Base- and metal-free C-H direct arylations of naphthalene and other unbiased arenes with diaryliodonium salts

Article abstract of DOI:10.1039/c2cc34592g

A novel metal-free direct arylation of unbiased arenes with diaryliodonium triflates in a process where the use of solvents and additives is not required has been established.

Full text of DOI:10.1039/c2cc34592g

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Base- and metal-free C–H direct arylations of naphthalene and other
unbiased arenes with diaryliodonium saltsw
a
b
a
a
´ ´ ´
˜
Susana Castro, Juan J. Fernandez, Ruben Vicente,* Francisco J. Fananas* and
a
´
´
Felix Rodrıguez*
Received 27th June 2012, Accepted 23rd July 2012
DOI: 10.1039/c2cc34592g
A novel metal-free direct arylation of unbiased arenes with
diaryliodonium triflates in a process where the use of solvents
and additives is not required has been established.
Table 1 Screening of conditions for the direct arylation of naphthalene
with diphenyliodonium triflate
The biaryl motif is a ubiquitous substructure in organic chemistry
that can be found in many relevant bioactive molecules, natural
products, molecular switches and motors or liquid crystals, among
others.1 By far, the most common methods to assemble this
framework rely on the C–C bond formation between both pre-
functionalised arenes via traditional cross-coupling reactions.1 In
recent years, an approach consisting of transition metal-catalysed
direct arylations of C–H-bonds has emerged as a more sustainable
strategy for the synthesis of biaryls.2 These methodologies, referred
to as ‘‘environmentally benign’’ because they do not require the
pre-functionalization of the arene, are simple regarding
substrate synthesis but the need of an expensive and often difficult
to remove transition metal catalysts constitutes a major drawback
for large scale applications in industry. In this sense, examples of
transition metal-free C–H arylation reactions have been very
recently developed.3 However, most of these methods are limited
to heteroarenes or electron rich arenes and they require the use of
strong inorganic bases.
Entry Solvent
Conditionsa
1a (%)/a : bb
c
1
2
Dodecane
Acetonitrile
100 1C, 72 h
85 1C, 72 h
—
—
c
c
3
N,N-Dimethylacetamide 100 1C, 72 h
—
—
c
4
5
6
Nitrobenzene
1,4-Dioxane
1,2-Dichloroethane
—
—
—
130 1C, 72 h
105 1C, 72 h
85 1C, 72 h
85 1C, 72 h
120 1C, 72 h
24/5 : 1
49/6 : 1
46/8 : 1
57/1.2 : 1
7d
8d
9d
MW, 120 1C, 30 min 70/7 : 1
a
Naphthalene (0.5 mmol), diphenyliodonium triflate (0.6 mmol; 1.2 equiv.),
solvent (2 mL). b Yields of isolated products after purification by column
chromatography (SiO2). The selectivity was determined by 1H-NMR
analysis. c 1a was not detected by GC/MS analysis. d Naphthalene
(2.5 mmol; 5 equiv.), diphenyliodonium triflate (0.5 mmol).
develop the direct arylation of unbiased arenes under base- and
metal-free reaction conditions. Herein, we wish to report our
findings regarding this remarkable transformation.
The use of diaryliodonium salts as arylating reagents in
transition metal-catalysed direct C–H-bond arylations has
experienced significant progress in very recent years.4 Surprisingly,
the use of these reagents in metal-free coupling reactions with arenes
has been scarcely studied.5,6 Thus, Gaunt et al. discovered that
direct arylations of electron rich arenes with diphenyliodonium
triflate could occur either in the presence or absence of copper
catalysts.5a,b On the other hand, Ackermann et al. disclosed metal-
free direct arylations of indoles and pyrroles with diaryliodonium
tosylates as arylating reagents.5c It is noteworthy that these
transformations do not require the use of bases or additives.
In view of that, we considered that it would be interesting to
We initially investigated the reaction shown in Table 1.
Thus, naphthalene was reacted with diphenyliodonium triflate
under different reaction conditions. As shown, we did not observe
any coupling product when the reaction was performed in
dodecane, acetonitrile, N,N-dimethylacetamide or nitrobenzene as
solvents (entries 1–4). However, a promising result was obtained
when we carried out the reaction in 1,4-dioxane at 105 1C (entry 5).
Under these reaction conditions, we observed the formation of
phenylnaphthalene as a mixture of a–b isomers (a : b = 5 : 1) in
24% combined yield after 72 hours of reaction. Interestingly, the
use of 1,2-dichloroethane as solvent gave rise to the desired product
in higher yield and the same selectivity (49%, a : b = 5 : 1) after 72
hours, and at a significantly lower reaction temperature of 85 1C
(entry 6). At this point we thought that the relatively low melting
point of naphthalene (80–82 1C) could allow its use not only as
reagent but also as solvent. Pleasantly, when we performed our
model reaction just using a slight excess of naphthalene (5 equiv.),
in the absence of any other solvent, at 85 1C, we observed the
a
´
Instituto Universitario de Quımica Organometalica ‘‘Enrique Moles’’,
Universidad de Oviedo, Julian Claverıa 8, 33006-Oviedo, Spain.
´
´
´
E-mail: vicenteruben@uniovi.es, fjfv@uniovi.es,
frodriguez@uniovi.es; Fax: +34 985103446; Tel: +34 985106224
b
´
R&D Department, Industrial Quımica del Nalon S. A.,
Avenida de Galicia 31, 33005-Oviedo, Spain
´
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
c2cc34592g
c
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Chem. Commun.

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formation of phenylnaphthalene in 46% yield (a : b = 8 : 1) after
72 hours (entry 7). The present transformation could be considered
close to an ideal process because the reaction does not require any
solvent, metal catalysts, bases or additives. In addition, iodobenzene
generated as a side product could be reused since it is the precursor
of the iodonium salt.
Table 3 Metal-free direct arylations of unbiased arenes with diaryl-
iodonium triflatesa
A slight improvement in the yield was observed when the
reaction was performed at 120 1C in a sealed tube (57%), but
disappointingly, the selectivity was very poor giving rise to an
almost equimolecular mixture of isomers (a : b = 1.2 : 1).
Considering that microwave heating has emerged as a versatile
method to speed up and improve many chemical processes,7
we decided to try our reaction under microwave irradiation.
Delightfully, when heating the reaction mixture, just consisting of
a 5 : 1 mixture of naphthalene and diphenyliodonium triflate, at
120 1C under microwave irradiation (entry 9), the yield of 1a was
increased to 70%. It should be pointed out that the reaction time
was remarkably reduced from 72 hours to 30 minutes. Moreover,
a gratifying 7 : 1 regioisomeric ratio favouring the formation of
1-phenylnaphthalene was observed.8 No further improvement
could be obtained from variations in temperatures, reaction times,
ratio of the reagents or the use of different diphenyliodonium salts
(see ESIw for details). With the aim of identifying potential metal
impurities, both naphthalene and diphenyliodonium triflate were
analysed by ICP-MS and only trace amounts of transition metals
were detected (see ESIw for details).9
With optimised reaction conditions in hand, we next investigated
the performance of various diaryliodonium triflates for the direct
arylation of naphthalene. As shown in Table 2, the reaction worked
well for a series of diaryliodonium salts bearing halogen atoms or
alkyl substituents.10 Thus, the use of the microwave irradiation
allowed the synthesis of the corresponding arylated naphthalenes
1a–f with synthetically useful yields and remarkably good
selectivities in short reaction times. The major 1-arylnaphthalene
regioisomer could be easily isolated by column chromatography.
As before, neither solvents nor metallic catalysts or additives
were necessary. Regarding the limitations of the process we
observed that the reaction did not afford appreciable amounts
of the desired coupling product when using an arylating reagent
containing electron-rich aryl groups, such as 4-methoxyphenyl.
a
Reaction conditions: arene (2.5 mmol; 5 equiv.), diaryliodonium triflate
(0.5 mmol). Yields are referred to isolated products after purification by
column chromatography (SiO2). Ratio of regioisomers, determined by GC,
is given in parentheses. See ESI for details. b At 160 1C, 30 min.
Moreover, when a non-symmetric diaryliodonium triflate such as
[(Mes)PhI]OTf (Mes = 2,4,6-trimethylphenyl) was used, under
the optimized reaction conditions we detected by GC/MS only a
trace amount of compound 1a.11
Finally, we examined the base- and metal-free microwave
assisted direct arylation of other unbiased arenes with diaryl-
iodonium triflates. As depicted in Table 3, phenanthrene was
converted into biaryls 2a–b in moderate yield and selectivity.
A
symmetrically substituted naphthalene derivative was
also used to provide biaryl derivative 3 in moderate yield.
Interestingly, pyrene was efficiently arylated under the present
reaction conditions to give arylpyrenes 4a–b.12
Considering previous works by Gaunt et al.5 and Kita et al.,6 two
mechanistic scenarios can be envisioned. Gaunt et al. suggested an
ionic Friedel–Crafts-type mechanism in the arylation of electron-
rich arene derivatives. On the contrary, Kita et al. proposed a
mechanism involving radical intermediates via single-electron-
transfer (SET) in iodonium- and TMSOTf-promoted oxidative
couplings of (hetero)arenes. Consequently, we conducted experi-
ments in the presence of a well-known radical-scavenger as
TEMPO. Thus, when our model reaction was carried out in
the presence of one equivalent of TEMPO, no reaction was
observed.13 Moreover, we also tested the reactivity of naphthalene
and diphenyliodonium bromide in the presence of triflic acid
(TfOH) in order to know if adventitious, or in situ formed, Brønsted
acids could act as activators of the diaryliodonium salt.14 Under our
standard reaction conditions, no arylation products were observed,
excluding a role of TfOH in the reaction. Therefore, at this
stage, we believe that a radical mechanism likely operates in the
present reaction. In this context, a tentative mechanism accounting
for the observed reactions is proposed in Scheme 1. For the
sake of simplicity, only the particular case of reaction
between naphthalene and diphenyliodonium triflate is shown.
Thus, considering that it is known that diaryliodonium salts
decompose into radicals,15 we propose that under the microwave
Table 2 Metal-free direct arylations of naphthalene with diaryliodonium
triflatesa
Entry
Ar
T (1C)/t (min)
1b (%)
a : bc
1
2
3
4
5
6
Ph
120/30
150/60
150/60
150/60
150/60
150/60
1a (70)
1b (79)
1c (59)
1d (69)
1e (76)
1f (74)
7 : 1
8 : 1
5 : 1
3 : 1
4 : 1
10 : 1
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-tBuC6H4
a
Reaction conditions: naphthalene (2.5 mmol; 5 equiv.), diaryliodonium
b
triflate (0.5 mmol), microwave irradiation. Yields of isolated products
c
after purification by column chromatography (SiO2). Selectivity was
estimated by 1H-NMR analysis.
c
Chem. Commun.
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3 (a) G. B. Bajracharya and O. Daugulis, Org. Lett., 2008, 10, 4625;
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M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972; (b) R. J. Phipps,
N. P. Grimster and M. J. Gaunt, J. Am. Chem. Soc., 2008, 130, 8172;
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Y.-X. Li and Y.-D. Wu, J. Am. Chem. Soc., 2011, 133, 7668;
(h) A. J. Hickman and M. S. Sanford, ACS Catal., 2011, 1, 170. For
a recent review on synthetic applications of diaryliodonium salts, see:
(i) E. A. Merrit and B. Olofsson, Angew. Chem., Int. Ed., 2009, 48, 9052.
5 (a) C.-L. Ciana, R. J. Phipps, J. R. Brandt, F.-M. Meyer and
M. J. Gaunt, Angew. Chem., Int. Ed., 2011, 50, 458;
(b) H. A. Duong, R. E. Gilligan, M. L. Cooke, R. J. Phipps and
M. J. Gaunt, Angew. Chem., Int. Ed., 2011, 50, 463;
(c) L. Ackermann, M. Dell’Acqua, S. Fenner, R. Vicente and
R. Sandmann, Org. Lett., 2011, 13, 2358.
6 For iodonium-promoted metal-free oxidative cross-coupling reactions,
see: (a) T. Dohi, M. Ito, K. Morimoto, M. Iwata and Y. Kita, Angew.
Chem., Int. Ed., 2008, 47, 1301; (b) T. Dohi, M. Ito, N. Yamaoka,
K. Morimoto, H. Fujioka and Y. Kita, Angew. Chem., Int. Ed., 2010,
49, 3334; (c) Y. Kita, K. Morimoto, M. Ito, C. Ogawa, A. Goto and
T. Dohi, J. Am. Chem. Soc., 2009, 131, 1668.
7 A. Loupy, Microwaves in Organic Synthesis, Wiley-VCH, Weinheim,
Germany, 2006.
8 We repeated the reaction several times and the results were
consistent in terms of yield (67–72%) and regioisomeric ratio
(5 : 1 to 8 : 1). The regioselectivity of the reaction did not vary
significantly with time/conversion (see ESIw for details).
9 We use naphthalene at highest purity available ( Z 99.9%) provided
by Industrial Quımica del Nalon, S. A (www.nalonchem.com).
10 To access to symmetric diaryliodonium triflates we followed published
procedures: (a) M. Bielawski, M. Zhu and B. Olofsson, Adv. Synth.
Catal., 2007, 349, 2610; (b) M. Zhu, N. Jalalian and B. Olofsson,
Synlett, 2008, 592; (c) M. Bielawski and B. Olofsson, Org. Synth., 2009,
86, 308. At present, the main limitation of the reaction described here is
the availability of this type of iodonium salts.
Scheme 1 Possible reaction mechanisms.
irradiation conditions a homolytic rupture of diphenyliodonium
triflate occurs to form phenyl radical 5 and radical species 6. From
here, two possible pathways could be suggested. Thus, phenyl
radical 5 could react with naphthalene to give a new aryl radical
species 7 (Scheme 1, mechanism A; only addition at the a-position
of naphthalene is shown). This radical 7 could react with a new
molecule of diphenyliodonium triflate to give 8 and a new molecule
of phenyl radical 5. Finally, a formal elimination of iodobenzene
and triflic acid from species 8 leads to the formation of product 2a.
Alternatively, a mechanism where naphthyl radical 9 is formed by a
hydrogen abstraction process could be proposed (Scheme 1, mecha-
nism B). Thus, reaction of naphthalene with radical species 6
delivers naphthyl radical 9, iodobenzene and triflic acid (only the
formation of the radical at a-position of naphthalene is shown).
Further reaction of naphthyl radical 9 with a new molecule of
diphenyliodonium triflate would deliver product 1a and a new
molecule of radical species 6. We believe that both the mechanisms
above commented are possible and that it is also likely that both are
operating at the same time. However, at present, other mechanisms
based on the formation of radical species cannot be ruled out.
In summary, we report a novel user-friendly protocol for the
direct arylation of unbiased arenes. The present procedure does not
require the use of a metal catalyst, a solvent or the addition of
additives such as strong bases. Thus, just by mixing a given arene
and a diaryliodonium triflate and subjecting the mixture to micro-
wave irradiation, it is possible to obtain the corresponding arylated
product after a short reaction time. Preliminary experiments suggest
that this transformation takes place via radical intermediates.
We acknowledge financial support from MINECO of Spain
(grant CTQ2010-16790) and Industrial Quımica del Nalon S. A.
(grant FUO-EM-297-10). R. V. is a Ramon y Cajal Fellow.
11 Unreacted naphthalene and [(Mes)PhI]OTf were the only other
compounds detected.
12 We were not able to perform the coupling reaction with benzene as
the unbiased arene. Also, under the optimized reaction conditions
we did not observe the formation of diarylated products.
13 Reviews on arylations involving radicals: (a) A. Studer and
D. P. Curran, Angew. Chem., Int. Ed., 2011, 50, 5018; (b) W. R.
Bowman and J. M. D. Storey, Chem. Soc. Rev., 2007, 36, 1803. See
also: (c) D. P. Curran and A. I. Keller, J. Am. Chem. Soc., 2006,
128, 13706.
Notes and references
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M. Lemaire, Chem. Rev., 2002, 102, 1359.
14 Decomposition of aryliodonium salts is known to generate the
corresponding acid by proton abstraction of the arene. See:
W. E. McEwen and J. W. DeMassa, Heteroat. Chem., 1996,
7, 349. Kita et al. reported the arylation of electron rich aromatics
with aryliodonium salts in the presence of TMSOTf that is supposed
to coordinate to the iodonium salt enhancing the electrophilicity of
the iodine atom (ref. 6b). In our case, it seems that adventitious, or
in situ formed, Brønsted acids do not play a similar role.
15 (a) R. B. Sandin and R. K. Brown, J. Am. Chem. Soc., 1947,
69, 2253; (b) J. V. Crivello and J. H. W. Lam, Macromolecules,
1977, 10, 1307; (c) D. D. Tanner, D. W. Reed and B. P. Setiloane,
J. Am. Chem. Soc., 1982, 104, 3917; (d) Y. Yagci, S. Jockusch and
N. J. Turro, Macromolecules, 2010, 43, 6245.
2 Reviews on metal-catalysed direct arylations of C–H-bonds:
(a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174; (b) L. Ackermann, R. Vicente and A. Kapdi, Angew. Chem.,
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun.