Base- and Additive-Free Ir-Catalyzed ortho-Iodination of Benzoic Acids: Scope and Mechanistic Investigations

Article abstract of DOI:10.1021/acscatal.7b02987

A protocol for the C-H activation/iodination of benzoic acids catalyzed by a simple iridium complex has been developed. The method described in this paper allows the ortho-selective iodination of a variety of benzoic acids under extraordinarily mild conditions in the absence of any additive or base in 1,1,1,3,3,3-hexafluoroisopropanol as the solvent. The iridium catalyst used tolerates air and moisture, and selectively gives ortho-iodobenzoic acids with high conversions. Mechanistic investigations revealed that an Ir(III)/Ir(V) catalytic cycle operates, and that the unique properties of HFIP enables the C-H iodination using the carboxylic moiety as a directing group.

Full text of DOI:10.1021/acscatal.7b02987

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Article
Base- and Additive-Free Ir-Catalyzed ortho-Iodination of
Benzoic Acids: Scope and Mechanistic Investigations
Elis Erbing, Amparo Sanz-Marco, Ana Vázquez-Romero, Jesper Malmberg,
Magnus J. Johansson, Enrique Gomez-Bengoa, and Belen Martin-Matute
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02987 • Publication Date (Web): 12 Dec 2017
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ACS Catalysis
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Base- and Additive-Free Ir-Catalyzed ortho-Iodination of Benzoic Ac-
ids: Scope and Mechanistic Investigations
Elis Erbing,1,‡ Amparo Sanz-Marco,1,‡ Ana Vázquez-Romero,1 Jesper Malmberg,2 Magnus J. Johans-
son,3 Enrique Gómez-Bengoa,4 Belén Martín-Matute1,*
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1 Department of Organic Chemistry, Stockholm University, Stockholm 10691, Sweden
2 RIA iMed, Medicinal Chemistry, AstraZeneca R&D, Mölndal 43183, Sweden
3 CVMD iMed, Medicinal Chemistry, AstraZeneca R&D, Mölndal 43183, Sweden
4 Departamento de Química Orgánica I, Universidad del País Vasco/UPV-EHU, Manuel de Lardizabal 3, Donostia – San
Sebastián 20018, Spain
ABSTRACT: A protocol for the CH activation/iodination of benzoic acids catalyzed by a simple iridium complex has been devel-
oped. The method described in this paper allows the ortho-selective iodination of a variety of benzoic acids under extraordinarily
mild conditions in the absence of any additive or base in 1,1,1,3,3,3-hexafluoroisopropanol as the solvent. The iridium catalyst used
tolerates air and moisture, and selectively gives ortho-iodobenzoic acids with high conversions. Mechanistic investigations revealed
that an Ir(III)/Ir(V) catalytic cycle operates, and that the unique properties of HFIP enables the CH iodination using the carboxylic
moiety as a directing group.
KEYWORDS: CH iodination, benzoic acids, iridium catalysis, 1,1,1,3,3,3-hexafluoroisopropanol, hydrogen bonding.
Carboxylic acids are ubiquitous in natural products.10
However, their use as ortho-directing groups in reactions
involving the activation of CH bonds has been challenging
in terms of yields and selectivity. This is partly due to that in
1. INTRODUCTION
Transition-metal-directed activation of inert CH bonds is
one of the most efficient ways to introduce functional groups
into organic molecules. The combined use of molecules
bearing directing groups with the aid of transition-metal
catalysts enables the regioselective activation and
functionalization of particular CH bonds.1
the absence of catalyst, the carboxylic acid moiety is a meta-
directing group. This is not the case with for example
anilines and derivatives,9h which direct the functionalization
to the ortho and para positions even in the absence of
Compounds containing aromatic halides are important
building blocks that are ubiquitous in synthetic organic
chemistry laboratories. They play pivotal roles in drug and
natural-product syntheses.2 Furthermore, aromatic bromides
and iodides have been extensively used in cross-coupling3
and in Grignard reactions.4 The functionalization of aromatic
compounds with halides through the direct activation of CH
bonds is a straightforward way to obtain halogenated
aromatics. The first examples have been reported only in the
Scheme 1. CH iodination of benzoic acids.
last decade, and were limited to the use of strong, nitrogen-
containing directing groups, using palladium catalysis.5 We
have also recently reported a heterogeneous Pd catalyst that
halogenates nitrogen-functionalized aromatics.6 More
recently, different arenes bearing several directing groups,
including amides, ketones, and even carbamates could be
halogenated in the ortho position by transition metal
catalysts.7,8,9 In this context, Nicholls and coworkers9h re-
ported the only example for this transformation employing
an Ir catalyst. They described the ortho-halogenation of
acetanilides employing [Cp*IrCl2]2. The use of catalytic
amounts of Boc-L-Phe and AgNTf2 were necessary to obtain
high yields and good regiocontrol.
catalysts. During the last few years, however, this field has
experienced significant development,11 and a variety of
methods to construct C−C and C−N bonds have been
described using Pd,12 Ru13 and Rh.14 With regard to the use
of iridium catalysts, Satoh and Miura,15 and Ison16 reported
the oxidative coupling reaction of benzoic acids with
alkynes, yielding naphthalenes and isocoumarines. Very
recently, Zeng´s group reported the o-alkynylation of
carboxylic acids using excess of KHCO3.17 Gooßen has
described the o-arylation of carboxylic acids with
arenediazonium salts in the presence of Ag2CO3 and
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Li2CO3.18 Iridium-catalyzed ortho-C–H amidation of benzoic
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solvents, such as CF3CO2H (TFA) (pKa = 0.2) the activity
was compromised (entry 12). Under the optimal conditions,
we evaluated again the catalytic activity of chloride complex
I, which afforded 2a in only 40% yield after 16 h (entry 13).
Upon increasing the temperature to 70 °C, 2a was obtained
in 77% yield after 48 h, together with 15% of starting mate-
rial, the reminder being unidentified by-products (entry 14).
A control experiment in the absence of catalyst resulted in
iodination of the meta position in 56% yield (entry 15). This
background meta-iodination is completely suppressed under
the catalytic conditions reported here. All reactions were
carried out under an atmosphere of air.
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acids with sulfonyl azides using AgNTf2, AcOH and Li2CO3
as additives was described by Cui and co-workers.19
The introduction of halides into benzoic acids through CH
activation has been, however, quite limited, despite the po-
tential utility of such substrates.11 There is only one report,
by Yu and coworkers, that describes the ortho-iodination of
carboxylic acids,20 where Pd(OAc)2 is used in the presence
of superstoichiometric amounts of IOAc. This method af-
forded good yields at 100 °C in 36 h. The direct CH io-
dination of benzoic acids under milder reaction conditions
would allow the introduction of iodide at a late stage, and a
CH iodination protocol avoiding the use of additives (i.e.,
bases, silver salts, or strong oxidants) would significantly
increase the functional-group tolerance as well as the atom
economy.
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Table 1. Screening of the reaction conditions.a
Our group has gained extensive knowledge about the se-
lective transition-metal-catalyzed halogenation of mole-
cules.21 We have reported 1,3-hydrogen shift / halogenation
protocols for aliphatic and aromatic allylic alcohols under
mild conditions using iridium catalysis. In this paper, we
report a mild, efficient, and extraordinarily simple method
for the selective ortho CH iodination of benzoic acids cata-
lyzed by a P/N-ligandless Ir(III) catalyst (Scheme 1). Exper-
imental and theoretical investigations elucidating the mecha-
nism and the unique role of the solvent are also presented.
NIS
(equiv.)
Yield
Entry
Solvent
Acetone
HFIP
T (°C)
60
Cat Additives
(%)b
AgBF4/
NaOAc
1
2
3
4
I
3
3
3
3
25
AgBF4/
NaOAc
60
I
86
90
86
AgBF4/
II
HFIP
60
NaOAc
AgBF4/
II
HFIP
40
NaOAc
2. RESULTS AND DISCUSSION
5
HFIP
HFIP
Acetone
DCEd
THF
iPrOH
TFEe
40
40
40
40
40
40
40
40
40
70
40
II
II
II
II
II
II
II
II
I
-
-
-
-
-
-
-
-
-
-
-
3
88
98c
5
We started using 2-methylbenzoic acid (1a) as the model
substrate with NIS (N-iodosuccinimide) as the halogenating
agent, and investigated the influence of a number of
parameters (Table 1 and S1). Due to their excellent
performance in halogenation reactions under both air and
water,21 and inspired by the reaction conditions reported by
Gooßen18 for CH arylations, we investigated complexes of
the general structure [Cp*Ir(III)]. Glorius has also reported
excellent results using related [Cp*Rh(III)X2] complexes in
the CH halogenation of other aromatic compounds.8
When 1a was treated with 3 equiv. of NIS and [Cp*IrCl2]2 in
the presence of catalytic amounts of AgBF4 and NaOAc
(Table 1), in acetone at 60 °C, a 25% yield of 2b was ob-
tained (entry 1). Other solvents were tested under otherwise
identical conditions (Table S1), but the best results were
obtained in HFIP (1,1,1,3,3,3-hexafluoroisopropanol), which
gave 2a in 86% yield (entry 2). With chloride-free
([Cp*Ir(H2O)3]SO4) II, easily prepared from I,22 the yield
increased to 90% (entry 3). The temperature could be low-
ered to 40 °C without compromising the yield (entry 4). In
the absence of additives, the yield did not decrease, giving
2a in 88% yield (entry 5). Furthermore, with only 1.5 equiv.
of NIS, 2a was formed in nearly quantitative yield (entry 6).
Intrigued by these excellent results without additives, we
wondered whether the solvent had a significant impact on
the reaction. In acetone, 1,2-dichloroethane (DCE), or THF
no product was obtained at 40 °C (entries 7-9). Interestingly,
iPrOH did not yield any product. In contrast, 2,2,2-
trifluoroethanol (TFE), gave a 73% yield (entry 11). Thus,
protic solvents with low pKa values such as HFIP (pKa = 9.3)
or TFE (pKa = 12.4) give the best results. In more acidic
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
6
7
8
0
9
0
10
11
12
13
14
15
0
73
0
TFAf
HFIP
HFIP
HFIP
40
77g
0h
I
-
aUnless otherwise noted, all experiments were carried out under air
atmosphere on 0.15 mmol scale of 1a and 0.1 M. AgBF4 (20 mol %),
NaOAc (30 mol %) for 16 h. bDetermined by 1H NMR spectroscopy
against an internal standard (1,2,4,5-tetrachloro-3-nitrobenzene). cIso-
lated yield. dDCE = 1,2-dichloroethane. TFE = 2,2,2-trifluoroethanol.
e
fTFA = trifluoroacetic acid. Yield of 2a after 48 h. The reminder being
g
15% of starting material and 8% of unidentified by-products hIodination
in meta position in 56% yield after 18 h.
The compatibility of the reaction conditions with different
functional groups was preliminary evaluated by performing a
robustness-screening test23 (Scheme 2). Thus, the iridium-
catalyzed CH iodination reaction in the presence of a varie-
ty of functionalized molecules. Under the optimal conditions
(Table 1, entry 6), amines, amides, ethers, esters, alcohols
and halogenated compounds were well tolerated, and 2a was
obtained in good yield (Scheme 2 and Table S2). On the
other hand, the reaction is non-compatible with double or
triple bonds, nor with carbonyl functional groups (see SI for
further details).
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from o-substituted benzoic acids (1a-1p) were obtained in
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very high yields (Scheme 3). Among these, substrates bear-
ing halogens substituents (1b-1d) gave yields from 70 to
98%. Lower yields were obtained for the more electron-
withdrawing CF3 and NO2 (1e-1f).¶ Alcohols, ethers, esters,
carboxylic acids,§ amines and amides are well tolerated in
agreement with the robustness test, and 2g-2p were obtained
in high yields showing the broad functional group tolerance
of this methodology. Selectively monoiodinated products
were obtained with meta-substituted 1q-1t. Highly substitut-
ed benzoic acids 1u-1ab were also iodinated. Full control
over the regioselectivity was also obtained in substrates with
two ortho CH positions (2q-v).¥ Benzoic acid itself gave a
mixture of mono- and diiodinated products 2ac and 3ac,
respectively. By increasing the catalyst loading and the
number of equivalents of NIS, 3ac was obtained as the major
product. Under these conditions, 1q gave diiodinated 3q, and
1ad and 1ae, the latter with two acid groups, were diiodinat-
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Scheme 2. Robustness screening test.
Based on the results from the robutness-screening test, the
scope of the reaction was investigated. Iodinated products
Scheme 3. Scope of the reaction. Isolated yields (yield by 1H NMR spectroscopy in parentheses). aThe reaction was carried out at 60 °C.
bThe reaction was carried out at 60 °C using a catalyst loading of 5 mol %. cAt 65 °C using 2 equiv. of NIS. dAt 65 °C using 3 equiv. of
NIS. eAt 40 °C using 3 equiv. of NIS.
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nation is the slowest step (25.6 kcal/mol), which is incon-
Page 4 of 7
ed in very good yields.
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4
sistent with the CH bond being broken in the rls.
These data are intriguing and could be related with the fact
that the experimental results were substantially better when
Mechanistic investigations were then undertaken. First, we
studied whether iridacycles in oxidation state +3 are inter-
mediates. When 1a was treated with a superstoichiometric
amount of II (1.1 equiv.) at 40 °C in HFIP, an iridacyclic
1
structure was formed and characterized by H NMR spec-
5
troscopy (See SI). The iridacycle thus prepared could not be
isolated. We therefore prepared DMSO-stabilized iridacycle
6a instead (Scheme 4a).16 Reaction of 6a with NIS at 0 °C
gave, within a few minutes, 2a (Scheme 4b). Furthermore,
when 6a was used as a catalyst (Scheme 4c), the results did
not differ from those obtained with II. The reversibility of
the CH activation was confirmed when a 1:1 mixture of
iridacycle 6a and 2-chlorobenzoic acid 1c was reacted in
HFIP at 40 °C (Scheme 4d and SI). After 1 h, a mixture of
both carboxylic acids 1a and 1c, as well as iridacycles, 6a
and 6c was observed. Similar results were obtained when 6a
was reacted with carboxylic acids 1e or 1f (See SI, S27).
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Scheme 5. Iodination of 6a in different solvents.
Scheme 6. KIE determination.
the reactions were carried out in HFIP, as opposed to other
solvents (Table 1 and Scheme 5). The similarity of the acti-
vation energies of the three steps, and the crucial role of
HFIP suggest a complex mechanism involving a change in
rls depending on the reaction conditions. It has been demon-
strated that fluorinated alcohols can be exceptional reaction
media for various transformations, including CH activa-
tions.24 Therefore, the cycle was re-computed in the presence
of HFIP, which can form H-bonds with NIS,25 facilitating or
disabling the different steps of the reaction. The Ea of the
three consecutive steps now became 21.4, 20.0 and 23.6
kcal/mol, respectively (Figure 1). The electron withdrawing
effect of the H-bonding with HFIP26 was found to destabilize
preferentially Ir(V) intermediate INT-2 (resting state in the
absence of HFIP, see SI), thus reducing the Ea of the reduc-
tive elimination (TS-RE), and accelerating the reaction. This
agrees well with the kinetic profile of the reaction of 6a with
NIS in different solvents (Scheme 5 and Table 1). The CH
activation step then becomes the rls (TS-CH, 23.6 kcal/mol)
and occurs via a concerted metalation-deprotonation (CMD)
pathway,27 agreeing well with the excellent results obtained
in the absence of any base, and explaining the superior
activity in HFIP as the solvent (Table 1).¶ Futher attempts to
support the proposed mechanism resulted in the
Scheme 4. Experimental mechanistic studies.
When comparing the iodination rates of 6a in different
solvents, it was observed that the reaction was significantly
accelerated in HFIP (Scheme 5).
A KIE (kinetic isotope effect) of 2.90 ± 0.36 was obtained
when comparing the rate of 1a to that of 1a-d1 (Scheme 6
and Figures S5-S6) under noncompetition conditions. The
reversibility of the CH activation (vide supra, Scheme 4d)
is in agreement with the magnitude of this KIE. The high
iodination rate of iridacycle 6a (Scheme 4b), together with
the KIE, indicates that the CH bond is broken in the rate-
limiting step (rls).
To obtain further information, DFT calculations were
carried out using M06/6-311G** (SDD for Ir, I) with a solv-
ation model (IEFPCM, solvent = TFE). Initially, taking the
iridacycle SM as the reference, and in the absence of HFIP,
activation energies of 21.8, 25.6 and 23.5 kcal/mol were
computed for the oxidative addition, reductive elimination
and CH activation, respectively (SI). The reductive elimi-
1
characterization by H NMR spectroscopy of an additional
iridacycle, formed exclusively upon addition of NIS, and that
may be assigned to INT2 (see SI). An alternative mechanism
without involving Ir(V) intermediates in which the iridacycle
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species are directly iodinated, was also considered. However,
1
we could not locate any effective TS below 30 kcal/mol for
2
3
4
5
6
7
8
9
Me
O
+
NIS + HFIP
O
Ir Cp*
Me
O
SM -1.6
O
Cp*
O
Ir
Me
Me
O
O
H
N
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O
HFIP
O
O
Ir Cp*
Ir Cp*
TS-OA 19.8
TS-CH 1.6
O
I
I
N
O
H
INT1
0
N
O
O
O
F3C
CF3
+ HFIP
Me
Me
O
O
O
Ir
O
INT2 -15.1
Cp*
Ir Cp*
H
INT4 -19.5
I
N
O
O
N
O
HFIP
O
HFIP
Me
COOH
O
Me
O
O
I
Cp*
r
I
O
Ir
TS-RE 4.9
Cp*
O
I
I
O
N
O
INT3 -22.0
COOH
HFIP
O
HFIP
N
H
resting state
Figure 1. Catalytic cycle. The energy values correspond to Free energies in kcal/mol.
that process.
3. CONCLUSION
Author Contributions
‡ E. E. and A. S.-M. contributed equally.
In summary, a very efficient catalytic method for the io-
dination of benzoic acids has been developed. A simple
Ir(III) complex is used, which, under very mild reaction
conditions and in the absence of any additive or base, selec-
tively gives o-iodinated carboxylic acids in excellent yields
when HFIP is used as the solvent. Air and moisture are well
tolerated. The mechanism for this mild CH iodination in-
volves a rate-limiting metalation, followed by iodination
through an Ir(III)/Ir(V) catalytic cycle. Most importantly, we
present for the first time strong evidence explaining the
unique role of the solvent HFIP in this CH activation; upon
formation of H-bonds, HFIP is able to lower the activation
energy of the reductive elimination step. These studies may
contribute to develop an understanding of the beneficial
effect of using HFIP as the solvent in catalytic reactions.
NOTES
¥ In contrast with the work reported by Yu and co-workers, the
iridium system reported here affords selectively monoiodinated
products from meta-substituted benzoic acids. This selectivity
may be due to the milder reaction conditions used here.
§ Phenylacetic acid under the optimal reaction conditions gave
only 10% yield of 2-iodophenylacetic acid. The low ability of
the CH2CO2H functional group to direct the iodination enables
selective formation of 2i from dicarboxylic acid 1i.
¶ The lower reactivity of electron-poor carboxylic acids 1e and
1f, when compared to that of 1a, can be explained as a result of
a decreased electron density on the iridium (III) center, reducing
its ability to effectively undergo oxidative addition to form the
Ir(V) intermediate, as confirmed computationally (see SI).
ASSOCIATED CONTENT
Supporting Information
ACKNOWLEDGMENT
Dedicated to Prof. J. E. Bäckvall on the occasion of his 70th
birthday.
Experimental procedures and full characterization of the prod-
ucts are available free of charge via the Internet at
http://pubs.acs.org
This project was supported by the Swedish Research Council
through Vetenskapsrådet and Formas, the Knut and Alice
Wallenberg Foundation, and AstraZeneca. A. S.-M. was
supported by the Generalitat Valenciana and Universitat de
València (Spain) through a postdoctoral grant, and A.V.-R.
was supported by the Wenner-Gren Foundation through a
postdoctoral grant. We thank IZO-SGI SGIker of UPV/EHU
AUTHOR INFORMATION
Corresponding Author
* E-mail: belen.martin.matute@su.se
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for human and technical support. We also thank Dr A. Ber-
Page 6 of 7
1
mejo Gomez for helpful discussions.
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O
O
[Cp*Ir(H2O)3]SO4
NIS
Me
O
OH
OH
R
R
O
H
HFIP
I
Ir Cp*
O
I
N
O
HFIP
O
through:
R
O
Ir
- Very mild conditions
- No base
- No additives
Cp*
- Regioselective
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