Facile preparation of aryl sulfides catalyzed by PEG400 and nickel without solvent

Article abstract of DOI:10.1080/00397910801914111

A variety of aryl sulfides were synthesized by aryl bromides with thiols, with PEG400 and nickel as catalysts under basic conditions in the absence of solvents. This article reported an easy and convenient method for formation of aryl-sulfur bonds. Copyright Taylor & Francis Group, LLC.

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Facile Preparation of Aryl Sulfides Catalyzed
by PEG400 and Nickel without Solvent
Yu‐Qing Cao a , Zhan Zhang a , Yan‐Xin Guo a & Guo‐Qiang Wu a
a College of Pharmacy, Hebei University, Baoding, China
Published online: 25 Apr 2008.
To cite this article: YuQing Cao , Zhan Zhang , YanXin Guo & GuoQiang Wu (2008) Facile Preparation of Aryl
Sulfides Catalyzed by PEG400 and Nickel without Solvent, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:9, 1325-1332, DOI: 10.1080/00397910801914111
To link to this article: http://dx.doi.org/10.1080/00397910801914111
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Synthetic Communicationsw, 38: 1325–1332, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801914111
Facile Preparation of Aryl Sulfides
Catalyzed by PEG400 and Nickel without
Solvent
Yu-Qing Cao, Zhan Zhang, Yan-Xin Guo, and Guo-Qiang Wu
College of Pharmacy, Hebei University, Baoding, China
Abstract: A variety of aryl sulfides were synthesized by aryl bromides with thiols,
with PEG400 and nickel as catalysts under basic conditions in the absence of
solvents. This article reported an easy and convenient method for formation of
aryl-sulfur bonds.
Keywords: Aryl bromides, aryl sulfides, nickel bromide, PEG400, solventless, zinc
INTRODUCTION
Aryl sulfides have been widely used as intermediates in synthetic chemistry
and as products in the pharmaceutical industry,[1,2] which have attracted
continued interest. Many methods have been developed profitably for
their synthesis. One traditional method for the preparation of aryl sulfides
was reduction of aryl sulfones or aryl sulfoxides,[3] which usually
required strong reducing agents, costly catalysts such as neocuproine,[4]
Pd(PPh3)4,[5] DiPPF,[6] and [Bmim]PF6.[7] The Sandmeyer reaction was
another method for the preparation of aryl sulfides by diazonium salts of
aromatic amino with thiols;[8] however, the troublesome procedures and
undesirable yields have been found. Recently, metal-catalyzed preparation
of aryl sulfides by the thiols with aryl halides, using a copper or
Received November 1, 2007
Address correspondence to Yu-Qing Cao, College of Pharmacy, Hebei University,
Baoding 071002, China. E-mail: pharm_hbu@yahoo.com
1325

1326
Y.-Q. Cao et al.
Scheme 1.
palladium catalyst under basic conditions, had been reported.[9,10] Tra-
ditional copper-mediated reactions suffered from drawbacks such as high
reaction temperatures, the use of copper salts in greater than stoichiometric
amounts, sensitivity to functional groups on the aryl halides, and
irreproducibility.[11]
The reaction of thiols with alkyl halides was a common method for the
preparation of aryl sulfides. The advantages of this reaction were mild con-
ditions and higher yields. Most of reactions were carried out in organic
solvents. Developing green chemical reactions is one of the most important
purposes of organic synthesis at present. Organic synthesis in the absence
of solvent was of greatly applied value and expansive prospects.[12,13] In
this regard, PEG400 had been used as phase-transfer catalyst (PTC) and
applied readily available reagents, which could be easily put into industrial
production.
Polyethylene glycols (PEGs) could be regarded as the acyclic crown-ether
and have been widely used as PTCs in many organic reactions because of their
stability, low cost, low toxicity, and easy availability.[14,15] It had been proved
that PEG incorporating seven to nine units was more effective in catalyzing
the reactions in which Naþ salts participated. In particular, because of the
liquid property, perfect solubility in water, and the participation of two
hydroxy groups during the destructing crystal lattice of the solids, PEG400
was more suitable for liquid–liquid or solid–liquid phase solvent-free
organic reactions. The sulfur anions could easily enter the liquid phase and
become a strong nucleophilic reagent that could promptly undergo nucleophi-
lic substitution.
In continuation of our research on the use of PEGs as PTCs in organic
synthesis without solvent,[16–18] we herein report a facile method for the prep-
aration of aryl sulfides by the reaction of aryl bromides with thiols catalyzed
by PEG400, nickel bromide, and zinc under basic conditions in the absence of
solvents. The reactions are shown in Schemes 1 and 2. The experimental
results are listed in Tables 1 and 2.
Scheme 2.

Facile Preparation of Aryl Sulfides
1327
Table 1. Reactions of aryl bromides with thiophenol
Entry
Aryl bromides
Product
Time (h)
12
Yield (%)
82
1
2
3
10
10
85
86
4
5
8
9
87
85
6
12
11
82
79
7a
8
9
8
90
84
10
10
14
46
aIt may be reacted with double thiols to form p-bis(phenylthio)benzene.
RESULTS AND DISCUSSION
Taking the reaction of phenyl bromide and thiophenol as an example, a yield
as low as 57% was obtained after the reaction was performed over 12 h
without the presence of PEG400. However, when 4% mol PEG400 was
added, the reaction time was greatly shortened and the yield was 90%. The
amount of 4% mol of PEG400 was adequate to catalyze the reaction effec-
tively. The more PEG400 employed, the more products would be lost
during the course of washing with water.

1328
Table 2. Reactions of aryl bromides with readily available alkyl thiols
Time Yield
Y.-Q. Cao et al.
Entry
Aryl bromides
Alkyl thiols
Product
(h)
(%)
1
HSC2H4OH
12
80
2
3
4
HSC2H4OH
HSC2H4OH
HSC2H4OH
10
10
8
82
81
85
5
HSC2H4OH
10
74
6a
HSC2H4OH
HSC2H4OH
10
8
77
89
7
8
HSC2H4OH
12
68
aIt may be reacted with double thiols to form p-bis(phenylthio)benzene.
Because the reaction should proceed under basic conditions, we
compared different kinds of bases, such as anhydrous K2CO3, NaOH, Et3N,
and CaO. Our initial choice of base was anhydrous K2CO3 because K2CO3
was found to be an effective base for this coupling reaction, but 2 equiv
were needed; the use of other bases such as CaO or Et3N gave somewhat
lower yields. NaOH can also give excellent yields, and the amount was
reduced to 1.2 equiv. NaOH is a more suitable base.
To shorten the reaction time, the reactions of thiophenol and aryl
bromides were heated at 110–120 8C. As shown as in Table 1, longer
reaction periods were needed in the reactions of 4-acetamide bromobenzene

Facile Preparation of Aryl Sulfides
1329
(entry 6) because of p–p conjugation of the carbonyl group with the benzene
ring and the steric effect of the benzene ring. It is the same reason that the
coupling of aryl bromides with electron-donating groups such as -CH3 and -
OCH3 in the aromatic ring and thiophenol could be carried out in a relatively
shorter time than with electron-withdrawing groups such as -Br and-NO2. In
particular, for entry 10, the yield was very low because -NO2 is a strong
electron-withdrawing group; another reason is that the reduction of the nitro
group with thiol will take place competitively.
Based on the results listed in Table 2, the coupling of aryl bromides with
some readily available alkanethiols could take place in these reaction con-
ditions. Moreover, 1,3,5-trimethyl-bromobenzene could be carried out in
excellent yield (entry 7 in Table 2).
This catalytic process requires a nickel salt and zinc, and it is clear that
neither NiBr2 nor zinc itself had the ability to insert into Ar-Br.[19] In
contrast, Ni(0) can insert into these bonds. The facts show that in the thiolation
of aryl bromide, at the first step, an Ni(0) species is formed by the reduction by
zinc. At the next step, this Ni(0) species inserts into Ar–Br bonds, and Ar–
Ni(II)–Br is produced. It is worth noting that Ar–Ni(II)–Br alone cannot
transform Ar–Br to ArSR. Actually, Ar–Ni(II)–Br is unavailable for the
synthesis of ArSR. However, the zinc was added as the reductive reagent.
Given these results, it is presumed that ArNi(I) is an activating species for
the thiolation. Hence, it is anticipated that the nickel-catalyzed thiolation of
aryl bromide is accelerated by ArNi(I). From these results, the reaction
mechanism is considered as follows (Scheme 3).
In summary, we have developed a convenient and efficient method for
preparing aryl sulfides by the reaction of aryl bromides with thiols
catalyzed by PEG400, nickel bromide, and zinc without solvent, which
offered carbon–sulfur bond formation for both aromatic and alkanethiols
under mild conditions. The advantages of this procedure are higher yield,
operational simplicity, low cost, and less pollution to environment. We
assume that the method is suitable to be put into industrial application.
Scheme 3.

1330
Y.-Q. Cao et al.
EXPERIMENTAL
Thin layer chromatography (TLC) was GF254 with petroleum ether/ethyl
acetate (10/1) as eluent. Aryl bromides, thiophenols, alkyl thiols, and
PEG400 were commercially available and used without further purification.
1H NMR spectra were obtained on a Brucker Avance (400-MHz) spectrometer
using TMS as internal standard and CDCl3 as solvent. IR spectra were
recorded on a Bio-Rad FTS-40 spectrometer (KBr).
Typical Procedure for the Preparation of 4-Methoxyphenyl Phenyl
Sulfide (Entry 4, Table 1)
Thiophenol (11 ml, 0.1 mol) was added to a mixture of nickel bromide (2.2 g,
0.01 mol), zinc (1 g, 0.015 mol), NaOH (4.8 g, 0.12 mol), and PEG400 (1.6 g,
0.004 mol), and the mixture was stirred in a 50-mL three-necked, round-
bottomed flask equipped with a magnetic stirrer for 1 h at 80 8C. Then
4-methoxy bromobenzene (13 ml, 0.1 mol) was added, and the mixture was
vigorously stirred at 120 8C. The progress of the reaction was monitored by
TLC. Upon completion, the reaction mixture was washed three times with
50 ml of water. The organic phase was separated and dried over magnesium
1
sulfate. Then 18 g of the title compound as a colorless oil was collected. H
NMR (CDCl3): d: 3.82 (s, 3H, CH3), 6.90 (d, J ¼ 8.8 Hz, 2H), 7.1–7.3
(m, 5H, ArH), 7.42 (d, J ¼ 8.8 Hz, 2H); IR (KBr, cm21) v: 3058, 3004,
2941, 2834, 1592, 1492, 1287, 1243, 1171.
Typical Procedure for the Preparation of Phenyl Alkyl Thioether
(Entry 1, Table 2)
2-Mercapto-ethanol (7.1 ml, 0.1 mol), was added to a mixture of nickel
bromide (2.2 g, 0.01 mol), zinc (1 g,0.015 mol), NaOH (4.8 g, 0.12 mol),
and PEG400 (1.6 g, 0.004 mol), and the mixture was stirred in a 50-mL
three-necked, round-bottomed flask equipped with a mechanical stirrer for
1 h at 80 8C. Then bromobenzene (10.47 ml, 0.1 mol) was added, and the
mixture was vigorously stirred at 120 8C. The progress of the reaction was
monitored by TLC. Upon completion, the reaction mixture was washed
three times with 50 ml of water. The organic phase was separated and dried
over anhydrous magnesium sulfate. Then 12 g of phenyl alky thioether was
1
collected. H NMR (CDCl3) d 2.52 (s, H, OH), 3.08 (d, 2H, CH2), 3.70
(d, 2H CH2), 7.1–7.5 (m, 5H, ArH); IR (KBr, cm21) v: 3076, 3059, 3020,
3005, 2955, 2877, 1640, 1574, 1425, 1385, 1333, 1225, 1168, 1157, 1088,
935, 836, 821, 616.

Facile Preparation of Aryl Sulfides
1331
Other Results
1
Compound 1 (Table 1). H NMR (CDCl3): d: 7.0–7.2 (m, 10H, ArH); IR
(KBr, cm21) n: 3146, 3073, 3059, 3020, 3004, 1949, 1879, 1800, 1734,
1500, 1384, 1327, 1302, 1270, 1169, 1157, 1068, 1000, 955, 916, 908, 901,
838, 616, 457.
Compound 2 (Table 1). 1H NMR (CDCl3): d: 2.35 (s 3H, CH3), 6.86
(d, J ¼ 8.8 Hz, 2H), 7.08 (d, J ¼ 8.8 Hz, 2H), 7.06–7.20 (m, 5H, ArH).
1
Compound 6 (Table 1). H NMR (CDCl3): d: 2.02 (s 3H, CH3), 7.0–7.20
(m, 5H, ArH), 7.18 (d, J ¼ 8.8 Hz, 2H), 7.44 (d, J ¼ 8.8 Hz, 2H), 8.0 (brs
1H, NH).
Compound 8 (Table 1). 1H NMR (CDCl3): d: 2.35 (s 3H, 3CH3), 6.47 (s 1H,
2CH), 7.0–7.20 (m, 5H, ArH).
1
Compound 9 (Table 1). H NMR (CDCl3): d: 2.35 (s 3H, 2CH3), 6.67–6.76
(m, 3H, ArH), 7.0–7.2 (m, 5H, ArH).
1
Compound 2 (Table 2). H NMR (CDCl3): d: 2.35 (s 3H, CH3), 2.52 (s, H,
OH), 3.06 (d, 2H, CH2), 3.87 (d, 2H CH2), 6.96–7.06 (m, 4H, ArH).
1
Compound 4 (Table 2). H NMR (CDCl3): d: 2.52 (s, H, OH), 3.06 (d, 2H,
CH2), 3.87 (d, 2H CH2), 3.82 (s 3H, CH3), 6.67–7.07 (m, 4H, ArH).
Compound 8 (Table 2). 1H NMR (CDCl3): d: 1.46–1.89 (m 2H, 5CH2), 2.48
(s 1H, CH), 2.50 (s, H, OH), 2.63 (d, 2H, CH2), 3.90 (d, 2H CH2).
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