Copper-catalyzed direct alkylation of heteroarenes

Article abstract of DOI:10.1039/c6sc05622a

An efficient and broadly applicable process is reported for the direct alkylation of C-H bonds in heteroarenes, privileged scaffolds in many areas of science. This reaction is based on the copper-catalyzed addition of alkyl radicals generated from activated secondary and tertiary alkyl bromides to a wide range of arenes, including furans, thiophenes, pyrroles, and their benzo-fused derivatives, as well as coumarins and quinolinones.

Full text of DOI:10.1039/c6sc05622a

View Article Online
View Journal
Chemical
Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: C. Theunissen, J.
Wang and G. Evano, Chem. Sci., 2017, DOI: 10.1039/C6SC05622A.
This is an Accepted Manuscript, which has been through the
Volume
7 Number 1 January 2016 Pages 1–812
Royal Society of Chemistry peer review process and has been
accepted for publication.
Chemical
Science
Accepted Manuscripts are published online shortly after
www.rsc.org/chemicalscience
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 2041-6539
EDGE ARTICLE
Francesco Ricci et al.
Electronic control of DNA-based nanoswitches and nanodevices
rsc.li/chemical-science

Please do not adjust margins
Page 1 of 7
Chemical Science
View Article Online
DOI: 10.1039/C6SC05622A
Chemical Science
EDGE ARTICLE
Copper-Catalyzed Direct Alkylation of Heteroarenes
Cédric Theunissen,a Jianjun Wanga and Gwilherm Evano*a
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and broadly applicable process for the direct alkylation of C-H bonds in heteroarenes, privileged scaffolds in
many areas of science, is reported. This reaction is based on the copper-catalyzed addition of alkyl radicals generated from
activated secondary and tertiary alkyl bromides to a wide range of arenes including furans, thiophenes, pyrroles and their
benzo-fused derivatives as well as coumarins and quinolinones.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Among the impressive and ever-growing number of chemical heteroarenes. A number of efficient reagents and procedures have
transformations, the alkylation of arenes is clearly of prime been indeed designed for the regioselective introduction of alkyl
importance, regioselectively alkylated arenes being major starting substituents to a variety of heteroarenes, mostly electron-deficient
materials and molecules relevant to most areas of science in which ones7 and azoles possessing acidic C-H bonds.7f,8 In sharp contrast,
there is a need for small organic molecules. They are indeed used much less attention has been paid to the direct alkylation of other
on a daily basis in pharmaceutical, agrochemical and material heteroarenes,6g,h,7f,8c,9 despite the strong synthetic potential of such
sciences, as building blocks in polymer chemistry or organic reactions.
electronics and they have had a profound effect in human health
and many other sectors.
Heteroarenes such as furans, thiophenes, pyrroles and their
benzo-fused derivatives being privileged scaffolds, the development
The regioselective alkylation of arenes is traditionally of efficient and broadly applicable procedures for their direct
performed through the venerable Friedel-Crafts reaction,1
a
alkylation is therefore still highly demanded. The most efficient and
reaction which requires harsh reaction conditions and often suffers general procedures available to date to perform such a task are
from low chemo- and/or regio- selectivities. This reaction is also indeed mostly limited to Ackermann’s alkylation of directing group-
hampered by significant limitations in terms of the electronic containing indoles with alkyl halides,6g,h Zhou’s remarkable
properties of the arene and performs poorly with some classes of alkylation of (benzo)furans, (benzo)thiophenes, pyrroles and indoles
alkyl halides. The main alternative strategies for the alkylation of possessing an electron-withdrawing group with cyclohexyl iodide,7f
arenes are mostly based on their stoichiometric metallation Nakao and Hiyama’s alkylation of activated indoles with styrenes,8c
followed by reaction with an electrophile2 – a sequence which Bach’s alkylation of indoles with alkyl bromides9b and Stephenson’s
suffers from limitations in terms of functional group compatibility photocatalytic alkylation of indoles, pyrroles and furans with
due to the requirement for strong bases – or on their stepwise pre- brominated malonates.9a,f While efficient, major limitations still
functionalization followed by a metal-mediated cross-coupling.3
remain with these procedures such as harsh reaction conditions
which can pose problem for late-stage alkylation, low substrate
scope with regards to the nature of the heteroarene and/or
alkylating agent or the need for directing/activating groups on the
heteroarene. There is therefore no general and broadly applicable
method reported for the direct alkylation of unactivated
heteroarenes.
Recent advances in transition-metal catalyzed C-H
functionalization have enabled the development of remarkably
efficient and reliable tools for the direct alkylation of arenes which
now appear as robust alternatives to the classical processes.4 The
most common strategy to ensure high levels of reactivity and
selectivity is mostly based on the introduction of a directing group
allowing for the selective alkylation of a single C-H bond of the
In an attempt to address some of these limitations and as part
starting arene. Following the pioneering work of Murai on the of our ongoing program in copper catalysis,10 we report in this
ortho-selective alkylation of arylketones,5 a range of directing manuscript an efficient and broadly applicable copper-catalyzed
groups and alkylating agents have been introduced for the direct radical direct alkylation of heteroarenes with secondary and tertiary
ortho- and, much more rarely, meta- alkylation of arenes.6
A
activated alkyl bromides (Scheme 1).
complementary strategy, which circumvents the use of directing
groups, is based on the innate alkylation of C-H bond in
a.Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques,
Université libre de Bruxelles (ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050
Brussels, Belgium.
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization and copies of 1H and 13C NMR spectra for all new compounds. See
DOI: 10.1039/x0xx00000x
Scheme 1. Copper-catalyzed radical direct alkylation of
heteroarenes
This journal is © The Royal Society of Chemistry 2017
Chem. Sci, 2017, 00, 1-6 | 1
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 2 of 7
EDGE ARTICLE
Chemical Science
Inspired by the recent and remarkable work of Nishikata on the be operative, although with less efficiency, when further decreasing
use of copper catalysts for the generation of tertiary alkyl radicals11 the catalyst loading to 2 mol% of copper(I) iodide andV4iemw Aorlt%icleoOfnLline,
DOI: 10.1039/C6SC05622A
14
and by copper-catalyzed atom transfer radical cyclization (ATRC)12 alkylated benzofuran 3a being formed with 58% yield under these
and polymerization (ATRP)13 reactions, we surmised that the right conditions.
copper complex should be able to promote the generation of alkyl
Having in hand an efficient optimized catalytic system, we then
moved to the study of the scope and limitations of this reaction by
first evaluating the reactivity of a series of alkyl bromides 2 for the
alkylation of benzofuran 1a (Figure 2) using 10 mol% of copper(I)
iodide and 20 mol% of TPMA in dioxane or ethanol at 110 °C for 2
days. The reaction was found to perform well with tertiary alkyl
bromides, providing the corresponding alkylated benzofuran
derivatives 3a, 3b, 3h-k, 3o and 3q with good to excellent yields.
Secondary alkyl bromides were also gratifyingly found to be
efficient alkylating agents, as demonstrated with the alkylation of
1a to 3c-e, 3l, 3m and 3p, the presence of an aryl group however
inhibiting the reaction (3f), probably due to the diminished
reactivity of the intermediate radical species. In sharp contrast, a
primary alkyl bromide only produced the alkylated derivative in low
yield (3g). Compared to the only general procedure reported to
date to perform such a direct alkylation of benzofuran, developed
by Hirano and Miura and which relies on a large excess of the
radicals by single electron reduction of the corresponding activated
alkyl bromides. Provided that these electron-poor radicals would
react with heteroarenes at a sufficient rate14 and that the oxidized
copper-catalyst could promote the oxidative rearomatization, an
efficient and broadly applicable system for the direct alkylation of
heteroarenes relying on the use of simple reagents and catalyst
could be potentially developed.
To test this working hypothesis, benzofuran 1a and ethyl -
bromoisobutyrate 2a were chosen as model substrates. After a
brief optimization of the source of copper(I), the base and the
solvent which validated our working hypothesis (data not shown,
see Supporting Information for details), the efficiency of a set of
representative ligands Lx was evaluated: selected results are shown
in Figure 1. While a NHC (L1) totally inhibited the reaction which was
shown to proceed with moderate efficiency in the absence of a
ligand, O,O-bidentate ligand L2 was found to moderately improve
the yield. N,O- and N,N- bidentate ligands L3-L11 were found to be
much more efficient, diimine L7 efficiently promoting the reaction
to 89% yield but being difficult to remove from the alkylated
product 3a obtained as a single regioisomer. Tridentate ligands L12-
L14 were finally evaluated, L14 (TPMA) being selected for its
efficiency. The reaction was found to perform equally well with this
ligand in dioxane in place of ethanol, an important point for
substrates bearing functional groups that wouldn’t be compatible
with this solvent. We finally attempted to decrease the catalyst
loading using L14 as the ligand: a combination of 5 mol% of copper(I)
iodide and 10 mol% of L14 resulted in a significant decrease of the
yield (50%) which could however be improved to 70% by increasing
the reaction time to 72h. Gratifyingly, the reaction was still found to
starting benzofuran and
a much more sensitive Ni(cod)2
catalyst,9d,15 our alkylation typically furnishes the alkylated
benzofuran with a 20-90% increase in yields. Other esters (benzyl
3h, tert-butyl 3i and even a labile phenyl ester 3j) were found to
proceed equally well and this electron-withdrawing group could
also be suitably replaced by a ketone (3k), a nitrile (3l), an imide
(3m) and a sulfone (3o,p), while a brominated amide (3n) or
Fig. 2. Scope of the copper-catalyzed direct alkylation with
b
c
representative alkyl bromides (a in dioxane;
in EtOH;
Fig. 1. Validation of the working hypothesis and optimization
reaction performed on a 5g scale of 1a with 5 mol% of CuI and
10 mol% of TPMA for 96h at 101 °C; starting from the
corresponding chloride; e using 2 equiv. of 1a and 1 equiv. of
2)
of the reaction (a with 5 mol% of CuI and 10 mol% of L14 b 72h;
;
d
c with 2 mol% of CuI and 4 mol% of L14
)
2 | Chem. Sci., 2017, 00, 1-6
This journal is © The Royal Society of Chemistry 2017
Please do not adjust margins

Page 3 of 7
Chemical Science
Please do not adjust margins
Chemical Science
EDGE ARTICLE
malonates (data not shown) were found to be respectively
inefficient or less reactive. This however demonstrates the variety
of functional groups that can be introduced and used for further
functionalization, as evidenced by the reductive desulfonylation of
3o and 3p to their simple alkylated derivatives 4 and 4’, the only
synthesis of the former reported to date being based on a low-
yielding (18%) metallation of benzofuran with tert-butyllithium
followed by alkylation with isopropyl iodide.16 It ought to be
mentioned that a secondary alkyl chloride could also be used in
place of the corresponding bromide, although with reduced
efficiency (3c, 51%) and that the alkylation of benzofuran could be
performed on a 5 gram (42 mmol) scale with 5 mol% of CuI and 10
mol% of TPMA in refluxing dioxane for 96h, yielding 4 grams of the
corresponding alkylated derivative 3a with 41% yield, the reduced
efficiency of the alkylation - which still enabled an easy gram-scale
synthesis of 3a - being due to the decreased catalyst loading and
reaction temperature. Finally, a complex alkylating agent derived
from cholesterol could also be successfully used, as exemplified
with the preparation of 3q (using a reversed stoichiometry).
View Article Online
DOI: 10.1039/C6SC05622A
We then moved to the study of the scope of our process with
respect to the other coupling partner and first examined the
alkylation of a series of benzofuran derivatives 1 with ethyl
-bromoisobutyrate 2a as the reference alkyl halide. As shown by
the results collected in Figure 3, the reaction was found to be fairly
general and tolerates a wide array of substituents - including
Fig. 3. Scope of the copper-catalyzed direct alkylation with
electron-donating and withdrawing groups
- and substitution
b
c
representative benzofurans (a in dioxane; in EtOH; using 3
patterns, including close to the reacting center (3ae). Interestingly,
the presence of a halide on the starting benzofuran does not
interfere with the reaction, as shown with the alkylation to 3u and
3v in 79 and 76% yields, therefore providing opportunities for
further chemical diversification. A range of functional groups were
found to be compatible with our procedure including an
unprotected alcohol (3w), a ketone (3aa), an aldehyde (3ab), a
nitrile (3ac), an alkyne (3x) and, to a lesser extent, a nitro (3ad),
while the presence of an alkene (3y) gave a complex reaction
mixture, probably due to its competitive alkylation.11
equiv. of 2a for 72h)
Importantly, the extension of the alkylation to other arenes was
next undertaken using
a set of heteroarenes possessing
representative electronic and steric properties with, as in the
previous case, ethyl -bromoisobutyrate 2a as the reference alkyl
halide (Figure 4). The alkylation was pleasingly found to be rather
general and efficient with
a range of heteroarenes. Furan
derivatives could indeed be efficiently and smoothly transformed to
a
b
Fig. 4. Scope of the copper-catalyzed direct alkylation with representative heteroarenes (R = CMe2CO2Et; in dioxane; in
EtOH; c at 110 °C; d with 3 equiv. 2a for 72h; e at 150 °C)
This journal is © The Royal Society of Chemistry 2017
Chem. Sci., 2017, 00, 1-6 | 3
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 4 of 7
EDGE ARTICLE
Chemical Science
their alkylated derivatives 5 in fair to excellent yields (40-93%) and
as single C-2 regioisomers. Substitution at C-3 (5h-l) had virtually no
effect on the alkylation and a pyridine (5b), a ketone (5d), an
aldehyde (5e), an unprotected alcohol (5g) or other aromatic rings
(5h,i,k,l) were well tolerated. The reaction was found to be more
substrate-dependent in the absence of a substituent at C2/C5:
while ethyl furan-3-carboxylate was cleanly and selectively
alkylated to 5m, a mixture of mono- (5n) and bis- (5n’) alkylated
furans was obtained starting from 3-phenylfuran. In these two
cases, the regioselective functionalization at C2 can be reasonably
rationalized by the formation of an intermediate radical species
stabilized by conjugation with either the phenyl ring or the ester, a
stabilization that does not occur when the radical attacks at C5. As
for furan itself, it unfortunately could not be alkylated due to its too
important volatility.
View Article Online
DOI: 10.1039/C6SC05622A
Fig. 5. Copper-catalyzed intramolecular alkylation of
-bromoacetanilides to indolones
Several mechanisms can possibly account for the observed
alkylation, including polar and radical pathways. To test the
possibility of single electron transfers and the intermediacy of
radical species, the alkylation of 1a with 2a was performed in the
presence of TEMPO 14 (1 equiv.) under our standard conditions
(Scheme 2). The alkylation of 1a was totally suppressed in this case,
the only product observed at the end of the reaction being the
TEMPO adduct 15 – a compound that is not formed in the absence
of the copper catalyst – which could be isolated in 44% yield.
Thiophenes could also be alkylated, although the reaction was
found to be more sluggish with these substrates and required an
increase of the reaction temperature to reach sufficient conversions
to their C-2 alkylated derivatives 6 which could be obtained with
yields in the 55-83% range.
The alkylation of pyrroles, which represents an important
chemical transformation for the design of bioactive molecules, was
next studied and was found to proceed reasonably well - even if the
yields were somehow lower compared to the furan and thiophene
series due to incomplete conversions - and did not require the
protection of the nitrogen atom. Pyrrole itself - whose direct
alkylation still remains challenging9f - could be readily alkylated to
7e, although with a modest yield, without competing bis-alkylation.
While the alkylation was shown to be remarkably efficient for
the direct functionalization of benzofurans, switching to their sulfur
and nitrogen analogues was found to be less efficient despite all
attempts at reoptimization made, even if the alkylation of
benzothiophenes to 8a,b (41-44%) and indoles to 9a,b (24-30%)
was still operative, the mass balances mostly corresponding to
unreacted starting materials. In the case of indoles, the C-2
selectivity, which is complementary to the Friedel-Crafts alkylation
occurring at C3, is worth noting. This selectivity, which is in
accordance with previously reported results,14 is consistent with the
significant HOMO coefficient at C-2 as well as the formation of a
stabilized benzylic radical. In the indole series, N-alkylation of the
starting materials was found to be detrimental and resulted in
either lower yields or total absence of reactivity, an effect that was
also observed with pyrroles.17
In an attempt to further broaden the scope of our copper-
catalyzed alkylation, the reactivity of other substrates that might be
able to react with electron-poor radical species was briefly
envisioned. While electron-rich benzene derivatives such as 1,3,5-
trimethoxybenzene failed to give the corresponding alkylated
arene, coumarins and quinolinone were found to be suitable
substrates for our copper-catalyzed alkylation, providing the
corresponding functionalized derivatives 10a,b and 11 in fair to
good yields.
Scheme 2. Radical trapping experiment
A plausible mechanism based on this experiment is shown in
Figure 6. The reaction would be initiated by single electron transfer
from the copper(I) catalyst (TPMA)CuII to the * orbital of the alkyl
halide 2, generating radical intermediate A and the oxidized catalyst
(TPMA)CuIIIX. Addition of this intermediate A to the electron-rich
heteroarene would afford a transient radical B which would then be
oxidized by (TPMA)CuIIIX to the corresponding carbocation C
together with regeneration of the copper(I) catalyst.
Rearomatization by loss of a proton, trapped by 2,4,6-collidine,
would finally afford the alkylated heteroarene. Alternatively, the
benzylic radical might directly react with (TPMA)CuIIIX to furnish,
after elimination of HX, the alkylated heteroarene.
After an extensive study of the scope of the copper-catalyzed
alkylation, we next briefly envisioned the possibility of its extension
to an intramolecular version. With this goal in mind,
-bromoacetanilides 12 - whose cyclization to the corresponding
indolones 13 was previously reported using nickel-18 and iridium-19
based catalysts - were submitted to our optimized reaction
conditions. To our delight, the cyclization was found to proceed
remarkably well, the cyclized indolones being obtained in 65-84%
yields (Figure 5).
Fig. 6. Possible mechanism for the copper-catalyzed direct
alkylation of heteroarenes
4 | Chem. Sci., 2017, 00, 1-6
This journal is © The Royal Society of Chemistry 2017
Please do not adjust margins

Page 5 of 7
Chemical Science
Please do not adjust margins
Chemical Science
EDGE ARTICLE
Yamada, N. Kashihara and T. Hiyama, J. Am. Chem. Soc. 2010,
Conclusions
View Article Online
132, 13666; (c) Y. Jujiwara, J. A. DiDxOonI:,10F.1.0O39’/HCa6rSaC,05E6.22DA.
Funder, D. D. Dixon, R. A. Rodriguez, R. D. Baxter, B. Herlé, N.
Sach, M. R. Collins, Y. Ishihara and P. S. Baran, Nature 2012,
492, 95; (d) B. Xiao, Z.-J. Liu, L. Liu and Y. Fu, J. Am. Chem.
Soc. 2013, 135, 616; (e) A. P. Antonchick and L. Burgmann,
Angew. Chem. Int. Ed. 2013, 52, 3267; (f) X. Wu, J. W. T. See,
K. Xu, H. Hirao, J. Roger, J.-C. Hierso and J. Zhou, Angew.
Chem. Int. Ed. 2014, 53, 13573; (g) J. Jin and D. W. C.
MacMillan, Nature 2015, 525, 87; (h) T. McCallum and L.
In conclusion, we have developed an efficient and broadly
applicable process for the direct alkylation of C-H bonds
heteroarenes, privileged scaffolds in many areas of science for
which only few methods enabling their direct alkylation are
available. This reaction is based on the copper-catalyzed addition of
alkyl radicals generated from activated secondary and tertiary alkyl
bromides to a wide range of arenes including furans, thiophenes,
pyrroles and their benzo-fused derivatives as well as coumarins and
quinolinones. Notable features of this reaction are its wide
substrate scope, the availability of the catalyst and reagents used as
well as its functional group tolerance.
Barriault, Chem. Sci. 2016, 7, 4754.
8
For examples, see: (a) K. L. Tan, R. G. Bergman and J. A.
Ellman, J. Am. Chem. Soc. 2002, 124, 13964; (b) O. Vechorkin,
V. Proust and X. Hu, Angew. Chem. Int. Ed. 2010, 49, 3061;
(c) Y. Nakao, N. Kashihara, K. S. Kanyiva and T. Hiyama,
Angew. Chem. Int. Ed. 2010, 49, 4451; (d) T. Yao, K. Hirano, T.
Satoh and M. Miura, Chem. Eur. J. 2010, 16, 12307; (e) L.
Ackermann, B. Punji and W. Song, Adv. Synth. Catal. 2011,
353, 3325; (f) T. Yao, K. Hirano, T. Satoh and M. Miura,
Angew. Chem. Int. Ed. 2012, 51, 775; (g) P. Ren, I. Salihu, R.
Scopelliti and X. Hu, Org. Lett. 2012, 14, 1748.
Acknowledgements
Our work was supported by the Université libre de Bruxelles
(ULB) and the Fédération Wallonie-Bruxelles (ARC Consolidator
2014-2019). C. T. and J. W. respectively acknowledge the
Fonds pour la formation à la Recherche dans l’Industrie et dans
l’Agriculture (F.R.I.A.) and the Chinese Scolarship Council for
graduate fellowships. The Fonds Emile Defay is gratefully
acknowledged for additional financial support.
9
(a) L. Furst, B. S. Matsuura, J. M. R. Narayanam, J. W. Tucker
and C. R. J. Stephenson, Org. Lett. 2010, 12, 3104; (b) L. Jiao
and T. Bach, J. Am. Chem. Soc. 2011, 133, 12990; (c) C. S.
Sevov and J. F. Hartwig, J. Am. Chem. Soc. 2013, 135, 2116;
(d) A. Nakatani, K. Hirano, T. Satoh and M. Miura, Chem. Eur.
J. 2013, 19, 7691; (e) X.-H. Ouyang, R.-J. Song, M. Hu, Y. Yang
and J.-H. Li, Angew. Chem. Int. Ed. 2016, 55, 3187; (f) E. C.
Swift, T. M. Williams and C. R. J. Stephenson, Synlett 2016,
27, 754.
Notes and references
10 For representative contributions from our group on copper-
catalyzed reactions, see: (a) M. Toumi, F. Couty and G.
Evano, Angew. Chem. Int. Ed. 2007, 46, 572; (b) A. Coste, M.
Toumi, K. Wright, V. Razafimahaléo, F. Couty, J. Marrot and
G. Evano, Org. Lett. 2008, 10, 3841; (c) M. Toumi, F. Couty, J.
Marrot and G. Evano, Org. Lett. 2008, 10, 5027; (d) A. Coste,
G. Karthikeyan, F. Couty and G. Evano, Angew. Chem. Int. Ed.
2009, 48, 4381; (e) A. Coste, F. Couty and G. Evano, Org. Lett.
2009, 11, 4454; (f) K. Jouvin, F. Couty and G. Evano, Org.
Lett. 2010, 12, 3272; (g) K. Jouvin, A. Bayle, F. Legrand and G.
Evano, Org. Lett. 2012, 14, 1652; (h) A. Pradal and G. Evano,
Chem. Commun. 2014, 50, 11907; (i) A. Nitelet and G. Evano,
Org. Lett. 2016, 18, 1904; (j) C. S. Demmer, E. Benoit and G.
Evano, Org. Lett. 2016, 18, 1438; (k) C. Deldaele and G.
1
R. M. Roberts and A. A. Khalaf, Friedel-Crafts Alkylation
Chemistry: a Century of Discovery; Marcel Dekker: New York,
1984.
2
3
4
R. Chinchilla, C. Nájera and M. Yus, Chem. Rev. 2004, 104,
2667.
For a borylation-alkylation sequence, see: D. W. Robbins and
J. F. Hartwig, Angew. Chem. Int. Ed. 2013, 52, 933.
For reviews, see: (a) L. Ackermann, Chem. Commun. 2010,
46, 4866; (b) S. Messaoudi, J.-D. Brion and M. Alami, Eur. J.
Org. Chem. 2010, 6495.
S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M.
Sonoda and N. Chatani, Nature 1993, 366, 529.
For recent examples of directed C-H alkylation of arenes,
see: (a) L. Ilies, Q. Chen, X. Zeng and E. Nakamura, J. Am.
Chem. Soc. 2011, 133, 5221; (b) M. Schinkel, I. Marek and L.
Ackermann, Angew. Chem. Int. Ed. 2013, 52, 3977; (c) Y.
Aihara and N. Chatani, J. Am. Chem. Soc. 2013, 135, 5308; (d)
5
6
Evano, ChemCatChem 2016, 8, 1319.
11 (a) T. Nishikata, Y. Noda, R. Fujimoto and T. Sakashita, J. Am.
Chem. Soc. 2013, 135, 16372. Also see, for a related
approach using nickel catalysis: (b) C. Liu, S. Tang, D. Liu, J.
Yuan, L. Zheng, L. Meng and A. Lei, Angew. Chem. Int. Ed.
2012, 51, 3638.
N. Hofmann and L. Ackermann, J. Am. Chem. Soc. 2013, 135
5877; (e) K. Gao and N. Yoshikai J. Am. Chem. Soc. 2013, 135
,
,
9279; (f) P. S. Thuy-Boun, G. Villa, D. Dang, P. Richardson, S.
Su and J.-Q. Yu J. Am. Chem. Soc. 2013, 135, 17508; (g) B.
Punji, W. Song, G. A. Shevchenko and L. Ackermann, Chem.
Eur. J. 2013, 19, 10605; (h) W. Song, S. Lackner and L.
Ackermann, Angew. Chem. Int. Ed. 2014, 53, 2477; (i) L. Illies,
T. Matsubara, S. Ichikawa, S. Asako and E. Nakamura, J. Am.
Chem. Soc. 2014, 136, 13126; (j) R.-Y. Zhu, J. He, X.-C. Wang
and J.-Q. Yu J. Am. Chem. Soc. 2014, 136, 13194; (k) S.-Y.
Zhang, Q. Li, G. He, W. A. Nack and G. Chen J. Am. Chem. Soc.
2015, 137, 531; (l) Z. Wang, Y. Kunonibu and M. Kanai J. Am.
Chem. Soc. 2015, 137, 6140; (m) P.-X. Shen, X.-C. Wang, P.
12 A. J. Clark, Eur. J. Org. Chem. 2016, 2231.
13 K. Matyjaszweski, Macromolecules 2012, 45, 4015.
14 For an example of addition of free alkyl radicals to pyrroles
and indoles, see: (a) M. A. Guerro and L. D. Miranda,
Tetrahedron Lett. 2006, 47, 2517. (b) Y. M. Osornio, R. Cruz-
Almanza, V. Jiménez-Montaño and L. D. Miranda, Chem.
Commun. 2003, 18, 2316. For a photocatalytic radical
alkylation of eletron-rich heteroarenes with brominated
malonates, see refs 9a and 9f.
15 For an isolated example of gold-catalyzed direct alkylation of
3-methylbenzofuran with phenyldiazoacetate, see: Y. Xi, Y.
Su, Z. Yu, B. Dong, E. J. McClain, Y. Lan and X. Shi, Angew.
Chem. Int. Ed. 2014, 53, 9817.
16 N. Ortega, S. Urban, B. Beiring and F. Glorius, Angew. Chem.
Int. Ed. 2012, 51, 1710.
Wang, R.-Y. Zhu and J.-Q. Yu J. Am. Chem. Soc. 2015, 137
,
11574; (n) G. Cera, T. Haven and L. Ackermann, Angew.
Chem. Int. Ed. 2016, 55, 1484; (o) Z. Ruan, S. Lackner and L.
Ackermann, Angew. Chem. Int. Ed. 2016, 55, 3153; (p) R.
Shang, L. Ilies and E. Nakamura, J. Am. Chem. Soc. 2016, 138
,
17 N-Methyl-pyrrole and N-methyl-indole failed to undergo the
alkylation, even when forcing the reaction conditions, while
10132.
7
For examples, see: (a) J. C. Lewis, R. G. Bergman and J. A.
Ellman, J. Am. Chem. Soc. 2007, 129, 5332; (b) Y. Nakao, Y.
This journal is © The Royal Society of Chemistry 2017
Chem. Sci., 2017, 00, 1-6 | 5
Please do not adjust margins

Please do not adjust margins
Chemical Science
Page 6 of 7
EDGE ARTICLE
Chemical Science
N-methyl-2-phenyl-pyrrole gave the corresponding C5-
alkylated product in 25% yield after 48h in dioxane at 150 °C.
18 C. Liu, D. Liu, W. Zhang, L. Zhou and A. Lei, Org. Lett. 2013,
15, 6166.
View Article Online
DOI: 10.1039/C6SC05622A
19 J.-Q. Chen, Y.-L.Wei, G.-Q. Xu, Y.-M. Liang and P.-F. Xu, Chem.
Commun. 2016, 52, 645.
6 | Chem. Sci., 2017, 00, 1-6
This journal is © The Royal Society of Chemistry 2017
Please do not adjust margins

Page 7 of 7
Chemical Science
View Article Online
DOI: 10.1039/C6SC05622A
134x33mm (150 x 150 DPI)