High-yielding, versatile, and practical [Rh(III)Cp*]-catalyzed ortho bromination and iodination of arenes

Article abstract of DOI:10.1021/ja302631j

We report a uniquely high-yielding, general, and practical ortho bromination and iodination reaction of different classes of aromatic compounds. This reaction occurs by Rh(III)-catalyzed C-H bond activation methodology and is therefore the first example of the application of this cationic catalyst for C-Br and C-I bond formation.

Full text of DOI:10.1021/ja302631j

Subscriber access provided by George Mason University Libraries & VIVA (Virtual Library of Virginia)
Communication
High yielding, versatile and practical [Rh(III)Cp*]-
catalyzed ortho-bromination and iodination of arenes
Nils Schroeder, Joanna Wencel-Delord, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja302631j • Publication Date (Web): 01 May 2012
Downloaded from http://pubs.acs.org on May 14, 2012
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
8
9
High yielding, versatile and practical [Rh(III)Cp*]-catalyzed or-
tho-bromination and iodination of arenes
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
Nils Schröder‡, Joanna WencelꢀDelord‡, Frank Glorius*
OrganischꢀChemisches Institut des Westfälischen WilhelmsꢀUniversität Münster, Corrensstrasse 40, 48149 Münster,
Germany
Supporting Information Placeholder
using a [Rh(III)Cp*]ꢀcatalyst. The particular advantage of this
strategy is its compatibility with many different, highly useful
directing groups which opens up new possibilities for the
synthesis of a panel of aromatic halides.
ABSTRACT: We report a uniquely high yielding, general and
practical orthoꢀbromination and iodination reaction of differꢀ
ent classes of aromatic compounds. This reaction occurs by
Rh(III)ꢀcatalyzed CꢀH bond activation methodology and is
therefore the first example of the application of this cationic
catalyst for CꢀBr and CꢀI bond formation.
For many decades, aromatic halides have been an important
class of compounds, due to their role as precursors for the
synthesis of organometallic reagents1 and for nucleophilic
substitution reactions.2 In addition, with the advent of crossꢀ
coupling chemistry,3 the importance of bromoꢀ and iodoarenes
has tremendously increased and hence they can be classified
In order to develop a catalytic system complementary to the
as the core building blocks of organic synthesis. Consequently
already known Pdꢀcatalyzed examples that are especially
efficient and selective methods to access this class of comꢀ
suited for electronꢀrich substrates, we selected the rather elecꢀ
tronꢀpoor tertiary benzamide 1 as initial substrate of our study.
pounds are highly valuable.
The metalꢀcatalyzed direct functionalization of CꢀH bonds has
emerged over the last decade as a modern and environmentally
friendly tool for organic synthesis.4 Due to the constant effort
of many research groups, a plethora of carbonꢀcarbon bond
formation reactions have been discovered. However, the apꢀ
plication of this strategy to create carbonꢀheteroatom bonds,
and, in particular, carbonꢀhalogen bonds, is still surprisingly
underdeveloped. The vast majority of the rare examples of
these CꢀX (X = Cl, Br, I) bond formation reactions use a palꢀ
ladium catalyst.5 Therefore, the catalytic systems reported by
the groups of Sanford,6 Yu,7 Bedford,8 Shi,9 Tanabe,10 Fabis,11
Xu12 and Dong13 illustrate the major importance of these or-
thoꢀselective transformations. However, they were generally
limited either by their scope (the use of a specific directing
group such as heteroaromatics or electronꢀdonating directing
groups), by their efficiency (moderate yields) or being suitable
for only for one type of CꢀX bond formation. Therefore, a
general method enabling the highꢀyielding and selective forꢀ
mation of most valuable and versatile (with regard to further
transformations) CꢀBr and CꢀI bonds, compatible with a large
scope of diverse arenes, is of prime synthetic value.
Moreover, with the aim of discovering halogenation strategies
compatible with both bromination and iodination reactions, the
commercially available, stable and rather inexpensive Nꢀhaloꢀ
succinimide derivatives were found to be ideal Br and I
sources. We commenced the bromination study using NBS in
the presence of [RhCp*Cl2]2 (2.5 mol%), AgSbF6 (10 mol%),
Cu(OAc)2 as oxidant and PivOH as additive. No desired prodꢀ
uct was detected when the reaction was run in dioxane at 140
°C, but we noticed with delight that the simple change of
solvent to 1,2ꢀDCE led to the formation of the orthoꢀ
brominated benzamide 1-Br with full conversion and 82%
isolated yield. Further investigations revealed that Cu(OAc)2
was not required for this transformation and that significantly
milder reaction conditions (temperature of only 60 °C) could
be successfully applied. Notably, decreasing the catalyst loadꢀ
ing to 1 mol% did not affect the efficiency of this transforꢀ
mation. A control reaction showed that omission of the Rh
precatalyst resulted in complete inactivity of this catalytic
system.
Under these optimized conditions, the scope of benzamides
bearing diverse substituents on the arene ring was examined
(Table 1). Electronꢀrich substituents such as Me or OMe in
both paraꢀand metaꢀpositions were well tolerated leading to
the formation of the desired products with excellent yields.
However, when 5 was used as a substrate, the small steric
hindrance of the methoxy group was not sufficient to control
the selectivity of this reaction and two easily separable regioiꢀ
somers of 5-Br were obtained in almost equal amount. In
contrast to electronꢀdonating groups, strongly electronꢀ
withdrawing groups, such as CF3, on either the paraꢀ or metaꢀ
Recently, Rh(III) has emerged as a highly useful CꢀH bond
activation catalyst. Indeed, it turned out to be a very efficient
catalyst for the CꢀH bond activation/olefination,14 alkynylaꢀ
tion15 and, more recently, nucleophilic additions16 and arylaꢀ
tion reactions.17 However, to the best of our knowledge, no
application of this catalyst system for carbonꢀhalogen bond
formation has been reported up to now. Herein, we report a
new, high yielding, versatile and general method for the synꢀ
thesis of orthoꢀbrominated and iodinated aromatic compounds
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
position had a significant influence on the activity of this To additionally establish the power of this methodology, we
1
catalytic system and an increased reaction temperature (120
°C) was required to complete this transformation. Similarly,
other electron deficient benzamides bearing a NO2 or CN
substituent in the para position could undergo the bromination
reaction sufficiently, but more sluggishly, leading to the forꢀ
mation of 8-Br and 9-Br in 87 and 70% yield, respectively.
Notably, this catalytic system turned out to be efficient and
totally selective even when benzamide 10 bearing an additionꢀ
al ester substituent, a potentially second chelating group, was
submitted to the reaction conditions. Haloꢀsubstituted benꢀ
zamides 11 and 12 were also well tolerated and therefore the
highly valuable bromoꢀchloroꢀ and bromoꢀiodoꢀsubstituted
arenes could be obtained in excellent yield (96 and 93%).
Moreover, the bromination of the benzamide bearing a
chloromethyl substituent (13) was also possible, leading to the
formation of the orthoꢀbrominated product in 87% yield. Exꢀ
panding the scope from the phenyl to the naphthylꢀsystem (14)
was also possible, leading to the formation of 14-Br. The
presence of an additional aromatic ring on the substrate was
tolerated as well, leading to the regioselective formation of 15-
Br. However, it is important to note that for this sterically
demanding tertiary benzamide directing group, an orthoꢀ
substitution turned out to be detrimental for this transforꢀ
mation: only trace amounts of brominated product 16-Br
could be detected by ESIꢀHR analysis of the crude mixture.14j,k
examined the possibility of performing the iodination reaction
(Table 2). We were pleased to observe that the simple reꢀ
placement of NBS by NIS under otherwise identical condiꢀ
tions led to the formation of the orthoꢀiodinated compound 1-I
in an excellent yield of 98%. Encouraged by these results, we
turned our attention to arenes bearing other directing groups.
These bromination and iodination reactions proved up to be
highly versatile. Firstly, the highly sterically demanding iso-
propyl substituent on the benzamide group could be replaced
by less hindered and less electronꢀrich methyl groups, leading
to the formation of the corresponding brominated and iodinatꢀ
ed compounds 17-Br and 17-I in 86 and 75% yield. Moreover,
the tertiary amide group could be efficiently replaced by a
secondary amide group, leading to the formation of 18-Br and
18-I with good yields of 80 and 78%. Notably, the use of the
secondary amide directing group enabled to obviate the intolꢀ
erance of the tertiary benzamide towards orthoꢀsubstituents;
19 underwent the bromination reaction smoothly, leading to
the formation of 19-Br in 87% yield. For a highly activated
arene, like the acetanilide, the ortho-bromination occurred
smoothly under the standard conditions. However, interestingꢀ
ly, this reaction failed when the stronger electrophile NIS was
used. In this case, the paraꢀiodinated product was selectively
obtained, which presumably results from the non rhodiumꢀ
catalyzed electrophilic aromatic substitution pathway (the
control reaction run in absence of rhodium gave the identical
result). When unsubstituted phenylpyridine 21 was used in the
presence of 2.2 equivalents of the halogenating agent, the
selective bihalogenation was observed for either the brominaꢀ
tion or iodination reaction. Thereafter, we focused our attenꢀ
tion on highly valuable substrates such as ketones or esters,
which are known to be difficult in CꢀH activation processes.
Under standard reaction conditions with the increased reaction
temperature (120 °C), the bromination of the tertꢀbutyl phenyl
ketone occurred smoothly leading to the formation of the
desired 22-Br in 78% yield. In contrast, the iodination reaction
turned out to be troublesome and the successive addition of
NIS in small portions was required to allow the successful
execution of this transformation. Encouraged by these results,
we submitted a simple acetophenone substrate to our halogenꢀ
ation reaction. Disappointingly, no desired product was
formed and a nonꢀcatalyzed bromination of the methyl group
occurred. The replacement of the PivOH additive by CsOPiv
led to the total inhibition of the reaction. However, we were
delighted to discover that when copper acetate was used inꢀ
stead of pivalic acid, the desired ortho-brominated acetopheꢀ
none could be isolated in 50% yield. These modified reaction
conditions turned out to be key to the successful halogenation
reaction of another enolisable, iso-propyl phenyl ketone and
benzoic ester substrates. Thus, the corresponding halogenated
products were obtained in moderate yields, probably due to the
instability of the substrates under high reaction temperature,
required for the less efficient CꢀH activation event. Finally, the
potential of a phenylꢀdimethylcarbamate to undergo the CꢀH
bond activation/CꢀX bond formation sequence was examined.
The bromination reaction run at 120 °C, with 5 mol% catalyst
loading and 2 equivalents of NBS led to the formation of the
mixture of monoꢀ and diꢀhalogenated product. The two species
could be separated, leading to isolation of 26a-Br and 26b-Br
in 35 and 49% yields.
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
Table 1. ortho-Bromination of benzamides.
a Isolated yields, reaction run on a 1 mmol scale. b 24 h reaction
time and 2 equiv of NBS were used. c 48 h reaction time and 2
d
equiv of NBS were used. Only traces of brominated product
e
could be detected by ESIꢀanalysis of the crude mixture. 2.5
mol% [RhCp*Cl2]2 and 10 mol% AgSbF6 were used.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Table 2. ortho-Bromination and iodination of various
arenes.
parison to the spectrum of 1 alone. The subsequent addition of
1
2
3
4
5
6
7
8
the NBS and PivOH resulted in the immediate initiation of the
expected reaction, however, no intermediate species could be
detected. These observations suggest that an equilibrium beꢀ
tween substrate + catalyst and the rhodacycle is in operation in
the absence of NXS and that this equilibrium is shifted in the
direction of the substrate. In the presence of NBS, the haloꢀ
genation step would be fast, leading to the rapid conversion of
the intermediate rhodacycle to the desired product. Furtherꢀ
more, a kinetic study of the reaction revealed that this transꢀ
formation requires no incubation time.19
[RhCp*Cl2]2 (1 mol%)
AgSbF6 (4 mol%)
(X)
DG
H
DG
X
+
NXS
(1.1 equiv)
PivOH (1.1 equiv)
1,2-DCE, T, t
X = Br, I
N(iPr)2
O
NHnBu
NMe2
O
NHnBu
H
N
O
O
9
O
X
Br
X
X
X
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
17-Br: 86%
70 °C; 24 h
17-I: 75%
18-Br: 80%
60 °C; 16 h
18-I: 78%
19-Br: 80%b
1-Br: 99%
60 °C; 16 h
1-I: 98%
20-Br: 89%
Based on these results we propose two different mechanistic
pathways (Scheme 2). Both of them start with the reversible
CꢀHꢀactivation and formation of rhodacycle A. Following
pathway a, the rhodacycle A can undergo the nucleophilic
addition type to NBS to directly lead to product 1-Br. On the
other hand, similar to some palladium catalyzed halogenaꢀ
tions, the intermediate A, in the presence of NBS, could potenꢀ
tially be oxidized to Rh(V) complex B, which then would
undergo the reductive elimination to form product 1-Br and
regenerate the Rh(III)ꢀcatalyst.
60 °C; 16 h
60 °C; 16 h
20-I: 0%c
60 °C; 16 h
90 °C; 24 h
60°C; 16 h
60 °C: 16 h
O
O
O
O
X
N
OEt
X
X
Br
X
X
21-Br: 73%d 22-Br: 78% 23-Br: 50%b,d,f 24-Br: 73%b,f
25-Br: 49%b,h,i
120 °C; 16 h
22I: 53%e
60 °C; 16 h
21-I: 88%d
60°C; 16 h
120 °C; 21 h
23-I: 62%b,f,g
120 °C; 22 h
120 °C; 21 h
24-I: 61%b,f
120 °C; 21 h
120 °C; 21 h
120 °C; 52 h
Br
O
NMe2
O
NMe2
O
NMe2
O
O
O
Br
Br
Br
26a-Br: 35%b,f,j
26b-Br: 49%b,f,j
27-Br: 76%b,f,k
120 °C; 48 h
120 °C; 24 h
a
Isolated yields, reactions run on a 1 mmol scale. b 2.5 mol%
c
[RhCp*Cl2]2, 10 mol% AgSBF6. Instead the 4ꢀIodoꢀAcetanilide
(82%) from SeꢀArꢀreaction was formed 2.2 equiv of NXS. 2.5
d
e
f
equiv of NIS was added in 5 portions. 2.2 equiv Cu(OAc)2 inꢀ
stead of PivOH. g 1.4 equiv of NIS. h 1.1 equiv Cu(OAc)2 instead
of PivOH I 2.0 equiv of NBS was added in 4 portions. 2.0 equiv
j
of NBS. k 1.5 equiv. Of NBS.
Scheme 2: Proposed catalytic cycle.
For obtaining more mechanistic insight, a deuteration experꢀ
iment was conducted (Scheme 1). Treatment of a 1:1 mixture
of 1 and 1-d5 under the typical reaction conditions revealed a
kinetic isotopic effect (KIE) of 3.9 for the initial reaction rate
(conversion of 20%, Experiment 1). This value is typical for
the CꢀHꢀactivation process. Moreover, in order to investigate
the nature of the rate determining step, the initial rate of the
reaction with 1 and 1-d5 was measured and revealed the KIE
of 2.0 (Experiment 2). This result suggests that the CꢀH bond
activation is a rate determining step. In addition, the analysis
of the recovered starting material showed significant H/Dꢀ
scrambling, which indicates the reversible character of the Cꢀ
H activation step.18
In conclusion, a general and practical strategy for the orthoꢀ
bromination and iodination of arenes by a cationic Rh(III)ꢀ
catalyst has been developed. This transformation is not only
compatible with tertiary benzamide substrates bearing a varieꢀ
ty of electronꢀrich and electronꢀpoor groups such as ester,
chloro or methoxyꢀsubstituents, but also with other classes of
arenes, such as secondary benzamides, acetamides and pheꢀ
nylpyridines. Moreover, this reaction is the first example of
the direct halogenations of simple ketones and benzoic esters
occurring via CꢀH bond activation. Due to its versatility, effiꢀ
ciency and, in many cases, fairly mild reaction conditions,4c
this reaction should be of high synthetic value.
ASSOCIATED CONTENT
Supporting Information Available. Experimental section and
characterization details. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Scheme 1: Deuteration Experiment.
1
Corresponding Author
Additionally, H NMR studies were undertaken in order to
* F. Glorius: glorius@uniꢀmuenster.de
characterize some key intermediates. 1 was added at 60 °C to a
preformed cationic catalyst [RhCp*(MeCN)3](SbF6)2 in a
stoichiometric and substoichiometric ratio. The 1H NMR analꢀ
ysis did not reveal any significant change of spectra in comꢀ
Author Contributions
‡These authors contributed equally.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(12) Song, B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal. 2010,
352, 329.
(13) Zhao, X.; Dimitrijević, Dong, V. M. J. Am. Chem. Soc. 2009,
131, 3466. Dubost, E.; Fossey, C.; Cailly, T.; Rault, S.; Fabis,
F. J. Org. Chem. 2011, 76, 6414.
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
Acknowledgments. We thank JuniorProfessor Frederic W.
Patureau for helpful discussion, Dr. Klaus Bergander for asꢀ
sistance with the NMR experiments and Tim Buscher for the
preparation of some substrates. Generous financial support by
the DFG (IRTG MünsterꢀNagoya) and by the European Reꢀ
search Council under the European Community's Seventh
Framework Program (FP7 2007ꢀ2013)/ERC Grant agreement
no 25936 is gratefully acknowledged.
(14) For selected examples of (directed) Rh(III)ꢀcatalyzed oxidaꢀ
tive Heck reactions see: (a) Ueura, K.; Satoh, T.; Miura, M.
Org. Lett. 2007, 9, 1407. (b) Umeda, N.; Hirano, K.; Satoh,
T.; Miura, M. J. Org. Chem. 2009, 74, 7094. (c) Mochida, S.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76,
3024. (d) Li, X.; Zhao, M. J. Org. Chem. 2011, 76, 8530. (e)
Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13, 2372.
(f) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman, J. A.
Org. Lett. 2011, 13, 540. (g) Chen, J.; Song, G.; Pan, C.ꢀL.;
Li, X. Org. Lett. 2010, 12, 5426. (h) Wang, F.; Song, G.; Li,
X. Org. Lett. 2010, 12, 5430. (i) Wang, F.; Song, G.; Du, Z.;
Li, X. J. Org. Chem. 2011, 76, 2926. (j) Patureau, F. W.; Gloꢀ
rius, F. J. Am. Chem. Soc. 2010, 132, 9982. (k) Patureau, F.
W.; Besset, T.; Glorius, F. Angew. Chem. Int. Ed. 2011, 50,
1064. (l) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J.
Am. Chem. Soc. 2011, 133, 2350. (m) Besset, T.; Kuhl, N.;
Patureau, F. W.; Glorius, F. Chem. Eur. J. 2011, 17, 7167. (n)
Li, H.; Li, Y.; Zhang, X.ꢀS.; Chen, K.; Wang, X.; Shi, Z.ꢀJ. J.
Am. Chem. Soc. 2011, 133, 15244. (o) Willwacher, J.;
Rakshit, S.; Glorius, F. Org. Biomol. Chem. 2011, 9, 4736.
For what is probably the first undirected Rh(III)ꢀcatalyzed oxꢀ
idative Heck reaction, see: (p) Patureau, F. W. ; Nimphius,
C. ; Glorius, F. Org. Lett. 2011, 13, 6346.
(15) For selected examples of Rh(III)ꢀcatalyzed alkynylation reacꢀ
tions see: (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M.
Angew. Chem. Int. Ed. 2008, 47, 4019. (b) Mochida, S.;
Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett.
2010, 39, 744. (c) Umeda, N.; Hirano, K.; Satoh, T.; Shibata,
N.; Sato, H.; Miura, M. J. Org. Chem. 2011, 76, 13. (d)
Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2011, 76, 2867. (e) Too, P. C.; Wang, Y.ꢀF.; Chiba, S. Org.
Lett. 2010, 12, 5688. (f) Hyster, T. K.; Rovis, T. J. Am. Chem.
Soc. 2010, 132, 10565. (g) Huestis, M. P.; Chan, L.; Stuart, D.
R.; Fagnou, K. Angew. Chem. Int. Ed. 2011, 50, 1338. (h)
Guimond, N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc.
2011, 133, 6449. (i) Rakshit, S.; Patureau, F. W.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 9585. (j) Patureau, F. W.;
Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133,
2154.
(16) For selected examples of Rh(III)ꢀcatalyzed nucleophilic addiꢀ
tion type reactions, see: (a) Tsai, A. S.; Tauchert, M. E.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133,
1248. (b) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2011, 133, 11430. (c) Li, Y.; Li, B.ꢀJ.; Wang, W.ꢀ
H.; Huang, W.ꢀP.; Zhang, X.ꢀS.; Chen, K.; Shi, Z.ꢀJ. Angew.
Chem. Int. Ed. 2011, 50, 2115. (d) Yang, L.; Correia, C. A.;
Li, C.ꢀJ. Adv. Synth. Catal. 2011, 353, 1269. (e) Park, J.; Park,
E.; Kim, A.; Lee, Y.; Chi, K.ꢀW.; Kwak, J. H.; Jung, Y. H.;
Kim, I. S. Org. Lett. 2011, 13, 4390. (f) Grohmann, C., Wang,
H., Glorius, F., Org. Lett. 2012, 14, 656.
(17) (a) WencelꢀDelord, J., Nimphius, C., Patureau, F. W., Gloriꢀ
us, F., Angew. Chem. Int. Ed. 2012, 124, 2290. (b) Wencelꢀ
Delord, J., Nimphius, C., Patureau, F. W., Glorius, F., Chem.
Asian J., DOI: 10.1002/asia.201101018.
(18) Simmons, E. M., Hartwig, J. F., Angew. Chem. Int. Ed. 2012,
51, 3066.
9
REFERENCES
(1) (a) Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275.
(b) Handbook of Grignard Reagents; Silverman, G. S.,
Rakita, P. E., Eds.; Dekker: New York, 1996.
(2) Crampton, M. R. Organic Reaction Mechanism; Wiley: New
York, 2003; p 275.
(3) Metal Catalyzed Cross Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; WileyꢀVCH: New York, 1998.
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
(4) For selected reviews on CꢀHꢀActivation, see: (a) Colby, D.
A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem.
Res. DOI: 10.1021/ar200190g (b) Engle, K. M.; Mei, T.ꢀS.;
Wasa, M.; Yu, J.ꢀQ. Acc. Chem .Res., DOI:
10.1021/ar200185g (c) WencelꢀDelord, J.; Dröge, T.; Liu, F.;
Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (b) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Satoh, T.;
Miura, M. Chem. Eur. J. 2010, 16, 11212. (d) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (e) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (f)
Xu, L.ꢀM.; Yang, Z.; Shi, Z.ꢀJ. Chem. Soc. Rev. 2010, 39,
712. (g) Sun, C.ꢀL.; Li, B.ꢀJ.; Shi, Z.ꢀJ. Chem. Commun.
2010, 46, 677. (h) Li, C.ꢀJ. Acc. Chem. Res. 2009, 42, 335. (i)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792. (j) Chen, X.; Engle, K. M.; Wang, D.ꢀH.;
Yu, J.ꢀQ. Angew. Chem., Int. Ed. 2009, 48, 5094. (k) Giri, R.;
Shi, B.ꢀF.; Engle, K. M.; Maugel, N.; Yu, J.ꢀQ. Chem. Soc.
Rev. 2009, 38, 3242. (l) Li, B.ꢀJ.; Yang,S.ꢀD.; Shi, Z.ꢀJ.
Synlett 2008, 949. (m) Kakiuchi, F.; Kochi, T. Synthesis 2008,
3013. (n) Satoh, T.; Miura, M. Top. Organomet. Chem. 2008,
24, 61. (o) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174.
(5) For a rare example of a Cu catalyzed orthoꢀhalogenation, see:
Wang, W.; Pan, C.; Chen, F.; Cheng, J. Chem. Commun.
2011, 47, 3978.
(6) (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
Tetrahedron 2006, 62, 11483. (b) Kalyani, D.; Dick, A. R.;
Anani, W. Q.; Sanford, M. S. Org. Lett. 2006, 8, 2523. (c)
Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (d) Whitfield, S. R., Sanford, M. S. J. Am.
Chem. Soc. 2007, 129, 15142. (e) Whitfield, S. R., Sanford,
M. S. Organometallics 2008, 27, 1683.
(7) (a) Mei, T.ꢀS.; Wang, D.ꢀH.; Yu, J.ꢀQ. Org. Lett. 2010, 12,
3140. (b) Li, J.ꢀJ.; Mei, T.ꢀS.; Yu, J.ꢀQ. Angew. Chem., Int.
Ed. 2008, 47, 6452. (c) Mei, T.ꢀS.; Giri, R.; Maugel, N.; Yu,
J.ꢀQ. Angew. Chem., Int. Ed. 2008, 47, 5215. (d) Giri, R.;
Chen, X.; Yu, J.ꢀQ. Angew. Chem., Int. Ed. 2005, 44, 2112.
(8) (a) Bedford, R. B.; Engelhart, J. U.; Haddow, M. F.; Mitchell,
C. J.; Webster, R. L. Dalton Trans. 2010, 39, 10464. (b) Bedꢀ
ford, R. B.; Haddow, M. F.; Mitchell C. J.; Webster, R. L.
Angew. Chem., Int. Ed. 2011, 50, 5524.
(9) Wan, X.; Ma, Z; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z.
J. Am. Chem. Soc. 2006, 128, 7416.
(10) Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano,
S.; Sato, M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc.
2009, 131, 11310.
(19) See Supporting Information for NMR studies.
(11) Dubost, E.; Fossey, C.; Cailly, T.; Rault, S.; Fabis, F. J. Org.
Chem. 2011, 76, 6414.
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