Sequential chelation-assisted aromatic C-H functionalisation via catalytic meta sulfonation

Article abstract of DOI:10.1055/s-0033-1340011

The sequential functionalisation of 2-phenylpyridine is presented using selective ortho- and meta-directing processes. It was found that performing a reaction sequence with meta functionalisation first followed by ortho functionalisation provided novel reaction products in good yields and with complete regioselectivity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340011

LETTER
▌2687
lSeteterquential Chelation-Assisted Aromatic C–H Functionalisation via Catalytic
meta Sulfonation
Sequential Chelation-Assisted Aromatic C–H Functionalisation
William R. Reynolds,a,b Po Man Liu,b Gabriele Kociok-Köhn,b Christopher G. Frost*a,b
a
Centre for Sustainable Chemical Technologies, University of Bath, Claverton Down, Bath, BA2 7AY, UK
b
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Fax +44(1225)386231; E-mail: c.g.frost@bath.ac.uk
Received: 30.08.2013; Accepted: 17.09.2013
TsCl
Abstract: The sequential functionalisation of 2-phenylpyridine is
[RuCl2(p-cymene)]2
presented using selective ortho- and meta-directing processes. It
was found that performing a reaction sequence with meta function-
alisation first followed by ortho functionalisation provided novel
reaction products in good yields and with complete regioselectivity.
K2CO3, MeCN
120 °C, 16 h
N
N
H
H
80%
Key words: catalysis, green chemistry, palladium, regioselectivity,
ruthenium
Ts
2
1
The catalytic functionalisation of C–H bonds is an impor-
tant synthetic transformation and has been a topic of much
interest in recent years.1 Moreover, the ability to function-
alise aromatic C–H bonds regioselectively provides a
powerful tool for the efficient synthesis of complex mo-
lecular structures. Chelation-assisted ortho functionalisa-
tion of arenes is well established in the literature and a
wide variety of substituents and catalyst systems have
been developed.2 More recently, examples of meta-selec-
tive catalytic C–H functionalisation have been reported
offering diversity in molecular design through alternative
reaction strategies. These include substrate-controlled
systems,3 chelation-assisted directing groups such as a
pseudo meta-directing carboxylic acid moiety4 and teth-
ered nitrile groups.5 We have reported a catalytic σ-acti-
vation protocol for C–H functionalisation that allows the
meta sulfonation of 2-phenylpyridines via cyclometallat-
ed ruthenium intermediates (Scheme 1).6 Recently,
Ackermann and coworkers have reported similar reactiv-
ity with secondary alkyl halides.7 In this communication
Ru–Caryl σ-bond
directs SEAr
N
Ru
Cl
H
Scheme 1 Catalytic meta-directed sulfonation
the sequential functionalisation of an aromatic core is ex-
plored using selective ortho- and meta-directing process-
es (Scheme 2). The catalytic σ-activation protocol
presented here provides a unique mechanism of operation
and meta selectivity that complements other sequential C–
H functionalisation procedures.8 Several novel, highly
substituted aromatic motifs are accessible in good yield
and complete regioselectivity in two efficient, catalytic re-
action steps.
First, several ortho substituents were installed on the phe-
nylpyridine backbone via established C–H activation pro-
tocols including OMe, OAc, and Br.9 The ortho-
ortho
N
N
meta
X
X
reaction
pathway 1
poor reactivity
and selectivity
N
SO2Ar
H
H
H
H
reaction
pathway 2
N
N
ortho
meta
X
single regioisomer
in good yield
SO2Ar
SO2Ar
Scheme 2 Comparison of two opposing reaction sequences
SYNLETT 2013, 24, 2687–2690
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340011; Art ID: ST-2013-D0836-L
© Georg Thieme Verlag Stuttgart · New York

2688
W. R. Reynolds et al.
LETTER
TsCl
[RuCl2(p-cymene)]2
K2CO3, MeCN
120 °C, 16 h
N
N
N
N
N
Refs 9a–c
X
+
+
X
X
X
X
N
Ts
Ts
1
3a = OMe
4a = OAc
5a = Br
3b (12%)
–
3d (37%)
–
–
4c (7%)
–
–
–
Scheme 3 Poor reactivity via ortho then meta functionalisation
substituted phenylpyridines were then subjected to the thetic processes for extending the sequential C–H func-
meta-sulfonation conditions using [RuCl2(p-cymene)]2 as tionalisation protocol.
the catalyst.10 Several products were obtained from these
reactions as shown in Scheme 3. For substrate 3a the ex-
pected regioselectivity was obtained with substitution at
Acknowledgment
We are grateful to the University of Bath, EPSRC DTC in Sustai-
nable Chemical Technologies for funding. We acknowledge the va-
luable assistance of Dr Anneke Lubben (Mass Spectrometry) and
Dr John Lowe (NMR Spectroscopy).
C8–C9 (3b) albeit in low yield, with the major product be-
ing dimer 3d. However, upon changing to an OAc substit-
uent 4a the opposite regioselectivity was obtained to give
C8–C11-substituted isomer 4c. This is likely due to a de-
crease in directing ability and an increase in steric bulk
making this the most favourable product. Increasing the
steric bulk even further and completely removing any sec-
ondary directing effects, as in 5a, prevented any reaction
from occurring, and only starting material was returned.
TsCl
[RuCl2(p-cymene)]2
(2.5 mol%)
K2CO3, MeCN
120 °C, 16 h
N
N
N
catalyst
'X'
X
In contrast to reaction pathway 1, pathway 2 proved to be
far more advantageous. Following an efficient catalytic
meta sulfonation of 2-phenylpyridine 2, a range of func-
tional groups were installed in the ortho position includ-
ing halogens, protected and unprotected alcohols, and a
sulfonamide (Scheme 4). Catalytic homocoupling to form
dimeric species 10 proceeded in good yield, including di-
brominated analogue 11. An important observation from
reaction pathway 2 is the complete regioselectivity it gave
for the C8–C11-substituted isomers.11
Ts
Ts
1
2
>100:1
selectivity
N
N
N
AcO
Br
Cl
Ts
Ts
Ts
4c (82%)a
6 (87%)c
7 (67%)c
As the ortho bromination product 6 was furnished in good
yield and holds the potential for further functionalisation,
the scope of that reaction was then explored with a range
of substituted sulfones.12 Scheme 5 shows the scope of
this two-step protocol. In general, electron-withdrawing
groups afforded the highest yields, with some weakly do-
nating groups being tolerated. Additional electron-donat-
ing functionality on the aromatic ring allowed the
selective synthesis of the tetrasubstituted benzene deriva-
tive 18 in good yield. The products from sequential C–H
functionalisation could be further elaborated as shown by
the Suzuki coupling of 6 with boronate 20 (Scheme 6).13
Ts
N
N
N
TsHN
HO
N
Ts
Ts
8 (43%)b
Ts
9 (10%)c
10 (81%)d
O
O
N
S
N
Br
Br
In conclusion a reaction protocol for sequential chelation-
assisted aromatic C–H functionalisation has been demon-
strated, via a catalytic meta-directed C–S bond formation
followed by an ortho-directed C–C or C–X bond-forming
process to give complete control over the reaction prod-
ucts, which were obtained in good yield and high regiose-
lectivity. Ongoing studies are focussed on expanding the
catalytic σ-activation protocol to a broader range of syn-
S
O
O
11 (63%)d
Scheme 4 Excellent selectivity via meta then ortho functionaliza-
a
tion. Reagents and conditions: Pd(OAc)2 (5 mol%), PhI(OAc)2,
Ac2O, in PhMe.9c PdCl2 (5 mol%), tert-butylhydroperoxide in
b
PhCl.9b c Cu(OAc)2 (1 equiv), halogen source in MeCN.9a d [RuCl2(p-
cymene)]2 (2.5 mol%), FeCl3 in PhCl.14 For full experimental details,
see Supporting Information.
Synlett 2013, 24, 2687–2690
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sequential Chelation-Assisted Aromatic C–H Functionalisation
2689
TMSO
O
B
O
MeS
20
MeS
N
N
Pd(PPh3)4 (1.0 mol%)
K2CO3, EtOH
Br
110 °C, 12 h
84%
Ts
Ts
21
6
Scheme 6 Product modification by Suzuki coupling
References
(1) Ackermann, L. Chem. Rev. 2011, 111, 1315.
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(10) meta-Sulfonation; General Procedure: To a nitrogen-
purged carousel tube was added [RuCl2(p-cymene)]2 (0.12
mmol, 0.060 g), phenylpyridine derivative (2 mmol),
sulfonyl chloride (6 mmol), potassium carbonate (4 mmol,
0.552 g), and acetonitrile (5 mL). The reaction was heated to
120 °C with stirring for 15 h before being cooled to r.t. The
reaction mixture was washed with brine, extracted with
dichloromethane, dried over MgSO4, and the solvent was
removed. The crude mixture was purified by flash column
chromatography.
Compound 3b: According to the general procedure, from
2-(2-methoxy)phenylpyridine (2 mmol, 0.372 g) and
p-toluenesulfonyl chloride (6 mmol, 1.144 g) in MeCN (5
mL), the title compound was obtained by flash column
chromatography eluting with CH2Cl2–2-propanol (1:0.01) to
give a white solid (12% yield); mp 160–163 °C. IR (neat): ν
= 2924.21, 1590.54, 1464.65, 1140.51, 1088.93, 989.91,
776.29, 685.44, 654.76 cm–1. 1H NMR (500 MHz, CDCl3): δ
= 8.68 (d, J = 4.7 Hz, 1 H), 8.17 (dd, J = 7.9, 1.8 Hz, 1 H),
7.93 (dd, J = 7.7, 1.7 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 2 H), 7.68
Scheme 5 Scope of sequential meta C–S and ortho C–Br bond for-
mation. Reaction conditions: sulfone (1 equiv), C2Cl4Br2 (2 equiv),
Cu(OAc)2 (1 equiv), MeCN, 130 °C, 24 h. Isolated yields.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2687–2690

2690
W. R. Reynolds et al.
LETTER
crude mixture was purified by column chromatography.
(d, J = 3.6 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.29 (d, J = 8.0
Hz, 2 H), 7.24 (q, J = 4.7 Hz, 1 H), 3.35 (s, 3 H), 2.39 (s, 3
H).13C NMR (75 MHz, CDCl3): δ = 156.3, 154.5, 150.0,
144.0, 138.9, 137.5, 136.5, 135.6, 135.0, 130.0, 129.4,
128.2, 124.4, 124.2, 122.7, 62.2, 21.7. HRMS calcd for
[M+H]+: 340.1008; found: 340.1090.
Compound 6: According to the general procedure, from
compound 2 (1 mmol, 0.31 g), the title compound was
obtained after purification by flash column chromatography
eluting with hexane–EtOAc–Et3N (4:1:0.01) to give a white
solid (87% yield); mp 198–200 °C. IR (neat): ν = 2925.64,
1592.48, 1478.05, 1402.41, 1311.17, 1296.68, 1151.63,
1107.45, 814.28, 692.52, 646.22 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.61 (d, J = 4.7 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1
H), 8.12 (d, J = 8.2 Hz, 1 H), 8.02 (t, J = 8.5 Hz, 1 H), 7.90
(d, J = 8.2 Hz, 2 H), 7.84 (dd, J = 8.7, 2.1 Hz, 1 H), 7.47–
7.40 (m, 1 H), 7.40–7.31 (m, 2 H), 7.15 (d, J = 8.7 Hz, 1 H),
2.46 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 164.2, 155.9,
145.6, 143.8, 139.4, 138.7, 131.4, 130.8, 130.0, 127.4,
126.5, 122.7, 119.7, 118.6, 21.6. HRMS calcd for [M+H]+:
389.9986; found: 390.0062.
Compound 18: According to the general procedure, from
compound 18a (1 mmol, 0.39 g), the title compound was
obtained after purification by flash column chromatography
eluting with hexane–EtOAc–Et3N (4:1:0.01) to give a white
solid (76% yield); mp 162–166 oC. IR (neat): ν = 3088.98,
2927.31, 1712.99, 1571.77, 1456.70, 1304.32, 1148.64,
1058.78, 1007.94, 892.75, 825.23, 751.21, 733.05 cm–1. 1H
NMR (250 MHz, CDCl3): δ = 8.74 (ddd, J = 4.9, 1.8, 0.9 Hz,
1 H), 8.36 (s, 1 H), 7.87–7.71 (m, 3 H), 7.69–7.54 (m, 4 H),
7.35 (ddd, J = 7.6, 4.9, 1.2 Hz, 1 H), 2.43 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 156.5, 149.6, 139.9, 139.8, 139.1,
138.0, 137.4, 136.3, 132.5, 132.3, 129.3, 128.7, 128.0,
124.8, 123.1, 19.8. HRMS calcd for [M+H]+: 467.9013;
found: 467.9096.
Compound 18a: According to the general procedure, from
2-(p-tolyl)pyridine (2 mmol, 0.341 ml) and 4-bromophenyl-
sulfonyl chloride (6 mmol, 1.533 g), the title compound was
obtained by flash column chromatography eluting with
hexane–EtOAc (4:1), followed by recrystallisation from
ethanol to give a white solid (46% yield); mp 196–198 °C.
IR (neat): ν = 2974.01, 1570.40, 1431.29, 1308.22, 1148.62,
1105.96, 1067.43, 1006.20, 808.79, 771.38, 742.25, 614.92
cm–1. 1H NMR (250 MHz, CDCl3): δ = 8.80 (d, J = 1.9 Hz,
1 H), 8.70 (d, J = 4.7 Hz, 1 H), 8.18 (dd, J = 7.9, 1.9 Hz, 1
H), 7.84 – 7.73 (m, 2 H), 7.74 (d, J = 8.7 Hz, 2 H), 7.61 (d, J
= 8.7 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.31 – 7.25 (m, 1
H), 2.45 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 155.3,
149.8, 140.3, 138.8, 138.5, 138.1, 137.2, 133.5, 132.4,
132.1, 129.3, 128.4, 127.8, 122.9, 120.6, 20.2. HRMS calcd
for [M+H]+: 389.9941; found: 389.9960
(11) (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
Tetrahedron 2006, 62, 11483. (b) Kakiuchi, F.; Kochi, T.;
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Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009, 131,
11310.
(12) ortho-Bromination; General Procedure: To a clean, dry
carousel tube, Cu(OAc)2 (1 mmol, 0.18 g) the required
substrate (1 mmol), C2Cl4Br2 (2 mmol, 0.65 g) and
acetonitrile (5 mL) were added in air. The reaction was
heated to 130 °C with stirring for 24 h before being cooled
to r.t. The reaction mixture was washed with sat. aq
NaHSO3, extracted with dichloromethane, filtered through
celite, dried over MgSO4, and the solvent was removed. The
(13) Allen, J. C.; Kociok-Kohn, G.; Frost, C. G. Org. Biomol.
Chem. 2012, 10, 32.
(14) Guo, X.; Deng, G.; Li, C.-J. Adv. Synth. Catal. 2009, 351,
2071.
Synlett 2013, 24, 2687–2690
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