Copper-catalyzed free-radical C-H arylation of pyrroles

Article abstract of DOI:10.1039/c3cc45240a

A room temperature copper-catalyzed radical arylation of pyrroles with anilines, through in situ generated aryl diazonium salts, has been developed under neutral conditions. Experimental and theoretical studies explain the crucial role of CaCO₃ and the high regioselectivity observed. the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc45240a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Honraedt, M. Raux, E. Le Grognec, D.
Jacquemin and F. Felpin, Chem. Commun., 2013, DOI: 10.1039/C3CC45240A.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
Chemical Communications
www.rsc.org/chemcomm
Volume 46 | Number 32 | 28 August 2010 | Pages 5813–5976
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1359-7345
COMMUNICATION
FEATURE ARTICLE
J. Fraser Stoddart et al.
Directed self-assembly of a
ring-in-ring complex
Wenbin Lin et al.
Hybrid nanomaterials for biomedical
applications
1359-7345(2010)46:32;1-H
www.rsc.org/chemcomm
Registered Charity Number 207890

Dynamic ArticlVeiewLAinrtikclesOn►line
ChemComm
Page 1 ofJ3ournal Name
DOI: 10.1039/C3CC45240A
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Copper-Catalyzed Free-Radical C-H Arylation of Pyrroles
Aurélien Honraedt,a Marie-Audrey Raux,a Erwan Le Grognec,a Denis Jacquemin,a,b François-Xavier
Felpin*,a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
reactivity and hazardous profile make these compounds
unsuitable for a safe handling, especially on large scale.10
Alternatively, they can be prepared in aqueous HCl, but this
approach reduces the window of compatible chemical
45 reactions due to harsh conditions. Recently we have
contributed to the use of aryl diazonium salts under unusual
and safe conditions for Pd-catalyzed reactions11 and to the
copper-catalyzed Meerwein-type arylation of highly sensitive
quinones.12 Inspired by these studies we developped an
50 unprecedented copper-catalyzed arylation of pyrroles with in
situ generated aryl diazonium salts under neutral conditions.13
Initial investigations focused on the arylation of acid-
sensitive N-Boc-pyrrole 2 with 4-nitroaniline 1a, through an
in situ generated aryl diazonium salt with only one equivalent
55 of MeSO3H and tBuONO (Table 1) in aqueous acetone.
CaCO3 (1 equiv) was used as a mild base in order to avoid any
acid-mediated azo compound formation. During our
optimization studies, we assessed various copper catalysts
from which Cu(OAc)2.H2O emerged as the best one (entry 5).
60 Although, CuCl2 was the standard catalyst for the copper-
catalyzed Meerwein arylation,14 it frequently led to
Sandmeyer-type side-products contrary to Cu(OAc)2.H2O.15
The reaction was highly regioselective at C2 provided that an
excess of pyrrole 2 was used to avoid the double arylation at
65 C2/C5. After extensive experimentation and evaluation of key
A room temperature copper-catalyzed radical arylation of
pyrroles with anilines, through in situ generated aryl
diazonium salts, has been developped under neutral
conditions. Experimental and theoritical studies explained the
10 crucial role of CaCO3 and the high regioselectivity observed.
The transition-metal-catalyzed C-H arylation of heteroarenes
with haloarenes has recently attracted considerable attention1
as such approach allows the preparation of ubiquitous
structures found in many organic materials2 and
15 pharmaceuticals, e.g., Atorvastatin, Tanaproget and Fendosal,
without a prefunctionalization step. While these approaches
changed the way chemists design chemical routes, forcing
conditions are usually required due to the inertness of the C-H
bond. On the other hand, free-radical C-H arylation of
20 heteroarenes through both metal- and non-metal-mediated
processes has recently emerged as a valuable alternative
enabling mild conditions.3 Amongst others, aryl diazonium
salts are well-known species giving free-radical aryl
intermediates
through
a
homolytic
dediazoniation
25 mechanism.4 The copper redox process involving aryl
diazonium salts, known as the Meerwein-type arylation5 has
been reported on several occasion for the arylation of furanes
and thiophenes.6,7 Unfortunately, the strong acidic conditions
required for this transformation precluded the arylation of
30 electron-rich heteroarenes such as pyrroles.8 From,
preliminary studies we observed that the C2-azo adduct was
obtained instead (Scheme 1a). With the aim of developping
copper-catalyzed C-H arylations of pyrroles9 under neutral
conditions at room temperature in aqueous solvents, we
35 reinvestigated the Meerwein-type arylation and unveiled
several interesting features (Scheme 1b).
parameters
including
temperature,
solvent
system,
concentration and reaction time, we discovered that degassed
and more concentrated solutions allowed the C-H arylation of
pyrrole 2 (4 equiv) in 1 hour at 25°C with 83% yield,
70 unreacted pyrrole 2 being easily recovered by bulb to bulb
distillation or flash chromatography (entry 6). Other
combinations of solvents including DMSO, and CH3CN in
association with H2O gave lower yields. When CaCO3 was
omitted (entry 7), the yield of 3a significantly decreased (55%
75 vs 83%). This result hints a twofold role for CaCO3 since it
acts as a buffer additive suppressing the formation of azo
compounds but also steps in the catalytic cycle (vide infra) to
improve the reaction efficiency. Importantly, the use of the
Traditional Meerwein reactivity with pyrroles
N2X
[Cu]
HCl-H2O
R1
(a)
+
N
N
N
R1
N
R2
R2
This work - Neutral Meerwein arylation of pyrroles
NH2
[Cu]
(b)
commercially
available
4-nitrophenyl
diazonium
R1
+
N
R2
N
R1
80 tetrafluoroborate instead of our in situ protocol dramatically
decreased the reaction yield (entry 8). These last results also
explain the failures encountered in the literature for the
Meerwein-type arylation of sensitive heteroarenes since both
neutral conditions and a specific in situ diazonium salt
R2
Scheme 1 Meerwein-type arylation of pyrroles
Aryl diazonium salts are traditionally used under their
40 tetrafluoroborate form as crystalline salts but their high
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
ChemComm
DOI: 10.1039/C3CC45P24a0gAe 2 of 3
generation are required for a successful coupling.8
45 Table 2 C-H Arylation of pyrroles
NH2
Table 1 Optimization studies.
t-BuONO, MeSO3H
R1
CaCO3
H
+
N
N
R2
Cu(OAc)2.H2O (10 mol%)
H2O, acetone, 25 °C
Boc
R1
3a-o
N
N
N
Entry Conditionsa
Yield (%)b
44
45
57
O2N
O2N
O2N
Boc
3a, 1 h, 83%
Ts
Me
3b, 3 h, 28%
3c, 1 h, -a
1
2
3
4
5
6
7
8
10% Cu(acac)2, 2 (6 equiv), [0.1 M], 12 h
10% CuO, 2 (6 equiv), [0.1 M], 12 h
10% CuCl2.2H2O, 2 (6 equiv), [0.1 M], 12 h
10% CuSO4.5H2O, 2 (6 equiv), [0.1 M], 12 h
10% Cu(OAc)2.H2O, 2 (6 equiv), [0.1 M], 12 h
10% Cu(OAc)2.H2O, 2 (4 equiv), [0.3 M], 1 h
10% Cu(OAc)2.H2O, 2 (4 equiv), [0.3 M], 1 h
10% Cu(OAc)2.H2O, 2 (4 equiv), [0.3 M], 1 h
O
N
O
N
N
NC
59
Boc
3d, 3 h, 75%
Boc
Boc
65
Ph
83c
55d
35c,e
3e
3h
, 4 h, 66%
3f
, 3 h, 70%
N
N
N
Br
Cl
MeO2C
a
Boc
Boc
Boc
Reactions performed on 1 mmol scale. Concentration of the diazonium
, 6 h, 66%
3i, 5 h, 69%
b
c
d
3g, 12 h, 76%
CO2Me
salt in brackets. Isolated yield. Degassed solvents. CaCO3 was
5 omitted. e 4-Nitrophenyl diazonium tetrafluoroborate was used.
N
N
N
N
O2N
S
Boc
Boc
Boc
Boc
O
With a solid set of optimized conditions, we evaluated the
scope of this methodology on a wide range of anilines (Table
2). The reaction time was based on the observation of the
10 nitrogen evolution. The electrophilic character of aryl radicals
could explain their low reactivity with strongly electron-
deficient pyrroles (3b). By contrast, electron-rich pyrrole only
reacted as a nucleophile onto the diazonium function to
furnish the unwanted azo adduct as the only isolable product
15 (3c). This highlights the fine tuning of the pyrrole properties
required for succeeding the arylation. This process was found
to be tolerant to a variety of functional groups including nitro
(3a, 3k), ketone (3d-e), ester (3i-j, 3m), cyano (3f), methoxy
(3k) and quinone (3l). Moreover, the halogen containing-
20 motifs, such as Br (3g) and Cl (3h), were compatible despite
the free-radical conditions, opening the door for further
OMe
, 1 h, 75%
CO2Me
O
3j, 4 h, 59%
3m, 5 h, 65%
3k
3l, 6 h, 58%
a : The C2-azo adduct was isolated in 72% yield.
Scheme 2 Synthesis of diarylated pyrroles
functionalization. Heteroarylation of pyrrole
2 was also
successful with thiophene derivative, leading to the
a
structurally interesting thiophenylpyrrole 3m in good yield.16
We also explored the opportunity for preparing diarylated
pyrroles (Scheme 2). For instance, in the presence of 4-
nitroaniline 1a, the pyrrole 3a can be arylated in 53% yield to
give the expected symmetrical pyrrole 4a. Unsymmetrical
structures can be obtained as well following the same strategy
50 The radical intermediate D is further oxidized by Cu(II)
species into the corresponding cation which upon
25
E
deprotonation provides the expected coupling products 3a-m.
The high regioselectivity of the arylation process at C2 versus
C3 was further explored with the assistance of DFT
55 calculations (see below). A similar regioselectivity has been
described for the Pd-catalyzed arylation of pyrrole due to
electronic preference for generating Pd-σ-heteroaryl
complexes at C2 and the higher acidity of the C2-H bond
favoring the initial palladation at this site. However, this
60 interpretation cannot account for our free-radical C-H
arylation process where the C-C bond is initially formed by
addition of an aryl radical onto pyrrole.
The regioselectivity was explained by examining the
stability of the radical intermediate (of type D) and the
65 corresponding transition states for the reaction of 1a
(R1=NO2) with 2 (R2=H). The radicals D present much lower
Gibbs energies for the C2 than the C3 products, the estimated
difference being 10.7 kcal.mol-1. The same holds for the
transition states with a relative Gibbs energy of 4.2 kcal.mol-1
70 in favour of the attack on C2.
30 (see 4b).
We assumed that the C-H arylation of pyrroles followed a
free-radical pathway and experimental evidences supported
this hypothesis. Indeed, when the arylation of pyrrole 2 with
4-aminobenzophenone 1b was conducted in the presence of
35 the persistent nitroxide radical TEMPO (1.5 equiv), the
expected coupling product 3d was not formed and the O-aryl-
TEMPO adduct was detected by mass spectroscopy. This
result confirms the involvement of free-radical intermediates.
On the basis of our experimental observations and assisted by
40 literature, the following catalytic cycle should account for the
mechanism involved in this transformation (Scheme 3). The
Cu(I)-catalyzed homolytic dediazoniation of the in situ
generated diazonium salt A gives the corresponding highly
reactive aryl radical B, quickly intercepted by the pyrrole C.
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
DOI: 10.1039/C3CC45240A
Page 3 of 3
ChemComm
Hémez is gratefully acknowledged for HRMS analyses.
Notes and references
40 a Université de Nantes, UFR Sciences et Techniques, UMR CNRS 6230,
CEISAM, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3,
France.. Fax: (+33) 251 125 40; E-mail: fx.felpin@univ-nantes.fr
b Institut Universitaire de France, 103, Boulevard Saint-Michel, 75005
Paris Cedex 05, France.
45 † Electronic Supplementary Information (ESI) available: Experimental
procedures for all new compounds and computational details are
provided. See DOI: 10.1039/b000000x/
1 For selected references, 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.
2 (a) Perrier, A.; Maurel, F.; Jacquemin, D. Acc. Chem. Res. 2012, 45,
1173; (b) Maeda, H.; Bando, Y. Chem. Commun. 2013, 49, 4100; (c)
Groenendaal, L.; Bruining, M. J.; Hendrickx, E. H. J.; Persoons, A.;
Vekemans, J. A. J. M.; Havinga, E. E.; Meijer, E. W. Chem. Mater. 1998,
10, 226. (d) Maeda, H.; Kinoshita, K.; Naritani, K.; Bando, Y. Chem.
Commun. 2011, 47, 8241.
3 For recent examples, see: (a) Hari, D. P.; Schroll, P.; König, B. J. Am.
Chem. Soc. 2012, 134, 2958. (b) Singh, P. P.; Aithagani, S. K.; Yadav,
M.; Singh, V. P.; Vishwakarma, R. A. J. Org. Chem. 2013, 78, 2639.
4 Galli, C. Chem. Rev. 1988, 88, 765.
Scheme 3 Proposed catalytic cycle.
The corresponding imaginary frequency mode that
characterizes the transition state presents a frequency of 384
cm-1 (see ESI). We also note that the 1a+2→D reaction is
exergonic with a ΔG of -24.7 kcal.mol-1. Therefore both
thermodynamic and kinetic criteria go in the same direction
and indicate a preferred C2 attack.
5
5 For recent reviews on the Meerwein arylation, see : (a) Heinrich, M. R.
Chem. Eur. J. 2009, 15, 820; (b) Hari, D. P.; König, B. Angew. Chem. Int.
Ed. 2013, 52, 4734.
6 For recent references, see: (a) Racanè, L.; Tralić-Kulenović, V.; Boykin,
D. W.; Karminski-Zamola, G. Molecules 2003, 8, 342; (b) Obushak, N.
D.; Gorak, Y. I.; Matiichuk, V. S.; Lytvyn, R. Z. Russ. J. Org. Chem.
2008, 44, 1689; (c) Obushak, M. D.; Matiychuk, V. S.; Lytvyn, R. Z.
Chem. Heterocycl. Compd. 2008, 44, 936. (d) Gorak, Y. I.; Obushak, N.
D.; Matiichuk, V. S.; Lytvyn, R. Z. Russ. J. Org. Chem. 2009, 45, 541; (e)
Matiychuk, V. S.; Obushak, N. D.; Lytvyn, R. Z.; Horak, Y. I. Chem.
Heterocycl. Compd. 2010, 46, 50.
7 Pratsch, G.; Anger, C. A.; Ritter, K.; Heinrich, M. R. Chem. Eur. J.
2011, 17, 4104.
10
Scheme 4 Kinetic isotope effect.
8 Wetzel, A.; Pratsch, G.; Kolb, R.; Heinrich, M. R. Chem. Eur. J. 2010,
16, 2547.
The role of CaCO3 was also investigated with labelled
9 For examples of copper-catalyzed arylation of heteroarenes with
iodonium salts, see: (a) Beck, E. M.; Hatley, R.; Gaunt, M. J.; Angew.
Chem. Int. Ed. 2008, 47, 3004; (b) Phipps, R. J.; Grimster, N. P.; Gaunt,
M. J. J. Am. Chem. Soc. 2008, 130, 8172.
10 For examples on large scale, see: (a) Nielsen, M. A.; Nielsen, M. K.;
Pittelkow, T. Org. Process Res. Dev. 2004, 8, 1059; (b) Molinaro, C.;
Mowa, J.; Gosselin, F.; O’Shea, P. D.; Marcoux, J.-F.; Angelaud, R.;
Davies, I. W. J. Org. Chem. 2007, 72, 1856; (c) Maligres, P. E.;
Humphrey, G. R.; Marcoux, J.-F.; Hillier, M. C.; Zhao, D.; Krska, S.;
Grabowski, E. J. J. Org. Process Res. Dev. 2009, 13, 525.
11 a) Le Callonnec, F.; Fouquet, E.; Felpin, F.-X. Org. Lett. 2011, 13,
2646. b) Susperregui, N.; Miqueu, K.; Sotiropoulos, J.-M.; Le Callonnec,
F.; Fouquet, E.; Felpin, F.-X. Chem. Eur. J. 2012, 18, 7210.
12 Honraedt, A.; Le Callonnec, F.; Le Grognec, E.; Fernandez, V.;
Felpin, F.-X. J. Org. Chem. 2013, 78, 4604.
13 For in situ generated diazonium salts, see : (a) Doyle, M. P.; Siegfried,
B.; Elliott, R. C.; Dellaria, J. F. J. Org. Chem. 1977, 42, 2431; (b) Andrus,
M. B.; Song, C.; Zhang, J. Org. Lett. 2002, 4, 2079; (c) Wu, X.-F.;
Neumann, H.; Beller, M. Chem. Commun. 2011, 47, 7959.
14 Rondestvedt, C. S. Org. React. 1976, 24, 225.
experiments (Scheme 4). A kinetic isotope effect (kH/kD
3.16) was observed between pyrrole 2 and its deuterated
15 analogue d4-2, indicating that the C-H bond cleavage could be
involved in a rate limiting step. Thereby, we suggest that
CaCO3 could facilitate the deprotonation of the pyrrolo cation
E which likely follows undesirable pathways decreasing the
=
reaction yield in the absence of
a base. Theoretical
20 calculations of the transition states corresponding to
deprotonation could be found with both OH- and HCO-3
anions (see ESI) but not for MeSO-3, hinting that a sufficiently
efficient base is indeed necessary.
In summary, we have developped a Meerwein-type arylation
25 of pyrroles under very mild conditions. The methodology
features aqueous solvents, room temperature, inexpensive
reagents and catalysts, as well as experimental simplicity.
Experimental and theoritical studies provided mechanistic
insights.
Authors are thankful to the “Université de Nantes”, the
“CNRS”, and the “Région Pays de la Loire” in the framework
of a “Recrutement sur poste stratégique” for funding. D.J.
acknowledges the European Research Council (ERC) for
funding in the framework of a Starting Grant (Marches -
15 Kochi, J. K. J. Am. Chem. Soc. 1955, 77, 5090.
30
16 For the cleavage of the Boc group, see: Basaric, N.; Baruah, M.; Qin,
W.; Metten, B.; Smet, M.; Dehaen, W.; Boens, N. Org. Biomol. Chem.
2005, 3, 2755.
35 278845). This research used resources of the GENCI-
CINES/IDRIS, the CCIPL (Centre de Calcul Intensif des Pays
de Loire) and a local Troy cluster (Nantes University). Julie
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3