Palladium-catalyzed desulfitative arylation of 3-haloquinolines with arylsulfinates

Article abstract of DOI:10.1016/j.tetlet.2013.01.018

3-Haloquinolines can be functionalized via a palladium-catalyzed desulfitative coupling of arylsulfinates. This method tolerates substitution upon the aromatic ring and shows good selectivity toward variously substituted aromatic rings. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.018

Tetrahedron Letters 54 (2013) 1471–1474
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Tetrahedron Letters
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Palladium-catalyzed desulfitative arylation of 3-haloquinolines with
arylsulfinates
⇑
Julie Colomb, Thierry Billard
University of Lyon, University Lyon 1, CNRS, Institute of Chemistry and Biochemistry (ICBMS—UMR CNRS 5246), 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France
CERMEP—Imagerie du vivant, Groupement Hospitalier Est, 59 Bd Pinel, F-69677 Lyon, France
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Haloquinolines can be functionalized via a palladium-catalyzed desulfitative coupling of arylsulfinates.
This method tolerates substitution upon the aromatic ring and shows good selectivity toward variously
substituted aromatic rings.
Received 21 November 2012
Revised 28 December 2012
Accepted 8 January 2013
Available online 16 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Palladium
Arylsulfinates
Desulfitative coupling
Quinoline
Throughout our investigations into the design of serotonin ligands,
arylation of the 3 position of 8-chloro-quinolines was a necessary
step. Palladium-catalyzed Suzuki reactions using arylboron reagents
could provide an efficient route to such functionalization.1–3
However, during the past few years, alternatives to transition-
metal-catalyzed cross-coupling, without the use of organometallic
reagents, have also been investigated. Decarboxylative cross-
couplings of aryl carboxylic acids have emerged as an interesting
strategy.4,5 Nevertheless, a high reaction temperature or micro-
wave heating is required for the decarboxylation step. More
recently, desulfitative coupling reactions have been described in
C–H activation6–9 or Heck reaction10–12 allowing the construction
of C–C bonds under relatively mild conditions.
Such a coupling with halo-aromatic substrates has been de-
scribed to a lesser extent. To our knowledge, since the pioneering
works of Garbes,13 only the work of Sato and Okoshi has so far re-
ported an efficient palladium-catalyzed desulfitative synthesis of
biaryls with sodium arylsulfinates and aromatic bromides.14 In this
patent, 3-bromo-pyridine is the only described heterocyclic sub-
strate. To our knowledge, no quinolines have been implied in such
reactions. Very recently, similar reactions starting from aryltri-
flates have been reported, once again, lacking heteroaromatic
examples.15 On the other hand, Cacchi et al. have described the pal-
ladium mediated reaction of 2-triflyl-quinoline with p-toluenesulf-
inate mediated by palladium, however, a sulfonylation reaction
(without SO2 extrusion) was observed.16
Consequently, we focused our interest on the desulfitative ary-
lation of 3-iodo-quinolines with arylsulfinates. This desulfitative
cross-coupling reaction was, initially, studied on 8-chloro-3-iodo-
quinolines (1a) with sodium phenylsulfinate as a model reaction
to screen several experimental parameters (Table 1).
Firstly, the presence of an ammonium salt appears to be crucial
(entries 1 and 2) because of the low solubility of sulfinate which
must be transferred into the organic phase. Concerning the phos-
phine ligand, apart from XantPhos (entry 1), all other tested phos-
phines furnish similar or better results with toluene as the reaction
solvent. Furthermore, this allows recycling of starting material 1
(entries 3–9). From this screening, DavePhos appears to be the best
ligand within the scope of the reaction. An increase in temperature
induces the C–C coupling (entries 11–14), with an optimal temper-
ature of 150 °C (entry 12). This effect can be explained by favoring
a better extrusion of gaseous SO2. When the reaction is carried out
in toluene, the nature of base used appears to have little influence
on the reaction outcome (entries 1, 3, and 4) however, in NMP,
K2CO3 furnishes a markedly improved yield and selectivity for
C–C coupling over Cs2CO3 (entries 10 and 11). Such observations
are difficult to explain but could be connected to the low dissocia-
tion of bases in toluene and of K2CO3 in NMP compared to the high
dissociation of Cs2CO3 in NMP. This increased dissociation should
modify the basicity and nucleophilicity of intermediate species
and consequently have an impact onto the mechanism. Finally,
an assay to reduce the loadings of palladium catalyst has been
⇑
Corresponding author. Tel.: +33 472 448 129.
E-mail address: Thierry.billard@univ-lyon1.fr (T. Billard).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.018

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J. Colomb, T. Billard / Tetrahedron Letters 54 (2013) 1471–1474
Table 1
Arylation of 3-iodo-8-chloro-quinoline (1) with sodium phenylsulfinate
No
Phosphine
Base
Solvent
T (°C)
1 (%)
2 (%)
3 (%)
1
XantPhos
XantPhos
XantPhos
XantPhos
XPhos
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
—
Cs2CO3
K2CO3
K2CO3
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
NMP
110
110
110
110
110
110
110
110
110
150
150
130
150
150
0
0a
0
31
<5a
28
28
38
35
34
41
47
30
81
71
83
70
12
0a
11
9
7
16
5
10
10
30
10
6
2a
3
4
5
6
7
8
9
10
11
12
13
14
0
55
15
41
49
12
0
0
10
0
DPPF
BINAP
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
DavePhos
NMP
NMP
NMP
Mesitylene
10
15
Cs2CO3
6
a
Without Bu4NCl.
Table 2
Desulfitative arylation of 3-iodo-quinolinesa,17
Entry
1
2
Yieldb (%)
81
1
2
3
71
60
4
61
5
6
84
63
7
8
91
89

J. Colomb, T. Billard / Tetrahedron Letters 54 (2013) 1471–1474
1473
Table 2 (continued)
Entry
1
2
Yieldb (%)
9
Complex mixture
10
0c
a
Reaction conditions: 1 (1 equiv), PhSO2Na (1.5 equiv), Pd2dba3 2.5 mol %, DavePhos 5 mol %, K2CO3 (1.5 equiv), nBu4NCl (1.2 equiv), 150 °C, overnight.
Isolated yields.
Formation of reduction product: 8-methoxy-quinoline.
b
c
Table 3
palladium mediated coupling would be Pd2(dba)3 (2.5 mol %),
DavePhos (5 mol %), NMP (0.5 M), K2CO3 (1.5 equiv), nBu4NCl
(1.2 equiv), 150 °C.
Desulfitative arylation of nitrogen heteroaromaticsa
Entry
HetAr-X
Product
Yieldb (%)
These optimized reactions have been applied to a range of 3-
iodo-quinolines (Table 2).
The developed coupling reaction gives good yields whatever the
position of substituent on the aromatic ring of quinoline (entries
1–8). The nature of the substituent appears to give a more signifi-
cant effect, since high electron-withdrawing group (NO2) and
mesomer-donating group (OMe) prevent the reaction from occur-
ring (entries 9 and 10). In the case of 8-methoxy-3-iodo-quinoline
(1j), only the formation of product of reduction (8-methoxy-quin-
oline) is observed. It is also worth noting that the reaction is highly
chemoselective between chloride and iodide as a leaving group
(entries 1–4).
1
40
X = I: 51
X = Br: 41
X = Cl: 23
2
3
4
50
64
With the aim of extending the scope of this reaction, several
other nitrogen containing heterocycles have been investigated
(Table 3).
a
In general, the reaction provides satisfactory yields. In the case of
3-halopyridines 5 (entry 2) the yield is decreasing from iodide to
chloride substituted starting materials, as could be expected from
other reported palladium mediated couplings. If the bromides still
give satisfactory results, lower yields are obtained with the chlo-
rides. With bromo substituted pyridine 5d, only the sulfonylation
product 9 is obtained. Appearance of this product could be explained
via a competitive SNAr reaction (favored by the presence of a CN
group in para position). This hypothesis was confirmed by the for-
mation of the same sulfone 9 without the use of palladium.
Other arylsulfinates can also be engaged within these reaction
conditions (Table 4, entries 1 and 2) however, no reaction was ob-
served when alkylsulfinates, such as methanesulfinate, were em-
ployed (entry 3).
Reaction conditions: HetAr-X (1 equiv), PhSO2Na (1.5 equiv), Pd2dba3 2.5 mol %,
DavePhos 5 mol %, K2CO3 (1.5 equiv), nBu4NCl (1.2 equiv), 150 °C, overnight.
Table 4
Desulfitative coupling of 1a with various arylsulfinatesa
Entry
1
Sulfinates
Product
Yieldb (%)
53
2
In conclusion, we have demonstrated a novel C–C coupling reac-
tion between arylsulfinates and 3-haloquinolines via a desulfitative
reaction with satisfactory to good yields in all cases. This protocol
provides an extension to heteroaromatic substrates of previous13,14
and very recent works15 and should contribute to the evolution of
desulfitative couplings as true synthetic alternatives to traditional
couplings of preformed organometallic reagents.
40
0
3
—
a
Reaction conditions: 1a (1 equiv), RSO2Na (1.5 equiv), Pd2dba3 2.5 mol %,
DavePhos 5 mol %, K2CO3 (1.5 equiv), nBu4NCl (1.2 equiv), 150 °C, overnight.
b
Acknowledgment
Isolated yields.
This work was supported by a ‘Région Rhône-Alpes’ grant.
François Liger is thanked for fruitful discussions.
performed (Pd 1%, phosphine 2%) however, the conversion was,
then, dramatically decreased.
References and notes
From an experimental point of view, purification of the crude
mixture was greatly aided when K2CO3 was added, even if this
one seems to be not necessary for the reaction (entries 11 and
13). Consequently, the optimal conditions for this desulfitative
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17. Synthesis of 8-chloro-3-phenylquinoline 2: A dry sealed tube was purged 3 times
with nitrogen and charged with NMP (2 mL), Pd2dba3 (23 mg, 2.5 mol %), and
DavePhos (20 mg, 5 mol %). Under nitrogen atmosphere was added 8-chloro-3-
iodoquinoline (289.5 mg, 1 mmol), sodium benzenesulfinate (246 mg,
1.5 mmol), K2CO3 (207 mg, 1.5 mmol), and nBu4NCl (334 mg, 1.2 mmol) and
the mixture was heated to 150 °C for 15 h. After cooling to room temperature,
diethyl ether was added and the organic layer was washed with brine 3 times
to remove NMP and dried over MgSO4. The solvents were removed under
vacuum and the residue was purified by column chromatography
(cyclohexane/ethyl acetate, 9:1). yellow oil; 1H NMR (400 MHz, CDCl3):
d = 9.26 (d, 4 J = 2.3 Hz, 1H), 8.24 (d, 4 J = 2.3 Hz, 1H), 7.78–7.72 (m, 2H), 7.66
(m, 2H), 7.49 (m, 2H), 7.45–7.41 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 150.8,
143.8, 137.5, 135.0, 133.9, 133.7, 129.8, 129.7, 128.9, 127.8, 127.6, 127.4; MS
(EI) m/z (%) 239 (100, M+); elemental Anal. Calcd (%) for C15H10ClN: C, 75.16; H,
4.21; N, 5.84. Found: C, 75.29; H, 4.27; N, 5.95.
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