One-Pot Two-Step Synthesis of Aryl Sulfur Compounds by Photoinduced Reactions of Thiourea Anion with Aryl Halides

Article abstract of DOI:10.1021/ol035545n

(Equation presented) The photoinduced reactions of aryl halides with the thiourea anion afford arene thiolate ions in DMSO. These species without isolation, and by a subsequent aliphatic nucleophilic substitution, S _RN1 reaction, oxidation, or protonation, yield aryl methyl sulfides, diaryl sulfides, diaryl disulfides, and aryl thiols with good yields (50-80%). This is a simple and convenient approach which involves the use of the commercially available and inexpensive thiourea in a one-pot two-step process for the synthesis of aromatic sulfur compounds.

Full text of DOI:10.1021/ol035545n

ORGANIC
LETTERS
2
003
Vol. 5, No. 22
133-4136
“
One-Pot” Two-Step Synthesis of Aryl
4
Sulfur Compounds by Photoinduced
Reactions of Thiourea Anion with Aryl
Halides
Juan E. Arg u1 ello, Luciana C. Schmidt, and Alicia B. Pe n˜ e´ n˜ ory*
INFIQC, Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias Qu ´ı micas,
UniVersidad Nacional de C o´ rdoba, Ciudad UniVersitaria, 5000 C o´ rdoba, Argentina
penenory@dqo.fcq.unc.edu.ar
Received August 15, 2003
ABSTRACT
The photoinduced reactions of aryl halides with the thiourea anion afford arene thiolate ions in DMSO. These species without isolation, and
by a subsequent aliphatic nucleophilic substitution, SRN1 reaction, oxidation, or protonation, yield aryl methyl sulfides, diaryl sulfides, diaryl
disulfides, and aryl thiols with good yields (50−80%). This is a simple and convenient approach which involves the use of the commercially
available and inexpensive thiourea in a “one-pot” two-step process for the synthesis of aromatic sulfur compounds.
-
Organosulfur compounds are versatile reagents for organic
synthesis and play an important role in biological systems.
Among the sulfur nucleophiles described, RS ions give a
mixture of substitution and fragmentation products, making
1
5
Aryl thiols and alkyl aryl sulfides can be synthesized by
aromatic nucleophilic substitution involving strong activated
this reaction of scarce synthetic value. However, straight-
forward substitution products can be achieved by the reaction
of RS with aromatic compounds, bearing EWGs (CN, CHO,
CONH , COMe, and COPh) and heteroaromatic halides (70-
90%). Symmetrical and unsymmetrical diaryl sulfides
can be synthesized in good yields by photostimulated
reactions of arene and heteroarene thiolate ions with aryl
-
-
2
-
aryl halides and HS or RS anions. For aromatic halides
bearing only one electron-withdrawing group (EWG) or
2
0
6
nonactivated, the employment of copper (CuI or Cu ) or
(
3 4
Ph P) Pd catalysis, high temperatures, and long reaction
3
times is necessary to obtain from moderate to good yields.
Another possibility is the conversion of Grignard reagents.
2
4
halides.
Radical nucleophilic substitution or SRN1 has proven to
be a versatile mechanism for the synthesis of aromatic sulfur
derivatives with formation of a new C-S bond by reaction
of arene and alkanethiolates, MeCOS and PhCOS ions.
These reactions proceed with nonactivated aryl derivatives.
The electrochemically induced reactions of the thiourea
anion (1) with aryl halides afford moderate yields of a
mixture of aryl thiol, diaryl disulfide, and diaryl sulfide,
ascribed to the fragmentation of the radical anions intermedi-
-
-
4
7
ates (Scheme 1).
(
1) Cremlyn, R. J. An Introduction to Organosulfur Chemistry; John
Wiley & Sons: Chischester, 1996.
2) March, J. AdVanced Organic Chemistry, 5th ed.; John Wiley &
Sons: New York, 2001.
(4) Rossi, R. A.; Pierini, A. B.; Pe n˜ e´ n˜ ory, A. B. Chem. ReV. 2003, 103,
71-167.
(
(5) Rossi, R. A.; Palacios, S. M. J. Org. Chem. 1981, 46, 5300-5304.
(6) Beugelmans, R.; Bois-Choussy, M.; Boudet, B. Tetrahedron 1983,
39, 4153-4161.
(
3) (a) Cu catalysis: Lindley, J. Tetrahedron 1984, 40, 1433-1456. (b)
Pd catalysis: Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-I.; Kato, Y.;
Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385-1389.
(7) Combellas, C.; Dellerue, S.; Mathey, G.; Thi e´ bault, A. Tetrahedron
Lett. 1997, 38, 539-542.
1
0.1021/ol035545n CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003

Following this approach, the main product in the reaction
of 1 with 2 was the 1-(methylthio)naphthalene (3) with a
smaller amount of bis(1-naphthyl) sulfide (4) and naphthalene
Scheme 1
(5) (Scheme 2).
Scheme 2
On the other hand, the photochemical aromatic substitution
of aryl halides by thiourea affords arylisothiuronium salts.
These reactions proceed under UV irradiation and thermal
hydrolysis, and oxidation of these salts leads to the formation
8
of the corresponding diaryl disulfides. For aryl derivatives
bearing electron-donating substituents such as NH
OMe, variable yields of the disulfides are obtained (25-
6%). However, 1-bromonaphthalene was unreactive under
2 2
, NR , and
7
The ratio 3/4 was improved when the reaction was
these reaction conditions.
performed with a 10-fold excess of 1. Similar results were
obtained after 1 h of irradiation, and even after only 15 min,
the conversion was almost complete. This photochemical
reaction was inhibited by the presence of di-tert-butyl
nitroxide (DTBN), a radical trap. This result, the lack of
reaction in the dark after 3 h (Table 1, entries 1-5), and the
presence of naphthalene suggest a radical chain mechanism
for this reaction and can be rationalized as follows (Scheme
3): The reaction is initiated by a photoinduced electron-
We report herein the photoinduced reaction of 1 with
haloarenes, as a “one-pot” method for the synthesis of aryl
thiols, alkyl aryl sulfides, symmetrical or unsymmetrical
diaryl sulfides, and diaryl disulfides from moderate to good
yields.
The photoinduced reactions of 1 with 1-bromonaphthalene
(2) were first studied, and the results are summarized in Table
1. The general procedure for these reactions is as follows:
Table 1. Photoinduced Reactions of 1 with
1
Scheme 3
-Bromonaphthalenea
b
conditions
product yield (%)
entry solvent time (h) conv (%) MB ArH ArSMec Ar2S
1
DMSO
3
3
1
0.25
100
100
100
91
25
0
100
24
94
45
98
84 13
83
92 11
37
50
54
48
9
32
22
24
19
8
2d
3d
4d
5d,e
6d,f
7d
8
9
87
94
9
2
0.25
3
3
3
3
3
3
DMF
MeCN
NH3
EtOH
HMPA
90 39
33
18
4
31
3
88
62
7.5
9
0.2
15
1.5
17
9
0
1d
1
1
95 35
94 65
9
a
ArX, 0.05 M; 1, 0.25 M. After irradiation under nitrogen atmosphere,
b
the reaction was quenched with MeI. Determined by GC using the internal
standard method, error 5%. The conversion was determined by quantification
of the unreacted substrate. Mass balance (MB). Together with e3% of
c
transfer reaction from 1 to the substrate to yield the
•
-
the 2-(methylthio)naphthalene from the 2-bromonaphthalene present as
corresponding radical anion 2 , which fragments to give
radical 6. Addition of 1 to radical 6 affords the radical anion
d
e
impurity of 2. Nucleophile/ArX ratio of 10:1. In the presence of 0.01 M
f
DTBN. In the dark.
•-
intermediate 7 , which fragments into the thiolate ion 8 and
radical 9 (step 2). To account for the chain reaction, two
To a solution of the bidentate anion 1 obtained by depro-
tonation of thiourea with t-BuOK in an appropriate solvent
was added the aryl halide, and then the solution was
irradiated for 3 h or the indicated time. After irradiation, the
(
9) Representative Experimental Procedure. The reactions were carried
out in a 10 mL three-necked Schlenk tube, equipped with nitrogen gas inlet
and magnetic stirrer. The tube was dried under vacuum, filled with nitrogen,
and then loaded with 10 mL of dried DMSO. 5.5 mmol of t-BuOK, 5 mmol
of the thiourea, and 0.5 mmol of the aryl halide were added to the degassed
solvent under nitrogen. After 3 h of irradiation with a medium-pressure Hg
lamp emitting maximally at 350 nm, the reaction was quenched with addition
of methyl iodide (6 equiv) and 30 mL of water, and then the mixture was
extracted with methylene chloride (3 × 20 mL). The organic extract was
washed twice with water and dried, and the products were quantified by
GLC with the internal standard method.
arene thiolate ion obtained by the SRN1 reaction was
quenched by methyl iodide.9
(
8) Frolov, A. N.; Klokova, E. M.; El’tsov, A. V. J. Org. Chem. USSR
(
Engl. Transl.) 1981, 17, 1926-1935.
4134
Org. Lett., Vol. 5, No. 22, 2003

different radical anion intermediates are possible. Deproto-
nation of 9 would render cyanamide radical anion which by
electron transfer to 2 may continue the SRN1 cycle. Another
Table 2. Photoinduced Reactions of 1 with Aryl Halidesa
7
b
products yield (%)
possibility is that coupling of ion 1 with radical 9 would
form a new radical anion able to continue the chain
propagation. In any case, the products after ET would
probably be water soluble and hydrolyze during workup.
Further studies are in progress in order to clarify this step in
the propagation cycle. The thiolate ion 8 is able to add to
radical 6 and follows a new cycle of SRN1 reaction to afford
the disubstitution product 4 (step 3). Hydrogen atom abstrac-
tion from the solvent by naphthyl radicals gives the reduction
product naphthalene (5) (step 4). After irradiation, the
reaction mixture was quenched by methyl iodide to afford
the 1-(methylthio)naphthalene (3) (step 5).
entry
ArX
conv (%) ArH
ArSMe
Ar2S
50c
54d
1
2
3e
4e
5
6
7
8e
9e
1-Br-naphthalene
2-Br-naphthalene
PhI
4-IC6H4OMe
4-BrC6H4OMe
4-BrC6H4SMe
4-BrC6H4CN
4-IC6H4NO2
4-PhCOC6H4Br
2-MeCOC6H4Br
3-Cl-pyridine
2-Cl-pyridine
2-Cl-quinoline
2-Cl-pyrazine
2-Cl-pyrimidine
100
100
f
9
7
f
22
25
26
7
8
23
9
28
21
20
42
49
77
81
64
58
87
64
83
36
100
96
62
60
14
4
100
100
100
100
100
100
100
100
100
100
5
2
f
f
2
f
1
0
3
15
f
11
12
The effects of the solvent were studied in the reaction of
ion 1 with 2 (Table 1, entries 7-11). From the dipolar aprotic
solvents employed, DMSO gave the best results, with a
product ratio for substitution/reduction of approximately 7.
In DMF, the conversion was completed but naphthalene was
produced in an amount similar to that of ArSMe. In this
reaction, the product ratio for substitution/reduction was 1.3
due to a competitive hydrogen atom abstraction from the
1
1
1
3e
4
5
f
a
ArX, 0.05 M; 1, 0.50 M. After irradiation for 3 h under nitrogen
b
atmosphere in DMSO, the reaction was quenched with MeI. Determined
by GC using the internal standard method, error 5%. The conversion was
determined by quantification of the unreacted substrate. Together with
c
d
2
1
.5% of the methyl 2-naphthyl sulfide. Together with 1% of the methyl
-naphthyl sulfide. e Nucleophile/ArX ratio of 5:1. Not quantified.
f
10
solvent with the coupling reaction. Conversely, in the
dipolar aprotic MeCN, the yields were low because of the
lower solubility of t-BuOK. The reaction performed in liquid
ammonia showed a poor mass balance, probably due to the
obtained by the SRN1 reaction were quenched by MeI to
afford the ArSMe derivatives from moderate to good yields
11
low recovery of the naphthalene. In comparison to the
reaction carried out in DMSO, the ratio Ar S toward ArSMe
(50-83%). Nevertheless, these yields were considerably
2
better than those reported by classical substitution mecha-
nisms. For example, an alternative synthesis of 3-mercap-
topyridine by a substitution reaction of the aryl bromide with
KHS in propylene glycol required 20 h of heating at 175-
increased. This finding can be ascribed to a higher selectivity
of the naphthyl radicals toward the two competing anions
(
1 and 8) at lower temperature.12 In EtOH and HMPA, the
formation of the reduction product naphthalene notably
increased in comparison to the coupling products. These
reactions yielded a product ratio for substitution/reduction
1
90 °C and copper catalysis to produce only 14% yield of
13
the thiol.
2
-Chloropyrimidine gave modest yield of the 2-(meth-
2
of 0.1 and 0.4, respectively. In t-BuOH or H O, thiourea
ylthio)pyrimidine, and it was less reactive than 2-chloropy-
razine. A similar difference on reactivity has been previously
observed in the photoinduced reactions of both chlorides with
potassium phenylacetonitrile and ketone enolates. These
results were explained on the basis of the reduction potential
difference of the halides.
and 2 are, respectively, slightly soluble but there was no
reaction at all. In summary, DMSO is the most suitable
solvent to perform these reactions.
14
15
The reactivity of thiourea anion toward 1-bromonaphtha-
lene under irradiation has encouraged us to further explore
the potential of this anion in the synthesis of sulfur
compounds. Table 2 condenses the results obtained in the
photoinduced reactions of 1 with a variety of aryl halides.
From Table 2, it is possible to conclude that this
methodology is appropriate for substrates bearing one EWG
or heteroaryl halides, providing, thus, more reactivity in the
coupling reaction. In these cases, the arene thiolate ions
For substrates giving both the mono- and disubstitution
products (ArS and Ar
-
2
S, respectively), optimization of the
reaction conditions is possible to afford preferentially the
symmetrical diaryl sulfide by increasing the amount of the
aromatic halide or the arylthiol by increasing the amount of
thiourea. Thus, the photoinduced reaction between 1-bro-
monaphthalene (2) and 1 with a ratio 2/1 of 1:1 yielded 38%
of bis (1-naphthyl) sulfide after 3 h.
Different chemical transformations are possible for the
arene thiolate ions formed in good yields in the SRN1 reaction
without isolation, namely oxidation to the diaryl disulfide,
(
10) The following hydrogen atom abstraction rates have been determined
5
-1
5 -1
for 1-naphthyl radicals: 2.5 × 10 s (MeCN), 3 × 10 s (DMSO) and
6
-1
8
3
× 10 s (DMF). Helgee, B.; Parker, V. D. Acta Chem. Scand. 1980,
8 -1
4, 129-156. Although for DMSO a kH value of 1 × 10 s determined
by Save a´ nt (Andrieux, C. P.; Sav e´ ant, J.-M.; Su, K. B. J. Phys. Chem. 1986,
0, 3815-3823) seems to be more adequate.
11) Part of naphthalene is lost during the reaction and with the
evaporation of the solvent.
12) The absolute rate constant for the coupling reaction of aryl radicals
protonation to yield the aryl thiols, or subsequent SRN
1
9
(
(13) Wuest, H. M.; Sakal, E. H. J. Am. Chem. Soc. 1951, 73, 1210-
1216.
(
with 1 and benzene thiolate ion have been electrochemically measured in
liquid NH3. Toward 3-pyridyl radical (similar reactivity to naphthyl radical),
benzene thiolate ion is 1 order of magnitude more reactive than ion 1 (ref
(14) Hermann, C. K. F.; Sachdeva, Y. P.; Wolfe, J. F. J. Heterocycl.
Chem. 1987, 24, 1061-1065.
(15) Carver, D. R.; Komin, A. P.; Hubbard, J. S.; Wolfe, J. F. J. Org.
Chem. 1981, 46, 294-299.
7
).
Org. Lett., Vol. 5, No. 22, 2003
4135

implies the handling of the not always stable diazonium salts
and the yields of the sulfur compounds were lower (31-
Scheme 4
6
6%) than the ones obtained in the present report.
In conclusion, the photoinduced reaction of thiourea ion
(1) with aryl halides provides a very good alternative to
introduce a sulfur functionality in aryl compounds by ipso
substitution of an adequate leaving group (X ) I, Br, or Cl).
Further reactions of the thiolate ions yield a variety of sulfur
compounds in a “one-pot” reaction. Scheme 4 summarizes
all these possible transformations. The use of commercially
available, easy to handle, inexpensive thiourea and the very
mild conditions make this process a simple and convenient
approach to obtain several sulfur aromatic compounds.
Further studies are in progress in order to optimize the
synthesis of unsymmetrical diaryl sulfides, extend this
methodology for the synthesis of sulfur compounds derived
from substrates reactive in radical reactions such as bridge-
head, neopentyl, and vinyl halides, as well as study the
possibility of polysubstitution.
reaction with a different aryl halide to afford unsymmetrical
diaryl sulfides. With this strategy, we synthesized a variety
of sulfur compounds. Thus, a solution of 4-benzoylbenzene
thiolate ion obtained by this methodology affords 4-mer-
captobenzophenone (80%) by protonation under nitrogen
atmosphere, bis(4-benzoylphenyl) disulfide (70%) after
Acknowledgment. This work was supported in part by
the Consejo Nacional de Investigaciones Cient ´ı ficas y
T e´ cnicas (CONICET) and FONCYT, Argentina, the Alex-
ander von Humboldt Foundation, and the Third World
Academic of Sciences (TWAS). J.E.A. gratefully acknowl-
edges the receipt of a fellowship from CONICET.
3
oxidation by KI , and by a subsequent photoinduced SRN1
reaction with iodobenzene 4-phenylthiobenzophenone (35%).
Although no efforts have been made to optimize these
reactions, they clearly show the versatility of the method to
obtain several organosulfur compounds.
The SRN1 reaction between MeCOSK and arenediazonium
tetrafluoroborates in DMSO has been reported as a method
for the “one-pot” access to aromatic sulfur derivatives,
without isolation of the aryl thioesters.1 This methodology
Supporting Information Available: General methods,
materials, experimental procedures, and literature references
for known compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
6
(16) Petrillo, G.; Novi, M.; Garbarino, G.; Filiberti, M. Tetrahedron 1989,
4
5, 7411-7420.
OL035545N
4136
Org. Lett., Vol. 5, No. 22, 2003