Pd(II) catalyzed ortho C-H iodination of phenylcarbamates at room temperature using cyclic hypervalent iodine reagents

Article abstract of DOI:10.1039/c5cc02533h

A novel approach to access ortho iodinated phenols using cyclic hypervalent iodine reagents through palladium(II) catalyzed C-H activation has been developed through weak coordination. The reaction showed excellent regioselectivity, reactivity and good functional group tolerance. A unique mechanism was proposed.

Full text of DOI:10.1039/c5cc02533h

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Pd (II) Catalyzed ortho C-H Iodination of Phenylcarbamates at
Room Temperature with Cyclic Hypervalent Iodine Reagents
Xiuyun Sun, † Xia Yao, † Chao Zhang and Yu Rao*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel approach to access ortho iodinated phenols with cyclic phenols. After many fruitless efforts, we turned our attentions to
hypervalent iodine agents through palladium (II) catalyzed C-H other type iodine sources
activation has been developed through weak coordination. The
ODGs
ODGs
Current C-H halogenation methods
reaction showed excellent regioselectivity, reactivity and good
functional group tolerance. A unique mechanism was proposed.
R
R
I
DGs = Directing Groups
Aryl iodides are indispensably important chemicals both in natural
product and pharmaceutical drug synthesis.1 Traditional approaches
to access aryl iodides involve ortho-deprotonative metalation,2
electrophilic aromatic substitution3 or Sandmyer reaction,4 which
usually suffer from several disadvantages, such as harsh reaction
conditions, dangerous operations and toxic reagents. In the last
decade, transition metal catalyzed C-H halogenation of arenes had
emerged as a powerful tool to prepare aryl halides.5 Among these
significant progress, direct C–H iodination through palladium
catalysis with IOAc or I2 as iodine source has been well established
by Yu’s group.6 Meanwhile, Glorius and coworkers reported the first
example of rhodium (III) catalyzed ortho iodination of ketones,
benozates and aromatic amides with NIS.7 Although the impressive
advances had been made, there are important challenges remain
for ortho C-H iodination in terms of substrate scope and efficiency
of these protocols. For instance, there is no effective and mild
method to obtain ortho iodinated phenols yet. Current C-H
iodination methods will provide para-iodinated phenols by
electrophilic iodination as the major products. Therefore, due to
their extreme significance, developing new practical method to
synthesize aryl iodides is still highly desired. Herein, we report the
development of an ortho-iodinated phenol synthesis under
palladium catalysis at room temperature with hypervalent iodine
reagents as effective iodination agents.
O
I
N
O
N
Pd(II), TfOH, DCE, I(III)-OMe
room temperature
R
R
O
O
OMe
I
Difficult to access
This work
O
I(III)-OMe =
O
Scheme 1 A new approach to access ortho-iodinated phenols.
Hypervalent iodine reagents have been broadly utilized as oxidants
in organic synthesis.9 In recent years, it has found further
applications in transition metal-catalyzed C-H functionalizations. For
example, PhI(OAc)2 were employed to build C-C bonds or as
powerful oxidants in C-H activation reactions.10 Two kinds of Togni’s
reagents (cyclic iodine(III)) were used for constructing C-
trifluoromethyl bonds.11 More recently, a new sp3 C-H alkoxylation
method by palladium(II) with cyclic iodine (III) reagents were
developed by our laboratory.12 During our investigations of this sp3
C-H alkoxylation reaction, a trace amount of sp2 C-H iodinated 4-
aminoquinoline derivatives were observed, which aroused our
curiosity. We proposed the cyclic iodine (III) reagents might
promote
a palladium-iodide complex intermediate formation
through oxidative addition, then reductive elimination can form C-I
bond under our reaction conditions. Inspired by this result, we
envisioned that the cyclic iodine (III) reagents may serve not only as
a critical oxidant but also a potential iodine source in sp2 C-H
iodination. Therefore, we describe the first example of employing
hypervalent iodine reagents in palladium catalyzed ortho iodination
of phenols at room temperature.
Recently we reported a new method to construct C-Cl and C-Br
bonds in arenes containing different weak coordinating groups.8 In
our group continuous studies of preparation of aryl halides via
transtion-metal catalysis, we tried to access ortho C-I bond with
phenol substrates by the same strategy. However, the attempt
failed with different iodine (I) reagents and palladium catalysts. In
those cases, electrophilic iodination always dominated the
regioselectivity outcome of reactions to give para-iodinated
To test our hypothesis, a model investigation was initiated with a
carbamate derivative 1. At the beginning of our studies, a variety of
hypervalent iodine oxidants including cyclic hypervalent iodine (III)
oxidants (I-OAc, I-OMe, Togni’s reagent) and acyclic hypervalent
PhI(OAc)2, etc, were examined in the presence of Pd(OAc)2 in DCE
a.MOE Key Laboratory of Protein Sciences, Department of Pharmacology and
Pharmaceutical Sciences, School of Medicine and School of Life Sciences, Tsinghua
University, Beijing 100084, China E-mail: yrao@mail.tsinghua.edu.cn
† These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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(Table 1). To our delight, desired ortho-iodinated phenol 2 was substituted substrates, C-H halogenation exclusively occured at
formed smoothly with Togni’s reagent at room temperature in a ortho-position of carbamate groups to give expected iodinated
yield of 20% and no para-iodination isomer can be observed (entry compounds (17-19). For substrate with a potential competing
1). Among all surveyed cyclic iodine (III) reagents, 1- methoxy-1,2- ketone directing group, corresponding products 20 can be obtained
benziodoxole-3(1H)-one (I(III)-OMe) was found to be superior over as well in a yield of 64%.
others.13 Further testing revealed that the combination of I(III)-
Figure 1 Reaction Scope
OMe/DCE/TfOH gave the best results (entry 9) in a good yield of
70%. In constrast, no product was detected with acyclic iodine (III)
reagents (entry 3-5). Remarkably, this reaction could be conducted
at room temperature and finished within several hours without the
need of air- and moisture-proof. It was found higher reaction
temperature (entry 10-12) resulted in lower yields because of the
potential decomposition of products. Additionally, conventional
iodine (I) reagents such as NIS or I2/ PhI(OAc)2 gave mainly
electronic iodinated products (entry 13-14) under this reaction
conditions. Further investigations confirmed that palladium catalyst
was essential for the reaction (entry 16). Meanwhile, Other metal
catalysts including Ru(II) and Rh(III), etc, cannot promote this
transformation under the reaction conditions (entry 17).
Table 1 Optimization of the reaction conditions
As illustrated in scheme 2, to prove the practicality of this method,
2-bromo-6-iodophenol 23 was readily synthesizd from 2-
bromophenyl dimethylcarbamate 1 through a one-pot procedure
With the optimized conditions in hand, we next set up to explore
the reaction scope. As displayed in figure 1, a variety of phenol
carbamates were efficiently converted into ortho-iodinated phenol including C-H iodination and deprotection. 23 can be further
derivatives in moderate to good yields.14 The scope of the
reactions were found to be broad. Both electron-donating and
electron-withdrawing subsituents in ortho, meta and para positions
(-Me, -CF3, halides, ester and benzoyl group, etc.) were well
tolerated, leading to the formation of the desired products (3-22).
For instance, satisfactory yields were obtained with substrates
which contained strong electron-withdrawing groups such as CF3
and F (13, 14). It is notable that the aldehyde group was found to be
compatible with the reaction conditions as well, albeit in a relatively
low yield of 15. To our delight, excellent ortho-selectivity was
consistantly observed and no corresponding para-isomers were
formed in all ortho-substituted substrates (4-8, 21). Only one
regioisomeric product was produced with meta-substituted
substrates due to the steric discrimination (9-16, 22). As to para-
transformed into compound 24 which serves as the synthetic
building block of Honokiol derivatives for the treatment of
proliferative disorders.15 To exemplify the synthetic utility of this
iodination reaction, 2-iodophenol 3 was converted into diverse
derivatives via different coupling reactions. For instance, biaryl
compound 21 can be prepared from 3 via a sequential Suzuki
coupling and C-H iodination reactions. With the newly installed
iodine atom, 21 can undergo an iterative coupling reaction to
provide various complex molecules.
3 was also successfully
employed in the sp3 C-H arylation reaction16 to give corresponding
compound 25, which can be further transformed into chroman-2-
one products. In addition, the cyanation reaction with 3 could
afford useful chemical 26 respectively.
2 | J. Name., 2012, 00, 1-3
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aromatic substrate reacted slower than its eletron-rich
counterparts to give iodinated products (please see SI for details).
These results suggested that C-H activation may not be involved in
the rate-limiting step of this transformation. Further NMR studies
were performed to gain more insight into the reaction mechanism.
As illustrated in scheme 4, some part of cyclic iodine (III) reagent A
will be quickly converted to oxidant B in the presence of TfOH. After
addition of substrate C and palladium catalysts, the amount of
product 7 gradually increased with the consumption of C and
oxidants A, B over 4 hrs at room temperature. During progress of
reaction, the formation of the possible methyl benzoperoxoate D17
can be found from proton-NMR. Corresponding mass signal of D
was observed by LC-MS analysis (please see SI for details). We also
found a small amount of F (2-iodobenzoic acid) which should result
from decomposition of oxidants.
Scheme 2 Semi one-pot synthesis and applications.
Although mechanism details remain to be ascertained, on the basis
of our experimental studies, a possible mechanism for this C-H
iodination reaction can be proposed as followings. In the plausible
catalytic cycle, step (i) would involve chelation of palladium(II) to
carbonyl oxygen atom from the carbamate substrates and the
formation of a six-membered cyclopalladium intermediate. In the
second step (ii), Pd(II) can be oxidized into possible Pd(IV)18
intermediate by the cyclic hypervalent iodine(III) oxidant. During
the process of oxidative addition, iodine was added to
cyclopalladium intermediate. Finally, the third step (iii) involves
carbon-iodine bond-forming reductive elimination to afford ortho-
iodinated phenol product and turned Pd(IV) back into Pd(II).
Scheme 3 KIE study.
In conclusion, we have established a unique Pd(II)-catalyzed ortho
C-H iodination reaction. This method provides
a novel and
convenient access to a broad range of highly valuble 2-iodine
phenols from readily accessible substrates. The cyclic hypervalent
iodine(III) oxidant plays a critical role in this reaction. A possible
Pd(II)/(IV) pathway might be involved. This reaction shows broad
functional-group tolerance, excellent reactivity and good yields.
Further studies into the mechanism and synthetic applications of
this reaction are in progress in our laboratory.
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