Inexpensive NaX (X = I, Br, Cl) as a halogen donor in the practical Ag/Cu-mediated decarboxylative halogenation of aryl carboxylic acids under aerobic conditions

Article abstract of DOI:10.1039/c8ob01095a

Versatile and practical Ag/Cu-mediated decarboxylative halogenation between readily available aryl carboxylic acids and abundant NaX (X = I, Br, Cl) has been achieved under aerobic conditions in moderate to good yields. The halodecarboxylation is shown to be an effective strategy for S-containing heteroaromatic carboxylic acid and benzoic acids with nitro, chloro and methoxyl substituents at the ortho position. A gram-scale reaction and a three-step procedure to synthesize iniparib have been performed to evaluate the practicality of this protocol. A preliminary mechanistic investigation indicates that Cu plays a vital role and a radical pathway is involved in the transformation.

Full text of DOI:10.1039/c8ob01095a

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Inexpensive NaX (X = I, Br, Cl) as a halogen donor in the practical
Ag/Cu-mediated decarboxylative halogenation of aryl carboxylic
acids under aerobic conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Zhengjiang Fu,a,b Ligao Jiang,a Qianming Zuo,a Zhaojie Li,a Yanzhu Liu,a Zhenhong Weia and Hu Cai*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
versatile and practical Ag/Cu-mediated decarboxylative Table 1. Previous and present halodecarboxylation of aryl
halogenations between readily available aryl carboxylic acids and aromatic acids
abundant NaX (X = I, Br, Cl) has been achieved under aerobic
conditions in moderate to good yields. This halodecarboxylation
shows to be an effective strategy for S-containing heteroaromatic
carboxylic acid and benzoic acids with nitro, chloro and methoxyl
substituents at the ortho position. A gram-scale reaction and
three-step procedure to synthesize iniparib have been performed
to evaluate the practicality of this protocol. Preliminary
mechanistic investigation indicates that the Cu plays a vital role
and a radical pathway is involved in the transformation.
Aryl halides are widely used building blocks in synthetic
chemistry to form C-C and C-Hetero bonds, furthermore, the
(Table 1, entry 2).7 Using 1,3-diiodo-5,5-dimethylhydantoin
sp2 aromatic C-X (X = halogen) units are significant structure
fragments found in bulk materials, pharmaceuticals and
bioactive compounds.1 Traditional methods embody SEAr
strategy through electrophilic halogen reagents (NXS, X2, etc.),2
Sandmeyer reaction of aryldiazonium salts with stoichiometric
CuX compounds3 and halogenation of moisture sensitive aryl
metal reagents,4 which have been established to prepare aryl
halides with inherent drawbacks under relatively harsh
conditions. Compared with traditional methods, synthesis of
aryl halides through decarboxylative halogenation with easily
available aryl carboxylic acids as starting materials is extremely
attractive from the viewpoint of simplicity, good
regioselectivity and environmental benignity.5-11 In this
context, Wu developed a route to synthesize aryl bromides
and chlorides via Ag-catalyzed decarboxylative halogenation of
electron-deficient aryl carboxylic acids with CuX2 (X = Br, Cl)
(Table 1, entry 1),6 whereas Liu explored bromo- and
chlorodecarboxylation of electron-rich aromatic carboxylic
acids with the same halogen source under Pd/Ag catalysis
(DIH) as iodine source, Gandelman found decarboxylative
transformation of aromatic and aliphatic carboxylic acids to
organic iodides under irradiative conditions (Table 1, entry 3).8
During the preparation of this paper, Larrosa disclosed an
elegant work on metal-free decarboxylative iodination of
benzoic acids with I2 (Table 1, entry 4).9 However, these
methods are generally limited to one or two types of C-X bond
formation. With
decarboxylative functionalization of aryl carboxylic acids,10 we
recently reported Pd/Cu-catalyzed decarboxylative
a consistent interest in Cu-mediated
halogenation and cyanation of aryl carboxylic acids with CuX (X
= I, Br, Cl) and K4[Fe(CN)6], respectively (Table 1, entry 5).11
Despite the significance of the above protocol to provide
versatile sp2 C-I, C-Br and C-Cl bonds with high efficiency, the
requirement for stoichiometric amounts of CuX as both
reaction promoter and halogen donation limits its further
application and improvement. Therefore, developing
a
catalytic and general method with readily available and
nontoxic sodium halides NaX as halogenation reagent would
remarkably improve the practicality of halodecarboxylation
strategy.
a.College of Chemistry, Nanchang University, Nanchang, 330031, China. E-mail:
caihu@ncu.edu.cn
In recent decade, utilizing low-cost and abundant halide salts
as halogen source has been a hot topic in the field of C-X bond
formation.12 In this regard, employing sodium halides NaX as
halogen donation, Buchwald,12a Hayashi,12b Sutherland12c and
b.State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, CAS, Fuzhou, 350002, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 2. Optimization of the reaction conditionsa
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Table 3. Substrate scope
aAcid (0.2 mmol), Ag2SO4 (0.1 equiv), Cu(OAc)2 (0.6 equiv), 2,9-
DMP (0.3 equiv), NaI (1.5 equiv), DMSO (4 mL), O2 (1 atm), 160
°C, 20 h. bAcid (0.2 mmol), Ag2SO4 (0.05 equiv), Cu(OAc)2 (1
equiv), NaX (1.2 equiv), DMSO (2 mL), O2 (1 atm), 160 °C, 30 h.
cAcid (0.2 mmol), Ag2SO4 (0.05 equiv), Cu(OAc)2 (1 equiv), NaI
aConditions: acid
1 (0.2 mmol), DMSO (2 mL), O2 (1 atm), 20 h.
bIsolated yield. cDMSO (4 mL).
Li12d reported aromatic Finkelstein interconversion of aryl
bromides and triflates via halogen exchange; Zhang,4b Fu12e
and Hartwig12f developed halodeborylation of arylboron
reagents; Stahl,12g Wang and Hong,12h Liu12i and others12j-o
illustrated C-H halogenation of aromatics under Cu, Ni, Rh and
Fe catalysis. Although encouraging achievements has been
made in the synthesis of aryl halides with using halide salts as
halogen source, to the best of our knowledge, the catalytic
halodecarboxylation of aryl carboxylic acids with NaX has not
been reported yet. Herein, we describe a new and practical
Ag/Cu bimetallic mediated decarboxylative halogenation of
aryl carboxylic acids with NaX as halogenating reagent (Table 1,
entry 6). Notably, significant advantage of this transformation
is the firstly construction of three types of sp2 C-X bond (X = I,
Br, Cl) with cheap aryl carboxylic acids and NaX as starting
materials under aerobic conditions.
d
(5 equiv), DMSO (1 mL), O2 (1 atm), 160 °C, 20 h. Acid (0.2
mmol), Ag2SO4 (0.1 equiv), Cu(OAc)2 (1 equiv), 2,9-DMP (0.3
equiv), NaX (1.5 equiv), DMSO (4 mL), O2 (1 atm), 160 °C, 20 h.
emixed with 39% yield of 2,4-dichloro-1-nitrobenzene by-
product.
tetramethyl-1,10-phenanthroline) and 4,7-DPP (4,7-diphenyl-
1,10-phenanthroline) (Table 2, entries 4-8). Considering that
4,7-DMP (TCI, > 98.0%, $ 470/g) is far more expensive than
2,9-DMP (TCI, > 98.0%, $ 18/g), thus, 2,9-DMP was chosen to
combine Cu(OAc)2 to evaluate Ag catalyst for optimization
studies with NaI. As investigation demonstrated, it wasn't too
much different for altering Ag catalyst from AgOAc to AgOTf or
Ag3PO4 in conversion efficiency. (Table 2, entries 8-10).
Pleasingly, an improved yield (51%) was observed when
Ag2SO4 was used as catalyst into reaction, thus, Ag2SO4
exhibited a beneficial effect on the transformation and was a
much better choice than other silver catalysts (Table 2, entry
11). Unfortunately, other iodide salts (LiI and CsI) delivered
useless yields under otherwise equal conditions (Table 2,
entries 12-13). It’s noted decreasing the loading of Ag2SO4
dramatically reduced the reaction conversion (Table 2, entry
14). Although increasing the loading of NaI had a detrimental
effect on the transformation (Table 2, entry 15), to our delight,
enlarging the quantities of Ag2SO4 and Cu(OAc)2 as well as
DMSO solvent gave final product 1a in a synthetically useful
level (60%) with 1.5 equivalents of NaI (Table 2, entry 16). Thus
the optimized reaction conditions were obtained as described
in entry 16 of Table 2.
We began our studies by investigating decarboxylative
iodination of 4,5-dimethoxy-2-nitrobenzoic acid
1
for
optimization studies under a dioxygen atmosphere. At the
outset, employing CuI (0.3 equiv) as catalyst and NaI (1.2
equiv) as iodine source didn’t furnish desired product 1-iodo-
4,5-dimethoxy-2-nitrobenzene 1a, presumably due to the
poorly reactive iodocuprate complexes from tight coordination
of copper catalyst and excess iodide ions (Table 2, entry 1).
Gratifyingly, when Phen (1,10-phenanthroline) (0.15 equiv)
was introduced into reaction and 26% yield of product 1a was
detected, which indicated the ligand played a key role in the
transformation (Table 2, entry 2). A combination of AgOAc (0.1
equiv) and CuI (0.3 equiv) catalyzed reaction to afford a slightly
enhanced yield in the presence of Phen and NaI (Table 2, entry
3), encouraged by this result, the efficiency was further
improved with Cu(OAc)2 instead of CuI under otherwise
identical conditions (Table 2, entry 4). A brief survey of ligands
represented that both 4,7-DMP (4,7-dimethyl-1,10-
The initial success of iododecarboxylation inspired us to
explore the scope and generality of this decarboxylative
halogenation method under aerobic conditions, and the
results were summarized in Table 3. Just as similar to our10 and
others' observation,11 this Ag/Cu-mediated decarboxylative
phenanthroline)
and
2,9-DMP
(2,9-dimethyl-1,10-
phenanthroline) were superior to Phen, Me4Phen (3,4,7,8-
2 | J. Name., 2012, 00, 1-3
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Scheme 1. Gram-scale synthesis of 10a and three-step Table 4. Studies to understand reaction mechanism
synthesis of iniparib 16
NaX (X = Br, Cl), which might ascribe the highly tight
coordination of bromide or chloride ions with transition metals
to suppress decarboxylation of electron-rich aryl carboxylic
acids substrates. Moreover, this method was also efficiently
halogenation transformation showed to be an effective
applied to S-containing heterocyclic carboxylic acid 14 with a
strategy for benzoic acids with nitro, chloro and methoxyl
chloro substituent at the position ortho to the carboxyl group.
substituents at the ortho position, as Table 3 illustrated, the
Although the obtained yields ranging from moderate to good
scope of aryl carboxylic acids included ortho-nitrobenzoic acids
in the protocol, high conversion was observed for the aryl
containing electron-withdrawing (trifluoromethyl, fluoro,
carboxylic acids substrates in this transformation, since by-
chloro) and -donating substituents (methoxyl, methyl)
1-
10
,
products including protodecarboxylation, decarboxylative
cyanation, methyl benzoate and other unidentified
compounds were detected along with the corresponding
decarboxylative product.
ortho-chlorobenzoic acid 11, ortho-methoxybenzoic acids 12
-
13 and S-containing heteroaromatic carboxylic acid 14. It’s
reported that ortho-substituted benzoic acids are inherently
destabilized starting materials compared with their meta- and
para-substituted counterparts, while the presence of an ortho-
electron-withdrawing group results in an additional
stabilization of the transition state,11 thus, ortho-nitro
substituent leads to a much lower activation energy barrier for
decarboxylation process compared with their meta and para
counterparts due to the combination of steric and electronic
effects. The transformation efficiency of decarboxylative
iodination ranked the most efficient in this protocol, followed
by the conversion of bromodecarboxylation and
chlorodecarboxylation, thus some minor modifications were
required to the reaction conditions toward smooth
halodecarboxylation in some cases. Similar to 4,5-dimethoxy-
To further evaluate the practicality and effectiveness of this
protocol, a gram-scale reaction was performed using 6 mmol
10 as the starting substrate with NaI to smoothly afford
decarboxylative iodination product 10a in 71% isolated yield
(1.20 g) under standard conditions (Scheme 1A). It is worth
mentioning that halo groups on desired aryl halides products
can be used for late-stage modification through activation of
carbon-halo bond, thus, the aryl halides products in this
halodecarboxylation protocol are useful precursors to provide
further potential application of this methodology. To our
delight, the decarboxylative halogenation process was used as
a key step in three-step procedure for synthesis of iniparib 16
Decarboxylative iodination between 4-methyl-2-nitrobenzoic
acid and NaI gave 1-iodo-4-methyl-2-nitrobenzene 4a in 53%
.
2-nitrobenzoic acid 1, a range of ortho-nitrobenzoic acids 1-10
4
smoothly participated in the decarboxylative halogenation
process to give corresponding aryl halides in moderate to good
yields. The substrate of 2-chloro-5-nitrobenzoic acid 11 that is
unreactive in previous decarboxylative halogenation
protocols,6-10 it was observed for the first time to undergo
decarboxylative halogenation with NaX to furnish expected
yield under standard conditions, and the methyl group of 4a
was converted into carboxyl 15 with CrO3/H5IO613a followed by
amidation of 15 to furnish iniparib 16 in 62% isolated yield as
an average of two runs (Scheme 1B).13b Compared with
previous synthetic protocols,12c,13b our three-step method
provides an alternative to prepare iniparib 16 with relatively
low-cost starting materials and additives. Although triple
negative breast cancer has inherent defects in DNA repair, it’s
reported iniparib was the first PARP (poly-ADP-ribose-
polymerase) inhibitor to be tested in phase III clinical trials for
the treatment of triple negative breast cancer.14
products 1,2-dihalo-5-nitrobenzenes 11a-c, although side
product 2,4-dichloro-1-nitrobenzene (39% yield) was isolated
to mix with the desired iododecarboxylation product 11a (28%
yield), they could be clearly distinguished via NMR spectra.
Ortho-methoxybenzoic acids 12-13 were also suitable
substrates for this iododecarboxylation route to afford ortho-
methoxyphenyl iodides with NaI, nevertheless, neither
halodecarboxylation nor protodecarboxylation was detected
Some studies were conducted in order to gain insight into
mechanism. Firstly, irrespective of the presence or absence of
mediators (Ag2SO4/Cu(OAc)2), no desired product 1a was
for decarboxylation of ortho-methoxybenzoic acids 12-13 with
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obtained when the model reaction was performed with I2
(0.75 equiv) instead of NaI as iodine source under aerobic
conditions (Table 4, entries 2-3), furthermore, any target
product 1a wasn’t detected when replaced standard
conditions with Larrosa’s metal-free iododecarboxylation
conditions (1 equiv K3PO4, 2 equiv I2, 1 mL CH3CN, 100 °C)9
(Table 4, entry 4), therefore, the results ruled out the
possibility that iodine was responsible for our protocol.
Notes and references
1
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Diederich and P. J. Stang, Wiley-VCH, New York, 1998; (b) A.
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Comprehensive Organic Transformations, Ed. R. C. Larock,
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X. Zhang, Chem. Eur. J., 2016, 22, 16783.
Secondly, Cu-catalyzed iododecarboxylation of
1 to form
3
4
desired product 1a in 39% yield without Ag (Table 4, entry 5),
whereas no corresponding product 1a was observed in the
absence of Cu under standard conditions (Table 4, entry 6),
thus, control experiments strongly supported Cu was essential
for the reaction, and the conclusion is consistent with the
literature reported by Hoover and coworkers.15 Thirdly, the
addition of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) as
radical scavenger resulted in dramatic decrease of conversion,
moreover, the transformation was nearly totally inhibited in
5
(a) J. D. Weaver, A. R. III, A. J. Grenning and J. A. Tunge,
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the presence of
2 equiv of BHT (2,4-di-tert-butyl-4-
methylphenol) (Table 4, entries 7-8), suggesting that a SET
(single electron transfer) process might be involved in the
reaction.
6
7
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8
9
Conclusions
In conclusion, we have developed a novel and practical Ag/Cu-
mediated protocol for highly regioselective decarboxylative
halogenation of easily available aryl carboxylic acids with
cheap halide salt NaX (X = I, Br, Cl) as “X” source. This protocol
represented broad substrate scope, well-tolerated functional
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group and highly efficient transformation.
A gram-scale
reaction and three-step synthesis of iniparib were conducted
to assess advantage of the method. Preliminary mechanistic
studies supported a SET mechanism was involved in the
reaction. Further investigations to detailedly elucidate reaction
mechanism and extend practical application of this method are
currently in progress.
Conflicts of interest
There are no conflicts to declare.
Y.-H. Liu, F. Hu and B.-F. Shi, Chem. Commun., 2016, 52
,
Acknowledgements
4934; (l) H. Liang, Z.-H. Ren, Y.-Y. Wang and Z.-H. Guan,
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Financial support from the National Natural Science
Foundation of China (NSFC) (21761021 and 21571094), Natural
Science Foundation of Jiangxi Province (20161BAB203074,
20171BAB203002 and 20161BAB203073), Sci & Tech Project of
Education Department of Jiangxi Province (60007), Science
Foundation of State Key Laboratory of Structural Chemistry
(20150022), Innovative Special Funds Project for Graduate
Students of Jiangxi Province (YC2016-S002) and Innovative
Training Program for College Students of Nanchang University
(2016066) is gratefully acknowledged.
Chem. Sci., 2017,
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4 | J. Name., 2012, 00, 1-3
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A practical Ag/Cu-catalyzed decarboxylative halogenation between
low-cost aryl carboxylic acids and NaX (X= I, Br, Cl) has been well
established.