S,O-Ligand-Promoted Palladium-Catalyzed C-H Functionalization Reactions of Nondirected Arenes

Article abstract of DOI:10.1021/acscatal.7b02356

Pd(II)-catalyzed C-H functionalization of nondirected arenes has been realized using an inexpensive and easily accessible type of bidentate S,O-ligand. The catalytic system shows high efficiency in the C-H olefination reaction of electron-rich and electron-poor arenes. This methodology is operationally simple, scalable, and can be used in late-stage functionalization of complex molecules. The broad applicability of this catalyst has been showcased in other transformations such as Pd(II)-catalyzed C-H acetoxylation and allylation reactions.

Full text of DOI:10.1021/acscatal.7b02356

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Letter
S,O-Ligand-Promoted Palladium-Catalyzed C-H
Functionalization Reactions of non-Directed Arenes
Kananat Naksomboon, Carolina Valderas, Melania Gómez-
Martínez, Yolanda Álvarez-Casao, and M. Ángeles Fernández-Ibáñez
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02356 • Publication Date (Web): 18 Aug 2017
Downloaded from http://pubs.acs.org on August 19, 2017
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ACS Catalysis
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S,O-Ligand-Promoted Palladium-Catalyzed C−H Functionalization
Reactions of Non-Directed Arenes
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Kananat Naksomboon, Carolina Valderas, Melania GómezꢀMartínez, Yolanda ÁlvarezꢀCasao, M.
Ángeles FernándezꢀIbáñez*
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherꢀ
lands.
Supporting Information Placeholder
acid functionality of the picolinic acid ligand promotes the C−H
bond cleavage via a concerted metalationꢀdeprotonation (CMD)
mechanism.12 In addition, the chelating ability of the ligand enꢀ
hances the stability of the catalyst. However, the irreversible forꢀ
mation of an inactive palladium complex bearing two picolinic
acid molecules is a major drawback for this system. We enviꢀ
sioned that a bidentate ligand with weaker coordination ability to
Pd(OAc)2 than the bidentate picolinic acid ligand would lead to a
more efficient catalyst. Thus, we decided to investigate the perꢀ
formance of bidentate thioethercarboxylates, which are easily
accessible and have hemilabile behavior in palladium chemistry.13
To the best of our knowledge, this type of ligands has never been
used in metalꢀcatalysis. Here, we report the discovery of a new
class of S,Oꢀligands, that enable nonꢀdirected Pdꢀcatalyzed C−H
functionalization reactions of arenes. These S,Oꢀligands show
higher activity and stronger influence on the site selectivity than
the wellꢀestablished pyridine based ligands in the C−H olefination
of simple arenes. The new methodology is also successful in preꢀ
parative scale and in lateꢀstage functionalization of complex molꢀ
ecules, a step that could not be taken with previously described
catalytic systems. Moreover, the new Pd/S,Oꢀligand catalyst is
also active in the C−H acetoxylation and allylation of benzene.
ABSTRACT: Pd(II)ꢀcatalyzed C−H functionalization of nonꢀ
directed arenes has been realized using inexpensive and easy acꢀ
cessible type of bidentate S,Oꢀligand. The catalytic system shows
high efficiency in the C−H olefination reaction of electron rich
and electron poor arenes. This methodology is operationally simꢀ
ple, scalable and can be used in lateꢀstage functionalization of
complex molecules. The broad applicability of this catalyst has
been showcasted in other transformations such as Pd(II)ꢀcatalyzed
C−H acetoxylation and allylation reactions.
Over the past decade, metalꢀcatalyzed C−H functionalization
has emerged as a powerful methodology for the synthesis of valuꢀ
able chemicals and materials.1 This approach brings the opporꢀ
tunity to introduce complexity in organic molecules in a most
efficient manner since no prefunctionalization of the starting maꢀ
terials is required. Many elegant and efficient methodologies have
been described for the direct functionalization of C−H bonds, but
the vast majority of these examples require the presence of a diꢀ
recting group to enhance the reactivity and selectivity of the proꢀ
cess.2 Reports of direct C−H functionalization of simple arenes,
without a directing group, are still scarce.3 An attractive alternaꢀ
tive to the use of directing groups is by developing suitable ligꢀ
ands that may lead to the discovery of new catalytic systems caꢀ
pable of promoting these transformations. However, to date, the
arsenal of ligands that enable metalꢀcatalyzed C−H functionalizaꢀ
tion reactions is very limited.4 The research in our group aims at
the development of novel ligands/catalytic systems capable of
promoting selective C−H functionalization reactions to broaden
the applicability of this strategy in organic synthesis. In this field,
groundbreaking developments by the groups of Yu,5 Sanford,6
Stahl7 and Glorius8 have identified pyridineꢀbased ligands as very
versatile and efficient ligands for nonꢀdirected Pdꢀcatalyzed C−H
functionalization reactions. In the particular case of the Pdꢀ
catalyzed C−H olefination (FujiwaraꢀMoritani reaction) of simple
arenes,9 Yu’s initial report shows good results with electron poor
arenes using a bulky pyridine ligand.5 Subsequent investigations
on the topic from Sanford’s group describe the beneficial effect of
3,5ꢀdichloropyridine ligand as a promotor of the Fujiwaraꢀ
Moritani reaction for electron rich and electron poor arenes.10
Thioethercarboxylic acid ligands can be easily made in gram
scale in two steps starting from commercially available carboxylic
acids.14,15 We started our investigations by studying the perforꢀ
mance of these thioethercarboxylic acid ligands in the Pd(II)ꢀ
catalyzed C H olefination reaction employing benzene and ethyl
−
acrylate as model substrates under standard reaction conditions
(Table 1). The reaction in the absence of ligand provided, after 2
h, the alkenylated product 1 in only 16% yield. In contrast, the
presence of 2ꢀethyꢀ2ꢀ(phenylthio)acetic acid (L1) resulted in an
increase in yield up to 64%. Other thioethercarboxylic acid ligꢀ
ands with different side chain of the thioetheracetic acid were
studied. Similar yields were obtained with ligands bearing aliphatꢀ
ic chains in αꢀposition (L2-L3), including the gemꢀdimethyl (L4)
and cyclopropane (L5) ligands. The phenylthioetheracetic acid
(L6), 2ꢀphenylꢀ2ꢀ(phenylthio)acetic acid (L7) and the 2ꢀ
(phenylthio)benzoic acid (L8) furnished the olefinated product 1
in lower yields (20ꢀ40%) than L1-L5. We next explored the reacꢀ
tivity of the catalytic system regarding the substituents attached to
the sulfur atom. In particular, electron rich, electron poor, bulky
aromatic (L9-L14) and aliphatic substituents (L15-L16) were
investigated. Unfortunately, all these ligands provided similar or
slightly lower yields than those obtained with L1-L5, with the
Recently, our group reported an increase in reactivity and site
selectivity in the C−H acetoxylation of simple arenes in the presꢀ
ence of picolinic acid ligands.11 We postulate that the carboxylic
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Page 2 of 6
exception of the bulky ligand L10, with a triphenylmethyl group,
which did not furnish any product. The reaction with the tetrahyꢀ
droꢀ2ꢀthiophenecarboxylic acid (L17) and the 2ꢀ
thiophenecarboxylic acid (L18) provided the desired product in
61% and 26% yield, respectively. From these initial studies, we
concluded that, in general, thioethercarboxylic acid ligands bearꢀ
ing aliphatic substituents in αꢀposition and with a neutral aromatic
ring attached to the sulfur atom constitute the most active catalyst
for the Pdꢀcatalyzed C−H olefination of benzene.
results confirmed that the presence of both functionalities, the
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2
3
4
5
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7
8
thioether and the carboxylic acid, are crucial for the acceleration
of the reaction. Different conditions for the oxidative Heck reacꢀ
tion were examined in the presence of L2 ( see Supporting Inforꢀ
mation, Table S2ꢀS5), but no improvement was observed comꢀ
pared to the standard conditions.
Scheme 1. Kinetic profile of the dehydrogenative Heck cou-
pling of benzene and ethyl acrylate without ligand and in the
presence of L2.
Table 1. Ligand optimization of dehydrogenative Heck reaction.
9
(1 equiv)
CO2Et
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Pd(OAc)2 (5 mol%)
Ligand (5 mol%)
H
CO2Et
Pd(OAc)2 (5 mol%)
Ligand (5 mol%)
H
CO2Et
+
CO2Et
(1 equiv)
PhCO3tBu (1 equiv)
PhCO3tBu (1 equiv)
AcOH, 100 oC, 2 h
AcOH, 100 oC, 2 h
excess
Entry
1
excess
1
Ligand
Yield (%)a
With the optimized conditions in hand, we set out to explore
the substrate scope of this transformation with different substitutꢀ
ed arenes (Table 2).16 All the reactions were carried out in a presꢀ
sure tube using 5 mol% of catalyst and stirring at 100 ºC for 6 h.
At this time, the formation of Pd black was observed in most casꢀ
es. The reaction of arenes with alkyl substituents such as ortho-
and metaꢀxylene and mesitylene provided the alkenylated prodꢀ
ucts 2, 3 and 4 with excellent yields (76%, 83% and 84%, respecꢀ
tively). Regarding the selectivity, the orthoꢀxylene provided a
1:1.9 ratio of the α(a) and β(b) isomers, respectively and the metaꢀ
xylene provided a mixture of isomers (a:b:c = 4.9:1:1.4 ratio) in
favor of the less sterically ortho olefinated product. In a similar
manner, 76% yield was obtained in the reaction using naphthalene
as starting material with a ratio 2:1 in favor to the αꢀolefinated
product 5. We also tested the reaction of arenes bearing strong
electron donating groups. Excellent yields were obtained employꢀ
ing anisole, 1,2ꢀ and 1,3ꢀdimethoxybenzene and 1,3,5ꢀ
trimethoxybenzene as starting materials (70ꢀ82%). Anisole proꢀ
vided a 1.5:1 ratio of the ortho and para isomers, respectively and
only traces of the meta isomer were detected. 1,2ꢀ
Dimethoxybenzene yielded a 1:4.9 ratio of the corresponding α(a)
and β(b) isomers. Similarly, the C−H olefination of 1,3ꢀ
dimethoxybenzene occurred mainly at the lest sterically hindered
C−H bond at the ortho position of the methoxy group (6:1 ratio).
The C−H olefination of electron poor arenes was also explored.
The reaction with ethyl benzoate provided the desired olefinated
products 10 in 42 % yield as a mixture of isomers in favor of the
meta olefinated product (o:m:p = 1.2:3.3:1). When 1,2ꢀ 1,3ꢀ and
1,4ꢀdichlorobenzene were employed as starting materials the deꢀ
sired products were obtained as mixture of regioisomers in good
yields (60ꢀ74%). The reaction with 1,3,5ꢀtrifluorobenzene furꢀ
nished the desired product 14 in 77% yield. When 4ꢀchloroanisole
was subjected to standard reaction conditions, the olefinated
product 15 was obtained in 60% yield in 4.3:1 ratio in favor of the
ortho product respect to the methoxy substituent. Moreover, the
direct C−H olefination of unprotected phenol provided the orthoꢀ
and paraꢀolefinated product 16 in excellent yield (82%) and in a
ratio of 1.9 to 1, respectively. Taking into consideration that only
few reports deal with the direct functionalization of phenols, both
the yield obtained and the preference for the ortho olefination are
remarkable.17 In all cases, we observed much higher yields using
L2 in comparison with those in which the ligand was absent (see
Supporting Information, Table S6). Finally, the C−H olefination
in preparative scale using mesitylene and 1,3,5ꢀtrifluorobenzene
as starting materials afforded the corresponding olefinated prodꢀ
ucts 4 and 14 with good yields without any significant erosion
from the original values.
1
No ligand
16
R1
Et
iPr
tBu
Me
R2
H
O
2
3
4
5
6
7
8
(L1)
64
63
64
71
61
40
20
R2
L2
( )
H
R1
OH
(L3)
(L4)
H
SPh
Me
L5
(
)
-CH2CH2-
(L6)
(L7)
H
H
H
O
Ph
OH
L8
)
9
(
16
SPh
O
R3
10
11
12
13
14
15
16
17
Mes
Tr
(L9)
62
NR
53
40
39
46
37
44
(L10)
OH
L11
( )
p-OMe-C6H4
SR3
2,4,6-(OMe) 3-C6H2 (L12)
C6F5
(L13)
L14
( )
p-CF3-C6H4
CH2C6H5
iPr
(L15)
(L16)
O
L17
L18
18
19
(
(
)
)
61
26
S
OH
O
S
OH
OH
O
20
21
(L19)
16
20
S
S
Ph
Ph
O
O
L20
L21
(
(
)
)
OH
O
O
S
22
23
27
37
O
(L22)
OMe
SPh
aYields weredetermined by 1H NMR analysis of the crude mixture, using CH2Br2 as internal standard.
The kinetic profile in Scheme 1 clearly indicates that 2ꢀiꢀ
propylꢀ2ꢀ(phenylthio)acetic acid (L2) increased the reaction rate
dramatically. Having established the positive effect of the S,Oꢀ
ligand in the dehydrogenative Heck reaction, different experiꢀ
ments were conducted to ascertain the role of each functionality in
the ligand (Table 1). First, we performed the reaction with the
corresponding sulfoxide (L19) and sulfone (L20) to confirm that
these species are not responsible for the observed catalytic activiꢀ
ty. Indeed, the reaction in the presence of either of these ligands
proceeded with similar outcome as the reaction carried out withꢀ
out any ligand. The use of thioanisole (L21) or methyl 2,2ꢀ
dimethylꢀ2ꢀ(phenylthio)acetate (L22) as ligands furnished the
olefinated product 1 in 27% and 37% yield, respectively. These
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Table 2. Substrate scope.
Table 3. Comparison of the site selectivity.
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Next, we explored the olefin scope. The reaction with methyl
acrylate and ethyl cinnamate furnished the olefinated products 17
and 18, respectively, in high yields. Other electrophilic alkenes
such as vinyl phosphonates, vinyl amides, vinyl nitriles and vinyl
sulfonates reacted efficiently with benzene, leading to the oleꢀ
finated products 19ꢀ22 in good yields (42ꢀ78%). Unfortunately,
we did not observe any improvement in the yield using nonꢀ
activated alkenes such as styrene when using L2 in comparison
with the reaction without ligand.
Having revealed the high reactivity of the new catalytic system
in simple arenes, we assessed the suitability of this methodology
for lateꢀstage functionalization of complex molecules (Scheme 2).
To the best of our knowledge, the intermolecular Fujiwaraꢀ
Moritani reaction of arenes without directing groups, has not been
applied in lateꢀstage functionalization. The reaction of Oꢀ
methylestrone (1 equiv) with ethyl acrylate (1.5 equiv) and 10
mol% of Pd(OAc)2 provided the desired product 23 in only 10%
conversion. In contrast, when the reaction was carried out in the
presence of L2, the olefinated product 23 was obtained in 88%
yield as a mixture of orho-olefinated isomers respect to the methꢀ
oxy substituents (a:b = 3:1). Moreover, we compared our catalytic
system with the one previously reported by Sanford for the C−H
olefination of simple arenes using 3,5ꢀdichloropyridine as
ligand.10 Under the same reaction conditions, only 30% converꢀ
sion was obtained. Similarly, when the reaction of the naproxen
derivative was carried out in absence of ligand, only traces of
1
olefinated product 24 were detected by H NMR. The same reacꢀ
tion in the presence of L2 furnished a mixture of products with a
combined isolated yield of 88%, being the main isomer the orthoꢀ
olefinated product respect to the methoxy substituent (a:other
isomers = 3:1). Again, for comparison, we performed the reaction
of the naproxen derivative using 3,5ꢀdichloropyridine as ligand.
Under the standard conditions, we obtained a mixture of olefinatꢀ
ed products in 27% NMR yield. To further prove the applicability
Regarding the site selectivity of the reaction, our results indiꢀ
cate that it is mainly dictated by the substrate and controlled by
electronic factors, with preferential functionalization at the most
electronicꢀrich position in the arene. However, when we compare
the site selectivity of the reaction with and without L2, it is eviꢀ
dent the influence of L2 on the site selectivity (see Supporting
Information, Table S6). In Table 3, we show some substrates
where different trend in site selectivity in the presence of L2 was
observed in comparison with the reaction without ligand. The
reaction of naphthalene in the absence of ligand provided a 1 to 1
ratio of isomers versus the 2 to 1 ratio obtained in the presence of
L2 in favor to the αꢀolefinated product. The reactions of anisole or
phenol without ligand provided a mixture of ortho- and paraꢀ
products with a clear preference for the former. In contrast, in the
presence of L2, the orthoꢀolefinated products were preferred. On
the other hand, similar trend in the site selectivity of the reaction
of naphthalene and anisole was observed without ligand and with
3,5ꢀdichloropyridine, which was the best ligand reported by Sanꢀ
ford for the C−H olefination of simple arenes.10 The reaction of
phenol using 3,5ꢀdichloropyridine provided a mixture of ortho-
and paraꢀproducts in 50% NMR yield with a small preference for
the orthoꢀproduct (1.4o:1p). These results indicate that the S,Oꢀ
ligand has stronger influence on the site selectivity of the C−H
olefination reaction than the pyridineꢀbased ligand.
of the new catalytic system, the C H olefination in preparative
−
scale of Oꢀmethylestrone (1.75 mmol) was performed. To our
delight, comparable yield than to the original value was found.
Scheme 2. Late-stage C−H olefination of (a) estrone and (b)
naproxen derivatives
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O
O
(a)
electron poor arenes in high yields. Remarkably, the Pd/S,Oꢀ
1
2
3
4
5
6
7
8
H
ligand system shows higher activity and influence in the site seꢀ
lectivity than the well establish Pd/pyridineꢀbased catalytic sysꢀ
tem. The catalytic power of the new methodology is convincingly
demonstrated in lateꢀstage functionalization of complex moleꢀ
cules. Furthermore, the new catalyst is also active in the C−H
acetoxylation and allylation reaction of benzene. We expect this
new class of ligands to find broad application in C−H functionaliꢀ
zation reactions. reaction of benzene. We expect this new class of
ligands to find broad application in C−H functionalization reacꢀ
tions.
H
Pd(OAc)2 (10 mol%)
Ligand (10 mol%)
EtO2C
a
H
H
H
H
PhCO3tBu (1 equiv)
+
CO2Et
MeO
MeO
AcOH, 100 oC, 16 h
b
(1 equiv)
(1.5 equiv)
23
No ligand
L2
10% conversion
88% yield (a:b = 3:1)
75% yield (a:b = 3:1)
on 1.75 mmol scale
3,5-Dichloropyridine
30% conversion
(b)
Pd(OAc)2 (10 mol%)
Ligand (10 mol%)
EtO2C
CO2Me
CO2Me
CO2Et PhCO3tBu (1 equiv)
+
9
MeO
MeO
AcOH, 100 oC, 16 h
a
(1 equiv)
(1.5 equiv)
24
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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No ligand
L2
traces
88% yield
(a:others = 3:1)
ASSOCIATED CONTENT
Supporting Information
3,5-Dichloropyridine
27% NMR yield
The Supporting Information is available free of charge on the
ACS Publications website.
In search for a general and efficient catalytic system capable of
promoting a large number of C−H functionalization reactions, we
decided to test L2 in C−H acetoxylation and allylation reactions
(Scheme 3). The C−H acetoxylation reaction was performed using
benzene as substrate and PhI(OAc)2 as oxidant. Under the standꢀ
ard reaction conditions, the presence of L2 significantly increased
the reaction rate of the process. A 64% yield was reached comꢀ
pared to the 15% obtained in the absence of the ligand (Scheme
3a). We monitored the reaction over time with L2 and without
ligand. Also, the reaction in the presence of pyridine was carried
out for comparison.6a The kinetic profile of these reactions indiꢀ
cates that the presence of L2 dramatically accelerated the reacꢀ
tion. Moreover, the S,Oꢀligand showed higher activity than the
pyridine ligand. In addition, the C−H allylation reaction using
benzene and allylbenzene as substrates was also conducted with
and without L2.18 Again, we observed an acceleration of the reacꢀ
tion rate in the presence of the S,Oꢀligand L2 and the correspondꢀ
ing allylated product was obtained in 54% yield (Scheme 3b). In
this case, no acceleration using pyridine as ligand was observed.
Experimental procedures and compounds characterization (PDF)
AUTHOR INFORMATION
Corresponding Author
*m.a.fernandezibanez@uva.nl
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We acknowledge financial support from NWO though a VIDI
grant (723.013.006). We acknowledge Daniël Verdoorn for the
synthesis of L5. M. GómezꢀMartínez acknowledges the Vicerrecꢀ
torate of Research, Development, and Innovation at the University
of Alicante (Spain) for the travel grant. We thank Prof. S. R.
Harutyunyan, Prof. B. Macia, Dr. Sergio Maroto and Dr.
Alejandro Orden for their helpful comments on the manuscript.
REFERENCES
Scheme 3. S,O-Ligand promoted Pd-catalyzed (a) C
toxylation and (b) allylation of benzene
−
H ace-
(1) For general reviews on C−H functionalization, see: (a)
Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174−238; (b) Yu, J.ꢀQ.; Shi, Z. C–H activation; Springer, 2010;
Vol. 292; (c) Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 2−24;
(d) Davies, H. M. L.; Morton, D. J. Org. Chem. 2016, 81,
343−350; For a special issue dedicated to this topic, see: (e) Acc.
Chem. Res. 2012, 45, 777−958.
(2) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147−1169; (b) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.;
Zhang, Y. Org. Chem. Front. 2015, 2, 1107−1295; (c) Maes, J.;
Maes, B.U.W. Adv. Heterocycl.Chem. 2016, 120, 137−194; (d)
Pototschnig, G.; Maulide, N.; Schnürch, M. Chem. Eur. J. 2017,
23, 9206−9232; (e) Ma, W.; Gandeepan, P.; Li, J.; Ackermann, L.
Org. Chem. Front. 2017, 4, 1435−1467.
(3) For a review on C−H functionalization of substrates that do
not bear directing groups, see: (a) Kuhl, N.; Hopkinson, M. N.;
WencelꢀDelord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51,
10236−10254; For selected examples, see: (b) Robbins, D. W.;
Hartwig, J. F. Angew. Chem. Int. Ed. 2013, 52, 933−937; (c)
Shrestha, R.; Mukherjee, P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F.
J. Am. Chem. Soc. 2013, 135, 8480−8483; (d) Ricci, P.; Krämer,
K.; Larrosa, I. J. Am. Chem. Soc. 2014, 136, 18082−18086; (e)
Cheng, C.; Hartwig, J. F. J. Am. Chem. Soc. 2015, 137, 592−595;
(f) Larsen, M. A.; Wilson, C. V.; Hartwig, J. F. J. Am. Chem. Soc.
2015, 137, 8633−8643; (g) Paudyal, M. P.; Adebesin, A. M.; Burt,
S. R.; Ess, D. H.; Ma, Z.; Kürti, L.; Falck, J. R. Science 2016,
(a)
PhI(OAc)2 (1 equiv)
Pd(OAc)2 (5 mol%)
Ligand (5 mol%)
OAc
H
AcOH:Ac2O (9:1)
100 oC, 3 h
25
No Ligand 15%
L2 64%
excess
(b)
(1 equiv)
Ph
Pd(OAc)2 (10 mol%)
Ligand (10 mol%)
H
Ph
AgOAc (1.5 equiv)
DCE, 80 oC, overnight
26
No Ligand 35%
L2 54%
excess
The precise role of the S,Oꢀligand in the C
toxylation and allylation reactions remains under investigation.19
However, considering that the C−H activation of the inert C
bond of the arene is common in all these transformation, it seems
−
H olefination, aceꢀ
−
H
reasonable to propose that the S,Oꢀligand is assisting the C
bond cleavage.
−
H
In summary, we have found a new catalytic system based on
Pd(OAc)2 and easily accessible S,Oꢀligands that enables nonꢀ
directed C
−
H functionalization reactions of arenes. The catalyst
promotes the C−H olefination reaction of both, electron rich and
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353, 1144−1147. (h) Luan, Y.ꢀX.; Zhang, T.; Yao, W.ꢀW.; Lu, K.;
Kong, L.ꢀY.; Lin, Y.ꢀT.; Ye, M. J. Am. Chem. Soc. 2017, 139,
1
2
3
4
5
6
7
8
9
1786−1789.
(4) For a general review, see: Engle, K. M.; Yu, J.ꢀQ. J. Org.
Chem. 2013, 78, 8927−8955.
(5) Zhang, Y.ꢀH.; Shi, B.ꢀF.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2009,
131, 5072−5074.
(6) (a) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S.
Angew. Chem. Int. Ed. 2011, 50, 9409−9412; (b) Cook, A. K.;
Emmert, M. H.; Sanford, M. S. Org. Lett. 2013, 15, 5428−5431;
(c) Gary, J. B.; Cook, A. K.; Sanford, M. S. ACS Catalysis 2013,
3, 700−703; (d) Cook, A. K.; Sanford, M. S. J. Am. Chem. Soc.
2015, 137, 3109−3118.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Izawa, Y.; Stahl, S. S. Adv. Synth. Catal. 2010, 352,
3223−3229.
(8) Wang, C.; Rakshit, S.; Glorius, F. J. Am. Chem. Soc. 2010,
132, 14006−14008.
(9) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 8,
1119−1122.
(10) Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett. 2012,
14, 1760−1763.
(11) Valderas, C.; Naksomboon, K.; FernándezꢀIbáñez, M. Á.
ChemCatChem 2016, 8, 3213−3217.
(12) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
16496−16497; (b) GarcíaꢀCuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128,
1066−1067; (c) Ackermann, L. Chem. Rev. 2011, 111,
1315−1345; (d) Granell, J.; Martínez, M. Dalton Trans. 2012, 41,
11243−11258.
(13) (a) Meyer, W. H.; Brüll, R.; Raubenheimer, H. G.;
Thompson, C.; Kruger, G. J. J. Organomet. Chem. 1998, 553,
83−90; (b) Esterhuysen, M. W.; Brüll, R.; Raubenheimer, H. G.;
Esterhuysen, C.; Kruger, G. J. J. Organomet. Chem. 2001, 619,
164−178.
(14) (a) Zhang, L. H.; Duan, J.; Xu, Y.; Dolbier Jr, W. R.
Tetrahedron Lett. 1998, 39, 9621−9622; (b) Yeh, P.ꢀP.; Daniels,
D. S. B.; Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett.
2014, 16, 964−967.
(15) The preferred ligand L2 is prepared in one step from
commercial available 2ꢀbromoꢀ3ꢀmethylbutanoic acid in 73%
isolated yield. See Supporting Information.
(16) We also tested the reaction of other arenes in the presence of
L4 (NMR yields): naphthalene 89% (2.2a:1b); mesitylene 93%
and 1,3,5ꢀtrifluorobenzene 62%. The yields obtained are similar
or lower than the ones provided using L2 as ligand.
(17) For selected examples of direct C−H functionalization of
unprotected phenols, see: (a) Bedford, R. B.; Coles, S. J.;
Hursthouse, M. B.; Limmert, M. E. Angew. Chem. Int. Ed. 2003,
42, 112−114; (b) Bedford, R. B.; Limmert, M. E. J. Org. Chem.
2003, 68, 8669−8682; (c) Luo, J.; Preciado, S.; Larrosa, I. J. Am.
Chem. Soc. 2014, 136, 4109−4112; (d) Yu, Z.; Ma, B.; Chen, M.;
Wu, H.ꢀH.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136,
6904−6907.
(18) Jin, W.; Wong, W.ꢀT.; Law, G.ꢀL. ChemCatChem 2014, 6,
1599−1603.
(19) In our preliminary investigations on the mechanism of this
transformation, we have isolated and fully characterized by Xꢀray
analysis the palladium complex bearing two molecules of L4
attached (CCDC 1567101 contains the supplementary crystalloꢀ
graphic data for Pd[OCOC(SPh)Me2]2). The model reaction using
this complex as catalyst furnished the olefinated product 1 in a
similar yield (22% NMR yield) to that obtained with Pd(OAc)2
(Table 1, entry 1), suggesting that this complex is not involved in
our catalytic system.
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