylbenzaldehyde (10 ) with phenylboronic acid
A
I
H
I
H
I
I
H
I
H
O
N
O
N
O
NaOAc (1.0 equiv.)
MeOH/H2O, 25 °C
N
+
Z
H2N
E
O
+
NH2
HN
N
NH2
Cl
I
Cl
Cl
H
15 min
NH2
8
A
18, 91% (E/Z = 10:1)
Scheme 5 Synthesis of (E)- and (Z)-2-(4-chloro-2,6-diiodobenzylidene) hydrazonecarboxamide (18) from 4-chloro-2,6-diiodobenzaldehyde (8 ) with
A
hydrazinecarboxamide
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 953–958

9
57
Synlett
R. M. Al-Zoubi et al.
Letter
In summary, we developed the first synthesis of 2,6-
diiodobenzaldehyde derivatives via highly regioselective
metal–iodine exchange strategy from 5-substituted 1,2,3-
(8) (a) Hu, P.; Tan, M.; Cheng, L.; Zhao, H.; Feng, R.; Gu, W.-J.; Han,
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Somekh, M.; Carmieli, R.; Neumann, R. Angew. Chem. Int. Ed.
16
triiodobenzenes. The regioselectivity is remarkably con-
trolled by using ethyl formate as a formylating agent pro-
viding the internal regioisomer as a sole product in good
isolated yields. The best yields were furnished with prod-
ucts bearing electron-rich groups on the aryl ring. The ge-
ometries of the products were further confirmed by X-ray
crystallographic analysis. The target products were em-
ployed as versatile intermediates in synthesis and were also
performed in different chemical transformations such as
Suzuki–Miyaura cross-couplings, nucleophilic addition and
reduction reactions. Having other iodo groups on these
products, further elaboration could be easily explored.
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ChemSusChem
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2735.
(q) Montazerozohori, M.; Nasr-Esfahani, M.; Joohari, S.;
This work was generously funded by Jordan University of Science and
Technology (JUST) - Deanship of Research - Jordan (Grant No.
Akhlaghi, P.; Dehghani, A. Asian J. Chem. 2011, 23, 1081.
(r) Zheng, P.; Yan, L.; Ji, X.; Duan, X. Synth. Commun. 2011, 41,
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J
ord
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v
ersity of
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c
i
e
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a
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h
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o
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Chem. Eur. J. 2016, 22, 16326. (w) Miller, M. T.; Anderson, C.;
Arumugam, V.; Bear, B. R.; Binch, H. M.; Clemens, J. J.; Cleveland,
T.; Conroy, E.; Coon, T. R.; Frieman, B. A.; Grootenhuis, P. D. J.;
Gross, R. S.; Hadida-Ruah, S. S.; Haripada, K.; Joshi, P. V.;
Krenitsky, P. J.; Lin, C.-C.; Marelius, G. E.; Melillo, V.; McCartney,
J.; Nicholls, G. M.; Pierre, F. J. D.; Silina, A.; Termin, A. P.; Uy, J.;
Zhou, J. US 20160095858A1, 2016. (x) Hong, K.-I.; Yoon, H.;
Jang, W.-D. Chem. Commun. 2015, 51, 7486. (y) Meng, L.; Cheng,
Q.; Kim, C.; Gao, W.-Y.; Wojtas, L.; Chen, Y.-S.; Zaworotko, M. J.;
Zhang, X. P.; Ma, S. Angew. Chem. Int. Ed. 2012, 51, 10082.
Acknowledgment
We thank the Department of Chemistry at University of Alberta for
X-ray crystallographic analysis.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1708004.
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References and Notes
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4) Zech, S. G.; Kohlmann, A.; Zhou, T.; Li, F.; Squillace, R. M.;
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(
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c) Mewshaw, R. E.; Yang, C. WO 2004099122A2, 2004.
d) Edsall, R. J.; Harris, H. A.; Manas, E. S.; Mewshaw, R. E. Bioorg.
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37, 8206. (k) Oslob, J.; Anderson, R.; Aubele, D.; Evanchik, M.;
Med. Chem. 2003, 11, 3457.
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6) (a) Tsuchiya, T.; Wasnaire, P.; Hoffmann, S.; Seitz, T.; Hillebrand,
S.; Benting, J.; Schmidt, J. P.; Cristau, P. WO 2013098229A2,
Fox, J. C.; Kane, B.; Lu, P.; McDowell, R.; Rodriguez, H.; Song, Y.;
Sran, A. WO 2014205223A1, 2014. (l) Sun, H.; DiMagno, S. G.
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013. (b) Ek, F.; Almen, T.; Gardner, R. WO 2000066544A1,
000. (c) Fouda, A. M.; Assiri, M. A.; Mora, A.; Ali, T. E.; Afifi, T.
(
(
10) Cvengroš, J.; Stolz, D.; Togni, A. Synthesis 2009, 2818.
H.; El-Agrody, A. M. Bioorg. Chem. 2019, 93, 103289.
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M.; Al-Zoubi, M. S.; Jaradat, K. T.; McDonald, R. Eur. J. Org. Chem.
(
7) Scifinder: 1 g/USD 4998 for CAS 1806389-59-2; 1 g/USD 5988
for CAS 21693922-49-6; 1 g/USD 4998 for CAS 1804422-78-3.
2017, 5800. (c) Al-Zoubi, R. M.; Al-Mughaid, H.; McDonald, R.
Aust. J. Chem. 2015, 68, 912. (d) Al-Zoubi, R. M.; Al-Zoubi, M. S.;
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 953–958

9
58
Synlett
R. M. Al-Zoubi et al.
Letter
1
Abazid, A. H.; McDonald, R. Asian J. Org. Chem. 2015, 4, 359.
e) Al-Zoubi, R. M.; Futouh, H. A.; McDonald, R. Aust. J. Chem.
013, 66, 1570. (f) Al-Zoubi, R. M.; Ibdah, A.; Al-Jammal, W. K.;
Al-Zoubi, M. S.; Almasalma, A. A.; McDonald, R. Synthesis 2018,
0, 384.
cm–1. H NMR (400 MHz, CDCl ):  = 9.73 (s, 1 H), 7.80 (d, 2 H,
3
13
(
2
J = 7.4 Hz). C NMR (100 MHz, CDCl ):  = 194.5, 164.5, 161.8,
131.3 131.29, 129.2 129.0, 97.7, 97.6. HRMS (ESI): m/z calcd for
3
+
C H FI O [M + H] : 376.8336; found: 376.8331.
7
4
2
5
4-Chloro-2,6-diiodobenzaldehyde (8A)
(
12) (a) DiMichele, L.; Menzel, K.; Mills, P.; Frantz, D.; Nelson, T.
Magn. Reson. Chem. 2006, 44, 1041. (b) Menzel, K.; Dimichele,
L.; Mills, P.; Frantz, D. E.; Nelson, T. D.; Kress, M. H. Synlett 2006,
Yellow solid (312 mg, 78% yield). Mp 65–67 °C. IR (cast film):
3012, 3004, 2941, 2876, 1709, 1621, 1587, 1008, 867, 726, 553
–1 1
cm . H NMR (400 MHz, CDCl ):  = 9.72 (s, 1 H), 8.05 (s, 2 H).
3
13
1948. (c) Menzel, K.; Mills, P. M.; Frantz, D. E.; Nelson, T. D.;
C NMR (100 MHz, CDCl ):  = 194.7, 141.1, 139.7, 133.5, 97.4.
3
+
Kress, M. H. Tetrahedron Lett. 2008, 49, 415. (d) Sämann, C.;
Haag, B.; Knochel, P. Chem. Eur. J. 2012, 18, 16145. (e) Al-Zoubi,
R. M.; Al-Jammal, W. K.; McDonald, R. New J. Chem. 2020, 44,
HRMS (ESI): m/z calcd for C H ClI O [M + H] : 392.8040; found:
7
4
2
392.8033.
4-Bromo-2,6-diiodobenzaldehyde (9A)
3
3
612. (f) Du, C. J. F.; Hart, H.; Ng, K. K. D. J. Org. Chem. 1986, 51,
162. (g) Liu, Y.; Kim, J.; Seo, H.; Park, S.; Chae, J. Adv. Synth.
Yellow solid (201 mg, 45% yield). Mp 101–103 °C. IR (cast film):
–1 1
3024, 3004, 2943, 2869, 1706, 1607, 1587, 943, 634 cm
. H
13
Catal. 2015, 357, 2205. (h) Wang, D.; Cai, Q.; Ding, K. Adv. Synth.
Catal. 2009, 351, 1722.
NMR (400 MHz, CDCl ):  = 9.70 (s, 1 H), 8.19 (s, 2 H). C NMR
3
(100 MHz, CDCl ):  = 194.8, 143.8, 134.0, 128.3, 97.6. HRMS
3
+
(
13) CCDC 1965598 and 1965599 contain the supplementary crys-
tallographic data for compounds 10A and 19, respectively. The
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/getstruc-
tures.
14) (a) Boehm, V. P. W.; Schulze, V.; Broenstrup, M.; Mueller, M.;
Hoffmann, R. W. Organometallics 2003, 22, 2925. (b) Hoffmann,
R. W.; Broenstrup, M.; Mueller, M. Org. Lett. 2003, 5, 313.
(ESI): m/z calcd for C H BrI O [M + H] : 436.7535; found:
7
4
2
436.7528.
2,6-Diiodo-4-methylbenzaldehyde (10A)
Yellow solid (288 mg, 76% yield). Mp 130–132 °C. IR (cast film):
–
1
3031, 3010, 3004, 2953, 2896, 1713, 1621, 1589, 981, 736 cm
.
1
(
H NMR (400 MHz, CDCl ):  = 9.76 (s, 1 H), 7.86 (s, 2 H), 2.31 (s,
3
13
3 H). C NMR (100 MHz, CDCl ):  = 195.5, 146.1, 142.5, 132.2,
3
+
98.0, 20.5. HRMS (ESI): m/z calcd for C H I O [M + H] :
8
7 2
(c) Mueller, M.; Broenstrup, M.; Knopff, O.; Schulze, V.;
372.8586; found: 372.8584.
Hoffmann, R. W. Organometallics 2003, 22, 2931. (d) Schulze, V.;
Bronstrup, M.; Bohm, V. P. W.; Schwerdtfeger, P.; Schimeczek,
M.; Hoffmann, R. W. Angew. Chem. Int. Ed. 1998, 37, 824.
15) Schnuerch, M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.;
Stanetty, P. Chem. Soc. Rev. 2007, 36, 1046.
2,6-Diiodo-4-methoxybenzaldehyde (11A)
Yellow solid (317 mg, 80% yield). Mp 83–85 °C. IR (cast film):
3027, 3011, 2945, 2879, 1713, 1621, 1587, 1207, 1186, 873,
–
1 1
(
(
736 cm . H NMR (400MHz, CDCl ):  = 9.71 (s, 1 H), 7.59 (s, 2
3
13
H), 3.86 (s, 3 H). C NMR (100 MHz, CDCl ):  = 194.8, 162.6,
3
16) General Procedure for the MIE Reaction between 5-Substi-
tuted 1,2,3-Triiodobenzenes and Ethyl Formate
127.8, 126.7, 99.4, 56.2. HRMS (ESI): m/z calcd for C H I O [M +
8
7
2
2
+
H] : 388.8535; found: 388.8529.
A flame-dried round-bottom flask was charged with 5-substi-
tuted 1,2,3-triiodobenzene (1.02 mmol, 1.0 equiv.) and 10 mL of
freshly dried THF. The mixture was cooled down under argon
gas to –78 °C. 2 M solution of isopropylmagnesium chloride
Methyl 4-formyl-3,5-diiodobenzoate (12A)
Yellow solid (280 mg, 66% yield). Mp 76–78 °C. IR (cast film):
3031, 3015, 2983, 2907, 1741, 1716, 1627, 1583, 1207, 1131,
–
1 1
867, 627 cm . H NMR (400 MHz, CDCl ):  = 9.78 (s, 1 H), 8.61
3
13
(1.15 mmol, 1.1 equiv.) was added dropewise over 1 h. The solu-
(s, 2 H), 3.96 (s, 3 H). C NMR (100 MHz, CDCl ):  = 195.2,
3
tion was stirred for 30 min at the same temperature. Ethyl
formate (1.53 mmol, 1.50 equiv.) was added and the mixture
163.5, 142.1, 139.4, 134.9, 96.1, 53.2. HRMS (ESI): m/z calcd for
+
C H I O [M + H] : 416.8485; found: 416.8477.
9
7
2
3
left to warm up overnight. Saturated NH Cl (20 mL) was added,
2-Chloro-6-iodobenzaldehyde (13A)
4
and the reaction mixture was extracted with diethyl ether
Yellow solid (209 mg, 77% yield). Mp 80–82 °C. IR (cast film):
–1
(2 × 50 mL). Organic layers were combined, washed with brine,
3021, 3002, 2937, 2889, 1719, 1641, 1599, 867, 764, 537 cm
.
1
dried with Na SO , filtered, and evaporated under reduced pres-
H NMR (400 MHz, CDCl ):  = 10.19 (s, 1 H), 7.94 (d, 1 H, J = 8.0
2
4
3
sure. The crude product was purified by flash chromatography
5% EtOAc/hexane) to yield the pure desired product.
,6-Diiodobenzaldehyde (6A)
Yellow solid (261 mg, 71% yield). Mp 58–60 °C. IR (cast film):
Hz), 7.48 (d, 1 H, J = 8.0 Hz), 7.13 (t, 1 H, J = 7.9 Hz). 13C NMR
(
2
(100 MHz, CDCl ):  = 191.7, 140.1, 136.9, 134.1, 133.1, 131.2,
3
+
96.4. HRMS (ESI): m/z for C H ClIO [M + H] : 266.9074; found:
7
5
266.9067.
2-Bromo-6-iodobenzaldehyde (14A)
3
026, 3008, 2913, 2887, 1715, 1613, 1598, 983, 864 cm–1
.
1
H NMR (400 MHz, CDCl ):  = 9.78 (s, 1 H), 8.01 (d, 2 H, J = 7.8
Hz), 6.86 (t, 1 H, J = 7.8 Hz). C NMR (100 MHz, CDCl ):  =
Yellow solid (238 mg, 75% yield). Mp 87–89 °C. IR (cast film):
3
13
–1 1
3019, 3004, 2983, 2876, 1714, 1607, 1596, 861, 584 cm . H
3
1
95.7, 141.6, 135.6, 134.6, 97.5. HRMS (ESI): m/z calcd for
NMR (400 MHz, CDCl ):  = 10.05 (s, 1 H), 7.98 (d, 1 H, J = 8.0
Hz), 7.68 (d, 1 H, J = 8.0 Hz), 7.03 (t, 1 H, J = 8.0 Hz). C NMR
3
+
13
C H I O [M + H] : 358.8430; found: 358.8425.
7
5 2
4
-Fluoro-2,6-diiodobenzaldehyde (7A)
Yellow solid (192 mg, 50% yield). Mp 91–93 °C. IR (cast film):
028, 3004, 2979, 2846, 1719, 1642, 1599, 976, 817, 688, 524
(100 MHz, CDCl ):  = 193.1, 140.9, 134.6, 134.4, 134.4, 125.4,
3
+
96.5. HRMS (ESI): m/z for C H BrIO [M + H] : 310.8568; found:
7
5
3
310.8564.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, 953–958