The oxygenation of thieno[2,3- b ]thiophenes

Article abstract of DOI:10.1021/jo100702f

(Figure presented) Members of thieno[2,3-b]thiophenes were oxidized using the HOF·CH₃CN complex, transforming the sulfur atom to the corresponding sulfonyl group in high yield and under very mild conditions.

Full text of DOI:10.1021/jo100702f

pubs.acs.org/joc
CN complex. A solution of this reagent is easily prepared by
The Oxygenation of Thieno[2,3-b]thiophenes
bubbling dilute fluorine through aqueous acetonitrile and is
considered today as one of the best oxygen-transfer agents
organic chemistry has to offer. The reagent’s oxygen atom is a
strong electrophile since it is weakly bonded to the most elec-
tronegative element, fluorine. This complex is able to serve as an
oxygen transfer agent even to very weak nucleophiles6 under
mild conditions. Some of the work with this reagent was des-
cribed in two reviews,7 and later we had used it for the prepa-
ration of episulfones,8 various N,N-diazafluorenes,9 tetrazole
3N-oxide derivatives believed to be inaccessible,10 and much
more.
Neta Shefer and Shlomo Rozen*
School of Chemistry, Tel-Aviv University, Tel-Aviv 69978,
Israel
rozens@post.tau.ac.il
Received April 12, 2010
Compounds 3,4-dimethylthieno[2,3-b]thiophene (1a) and
3,4-diphenylthieno[2,3-b]thiophene (1b),11 both with two
indistinguishable sulfur atoms, were reacted with 2 molar
equiv of HOF CH3CN at 0 °C. Within a few seconds, the
3
previously unknown 3,4-dimethylthieno[2,3-b]thiophene-
1,1-dioxide (2a) and 3,4-diphenylthieno[2,3-b]thiophene-
1,1-dioxide (2b) were formed in quantitative yield. No other
byproducts, usually associated with long reaction times and
high temperatures, were observed. When only 1 molar equiv
Members of thieno[2,3-b]thiophenes were oxidized using
the HOF CH3CN complex, transforming the sulfur atom
to the corresponding sulfonyl group in high yield and
under very mild conditions.
3
of HOF CH3CN was applied to 1a, 50% was converted to
3
the sulfone 2a while the rest proved to be the starting material
with no sulfoxide in sight. Parallel results have been ob-
served and explained previously.8,12 Attempts to fully oxi-
dize either 1a or 1b to their tetraoxide derivatives by adding
an excess of HOF CH3CN were unsuccessful. At this point, we
3
Thiophene derivatives represent a class of important and
well-studied heterocycles.1 In the past few years, there has
been a resurgence of interest concentrated around oligothio-
phenes. This family is among the most explored π-systems
with favorable electronic and optical properties for a wide
range of new technologies.2
emphasize that no two adjacent thiophene units in any thieno-
[2,3-b]thiophene we tried could be converted to the tetraoxide.
Since both sulfur atoms are attached to the same carbon, it
appears that the first SO2 moiety formed reduces the nucleo-
philic character of the second sulfur to almost nonexistence,
and even the strong electrophilic oxygen of the HOF CH3CN
3
In our previous works we described the first syntheses and
some key properties of conjugated oligothiophene [all]-S,S-
dioxides3 as well as fused thieno[3,2-b]thiophene S,S-di-
oxides,4 both promising classes of organic materials. In gen-
eral, unlike the thieno[3,2-b]thiophenes, thieno[2,3-b]thio-
phenes contain two annulated thiophene rings with the two
sulfur atoms facing the same direction. These compounds are
planar, rigid, and highly stable heterocycles with a central
cross-conjugated double bond. Previous attempts to obtain
thieno[2,3-b]thiophene S,S-dioxide by orthodox oxidations
either failed or resulted in very low yields even after prolonged
reaction times.5 Such an oxidation is not easy since the harsh
conditions, usually required to overcome the aromatic stabi-
lization, could lead to Diels-Alder-type reactions, SO2 elim-
inations, and more.5a
could not be attracted to it anymore. Support for this assump-
tion is also provided by DFT calculations (B3LYP/6-311G-
(d,p)) carried out on the parent skeletons and focused on the
Mulliken charge distribution of each sulfur atom before and
after oxidation. Table 1 clearly shows that the partly oxidized
fused oligothiophenes considerably reduce the negative charges
on the remaining sulfur, compared to the starting materials,
rendering the second sulfur oxidation improbable by any
known oxygen-transfer agent.5 This is in contrast to oligothio-
phenes where although the first sulfur oxidation naturally
reduces the electron density of the second sulfur atom, it still
leaves enough negative charge for the efficient HOF CH3CN
3
to transfer additional oxygen atoms to it as well.3
The incorporation of an electron-withdrawing group at the
2 and 5 positions,11,13 as in 1c and 1d, naturally decreases the
We report here a general method for the direct oxidation
of thieno[2,3-b]thiophene derivatives using the HOF CH3-
3
(6) (a) Kol, M.; Rozen, S. J. Org. Chem. 1993, 58, 1593–1595. (b) Kol, M.;
Rozen, S. J. Chem. Soc. Chem. Commun. 1991, 567–568.
(7) (a) Rozen, S. Eur. J. Org. Chem. 2005, 2433–2447. (b) Rozen, S. Acc.
Chem. Res. 1996, 29, 243–248.
(8) Harel, T.; Amir, E.; Rozen, S. Org. Lett. 2006, 8, 1213–1216.
(9) Harel, T.; Shefer, N.; Hagooly, Y.; Rozen, S. Tetrahedron 2010, 66,
3297–3300.
(1) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Hetero-
cycles; Wiley-VCH: New York, 2003; Chapter 5, Five-member Heterocycles,
Section 5.6 Thiophene.
(2) Rajca, A.; Miyasaka, M.; Pink, M.; Wang, H.; Rajca, S. J. Am. Chem.
Soc. 2004, 126, 15211–15222.
(3) Amir., E.; Rozen, S. Angew. Chem., Int. Ed. 2005, 44, 7374–7378.
(4) Shefer, N.; Harel, T.; Rozen, S. J. Org. Chem. 2009, 74, 6993–6998.
(5) (a) Chen, H. H.; May, J. A.; Lynch, V. M. J. Heterocycl. Chem. 1999,
32, 249–256. (b) Litvinov, V. P.; Gol’dfarb, Ya. L. Izv. AN SSSR Ser. Khim.
1963, 12, 2183–2192.
(10) Harel, T.; Rozen, S. J. Org. Chem. 2010, 75, 3141–3143.
(11) Comel, A.; Kirsch, G. J. Heterocycl. Chem. 2001, 38, 1167–1171.
(12) Rozen, S.; Bareket, Y. J. Org. Chem. 1997, 62, 1457–1462.
(13) Wang, Y.; Dong, D.; Yang, Y.; Huang, J.; Ouyang, Y.; Liu, Q.
Tetrahedron 2007, 63, 2724–2728.
DOI: 10.1021/jo100702f
r
Published on Web 06/03/2010
J. Org. Chem. 2010, 75, 4623–4625 4623
2010 American Chemical Society

Shefer and Rozen
JOCNote
SCHEME 2. Oxidation Competition between Bithiophene and
Thieno[2,3-b]thiophene Derivatives
TABLE 1. Mulliken Charge on Sulfur Atoms in Atomic Units
SCHEME 1. Oxygenation of thieno[2,3-b]thiophenes
hydrogen at the 5 position of 2f was up-fielded by 0.6 ppm
relative to the starting material, while the same hydrogen in 3f
exhibited a downfield shift of 0.4 ppm, as expected.
The reason for the oxidation of one of the sulfur atoms in
the thieno[2,3-b]thiophene, rather than a reaction on the
sulfur of the isolated thiophene, is understandable since the
extent of the aromaticity of the latter is higher. The two fused
thiophene rings of the thieno[2,3-b]thiophene have similar
aromaticity, and the electron-withdrawing substituents seem
to be responsible for the somewhat preferred regioselectivity
of the oxygenation.
In order to assess the aromaticity difference between
bithiophenes and thienothiophenes, we reacted a mixture
of 1a and 5,50-dimethyl[2,20]bithiophene (4) with 2 molar
equiv of HOF CH3CN at 0 °C. The corresponding S,S-di-
3
oxide 2a was obtained in about 10 s in quantitative yield,
while 4 was recovered unchanged (Scheme 2). It is worth
noting, however, that 4 could be fully oxidized if needed.3
When bis-aryl thienothiophene (1g)13 was reacted with
2 molar equiv of HOF CH3CN, once again the attack was on
3
the less aromatic system of the thieno[2,3-b]thiophene only,
forming 2,5-di(5-acetylthiophene-2-yl)-3,4-dimethylthieno-
[2,3-b]thiophene 1,1-dioxide (2g) in 95% yield (scheme 1).
All attempts to further oxidize the substituted 2-acetyl-
thiophene ring in 2f, 3f, and 2g were unsuccessful because
of the two strong electron-withdrawing groups, sulfonyl and
acetyl, in positions 2 and 5 of the thiophene skeleton.
The electronic properties of the products discussed were
studied by UV-vis. Table 2 lists the maximum wavelength
absorption (λmax), the HOMO-LUMO energy gap (ΔEg),
and the lowering of the HOMO-LUMO energy gap follow-
ing the oxygen-transfer reaction (ΔΔEg).
One can clearly see that the oxidation of one of the sulfur
atoms in thieno[2,3-b]thiophene (2a-d) causes a red shift of
about 50-72 nm. This indicates that a desirable lowering of
the HOMO-LUMO energy gap (ΔΔEg) has taken place.
The mono- and diarylthieno[2,3-b]thiophene (2e-g, 3f), on
the other hand, exhibit a blue shift apparently due to the
oxidation of the sulfur atom that causes the molecule to
break the π-conjugation.
propensity of the sulfur atom to undergo oxidation, but not to a
degree of preventing the hypofluorous acid from accomplishing
the oxygen-transfer process. When 2 molar equiv of HOF
CH3CN was used, the unknown diethyl 3,4-dimethylthieno-
[2,3-b]thiophene-2,5-dicarboxylate 1,1-dioxide (2c) and diethyl
3,4-diphenylthieno[2,3-b]thiophene-2,5-dicarboxylate 1,1-dio-
xide (2d) were both obtained in 95% yield. Replacing the ester
groups with the benzonitrile as in the 2,5-di-p-benzonitrile-3,4-
dimethylthieno[2,3-b]thiophene (1e)14 gave similar results, and
3
2 molar equiv of HOF CH3CN complex was enough to form
3
2,5-di-p-benzonitrile-3,4-dimethylthieno[2,3-b]thiophene 1,1-di-
oxide (2e) in 95% yield (Scheme 1). As was the case with 1a and
1b, addition of excess reagent to each of the starting materials 1
did not change the results.
When coupling thieno[2,3-b]thiophene units with one
thiophene derivative as in 2-(5-acetylthiophene-2-yl)-3,4-
dimethylthieno[2,3-b]thiophene (1f),13 and then reacting it
with 2 molar equivalents of HOF•CH3CN at 0 °C, two pro-
ducts were isolated. The first identified as 2-(5-acetylthio-
phene-2-yl)-3,4-dimethylthieno[2,3-b]thiophene-6,6-dioxide
(2f), while the second proved to be 2-(5-acetylthiophene-
2-yl)-3,4-dimethylthieno[2,3-b]thiophene-1,1-dioxide (3f) in
65% and 35% yields receptively (scheme 1).
In conclusion, we have demonstrated that the HOF CH3-
3
CN electrophilic oxygen atom could be transferred to a wide
range of thieno[2,3-b]thiophenes forming the corresponding
S,S-dioxides in unparalleled high yields and under very mild
conditions. While the reaction requires working with fluorine, it
is much less complicated than what many may think. One can
dilute the commercial fluorine on the spot or purchase pre-
mixed fluorine/nitrogen mixtures. In both cases, the technical
ease of the reaction producing solutions of the reagent (no
special equipment is needed) offers an easy way for transferring
The regiochemistry of the products resulting from the oxida-
tion of 1f was evident from the respective 1HNMRspectra. The
(14) Mashraqui, S. H.; Ashraf, M.; Ghadigaonkar, S. G. Synlett 2006, 15,
2423–2426.
4624 J. Org. Chem. Vol. 75, No. 13, 2010

Shefer and Rozen
JOCNote
TABLE 2. Absorption λmax (in nm) and HOMO-LUMO Energy Gap
precautions are taken, the work with fluorine is simple, and we
have never experienced difficulties working with it.
General Procedure for Producing HOF CH3CN. A mixture of
(ΔEg,a in eV) in Solutionb
c
compd
λmax (ΔEg)
ΔΔEg
3
10-20% F2 in nitrogen was used throughout this work. The gas
mixture was prepared in a secondary container prior to the
reaction15 and passed at a rate of about 400 mL per minute
through a cold (-15 °C) mixture of 100 mL of CH3CN and
10 mL of H2O in a regular glass reactor. The development of the
oxidizing power was monitored by reacting aliquots with an
acidic aqueous solution of KI. The liberated iodine was then
titrated with thiosulfate. Typical concentrations of the oxidizing
reagent were around 0.4-0.6 mol/L.
1a
2a
1b
2b
1c
2c
1d
2d
1e
2e
1f
224 (5.54)11
296 (4.19)
230 (5.39)11
282 (4.40)
270 (4.59)
319 (3.89)
271 (4.58)
321 (3.86)
318 (3.90)
295 (4.20)
364 (3.41)
316 (3.92)
301, 369 (3.36)
370 (3.35)
334 (3.71)
(1.35)
(0.99)
(0.70)
(0.72)
(-0.30)
General Procedure for Working with HOF CH3CN. A fused
3
thiophene derivative was dissolved in CH2Cl2, and the mixture
was cooled to 0 °C. The oxidizing agent was then added in one
portion to the reaction vessel. The reaction was stopped after a
2f
3f
1g
2g
(-0.51)
(0.05)
few seconds, and the excess of HOF CH3CN was quenched with
(-0.36)
3
aΔΕg = hc/λ. bCH2Cl2 solution cΔΔΕg = ΔΕg(SM) - ΔΕg(product)
saturated sodium bicarbonate. The mixture was then poured
into water and extracted with CH2Cl2, the organic layer dried
over MgSO4, and the solvent evaporated. The crude product
was usually purified either by vacuum flash chromatography
using silica gel 60-H (Merck) with increasing portions of EtOAc
in PE as an eluent or by recrystallization.
oxygen atoms to desirable sites. We hope that this oxygen
transfer reaction may become the method of choice in many
cases where the alternatives are not potent enough.
3,4-Dimethylthieno[2,3-b]thiophene 1,1-Dioxide (2a). Com-
pound 2a was prepared from 1a11 (0.4 g, 2.38 mmol) as described
above, using 2 equiv of the oxidizing agent and chromatographed
on silica gel using PE/ EtOAc 70:30 as eluent. A pale yellow product
(0.47 g, 98% yield) was obtained: mp 155 °C (from 2-propanol);
Experimental Section
General Experimental Procedures. 1H NMR spectra were
recorded using a 400 MHz spectrometer with CDCl3 as a solvent
and Me4Si as an internal standard. The proton broadband
decoupled 13C NMR spectra were recorded at 100.5 MHz. Here
too, CDCl3 served as a solvent and Me4Si as an internal
standard. IR spectra were recorded in KBr on an FTIR spectro-
meter. MS spectra were measured under EI conditions. UV
spectra were recorded in CH2Cl2.
λ
max 296 nm; IR 1292, 1164 cm-1; 1H NMR 7.22 (q, 4J=0.8 Hz,
1H), 6.26 (q, 4J=1.6 Hz, 4J=1.6 Hz, 1H), 2.34 (d, 4J=0.8 Hz, 3H),
2.27 ppm (d, 4J=1.6 Hz, 3H); 13C NMR 15.2, 16.1, 130.0, 131.8,
132.5, 136.9, 140.9, 142.3 ppm; HRMS (EI) m/zcalcd for C8H8O2S2
199.9966 (M)þ, found 199.9966. Anal. Calcd for C8H8O2S2: C,
47.98; H, 4.03; S, 32.02. Found: C, 48.31; H, 4.00; S, 32.29.
General Procedure for Working with Fluorine. Fluorine is a
strong oxidant and a corrosive material. It should be used only with
an appropriate vacuum line.15 For the occasional user, however,
various premixed mixtures of F2 in inert gases are commercially
available, thereby simplifying the process. Unreacted fluorine
should be captured by a simple trap containing a base such as soda
lime located at the outlet of the glass reactor. If elementary
Acknowledgment. This work was supported by the Israel
Science Foundation. N.S. thanks the Israel Ministry of
Science and Technology for a scholarship.
Supporting Information Available: 1H and 13C NMR data
of all new compounds and theoretical calculations details
(including z-matrix). This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Dayan, S.; Kol, M.; Rozen, S. Synthesis 1999, 1427–1430.
J. Org. Chem. Vol. 75, No. 13, 2010 4625