Facile, One-Pot, and Gram-Scale Synthesis of 3,4,5-Triiodoanisole through a C-H Iodination/ipso-Iododecarboxylation Strategy: Potential Application towards 3,4,5-Trisubstituted Anisoles

Article abstract of DOI:10.1002/ejoc.201500887

A facile, efficient, and gram-scale method for the conversion of para-anisic acid into 3,4,5-triiodoanisole through a one-pot C-H iodination/ipso-iododecarboxylation reaction was investigated. Commercially available benzoic acid was used, which allowed the reaction to be performed on a multigram scale in good yield. This report discloses a practical method for the one-pot synthesis of hitherto unknown 3,4,5-triiodoanisole that is catalytic, scalable, efficient, and easy to work up and purify. Potential application of the target compound as a precursor for novel site-selective metal-iodine exchange and Suzuki-Miyaura cross-coupling reactions were also explored. 3,4,5-Trisubstituted anisole derivatives were provided in a highly regioselective fashion; these compounds are useful building blocks in synthesis and indeed are hard to prepare by any other means. The facile and efficient synthesis of hitherto unknown 3,4,5-triiodoanisole in a tandem one-pot C-H iodination/ipso-iododecarboxylation reaction that is catalytic, scalable, easy to work up, and easy to purify is disclosed. Potential application of the target compound as a precursor for novel site-selective metal-iodine exchange and Suzuki-Miyaura cross-coupling reactions are demonstrated.

Full text of DOI:10.1002/ejoc.201500887

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500887
Facile, One-Pot, and Gram-Scale Synthesis of 3,4,5-Triiodoanisole through a
C–H Iodination/ipso-Iododecarboxylation Strategy: Potential Application
towards 3,4,5-Trisubstituted Anisoles
Raed M. Al-Zoubi,*[a] Hussein Al-Mughaid,[a] Mariam A. Al-Zoubi,[a] Khaled T. Jaradat,[a]
and Robert McDonald[b]
Keywords: Iodine / C–H activation / Iododecarboxylation / Regioselectivity / Metal–iodine exchange
A facile, efficient, and gram-scale method for the conversion
of para-anisic acid into 3,4,5-triiodoanisole through a one-pot
C–H iodination/ipso-iododecarboxylation reaction was in-
vestigated. Commercially available benzoic acid was used,
which allowed the reaction to be performed on a multigram
scale in good yield. This report discloses a practical method
for the one-pot synthesis of hitherto unknown 3,4,5-tri-
iodoanisole that is catalytic, scalable, efficient, and easy to
work up and purify. Potential application of the target com-
pound as a precursor for novel site-selective metal–iodine ex-
change and Suzuki–Miyaura cross-coupling reactions were
also explored. 3,4,5-Trisubstituted anisole derivatives were
provided in a highly regioselective fashion; these compounds
are useful building blocks in synthesis and indeed are hard
to prepare by any other means.
ated anisole boronic acid derivative that is reported to have
unique room-temperature organocatalytic activity for green
amide bond formation between amines and carboxylic
acids.[1a,1d,1g]
Introduction
Halogenated anisoles and particularly iodinated motifs
are ubiquitous and versatile intermediates in the synthesis
of many biologically active targets and essential intermedi-
ates.[1] For instance, [3-(4-chloro-2-methylphenyl)-1-methyl-
1H-pyrazol-5-yl](2-fluoro-6-iodo-4-methoxyphenyl)meth-
anol (1; Figure 1) is a substituted pyrazole derivative that
contains iodo and fluoro groups at the C6 and C2 atoms
of the anisyl ring, respectively, and is found to have unique
activity for controlling plant disease caused by a fungal
pathogen.[2] Additionally, 9-iodo-7-methoxy-3,4-dihydro-
1H-benzo[e][1,4]diazepine-2,5-dione (2) is a substituted
benzodiazepinone derivative that contains an iodo group at
the C9 atom of the aromatic ring and is found to increase
abiotic stress tolerance in plants for strengthening plant
growth and increasing plant yield.[3] Furthermore, 2-iodo-
5-methoxy-1,1Ј-biphenyl (3) is a small iodinated anisole de-
rivative that contains an iodo group at the C2 atom of the
aromatic ring and is found to have antifungal activity
against Aspergillus niger.[4] Lastly, (2-iodo-5-meth-
oxyphenyl)boronic acid (MIBA, 4; Figure 1), is an iodin-
Figure 1. Some important iodinated anisole derivatives in medicine
and industry.
[a] Department of Chemistry,
Jordan University of Science and Technology,
P. O. Box 3030, Irbid 22110, Jordan
E-mail: rmzoubi@just.edu.jo
A broad palette of synthetic protocols for aromatic iod-
ination has been reported.[5] For instance, classical Friedel–
Crafts halogenation reactions of aromatic and polycyclic
aromatic compounds readily proceed with moderate regio-
selectivity in the presence of chloride and bromide deriva-
tives, whereas the reaction with iodide derivatives fails. Al-
ternatively, ipso-displacement reaction of amines, bromides,
and carboxylic acids on an aromatic ring such as the diazo-
http://www.just.edu.jo/eportfolio/Pages/
Default.aspx?email=rmzoubi
[b] Department of Chemistry, Gunning-Lemieux Chemistry
Centre,
University of Alberta,
Edmonton, Alberta, T6G 2G2, Canada
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500887.
Eur. J. Org. Chem. 2015, 5501–5508
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R. M. Al-Zoubi et al.
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tization of the corresponding amines, the conversion of aro- matic C–H and ipso functionalizations, as they provide one
matic bromides into aryllithium or arylmagnesium reagents regioisomer at the ortho and ipso positions, respectively.[13]
followed by reaction with iodine or the iododecarboxyl- Accordingly, we envisioned that the sequence of C–H
ation of carboxylic acids provides exclusively one regio- iodination/ipso-iododecarboxylation of benzoic acids could
isomer.[6]
be achieved in a one-pot fashion to form the desired 1,2,3-
ipso-Iododecarboxylation and directed C–H iodination triiodoarenes, as shown in Scheme 1.
of aromatic carboxylic acids have recently emerged as alter-
native and effective methods for C–H transformations for
which the position of the carboxylic acid group controls the
regioselectivity of the iodination, whereas in common C–H
activation reactions, regioselectivity is still a problem. Ad-
ditionally, aromatic carboxylic acids are inexpensive sub-
strates, broadly available, and easily removed from the prod-
uct by a simple basic workup.[7]
1,2,3-Triiodoarenes are important substrates in both syn-
thesis and biology. They exist in several biologically active
compounds that show adrenoceptor activity[7f–7q] and anal-
gesic activity,[8] they can be used as X-ray contrast agents,[9]
and they additionally show pesticidal and fungicidal activi-
Scheme 1. Synthetic approach to 1,2,3-triiodoarenes through a one-
pot C–H iodination/ipso-iododecarboxylation strategy.
Multiple examples of carboxylate-directed ortho- or ipso-
ties.[10] Owing to the relatively weak nature of the C–I bond, iodinations have been reported.[13,14] A very interesting
a particular use is found in different organic transforma- ortho-iodination and -bromination approach was developed
tions such as transition-metal-catalyzed coupling reactions recently by Yu and co-workers. It involved the PdII-cata-
and nucleophilic displacement reactions.[11] Recently, we lyzed activation of C–H bonds at 100 °C in the presence of
disclosed two practical methods for the synthesis of 1,2,3- iodine and (diacetoxy)iodobenzene (DAIB) to provide, as
triiodoarene compounds by two-step protocols from current state of the art, good substrate scope and
aromatic amines and aromatic carboxylic acids.[6a,6b] Re- yields.[13e] Other protocols for the ortho-halogenation and
markably, 1,2,3-triiodoarenes are crystalline and bench- arylation of C–H bonds have been previously devel-
stable solids. Although these methods have proven success- oped.[7g,7i–7q,13a,13f,13i,14a,15]
ful in providing the desired 1,2,3-triiodoarenes in good
Alternatively, ipso-halodecarboxylation is a fundamental
yields, activated aromatic derivatives remain a challenging organic reaction that has received considerable attention in
task. A general method allowing direct synthesis of 1,2,3- recent years as the heart of numerous C–X and C–C bond
triiodoarenes from readily available activated benzoic acids transformations.[7a–7c,7f,14f,14g,14i,14k,16] It is believed that ex-
would be highly useful.
trusion of CO2 to form the arylmetal species is the rate-
Herein, we report the first synthesis of hitherto unknown determining step in these transformations. Several stoichio-
3,4,5-triiodoanisole in a tandem one-pot C–H iodination/ metric procedures have been developed by Hunsdiecker[17]
ipso-iododecarboxylation from para-anisic acid that is cata- and Borodine,[18] including the Cristol–Firth–Hunsdiecker
lytic, scalable, efficient, and easy to work up and purify. modification,[19] Suárez modification,[7c,7d] Kochi modifica-
Potential application of the target compound as a precursor tion,[20] Barton modification,[21] and Larrosa modifica-
for novel site-selective metal–iodine exchange and Suzuki– tion,[7b] in addition to the metal-free ipso-iododecarboxyl-
Miyaura cross-coupling reactions is also demonstrated. ation of aromatic carboxylic acids developed recently by
3,4,5-Trisubstituted anisole derivatives, which are useful Gandelman and co-workers.[7a] Notably, no catalytic
building blocks in synthesis and hard to prepare by any method for the ipso-iododecarboxylation of aromatic acids
other means, are provided in a highly regioselective manner. have been reported to date.
The use of (diacetoxy)iodobenzene and iodine under UV
photolysis (Suárez modification) is an interesting approach
for the ipso-iododecarboxylation of aliphatic and aromatic
Results and Discussion
Owing to our interest in the chemistry of 1,2,3-triiodo- carboxylic acids.[7c,7d] The reaction conditions are similar
arenes, we sought to pursue new synthetic methodologies to those used by Yu (ortho-iodination) and Suárez (ipso-
to expand the scope of these substrates and also their appli- iododecarboxylation), and we envisioned that a combina-
cations in synthesis and medicine. The ability to use effec- tion of these two protocols under suitable conditions might
tive and convenient protocols to quickly generate highly be of intrinsic value to obtain a good and direct approach
functionalized building blocks for the synthesis of complex to access elusive 1,2,3-triiodoarenes quickly in a one-pot
molecules is of great interest to synthetic chemists. Our ap- fashion. We were further encouraged by recent DFT studies
proach originated by screening the literature for an efficient on ipso-decarboxylation, which revealed that ortho substitu-
method for the ortho-iodination and ipso-iododecarboxyl- ents can significantly enhance the metal-catalyzed ipso-de-
ation of benzoic acid. In spite of the number of reports on carboxylation pathway.[22] According to these studies, dou-
the iodination of aromatic compounds,[6f,12] aromatic carb- bly ortho-substituted benzoic acid is expected to be more
oxylic acids proved to be excellent directing groups for aro- reactive than the mono-ortho-substituted derivative. Conse-
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Facile, One-Pot, and Gram-Scale Synthesis of 3,4,5-Triiodoanisole
quently, it can be imagined that the Pd-catalyzed ipso-de- tion time was not beneficial, as the product was obtained
carboxylation event is switched off and is only switched on in 38% yield in this case (Table 1, Entry 12). We then inves-
after C–H iodination has occurred.
tigated whether irradiation (Suárez conditions) could fur-
To examine this hypothesis, experiments were performed ther improve this transformation. The use of a 100 W bulb
by using para-anisic acid under different reaction condi- (tungsten lamp) improved the yield and afforded desired
tions. Three possible iodoarene products can be formed by product 7 in 59% yield (Table 1, Entry 13). Other power
this transformation. The results are summarized in Table 1. sources such as 250 and 400 W bulbs dramatically lowered
The C–H iodination/ipso-iododecarboxylation reaction by the yield of desired product 7 (Table 1, Entries 15 and 16).
using palladium(II) acetate (5 mol-%), PhI(OAc)2 The best yield for the one-pot C–H iodination/ipso-iodode-
(1.5 equiv.), and molecular iodine (1.5 equiv.) in DMF at carboxylation reaction was obtained by using 10.0 mol-%
100 °C for 24 h (Yu conditions) afforded desired product 7 Pd(OAc)2, 2.0 equiv. PhI(OAc)2, and 4.0 equiv. molecular
in only 4% yield along with 2% yield of diiodinated anisole iodine in DMF under 100 W irradiation at 120 °C (Table 1,
6 (Table 1, Entry 1). The formation of para-iodoanisole iso- Entry 17). Using these conditions, the reaction also worked
mer 5 was not observed. Changing the reaction temperature well on a gram scale (Table 1, Entry 18).
and time slightly improved the yield (Table 1, Entries 2–4).
The geometry of 3,4,5-triiodoanisole (7) is supported by
Raising the catalyst loading appeared to be insignificant in X-ray crystallographic analysis (Figure 2),[23] which clearly
promoting the extrusion of CO2, as this resulted in only 15– shows the positions of the three iodo substituents. The mo-
19% conversion of product 7 (Table 1, Entries 5 and 6). The lecular geometry indicates an intermolecular steric repul-
use of 2.0 equiv. of PhI(OAc)2 improved the ipso-iodode- sion between the vicinal iodo substituents. This intermo-
carboxylation step and afforded desired product 7 in 27% lecular repulsion is released by reducing the endocyclic an-
yield (Table 1, Entry 7). These results led us to hypothesize gle (C3–C4–C5 117.1°) rather than by elongating the C–I
that an excess amount of PhI(OAc)2, which is a strong oxi- bonds.[23]
dant, resulted in oxidation of the aryl–PdII species to the
Various approaches for the activation of C–H bonds and
PdIV species, and this allowed reductive elimination to take ipso bonds through the PdII carboxylate directed function-
place in both the ortho- and ipso-iodinations. On the other alization of benzoic acids have been previously employed
hand, the use of an excess amount of PhI(OAc)2 dramati- and reported.[13b,13e,13n,24] Although our mechanism has not
cally lowered the yield of ipso-iododecarboxylation and fa- been fully studied, a plausible catalytic cycle for the one-
vored undesired processes (Table 1, Entries 8 and 9). The pot C–H iodination/ipso-iododecarboxylation is proposed
use of an excess amount of molecular iodine slightly im- in Scheme 2. Ligand exchange/PdII-initiated C–H cleavage
proved the yield (Table 1, Entries 10 and 11). A longer reac- through coordination of the lone pair of electrons of the
Table 1. Conditions for the one-pot C–H iodination/ipso-iododecarboxylation reaction of para-anisic acid.[a]
[a] All reactions were performed by using para-anisic acid (0.27 m, 3.29 mmol 1.0 equiv.) in DMF (12.0 mL). [b] Yield was determined by
1H NMR spectroscopy. [c] Yield of isolated product. [d] Tungsten lamp. [e] 5 g scale (32.86 mmol).
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R. M. Al-Zoubi et al.
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mediate in synthesis. Different synthetic transformations
were performed by using Knochel’s chemistry. The di-
iodoarene products were isolated in moderate to good
yields, as shown in Scheme 3. Having only two regiochem-
ically different sites occupied with iodine, the metal–iodine
exchange/functionalization reaction sequence can afford no
more than two possible regioisomers in this transformation,
internal H and terminal I. As we previously observed in
the metalation and reaction with 1,2,3-triiodobenzene and
3,4,5-triiodotoluene as electrophiles,[6a,6b,11a] the nature of
the electrophile has a great influence on the regioselectivity
of the reaction. For instance, the use of aldehydes as electro-
philes provided a mixture of internal and terminal benzyl
alcohol products (Scheme 3; see 8–10). Interestingly, aro-
matic aldehydes were found to favor the formation of the
internal benzyl alcohol product (see 8H and 9H), whereas
aliphatic aldehydes favored terminal products (see 10I).
Furthermore, the use of DMF as an electrophile afforded
the terminal product as a sole regioisomer (Scheme 3; see
11I). On the other hand, the use of iodomethane and water
as electrophiles afforded exclusively the internal products
(Scheme 3; see 12H and 13H).
The ability to use inexpensive and readily available start-
ing materials and intermediates to prepare highly function-
alized molecules is crucial in synthesis. Screening the litera-
ture with respect to substitutions at C1, C2, and C3 as a
core structure revealed that 1,2,3-trisubstituted arenes are a
demanding class of compounds in synthesis and medicinal
chemistry.[26] We decided to test whether our previous re-
ports could be extended and used to quickly synthesize
3,4,5-trisubstituted anisoles in a regioselective manner.
The synthesis is described in Scheme 3. The internal iodo
Figure 2. ORTEP view of 3,4,5-triiodoanisole (7). Thermal
Gaussian ellipsoids at 30% probability level.
carboxyl group results in the formation of five-membered
palladacycle A. Palladium(II) intermediate A is then oxid-
ized by IOAc, which is generated in situ from PhI(OAc)2
and molecular iodine,[25] to afford palladium(IV) intermedi-
ate B; this is followed by reductive elimination to form or-
tho-iodinated product C. The former steps are repeated to
afford ortho-diiodinated species D, which enters into the
next catalytic cycle. Irradiation-assisted decarboxylation is
likely a process that follows a single-electron transfer
mechanism via transition state E, followed by palladium
transfer to form intermediate F. Palladium(II) intermediate
F is then oxidized once more by IOAc to afford palladi-
um(IV) intermediate G, which is followed by reductive eli-
mination to form desired product 7 and to regenerate palla-
dium(II) acetate so that it can once again enter the first
catalytic cycle.
Having the optimized reaction conditions for this one- group was exchanged with excellent regioselectivity by
pot transformation in hand, we were encouraged to show using Knochel’s chemistry and iodomethane as the electro-
the application of 3,4,5-triiodoanisole (7) as a useful inter- phile to form diiodoarene 12H. Suzuki–Miyaura cross-cou-
Scheme 2. Proposed mechanism for the one-pot PdII-catalyzed C–H iodination/ipso-iododecarboxylation of para-anisic acid.
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Facile, One-Pot, and Gram-Scale Synthesis of 3,4,5-Triiodoanisole
Scheme 3. Terminal versus internal diiodinated anisole derivatives from metal–iodine exchange (MIE) of 3,4,5-triiodoanisole and different
electrophiles.
pling of 12H provided the expected monocoupled product in boronic acid (2 equiv.) was also performed to afford the bis-
91% yield (Scheme 4; see 14). Moreover, a one-pot double coupled product in moderate yield (Scheme 4; see 15).[27]
Suzuki–Miyaura cross-coupling reaction by using an aryl- Consequently, diiodoarene 12H was followed by another
Scheme 4. Possible chemical transformations toward disubstituted and trisubstituted anisole derivatives from 3,4,5-triiodoanisole (7).
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R. M. Al-Zoubi et al.
SHORT COMMUNICATION
55.9 ppm. IR (cast film): ν = 3054, 2986, 1583, 1426, 1394,
˜
metal–iodine exchange by using two different aldehydes to
provide the expected iodobenzyl alcohols in good yields
(Scheme 4; see 16 and 17).
943 cm–1. HRMS (CI): calcd. for C7H5I3O [M]+ 485.7474; found
485.7468.
Acknowledgments
Research reported in this publication was supported by the Jordan
University of Science and Technology (JUST), Faculty of Research,
under application number F#20150044. We thank the Department
of Chemistry at the University of AlbertaϾ for X-ray crystallo-
graphic analysis.
Conclusions
We described the first one-pot synthesis of 3,4,5-tri-
iodoanisole on a gram scale from para-anisic acid through a
directed C–H iodination/ipso-iododecarboxylation strategy.
This reaction is operationally simple, catalytic, scalable, and
easy to work up and purify. 3,4,5-Triiodoanisole is a crystal-
line and remarkably bench-stable solid. The molecular ge- [1] a) N. Gernigon, R. M. Al-Zoubi, D. G. Hall, J. Org. Chem.
2012, 77, 8386–8400; b) S. A. Mousa (Vascular Vision Pharma-
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H. Tsukada, A. Hirabayashi, Y. Takahashi, Y. Aoki, A. Kawa-
stituted anisole derivatives in a series of regioselective
metal–iodine exchange and Suzuki–Miyaura cross-coupling
reactions. The products were isolated in moderate to good
yields, are valuable building blocks, and are difficult to pre-
pare by other means. With other iodo groups on the aryl
ring, further elaboration can easily be explored.
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Experimental Section
General: All commercial reagents and chromatography solvents, in-
cluding diethyl ether, ethyl acetate, hexanes, palladium(II) acetate
[Pd(OAc)2], (diacetoxy)iodobenzene (DAIB), anhydrous sodium
sulfate (Na2SO4, BDH), isopropylmagnesium chloride (iPrMgCl,
2 m in THF), and molecular iodine (I2), were used as obtained un-
less otherwise stated. Anhydrous solvents were distilled from appro-
priate drying agents prior to use. Analytical thin-layer chromatog-
raphy (TLC) was performed on Merck silica gel 60 F254. Merck
silica gel 60 (0.063–0.2 mm) was used for column chromatography.
Visualization of TLC was accomplished with UV light (254 nm).
NMR spectra were recorded with a Bruker-Avance 400 MHz spec-
trometer. The residual solvent protons (1H) or the solvent carbon
atoms (13C) were used as internal standards. Chemical shifts are
given downfield from tetramethylsilane. High-resolution mass spec-
tra were recorded by using chemical ionization (CI) and electro-
spray ionization (ESI) techniques.
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Synthesis of 3,4,5-Triiodoanisole (7) through the One-Pot Directed
C–H Iodination/ipso-Iododecarboxylation of para-Anisic Acid: A
flame-dried, 100 mL round-bottomed flask was charged with para-
anisic acid (3.29 mmol, 1.00 equiv.), palladium(II) acetate
(0.33 mmol, 0.10 equiv.), (diacetoxy)iodobenzene (6.57 mmol,
2.0 equiv.), iodine (13.14 mmol, 4.00 equiv.), and anhydrous N,N-
dimethylformamide (12.2 mL) in air. The flask was then sealed with
a septum, and the mixture was stirred at 120 °C and irradiated
(100 W bulb) for 24 h. The mixture was cooled to room tempera-
ture, diluted with ethyl acetate (50 mL), and filtered through a pad
of Celite (545). The organic phase was washed with 0.5 n HCl (4ϫ
20 mL), brine, dried (Na2SO4), and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (100% hexanes) and washed with cold hexanes to yield
the desired product as a white solid (64% yield). M.p. 79–81 °C.
1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 2 H), 3.74 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 159.8, 138.5, 125.5, 110.0, 106.3,
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[27] For other examples of the site-selective Suzuki–Miyaura cross-
coupling reaction of 3,4,5-triiodoanisole (7) with different aryl-
boronic acids, see ref.[11b]
Received: July 6, 2015
Published Online: August 6, 2015
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