Ruthenium-catalyzed meta sulfonation of 2-phenylpyridines

Article abstract of DOI:10.1021/ja208286b

A selective catalytic meta sulfonation of 2-phenylpyridines was found to occur in the presence of (arene)ruthenium(II) complexes upon reaction with sulfonyl chlorides. The 2-pyridyl group facilitates the formation of a stable Ru-C_aryl σ bond that induces a strong para-directing effect. Electrophilic aromatic substitution proceeds with the sulfonyl chloride to furnish a sulfone at the position meta to the chelating group. This new catalytic process offers access to atypical regioselectivity for reactions involving chelation-assisted cyclometalation.

Full text of DOI:10.1021/ja208286b

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Ruthenium-Catalyzed Meta Sulfonation of 2-Phenylpyridines
Ourida Saidi, Jameel Marafie, Araminta E. W. Ledger, Po Man Liu, Mary F. Mahon, Gabriele Kociok-K€ohn,
Michael K. Whittlesey, and Christopher G. Frost*
Department of Chemistry, University of Bath, Bath BA2 7AY, U.K.
S Supporting Information
b
Scheme 1. Chelation-Assisted CÀH Activation
ABSTRACT: A selective catalytic meta sulfonation of
2-phenylpyridines was found to occur in the presence of
(arene)ruthenium(II) complexes upon reaction with sulfo-
nyl chlorides. The 2-pyridyl group facilitates the formation
of a stable RuÀCaryl σ bond that induces a strong para-
directing effect. Electrophilic aromatic substitution proceeds
with the sulfonyl chloride to furnish a sulfone at the position
meta to the chelating group. This new catalytic process
offers access to atypical regioselectivity for reactions involv-
ing chelation-assisted cyclometalation.
common approach for the functionalization of aromatic
substrates involves the chelation-assisted cleavage of a CÀH
A
bond to afford a metallacycle that facilitates subsequent ortho-
directed CÀC or CÀX bond-forming processes (Scheme 1a).1
These studies have disclosed a wide-range of directing groups
and different coupling partners for new ortho-functionalization
reactions within this mechanistic setting. Many successful stra-
tegies involve Pd-catalyzed ortho-coupling reactions with CÀH
bonds through cyclopalladation of 2-phenylpyridine (1).2 De-
spite the phenomenal progress in this area, selective catalytic
CÀH bond activation methods for CÀS bond formation remain
relatively undeveloped.3 One notable example is the catalytic
ortho-sulfonation protocol reported by Dong and co-workers.4
The use of Pd(CH3CN)2Cl2 as the catalyst in the presence of
K2CO3 allowed the isolation of the o-sulfone product in good
yield (Scheme 1b). From a synthetic perspective, the direct
introduction of functional groups to an aromatic ring to afford a
regioselectivity complementary to the established chelation-
assisted cleavage of a CÀH bond that gives ortho functionalization
continues to challenge contemporary catalytic methodology.5 In
this communication, we present a study indicating that changing
the precatalyst from Pd(II) to Ru(II) in the sulfonation of 1
switches the regioselectivity to afford the meta-sulfonation
products 3aÀi (Scheme 1c, Table 1, and Table 2). The remark-
able switch in regioselectivity implies a change in mechanistic
pathway and offers new design principles for reactions involving
chelation-assisted cyclometalation.
major product isolated from the reaction mixture in all cases was
the meta-sulfonation product 3a, the structure of which was
unequivocally confirmed by single-crystal X-ray diffraction
(Figure 1).7 In each case, the isolated yield reflected the conver-
sion of 1. As [Ru(p-cymene)Cl2]2 showed the highest level of
catalytic activity (Table 1, entries 1À6), attempts were made to
increase the isolated yield. After extensive screening, an im-
proved process was realized by simply switching the solvent to
CH3CN (Table 1, entries 6À11).8 Control experiments showed
that no coupling between 1 and 2a took place in the absence of
ruthenium (entries 12 and 13).
The recent significant achievements of selective catalytic
CÀH bond activations with Ru(II) species prompted us to
explore the catalytic chelation-assisted cyclometalation and sub-
sequent sulfonation of 1 with p-toluenesulfonyl chloride (2a) in
the presence of six different Ru precatalysts (Table 1).6 The
initial results were unexpected, as none of the ruthenium com-
plexes gave the ortho product upon spectroscopic analysis of the
crude reaction mixture. Although the conversions were low, the
To account for the switch in regioselectivity from Pd to Ru, we
hypothesized that the chelating group facilitates the formation of
a stable RuÀCaryl σ bond that induces a strong para-directing
effect.9 Substitution of the metalated aromatic ring proceeds with
Received: September 2, 2011
Published: November 02, 2011
r
2011 American Chemical Society
19298
dx.doi.org/10.1021/ja208286b J. Am. Chem. Soc. 2011, 133, 19298–19301
|

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Table 1. Optimization Studies for the Ruthenium-Catalyzed
Meta Sulfonation of 2-Phenylpyridine (1)a
Figure 1. Single-crystal X-ray structure of the novel meta product 3a.
Ellipsoids are represented at 30% probability.
entry
[Ru] complex
Ru(PPh3)3HCl
solvent
yield (%)b
1
2
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
EtOAc
25
7
Ru(dppf)(PPh3)HCl
Ru(xantphos)(PPh3)HCl
Ru(PPh3)3(CO)H2
Ru3CO12
Scheme 2. Catalytic Sulfonation via Chelation-Assisted σ
Activation
3
trace
8
4
5
0
6
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
À
27
24
28
5
7
8
THF
9
toluene
CH3CN
CH3CN
CH3CN
dioxane
10
11
12
13
62
80c
0
À
0
a Unless otherwise noted, the reaction conditions were as follows:
1 (1.0 mmol), 2a (3.0 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %),
K2CO3 (2 equiv), solvent (3 mL), 115 °C, 15 h. b Isolated yields,
with the mass balance being recovered starting material 1. c 5 mol %
[Ru(p-cymene)Cl2]2.
the sulfonyl chloride to furnish a sulfone at the meta position
relative to the original chelating group. To test this hypothesis,
the cyclometalated Ru complex 4 was prepared by the literature
protocol.10,6r Treatment of the isolated complex with 3 equiv of
2a under the standard reaction conditions (Scheme 2) afforded
quantitative conversion to 3a. Demetalation under the reaction
conditions would be necessary for catalyst turnover, and indeed,
when 1 was reacted with 3 equiv of 2a in the presence of a
catalytic amount of 4 (10 mol %), the meta-sulfonation product
3a was isolated in 65% yield, indicating the likely involvement
of RuÀCaryl σ-bond complexes in the catalytic cycle.11 Although
σ activation of aromatics has been studied for a range of
stoichiometric processes such as electrophilic halogenation,
acylation, and nitration, to the best of our knowledge, this is
the first example of a catalytic σ-activation process.12 Preliminary
experiments with isotopically labeled 2-phenylpyridine 1-[D5]
showed no evidence of D/H exchange from adventitious water
or solvent. Stopping the reaction after 10 h afforded the meta-
sulfonation product 3a-[D4] in 27% yield along with unreacted
1-[D5].13 A kinetic isotope effect (kH/kD = 3.0) was observed,
suggesting that CÀH bond cleavage is kinetically significant in
the catalytic cycle.
patterns was tolerated. The use of mesitylenesulfonyl chloride
afforded product 3e in lower yield, presumably because of the
increased steric demands of the two o-methyl substituents.
Notably, the reaction proceeded with substituents on the
aromatic ring (5a and 6a), the chelating pyridine ring (7a and
8a), or both rings (9a). Interestingly, the blocking of one of the
meta positions on the substrate resulted in no sulfone product
(10a) being obtained from the reaction. This substantiates a
We next explored the scope of the ruthenium-catalyzed meta
sulfonation (Table 2). Variation of the sulfonyl chloride
afforded a useful range of products in good isolated yields
(3bÀd and 3fÀi). A range of functionality and substitution
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dx.doi.org/10.1021/ja208286b |J. Am. Chem. Soc. 2011, 133, 19298–19301

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Table 2. Scope of Ruthenium-Catalyzed Meta Sulfonationa
Scheme 3. Palladium-Catalyzed Cross-Coupling
chelation-assisted σ activation and additional mechanistic studies
are in progress.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, characterization data for all new compounds, and crystal-
lographic data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
a The reaction conditions were as follows: 1 (1.0 mmol), arylsul-
fonyl chloride (3.0 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), K2CO3
(2 equiv), CH3CN (3 mL), 115 °C, 15 h. b Isolated yields, with
’ AUTHOR INFORMATION
c
the mass balance being recovered starting material 1. The X-ray
Corresponding Author
c.g.frost@bath.ac.uk
structure was obtained (see the Supporting Information for
details).
’ ACKNOWLEDGMENT
chelation-assisted σ-activation pathway, as the cyclometalation
presumably proceeds via the least hindered CÀH bond, result-
ing in a complex where the methyl substituent is para to the
activating RuÀCaryl σ bond. With this site blocked, no reaction
can take place.9b
We are grateful to the University of Bath, the EPSRC, and
GlaxoSmithKline for funding. We acknowledge the valuable
assistance of Dr. Matthew Jones (GCÀMS), Dr. Anneke Lubben
(mass spectrometry), and Dr. John Lowe (NMR).
The incorporation of a bromo substituent in the product
(3g) allowed for further synthetic modification utilizing Pd(0)-
catalyzed SuzukiÀMiyaura cross-coupling and BuchwaldÀ
Hartwig amination reactions (Scheme 3).14,15 The exemplar
reactions proceeded in good isolated yield, offering the cap-
ability to access a broader range of functional molecules in just
two steps.
In summary, we have a developed a ruthenium-catalyzed
sulfonation of 2-phenylpyridines that affords the meta prod-
uct. The remarkable switch in regioselectivity implies a
change in mechanistic pathway and offers new design prin-
ciples for reactions involving chelation-assisted cyclometala-
tion. Further work to establish the synthetic scope of catalytic
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