Synthesis of 4,6-dimethyl-tetrahydro- and hexahydro-dibenzothiophene

Article abstract of DOI:10.1016/j.tetlet.2008.02.003

2-Bromo-3-methylcyclohexanone was synthesized by conjugate addition of trimethylaluminium to 2-bromo-2-cyclohexen-1-one with copper bromide as catalyst, coupled with 2-methylthiophenol and annulated with the aid of polyphosphoric acid to 4,6-dimethyl-1,2,

Full text of DOI:10.1016/j.tetlet.2008.02.003

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2063–2065
Synthesis of 4,6-dimethyl-tetrahydro- and hexahydro-dibenzothiophene
Yinyong Sun, Huamin Wang, Roel Prins *
Institute of Chemical and Bioengineering, ETH Zurich, 8093 Zurich, Switzerland
Received 8 January 2008; revised 28 January 2008; accepted 1 February 2008
Available online 7 February 2008
Abstract
2-Bromo-3-methylcyclohexanone was synthesized by conjugate addition of trimethylaluminium to 2-bromo-2-cyclohexen-1-one with
copper bromide as catalyst, coupled with 2-methylthiophenol and annulated with the aid of polyphosphoric acid to 4,6-dimethyl-1,2,3,4-
tetrahydrodibenzothiophene. The latter was hydrogenated to 4,6-dimethyl-1,2,3,4,4a,9b-hexahydrodibenzothiophene, another inter-
mediate in the hydrodesulfurization of 4,6-dimethyldibenzothiophene, by zinc and trifluoroacetic acid, and dehydrogenated to
4,6-dimethyldibenzothiophene.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Conjugate addition; 2-Bromo-3-methylcyclohexanone; Tilak annulation; 4,6-Dimethyldibenzothiophene
Polyaromatic sulfur compounds and their substituted
derivatives are present in oil fractions such as naphtha
(the precursor for gasoline) and diesel fuels. Environmental
regulations in many countries demand that the maximum
amount of sulfur in fuels be reduced to 10–15 ppm by
2010. Derivatives of dibenzothiophene with the alkyl
substituents in the 4- and 6-positions on the aromatic ring,
adjacent to the sulfur atom, are the most refractory com-
pounds in the hydrodesulfurization (HDS) process that is
industrially used to remove sulfur from fuel.1 Therefore,
4,6-dimethyldibenzothiophene (4,6-DMDBT) is often used
as a model compound in HDS studies.2 The HDS of 4,6-
DMDBT occurs mainly by hydrogenation to partially
and totally hydrogenated intermediates, followed by the
breaking of the C–S bonds to form 3,30-dimethylcyclo-
hexylbenzene and 3,30-dimethylbicyclohexyl.3
phene (4,6-DM-THDBT), 4,6-dimethyl-1,2,3,4,4a,9b-hexa-
hydrodibenzothiophene (4,6-DM-HHDBT) and 4,6-di-
methyl-dodecahydrodibenzothiophene (4,6-DM-DHDBT).
These intermediates have been synthesized by hydrogena-
tion of 4,6-DMDBT,4 but this method is inefficient,
because the conversion of 4,6-DMDBT must be kept low
to avoid further reaction of the hydrogenated intermediates
to desulfurized hydrocarbons. As a consequence, laborious
column-chromatographic separations of the product mix-
ture and recyclcling of unreacted 4,6-DMDBT have to be
performed. In addition, commercial 4,6-DMDBT is expen-
sive. It can be synthesized in two steps from DBT by lith-
iation of the 4- and 6-positions of DBT and subsequent
reaction with methyl iodide, but for safety reasons one
should not make more than a few grams per batch. How-
ever, in the synthesis of 10 g of 4,6-DM-THDBT and 4,6-
DM-HHDBT from 4,6-DMDBT, one needs about 50 g
4,6-DMDBT. 4,6-DMDBT has also been synthesized from
2-bromo-3-nitrotoluene and 2-methylthiophenol (o-thio-
cresol) by reduction of the nitro group followed by diazo-
tation and ring closure by the Pschorr reaction, in which
the diazonium group attacks the ortho carbon atom on
the other phenyl ring.5 The yield of this cyclization step
was, however, low (26%). A future method for synthesizing
4,6-DMDBT could be a Pd-catalyzed domino cyclization
To achieve a low level of sulfur in fuels, a detailed knowl-
edge of the mechanism of the HDS reaction and of the
behaviour of the reaction intermediates is required. Three
hydrogenated intermediates play a role in the HDS of
4,6-DMDBT: 4,6-dimethyl-1,2,3,4-tetrahydrodibenzothio-
*
Corresponding author. Tel.: +41 44 6325490; fax: +41 44 6321162.
E-mail address: prins@chem.ethz.ch (R. Prins).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.003

2064
Y. Sun et al. / Tetrahedron Letters 49 (2008) 2063–2065
reaction of 2-chloro-6-methylthiophenol with 2-bromotol-
uene, analogous to the domino reaction of anilines and
1,2-dihaloarenes to carbazoles.6 We did not explore this
reaction, first because 2-chloro-6-methylthiophenol and
even 2-chloro-6-methylphenol are not commercially avail-
able, and second because we were not only interested in
synthesizing 4,6-DMDBT in an efficient way and on a size-
able scale (10–30 g), but also the hydrogenated 4,6-TH-
DMDBT and 4,6-HH-DMDBT intermediates.
S
O
S
S
Scheme 2.
O
O
OAl(CH3)2
Br
Br
Br
(CH3)3Al
The Tilak annulation of thiophenol with 2-halocyclo-
hexanone is an established reaction that leads in two easy
steps to TH-DBT.7 Analogously, one could react o-thiocre-
sol (2-methylthiophenol) with 2-halo-3-methylcyclohexa-
none and obtain TH-DMDBT (Scheme 1); this, in turn,
could be hydrogenated to HH-DMDBT and dehydro-
genated to DMDBT (Scheme 2). o-Thiocresol is commer-
cially available or can easily be made from cheap o-cresol
by the Newman–Kwart reaction.8 2-Bromo-3-methyl- and
2-chloro-3-methylcyclohexanone are unfortunately not
commercially available. Several methods for synthesizing
2-bromo-3-methylcyclohexanone were considered and
some of them were tried. Aromatic molecules are more
reactive than aliphatic molecules and, therefore, we first
considered synthesis routes via aromatic substitution reac-
tions. However, first synthesizing 2-bromo-3-methylphenol
and then hydrogenating it to 2-bromo-3-methylcyclohexa-
none had to be rejected because the literature gives no hope
that a phenyl ring can be hydrogenated without the loss of
the halogen atom.
Instead of aromatic precursors, aliphatic cyclohexane
educts can be used. We first tried the bromination and
iodination of 3-methylcyclohexanone. This reaction is easy
to perform and the literature even promised that 2-iodo-3-
methylcyclohexanone would be formed preferentially.9
Unfortunately, but not surprisingly, this turned out not
to be the case and the reaction, both for bromine and
iodine, quantitatively led to a mixture of four isomers (cis
and trans 2-halo-3-methyl- and 2-halo-5-methylcyclohexa-
none), that proved too difficult to separate. Of the two
commercially available molecules with the cyclohexenone
structure (2-cyclohexen-1-one and 3-ethoxy-2-cyclohexen-
1-one), we tried 2-cyclohexen-1-one, because it promised
to give 2-bromo-3-methylcyclohexanone in only three steps
(Scheme 3). While the first step, the bromination of 2-
cyclohexen-1-one, and the last step, the hydrolysis of the
aluminium–oxygen bond, are easy, the second step, the
conjugate addition of trimethylaluminium to 2-bromo-2-
cyclohexen-1-one,10 needs more precaution. We were able
to obtain complete conversion of 2-bromo-2-cyclohexen-
1-one and better than 90% yield of the desired product
2-bromo-3-methylcyclohexanone by using CuBr as a cata-
Scheme 3.
lyst, triphenylphosphine as a ligand, toluene as a solvent
and controlling the temperature below ꢀ30 °C.11 A draw-
back of this method is that, because of safety precautions,
we could only make small batches (2 g) at the time.
With the thus obtained 2-bromo-3-methylcyclohexa-
none cis/trans mixture and o-thiocresol we were able to
synthesize 4,6-DM-THDBT without any problem (Scheme
1).12 We tried to synthesize 4,6-DM-HHDBT in a similar
way by reducing 2-bromo-3-methylcyclohexanone with
NaBH4 to 2-bromo-3-methylcyclohexanol and reacting
the latter with o-thiocresol in the presence of polyphospho-
ric acid (PPA). While the reduction of ketone and the
subsequent coupling of thiol with 2-bromo-3-methylcyclo-
hexanol to 2-(2-methylthiophenolate)-3-methylcyclohexa-
nol proceeded smoothly, the final ring closure by the
reaction of the OH group with the ortho carbon atom of
the phenyl ring was not successful. As an alternative, we
reacted 2-(2-methylthiophenolate)-3-methylcyclohexanol
to 2-(2-methylthiophenolate)-3-methylcyclohexanechloride
and tried to cyclize the latter molecule with the aid of AlCl3
or ZnCl2. However, also this last step was not successful.
Apparently, Friedel–Crafts reactions are not only difficult
for phenols, but also for thiophenols. We successfully syn-
thesized 4,6-DM-HHDBT instead by the reduction of 4,6-
DM-THDBT with the Zn–trifluoroacetic acid couple.13
Alternatively, 4,6-DM-THDBT can be hydrogenated by
transfer hydrogenation with a secondary alcohol, as in
the dehydrogenation of secondary alcohols with styrene
over a Cu catalyst.14 4,6-DM-THDBT can be easily dehy-
drogenated to 4,6-DMDBT by reaction with sulfur, sele-
nium or a Pd catalyst, or by transfer dehydrogenation
(Scheme 2).
In conclusion, the Tilak annulation is a convenient way
to synthesize 4,6-dimethyl-1,2,3,4-tetrahydrodibenzothi-
ophene, but requires the synthesis of 2-bromo-3-methylcy-
clohexanone. This can be achieved by the conjugate
addition of trimethylaluminium to 2-bromo-2-cyclohexen-
1-one with a copper salt as the catalyst. 4,6-Dimethyl-
O
O
NaOH
PPA
Br
SH
S
S
Scheme 1.

Y. Sun et al. / Tetrahedron Letters 49 (2008) 2063–2065
2065
11. Synthesis of 2-bromocyclohexenone: A solution of Br2 (157.5 mmol,
9 ml) in 150 ml CH2Cl2 was added dropwise over a period of 3 h to a
stirred, 0 °C solution of cyclohexenone (150 mmol, 15 ml) in 400 ml
CH2Cl2. The solution was stirred at 0 °C for 3 h, then Et3N
(250 mmol, 35 ml) was added dropwise and the mixture was stirred
at room temperature for another 3 h. It was washed with 3% HCl and
brine, and dried over anhydrous MgSO4. Recrystallization using
hexane/ether gave the pure product (15 g, 60% yield). 1H NMR
(200 MHz, CDCl3): d 2.10–2.15 (m, 2H, CH2), 2.48–2.52 (m, 2H,
CH2), 2.66–2.69 (t, 2H, CH2), 7.46–7.48 (t, 1H, CH). 13C NMR: d
22.71, 28.40, 38.39, 123.92, 151.22, 191.32.
1,2,3,4-tetrahydrodibenzothiophene can easily be hydro-
genated to 4,6-dimethyl-1,2,3,4,4a,9b-hexahydrodibenzo-
thiophene and dehydrogenated to 4,6-dimethyldibenzo-
thiophene. The Tilak reaction thus provides easy access
to 4,6-DMDBT and its hydrogenated intermediates, which
are used as model molecules in hydrodesulfurization
studies.15
Acknowledgement
Synthesis of 2-bromo-3-methylcyclohexanone: To a mixture of CuBr
(100 mg) and PPh3 (300 mg) were added 50 ml of dry toluene under
nitrogen. The solution was stirred at room temperature for 30 min
and then cooled to ꢀ60 °C (acetone + dry ice). Trimethyl aluminium
(12 ml, 2 M in toluene) was added dropwise, maintaining the
temperature below ꢀ60 °C. The solution was stirred for 5 min and
3 g of 2-bromocyclohexenone in 50 ml toluene were added dropwise.
The reaction mixture was stirred below ꢀ60 °C for 2 h and then
allowed to warm to room temperature until all starting material was
consumed. The solution was diluted with dimethyl ether, quenched
with MeOH, and successively washed with 2 N HCl and brine. The
organic layer was dried over anhydrous sodium sulfate. After
evaporation, the product (2.4 g, 75% yield, cis/trans mixture) was
obtained. This procedure was repeated five times to obtain 12 g
product.
The authors would like to thank Dr. Wenjian Shi for
helpful discussions and experimental assistance.
References and notes
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Synthesis of 4,6-DM-THDBT: The 2-(o-tolylthio)-3-methylcyclohexa-
none sample (11 g) was poured into a round bottom flask containing
100 g of polyphosphoric acid and the mixture was slowly heated in an
oil bath with continuous stirring for 3 h at 165 °C. After cooling, the
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7.45–7.50 (H-1, 1H, ArH). 13C NMR: d 20.04, 20.31, 21.48, 22.99,
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