Novel one-pot synthesis of thiophenols from related triazenes under mild conditions

Article abstract of DOI:10.1055/s-0032-1316557

In this work, at first, triazenes were synthesized from primary aryl amines. Afterwards, triazenes were converted into the corresponding thiophenols in one-pot using sodium sulfide in acidic media, by in situ generation of diazonium counterion beside hydrogen sulfide as anionic sulfur nucleophile at room temperature. The procedure can be a convenient shortcut for the preparation of thiophenols from primary aryl amines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316557

LETTER
▌1893
lNettoervel One-Pot Synthesis of Thiophenols from Related Triazenes under Mild
Conditions
One-Pot Synthesis of Thiophenols
Ardeshir Khazaei,a Masoud Kazem-Rostami,*a Ahmad Reza Moosavi-Zare,a Mohammad Bayat,b Shahnaz Saedniaa
a
Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, 65178-38683 Hamedan, Iran
Fax +98(811)8257407; E-mail: Masoud.kr@gmail.com
b
Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran
Received: 07.05.2012; Accepted: 24.05.2012
This paper is dedicated to Professor Rudolf Leuckart for his studies on mercaptans.
times, side reactions, tedious workup, and the production
Abstract: In this work, at first, triazenes were synthesized from pri-
of explosive gases.
mary aryl amines. Afterwards, triazenes were converted into the
corresponding thiophenols in one-pot using sodium sulfide in acidic
media, by in situ generation of diazonium counterion beside hydro-
gen sulfide as anionic sulfur nucleophile at room temperature. The
procedure can be a convenient shortcut for the preparation of thio-
phenols from primary aryl amines.
The Leuckart thiophenol synthesis allows the preparation
of thiophenols from primary aryl amines. The first step of
the Leuckart reaction is the diazotization of primary aryl
amines in the presence of HCl and NaNO2, and the second
step is the reaction of aryl diazonium salt with potassium
alkyl xanthate to give aryl xanthate. Then, aryl xanthate is
hydrolyzed in basic media to afford aryl mercaptans.16
Unfortunately, this method is accompanied with the gen-
eration of wasted water polluted with carbonothioate de-
rivatives and alkyl xanthate (known as a toxic agent and
harmful for environment) besides some side reactions.17,18
Xanthate salts can be produced by the reaction of alcohol
with sodium or potassium hydroxide and carbon disulfide
which is very hazardous.16,18 In the Newman–Kwart reac-
tion, phenols are converted into the corresponding O-thio-
carbamates, then, by an intramolecular aryl migration at
high temperatures, S-thiocarbamates are produced, which
finally becomes hydrolyzed to afford thiophenols.19 But
this method needs long reaction time and high
temperature20 (about 300 °C) in which some side reactions
could occur. Moreover, in the similar reaction, thiophe-
nols are prepared by the treatment of phenolates with N,N-
dimethylthiocarbamoyl chloride.21 Another route for the
thiophenol synthesis is the reduction of benzenesulfonyl
chloride by zinc powder in acidic media.22 The disadvan-
tages of this method are releasing of high explosive hy-
drogen gas and formation of voluminous and gummy
organozinc intermediate bulk which is hard to stir. This
reaction has been successfully performed using triphe-
nylphosphine as a deoxygenation reagent.23 Thiophenols
are also prepared from the reaction of elemental sulfur on
phenylmagnesium halide or phenyllithium followed by
acidification.24 However, phenylmagnesium halide or
phenyllithium are very sensitive materials and expensive.
Recently, coupling reaction of aryl iodides and sulfur
Key words: thiophenol, aryl amine, triazene, diazonium salt, one-
pot synthesis
Aromatic mercaptans or thiophenols are a broad group of
organosulfur compounds. The chemical structures of thio-
phenols are analogous of phenols except that the hydroxy
group is replaced by a sulfhydryl group (SH). Thiophe-
nols have been used for the synthesis of heterocyclic com-
pounds, like biological activated substances such as
benzothiazoles,1 thiacrown ethers,2 and clusters, particu-
larly gold structures.3 The sulfhydryl group as an active
site of molecules can form noncovalent bonds with differ-
ent substrates; this functional group has been used as co-
ordinating agent in inorganic chemistry. Thiophenolates,
the conjugate bases derived from thiophenols, form strong
complexes with many metal ions,4 especially those classi-
fied as soft, and make polymeric metal cations from thio-
phenolates.5 Thioridazine (an antipsychotic and
neuroleptic agent),6 butoconazole (antifungal),7 azathio-
prine (prevent organ rejection agent following organ
transplantation),8 albendazole (worm treatment),9 merthi-
olate (antiseptic and antifungal agent),10 and riluzole (treat
amyotrophic lateral sclerosis)11 are some of the common
drugs which are derived from thiophenols. The organosul-
fur medicines like sulfonamides are also prepared from
thiophenols.12 Furthermore, these materials are used in the
synthesis of nanoparticles,13 semiconductor knowledge
development,14 and rubber industries.15 Thus, the thiophe-
nol group plays an important role in many fields.
Some methods have been applied for the synthesis of thio- powder has been reported, but this procedure needs sever-
phenols; nevertheless, most of the methods suffer from al hours and hard conditions to afford thiophenols.25
one or more disadvantages such as the use of poisonous,
Having the above points in mind, we report a novel con-
harmful, sensitive, and expensive materials, long reaction
version of aromatic amines into their corresponding thio-
phenols (Scheme 1). In this protocol, at first, aryl amines
were converted into triazenes, then triazenes were reacted
with sodium sulfide in the presence of trichloroacetic acid
(as organic acid) at room temperature to give the corre-
sponding thiophenols; under these conditions, diazonium
SYNLETT 2012, 23, 1893–1896
Advanced online publication: 23.07.2012
DOI: 10.1055/s-0032-1316557; Art ID: ST-2012-B0204-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1894
A. Khazaei et al.
LETTER
salts were produced in situ, which reacted with hydrogen ternary amine salt (as a leaving group in organic media)
sulfide to afford thiophenols. Interestingly, this method and a diazonium salt. This diazonium salt releases a nitro-
for the preparation of thiophenol derivatives has none of gen molecule at room temperature31 to replace by hydro-
the above-mentioned drawbacks at all.
gen sulfide anion and give aryl thiols (Scheme 2).
In the reported methods for the synthesis of thiophenols Not only symmetric but also asymmetric triazenes give
from primary aryl amines, the first step is the production only one diazonium salt in this reaction. In asymmetric tri-
of diazonium salts from primary aryl amines. For this pur- azenes, the nitrogen bonded to aliphatic group is more ba-
pose, application of NaNO2/HCl(aq) system is inevitable, sic than others. Therefore, it is clear that this nitrogen
and the addition of hydrogen sulfide to this acidic media attracts a proton and acts as a leaving group to decompose
makes it inactivated for successful nucleophilic attack to triazenes, and consequently produce only aryl diazonium
diazonium salts. Furthermore, Na2S after being added to salt.
water, makes the solution extremely alkali with large
In our investigations for the preparation of triazene salts,
amounts of hydroxy anions, which could produce byprod-
we examined several acids such as oleum, pure sulfuric
ucts. Thus, it is necessary to isolate and transfer diazoni-
acid, silica sulfuric acid, trichloro and trifluoro acetic ac-
um salts to organic media, which is not possible; it
id, in which triazene salt was made through a proton ex-
decomposes and may be explosive in the dry state. So, we
change (Scheme 2). Among the acids, trichloroacetic acid
decided to convert primary amines into triazenes and then
had several advantages including lack of acidic vapor, so-
prepare thiophenols from triazenes, as in situ diazonium
lidity at room temperature, low nucleophilicity of the cor-
source, in organoacidic media (trichloroacetic acid).
responding anion, cleaner reaction profile, and more
In fact, triazenes decomposes,26 in the presence of proton- controlled reactivity. Moreover, silica sulfuric acid could
ating agents27 such as trifluoroacetic acid28 and alkylating not give proper results in the reaction because its silica
agent like dimethyl sulfate29 or iodomethane,30 into a qua- moiety catalyzes some side reactions such as rearrange-
H
CCl3CO2H, Na2S
1) NaNO2, HCl
Ar1 NH2
Ar1
SH
N
N
Ar1
Ar2 (or R)
N
2) NaOAc, Ar2NH2
or Na2CO3, RNH2
Scheme 1 The conversion of aromatic amines into the corresponding thiophenols
Table 1 Conversion of Triazenes into the Corresponding Thiophenols
Entry
Ar1NH2
Ar2(or R)NH2
Time (min) Yield (%)a Product (Ar1SH)
1
2
aniline
aniline
3
5
85
benzenethiol
aniline
4-toluidine
65
benzenethiolb
3
4-toluidine
4-toluidine
6
80
4-methylbenzenethiol
4-methylbenzenethiol
4-bromobenzenethiolc
4-bromobenzenethiolc
4-chlorobenzenethiolc
4
4-toluidine
ethanamine
6
70
5
4-bromoaniline
4-bromoaniline
4-chloroaniline
4-nitro aniline
4-bromoaniline
ethanamine
11
9
65
6
70
7
4-chloroaniline
ethanamine
8
80
d
8
60
12
9
trace
66
–
9
4-methoxyaniline
4-methoxyaniline
3,4-(methylenedioxy) aniline
3,4-(methylenedioxy) aniline
2-naphthylamine
2-naphthylamine
4-methoxyaniline
ethanamine
4-methoxybenzenethiol
4-methoxybenzenethiol
3,4-(methylenedioxy)thiophenol
3,4-(methylenedioxy)thiophenol
2-naphthalenethiole
10
11
12
13
14
70
ethanamine
35
40
60
80
20
3,4-(methylenedioxy)aniline
ethanamine
25
trace
trace
2-naphthylamine
2-naphthalenethiole
a Isolated product percentage obtained by weight.
b In this reaction, trace amount of 4-methylbenzenethiol was also produced.
c Corresponding bisulfide was also obtained.
d In this entry, the nitro group34 was reduced with Na2S which caused unwanted side reactions.
e In this reaction, the trace product yield maybe due to the several possible resonance forms of naphthyl cation wherein there was no proper site
for nucleophile attack of HS–.
Synlett 2012, 23, 1893–1896
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Thiophenols
1895
Ar1
N N
H
H
CCl3CO2H
CCl3CO2H
N
Ar1
N
N
+
H3N Ar2 (or R)
N
Ar1
Ar2 (or R)
N
H
N
Ar2 (or R)
CCl3CO2H
Na2S
CCl3CO2
SH
– N2 (g)
Ar1 SH
N
N
Ar1
Scheme 2 Plausible mechanism for the synthesis of thiophenols from triazenes, based on the literature
ments, decompositions, and oxidation on the triazenes32
and thiophenols.33
The solvent was removed by reduced pressure to give the crude
which purified by recrystallization from dry CHCl3 (5 mL) or sub-
limation. The liquid products were purified by distillation.
In another study, the effect of several solvents such as
chloroform, methanol, acetone, and ethyl acetate were in-
vestigated on the reaction of 1,3-di-p-tolyltriazene as a
model reaction. Among these solvents, ethyl acetate was
selected, owing to its lower toxicity and its better compat-
ibility in the reaction.
Analytical Data of Selected Compounds
1-(4-Bromophenyl)-3-ethyltriaz-1-ene (Table 1, Entry 6)
Pale orange powder. IR (KBr): νmax = 3349 (NH), 3167 and 2962
(CH) cm–1. Anal. Calcd (%) for C8H10BrN3 (227.01): C, 42.13; H,
1
4.42; Br, 35.03; N, 18.42. Found: C, 41.94; H, 4.36; N, 17.93. H
NMR (90 MHz, CDCl3): δ = 1.30 (3 H, t, J = 7.2 Hz, CH3), 3.69 (2
H, q, J = 7.56 Hz, CH2), 7.15–7.47 (4 H, m, CH), 7.58 (1 H, s, NH)
ppm.
After optimization of the reaction conditions, to assess the
generality and the efficiency of the method, various
amines were converted into triazenes, and subsequently to
the desired thiophenol derivatives. The results are summa-
rized in Table 1. As it is shown in Table 1, our method was
general and efficient, and the products were prepared in
good to high yields.
4-Methoxybenzenethiol (Table 1, Products 9 and 10)
Colorless liquid with unpleasant odor. IR (Nujol): νmax = 2908 and
3031 (CH), 2564 (SH) cm–1. 1H NMR (90 MHz, CDCl3): δ = 3.68
(1 H, s, SH), 3.81 (3 H, s, OMe), 6. 86 (2 H, d, J = 8.55 Hz), 7.24 (2
H, d, J = 8.64 Hz) ppm. Anal. Calcd (%) for C7H8OS (140.03): C,
59.97; H, 5.75; O, 11.41; S, 22.87. Found: C, 60.35; H, 4.80. MS:
m/z = 140, 139.
The FT-IR Perkin Elmer spectrometer was served to obtain FT-IR
spectra in the range of 4000–400 cm–1 by KBr powder-pressed pel-
lets and mull for liquid samples. Agilent mass spectrometer (MS)
5973 was used with network mass selective detector and a 70 eV
electron impact as the ion source and quadrupole analyzer. Elemen-
tal analysis was done by a 2400 Perkin Elmer CHN micro analyzer.
1H NMR spectra were obtained in deuterated DMSO or CHCl3 with
TMS as an internal standard using a Jeol 90 MHz FT-NMR spec-
trometer. Deuterated solvents were purchased from Sigma-Aldrich.
All other chemicals were of analytical grade purchased from Merck
chemical company and used as received without any further purifi-
cation.
General Procedure for the Preparation and Purification of
Asymmetrical Triazenes
A solution of aromatic amine (10 mmol) in HCl (8 mL HCl 37%,
diluted by 100 mL H2O) with an appropriate amount of cracked ice
(20 g) was prepared. Afterwards, NaNO2 solution (0.7 g, 10 mmol
in 25 mL cold H2O) was added dropwise with continuous stirring
for about 5 min, and the resulting solution was stirred for another 10
min. The reaction mixture was basified by Na2CO3, and then the
second aqueous aliphatic amine solution was added immediately,
and the mixture was stirred rapidly for about 20 min at r.t. to com-
plete the reaction. By addition of NaCl, the precipitated triazene
was filtered and purified by chromatographic column filled with
alumina.
Acknowledgment
General Procedure for the Preparation and Purification of
Symmetrical Triazenes
The authors acknowledge to Bu-Ali Sina University (development
of chemical methods, reagents, and molecules) and research council
and national center of excellence in development of chemical me-
thods for financial support provided of this work and Dr. Abdolka-
rim Zare (chemistry department, Payame Noor University, Iran) for
revising this paper.
A solution of aromatic amine (10 mmol) in diluted HCl (8 mL HCl
37%, in 100 mL H2O) with an appropriate amount of cracked ice
(20 g) was prepared. Afterward, NaNO2 solution (0.35 g, 5 mmol in
25 mL cold H2O), was added dropwise with continuous stirring for
about 15 min. The resulting solution was buffered by NaOAc, and
stirred rapidly for about 20 min at r.t. to complete the reaction. The
precipitated triazene was then filtered and purified by recrystalliza-
tion from CHCl3–n-hexane (1:9).
References
General Procedure for the Preparation and Purification of
Thiophenols
(1) Fan, X.; He, Y.; Wang, Y.; Xue, Z.; Zhang, X.; Wang, J.
Tetrahedron Lett. 2011, 52, 899.
(2) Ławecka, J.; Olender, E.; Piszcz, P.; Rykowski, A.
Tetrahedron Lett. 2008, 49, 723.
(3) Remacle, F.; Kryachko, E. S. Mol. Struct. 2004, 708, 165.
(4) Blower, P. J.; Dilworth, J. R. Coord. Chem. Rev. 1987, 76,
121.
(5) Fleischer, H. Coord. Chem. Rev. 2005, 249, 799.
(6) Milnes, J. T.; Witchel, H. J.; Leaney, J. L.; Leishman, D. J.;
Hancox, J. C. Biochem. Biophys. Res. Commun. 2006, 351,
273.
A mixture of triazene (1 mmol), Na2S·9H2O (1.5 mmol, 0.36 g), tri-
chloroacetic acid (3.5 mmol, 0.56 g), and EtOAc (4 mL) in a 10 mL
round-bottomed flask connected to a reflux condenser, was stirred
for a few minutes as mentioned in Table 1 to emit N2 gas under lab
vent. After completion the reaction as monitored by TLC, the reac-
tion mixture was washed with H2O (20 mL), EtOAc (5 mL) was
added, and shaken for 3 min. The organic layer was collected and
washed with solution of KOH (5%). The alkali solution of the aque-
ous layer was cautiously acidified with concentrated HCl, was shak-
en twice with 5 mL of CHCl3, and dried by adding anhyd MgSO4.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1893–1896

1896
A. Khazaei et al.
LETTER
(22) Levy, J.; Paramus, N.; Psihas, J. US 3326981, 1967.
(23) Bellale, E. V.; Chaudhari, M. K.; Akamanchi, K. G.
Synthesis 2009, 3211.
(24) Crenshaw, R. R. US 3413305, 1968.
(25) Jiang, Y.; Qin, Y.; Xie, S.; Zhang, X.; Dong, J.; Ma, D. Org.
Lett. 2009, 11, 5250.
(26) Bräse, S.; Banert, K. Organic Azides: Syntheses and
Applications; Wiley: Chichester, 2009.
(27) (a) Rakotondradany, F.; Williams, C. I.; Whitehead, M. A.;
Jean-Claude, B. J. J. Mol. Struct. (Theochem) 2001, 535,
217. (b) Pages, T.; Langlois, B. R. Fluorine Chem. 2001,
107, 321. (c) Picherit, C.; Wagner, F.; Uguen, D.
Tetrahedron Lett. 2004, 45, 2579.
(28) (a) Reingruber, R.; Vanderheiden, S.; Muller, T.; Nieger,
M.; Es-Sayed, M.; Bräse, S. Tetrahedron Lett. 2009, 50,
3439. (b) Lazny, R.; Poplawski, J.; Kobberling, J.; Enders,
D.; Bräse, S. Synlett 1999, 1304. (c) Arseniyadis, S.;
Wagner, A.; Mioskowski, C. Tetrahedron Lett. 2002, 43,
9717.
(7) Rotstein, D. M.; Walker, K. A. M. Tetrahedron: Asymmetry
1993, 4, 1521.
(8) Remuzzi, G.; Lesti, M.; Gotti, E.; Ganeva, M.; Dimitrov, B.
D.; Ene-Iordache, B.; Gherardi, G.; Donati, D.; Salvadori,
M.; Sandrini, S.; Valente, U.; Segoloni, G.; Mourad, G.;
Federico, S.; Rigotti, P.; Sparacino, V.; Bosmans, J.-L.;
Perico, N.; Ruggenenti, P. Lancet 2004, 364, 503.
(9) Sacko, M.; De Clercq, D.; Behnke, J. M.; Gilbert, F. S.;
Dorny, P.; Vercruysse, J. Trans. R. Soc. Trop. Med. Hyg.
1999, 93, 195.
(10) O’Connor, G. B. Am. J. Surg. 1939, 45, 563.
(11) Desiato, M. T.; Palmieri, M. G.; Giacomini, P.; Scalise, A.;
Arciprete, F.; Caramia, M. D. J. Neurol. Sci. 1999, 169, 98.
(12) Bahrami, K.; Khodaei, M. M.; Abbasi, J. Tetrahedron 2012,
68, 5095.
(13) (a) Sambasivam, S.; Joseph, D. P.; Reddy, D. R.; Reddy, B.
K.; Jayasankar, C. K. Mater. Sci. Eng., B 2008, 150, 125.
(b) Pattabi, M.; Amma, B. S. Sol. Energy Mater. Sol. Cells
2006, 90, 2377.
(14) (a) Azizian-Kalandaragh, Y.; Khodayari, A.; Behboudnia,
M. Mater. Sci. Semicond. Process. 2009, 12, 142. (b) Kamat,
P. V. In Studies in Surface Science and Catalysis; Vol. 103;
Meisel, D., Ed.; Elsevier, 1997, 237.
(29) Hansen, M. N.; Farjami, E.; Kristiansen, M.; Clima, L.;
Pedersen, S. U.; Daasbjerg, K.; Ferapontova, E. E.; Gothelf,
K. V. Org. Chem. 2010, 75, 2474.
(30) Harmata, M.; Hong, X.; Zheng, P. Tetrahedron Lett. 2006,
47, 7343.
(15) Schneider, P. US 2784167, 1957.
(16) Leuckart, R. J. Prakt. Chem. 1890, 41, 179.
(17) Cox, J. R. Jr.; Gladys, C. L.; Field, L.; Pearson, D. J. Org.
Chem. 1960, 25, 1083.
(31) Pool, B. J. Cancer Res. Clin. Oncol. 1979, 93, 221.
(32) Kawanisi, M.; Ôtani, I.; Nozaki, H. Tetrahedron Lett. 1968,
9, 5575.
(18) Tournier, L.; Zard, S. Z. Tetrahedron Lett. 2005, 46, 971.
(19) Li, J. J. Name Reactions: Newman–Kwart Rearrangement
3rd ed., Vol. 34, 2009.
(33) (a) Shirini, F.; Zolfigol, M. A.; Khaleghi, M. Mendeleev
Commun. 2004, 14, 34. (b) Zolfigol, M. A. Tetrahedron
2001, 57, 9509.
(20) Moseley, J. D.; Sankey, R. F.; Tang, O. N.; Gilday, J. P.
Tetrahedron 2006, 62, 4685.
(34) Yu, B. C.; Shirai, Y.; Tour, J. M. Tetrahedron 2006, 62,
10303.
(21) Flores-Figueroa, A.; Arista, M. V.; Talancón-Sánchez, D.;
Castillo, I. J. Braz. Chem. Soc. 2005, 16, 397.
Synlett 2012, 23, 1893–1896
© Georg Thieme Verlag Stuttgart · New York