Cobalt-catalyzed C-H bond functionalizations with aryl and alkyl chlorides

Article abstract of DOI:10.1002/chem.201301409

Inexpensive cobalt catalysts derived from N-heterocylic carbenes (NHC) allowed efficient catalytic C-H bond arylations on heteroaryl-substituted arenes with widely available aryl chlorides, which set the stage for the preparation of sterically hindered tr

Full text of DOI:10.1002/chem.201301409

FULL PAPER
ꢀ
C H Activation
B. Punji, W. Song, G. A. Shevchenko,
L. Ackermann* ............... &&&& — &&&&
ꢀ
Cobalt-Catalyzed C H Bond Func-
tionalizations with Aryl and Alkyl
Chlorides
Inexpensive cobalt catalysts derived
from N-heterocyclic carbene (NHC)
using widely available aryl as well as
primary and secondary alkyl chlorides
with ample scope and removable
directing groups.
ꢀ
ligands enabled efficient C H bond
functionalizations of (hetero)arenes
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DOI: 10.1002/chem.201301409
ꢀ
Cobalt-Catalyzed C H Bond Functionalizations with Aryl and Alkyl
Chlorides
Benudhar Punji, Weifeng Song, Grigory A. Shevchenko, and Lutz Ackermann*[a]
Abstract: Inexpensive cobalt catalysts
derived from N-heterocylic carbenes
hydrogen-containing primary and even
secondary alkyl chlorides proceeded on
occurred efficiently at ambient reaction
temperature with excellent levels of
site-selectivities and ample scope.
Mechanistic studies highlighted that
electron-deficient aryl chlorides react-
ed preferentially, while the arenes ki-
ꢀ
(NHC) allowed efficient catalytic C H
pyridyl-
and
pyrimidyl-substituted
bond arylations on heteroaryl-substitut-
ed arenes with widely available aryl
chlorides, which set the stage for the
preparation of sterically hindered tri-
ortho-substituted biaryls. Likewise,
challenging direct alkylations with b-
arenes and heteroarenes. The cobalt-
ꢀ
catalyzed C H bond functionalizations
ꢀ
netic C H bond acidity was found to
Keywords: alkylation · arylation ·
largely govern their reactivity.
ꢀ
catalysis · C H activation · cobalt
Introduction
Aryl chlorides are the most attractive electrophilic aryl
halides for biaryl syntheses, since they are cost-effective and
widely available.[14] Thus far, direct arylations with inexpen-
sive aryl chlorides were predominantly achieved with rather
expensive transition-metal catalysts, such as ruthenium[15] or
Regioselectively substituted biaryls are key structural motifs
in bioactive compounds, natural products, and advanced
functional materials, among others.[1–3] Traditionally, their
syntheses have mostly been accomplished through transi-
tion-metal-catalyzed cross-coupling reactions with prefunc-
tionalized starting materials.[1,2] However, recent years have
witnessed remarkable progress in the development of more
atom- and step-economical direct arylations of ubiquitous
palladium complexes.[4,14] Given our interest in C H bond
ꢀ
arylations with user-friendly aryl chlorides,[16] we conse-
quently probed our recently developed reaction condi-
tions[13] for the cobalt-catalyzed C H bond arylation with
ꢀ
challenging chlorides as the electrophilic substrates. A very
recent report from Yoshikai and co-workers on useful
cobalt-catalyzed arylations of ketimines[17] prompted us to
now disclose a full account on a versatile cobalt catalyst for
ꢀ
C H bonds, which enabled an overall streamlining of organ-
ic syntheses.[3,4] As of yet, catalyzed direct arylations of
arenes were mostly achieved with relatively expensive
second-row transition-metal complexes.[4] Conversely, proto-
cols that utilize naturally more abundant first-row transi-
ꢀ
high-yielding C H bond arylations of heteroaryl-substituted
arenes with cost-economical aryl chlorides. Further notable
features of the user-friendly cobalt catalyst include remarka-
bly mild reaction temperatures (238C),[18] and widely appli-
ꢀ
tion-metal catalysts for C H bond arylations continue to be
scarce.[5] Significant progress in cobalt-catalyzed[6] C H
ꢀ
2
(sp3) bond formations with challenging b-hy-
ꢀ
bond functionalizations was, however, recently accomplished
by Nakamura, Yoshikai, and co-workers through the elegant
cable C
(sp ) C
drogen-containing primary and secondary alkyl[19,20] chlor-
ides—transformations that hitherto were solely accomplish-
ed by using secondary benzamides, along with primary alkyl
chlorides.[21]
ꢀ
development of direct C H bond alkylations by means of
chelation-assisted hydroarylations,[7,8] as well as oxidative
ꢀ
C H bond functionalizations with nucleophilic Grignard re-
agents.[9,10,11] In contrast, we recently devised reaction condi-
tions for cobalt-catalyzed direct arylations by challenging
[12]
ꢀ
ꢀ
C H/C O bond cleavages
with phenol-derived sulfa-
Results and Discussion
mates, carbamates, and phosphates as the electrophilic sub-
strates.[13]
C H bond arylation: At the outset of our studies, we tested
ꢀ
representative ligands and solvents for the desired direct ar-
ylation of the pyridyl-substituted arene 1a with the electron-
rich aryl chloride 2a (Table 1). Preliminary experiments in-
dicated N-heterocyclic carbene (NHC) precursors to exert a
remarkable rate acceleration. Particularly, N,N-bis-
[a] Dr. B. Punji, W. Song, G. A. Shevchenko, Prof. Dr. L. Ackermann
Institut fꢁr Organische und Biomolekulare Chemie
Georg-August-Universitꢂt
AHCTUNGTREG(NNUN mesityl)imidazolium chloride (IMesHCl) proved to be opti-
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: lutz.ackermann@chemie.uni-goettingen.de
mal among various NHC ligand precursors (Table 1, en-
tries 1–5). The cobalt-catalyzed direct arylation proceeded
most efficiently with 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301409.
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Cobalt-Catalyzed C H Bond Functionalizations
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Table 1. Optimization of direct arylation with aryl chloride 2a.[a]
Entry
Ligand
CyMgCl
[equiv]
Solvent
Yield
[%]
AHCTUNGTRENNUNG
1
2
3
4
5
6
7
8
—
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.6
1.6
1.6
DMPU
DMPU
DMPU
DMPU
DMPU
1,4-dioxane
THF
NMP
DMF
DMPU
DMPU
DMPU
27
82
66
39
32
39
50
49
IMesHCl
sIMesHCl
IPrHCl
sIPrHCl
IMesHCl
IMesHCl
IMesHCl
IMesHCl
IMesHCl
IMesHCl
IMesHCl
9
—
10
11
12
89
76[b]
66[c]
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.60 mmol), CoACTHNUTRGNEUNG(acac)2
(5.0 mol%), ligand (10 mol%), CyMgCl, solvent (1.0 mL), 238C, 16 h;
yields of isolated products; (S)IMesH=N,N-bis-(mesityl)imidazol(in)ium,
(S)IPrH=N,N-bis-(2,6-diisopropylphenyl)imidazol(in)ium. [b] CoACHTGNUTRENNUNG
(5.0 mol%), IMesHCl (5.0 mol%). [c] Co
(1.0 mol%).
ACHTUNGTRENNUNG
pyrimidinone (DMPU) as the solvent (Table 1, entries 2 and
6–11), and the catalyst loading could be successfully reduced
to only 0.5 mol% (Table 1, entry 12). Intriguingly, the
cobalt-catalyzed direct arylation on the meta-substituted
arene 1a proceeded site-selectively at the sterically more
hindered C-2 position.
Scheme 1. Scope of cobalt-catalyzed direct arylations with aryl chlorides
2.
With a highly efficient cobalt catalyst in hand, we tested
its versatility in the direct arylation of various arenes 1
(Scheme 1). Thus, both electron-rich as well as electron-defi-
cient substrates (1b and 1c) were successfully employed.
Moreover, various substituted pyridine or pyrimidine deriva-
tives 1d–1i were found to be viable starting materials, as
was benzo[h]quinoline (1j), thereby furnishing the desired
products 3da–3jf in high yields. The cobalt catalyst was not
limited to electron-deficient, thus electronically activated,
aryl chlorides 2. Indeed, electron-rich aryl chlorides were
converted with a comparable catalytic efficacy (vide infra),
even when being sterically more demanding (3jf).
We were particularly intrigued by the remarkable site se-
lectivity observed with meta-alkoxy-substituted arenes 1
(Scheme 2), which exclusively delivered the sterically more
congested biaryls 3 as the sole products, likely through a sec-
ondary directing group effect. It is noteworthy that the
cobalt catalyst thereby even enabled the preparation of tri-
ortho-substituted biaryl 3af, which bears considerable poten-
Scheme 2. Direct C-2-arylations with meta-substituted arenes 1.
ꢀ
tial for the future development of asymmetric C H bond ar-
ylations.[22]
bond alkylations[19,20,21] with b-hydrogen-containing alkyl
chlorides 4 under non-acidic reaction conditions (Table 2).
While direct alkylations of secondary benzamides were pre-
viously shown to proceed in the absence of additional s-
ꢀ
C H bond alkylation: Having identified a highly effective
cobalt catalyst for direct arylations with aryl chlorides, we
ꢀ
were subsequently interested in exploring challenging C H
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Table 2. Optimization of direct alkylation with alkyl chloride 4a.[a]
Entry
Ligand
RMgCl (equiv)
5da
[%]
1
2
3
4
5
6
7
8
—
—
—
dppe
tBuMgCl (3.0)
MeMgCl (3.0)
CyMgCl (3.0)
MeMgCl (3.0)
MeMgCl (3.0)
MeMgCl (3.0)
MeMgCl (3.0)
MeMgCl (3.0)
CyMgCl (3.0)
CyMgCl (1.6)
CyMgCl (2.0)
CyMgCl (2.0)
5
15
27
6
10
27
34
30
67
78
90
PCy3
phenanthroline[b]
IMesHCl
IPrHCl
IPrHCl
IPrHCl
IPrHCl
IPrHCl
9
10
11
12
[c]
—
[a] Reaction conditions: 1d (0.5 mmol), 4a (0.75 mmol), Co
(10 mol%), ligand (20 mol%), RMgCl, solvent (1.0 mL), 238C, 16 h;
yields of isolated products. [b] 10 mol%. [c] Ni(acac)2 (10 mol%).
ACHTUNGERTN(NUNG acac)2
AHCTUNGTRENNUNG
donor ligands,[21] here only unsatisfactorily low conversions
of pyridyl-substituted arene 1d were observed in the ab-
sence of an additional ligand (Table 2, entries 1–3). A set of
representative ligands was therefore subsequently probed,
and improved results were accomplished with NHC-coordi-
nated cobalt catalysts (Table 2, entries 4–11). Notably, a
nickel(II) complex did not deliver the desired product 5da
under otherwise identical reaction conditions (Table 2,
entry 12), thus highlighting the power of cobalt-catalyzed
Scheme 3. Scope of cobalt-catalyzed direct alkylations with unactivated
alkyl chlorides 4.
ꢀ
C H bond functionalizations.
The scope of the optimized catalytic system was thereafter
explored for the direct alkylation of arenes 1 with unactivat-
ed, b-hydrogen-containing alkyl chlorides 4 (Scheme 3). Dif-
ferently decorated arenes 1 thereby delivered the desired
products 5 with excellent chemo- and site-selectivities using
a variety of primary alkyl chlorides 4.
Indole functionalization: Indoles are the key structural
motifs in numerous biologically active compounds and natu-
ral products.[23] The central importance of this heteroaromat-
ic scaffold in medicinal chemistry and drug discovery has,
hence, resulted in a continued strong demand for general
methods for their assembly and direct functionalization.[24,25]
Consequently, we became attracted by applying the opti-
mized cobalt catalysts in the direct functionalization of N-
heteroaryl indoles 6 (Scheme 4). Notably, both N-pyridyl- as
well as N-pyrimidyl-substituted heteroarenes 6 were effi-
ciently converted, the latter of which being particularly at-
tractive because of their removable directing group.[26,27] The
catalytic system displayed a notably wide substrate scope, as
was among others illustrated by the successful use of various
n-alkyl chlorides 4. Furthermore, substituted indoles 6c–e
proved to be viable substrates, even when being sterically
congested through substituents in the position C-3 or C-7 of
the indole nucleus.
Scheme 4. Cobalt-catalyzed direct alkylations of indoles 6.
The cobalt catalyst was not restricted to direct alkylations
2
of heteroarenes, but also enabled direct C
G
(sp2) bond-
ꢀ
forming processes on indoles, as highlighted by the high-
yielding preparation of 2-anisyl derivative 8aa (Scheme 5).
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Cobalt-Catalyzed C H Bond Functionalizations
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Scheme 5. C H bond arylation on indole 6a.
Scheme 8. Intermolecular competition experiment between aryl chlorides
2a and 2c.
Mechanistic studies: Given the high catalytic activity and se-
lectivity of the cobalt catalysts under mild conditions, we
became intrigued in gaining insight into their mode of
action. To this end, we performed a series of competition ex-
periments, which revealed that electron-deficient arenes
react preferentially in the cobalt-catalyzed direct alkylations
Competition experiments between differently substituted
aryl chlorides 2 revealed electron-deficient derivatives to be
inherently more reactive (Scheme 8).
Furthermore, we performed cobalt-catalyzed direct aryla-
tions and alkylations in the presence of stoichiometric
amounts of the radical scavenger TEMPO (Scheme 9), the
results of which are in good agreement with SET-type ele-
mentary steps.[28]
ꢀ
(Scheme 6a), thus rendering a simple electrophilic C H
ꢀ
Scheme 6. Intermolecular competition experiments: C H bond alkyla-
tion.
ꢀ
Scheme 9. Influence of TEMPO on C H bond functionalizations.
bond activation manifold less likely to be operative. More-
over, the functionalization of the electron-rich heteroaro-
matic indole 6b occurred preferentially (Scheme 6b), which
ꢀ
can be rationalized in terms of its increased kinetic C H
bond acidity due to the inductive effect exerted by the het-
eroatom.
Secondary alkyl halides: Finally, we were particularly
pleased to observe that the optimized cobalt catalyst even
allowed for direct alkylations with challenging secondary
ꢀ
Likewise, comparable observations were made for inter-
molecular competition experiments utilizing aryl chloride 2a
in that the electron-deficient arene 1r was found to be more
reactive (Scheme 7). Notably, the reaction occurred again
with an excellent site-selectivity,[17] delivering the C-2 alky-
lated arene 3ra as the sole product.
alkyl halides. Notably, these C H bond functionalizations
occurred with excellent ortho-selectivity[20q] through chela-
tion assistance and proved amenable to direct arene as well
as heteroarene functionalizations (Scheme 10).
Conclusion
In summary, we have reported on the development of cobalt
ꢀ
catalysts for direct C H bond arylations and alkylations of
heteroaryl-substituted arenes and heteroarenes with cost-ef-
fective chlorides[29] as electrophiles. Particularly, complexes
derived from inexpensive CoACHTNUTRGENNG(U acac)2 and N-heterocyclic car-
bene (NHC) precursors proved to be highly effective at am-
bient reaction temperature and low catalyst loadings. The
ꢀ
Scheme 7. Intermolecular competition experiment: C H bond arylation.
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Acknowledgements
Generous support by the European Research Council under the Europe-
an Communityꢄs Seventh Framework Program (FP7 2007–2013)/ERC
Grant agreement no. 307535, the Alexander von Humboldt foundation
(fellowship to B.P.) and the Chinese Scholarship Council (fellowship to
W.S.) is gratefully acknowledged.
[1] M. Beller, C. Bolm, Transition Metals for Organic Synthesis 2nd ed.,
Wiley-VCH, Weinheim, 2004.
[2] J. Tsuji, Palladium Reagents and Catalysts, 2nd ed., Wiley, Chiches-
ter, 2004.
[3] L. Ackermann, Modern Arylation Methods, Wiley-VCH, Weinheim,
Scheme 10. Cobalt-catalyzed direct alkylations with secondary alkyl
chloride 8a.
2009.
ꢀ
[4] Illustrative reviews on catalyzed C H bond functionalizations: a) L.
Ackermann, Acc. Chem. Res. 2013, 46, DOI:10.1021/ar3002798;
b) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012, 45, 936–946;
c) K. M. Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012,
45, 788–802; d) O. Daugulis, Top. Curr. Chem. 2009, 292, 57–84;
e) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Commun. 2010, 46, 677–685;
f) T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 11212–11222; g) L.
Ackermann, R. Vicente, A. Kapdi, Angew. Chem. 2009, 121, 9976–
10011; Angew. Chem. Int. Ed. 2009, 48, 9792–9826; h) P. Thansan-
dote, M. Lautens, Chem. Eur. J. 2009, 15, 5874–5883, and references
therein.
ꢀ
C H bond functionalizations proceeded with excellent
chemo- and site-selectivities as well as ample scope. Notably,
the cobalt-NHC catalysts allowed direct arylations with ster-
ically demanding aryl chlorides as well as difficult direct al-
kylations with various b-hydrogen-containing alkyl chlorides.
Moreover, challenging secondary alkyl chlorides proved to
be for the first time suitable substrates for ortho-selective
[5] Recent reviews on the use of inexpensive first-row transition-metal
ꢀ
C H bond alkylations. Detailed studies on the scope of
ꢀ
catalysts for C H bond functionalization: a) J. Yamaguchi, K. Muto,
cobalt-catalyzed direct alkylations with secondary alkyl hal-
ides are currently ongoing in our laboratories and will be re-
ported in due course.
K. Itami, Eur. J. Org. Chem. 2013, 19–30; b) N. Yoshikai, Synlett
2011, 1047–1051; c) Y. Nakao, Chem. Rec. 2011, 11, 242–251; d) E.
Nakamura, N. Yoshikai, J. Org. Chem. 2010, 75, 6061–6067; e) A.
Kulkarni, O. Daugulis, Synthesis 2009, 4087–4109.
[6] G. Cahiez, A. Moyeux, Chem. Rev. 2010, 110, 1435–1462.
ꢀ
[7] For examples of cobalt-catalyzed direct C H bond alkylations
Experimental Section
through hydroarylations, see: a) T. Andou, Y. Saga, H. Komai, S.
Matsunaga, M. Kanai, Angew. Chem. 2013, 125, 3295–3298; Angew.
Chem. Int. Ed. 2013, 52, 3213–3216; b) P.-S. Lee, N. Yoshikai,
Angew. Chem. 2013, 125, 1278–1282; Angew. Chem. Int. Ed. 2013,
52, 1240–1244; c) L. Ilies, Q. Chen, X. Zeng, E. Nakamura, J. Am.
Chem. Soc. 2011, 133, 5221–5223; d) K. Gao, N. Yoshikai, Angew.
Chem. 2011, 123, 7020–7024; Angew. Chem. Int. Ed. 2011, 50, 6888–
6892; e) Q. Chen, L. Ilies, N. Yoshikai, E. Nakamura, Org. Lett.
2011, 13, 3232–3234; f) K. Gao, N. Yoshikai, J. Am. Chem. Soc.
2011, 133, 400–402.
Representative procedure A: Cobalt-catalyzed direct arylation with aryl
chlorides 2; synthesis of 3aa (Table 1, entry 10): To a mixture of 1a
(93.0 mg, 0.50 mmol), 2a (86.0 mg, 0.60 mmol), CoACTHNURGTNEUNG(acac)2 (6.4 mg,
5.0 mol%), and IMesHCl (17.0 mg, 10.0 mol%) in DMPU (1.0 mL) was
slowly added CyMgCl (0.40 mL, 0.80 mmol). Thereafter, the reaction
mixture was stirred under N2 at 238C for 16 h. At ambient temperature,
aqueous saturated NH4Cl (2.0 mL) and H2O (2.0 mL) were added, and
the reaction mixture was extracted with methyl tert-butyl ether (MTBE;
3ꢃ30 mL). The combined organic phase was washed with brine (50 mL)
and dried over Na2SO4. After filtration and evaporation of the solvents
in vacuo, the crude product was purified by column chromatography on
silica gel (n-hexane/EtOAc 10:1!5:1) to yield 3aa as a white solid
(130 mg, 89%).
ꢀ
[8] For further recent examples of cobalt-catalyzed C H bond function-
alization, see: a) T. Yamakawa, N. Yoshikai, Org. Lett. 2013, 15,
196–199; b) T. Yoshino, H. Ikemoto, S. Matsunaga, M. Kanai,
Angew. Chem. 2013, 125, 2263–2267; Angew. Chem. Int. Ed. 2013,
52, 2207–2211; c) K. Gao, N. Yoshikai, Chem. Commun. 2012, 48,
4305–4307; d) Z. Ding, N. Yoshikai, Angew. Chem. 2012, 124, 4776–
4779; Angew. Chem. Int. Ed. 2012, 51, 4698–4701; e) P.-S. Lee, T.
Fujita, N. Yoshikai, J. Am. Chem. Soc. 2011, 133, 17283–17295; f) Z.
Ding, N. Yoshikai, Org. Lett. 2010, 12, 4180–4183; g) K. Gao, P.-S.
Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc. 2010, 132, 12249–
12251, and references therein.
Representative procedure B: Cobalt-catalyzed direct alkylation with
alkyl chlorides 4; synthesis of 5da (Table 2, entry 11): To a mixture of 1d
(78 mg, 0.50 mmol), 4a (90 mg, 0.75 mmol), CoACTHNURTGNENG(U acac)2 (12.8 mg,
10.0 mol%), and IPrHCl (42.5 mg, 20.0 mol%) in DMPU (1.0 mL) was
slowly added CyMgCl (0.50 mL, 1.00 mmol). Thereafter, the reaction
mixture was stirred under N2 at 238C for 16 h. At ambient temperature,
aqueous saturted NH4Cl (2.0 mL) and H2O (2.0 mL) were added, and the
reaction mixture was extracted with MTBE (3ꢃ30 mL). The combined
organic phase was washed with brine (50 mL) and dried over Na2SO4.
After filtration and evaporation of the solvents in vacuo, the crude prod-
uct was purified by column chromatography on silica gel (n-hexane/
EtOAc 20:1) to yield 5da as a colorless oil (106 mg, 90%).
[9] W. Liu, H. Cao, J. Xin, L. Jin, A. Lei, Chem. Eur. J. 2011, 17, 3588–
3592.
[10] H. Li, C.-L. Sun, M. Yu, D.-G. Yu, B.-J. Li, Z.-J. Shi, Chem. Eur. J.
2011, 17, 3593–3597.
[11] See also: a) C. T. To, T. L. Chan, B. Z. Li, Y. Y. hui, T. Y. Kwok,
S. Y. Lam, K. S. Chan, Tetrahedron Lett. 2011, 52, 1023–1026; b) B.
Li, Z. Wu, Y. Gu, C. Sun, B. Wang, Z.-J. Shi, Angew. Chem. 2011,
123, 1141–1145; Angew. Chem. Int. Ed. 2011, 50, 1109–1113; c) M.
Tiecco, J. Chem. Soc. Chem. Commun. 1965, 555–556.
[12] A recent review: S. I. Kozhushkov, H. K. Potukuchi, L. Ackermann,
Catal. Sci. Technol. 2013, 3, 562–571.
[13] W. Song, L. Ackermann, Angew. Chem. 2012, 124, 8376–8379;
Angew. Chem. Int. Ed. 2012, 51, 8251–8254.
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Cobalt-Catalyzed C H Bond Functionalizations
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[14] Selected reviews: a) A. Littke, in Modern Arylation Methods (Ed.:
L. Ackermann), Wiley-VCH, Weinheim, 2009, pp. 25–67; b) A. F.
Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350–4386; Angew.
Chem. Int. Ed. 2002, 41, 4176–4211.
[15] Representaive reviews: a) P. B. Arockiam, C. Bruneau, P. H. Dix-
neuf, Chem. Rev. 2012, 112, 5879–5918; b) L. Ackermann, R. Vice-
nte, Top. Curr. Chem. 2009, 292, 211–229.
Hirano, T. Satoh, M. Miura, Chem. Eur. J. 2010, 16, 12307–12311;
m) O. Vechorkin, V. Proust, X. Hu, Angew. Chem. 2010, 122, 3125–
3128; Angew. Chem. Int. Ed. 2010, 49, 3061–3064; n) L. Ackermann,
S. Barfꢁßer, J. Pospech, Org. Lett. 2010, 12, 724–726; o) W. Yue, Y.
Li, W. Jiang, Y. Zhen, Z. Wang, Org. Lett. 2009, 11, 5430–5433;
p) C. Verrier, C. Hoarau, F. Marsais, Org. Biomol. Chem. 2009, 7,
647–650, and references therein; q) for
a recent meta-selective
ꢀ
[16] For selected examples of ruthenium- and palladium-catalyzed C H
direct alkylation, see: N. Hofmann, L. Ackermann, J. Am. Chem.
Soc. 2013, 135, 5877–5884.
bond functionalizations with aryl chlorides from our laboratories,
see: a) L. Ackermann, E. Diers, A. Manvar, Org. Lett. 2012, 14,
1154–1157; b) L. Ackermann, R. Born, P. ꢅlvarez-Bercedo, Angew.
Chem. 2007, 119, 6482–6485; Angew. Chem. Int. Ed. 2007, 46, 6364–
6367; c) L. Ackermann, A. Althammer, Angew. Chem. 2007, 119,
1652–1654; Angew. Chem. Int. Ed. 2007, 46, 1627–1629, and refer-
ences therein.
[21] For a direct alkylation of secondary benzamide in the absence of an
additional s-donor ligand, see: Q. Chen, L. Ilies, E. Nakamura, J.
Am. Chem. Soc. 2011, 133, 428–429.
[22] An elegant recent example: K. Yamaguchi, J. Yamaguchi, A. Studer,
K. Itami, Chem. Sci. 2012, 3, 2165–2169.
[23] J. Alvarez-Builla, J. J. Vaquero, J. Barluenga, Modern Heterocyclic
Chemistry, Wiley-VCH, Weinheim, 2011.
[17] For a recent independent report on direct arylations of aromatic ke-
timines, see: K. Gao, P.-S. Lee, C. Long, N. Yoshikai, Org. Lett.
2012, 14, 4234–4237.
[18] J. Wencel-Delord, T. Droege, F. Liu, F. Glorius, Chem. Soc. Rev.
2011, 40, 4740–4761.
[24] Select reviews on the preparation of indoles: a) S. Cacchi, G. Fabrizi,
A. Goggiamani, Org. React. 2012, 76, 281–534; b) M. Platon, R.
Amardeil, L. Djakovitch, J.-C. Hierso, Chem. Soc. Rev. 2012, 41,
3929–3968; c) S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol.
Chem. 2011, 9, 641–652; d) K. Krꢁger, A. Tillack, M. Beller, Adv.
Synth. Catal. 2008, 350, 2153–2167; e) L. Ackermann, Synlett 2007,
507–526; f) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106,
2875–2911; g) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–
2920; h) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.
2003, 103, 893–930, and references therein.
[25] L. Joucla, L. Djakovitch, Adv. Synth. Catal. 2009, 351, 673–714.
[26] L. Ackermann, A. V. Lygin, Org. Lett. 2011, 13, 3332–3335.
[27] See also: M. Nishino, K. Hirano, T. Satoh, M. Miura, Angew. Chem.
2012, 124, 7099–7103; Angew. Chem. Int. Ed. 2012, 51, 6993–6997.
[28] Attempted direct alkylations with cyclopropylmethyl chloride only
led to the recovery of unreacted starting material 1o.
[19] A review: L. Ackermann, Chem. Commun. 2010, 46, 4866–4877.
[20] For examples of metal-catalyzed direct alkylations through chelation
assistance, see: a) Y. Aihara, N. Chatani, J. Am. Chem. Soc. 2013,
135, 5308–5311; b) Y. Zhao, G. Chen, Org. Lett. 2011, 13, 4850–
4855; c) L. Ackermann, N. Hofmann, R. Vicente, Org. Lett. 2011,
13, 1875–1877; d) Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, Angew. Chem.
2009, 121, 6213–6216; Angew. Chem. Int. Ed. 2009, 48, 6097–6100;
e) L. Ackermann, P. Novak, R. Vicente, N. Hofmann, Angew. Chem.
2009, 121, 6161–6164; Angew. Chem. Int. Ed. 2009, 48, 6045–6048;
for examples of metal-catalyzed direct alkylations of heteroarenes
without directing groups, see: f) B. Xiao, Z.-J. Liu, L. Liu, Y. Fu, J.
Am. Chem. Soc. 2013, 135, 616–619; g) T. Yao, K. Hirano, T. Satoh,
M. Miura, Angew. Chem. 2012, 124, 799–803; Angew. Chem. Int.
Ed. 2012, 51, 775–799; h) L. Jiao, T. Bach, J. Am. Chem. Soc. 2011,
133, 12990–12993; i) L. Ackermann, B. Punji, W. Song, Adv. Synth.
Catal. 2011, 353, 3325–3329; j) L. Ackermann, S. Barfꢁßer, C.
Kornhaaß, A. R. Kapdi, Org. Lett. 2011, 13, 3082–3085; k) L. D.
Tran, O. Daugulis, Org. Lett. 2010, 12, 4277–4279; l) T. Yao, K.
[29] Cobalt-catalyzed direct arylations of substrate 1a with aryl bromides
or aryl iodides were thus far less successful under otherwise identi-
cal reactions conditions.
Received: April 13, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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