An organic cation as a silver(i) analogue for the arylation of sp 2 and sp3 C-H bonds with iodoarenes

Article abstract of DOI:10.1039/c4sc01215a

Reactions promoted by stoichiometric amounts of silver salts suffer from high cost, limited availability and raise environmental concerns. This manuscript describes studies leading to the discovery of a general replacement for silver with an inexpensive and convenient organic salt in palladium catalyzed direct C(sp²)-H and C(sp³)-H arylation reactions.

Full text of DOI:10.1039/c4sc01215a

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An organic cation as a silver(I) analogue for the
arylation of sp2 and sp3 C–H bonds with
iodoarenes†
Cite this: Chem. Sci., 2014, 5, 3509
Carlos Arroniz,ab J. Gabriel Denis,a Alan Ironmonger,b Gerasimos Rassias‡b
a
*
and Igor Larrosa
Received 27th April 2014
Accepted 4th June 2014
Reactions promoted by stoichiometric amounts of silver salts suffer from high cost, limited availability and
raise environmental concerns. This manuscript describes studies leading to the discovery of a general
replacement for silver with an inexpensive and convenient organic salt in palladium catalyzed direct
C(sp2)–H and C(sp3)–H arylation reactions.
DOI: 10.1039/c4sc01215a
www.rsc.org/chemicalscience
One of the fundamental goals in chemical research is the waste. Therefore those transformations are prohibitively
development of broadly applicable, cost-effective, practical and expensive for industry. Importantly, whereas there are alterna-
sustainable synthetic methods. In this context, the development tives to Ag salts in their role of oxidants, the only other well-
of C–H bond arylation processes has attracted signicant known halide scavengers (Pb, Tl and Hg salts) are highly toxic
interest as more environmentally-friendly alternatives to tradi- and rarely used for this purpose.
tional cross-couplings. These new transformations use readily
Recent studies on the use of Ag salts as additives in Au-
available starting materials, thus avoiding the preparation catalyzed reactions have shown that, in addition to abstracting a
and use of organometallic reagents as coupling partners and halogen, Ag may play additional roles essential to the catalytic
the associated generation of stoichiometric amounts of metallic process and form mixed Au–Ag active species.8 In the case of
waste.1
In 2005, Daugulis and Zaitsev developed a method for the
C–H arylation reactions, it is possible that Ag salts may also be
direct arylation of anilides with iodoarenes using a catalytic
system involving Pd(OAc)2 in combination with stoichiometric
AgOAc.2 This powerful system and its various modications
have since been successfully applied to a great variety of C–H
arylation processes involving iodoarene coupling partners
(Scheme 1).3,4 However, to date one of the major drawbacks of
these methodologies is the requirement for stoichiometric
silver additives.5 Silver(I) salts are a uniquely appropriate
partner for Pd, Au, Cu, Rh, Ru and Pt catalysts, particularly
when halide abstraction is required in the catalytic process.6
However, due to the ability of silver salts to also act as oxidants
and Lewis acids, sometimes undesired side reactions are
observed.7 Furthermore, when used as stoichiometric reagents,
these expensive silver salts considerably increase the overall
cost of the process and generate signicant amounts of metal
aSchool of Biological and Chemical Sciences, Queen Mary University of London, Joseph
Priestley Building, Mile End Road, E1 4NS, London, UK. E-mail: i.larrosa@qmul.ac.uk;
Tel: +44 (0) 20 7882 8404
bGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1
2NY, Hertfordshire, UK
† Electronic supplementary information (ESI) available: Complete experimental
procedures, characterization data and NMR spectra. See DOI: 10.1039/c4sc01215a
‡ Present address: Department of Chemistry, University of Patras. 26500, Patras,
Greece.
Scheme
1 Selected examples of the general scope of current
protocols for C–H arylation using iodoarenes and stoichiometric silver
salts.
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acting as terminal oxidants, assisting in the oxidative addition
step or facilitating the C–H activation. A recent mechanistic
study on the role of additives in palladium acetate-catalyzed
ortho-C–H bond functionalizations suggested that Ag interacts
with Pd in a cooperative manner for an enhanced hetero-
bimetallic C–H activation.9 We now report studies that
demonstrate that the role of silver salts in several C–H arylation
processes with iodoarenes is exclusively that of iodide capture.
Furthermore, we have identied that in these processes silver
salts can be conveniently replaced with a more redox stable and
inexpensive quaternary ammonium salt while maintaining the
high reactivity and broad substrate class scope displayed by the
previous Pd/Ag systems. To the best of our knowledge, this is
the rst example of a silver replacement of general applicability
to a wide range of C–H arylation processes.
Our initial efforts were directed at assessing the role of Ag
salts in a common C–H arylation methodology: the ortho-ary-
lation of benzoic acid 1a with iodoarene 2a (Table 1). Reaction
under standard, Ag salt-mediated, conditions led to formation
of biaryl product 3aa in 87% yield (entry 1).4ac Replacement of
AgOAc with KOAc led to a reduction in yield to 9%, roughly
consistent with two turnovers of the Pd catalyst (entry 2). A
qualitative colorimetric test suggested the presence of PdI2 in
the reaction mixture.10 Replacing Pd(OAc)2 with PdI2 led to no
reaction (entry 3). Finally, using PdI2 in combination with
AgOAc fully restored the high reactivity of the system (entry 4).
These results suggest that in these reactions Pd(OAc)2 is a
competent catalyst for the C–H arylation process, but is
poisoned by iodide aer two turnovers (Scheme 2). Thus, the
silver salt is required for regenerating catalytically active
Pd(OAc)2 from inactive PdI2 via the formation and precipitation
of the highly insoluble AgI salts, and not for the C–H arylation
itself.
Scheme 2 Poisoning and regeneration of Pd catalyst in C–H arylation.
the validity of this hypothesis we investigated the replacement
of AgOAc with a variety of acetate salts (Table 2). The addition of
NaOAc, CsOAc or Cu(OAc)2 proved to be ineffective for the
regeneration of the catalyst (entries 1–3).11 To our delight, a
survey of quaternary ammonium salts (entries 4–7) revealed
that tetramethylammonium acetate could be used to regenerate
the catalyst (entry 5), leading to the product in 45% yield (ca. 9
catalyst turnovers). Further, NMe4OAc could be formed in situ
by the equimolar combination of the more readily available and
inexpensive NMe4Cl and KOAc (entry 8). An experiment using
unreactive PdI2 demonstrated that, like AgOAc, NMe4OAc salts
are able to regenerate catalytically active Pd species in situ (entry
9). Increasing the equivalents of base and iodide abstractor gave
an improved yield (entries 10 and 11), with 2.05 equiv. of
NMe4Cl affording similar yields of product to those obtained
using AgOAc (compare entry 11 with entry 1 in Table 1).12
The effect of NMe4 salts on the catalytic activity is remark-
able, in particular when compared with the ineffective ammo-
nium salts bearing much larger (NBu4 and NEt4) or smaller
(NH4) cations. This may be due to a more favourable cation/
anion radii ratio, leading to a more effective crystal packing of
Having established that Ag salts are not intrinsically
required for the C–H arylation process, we hypothesised that a
more benign acetate salt could equally facilitate regeneration of
the Pd catalyst if the acetate counter-cation produced a highly
insoluble iodide salt within the reaction medium. To examine
Table 2 Selected optimization resultsa
Table 1 Mechanistic studies on the role of Ag salt additivesa
Entry
Pd cat.
Additive (equiv.)
3aab (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdI2
NaOAc (1)
Cu(OAc)2 (1)
CsOAc (1)
NH4OAc (1)
NMe4OAc (1)
NEt4OAc (1)
NBu4OAc (1)
NMe4Cl (1) + KOAc (1)
NMe4Cl (1) + KOAc (1)
NMe4Cl (1.25) + KOAc (1.25)
NMe4Cl (2.05) + KOAc (1.8)
9
9
10
4
45
9
12
44
42
62
85
Entry
Pd cat.
Additive (equiv.)
3aab (%)
1
2
3
4
Pd(OAc)2
Pd(OAc)2
PdI2
AgOAc (1)
KOAc (1)
KOAc (1)
AgOAc (1)
87
9
0
9
10
Pd(OAc)2
Pd(OAc)2
11c
PdI2
84
a
Unless otherwise noted, all reactions were carried out using 0.5 mmol
a
1
Reactions were carried out using 0.5 mmol of 1a and 3 equiv. of 2a. of 1a and 3 equiv. of 2a. b Yields were determined by H NMR analysis
b
c
Yields were determined by 1H NMR analysis using an internal using 1,3,5-trimethoxybenzene as an internal standard. Reaction run
standard.
for 48 h. NMe4Cl and KOAc added in two portions.
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the corresponding iodide salt.13 The solubility of NMe4I in
AcOH was determined to be lower than 0.3 mg mLÀ1, which
compares favourably to the higher solubilities of NH4I
(4.7 mg mLÀ1), NEt4I (6.5 mg mLÀ1) and NBu4I (647 mg mLÀ1).
Having found a suitable cheap and benign replacement for
Ag(I) salts, we explored the effects of substitution in both the
benzoic acid and the iodoarene coupling partners (Scheme 3).
Gratifyingly, both electron-poor and electron-rich iodoarenes
led to the corresponding biaryl products in yields similar to, or
higher than, those reported for the same AgOAc mediated
process (3ab–ae).4ac Varied substitution was also possible on the
benzoic acid coupling partner, with high yields observed for
ortho, meta and/or para substituted benzoic acids (3ba–ha).
We envisaged that formation of unreactive PdI2 may be a
common intermediate in the majority of Pd(II)-catalysed C–H
arylation reactions with iodoarene coupling partners. There-
fore, we explored the general applicability of NMe4OAc as an
organic analogue for Ag(I)-salts to a wide variety of C–H aryla-
tion reactions (Scheme 4). It is noteworthy that simply by
adjusting a few reaction parameters the system could be applied
to other classes of substrates. Using free amides instead of
carboxylic acids as the directing group, the NMe4-mediated
protocol furnished the biaryl products in good yield (3ia–jd).
Other common directing groups for C–H arylation, pyridine and
Scheme 4 Generality of the silver-free C–H arylation of arenes with
iodoarenes. All reactions were carried out on 0.5 mmol scale. Yields
are of the isolated pure material.
benzoquinoline, were also successfully used under silver-free
conditions (3kg–lg). We then explored the application of our
arylation protocol to other heteroarenes in the absence of a
directing group. Remarkably, this protocol also allowed the
arylation of N-methylindole and 2-chlorothiophene in good
yields (3ma–ng). These reactions proceeded with high C2 and
C5 regioselectivity, respectively (>95 : 5 by 1H NMR). Finally, the
C–H arylation of electron-poor arenes was also tested and, to
our delight, silver-free couplings with pentauorobenzene
could be successfully achieved (3oa–od).
To further highlight the applicability and signicance of the
new catalytic system, we then examined C(sp3)–H bond aryla-
tion reactions (Scheme 5). Importantly, functionalization at the
benzylic position of 8-methylquinoline proceeded well under
Scheme 3 Scope of the silver-free C–H arylation of benzoic acids
with iodoarenes. All reactions were carried out on 0.5 mmol scale.
Yields are of the isolated pure material.
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Scheme 6 Scale-up of the silver-free arylation reaction. See ESI† for
full details.
Scheme 5 Scope of the C(sp3)–C(sp2) coupling. All reactions were
carried out on 0.5 mmol scale. Yields are of the isolated pure material.
silver-free conditions for iodoarenes containing both electron-
donating and electron-withdrawing groups (3pa–pj).
The development of NMe4-promoted reactions offers major
economical and practical advantages over existing Ag-mediated
methods. Firstly, the method provides a new avenue to reduce
the cost of a number of chemical processes; NMe4Cl is ca. 50
times cheaper than AgOAc,14 and is produced in large scale
(>5000 tons per year). Secondly, the synthetic advancement is
also favourable from an environmental point of view; while
AgOAc and AgI are both classed as very toxic to the aquatic
environment, NMe4OAc and its by-product NMe4I15 are only
classed as irritants. Moreover, the tolerance of the system covers
a broad range of chemical motifs and the procedure is opera-
tionally trivial; the reaction proceeds smoothly under air with
no special precautions needed. Overall, the methodology greatly
increases the potential for C–H bond direct arylations to be
exploited in pharmaceutical and agrochemical industries,
where the value of a synthetic process is mainly assessed by the
viability in terms of cost and environmental impact.
In order to demonstrate the utility of the new silver-free
coupling for process chemistry, we scaled-up the reaction more
than 3000 times in a 5 L reactor. Further optimization of the
method allowed the arylation of 1.6 mol (218 g) of o-toluic acid
1c with 2 equiv. of iodobenzene (2b) and 2 mol % Pd(OAc)2
(Scheme 6). Aer an acid–base work-up, the reaction afforded
295 g of product 3cb in 87% yield with a 97% a/a purity by HPLC
suitable for most applications. The purity could be upgraded to
>99.9% if required by a simple re-slurry process in n-heptane.10
The analogous reaction using AgOAc would have required 267 g
of the silver salt, worth £840, and would have generated 376 g of
Scheme 7 Proposed general catalytic cycle.
Our study helps to dene the mechanism of previously
reported Ag-promoted systems.3,4 The comparable reactivity,
and required reaction times, observed between the NMe4-
mediated method and those using silver salts suggests that the
role of Ag(I) is purely that of a halophile in the catalyst regen-
eration step. Therefore, other functions attributed to Ag(I) such
as terminal oxidant, activator of iodoarenes or assistant in the
C–H activation step can most likely be ruled out for this type of
arylation processes. Based on these results, a proposed general
catalytic cycle for the reactions here reported is depicted in
Scheme 7. We postulate a Pd(II/IV) cycle where the C–H activa-
tion of the arene would take place rst to form an aryl Pd(II)
complex I. This intermediate may then undergo oxidative
addition to Pd(IV) species II which, aer reductive elimination,
would release the biaryl product and the catalyst in the form of
PdIOAc (III). This intermediate could undergo ligand exchange
with NMe4OAc to form Pd(OAc)2, disproportionate to PdI2 and
Pd(OAc)2 or could also initiate a second catalytic cycle which
would result in unreactive PdI2. Finally, PdI2 would react with
NMe4OAc, regenerating catalytically active Pd(OAc)2.
Conclusions
waste in the form of AgI.16 Excluding costs associated with waste In summary, we have described the discovery of an organic
streams, this new process represents savings of ca. 70%. We are analogue of silver(I)-salts, and develop reaction conditions
condent that our NMe4-promoted methodology could be that allow the Pd-catalysed C–H coupling reaction of a
readily carried out on multi-kilogram scale.
variety of classes of substrates: benzoic acids, benzamides,
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2-phenylpyridines, benzoquinolines, indoles, thiophenes, poly-
uorobenzenes and 8-methylquinolines with diverse
substituted iodoarenes under silver-free conditions. The new
method is easily scalable and benets from the use of inex-
pensive and readily available reactants, an operationally simple
procedure, high functional group tolerance and low-toxicity
waste. We believe that this discovery will provide a pathway for
facilitating application of numerous existing, and new, direct
C–H bond functionalizations to industry, in addition to opening
the door to other novel silver-free transition metal catalysed
processes.
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Acknowledgements
We gratefully acknowledge GlaxoSmithKline and the Engi-
neering and Physical Sciences Research Council for generous
support via ImpactQM KTA, the European Research Council for
a Starting Research Grant (to I.L.) and MINECO-Spain for a FPI
Fellowship (to J.G.D.). We thank Stephen Hermitage (GSK) for
helpful discussions.
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(d)
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M. M. S. Andappanb and N. Kommu, Green Chem., 2014,
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some organic solvents are also tolerated. For example,
running the reaction 1 M in dioxane, EtOAc or PhCl led to
64%, 53% and 46%, respectively. See Table S1 in the ESI†
for more details.
´
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103.
14 Based on Sigma-Aldrich catalogue prices (April 2014),
NMe4Cl costs £10.5 molÀ1 whereas AgOAc costs £526 molÀ1
15 NMe4I was isolated from the reaction mixture by ltration
and characterized, see ESI.†
10 See ESI† for details.
11 Recently, Yu and co-workers have identied a viable 16 In addition, work-up of reaction mixtures is more difficult
alternative for catalyst regeneration in iodination reactions
by the effective combination of a specic amide auxiliary
and CsOAc as iodide scavenger, see: (a) X.-C. Wang, Y. Hu,
S. Bonacorsi, Y. Hong, R. Burrell and J.-Q. Yu, J. Am. Chem.
Soc., 2013, 135, 10326, Earlier studies on halogenation of
C–H bonds showed that Pd(OAc)2 can be obtained from
when silver is present in the systemdue to its poor
ltration properties. Also, recycling of metal catalysts is
hampered by the presence of other metals in the waste,
˜
see: (a) E. Jimenez-Nunez and A. M. Echavarren, Chem.
Rev., 2008, 108, 3326; (b) H. Schmidbaur and A. Schier, Z.
Naturforsch., 2011, 66b, 329.
3514 | Chem. Sci., 2014, 5, 3509–3514
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