Completely regioselective direct C-H functionalization of benzo[b]thiophenes using a simple heterogeneous catalyst

Article abstract of DOI:10.1021/ja403130g

The first completely selective C3 C-H arylation of benzo[b]thiophenes is reported, demonstrating previously unexploited reactivity of palladium. Benzo[b]thiophenes are coupled with readily available aryl chlorides using a ligand-free, dual catalytic system of heterogeneous Pd/C and CuCl. The reaction is operationally simple and insensitive to air and moisture, and it provides valuable products with complete selectivity. Significant investigations into the nature of the active catalytic species and mechanistic considerations are discussed.

Full text of DOI:10.1021/ja403130g

Subscriber access provided by Caltech Library Services
Communication
Completely regioselective direct C–H functionalization of
benzo[b]thiophenes using a simple heterogeneous catalyst
Dan-Tam Daniel Tang, Karl D Collins, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja403130g • Publication Date (Web): 06 May 2013
Downloaded from http://pubs.acs.org on May 7, 2013
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
Completely regioselective direct C–H functionalization of
benzo[b]thiophenes using a simple heterogeneous catalyst
8
9
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
Dan-Tam D. Tang, Karl D. Collins and Frank Glorius*
Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Corrensstraße 40, 48149, Münster, Germany.
Supporting Information Placeholder
ity of coupling partners, and super-stoichiometric use of oxidants.
Limitations in the C2/C3 selectivity of these methods are also
apparent.
ABSTRACT: The first completely selective C3 C–H arylation
of benzo[b]thiophenes is reported, demonstrating previously
unexploited reactivity of palladium. Benzo[b]thiophenes are
coupled with readily available aryl chlorides using a ligand free,
dual catalytic system of heterogeneous Pd/C, and CuCl. The
reaction is operationally simple, insensitive to air and moisture,
and provides valuable products with complete selectivity. Signifi-
cant investigation into the nature of the active catalytic species
and mechanistic considerations are discussed.
In the course of investigating novel reactivity of heterogeneous
catalysts19 we have established an operationally simple, completeꢀ
ly selective C3-arylation of unsubstituted benzo[b]thiophenes,
addressing many of the limitations of existing methods. Herein we
describe the coupling of benzo[b]thiophenes with inexpensive and
widely available aryl chlorides, using Pd/C with CuCl as co-
catalyst (Scheme 1d). The reaction is ligand free, scalable, insen-
sitive to air and moisture, and represents reactivity for Pd/C be-
yond its typical application in cross-coupling and hydrogenation
reactions.4,20 Furthermore, our investigations suggest the active
Despite significant advances in homogeneous catalysis in recent
times, this knowledge has at large proved resistant to development
in an industrial environment, with the majority of industrial cata-
lytic processes continuing to employ heterogeneous catalysts.1
The high costs associated with homogenous catalysis due to the
use of unrecoverable metals and ligands, as well as practical
limitations with regard to catalyst handling, recyclability and the
separation of the catalyst from products impede the transfer of
advances in homogeneous catalysis to large scale industrial pro-
cesses. In contrast, many of these limitations can be obviated by
use of heterogeneous catalysts, and consequently, the develop-
ment of such processes is desirable.2-5
catalytic species is likely to be heterogeneous in nature
.
We initially found that reaction of benzo[b]thiophene 1 and
chlorobenzene 2 in the presence of Pd/C (K-0219 from Heraeus)
gave 3-phenylbenzo[b]thiophene 3 in 18% isolated yield with
excellent C3/C2 selectivity (Table 1, entry 1). Solvent screening
and standard optimization of catalyst loading, temperature, ratio
of reagents etc. gave a maximum yield of 60% (entry 5), though
complete C2/C3 selectivity was maintained. In an attempt to
increase the yield of reaction further, we proposed a number of
additives to enhance reactivity. Pivalic acid, a common additive in
C–H activation chemistry,8 proved detrimental to reactivity (entry
2), as did silver salts which were proposed to facilitate the poten-
tial formation of cationic palladium species as proposed by Itami
and Studer (entries 3 and 4).16,17 Pleasingly, in attempts to facili-
tate reaction by Lewis acid activation of 1, we established a num-
ber of zinc, iron, gold and copper salts enhanced reactivity, with
CuCl proving most efficacious. A catalyst loading of 9.4 mol%
was determined to be optimal. Interestingly, CuBr gave a similar
result whereas CuI retarded the reaction completely (entries 10
and 11). Control experiments demonstrated that base is essential
for reactivity, copper did not catalyze the reaction in the absence
of palladium, and no reaction was observed in the absence of
copper and palladium (entries 12-14). We also assessed numerous
Pd/C sources and observed significant variation in activity, though
‘standard’ Pd/C from Heraeus and Sigma-Aldrich both showed
excellent reactivity. See SI for all additional experimental data.
Arylated heterocycles are valuable structural motifs and are pre-
sent in many natural products and biologically active molecules.6
Commonly these are prepared via transition metal catalyzed
cross-coupling of functionalized heterocycles and suitable cou-
pling partners,7 though more sustainable methods are desirable.
Recently, significant development of the field of C–H activation
has enabled the direct arylation of heterocycles,8 circumventing
the need for pre-functionalization. Unfortunately though, multi-
component and expensive catalyst systems are often required, and
directing groups to control regioselectivity are necessary. Alterna-
tively, many metal catalyzed direct C–H functionalizations ex-
ploiting the inherent reactivity of heterocycles are established,8c,9
providing viable alternatives, though methods that selectively
functionalize the less reactive C–H bonds without recourse to
directing groups,10 or exploiting the steric bulk of ligands,11 sub-
stituents12 or additives13 remain underdeveloped.
For valuable benzo[b]thiophenes motifs14,15 the transition metal
catalyzed direct arylation of the C2-position is well established,9c
though efficient methods for the more challenging direct C3-
arylation remain more elusive with only three reports to date
(Scheme 1a-c).16-18 Of the three reports, two provide a single
example, and other limitations include expensive catalyst systems,
large excesses of reagents or coupling partners, limited availabil-
In addition to Pd/C, the reactivity of several alternative hetero-
geneous catalysts under identical conditions was also investigated.
Several supported palladium systems were investigated, as well as
other transition metals. In all instances no appreciable reactivity
was observed, highlighting the unique catalytic activity of Pd/C
with respect to this transformation (see SI).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
1
2
3
4
5
6
7
8
fluoride heteroatoms proceeded in high yield and acceptable
Scheme 1. C3-Selective Arylation of Benzo[b]thiophenes.
reaction time, indicating that the electron deficient nature of the
aryl chloride alone is not significantly detrimental to reactivity.
Furthermore, C5-substituted benzo[b]thiophenes were amenable
to the reaction conditions and were coupled in very high yield and
pleasingly, reaction of 1 with 1,4-dichlorobenzene gave the bis-
benzo[b]thiophene adduct 15 in 41% yield. The scalability of the
reaction has also been demonstrated, with reaction to give 3 un-
dertaken on a 3 mmol scale. Unfortunately, efficient recycling of
the catalyst has not been established.
9
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
Table 2. Reaction Scope
Table 1. Optimization of Reaction Conditions
Entry
1
Additive (mol%)
-
Yielda C3/C2b
30%
22%
n. r.
>98:2
>99:1
-
2
PivOH (10)
Ag2CO3 (5)
AgSbF6 (5)
-
3
4
traces >99:1
5c
60%
64%
78%
88%
69%
77%
n. r.
n. r.
n. r.
n. r.
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
-
6c
AuCl3 (5)
CuCl (5)
CuCl (10)
CuCl (15)
CuBr (5)
CuI (5)
7c
8c
9c
10c
11c
12c,d
13c,d
14c,e
General conditions: Benzo[b]thiophene (0.300 mmol), ArCl (2.0
equiv.) Pd/C (9.4 mol%), Cs2CO3 (1.1 equiv.), 1,4-dioxane
(1.5 ml), 48-72 h. Yields given are isolated. C3/C2 ratios deter-
mined by GC-MS of crude reaction mixture. a 3 mmol scale,
reaction time 72 h, GC yield. b Product isolated as mixture with
corresponding homo-coupled ArCl. Yield given refers to denoted
CuCl (10)
-
-
-
CuCl (10)
-
General conditions: 1 (0.300 mmol), 2 (1.0 equiv.), Cs2CO3
compound. c Reaction time 96 h. d ArCl (0.300 mmol),
(3.0 equiv.).
1
(1.1 equiv.), Pd/C (9.4 mol%), 1,4-dioxane (1.5 ml), 150 °C, 48 h.
a
Yields determined by GC of crude reaction mixture; mesitylene
as internal standard. b C3/C2 ratios determined by GC-MS of
crude reaction mixture. c 1 (0.300 mmol), 2 (2.0 equiv.), 1,4-
dioxane (1.5 ml). d W/o Pd/C. e W/o base.
The application of this method to other heterocycles has provid-
ed limited success to date. Only thiophenes have demonstrated
any notable reactivity, though poor C3/C2 selectivity is observed.
Pleasingly though, we have demonstrated the selective nature of
this reaction in an intermolecular competition experiment. Using
the standard reaction conditions, a 1:1:1 mixture of ben-
zo[b]thiophene 1, 2-nꢀbutylthiophene and pyridine showed almost
exclusive reactivity for benzo[b]thiophene 1, suggesting this
method is appropriate for application to more complex substrates
(Scheme 2).
With optimized conditions established we explored the scope of
the reaction (Table 2). Electron-rich and electron-neutral aryl
chlorides gave reaction products in typically excellent yield.
Sterically encumbered aryl chlorides also proceeded in excellent
yield, though extended reaction times were required; the reaction
of 2-chloro-m-xylene is of particular note. Reaction with electron-
deficient aryl halides including nitro- and ester-substituted sys-
tems proceeds, though the rate of reaction was significantly re-
duced.21 Interestingly, electron deficient systems bearing only
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
1
2
activation/palladation at C3 to give 18 followed by reductive
Scheme 2. Intermolecular Competition Experiment
elimination. As described by Hartwig, homogeneous C-H activa-
tion mechanisms are highly amenable to investigation using kinet-
ic isotope studies.24 In this instance, a ‘homogenous type’ C–H
activation mechanism is directly refuted by the absence of a KIE
in the appropriate kinetic and competition experiments proposed
by Hartwig. Furthermore, palladation at the more acidic C2-
position would be expected for typical C–H activation mecha-
nisms.8 ii) Palladation at C2 generating cationic species 19, fol-
lowed by aryl-migration and elimination of palladium as proposed
by Itami.16 This mechanism was deemed improbable as unlike in
the report of Itami, when silver salts were employed to promote
formation of cationic palladium species via sequestering of hal-
ides, retardation of reaction was observed. Furthermore, no reac-
tion of 3-methylbenzo[b]thiophene 22 under identical reaction
conditions was observed. We suggest it is likely arylation at C2
would be expected in this instance via the reductive elimination of
19b, as the migratory pathway is shut down. We appreciate subtle
steric effects may also account for the lack of reactivity. iii) A
Heck type mechanism. This was ruled out due to the mechanistic
requirement for syn β-hydride elimination, thus requiring C-C
bond rotation of cyclic intermediate 20 which is not possible.
Alternatively, base catalyzed elimination of the palladium driven
by re-aromatization may be considered, though the selectivity
observed in the hypothetical migratory insertion to ben-
zo[b]thiophene is contrary to that expected.25 iv) Electrophilic
palladation at C3 to give 21, followed by reductive elimination
and re-aromatization. Reaction of 2-methylbenzo[b]thiophene 23
and 3-methylbenzo[b]thiophene 22 under the standard reaction
conditons gave 11% and 0% yield, respectively. Although elec-
trophilic arylation in a manner analogous to indole would give
preferential reactivity at C3, the complete inhibition of reactivity
with 22, rather than a shift in selectivity is unlikely; additionally,
the relatively small and electronically neutral substitution at C2 as
present in 22, would not be expected to inhibit reactivity to such
an extent using simple such simple catalytic systems.26 As a result
of the discussed mechanistic considerations, we propose that
traditional mechanisms associated with homogeneous catalysis
are not directly applicable in this instance, and consequently that
the supported nature of the catalyst may have a direct impact on
the regioselectivity of the reaction.
3
4
5
6
7
8
9
The hetero- or homogeneous nature of the active catalyst in
many reactions is often highly contentious, and specifically with
regard to Pd/C the active species is often thought to be homoge-
neous following leaching of palladium into solution.22 Conse-
quently, we have undertaken significant effort to determine the
nature of the active species in our system. Considering both the
high temperature of the reaction and the presence of aryl chlorides
– which in given examples are known to leach palladium from
carbon supports via an oxidative addition process23 – it is highly
notable that we have demonstrated that the active catalyst is very
likely to be heterogeneous in nature.
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
Although no current methods evaluating the ho-
mo/heterogeneous nature of an active catalyst can be considered
completely definitive,22 the results of numerous experimental tests
and literature precedent for the conclusions drawn has led us to
propose that the active catalytic species is highly likely to be
heterogeneous in nature. Key experiments include: i) Two 3-phase
tests,22 whereby one reagent (the aryl chloride or ben-
zo[b]thiophene) is immobilized on a solid support, showed that
active homogeneous catalytic species are not generated under
these reaction conditions. ii) Standard Hg(0) poisoning and hot
filtration tests are positive for heterogeneous catalysis.22 iii) The
introduction of PPh3 (10 mol%), an established poison for hetero-
geneous catalysts results in significant inhibition of reactivity.
Complete inhibition of the catalyst is typically expected with sub-
stoichiometric quantities of PPh3 (with respect to the catalyst) due
to irreversible binding of the phosphine to the surface, though in
this instance we propose that the high reaction temperature results
in dynamic rather than irreversible binding of the phosphine, and
thus trace reaction is observed. iv) Numerous comparable homo-
geneous Pd catalysts showed no reactivity. Reactivity of
PdCl2(PPh3)2 and Pd(PPh3)4 was observed, though resulted excluꢀ
sively in C2-arylation. v) An analysis of the reaction mixture by
X-ray fluorescence spectroscopy (XRF) after filtration showed
palladium present at a concentration of <4 ppm, corresponding to
0.01% of the initial palladium loading. Additional experiments,
clarification of results, and further circumstantial evidence are
provided in the supporting information.
The results of our investigation strongly suggest a heterogene-
ously catalyzed reaction. The 3-phase tests, and experiments
demonstrating that site-selectivity is reversed when employing
active homogeneous Pd(0) are particularly compelling. This
change in selectivity highlights the unique reactivity possible
when employing a heterogeneous catalyst. It should be noted a
short induction period was observed when investigating the kinet-
ic progress of the reaction. We propose this could be accounted
for by the initial reduction/modification of the catalyst surface, to
generate the active catalyst. Alternatively, leaching of palladium
into solution could account for the induction period, though
should this be the case, our results suggest likely agglomeration of
leached palladium, and formation of a new heterogeneous active
species rather than generation of a homogeneous active species.22a
Figure 1. Hypothetical Intermediates for Refuted Homo-
geneous Reaction Mechanisms.
In summary, we have described the first heterogeneously cata-
lyzed C–H arylation of benzo[b]thiophenes, demonstrating novel
reactivity mediated by a simple palladium catalyst. The reaction
appears intrinsically selective for the typically less reactive C3-
position, requiring no additional ligands or directing groups.
Cheap and widely available catalysts and coupling partners are
employed, and the reaction is both operationally simple, and
tolerant of air and water. Our mechanistic investigation suggests
typical homogeneous reaction mechanisms are unlikely to be in
operation. Further studies relating to the interaction of the sub-
strate and catalyst, the mechanism of reaction, and the role of
CuCl are ongoing within our laboratory.
In addition to our empirical investigation into the physical na-
ture of the active catalyst, we have also evaluated possible mech-
anistic pathways. A number of viable homogeneous mechanistic
pathways have been considered, though none is satisfactory (Fig-
ure 1, see SI for associated experimental data): i) Direct C–H
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
1
2
3
4
5
6
7
8
Q. Chem. Soc. Rev. 2009, 38, 3242. (h) Daugulis, O.; Do, H.-Q.;
ASSOCIATED CONTENT
Shabashov, D. Acc. Chem. Res, 2009, 42, 1074. (i) Jazzar, R.; Hitce,
J, Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010,
16, 2654. (j) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (k) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624. (l) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16,
11212. (m) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc.
Rev. 2011, 40, 5068. (n) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glori-
us, F. Chem. Soc. Rev. 2011, 40, 4740. (o) Newhouse, T.; Baran, P. S.
Angew. Chem., Int. Ed. 2011, 50, 3362. (p) Ackermann, L. Chem.
Rev. 2011, 111, 1315. (q) McMurray, L.; O’Hara, F;. Gaunt, M. J.
Chem. Soc. Rev. 2011, 40, 1885. (r) Yeung, C. S.; Dong, V. M. Chem
Rev. 2011, 111, 1215. (s) White, M. C. Science 2012, 335, 807. (t)
Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
45, 788. (u) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew.
Chem., Int. Ed. 2012, 51, 8960. (v) Neufeldt, S. R.; Sanford, M. S.
Acc. Chem. Res. 2012, 45, 936. (w) Kuhl, N.; Hopkinson, M. N.;
Wencel-Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
10236. (x) Wencel-Delord, J.; Glorius, F. Nature Chem. 2013, 5, 369.
(9) For selected reviews on direct arylation of (hetero)aromatics
see: (a) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673.
(b) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (c) Satoh, T.;
Miura, M. Chem. Lett. 2007, 36, 200.
(10) For recent reports see: (a) Larbi, K. S.; Fu, H. Y.; Laidaoui,
N.; Beydoun, K.; Miloudi, A.; El Abed, D.; Djabbar, S.; Doucet, H.
ChemCatChem 2012, 4, 815. (b) Schnapperelle, I.; Breitenlechner, S.;
Bach, T. Org. Lett. 2011, 13, 3640. (c) Yanagisawa, S.; Ueda, K.;
Sekizawa, H.; Itami, K. J. Am. Chem. Soc. 2009, 131, 14622.
(11) Ackermann, L.; Barfüßer, S. Synlett 2009, 20, 808.
(12) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm.
Bull. 1989, 37, 1477.
(13) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc.
2005, 127, 8050.
(14) For illustrative examples of benzo[b]thiophenes in biological-
ly active molecules see: (a) Zhang, T. Y.; O’Toole, J.; Proctor, C. S.
Sulfur reports 1999, 22, 1. (b) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893.
Supporting Information. Experimental procedures and full
spectroscopic data for all new compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
9
glorius@uni-muenster.de
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
ACKNOWLEDGMENT
This paper is dedicated to Prof. Andreas Pfaltz, a great teacher
and pioneer of asymmetric catalysis, on the occasion of his 65th
birthday. Generous financial support by the Deutsche For-
schungsgemeinschaft (SFB 858) and the Fonds der Chemischen
Industrie (D.-T. D. T.) is gratefully acknowledged. We thank Prof.
Dr. Uwe Karst and Christoph Wehe for TXRF analyses, Karin
Gottschalk for experimental support and Dr. Rainer Kiemel
(Heraeus) and Dr. Sébastien Parisel and Dr. Steve Hawker (both
Johnson Matthey) for stimulating discussions and for the kind
donation of catalyst samples (Johnson Matthey).
REFERENCES
(1) (a) Fine chemicals Through Heterogeneous Catalysis; Sheldon,
R. A.; van Bekkum, H., Eds.; Wiley-VCH, Weinheim, 2001. (b)
Asymmetric Catalysis on Industrial Scale, Blaser, H. U.; Schmidt, E.,
Eds.; Wiley-VCH, Weinheim, 2004.
(2) For illustrative reviews on asymmetric heterogeneous catalysis
see: (a) Heitbaum, M.; Glorius, F.; Escher, I. Angew. Chem., Int. Ed.
2006, 45, 4732. 2. (b) Mallat, T.; Orglmeister, E.; Baiker, A. Chem.
Rev. 2007, 107, 4863. (c) Trindade, A. F.; Gois, P. M. P.; Afonso, C.
A. M. Chem. Rev. 2009, 109, 418. (d) Wang, Z.; Chen, G.; Ding, K.
L. Chem. Rev. 2009, 109, 322. For a recent example, see: (e) Gross,
E.; Liu, J. H.; Alayoglu, S.; Marcus, M. A.; Fakra, S. C.; Toste, F. D.;
Somorjai, G. A. J. Am. Chem. Soc. 2013, 135 3881.
(15) For illustrative examples of benzo[b]thiophenes in organic
materials see: (a) Murphy, A. R.; Fréchet, J. M. J. Chem. Rev. 2007,
107, 1066. (b) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Chem.
Rev. 2012, 112, 2208.
(16) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew.
Chem. Int. Ed. 2010, 49, 8946.
(3) Thayer, A. Chem. Eng. News 2005, 83, 55.
(4) Review on heterogeneous palladium catalyzed couplings: Yin,
L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
(5) For selected reviews on the application of nanocatalysts see: (a)
Polshettiwar, V.; Luque, R.; Fihri, A.; Zhu, H.; Bouhrara, M.; Basset,
J.-M. Chem. Rev. 2011, 111, 3036. (b) Ranganath, K. V. S.; Glorius,
F. Catal. Sci. Technol. 2011, 1, 13. (c) Schätz, A.; Reiser, O.; Stark,
W. J. Chem. Eur. J. 2010, 16, 8950. (d) Shylesh, S.; Schünemann, V.;
Thiel, W. R. Angew. Chem., Int. Ed. 2010, 49, 3428. (e) Lu, A.-H.;
Salabas, E. L.; Schüth, F. Angew. Chem., Int. Ed. 2007, 46, 1222. (f)
Astruc, D.; Lu, F.: Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44,
7852. For a recent example, see: (h) Gross, E.; Liu, J.H-C.; Toste, F.
D.; Somorjai, G.A. Nature Chem. 2012, 4, 947.
(6) (a) Nicolaou, K. C.; Hale, C. R. H.; Nilewski, C.; Ioannidou,
H. A. Chem. Soc. Rev. 2012, 41, 5185. (b) McGlacken, G. P.; Bate-
man, L. M. Chem. Soc. Rev. 2009, 38, 2447. (c) Bioactive Heterocyꢀ
clic Compound Classes: Pharmaceuticals and Agrochemicals; Lam-
berth, C.; Dinges, J., Eds.; Wiley-VCH, New York, 2012.
(7) For reviews on transition metal catalyzed cross-coupling of het-
erocycles see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev.
2011, 111, 1417. (b) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359.
(8) For recent reviews on C–H activation see: (a) Beccalli, S.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107,
5318. (b) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 7, 949. (c)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792. (d) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094. (e) Lautens, M.; Thansandote,
P. Chem. Eur. J. 2009, 15, 5874. (f) Kitamura, T. Eur. J. Org. Chem.
2009, 1111. (g) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-
(17) Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.;
Itami, K. Angew. Chem. Int. Ed. 2011, 50, 2387.
(18) Funaki, K.; Sato, T.; Oi, S. Org. Lett. 2012, 14, 6186.
(19) (a) Ranganath, K. V. S.; Kloesges, J.; Schäfer, A. H.; Glorius,
F. Angew. Chem., Int. Ed. 2010, 49, 7786. (b) Ranganath, K. V. S.;
Schäfer, A. H.; Glorius, F. ChemCatChem 2011, 3, 1889.
(20) Blaser, H.-U.; Indolese, A.; Schnyder, A.; Steiner, H.; Studer,
M. J. Mol. Catal. A: Chem. 2001, 173, 3.
(21) Significant amounts of 1 and the respective aryl chloride re-
mained after the given reaction time.
(22) For application and limitations see: (a) Crabtree, R. H. Chem.
Rev. 2012, 112, 1536. (b) Widegren, J. A.; Finke, R. G. J. Mol. Catal.
A: Chem. 2003, 198, 317 and references within.
(23) (a) Lamblin, M.; Nasser-Hardy, L; Hierso, J-C.; Fouquet, E.;
Felpin, F-X; Adv. Syn. Catal. 2010, 352, 33. (b) Huang, L.; Wong, P.
W.; Tan, J.; Ang, T. P.; Wang, Z.; J. Phys. Chem. C 2009, 113,
10120.
(24) Simmons, E. M.; Hartwig, J. F.; Angew. Chem. Int. Ed. 2012,
51, 3066.
(25) (a) de Meijere, A.; Meyer, Jr., F. E. Angew. Chem. Int. Ed.
Engl. 1994, 33, 2379. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2000 100, 3009.
(26) See Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org.
Chem., 2010, 75, 1047 and references within.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
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
5
ACS Paragon Plus Environment