Dimethyl sulfoxide/potassium hydroxide: A superbase for the transition metal-free preparation of cross-coupling products

Article abstract of DOI:10.1002/adsc.201000575

Potassium hydroxide (KOH) in dimethyl sulfoxide (DMSO) forms a superbasic medium that allows one to access cross-coupling products from reactions between aryl halides with various sulfur-, oxygen- and nitrogen-based nucleophiles under transition metal-free conditions. Copyright

Full text of DOI:10.1002/adsc.201000575

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DOI: 10.1002/adsc.201000575
Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase for the
Transition Metal-Free Preparation of Cross-Coupling Products
Yu Yuan,a,* Isabelle Thomꢀ,b Seok Hwan Kim,b,c Duanteng Chen,a Astrid Beyer,b
Julien Bonnamour,b Erik Zuidema,b Sukbok Chang,c and Carsten Bolmb,*
a
College of Chemistry and Chemical Engineering, Yangzhou University, 225002 Yangzhou, Peopleꢁs Republic of China
Institut fꢂr Organische Chemie der RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
b
Fax : (+49)-241-809-2391; phone: (+49)-241-809-4675; e-mail: carsten.bolm@oc.rwth-aachen.de
Department of Chemistry and Molecular-Level Interface Research Center, Korea Advanced Institute of Science and
c
Technology (KAIST), Daejeon 305-701, Republic of Korea
Received: July 21, 2010; Revised: August 25, 2010; Published online: October 28, 2010
Abstract: Potassium hydroxide (KOH) in dimethyl
sulfoxide (DMSO) forms a superbasic medium that
allows one to access cross-coupling products from
reactions between aryl halides with various sulfur-,
oxygen- and nitrogen-based nucleophiles under
transition metal-free conditions.
tonations of the aryl halides followed by halide elimi-
nations.[11]
In many cases, strong bases such as metal amides or
metal tert-butoxides are used to facilitate the reac-
tions. We wondered if also the simple and inexpensive
mixture of KOH and DMSO would be a medium for
arylation reactions of S-, O-, and N-based nucleo-
philes. This combination of base and solvent has ex-
tensively been investigated by Trofimov.[12] His studies
of the physical organic properties and reactivity of
KOH/DMSO mixtures revealed an extraordinary ba-
sicity (pKa 30–32) that was suggested to result from a
synergism of two bases.[13] To describe the phenomen-
on, the term ꢃsuperbase mediaꢁ was introduced. In the
Keywords: arylation; catalysis; cross-coupling; di-
methyl sulfoxide/potassium hydroxide (DMSO/
KOH); superbase; transition metal-free conditions
Cross-coupling reactions belong to the most relevant light of the presented literature data we hypothesized
transformations in modern organic synthesis.[1] For N-, that this in situ formed superbase would be active
O-, and S-arylations numerous protocols have been enough to allow arylations of nucleophiles leading to
developed, and most commonly palladium complexes cross-coupling products under transition metal-free
and copper salts are utilized as catalysts.[2] To our sur- conditions. Here, we report our findings of this
prise, many other metal species such as salts, oxides study.[14]
and nanoparticles of indium,[3a,b] zinc,[3a] cadmium,[3c]
As a starting point, arylations of thiols using KOH
lanthanum,[3d] just to mention a few, have recently in DMSO were studied (Table 1).[15] To our delight,
been reported to be catalytically active as well.[4] reactions between thiophenol and electron-poor aryl
Looking at the reaction conditions and comparing de- halides were greatly facilitated leading to the corre-
tails indicated that two components played a critical sponding cross-coupling products in good to high
role in most of these prosesses: KOH and DMSO. yields (entries 1 and 2).[16,17] The reactions had to be
N-,[5] O-,[6] S-,[7] and C-arylations[8] are also known to performed at 1308C, because at lower temperature
occur without the support of a metal catalyst. For (1108C) the conversions remained incomplete. Also
electron-poor aryl fluorides, chlorides and bromides, less activated iodo- and bromobenzenes coupled well
the reactions proceed through the well-known SNAr providing diphenyl sulfide in 95 and 96% yield, re-
mechanism.[9] For these transformations, dipolar spectively (entries 3 and 4). Chlorobenzene, which
aprotic solvents such as DMF, NMP and DMSO are was expected to be more reactive in a substitution re-
the media of choice, especially when anionic nucleo- action proceeding by the SNAr mechanism, afforded
philes are arylated.[10] Less activated aryl halides that the product in only 60% yield (entry 5). This result as
do not readily undergo nucleophilic aromatic substitu- well as the formation of regioisomeric mixtures in re-
tion by the SNAr mechanism, can be used as arylating actions of the more electron-rich 2- and 4-substituted
agents of nucleophiles under strongly basic reaction tolyl and anisyl halides (entries 6–11) pointed to the
conditions. In this case, the reactions involve reactive involvement of aryne-type intermediates.
aryne intermediates that are formed by ortho-depro-
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Adv. Synth. Catal. 2010, 352, 2892 – 2898

Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase
Table 1. Intermolecular S-arylations.[a]
Table 2. Intermolecular O-arylations.[a]
Entry R
X
Time [h] Yield [%][b] Isomeric ratio[c,d]
Entry
R1
R2
Time
[h]
Yield
[%][b]
Isomeric
ratio[c]
1
4-NO2
I
I
I
6
24
6
55
98
95
96
60
95
98
92
90
88
56
70
2
3
2-NO2
H
1[d]
2[d,e]
3[d]
4
5
6
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-Me
H
H
4-OMe
4-OMe
4-NO2
H
24
24
24
24
24
72
48
82
81
52
85
27[f]
50
52
4
H
Br 24
Cl 24
5
H
6
7
8
9
4-Me
4-Me
2-Me
2-Me
I
24
Br 24
24
Br 24
p:m=51:49
p:m=51:49
p:m=52:48
p:m=52:48
p:m=50:50
p:m=51:49
m:p=46:54
o:m=49:51
I
7
2-Me
H
[a]
Reaction conditions: aryl halide (1.0 mmol), phenolic
substrate (0.5 mmol), KOH (1.0 mmol), DMSO (1 mL),
1358C, argon atmosphere.
After column chromatography.
p=para, m=meta, o=ortho.
Aryl halide (0.5 mmol) and phenolic substrate (1 mmol)
were used.
Cs2CO3 was used instead of KOH.
10
11
12
4-OMe I 24
4-OMe Br 24
3-OMe I 24
[b]
[c]
[d]
[a]
Reaction conditions: aryl halide (1.1 mmol), thiophenol
(1.0 mmol), KOH (2.0 mmol), DMSO (2 mL), 1308C,
argon atmosphere.
After column chromatography.
Determined using gas chromatography.
p=para, m=meta, o=ortho.
[b]
[c]
[d]
[e]
[f]
Together with 8% of 4-nitrothioanisole.
(entry 5) could be explained by an extensive decom-
For both ortho- and para-substituted electron-rich position of the product under the reaction conditions.
aryl halides, the isomeric ratio of the products was es- After 24 h, the desired diaryl ether was obtained in
sentially 1:1. Although for 3-methoxyiodobenzene the only 27% yield, along with 8% of 4-nitrothioani-
aryne mechanism would allow for the formation of sole.[19] When the reaction mixture was allowed to
three different isomers, only a single isomer of the react for additional 48 h, the thiomethyl-substituted
final product was obtained (entry 12), in line with pre- compound was the only product (51% yield).
vious studies involving this substrate.[11] The 3-me-
The reactions between phenol and the more elec-
thoxy group activated this substrate towards both the tron-rich 4-methyl- and 2-methylphenyl iodides re-
direct halide substitution by the SNAr mechanism and quired longer reaction times (entries 6 and 7). As ob-
the deprotonation of the substrate needed for the served in the S-arylations and indicative for an aryne
aryne formation. In the second case, deprotonation mechanism, approximately 1:1 mixtures of regioisom-
should occur on ortho- and para-positions to the me- ers were obtained with these aryl halides. Attempts to
thoxy group, which seems to be completely inhibited arylate benzylic and aliphatic alcohols with either
by the strong inductive and resonance effect of me- electron-rich or electron-poor aryl halides remained
thoxy group. In contrast, 4-methoxyiodobenzene, unsuccessful. Probably, the solvent/base system was
which has protons on the meta-position of the me- not basic enough to sufficiently deprotonate these nu-
thoxy group for the formation of aryne afforded two cleophiles under the applied conditions.[18b]
isomers.
Encouraged by these results, other C X bond-form- nucleophiles were investigated. For two reasons these
ing reactions were studied. Less acidic (pKa =18.0[18a]
were expected to be more challenging. Firstly, most
Next, reactions of commonly used nitrogen-based
À
)
and nucleophilic phenol could be arylated with 4-ni- substrates had higher pKa values in DMSO than the
troiodobenzene in KOH/DMSO providing the corre- thiols and phenols studied above,[18c] and consequent-
sponding diaryl ether in 82% yield (Table 2, entry 1). ly, their deprotonations were more difficult. If the
For this substrate combination, even the weaker base aryne formation was too facile compared to the
Cs2CO3 could be employed (entry 2). The more elec- generation of the anionic nucleophile, decomposition
tron-rich 4-methoxyphenol was coupled with KOH as of the aryl halide could occur. Secondly, in the case of
base (entries 3 and 4). In this case, the relative heterocyclic or anilinic substrates, the negative charge
amounts of the two substrates and the base proved to generated upon deprotonation was (partly) delocal-
be important. Probably, more base was needed to ized over the aromatic ring, leading to a significant
propagate the deprotonation of this less acidic sub- decrease of the anion nucleophilicity.
strate (pKa =19.1[18a]). The low yield in the reaction
Despite these uncertainties, 3-methylpyrazole (pKa
between 4-nitroiodobenzene and 4-nitrophenol ꢀ20[18c]) reacted with 4-nitroiodobenzene and iodo-
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Yu Yuan et al.
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Table 3. Intermolecular N-arylations.[a]
occur after the nucleophilic attack, altering the reac-
tion path for this substrate to a significant extend.
Because of the interest in metal-free routes towards
heterocyclic compounds for the production of phar-
maceutical and agrochemical compounds,[20] we ap-
plied the KOH/DMSO-based protocol to the forma-
tion of heterocycles through intramolecular N-aryla-
tion. To this end, compounds 1, 3 and 5 were synthe-
sized by transition metal-free procedures, and subse-
quently subjected to the mixture of KOH and DMSO.
Entry
R1
H-Nuc
Yield [%][b]
1
2
3
4
4-NO2
H
4-NO2
H
51
28
0
31
À
To our delight, the intramolecular C N couplings
proved highly efficient in all three cases, leading to
the formation of the corresponding 5- and 6-mem-
bered heterocycles 2, 4 and 6 in yields of 89, 82 and
94%, respectively (Scheme 1). In two cases the reac-
tion temperature could even be as low as 408C, with-
out affecting the overall yield. Note that for the cycli-
zation of compound 5 the presence of the N-methyl
substituent proved crucial. Hence, the analogous com-
pound containing a primary amino group did not cy-
clize. When the methyl group was replaced by an
acetyl moiety, the cyclization proceeded under loss of
the acetyl group affording a light-sensitive product,
which readily decomposed.
5
H
10
6
7
4-NO2
H
0
0
8
4-NO2
0
9
10
4-NO2
H
57
44
[a]
Reaction conditions: aryl halide (1.0 mmol), nucleophile
(0.5 mmol), KOH (1.0 mmol) in DMSO (1 mL), 1358C,
24 h.
[b]
After column chromatography.
Finally, intramolecular O-arylations were tested.
Using N-(2-iodophenyl)benzamide (7a) as starting
material, the corresponding benzoxazole 8 was isolat-
benzene providing the corresponding products in 57 ed in 96% yield after stirring for 24 h at 1408C in
and 28% yield, respectively (Table 3, entries 1 and 2). DMSO/KOH (Scheme 2). Almost the same yield
Surprisingly, indole was not arylated with 4-nitroiodo- (94%) was achieved when K2CO3 was used instead of
benzene (entry 3), despite being only slightly more KOH. Only 11% yield of 8 resulted from the cycliza-
basic (pKa =21.0[18c]) than 3-methylpyrazole. Probably tion of arylbromide 7b in DMSO/KOH.[21]
the deprotonation of indole occurred, but the result-
To our surprise, 4-methoxybenzamide 9 proved
ing anion was not nucleophilic enough. Consequently, much more reactive, and this bromo-substituted deriv-
4-nitroiodobenzene decomposed faster than it could ative led to the corresponding benzoxazole 10 in 96%
react with the indolate. Confirming this hypothesis, yield after only 12 h (in KOH/DMSO at 1408C). Di-
the more stable iodobenzene and the deprotonated minished yields were observed at lower temperatures.
indole reacted providing the expected product
(entry 4), albeit in low yield (31%). Probably because
of their high pKa values in DMSO (of 23.3 and
30.6,[18c] respectively) in combination with a reduced
nucleophilicity of the anionic intermediates due to
charge delocalization, use of benzylamide and 4-
methylaniline as N-nucleophile proved unproductive
(enties 5–7). 2-Oxazolidinone (pKa =20.8[18d]) decom-
posed under the reaction conditions (entry 8).
In light of these results we were initially surprised
to note that under the same reaction conditions pyr-
rolidine (with a pKa of 44 in DMSO[18e]) was arylated
by both electron-poor and electron-rich aryl halides
(entries 9 and 10). However, these results could be ex-
plained assuming that the highly localized and high-
energy lone pair of pyrrolidine allowed it to partici-
pate in the reaction without prior deprotonation, as
generally accepted for the nucleophilic aromatic sub-
stitution of electron-poor aryl halides with sp3-hybrid-
ized amines.[5b] Consequently, deprotonation might Scheme 1. Intramolecular N-arylations.
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Adv. Synth. Catal. 2010, 352, 2892 – 2898

Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase
data of all products corresponded to reported data or those
obtained for commercial samples of the products.
General Procedure for the Intermolecular O- and
N-Arylations
In a typical experiment, a sealable tube equipped with a
magnetic stir bar was charged with the aryl halide
(1.0 mmol), KOH (56 mg, 1.0 mmol) and, if a solid, the O-
or N-nucleophile (0.5 mmol). The aperture of the tube was
then covered with a rubber septum, and an argon atmos-
phere was established. Dry DMSO (1 mL) and other liquid
reaction components were then added by syringe. The
septum was replaced by a teflon-coated screw cap, and the
reaction vessel was placed in an oil bath at 1358C for the
stated reaction time. After pouring the mixture into water,
ethyl acetate was added and the two phases were separated.
The aqueous layer was extracted with ethyl acetate, and the
combined organic layers were dried over anhydrous MgSO4.
After removal of the solvent the residue was purified by
column chromatography to obtain the corresponding prod-
uct.
Scheme 2. Intramolecular O-arylations.
In conclusion, we have shown that a simple and in-
expensive mixture of KOH in DMSO can be used for
transition metal-free arylations of nucleophiles. The
in situ generated superbasic medium allows efficient
À
À
À
C S, C O, and to a lesser extent, C N bond forma-
tions. As was observed in other studies on nucleophil-
ic aromatic substitutions,[11] the product yield and re-
gioselectivity strongly depend on the basicity and nu-
cleophilicity of the nucleophile and the nature of the
aryl halide. Intramolecular reactions proved especially
efficient, allowing the transition metal-free formation
of heterocycles at close to ambient temperature.[22]
The spectral data of all products corresponded to reported
data or those obtained for commercial samples of the prod-
ucts.
Procedures for the Intramolecular N-Arylations
(Affording Previously Unknown Products)
1-Benzyl-3-phenyl-1H-benzoimidazole-2(3H)-one (2): 1-
Benzyl-1-(2-iodophenyl)-3-phenylurea
(1)[23]
(100 mg,
0.233 mmol) and KOH (26 mg, 0.47 mmol, 2.0 equiv.) were
placed in a sealable tube, and dry DMSO (1.5 mL) was
added under an argon atmosphere. The tube was sealed
with a teflon-coated screw cap, and the mixture was stirred
at 408C for 24 h. Then, the reaction mixture was cooled to
room temperature and water (2 mL) and ethyl acetate
(4 mL) were added. The two phases were separated and the
aqueous layer was extracted with ethyl acetate (3ꢅ3 mL).
The combined organic layers were dried over anhydrous
Na2SO4 and the solvent was removed under vacuum. The
product was purified by silica gel column chromatography
(pentane/ethyl acetate 10:1) to afford the product as a pale
yellow solid; yield: 62 mg (0.21 mmol, 89%); mp 99.8–
100.78C. 1H NMR (400 MHz, DMSO): d=7.58 (d, J=
4.2 Hz, 4H), 7.49–7.43 (m, 1H), 7.41 (d, J=7.1 Hz, 2H),
7.35 (t, J=7.4 Hz, 2H), 7.29–7.24 (m, 1H), 7.21 (d, J=
7.4 Hz, 1H), 7.12–7.06 (m, 1H), 7.04 (d, J=4.0 Hz, 2H),
5.14 (s, 2H); 13C NMR (100 MHz, DMSO): d=152.4, 136.5,
134.2, 129.2, 128.7, 128.6, 128.4, 127.4, 127.30, 127.25, 125.8,
121.7, 121.3, 108.5, 108.1, 43.8; IR (KBr): n=3054, 1701,
1593, 1484, 1397, 1223, 1172, 739, 697 cmÀ1; MS (EI): m/z
(%)=301 ([M+H]+, 21), 300 ([M]+, 100), 209 (5), 167 (10),
91 (57), 65 (5); elemental analysis calcd. for C20H16N2O: C
79.98, H 5.37, N 9.33; found: C 79.76, H 5.34, N 9.26.
Experimental Section
General Methods
1H NMR and 13C NMR spectra were recorded either on a
Bruker AVANCE 600, a Varian Mercury 300 or a Varian
Inova 400 spectrometer, in CDCl3 using TMS as an internal
standard. Infrared spectra were recorded on a Bruker
TENSOR 27 FT-IR spectrophotometer (KBr) or on a
Perkin–Elmer FT-IR Spectrum 100 (neat). HR-MS were re-
corded on a FinniganMAT 95 spectrometer (ESI). Elemen-
tal analyses were measured on an Elementar Vario EL in-
strument. GC was performed on an AGILENT 6890N GC
chromatograph.
General Procedure for S-Arylations
A typical experiment was carried out in a Schlenk tube
fitted with a condenser. The aryl halide (1.1 mmol) was
added to the mixture of KOH (112 mg, 2.0 mmol) and the
thiol (1.0 mmol) in freshly distilled DMSO (2 mL) under
argon. The mixture was stirred at 1308C, and the reaction
was monitored by GC and TLC. When the conversion was
complete, the reaction mixture was cooled to room tempera-
ture. After pouring the mixture into water, ethyl acetate was
added and the two phases were separated. The aqueous
layer was extracted with ethyl acetate. The combined organ-
ic layers were dried over anhydrous Na2SO4. After removal
of the solvent the residue was purified by column chroma-
tography to obtain the corresponding product. The spectral
10-Methyl-10H-phenoxazine (6):
equipped with a magnetic stir bar was charged with 2-(2-io-
dophenoxy)-N-methylaniline (5, 100 mg, 0.31 mmol,
A
sealable tube
1.0 equiv.) and KOH (35 mg, 0.62 mmol, 2.0 equiv.). The
aperture of the tube was then covered with a rubber
septum, and an argon atmosphere was established. Dry
DMSO (1 mL) was added by syringe. The septum was then
Adv. Synth. Catal. 2010, 352, 2892 – 2898
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Yu Yuan et al.
COMMUNICATIONS
replaced by a teflon-coated screw cap, and the reaction
vessel was placed in an oil bath at 408C for 24 h. The mix-
ture was cooled to room temperature and diluted with di-
chloromethane (10 mL). The resulting solution was directly
filtered through a pad of silica. Water (2 mL) and ethyl ace-
tate (4 mL) were added. Then the two phases were separat-
ed. The aqueous layer was extracted with ethyl acetate (3ꢅ
3 mL). The combined organic layers were dried over anhy-
drous MgSO4, and the solvent was removed under reduced
pressure to yield the N-arylated product, which was purified
by silica gel chromatography (pentane/ethyl acetate 10:1) to
afford the corresponding product as a pale orange liquid;
yield: 57 mg (0.29 mmol, 94%). 1H NMR (300 MHz,
DMSO): d=6.91–6.82 (m, 2H), 6.69 (d, J=6.4 Hz, 6H),
3.01 (s, 3H); 13C NMR (100 MHz, DMSO): d=145.1, 135.1,
124.6, 121.3, 115.3, 112.5, 31.1. IR (CHCl3): n=2918, 1489,
1360, 1269, 740 cmÀ1; HR-MS (ESI): m/z=197.0835, calcd.
for C13H11NO: 197.0839.
combined organic phases were washed using water (3ꢅ
100 mL) and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure, and the product was puri-
fied by flash chromatography on silica gel using a mixture of
pentane and diethylether as eluent to afford the correspond-
ing product as a pale yellow liquid; yield: 1.06 g (3.27 mmol,
35%). 1H NMR (400 MHz, CDCl3): d=8.30 (d, J=1.0 Hz,
1H), 7.66 (dd, J=10.8, 4.2 Hz, 1H), 7.58 (t, J=7.4 Hz, 1H),
7.29–7.20 (m, 4H), 7.12 (t, J=7.0 Hz, 1H), 4.31 (s, 1H), 2.90
(s, 3H); 13C NMR (100 MHz, CDCl3): d=156.6, 142.7, 141.4,
139.7, 129.7, 124.7, 116.9, 111.2, 87.5, 30.6; IR (neat): n=
3430, 2965, 2918, 2852, 1609, 1575, 1516, 1464, 1433, 1329,
1257, 1226, 1181, 1163, 1018, 744 cmÀ1; HR-MS (ESI): m/z=
326.0036, calcd. for C13H13INO: 326.0031.
Acknowledgements
This research was supported by the Fonds der Chemischen
Industrie and, in part, by the Cluster of Excellence funded by
the Excellence Initiative of the German federal and state gov-
ernments. We also acknowledge RWTH Aachen University
for financing a pre-doctoral Short Term Scientific Stay for S.
H. K. and thank Ms. S. Kohlhepp for valuable synthetic con-
tributions.
General Procedure for the Intramolecular O-
Arylations
As for the intermolecular O-arylations, but using 0.5 mmol
of the aryl halide and 56 mg (1.0 mmol) of KOH in DMSO
(1.0 mL) at 1408C. The spectral data of the products corre-
sponded to reported data.
Synthetic Procedures and Analytical Data for Other
Previously Unknown Products
References
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chloromethane was slowly added triflouromethanesulfonic
anhydride (0.49 mL, 0.83 g, 2.50 mmol, 1.1 equiv.) at 08C.
The ice bath was removed, and the reaction mixture was
stirred at room temperature for 45 min. Then, aniline
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and the solution was stirred for 17 h. Subsequently, an aque-
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dichloromethane (3ꢅ5 mL), and the combined organic
layers were dried over anhydrous Na2SO4. After removal of
the solvent under reduced pressure the product was purified
by column chromatography (pentane/ethyl acetate 9:1) to
give 3 as a white solid; yield: 490 mg (1.46 mmol, 54%); mp
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K. R. Rao, J. Org. Chem. 2009, 74, 7514 (Fe); g) V. K.
1
132.0–132.78C. H NMR (400 MHz, CDCl3): d=7.82 (d, J=
7.8 Hz, 1H), 7.57 (br.s, 2H), 7.36–7.24 (m, 4H), 7.06 (br. s,
2H), 6.74 (t, J=7.9 Hz, 1H), 1.92 (s, 3H); 13C NMR:
(75 MHz, CDCl3): d=153.6, 138.9, 128.9, 124.1, 123.2, 121.6,
120.8, 93.2, 19.1. IR (KBr): n=3020, 1545, 1216, 1015, 758,
718, 690 cmÀ1; MS (EI): m/z (%)=337 ([M+H]+, 3), 336
([M]+, 15), 335 (12), 244 (61), 209 (37), 203 (17), 118 (62),
77 (100), 65 (34); elemental analysis: calcd. for C14H13IN2: C
50.02, H 3.90, N 8.33; found: C 49.92, H 3.85, N 8.27.
2-(2-Iodophenoxy)-N-methylaniline (5): To a solution of
2-(2-iodophenoxy)aniline[25] (2.92 g, 9.35 mmol) in DMSO
(100 mL) iodomethane (1.33 g, 0.58 mL, 9.35 mmol) was
added. The reaction mixture was stirred at room tempera-
ture and, the conversion was monitored by TLC. After the
reaction was completed, the mixture was diluted with water
(150 mL) and extracted with ethyl acetate (3ꢅ150 mL). The
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Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase
Akkilagunta, V. P. Reddy, K. R. Rao, Synlett 2010, 1260
(Fe).
[9] J. March, Advanced Organic Chemistry, 3rd edn., Wiley-
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[14] Recently, cross-couplings with ppm quantities of metal
salts have been reported. For examples, see: a) S. L.
Buchwald, C. Bolm, Angew. Chem. 2009, 121, 5694;
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trace metals were not affecting the arylations reported
here, new glass-ware and plastic spatulas were used in
each reaction (N- and O-couplings). Furthermore, only
reagents with high purities (99+%) were applied and
metal reagents were avoided in synthetic steps wher-
ever possible. With respect to the S-arylations the fol-
lowing values for metal quantities were obtained by
atom absorption spectroscopy: For KOH 10 ppm of Pd,
<1 ppm of Cu, 2 ppm of Ni; for NaOH 5 ppm of Pd,
<1 ppm of Cu, 3 ppm of Ni; for KO-t-Bu 8 ppm of Pd,
<1 ppm of Cu, <1 ppm of Ni; for K2CO3 10 ppm of
Pd, <1 ppm of Cu, 3 ppm of Ni; for LiOH-H2O 8 ppm
of Pd, <1 ppm of Cu, 1 ppm of Ni. From all available
data we have no indication that such trace metal
amounts have an effect on the reported transforma-
tions under the given conditions.
[7] Selected examples of metal-free S-arylations: a) J. S.
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À
system for C S cross-couplings based on the use of
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[16] Also other bases than KOH were effective in promot-
ing the formation of diphenyl sulfide in DMSO under
these conditions. The following yields were obtained:
35% (NaOH), 85% (NaH), 90% (KO-t-Bu), 56%
(LiOH-H2O) and 25% (K2CO3).
[17] Rao reported the formation of diphenyl disulfide under
these conditions. a) This result was not confirmed by
our findings. We see our observations in line with those
reported by Adapa and co-workers who studied transi-
tion metal-free diaryl sulfide formations with CsOH-
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Yu Yuan et al.
COMMUNICATIONS
H2O in DMSO at 1208C starting from aryl halides and
thiols. b) Relevant for this discussion are also Adapaꢁs
arene selenenylations starting from aryl halides and di-
phenyl diselenide mediated by CsOH-H2O in DMSO
at 1108C (R. Varala, E. Ramu, S. R. Adapa, Bull.
Chem. Soc. Jpn. 2006, 79, 140). Interestingly, Rao and
co-workers reported a very similar system for the latter
reaction using CuO nanoparticles as catalysts (with
KOH as base in DMSO at 1108C).[4f].
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DMSO mixtures at elevated temperatures we detected
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[21] In a study of this reaction focusing on iron catalysis it
was found that with Cs2CO3 in DMF at 1358C the un-
catalyzed cyclization of 7b gave 8 in 42% yield. At
1208C only trace of 8 were found under those condi-
tions. J. Bonnamour, C. Bolm, Org. Lett. 2008, 10, 2667.
[22] It should be noted that this particular base/solvent
system has found extensive application in metal-cata-
lyzed cross-coupling processes.[3,4] In some of these
studies, DMSO/KOH was reported as being the only
successful solvent/base combination. The results pre-
sented here demonstrate that under those conditions
particular care should be taken and that possible
metal-free “background” reactions mediated by the su-
perbase KOH/DMSO should be considered.
[23] J. Clayden, H. Turner, M. Pickworth, T. Adler, Org.
À
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2898
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Adv. Synth. Catal. 2010, 352, 2892 – 2898