A mild and efficient carboxylate-directed C-H arylation of aryl carboxylic acids with iodobenzenes in water

Article abstract of DOI:10.1016/j.tetlet.2014.12.001

An efficient and environmental friendly Pd-catalyzed carboxylate-directed C-H arylation reaction of aryl carboxylic acids with iodobenzenes has been developed in water where Tween 20 was added (2% w/w) to form aqueous micelles to increase the solubility of starting materials. In this aqueous protocol, the reactions proceeded at a lower temperature (80 °C) compared with the traditional procedures using organic solvents (100 °C and above) and wide substrate scopes were demonstrated (15 examples, 62-92% yields).

Full text of DOI:10.1016/j.tetlet.2014.12.001

Tetrahedron Letters 56 (2015) 475–477
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild and efficient carboxylate-directed C–H arylation of aryl
carboxylic acids with iodobenzenes in water
⇑
Zhongmiao Xu, Ting Yang, Xichen Lin, John D. Elliott, Feng Ren
Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and environmental friendly Pd-catalyzed carboxylate-directed C–H arylation reaction of aryl
carboxylic acids with iodobenzenes has been developed in water where Tween 20 was added (2% w/w) to
form aqueous micelles to increase the solubility of starting materials. In this aqueous protocol, the reac-
tions proceeded at a lower temperature (80 °C) compared with the traditional procedures using organic
solvents (100 °C and above) and wide substrate scopes were demonstrated (15 examples, 62–92% yields).
Ó 2014 Elsevier Ltd. All rights reserved.
Received 9 October 2014
Revised 23 November 2014
Accepted 1 December 2014
Available online 8 December 2014
Keywords:
C–H functionalization
Carboxylate-directed C–H arylation
Aryl carboxylic acid
Aqueous micelle
Tween 20
During the past decade, C–H functionalization was extensively
explored due to its high atom efficiency and potential to enable
structural diversities without pre-functionalized starting materials
such as iodines, triflates, boronic acids, etc.1 To achieve the regio-
selectivity of the C–H activation, a number of directing groups con-
taining nitrogen, sulfur, and phosphine were discovered to bind
with the transition metal catalysts and position them at the
desired site for the C–H bond cleavage.1 Recently, the ‘weakly coor-
dinating directing groups’ were developed for regio-selective C–H
functionalization including ketones, aldehydes, ethers, and carbox-
ylic acids.2 Among them, carboxylic acids deserved special atten-
tion due to their ready availability and greater flexibility for
removal after the reaction completes.3 The palladium-catalyzed
C–H arylation using carboxylic acid as the directing group was pio-
neered in 2007 when the Yu group and the Daugulis group inde-
pendently developed the ortho-arylation of C–H bonds in benzoic
acids.4 High temperature (100–130 °C) was reported in the reac-
tion conditions from both groups, and moderate to low yields were
observed in Yu’s protocol4a while in Daugulis’ protocol acetic acid
had to be used as the solvent for arylations with aryl iodides as
starting materials.4b Since then, the carboxylate-directed C–H ary-
lation reactions have attracted tremendous interests from the syn-
thetic chemistry community and significant progress has been
made to optimize the conditions.5 Recently, the Zhou group has
reported the C–H ortho-arylation of benzoic acids in the environ-
mentally friendly solvent, water, where diaryliodonium salts were
used for arylation.6 Even though palladium-catalyzed C–H bond
activation/cross-coupling reaction cascades were known to happen
in water for several cases,7 the carboxylate-directed C–H ortho-ary-
lation in water was rarely reported. Zhou’s protocol, to the best of
our knowledge, was the only example reported but it suffered from
the inconvenience of the preparation of diaryliodonium salts as the
required starting materials.6 Furthermore, high reaction tempera-
ture (100 °C) was required in order to achieve reasonable yields
(70–91%). Herein, we reported the carboxylate-directed C–H aryla-
tion of aryl carboxylic acids in water with readily available iodo-
benzenes and at a lower temperature (80 °C).
The common challenge to organic reactions in water is the
insolubility of starting materials/catalysts, and one potential solu-
tion for this issue relies on adding surfactants to form aqueous
micelles to improve solubility.8 The Lipshutz group developed a
palladium-catalyzed C–H activation/cross-coupling reaction cas-
cade of aryl ureas in water using Brij 35 as the surfactant to form
aqueous micelles.9 A C–H acylation of anilides in aqueous solution
was also reported by Stirling and co-workers using sodium dodecyl
sulfate (SDS) as the surfactant.10 However, the C–H arylation of
aryl carboxylic acids, which are readily available but less reactive,
in aqueous solutions has not yet been developed.
We started our exploration using 2-naphthoic acid (1) and
1-chloro-4-iodobenzene (2) as starting materials and polysorbate
80 (Tween 80) as the surfactant (Table 1). To our delight, we
observed a moderate conversion (50%) of the desired C–H arylation
product (3a) using Pd(OAc)2 as the catalyst and AgOAc as the
⇑
Corresponding author. Tel.: +86 186 1674 3377; fax: +86 021 6159 0730.
E-mail address: feng.q.ren@gsk.com (F. Ren).
http://dx.doi.org/10.1016/j.tetlet.2014.12.001
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

476
Z. Xu et al. / Tetrahedron Letters 56 (2015) 475–477
Table 1
reaction and the mono-arylated products (3) were the main
products observed. Para-substituted iodobenzenes bearing both
Optimization of the Pd-catalyzed carboxylate-directed C–H arylation conditions
O
electron-withdrawing
and
electron-donating
substitutions
O
I
Pd catalyst (5 mol%)
resulted in the C–H arylation products (3a–3e) in moderate to good
isolated yields (67–88%). Iodobenzene with meta-substitution
(1-iodo-3-methylbenzene, entry 6) demonstrated similar reactivity
to provide the C–H arylation product (3f) in a reasonable yield
(78%). Increasing the steric hindrance of the iodobenzene by
introducing the chlorine atom at the ortho-position (1-chloro-2-
iodobenzene, entry 7) resulted in a slower reaction and product
3g was obtained in 72% yield after a prolonged reaction (24 h).
The scope of the aryl carboxylic acid substrate was also
investigated (Table 3). To our delight, different substituted benzoic
OH
OH
+
Ag salt (1.3 equiv)
surfactant/H2O (2% w/w)
4h, temperature
Cl
(1.1 equiv)
3a
1
2
Cl
Entry
Pd catalyst
Ag salt
Surfactant
Temp (°C)
Conva (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19b
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
AgOAc
Ag2O
AgOTf
AgTFA
Ag2CO3
None
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
Tween 80
Tween 80
Tween 80
Tween 80
Tween 80
Tween 80
Tween 20
Tween 40
Tween 60
Brij 35
SDS
HTAB
None
Tween 20
Tween 20
Tween 20
Tween 20
Tween 20
Tween 20
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
80
50
44
59
82
53
Trace
87
77
55
67
10
40
0
80
70
15
0
Trace
95
Table 2
Scope of iodobenzenes for Pd-catalyzed carboxylate-directed C–H arylation in watera
O
Pd(OAc)2 (5 mol%)
O
I
AgTFA (1.3 equiv)
OH
R
OH
+
Tween 20/H2O (2% w/w)
R
80 o
C
1
3
Aryl iodide
(2 equiv)
Pd(dppf)Cl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Entry
1
Aryl iodide
Product
Yieldb (%)
I
O
O
a
Conversion was measured using LC–MS.
2 equiv of 1-chloro-4-iodobenzene was added.
b
OH
OH
Cl
88
additive (entry 1). We firstly investigated the effect of different sil-
ver(I) salts and discovered the silver(I) trifluoroacetic acid salt
(AgTFA) to be the most effective additive, providing the highest
conversion (82%) to product 3a (entries 2–5). Without the silver(I)
salt, there was only a trace amount of product (entry 6), suggesting
the critical role of the silver(I) additives which was reported for the
removal of iodide from coordination with palladium in the cata-
lytic cycle.11 The type of surfactants used also demonstrated a sig-
nificant impact on the C–H arylation (entries 7–12). Polysorbate 20
(Tween 20) was somewhat more effective than Tween 80, and it
was the most effective surfactant among all the polysorbates.12
Another non-ionic surfactant Brij 35 was also effective for the reac-
tion, albeit resulted in a lower conversion compared with that of
Tween 20. On the other hand, ionic surfactants such as sodium
dodecyl sulfate (SDS) and hexadecyltrimethylammonium bromide
(HTAB) provided low conversions to the C–H arylation product 3a.
Without the addition of surfactant, no desired product was
observed (entry 13) probably due to the insolubility of starting
materials in water. Pd-catalysts were also screened, and Pd(OAc)2
proved to be the most effective catalyst (entries 7, 14–17). It is
noteworthy that Pd2(dba)3 was totally inactive in catalyzing the
C–H arylation (entry 17), suggesting a Pd(II)/Pd(IV) mechanism.4
When the reaction temperature was decreased to 60 °C, only a
trace amount of the C–H arylation product (3a) was detected
(entry 18). Instead, we observed a significant amount of bi-product
4,40-dichloro-1,10-biphenyl which was formed from the homo-cou-
pling of the starting material 1-chloro-4-iodobenzene (2). Indeed,
the homo-coupling bi-product was also observed in reactions at
the elevated temperature (80 °C) to a less extent but this might
be the reason why the reaction could not proceed to full conversion
when a stoichiometric amount of 2 was used. Increasing the
amount of 2 (two equivalents) in the reaction mixture provided
much improved conversion (95%, entry 19).
3a
Cl
I
I
Me
2
3
4
75
67
70
3b
3c
3d
3e
3f
Me
OMe
CF3
O
OH
OMe
CF3
I
O
O
OH
OH
I
I
F
5
6
7
85
78
F
Me
O
O
OH
OH
Me
Cl
I
72c
3g
Cl
a
The reaction was conducted with 2-naphthoic acid (100 mg), substituted
With the optimized reaction condition in hand, the scope of iod-
obenzenes was examined in the C–H arylation reactions with
2-naphthoic acid (1). As shown in Table 2, iodobenzenes with a
variety of different substitutions were well tolerated for the
iodobenzene (2 equiv), silver(I) trifluoroacetate (1.3 equiv), and diacetoxypalladium
(0.05 equiv) in Tween 20/H2O (3 mL, 2% w/w) at 80 °C for 4 h.
b
Isolated yield.
Reaction run for 24 h.
c

Z. Xu et al. / Tetrahedron Letters 56 (2015) 475–477
477
Table 3
Pd(OAc)2 (5 mol%)
AgTFA (1.3 equiv)
O
Scope of aryl carboxylic acids for Pd-catalyzed carboxylate-directed C–H arylation in
I
O
watera
+
OH
7 (65%)
HO
Cl
Tween 20/H2O (2% w/w)
80 oC, 8 h
Cl
O
Pd(OAc)2 (5 mol%)
AgTFA (1.3 equiv)
O
6
2
I
OH
(10 equiv)
R
OH
+
R
Cl
Tween 20/H2O (2% w/w)
80 oC
Figure 1. Pd-catalyzed C–H arylation of acetic acid in water.
2
Cl
Aryl acid
5
(2 equiv)
and the reaction was completed in 30 min. In addition, 5f and 5h
were scaled up to ꢀ1 g scales and good yields were observed
(63% and 71%, respectively). These results further demonstrated
the practicality of this catalytic procedure.
Pd-catalyzed C–H arylation of aliphatic acids with 2 was
explored. Encouragingly, coupling product (7) of acetic acid with
2 was isolated in 65% yield after stirring in the Tween 20/H2O
aqueous micelles for 8 h at 80 °C (Fig. 1). Small amount of bis-
coupling product with 2 was also observed. We are currently
optimizing the reaction conditions for improved yields at the same
time expanding the aliphatic acid substrate scope to make the
reaction more synthetically appealing.
Entry
Aryl acid
Product
O
Yieldb (%)
O
OH
OH
1
2
3
88
Cl
5a
O
O
MeO
MeO
F
OH
OH
86
82
5b
Cl
O
O
In summary, we have developed
a mild and efficient
F
OH
OH
O
Pd-catalyzed carboxylate-directed C–H arylation reaction of aryl
carboxylic acids with iodobenzenes in water, where Tween 20
was added (2% w/w) to form micelles to improve the solubility of
starting materials. In our protocol, the C–H arylation reactions pro-
ceeded at a lower temperature (80 °C) compared with the reported
procedures (100 °C and above) wherein organic solvents were used
as solvents. A wide scope of substrates of both aryl carboxylic acids
and iodobenzenes were demonstrated (15 examples, 62–92%
yields). Further investigation of this protocol on C–H arylation of
aliphatic acids is ongoing.
5c
Cl
O
F3C
F3C
OH
OH
4
68
80
62
Cl
5d
O
O
O
O
HO
OH
HO
OH
5
6
Acknowledgments
Cl
5e
We thank Mr. Morris Sui for NMR analysis and Dr. Ruina Gao for
HRMS analysis.
O
O
OH
OH
Supplementary data
F3C
F3C
Cl
5f
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.12.
001.
O
OH
O
OH
7
8
92
References and notes
Cl
5g
1. For selected recent reviews on C–H functionalization, see: (a) Chen, X.; Engle, K.
M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (b) Wencel-
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740; (c) Li, B.-J.;
Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588; (d) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879; (e) Rossi, R.; Bellina, F.; Lessi, M.;
Manzini, C. Adv. Synth. Catal. 2014, 356, 17; (f) Giri, R.; Thapa, S.; Kafle, A. Adv.
Synth. Catal. 2014, 356, 1395.
2. For recent reviews, see (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem.
Res. 2012, 45, 788; (b) Sarkar, S. D.; Liu, W.; Kozhushkov, S. I.; Ackermann, L.
Adv. Synth. Catal. 2014, 356, 1461.
O
O
OH
OH
75c
Cl
N
H
N
H
5h
a
The reaction was conducted with acid (100 mg), 1-chloro-4-iodobenzene
3. (a) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed. 2011, 50, 9429; (b)
Arroniz, C.; Ironmonger, A.; Rassias, G.; Larrosa, I. Org. Lett. 2013, 15, 910.
4. (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Lindsey, B.;
Saunders, L. B.; Yu, J. Q. J. Am. Chem. Soc. 2007, 129, 3510; (b) Chiong, H. A.;
Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879.
(2 equiv), silver(I) trifluoroacetate (1.3 equiv), and diacetoxypalladium (0.05 equiv)
in Tween 20/H2O (3 mL, 2% w/w) at 80 °C for 4 h.
b
Isolated yield.
Reaction run for 30 min.
c
5. Shi, G.; Zhang, Y. Adv. Synth. Catal. 2014, 356, 1419.
6. Wu, Z.; Chen, S.; Hu, C.; Li, Z.; Xiang, H.; Zhou, X. ChemCatChem 2013, 5, 2839.
7. Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744.
8. (a) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68; (b) Dwars, T.; Paetzold, E.;
Oehme, G. Angew. Chem., Int. Ed. 2005, 44, 7174.
acids (with electron-donating or electron-withdrawing substitu-
tions at ortho-, meta-, or para-positions) underwent C–H arylation
smoothly with moderate to good yields (entries 1–6). The main
products formed were the mono-arylated products at the ortho-
position of the carboxylic acid. In addition, 2-(o-tolyl)acetic acid
(entry 7) could also be arylated with high efficiency. Carboxylate-
directed C–H arylation of indole (entry 8) proceeded much faster
9. Nishikata, T.; Abela, A. R.; Lipshutz, B. H. Angew. Chem., Int. Ed. 2010, 49, 781.
9
10. Szabó, F.; Daru, J.; Simko, D.; Nagy, T. Z.; Stirling, A.; Novák, Z. Adv. Synth. Catal.
2013, 355, 685.
11. Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
12. Dynamic light scattering (DLS) experiment of Tween 20 in water (2% wt) at
80 °C demonstrated micelle formation with average size of 10 nanometers.