Solvent free catalytic C-H functionalisation

Article abstract of DOI:10.1039/c003074k

Solvent-free reaction conditions facilitate a range of aromatic C-H functionalisations that traditionally require acidic or disfavoured solvents. These reactions include selective ortho- and meta-arylation of aryl carbamates and anilides and selective halogenation reactions. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c003074k

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Solvent free catalytic C–H functionalisationwz
Robin B. Bedford,*a Charlotte J. Mitchellb and Ruth L. Webstera
Received 12th February 2010, Accepted 12th March 2010
First published as an Advance Article on the web 30th March 2010
DOI: 10.1039/c003074k
Solvent-free reaction conditions facilitate a range of aromatic
C–H functionalisations that traditionally require acidic or
disfavoured solvents. These reactions include selective ortho-
and meta-arylation of aryl carbamates and anilides and selective
halogenation reactions.
Table 1 Solvent free catalytic ortho- and meta-arylation of carba-
mates and anilides
The direct transition metal-catalysed C–H functionalisation of
aromatic compounds (Scheme 1) is rapidly growing in impor-
tance, due in no small part to the greater step-economy and
sustainability engendered compared with more traditional
aromatic modifications.1,2 While highly desirable, such
reactions can be exacting, not least with regards to the choice
of solvent. For instance many palladium-catalysed functiona-
lisations are conducted in acidic media, such as acetic or
trifluoroacetic acid, which can be deleterious to acid-sensitive
functionality, or else require the use of industrially disfavoured
solvents such as 1,2-dichloroethane (DCE).
Entry
1a
Product
Entry
2a
Product
3a
4a
5a
6a
We recently reported the palladium-catalysed ortho-arylation
of arylcarbamates with aryl iodides or diaryliodonium salts.3
The reactions require the use of acetic or trifluoroacetic acid as
solvent, hampering activity with acid-sensitive functional
groups. A brief examination of alternative solvents proved
unsuccessful, as did an attempt to run reactions ‘on water’
(see ESIz),4,5 but we were delighted to discover that the
reaction of aryl N,N-diethyl carbamates with diaryliodonium
salts, [ArI(mes)][OTf], proceeded with excellent selectivity for
the mono-arylated free phenol products, 1,y in the absence of
solvent (Table 1, entries 1–8). The preparation of the reaction
mixtures proved to be very simple: the starting materials were
ground using a pestle and mortar for about 30 seconds to one
minute until homogeneous, transferred to a tube and heated
under air for the requisite time. Stirring was not necessary. The
isolated yields of the phenols 1 were higher than those
achieved previously in acetic acid.3 Steric hindrance in the
ortho position of the aryl carbamate prevented loss of the
carabamate function (entry 7) while the reaction using mesityl-
(2-(methoxycarbonyl)phenyl)iodonium triflate with 4-(tert-
butyl)phenyl diethylcarbamate yielded the dibenzopyranone
3 (entry 8) via direct arylation followed by lactonisation.
7a
8a,b
9c
10d
12d
14d
16c
18e
20e
22f
24e
11c
13d
15d
17c
19f
21f
Scheme 1 Catalytic aromatic C–H functionalisation.
23e
a School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
BS8 1TS, UK. E-mail: r.bedford@bristol.ac.uk
a
b
ArOC(O)NEt2 (0.18 mmol), Pd(OAc)2 (5 mol%), 120 1C, 4 h. From
mesityl(2-(methoxycarbonyl)phenyl)iodonium triflate. c Anilide(0.18 mmol),
Pd(OAc)2 (5 mol%), 120 1C, 4 h. d 0.5 mmol scale, 18 h. e Anilide
(0.5 mmol), Cu(OTf)2 (10 mol%) 100 1C, 18 h. f 0.18 mmol scale, 4 h.
b GlaxoSmithKline, Stevenage, SG1 2NY, UK
w Dedicated to the memory of Professor Keith Fagnou.
z Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data. See DOI: 10.1039/c003074k
ꢀc
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Such solvent-free ortho-C–H functionalisation reactions are
very rare6 and we were thus keen to widen the scope of this
arylation reaction beyond aryl carbamates. Accordingly
we found that anilide substrates were also well tolerated
(entries 9–17). In these cases we again observed high mono-
selectivity,y in stark contrast to an equivalent reaction
reported by Daugulis and Zaitsev who obtained a di-arylated
product when using acetic acid as solvent.7
reaction also worked well with an aryl carbamate substrate
(entry 7).
Solvent-free bromination proceeded with high yields
(entries 8–10) and good scalability—the reaction can be
readily performed with B0.1 mol starting material—however
the observed selectivity is somewhat different to that in the
chlorination reactions. While N-(p-tolyl)acetamide yielded the
ortho-brominated product 10 (entry 8), N-(m-tolyl)acetamide
gave a mixture of para-bromo (major) and ortho,para-dibromo
products 12 and 13 respectively (entry 9). When the reaction
was repeated in the absence of palladium (entry 10) little ortho-
bromination occurred. This implies that in the latter case,
simple electrophilic bromination alone occurred, while in the
former there was a competitive C–H functionalisation process
operative. Such disparity in the mechanisms of halogenation
with copper chloride or bromide salts has very recently been
reported by Stahl and co-workers for reactions in solution.11 It
is interesting to note that in Shi and co-workers’ original
publication,10 the only substrate with a free para-position
employed in the bromination reactions was N-(m-tolyl)
acetamide. When we reproduced this reaction under Shi’s
conditions (entry 11) we actually obtained the para-substituted
product 12 in 80% yield, along with trace amounts of 13, and
not the ortho-bromo product claimed. The spectroscopic data
for 12 are essentially identical to those claimed by Shi for the
ortho product. We suggest that the products of their bromina-
tions, although not their chlorinations, are in fact derived
from simple electrophilic substitution rather than
The solvent free approach is not limited to ortho-
functionalisation. Recently Phipps and Gaunt reported an
elegant, copper-catalysed meta-arylation of anilides using
diaryliodonium salts in DCE.8 Gratifyingly, we found that
these unusual reactions were also amenable to solvent free
conditions (Table 1, entries 18–24). Solvent-free C–H
functionalisation is not limited to direct arylation reactions
but can also be extended to halogenation (Table 2).
The solvent free ortho-chlorination and -bromination of
2-phenylpyridine and N-phenylpyrrolidin-2-one with N-halo-
succinimides (entries 1–3) works comparably or better than
similar reactions in acetic acid reported by Sanford and
co-workers.9 In the reaction of N-phenylpyrrolidin-2-one with
N-chlorosuccinimide some competitive electrophilic para-
chlorination is observed (entry 3). The solvent free ortho-
chlorination of anilides using a mixture of copper acetate
and copper chloride produced good to excellent yields of the
desired products 9 in 2 h (entries 4–6), by contrast Shi
and co-workers reported that equivalent reactions in DCE
require heating for two days.10 The ortho-chlorination
Table 2 Solvent free, palladium-catalysed direct halogenations
Entry
1a
Product(s)
Entry
2a
Product(s)
3a
5c
7c
4c
6c
8d
10d,f
11g
12, 82% + 13, trace
12, 80% + 13, trace
12, 80% + 13, trace
9d
12g,f,b
a
b
Substrate (1 mmol), NCS or NBS (1.2 equiv.), Pd(OAc)2 (5 mol%), 120 1C, 2 h. Spectroscopic yield (NMR, 1,3,5-MeOC6H3 internal
c
d
standard). Substrate (1 mmol), Cu(OAc)2 (2 equiv.), CuCl2 (2 equiv.), Pd(OAc)2 (5 mol%), 120 1C, 2 h. Substrate (0.5 mmol), Cu(OAc)2
(2 equiv.), CuBr2 (2 equiv.), Pd(OAc)2 (5 mol%), 120 1C, 1 h. 0.089 mol anilide scale. Pd-free. Substrate (0.5 mmol), Cu(OAc)2 (2 equiv.),
CuBr2 (2 equiv.), Pd(OAc)2 (10 mol%), DCE (4 ml), 90 1C, 48 h.
e
f
g
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phase effects further as well as expanding the scope of the
solvent free reactions.
We thank EPSRC and GSK for funding.
Notes and references
y In all cases, no diarylated product was observed in crude product
mixtures, only unreacted starting material.
1 For recent overviews, see: (a) Selective Functionalization of
C–H Bonds (thematic issue), Chem. Rev., 2010, 110, 575–1211;
(b) Catalytic Aromatic C–H Activation (Symposium in Print),
Tetrahedron, 2008, 64, 5963–6138; (c) Handbook of
C–H Transformations, ed. G. Dyker, Wiley-VCH, Weinheim, 2005.
2 (a) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094; (b) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174; (c) I. V. Seregin and
V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 117; (d) K. Godula and
D. Sames, Science, 2006, 312, 67.
3 R. B. Bedford, R. L. Webster and C. J. Mitchell, Org. Biomol.
Chem., 2009, 7, 4853.
4 For recent examples of C–H functionalisation reactions run
‘on water’ see: G. L. Turner, J. A. Morris and M. F. Greaney,
Angew. Chem., Int. Ed., 2007, 46, 7996.
5 For a recent example of arylation of ureas in water see:
T. Nishikata, A. R. Abela and B. H. Lipshutz, Angew. Chem.,
Int. Ed., 2010, 49, 781.
6 Selected examples of solvent free, catalytic C–H activation
reactions: (a) C. M. Rao Volla and P. Vogel, Org. Lett., 2009,
11, 1701; (b) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am.
Chem. Soc., 2005, 127, 13154; (c) Z. Shi and C. He, J. Org. Chem.,
2004, 69, 3669.
Scheme 2 Sequential solid-state bromination/Suzuki coupling.
palladium-catalysed C–H functionalisation. Indeed, when the
reaction is repeated in solution in the absence of palladium
(entry 12) similar results are obtained.
In order to extend the utility of the solvent free methodo-
logy, we briefly examined sequential solid-phase bromination/
Suzuki couplings of N-(p-tolyl)acetamide (Scheme 2). This two
step methodology again proved very simple: the powder
obtained from the solid-phase bromination was reground with
the appropriate arylboronic acid, K3PO4 and palladium
acetate and then heated. Such solid-phase Suzuki reactions
are rare.12
7 O. Daugulis and V. G. Zaitsev, Angew. Chem., Int. Ed., 2005, 44,
4046.
8 R. J. Phipps and M. J. Gaunt, Science, 2009, 323, 1593.
9 D. Kalyani, A. R. Dick, W. Q. Anani and M. S. Sanford,
Org. Lett., 2006, 8, 2523.
10 X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang and Z. Shi,
J. Am. Chem. Soc., 2006, 128, 7416.
11 L. Yang, Z. Lub and S. S. Stahl, Chem. Commun., 2009, 6460.
12 For a recent example see: F. Schneider and B. Ondruschka,
ChemSusChem, 2008, 1, 622.
In summary, we have developed a range of highly expedient
solvent-free aromatic CH functionalisation reactions. In most
cases these proceed with comparable or higher yields and
better selectivity than the equivalent reactions in solution,
which require acidic or toxic solvents. Most, but not all of
the arylation reactions occur in the melt phase, while many of
the halogenation reactions occur in the solid state, yielding the
products as powders, and we are currently exploring these
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Chem. Commun., 2010, 46, 3095–3097 | 3097