Mild persubstitution of di- and tetrabrominated arenes with arylthiolate nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2010.10.069

A mild selective protocol was used to prepare tetrakis(2-chlorophenylthio) anthracene from tetrabromoanthracene and sodium 2-chlorobenzenethiolate avoiding the thiolate self-attack. The uncatalyzed nucleophilic substitution of a series of mono-, di-, and tetrabrominated arenes by arylthiolate ions was attempted in mild conditions to investigate the scope of the substitution reaction regarding the size of the aromatic system as well as the number of bromine atoms. Successful reactions afforded only the persubstituted products in good purity and yield after a simple workup and chemoselectivity of Br versus Cl substituents was achieved for the tetrabromide.

Full text of DOI:10.1016/j.tetlet.2010.10.069

Tetrahedron Letters 51 (2010) 6730–6733
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild persubstitution of di- and tetrabrominated arenes
with arylthiolate nucleophiles
⇑
Pablo G. Del Rosso , Marcela F. Almassio, Mattia Bruno, Raúl O. Garay
INQUISUR, Departamento de Química, Universidad Nacional del Sur, CP 8000 Bahía Blanca, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild selective protocol was used to prepare tetrakis(2-chlorophenylthio)anthracene from tetrabromo-
anthracene and sodium 2-chlorobenzenethiolate avoiding the thiolate self-attack. The uncatalyzed nucle-
ophilic substitution of a series of mono-, di-, and tetrabrominated arenes by arylthiolate ions was
attempted in mild conditions to investigate the scope of the substitution reaction regarding the size of
the aromatic system as well as the number of bromine atoms. Successful reactions afforded only the per-
substituted products in good purity and yield after a simple workup and chemoselectivity of Br versus Cl
substituents was achieved for the tetrabromide.
Received 18 August 2010
Revised 9 October 2010
Accepted 12 October 2010
Available online 20 October 2010
Keywords:
Selective sulfuration
Aromatic substitution
Persulfurated arenes
Organic materials
Ó 2010 Elsevier Ltd. All rights reserved.
The substitution of bromine atoms by an alkyl or aryl thiolate
anion is a highly effective synthetic tool in the making of organic
materials ranging from polymers,1 oligomers2, and dendrimers3
to molecular compounds, such as organic semiconductors4 or
pharmaceutical drugs.5
In particular, the substitution of bromine atoms by arene
thiolates, followed by sulfide derivatization and intramolecular
acid-induced cyclization, has been used as the initial step in
the synthetic route to fused-ring semiconductors, such as
dibenzothienobisbenzothiophene.6 Likewise, diverse polycyclic
aromatic or heteroaromatic systems including dibenzofurans,7
dibenzopyrans and phenanthridines,8 phenanthrenes,9 benzofluo-
ranthenes10, and fluoranthenes11 have been obtained by sequential
or cascade11 two-step ring-formation pathways involving several
types of coupling reactions followed by intramolecular Heck-type
dehydrohalogenations.12
olates can take place in inactivated or slightly activated mono- and
polyhalogenoarylenes under a variety of reaction conditions. Thus,
asymmetric thioethers have been obtained mainly by aromatic
nucleophilic substitutions with alkyl thiolates at moderate
temperatures4a or aryl thiolates at high temperatures,13 micro-
wave-assisted coupling,14 photoirradiation15, and transition metal
catalyzed substitution of aryl halides by aryl thiolates using
Pd2c,16 or Cu14,17 complexes.
However, most of the conditions employed by these reactions
lack selectivity between chloride and bromine displacement or
require the use of the more expensive and often unavailable poly-
iodide arenes to achieve chemoselectivity.2c Therefore, a careful
selection of reaction conditions is needed to avoid the sodium
2-chlorophenythiolate self-attack. Hence, we carried out a series
of blank reactions between 30 °C and 100 °C using a suspension
In this context, we investigated the feasibility of using the
simple uncatalyzed nucleophilic substitution of aryl bromides by
phenylthiolate ions bearing a chloride atom as a key step in the
route to sulfur-containing polycyclic aromatic semiconductors by
Heck-type annulations. Thus, this communication reports a mild
selective protocol for preparing polysubstituted arylthioethers
from sodium arylthiolates and aryl bromides bearing no activating
groups other than the bromine atoms themselves.
X
S
X
Br
S
n
X = H, Cl
π
π
+
n
1-10 n = 1,2,4
1-10, a X = H; b X = Cl
X = Cl
SH
S
Cl
Although the presence of electron withdrawing groups is of
importance for the outcome of aromatic nucleophilic substitution
reactions, the halogen displacement reactions by alkyl and aryl thi-
S
y
oligomers
Scheme 1.
⇑
Corresponding author. Tel.: +54 291 459 5101; fax: +54 291 459 5187.
E-mail address: delrosso@uns.edu.ar (P.G. Del Rosso).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.069

P. G. Del Rosso et al. / Tetrahedron Letters 51 (2010) 6730–6733
6731
of sodium 2-chlorophenylthioate in 1,3-dimethyl-2-imidazolidi-
none (DMI) with all the reactants present except the aryl bromide
which indicated that oligomerization of the nucleophile would oc-
cur as a competitive side reaction above 40 °C (see Scheme 1). DMI
is the safe polar solvent of choice for polysulfuration of aromatic
halides having replaced18 HMPA, the recommended solvent for
thiolate ionic aromatic nucleophilic substitutions used in early
studies.19
Table 1
Nucleophilic substitution of aryl bromides by arylthiolate ions
Compound
Aryl bromide
Xa
H
Yield %b
NR
D
Hrc
Br
1
À4.9
À2.4
Br
2
3
H
H
NR
NR
Br
À8.8
À3.9
Br
4
5
H
NR
Br
H
H
NR
NR
À10.6
À3.3
Br
6
7
Br
Br
Br
H
Cl
86d
NR
À19.3
À12.6
8
9
Br
Br
H
Cl
99d
NR
À16.7
À13.9
O(CH2CH2O)2Et
Et(OCH2CH2)2O
Br
H
Cl
72
NR
À15.3
À12.9
Br
Br
Br
10
H
38e
À24.8f; À15.9g
À21.6f
Br
Br
H
Cl
Cl
65
47e
78
a
b
c
The reactions of phenylthiolate ion (X = H) or 2-chlorophenylthiolate ion (X = Cl) with 1–10 were carried out at 40 °C for a week, unless otherwise stated.
Isolated yields. NR = No reaction. Products where characterized by 1H and 13CNMR and elemental analysis.
Reaction heats,
D
Hr =
D
HMf À (
D
HAf B
+
D
Hnf ucl), calculated for the first substitution reaction. In Kcal/mol. Phenylthiolate ion,
D
Hnf ucl = À1.665 Kcal/mol and 2-chlorophe-
nylthiolate ion,
D
Hnf ucl = À10.527 Kcal/mol.
d
The reaction was carried out for one day.
e
f
The reaction was carried out for four days.
Calculation done for the attack at the anthracene 9-position.
Calculation done for the attack at the anthracene 2-position.
g

6732
P. G. Del Rosso et al. / Tetrahedron Letters 51 (2010) 6730–6733
Subsequently, a series of screening reactions using an excess of
Similarly, only 10a was obtained after the week-long treatment
of 10 with the phenylthiolate anion (2 equiv) when the workup
protocol was modified to recover all anthracene derivatives, that
is, the reaction mixture was thoroughly extracted with chloroform.
However, when less phenylthiolate anion (1 equiv) was used, the
chloroformic extract of the reaction mixture contained a significant
quantity of 2,6-dibromo-9,10-diphenylthioanthracene 11 (85%)
along with a little 10a (8%), a bromotriphenylthioanthracene
(7%), and traces of the tetrabromide (1%). The dibromide 11 was
isolated for characterization from a mixture of starting tetrabro-
mide 10 (64%) and 11 (36%), which were the only products ob-
tained when a deficit of the phenylthiolate anion (0.5 equiv) was
used. These results show that the 9- and 10-positions of 10 are
more reactive than the 2- and 6-positions and that an excess of
the phenylthiolate anions is needed to achieve persubstitution.
In summary, the procedure is very convenient when an excess
of phenylthiolate anions is used since each successful reaction
afforded only the persubstituted products in good purity and yield
after a simple workup and chemoselectivity of Br versus Cl substit-
uents was achieved for the tetrabromide 10.
the unsubstituted phenylthiolate anion (2 equiv) were performed
to investigate the scope of the substitution reaction at 40 °C
regarding the size of the aromatic system as well as the number
of attached bromine atoms. The results are presented in Table 1.
We found that monobromides 1–5 as well as the dibromide 6 do
not react at such a moderate temperature. Reaction mixtures re-
mained pale yellow for a week and from these most of the starting
bromides were recovered unchanged (>70%). Moreover, no evi-
dence of the formation of the aryl thioethers 1–6a was obtained
from these reaction mixtures.
On the contrary, the anthracene and pyrene dibromides, 7, and
9 underwent smooth reactions with the phenylthiolate anion.
Thus, the reaction mixtures turn orange or dark orange after 2 h.
An additional reaction time of 22 hours and a simple workup were
needed to obtain the corresponding di(arylthio)arenes 7a and 9a in
very good yields and purity. Neither the dibromides nor the mon-
osubstituted bromides were detected in the crude products by GC-
MS. We also verified that the solvents DMSO and DMAc are not as
convenient as DMI. Reaction times of one week were needed in
DMSO and DMAc to match the yield of 7a achieved after one day
in DMI. In addition, we detected 1% of 7 in the crude product ob-
tained using DMSO while 2–3% of 7 and 1% of the monosubstituted
bromide where found in the case of DMAc. Unfortunately, the reac-
tions of the dibromides 7 and 9 with the less nucleophilic 2-chlo-
robenzenethiolate anion were unsuccessful even after a week. We
noted that the successful reactions took place in heterogeneous
conditions; as the sodium thiolate, the dibromides 7 and 9 and
their related 9,10-diphenylthioanthracene, 7a, and 2,6-diphenyl-
thiopyrene, 9a, were not appreciably soluble in DMI. So in an effort
to counterbalance the reduced nucleophilicity of the Cl-substituted
thiolate with an increased solubility of the substrate, the dibromo-
anthracene 8 bearing two polar side chains was treated with the
thiolate anion and the 2-chlorothiolate anion. However, 8 and its
chainless counterpart 7 showed the same reaction patterns, sug-
gesting that their reactivity depends mainly on intrinsic structural
factors.
The treatment of 2,6,9,10-tetrabromoanthracene, 10, (see
Scheme 2) with 2 equiv of either the phenylthiolate or the 2-chlo-
robenzenethiolate anion for a week then afforded the persubstitut-
ed tetrakis(phenylthio)- anthracenes 10a (65%) and 10b (78%) in
good yields although at a slower pace than the dibrominated
anthracenes 7 and 8, which could possibly be due to a lower reac-
tivity of the bromine in the positions 2 and 6 coupled with the very
low solubility of 10 in DMI. Shortening the reaction times to four
days results in lower yields, for example, 10 yielded 38% (X = H)
and 47% (X = Cl) of its perthioethers. The higher yield of 10b com-
pared to 10a probably results from a better recovery due to its low-
er solubility. Thus, the solubility of 10a in DMI at 40 °C is 0.8% w/v
while that of 10b is <0.2 % w/v. Again, no significant amounts of
unreacted or partially substituted bromides were detected in the
crude products 10a and 10b that were isolated by filtration after
either four or seven days.
We also tested the use of molecular modeling as a practical pre-
dictive tool for selecting synthetic targets within this substitution
reaction framework. We assumed that the nucleophilic substitu-
tion reaction operates through an ionic mechanism. Thus, the reac-
tion heats,
formation of the aryl bromides,
senheimer complex,
HMf , formed in the first attack of the thiolate
to the mono-, di-, or tetrabromide. The analysis of the last column
of Table indicates that all successful reactions have
Hr <À15 Kcal/mol. It also shows that the substitution would oc-
cur with preference at the 9-position of 10. Indeed, the calculated
D
Hr, were calculated at the AM1 level from the heats of
D
HAf B, and the corresponding Mei-
D
1
D
D
Hr for the second attack to give 11 is À30.0 Kcal/mol and the
values obtained for the two subsequent attacks to the 2- and
6-positions are À17.0 and À17.7 Kcal/mol, indicating that 11 accu-
mulates to gradually give 10a. Moreover, we calculated a
DHr value
of À22.5 Kcal/mol for the reported20 persubstitution of tetrabro-
mopyrene by sodium phenylthiolate, that is, in agreement with
this thermodynamic criteria. Though they have to be handed with
great care, molecular modeling results suggest that, for example,
selective substitution of bromide could hardly be achieved with
2,3,6,7-tetrabromo anthracene (
very likely that the isomeric 2,3,9,10-tetrabromoanthracene
Hr = À24.3 Kcal/mol) or the 2,3,6,7,10,11-hexabromotriphenyl-
ene (
D
Hr = À12.2 Kcal/mol) while it is
(D
D
Hr = À15.9) could render their corresponding perthioethers,
making these bromides interesting synthetic targets. Further
experimental work is in progress regarding the last two above
mentioned bromides.
The typical synthetic procedure is exemplified by the synthesis
of tetrakis(2-chlorophenylthio)anthracene. First, 2,6,9,10-tetrab-
romoanthracene, 10, was synthesized as follows: a solution of bro-
mine (0.57 g, 3.59 mmol, 0.19 mL) in nitrobenzene (0.35 mL) was
added to a solution of 9,10-dibromoanthracene (0.50 g, 1.5 mmol)
in nitrobenzene (3.5 mL) at 100 °C. The solution was stirred at
160 °C for 6 h. and for 30 min. at 200 °C. The mixture was cooled
at room temperature and stirred overnight. The resulting solid
was filtered off and washed with hot CH2Cl2 (3 Â 15.0 mL) to give
a yellow solid. Yield: 0.30 g (40%). mp: 296 °C (lit.21, mp 294 °C). 1H
NMR: (300 MHz, CDCl3): d = 8.33 (d, J = 1.75 Hz, 1H), 8.05 (d,
J = 9.34 Hz, 1H), 7.32 (dd, J = 9.34, 1.75 Hz, 1H). 13C NMR: (CDCl3)
d = 137.4, 131.9, 131.8, 131.7, 130.4, 130.2, 129.1, GC–MS: m/
e = 494 (100%), 492 (68%), 496 (64%), 490 (17%), 498 (15%).
X
SH
S
X
X
40 °C
Br
S
Br
S
Br
EtONa/DMI
X
S
X
Br
10
Secondly, in
a Schlenk tube, 2-chlorothiophenol (0.18 mL,
1.60 mmol) was added with stirring to a solution of sodium
(0.04 g, 1.60 mmol) in ethanol (5.0 mL). The resulting sodium thio-
phenolate solution was evaporated to dryness in vacuo and the
whitish residue was suspended in DMI (2.0 mL). Then, tetrabro-
10a; X = H
10b; X = Cl
Scheme 2.

P. G. Del Rosso et al. / Tetrahedron Letters 51 (2010) 6730–6733
6733
Chapter 32 (b) Testaferri, L.; Tingoli, M.; Tiecco, M. J. Org. Chem. 1980, 45, 4376;
(c)J. Polym. Sci., Part A: Polym. Chem 1988, 26, 2581; (d) In, I.; Kim, S. Y. J. Polym.
Sci., Part A: Polym. Chem. 2006, 44, 2440.
mide 10 (0.100 g, 0.202 mmol) was added to the reaction mixture
and the suspension was stirred for 1 h. at room temperature and
seven days at 40 °C. After the addition of MeOH (5 ml), the sus-
pended greenish yellow solid was filtered off, washed with meth-
anol and dried. Yield: 0.116 g (78%), mp: 230–232 °C. 1H NMR
(300 MHz, CDCl3): d = 8.75 (d, J = 9.12 Hz, 2H), 8.43 (d, J = 1.57 Hz,
2H), 7.40 (dd, J = 9.12 Hz, 1.57 Hz, 2H), 7,36 (m, J = 7.73 Hz,
1.42 Hz, 4H), 7.33 (dd, J = 7.64 Hz, 1.62 Hz, 2H), 7.25 (dt,
J = 7.78 Hz, 1.62 Hz, 2H), 7.13 (dt, J = 7.64 Hz, 1.42 Hz, 2H), 7.01
(dt, J = 7.88 Hz, 1.48 Hz, 2H), 6.82 (dt, J = 7.92 Hz, 1.34 Hz, 2H),
6.06 (dd, J = 7.88 Hz, 1.40 Hz, 2H). 13C NMR (CDCl3) d = 136.8,
136.2, 136.1, 135.2, 134.6, 134.3, 133.8, 132.2, 131.7, 131.1,
130.8, 130.3, 129.6, 129.1, 128.9, 128.8, 128.0, 127.7, 127.4,
127.1, 127.0, 126.9, 126.1, 125.7, 125.6, 125.3. 10a was recrystal-
ized from THF–MeOH. Anal. Calcd for C38H22Cl4S4: C, 60.96; H,
2.96; Cl, 18.94; S, 17.13. Found: 60.79; H, 2.91; S, 16.97.
2. (a) Szigeti, Z.; Malon, A.; Vigassy, T.; Csokai, V.; Grun, A.; Wygladacz, K.; Ye, N.;
Xu, C.; Chebny, V. J.; Bitter, I.; Rathore, R.; Bakker, E.; Pretsch, E. Anal. Chim. Acta
2006, 572, 1; (b) Vicente, J.; Abad, J. A.; Lopez-Nicolas, R. M. Tetrahedron Lett.
2005, 46, 5839; (c) Vicente, J.; Abad, J. A.; Lopez-Nicolas, R. M. Tetrahedron
2008, 64, 6281.
3. (a) Van Bierbeek, A.; Gingras, M. Tetrahedron Lett. 1998, 39, 6283–6286; (b)
Gingras, M.; Placide, V.; Raimundo, J.-M.; Bergamini, G.; Ceroni, P.; Balzani, V.
Chem. Eur. J. 2008, 14, 10357.
4. (a) Cammidge, A. N.; Gopee, H. J. Mater. Chem. 2001, 11, 2773; (b) Gurek, A. G.;
Durmus, M.; Ahsen, V. New J. Chem. 2004, 28, 693; (c) Sergeyev, S.; Pisula, W.;
Geerts, Y. H. Chem. Soc. Rev. 2007, 36, 1902; (d) Atilla, D.; Aslıbay, G.; Gürek, A.
G.; Can, H.; Ahsen, V. Polyhedron 2007, 26, 1061.
5. (a) Herradura, P. D.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019; (b)
Jampilek, J.; Dolezal, M.; Kunes, J.; Raich, I.; Liska, F. Chem. Pap. 2005, 59, 182.
6. Sirringhaus, H.; Friend, R. H.; Wang, C.; Leuningerb, J.; Mullen, K. J. Mater. Chem.
1999, 9, 2095.
7. Ames, D. E.; Opalko, A. Synthesis 1983, 234.
8. Hennings, D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2.
9. Rice, J. E.; Cai, Z. W. J. Org. Chem. 1993, 58, 1415.
10. Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem.
Soc. 2006, 128, 1066.
Acknowledgments
11. Wegner, H. A.; Scott, L. T.; de Meijere, A. J. Org. Chem. 2003, 68, 883.
12. (a) Wang, J.-X.; McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.;
Mulvihill, M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923; (b) Dyker, G. Chem. Ber.
Recl. 1997, 130, 1567.
13. (a) Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D. Synthesis 1983, 751; (b)
Caruso, A. J.; Colley, A. M.; Bryant, G. L. J. Org. Chem. 1991, 56, 862.
14. Chan, S.-C.; Jang, J.-P.; Cherng, Y.-J. Tetrahedron 2009, 65, 1977.
15. Pierini, A. B.; Baumgartner, M. T.; Rossi, R. A. J. Org. Chem. 1991, 56, 580.
16. (a) Fernandez-Rodrıguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 2180; (b) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587; (c) Murata, M.;
Buchwald, S. L. Tetrahedron 2004, 60, 7397.
17. (a) Carril, M.; San Martin, R.; Dominguez, E. Chem. Soc. Rev. 2008, 37, 639; (b)
Zhu, D.; Xu, L.; Wu, F.; Wan, B. S. Tetrahedron Lett. 2006, 47, 5781; (c) Bates, C.
G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org. Lett. 2004, 6, 5005.
18. MacNicol, D. D.; Mallinson, P. R.; Murphy, A.; Sym, G. J. Tetrahedron Lett. 1982,
23, 4131.
Financial support from SGCyT-UNS and SPU-MCyT is acknowl-
edged. P.G.D.R. is member of the research staff of CIC-PBA. R.O.G.
is member of the research staff of CONICET.
Supplementary data
Supplementary data associated (the synthesis of the aryl bro-
mides, characterization of 11, 1H NMR and 13C NMR characteriza-
tion of crude products and computational details) with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.069.
19. Cogolli, P.; Maiolo, F.; Testaferri, L.; Tingolli, M.; Tiecco, M. J. Org. Chem. 1979,
44, 2642.
20. Heywang, G.; Jonas, F. U.S. Patent 5008430, 1991.
References and notes
21. Mattes, S. L.; Farid, S. Y. U.S. Patent 4341852, 1982.
1. (a) Geibel, J. F.; Campbell, R. W. In Comprehensive Polymer Science; Eastmond, G.
C., Ledwith, A., Russo, S., Sigwalt, P., Eds.; Pergamon: Oxford, UK, 1989; Vol. 5,.