From transient sulfenic acids to disulfide-functionalized tripodal structures

Article abstract of DOI:10.1055/s-0030-1259306

The condensation of transient polysulfenic acids with thiols, some of which containing privileged structures, has been applied to the synthesis of tripodal disulfides. The easy access to this new kind of conformationally constrained polyfunctionalized com

Full text of DOI:10.1055/s-0030-1259306

254
LETTER
From Transient Sulfenic Acids to Disulfide-Functionalized Tripodal
Structures
FromSulfenic
A
cidsto
a
Tripodal
D
r
isulfide
i
s
a Chiara Aversa, Anna Barattucci,* Paola Bonaccorsi
Dipartimento di Chimica Organica e Biologica, Università degli Studi di Messina, Viale F. Stagno d’Alcontres 31 (vill. S. Agata),
98166 Messina, Italy
Fax +39(090)393895; E-mail: abarattucci@unime.it
Received 19 October 2010
Dedicated to Professor Alberto Brandi on the occasion of his 60th birthday
We wish to report here the first mild and efficient synthet-
Abstract: The condensation of transient polysulfenic acids with
ic route, starting from thiols 1 (Figure 1), to generate tran-
sient trisulfenic acids 2 and their in situ condensation with
suitable thiols to afford disulfide-functionalized tripodal
thiols, some of which containing privileged structures, has been ap-
plied to the synthesis of tripodal disulfides. The easy access to this
new kind of conformationally constrained polyfunctionalized com-
pounds opens the way to their application in supramolecular chem- molecules decorated with different kinds of privileged
istry.
structures, from pyrimidine rings to amino acid and carbo-
hydrate moieties.
Key words: sulfoxides, thiols, condensation, carbohydrates,
pyridines
SH
R
SOH
R
SH
SOH
Hexafunctionalized 1,3,5-(R1)3-2,4,6-(R2)3 benzenes,
where R1 is a linear aliphatic chain containing two or more
carbon atoms, have found many applications as host mol-
ecules in the last decade1 because of their tendency to
adopt the most thermodynamically stable tripodal confor-
mation, with an alternate geometrical orientation of the
ring substituents above and below the benzene plane, suit-
able to interact with a large variety of guests. Among
these multi-armed molecules, sulfurated systems have
found application as building blocks in the formation of
macrocycles, chemiluminescent materials, coordination
polymers, and metal sensors.2
R
R
R
R
1a R = Et 2a
1b R = Me 2b
1c R = H 2c
HS
HOS
Figure 1 Transient trisulfenic acids 2 coming from trithiols 1
The synthetic path utilized to prepare sulfoxide 6a, pre-
cursor of the trisulfenic acid 2a, and its condensation with
thiols 7–12 (Table 1), to obtain tripodal disulfides 13–16,
17a, 18, is depicted in Scheme 1.
Commercially available 1,3,5-triethylbenzene (3) was
subjected to an initial bromomethylation7 to give tribro-
mide 4 in quantitative yield. Reaction of 4 with thiourea
gave the corresponding tris(isothiouronium) salt8 that af-
forded trithiol 1a in good yield (80%). Two steps were
then required to obtain sulfoxide 6a as sulfur diastereo-
meric mixture, precursor of sulfenic acid 2a: an almost
quantitative nucleophilic conjugated addition9 of the thi-
olate of 1a to methyl acrylate, and a controlled oxidation10
of the obtained trisulfide 5 by means of MCPBA at –78 °C.
Starting from the thiols 1b and 1c, prepared from the cor-
responding commercial tribromides following literature
procedures,8 the same route can be used for the formation
in situ of trisulfenic acids 2b and 2c, generated in a previ-
ous work11 by the thermolysis at 40 °C of sulfinyl precur-
sors, different from triesters 6. Going on with our research
we have now found in b-methoxycarbonylethanesulfox-
ides 6 the best precursors of 2 for the good handling and
optimal results in cleanness and yields of the condensation
reactions with thiols 7–12 to give the trivalent disulfides
13–18. Reaction conditions, starting and final products
are shown in Table 1.
Recently, we have described the application of the con-
densation of transient sulfenic acids with thiols to the syn-
thesis of unsymmetrically substituted disulfides.3 Except
few cases, sulfenic acids are transient compounds,4 that
can be generated in situ through a b-elimination from suit-
able sulfoxides, and, until now, their most exploited reac-
tion has been the concerted syn-addition to unsaturations
for the obtainment of alkyl and alkenyl sulfoxides.
The effectiveness and modularity of this synthetic path-
way, and the mild conditions required for the obtainment
of the disulfide bond via sulfenic acid intermediation,
have opened a route for the preparation of even uncom-
mon molecules such as those described in this letter. Fur-
thermore, it is widely recognized the central role of
disulfide group in many biological redox events,5 and,
thanks to its very flexible and adaptable structure, it can
hold a relevant role in supramolecular and coordination
chemistry.6
In order to obtain the best results in terms of yields, the
condensation requires a large excess of thiol, but this ex-
cess is easily recovered by column chromatography or
SYNLETT 2011, No. 2, pp 0254–0258
Advanced online publication: 05.01.2011
DOI: 10.1055/s-0030-1259306; Art ID: G31510ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

LETTER
From Sulfenic Acids to Tripodal Disulfides
255
Br
SH
SH
(CH2O)n, ZnBr2
HBr, AcOH
1) thiourea, EtOH
r.t., 20 h
Br
reflux,
overnight
2) NaOH (aq)
reflux, 4 h
3) HCl
Br
HS
3
4
1a
Triton B
THF, –78 °C
CO2Me
CO2Me
MeO2C
CO2Me
SO
CO2Me
S
S
S
O
MCPBA
CH2Cl2, –78°C
S
OS
MeO2C
5
CO2Me
6a
S
R
S
Δ
CO2Me
S
S
R
RSH
7–12
2a
(– H2O)
S
S
R
13–16, 17a, 18
Scheme 1 Synthesis of 2,4,6-triethyl-1,3,5-tri(dithiomethyl)benzenes 13–16, 17a, 18
crystallization, and can be reused. The best conditions for end of the reaction, all the final products have been puri-
the in situ generation of 2a were obtained when the reac- fied by simple column chromatography.12
tion was performed in 1,2-dichloroethane or 1,4-dioxane,
The use of the obtained library of trivalent disulfides can
depending on their boiling point and the solubility of thi-
space in many chemical fields. The presence of three or
ols 7–12. Even if reaction times are longer in 1,2-dichlo-
six aromatic nitrogen atoms in 13–15 opens the way to
roethane (bp 83 °C) than in 1,4-dioxane (bp 101 °C),
their application in coordination chemistry.6,13 On the oth-
because of the major difficulty of the sulfoxide to thermo-
er hand, disulfides 16–18 containing naturally occurring
residues of cysteine, galactose, and glucose can be tested
lyze at lower temperature, dichloroethane represents the
right solvent for more sensitive and thermolabile thiols,
for their biological potentiality.14 Not conformationally
such as amino acid and sugar derivatives 10–12, in order
constrained glucocompounds 17b,c have been synthe-
sized to be compared with tripodal 17a (Table 1): tris(di-
sulfides) 17a–c have been obtained in good yields, fully
characterized, and subjected to acetyl deprotection to give
to minimize their decomposition and favor their recovery
at the end of the reaction. When heteroaromatic thiols 7–
9 have been used, where thermolabile functional groups
are absent, thermolysis at the reflux temperature of diox-
water-soluble macromolecules ready for biological tests.
ane has been preferred because of the shorter reaction
In conclusion we have reported in this letter an efficient
times and higher yields. The best way to recognize the ul-
way to synthesize, via sulfenic acid intermediates, tripo-
timate completion of the thermolysis of all the three sulfi-
dal polyfunctionalized disulfide molecules that can find
nyl arms, and the formation of all the three disulfide
application in the preparation of a large number of differ-
bonds, has been the periodic control of the reaction crudes
ent substrates, allowing an easy introduction of exotic
substituents into the 1,3,5-(R1)3-2,4,6-(R2)3 benzene core.
by 1H NMR. The contemporaneous disappearance of the
typical 3.71 ppm singlet of the methoxy group and the
corresponding broad AB system due to the diastereotopic
near-to-sulfoxide methylene hydrogens in 6 have been di-
agnostic for the determination of the reaction times. At the
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 2, 254–258 © Thieme Stuttgart · New York

256
M. C. Aversa et al.
LETTER
Table 1 Synthesis of 1,3,5-Tri(dithiomethyl)benzenes 13–18
Entry Sulfenic Reaction conditions12
Thiol
Product12
acid
solvent (Treflux), trisulfoxide/thiol
molar ratio, time, yield
NH2
N
S
N
S
N
S
N
S
NH2
NH2
N
1
2a
1,4-dioxane (101 °C), 1:9, 4 h, 80%
N
SH
S
S
7
H2N
N
S
N
S
13
N
N
S
S
2
2a
1,4-dioxane (101 °C), 1:9, 3 h, 47%
N
SH
S
S
8
N
14
N
S
S
N
S
S
N
3
2a
1,4-dioxane (101 °C), 1:9, 4 h, 35%
SH
S
9
S
N
15
OAc
OAc
O
S
AcO
S
OAc
OAc
OAc
AcO
S
OAc
O
S
O
4
2a
DCE (83 °C), 1:6, 72 h, 40%
AcO
SH
OAc
AcO
OAc
OAc
10
OAc
O
S
S
AcO
OAc
16
Synlett 2011, No. 2, 254–258 © Thieme Stuttgart · New York

LETTER
From Sulfenic Acids to Tripodal Disulfides
257
Table 1 Synthesis of 1,3,5-Tri(dithiomethyl)benzenes 13–18 (continued)
Entry Sulfenic Reaction conditions12
Thiol
Product12
acid
solvent (Treflux), trisulfoxide/thiol
molar ratio, time, yield
OAc
O
AcO
AcO
S
S
OAc
OAc
OAc
OAc
S
S
S
OAc
O
O
AcO
S
AcO
AcO
5
6
7
2a
DCE (83 °C), 1:6, 72 h, 51%
SH
OAc
11
OAc
O
S
S
AcO
AcO
AcO
AcO
OAc
17a
OAc
O
AcO
AcO
S
S
OAc
OAc
OAc
OAc
O
AcO
S
2b
DCE (83 °C), 1:6, 72 h, 52%
11
OAc
O
S
S
AcO
OAc
17b
OAc
O
AcO
AcO
S
S
OAc
OAc
OAc
OAc
S
O
AcO
2c
DCE (83 °C), 1:6, 72 h, 50%
11
OAc
O
S
S
AcO
OAc
17c
NHBoc
NHBoc
CO2Me
S
MeO2C
S
S
O
S
MeO
SH
NHBoc
8
2a
DCE (83 °C), 1:6, 120 h, 30%
S
12
MeO2C
S
NHBoc
18
Ballester, P.; Deyà, P. M.; Anslyn, E. V. J. Org. Chem. 2006,
71, 7185. (d) Amendola, V.; Boiocchi, M.; Colasson, B.;
Fabbrizzi, L.; Monzani, E.; Douton-Rodriguez, M. J.;
Spadini, C. Inorg. Chem. 2008, 47, 4808. (e) Dell’Anna,
G. M.; Annunziata, R.; Benaglia, M.; Celentano, G.; Cozzi,
F.; Francesconi, O.; Roelens, S. Org. Biomol. Chem. 2009,
7, 3871.
Acknowledgment
We are grateful to the Ministero dell’Istruzione, dell’Università e
della Ricerca and Università di Messina, Italy, for financial support
(PRIN 2008).
References and Notes
(2) (a) Walsdorff, C.; Saak, W.; Pohl, S. J. Chem. Soc., Dalton
Trans. 1997, 1857. (b) Tam-Chang, S.-W.; Stehouwer, J. S.;
Hao, J. J. Org. Chem. 1999, 64, 334. (c) Yang, C.; Wong,
W.-T. J. Mater. Chem. 2001, 11, 2898. (d) Li, J.-R.; Bu,
X.-H.; Zhang, R.-H. Eur J. Inorg. Chem. 2004, 1701.
(e) Kaur, N.; Singh, N.; Cairns, D.; Callan, J. F. Org. Lett.
(1) (a) Hennrich, G.; Anslyn, V. N. Chem. Eur. J. 2002, 8,
2218. (b) Kim, J.; Ryu, D.; Sei, Y.; Yamaguchi, K.; Ahn, K.
H. Chem. Commun. 2006, 1136. (c) Frontera, A.; Morey, J.;
Oliver, A.; Neus Piña, M.; Quiñonero, D.; Costa, A.;
Synlett 2011, No. 2, 254–258 © Thieme Stuttgart · New York

258
M. C. Aversa et al.
LETTER
2009, 11, 2229. (f) Lélias-Vanderperre, A.; Aubert, E.;
Chambron, J.-C.; Espinosa, E. Eur. J. Org. Chem. 2010,
2701.
3 × CH2CH3). Anal. Calcd for C27H42O9S3 (606.8): C, 53.44;
H, 6.98. Found: C, 53.70; H, 7.20.
(11) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Faggi, C.;
Papalia, T. J. Org. Chem. 2007, 72, 4486.
(12) General Procedure for Thermolysis of Trisulfoxides 6a–
c and Their Coupling with Thiols 7–12
(3) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P. Eur. J. Org.
Chem. 2009, 6355.
(4) (a) Hogg, D. R. In The Chemistry of Sulfenic Acids and
Derivatives; Patai, S., Ed.; Wiley and Sons: Chichester,
1990, 361. (b) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P. Curr. Org. Chem. 2007, 11, 1034.
(5) (a) Hozoji, M.; Kimura, Y.; Kioka, N.; Ueda, K. J. Biol.
Chem. 2009, 284, 11293. (b) Beckwith, J. Genetics 2007,
176, 733. (c) Tu, B. P.; Ho-Schleyer, S. C.; Travers, K. J.;
Weissman, J. S. Science 2000, 290, 1571. (d) Creighton,
T. E. Biol. Chem. 1997, 378, 731.
(6) (a) Hanton, L. R.; Hellyer, R. M.; Spicer, M. D. Inorg. Chim.
Acta 2006, 359, 3659. (b) Manna, S. C.; Ribas, J.;
Zangrando, E.; Chaudhuri, N. R. Polyhedron 2007, 26,
4923. (c) Sun, J.; Patrick, B. O.; Sherman, J. C. Tetrahedron
2009, 65, 7296.
A solution of 1 mmol of sulfoxide 6 and an excess of thiol in
20 mL of solvent (see Table 1) was maintained under stirring
at the reflux temperature. The reaction was monitored via
TLC and 1H NMR. Except for 7, directly precipitated from
1,4-dioxane solution after simple cooling at r.t., the excess of
thiols 8–12 and the purified disulfides 13–18 were recovered
from the chromatographic column.
1,3,5-Tri{[(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-
dithio]methyl}-2,4,6-triethylbenzene (17a)
TLC: Rf = 0.32 (PE–EtOAc, 50:50). White solid, mp 84 °C.
[a]D28 –95.9 (c 0.02, CHCl3). 1H NMR (300 MHz, CDCl3):
d = 5.30–5.10 (m, 9 H, H-2¢-4¢,2¢¢-4¢¢,2¢¢¢-4¢¢¢), 4.66 (m, 3 H,
H-1¢,1¢¢,1¢¢¢), 4.33 (AB dd, J5,6A = 5.0 Hz, J6A,6B = 12.3 Hz, 3
H, HA-6¢,6¢¢,6¢¢¢), 4.19 (s and AB dd, 9 H, 3 × CH2S and HB-
6¢,6¢¢,6¢¢¢), 3.83 (m, 3 H, H-5¢,5¢¢,5¢¢¢), 2.94 (m, 6 H,
3 × CH2CH3), 2.09, 2.05, 2.04 and 2.03 [4 s, 36 H,
12 × C(O)CH3], 1.30 (t, 9 H, 3 × CH2CH3). 13C NMR (75
MHz, CDCl3): d = 170.6, 170.2, 169.4 and 169.1 (12 × CO),
144.0 (C-1,3,5), 130.5 (C-2,4,6), 88.2 (C-1¢,1¢¢,1¢¢¢), 76.3,
73.7, 69.3 and 68.1 (C-2¢-5¢,2¢¢-5¢¢,2¢¢¢-5¢¢¢), 62.3 (C-
6¢,6¢¢,6¢¢¢), 40.5 (3 × CH2S), 23.4 (3 × CH2CH3), 20.8
(12 × OCH3), 16.3 (3 × CHCH3). Anal. Calcd for
C57H78O27S6 (1387.6): C, 49.34; H, 5.67. Found: C, 49.51;
H, 5.34.
(7) Vacca, A.; Nativi, C.; Cacciarini, M.; Pergoli, R.; Roelens,
S. J. Am. Chem. Soc. 2004, 126, 16456.
(8) Houk, J.; Whitesides, G. M. J. Am. Chem. Soc. 1987, 109,
6825.
(9) 2,4,6-Triethyl-1,3,5-tri{[(2-methoxycarbonylethyl)-
thio]methyl}benzene (5)
To a solution of thiol 1a (6.73 g, 22.40 mmol) in dry THF
(109 mL) under argon atmosphere at –78 °C, 4.7 mL of a 40
wt% Triton B solution in MeOH (10.62 mmol) were added.
After 5 min stirring at –78 °C, 18 mL of methyl acrylate
(197.88 mmol) were added. The reaction, monitored by TLC
every 5 min, appeared complete after 30 min. The reaction
mixture, evaporated under reduced pressure, was submitted
to flash column chromatography, giving 9.90 g (17.72
mmol) of 5 (79% yield). TLC: Rf = 0.42 (PE–EtOAc, 60:40).
Low-melting solid. 1H NMR (300 MHz, CDCl3): d = 3.74 (s,
6 H, 3 × ArCH2S), 3.67 (s, 9 H, 3 × OCH3), 2.83 (m, 12 H,
3 × CH2CH3 and 3 × CH2CH2CO2CH3), 2.63 (t, 6 H, 3J = 7.0
Hz, 3 × CH2CO2CH3), 1.26 (t, 9 H, 3J = 7.6 Hz,
1,3,5-Tri({[(R)-2-tert-Butoxycarbonylamino-2-
methoxycarbonylethyl]dithio}methyl)-2,4,6-
triethylbenzene (18)
TLC: Rf = 0.60 (PE–EtOAc, 50:50). Transparent oil. 1H
NMR (300 MHz, CDCl3): d = 5.35 (br d, 3J = 8.1 Hz, 3 H,
3 × NH), 4.61 (m, 3 H, H-2¢,2¢¢,2¢¢¢), 4.06 and 4.03 (two AB
d, 2J = 11.8 Hz, 6 H, 3 ´ ArCH2S), 3.75 (s, 9 H, 3 × OCH3),
3.11 and 3.06 (two AB dd, J1A,1B = 13.4 Hz,
3 × CH2CH3). 13C NMR (75 MHz, CDCl3): d = 172.3 (3 ×
CO), 142.3 and 131.1 (C-1-6), 51.6 (3 × CH3), 34.5
(3 × CH2CO2CH3), 31.2 and 28.3 (3 × CH2SCH2), 22.7
(3 × CH2CH3), 16.0 (3 × CH2CH3). Anal. Calcd for
C27H42O6S3 (558.8): C, 58.03; H, 7.58. Found: C, 58.17; H,
7.45.
J1A,2 = J1B,2 = 4.7 Hz, 6 H, H2-1¢,1¢¢,1¢¢¢), 2.88 (q, 3J = 7.6 Hz,
6 H, 3 × CH2CH3), 1.44 [s, 27 H, 3 ´ C(CH3)3], 1.26 (t, 9 H,
3 × CH2CH3). 13C NMR (75 MHz, CDCl3): d = 171.2
(3 × CO2CH3),155.1 (3 × NHCO), 143.9 (C-1,3,5), 130.1
(C-2,4,6), 80.2 [3 × C(CH3)3], 52.9 (C-2¢,2¢¢,2¢¢¢), 52.7
(3 × OCH3), 41.3 and 38.5 (3 × ArCH2S, C-1¢,1¢¢,1¢¢¢), 28.3
[3 × C(CH3)3], 23.3 (3 × CH2CH3), 16.0 (3 × CH2CH3).
Anal. Calcd for C42H69N3O12S6 (1000.4): C, 50.42; H, 6.95;
N, 4.20. Found: C, 50.56; H, 6.75; N, 4.26.
(10) 2,4,6-Triethyl-1,3,5-tri{[(2-methoxycarbonylethyl)-
sulfinyl]methyl}benzene (6a)
To a CH2Cl2 solution of 5 (1.36 g, 2.43 mmol in 23 mL) at
–78 °C under continous stirring, 1.57 g of MCPBA (80 wt%,
7.28 mmol) in 50 mL of CH2Cl2 were added slowly. The
reaction, monitored by TLC, appeared complete at the end of
the oxidant addition. The reaction was quenched by adding
a 10 wt% aq solution of Na2S2O3. The organic layers were
separated and washed twice with a sat. NaHCO3 solution and
then twice with brine. After Na2SO4 dehydration, filtration,
and evaporation under reduced pressure, 6a was obtained in
an almost quantitative yield as a diastereomeric mixture.
TLC: Rf = 0.30 (PE–acetone, 25:75). Low-melting solid. 1H
NMR (300 MHz, CDCl3): d = 4.33 and 4.04 (two br AB d, 6
H, 3 × ArCH2SO), 3.71 (s, 9 H, 3 × OCH3), 3.20–2.60 (m, 18
H, 3 × CH2CH3 and 3 × CH2CH2), 1.24 (br t, 9 H,
(13) (a) Walsdorff, C.; Park, S.; Kim, J.; Heo, J.; Park, K.-M.; Oh,
J.; Kim, K. J. Chem. Soc., Dalton Trans. 1999, 923.
(b) McMorran, D. A.; Hartshorn, C. M.; Steel, P. J.
Polyhedron 2004, 23, 1055. (c) Cordes, D. B.; Hanton, L. R.
Inorg. Chem. Commun. 2005, 8, 967.
(14) (a) Gottschaldt, M.; Pfeifer, A.; Koth, D.; Görls, H.; Dahse,
H.-M.; Möllmann, U.; Obata, M.; Yano, S. Tetrahedron
2006, 62, 11073. (b) Murthy, B. N.; Sinha, S.; Surolia, A.;
Jayaraman, N.; Szilágyi, L.; Szabó, I.; Kövér, K. E.
Carbohydr. Res. 2009, 344, 1758. (c) Aversa, M. C.;
Barattucci, A.; Bonaccorsi, P.; Marino-Merlo, F.; Mastino,
A.; Sciortino, M. T. Bioorg. Med. Chem. 2009, 17, 1456.
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