Two routes to (11,12)-dihydrodibenzo[c,g][1,2]dithiocine

Article abstract of DOI:10.1039/b315491b

The title compound is made by two routes. One route features the separate introduction of two sulfur atoms and a double Pummerer reaction while the other route contains a direct introduction of both sulfur atoms using disulfur diimidazole.

Full text of DOI:10.1039/b315491b

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Two routes to (11,12)-dihydrodibenzo[c,g][1,2]dithiocine
Paul Wyatt* and Andrew Hudson
School of Chemistry, Cantock’s Close, Bristol, UK BS8 1TS. E-mail: paul.wyatt@bris.ac.uk;
Fax: ϩ44(0)117 929 8611; Tel: ϩ44 (0)117 928 9183
Received 1st December 2003, Accepted 12th March 2004
First published as an Advance Article on the web 26th April 2004
The title compound is made by two routes. One route features the separate introduction of two sulfur atoms and a
double Pummerer reaction while the other route contains a direct introduction of both sulfur atoms using disulfur
diimidazole.
sodium alkyl thiolates was too harsh for our more sensitive
Introduction
substrates, we used the milder method of Young et al.7 Thus a
double Pummerer reaction followed by immediate treatment of
the Pummerer product 6 with methanolic ammonia gave the
dithiol 7 in 30% yield. Oxidation with KI3 gave the dithiocine 2
in 94% yield (Scheme 2).
As part of a project concerned both with the use of chiral
derivatives of thiepine 1,1 and with higher sulfides, we needed
dithiocine 2. This dithiocine 2 has been made before in an over-
all yield of 14% by a route involving five steps starting from
sulfonic acid 3 (Scheme 1).2 This acid is not readily available.
Scheme 1 Known synthesis of dithiocine 2.2
We needed to synthesise dithiocine 2 in a higher yield and by
a route convenient for dithiocine itself and with a view to appli-
cation to more complicated substrates. Dibromide 4 was avail-
able to us in gram quantities as it can readily be made by the
method of Letsing and Skoog or associated modifications.3,4 It
occurred to us that sulfur could be introduced to its bislithiated
derivative.
Results and discussion
Sulfur atoms can be introduced with electrophilic sulfur
reagents but there are potential problems when this is done at
two sites in a molecule simultaneously. With some reagents the
two sites can work together and give alternative products. This
problem is especially acute when the source is S8 itself as there
are numerous possibilities (like the sulfide or trisulfide). Instal-
lation of the two sulfur atoms independently is one strategy to
avoid several possible products. Another is to use an electro-
philic reagent that contains only two sulfur atoms. We present
routes featuring each strategy in turn.
Scheme 2 Route one to dithiocine 2—a double Pummerer rearrange-
ment.
The overall yield from dibromide 3 was thus 28%. Although
this doubled the best yield known to date it was not really
good enough for our purposes and we moved on to our second
strategy for the dithiocine.
Route two: disulfur diimidazole
Unlike Me2S2 where every molecule of reagent donates only one
of its sulfur atoms to the product, the idea with S2Im2 is that
both are used. We have previously shown that sulfur diimid-
azole8 can be used as a doubly electrophilic source of sulfur in
reactions with organolithium species.1 The analogous S2Im2 can
be prepared in a similar way.8 Potentially, more things can go
wrong with S2Im2 as a reagent because it has more than one
variety of leaving group—both an imidazole anion (arrow b)
and a sulfurimidazole anion (arrow a)(Scheme 3).
Route one: use of Me2S2
Syntheses of disulfides will often be approached by the oxid-
ation of the appropriate dithiol5 and this strategy was used in
the first route. Double lithiation of dibromide 4 followed by
reaction with Me2S2 as the sulfur reagent gave the double sulfide
product 5. The reaction was very clean and the yield 92%.
Demethylation of this compound was then needed. Because we
had established that the method of Gingras et al.6 involving
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T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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When using alkyl lithium reagents, best results were obtained
using Hamilton 1700 series gas-tight teflon tipped micro-
syringes (<1000 µl) which did not require lubrication, and
Hamilton 1700 series gas-tight teflon tipped syringes (>1 ml)
lubricated with poly(dimethylsiloxane) 200® fluid with a vis-
cosity of 100 centistokes. All solvents were distilled before use;
dry solvents were purchased from Fluka. Distilled 40–60 ЊC
petroleum ether was used for flash chromatography and
distilled 60–80 ЊC petroleum ether for recrystallisations.
S,SЈ-Dimethylbibenzyl-2,2Ј-dithiol 5
Bibenzyl 4 (2.00 g, 5.88 mmol) was dissolved in dry THF
(20 ml) under an argon atmosphere and cooled to Ϫ78 ЊC. Then
n-BuLi (5.18 ml of a 2.5 M solution, 13.0 mmol) was added
dropwise to the stirred solution. After the addition was com-
plete the reaction solution is stirred for a further 0.5 h at
Ϫ78 ЊC. Dimethyl disulfide (3.18 ml, 35.3 mmol) was then
added and the reaction was stirred for a further 1 h at this
temperature before being allowed to warm to room temperature
overnight. Water (10 ml) was added and the reaction stirred for
0.5 h. The layers were separated and the aqueous layer extracted
with dichloromethane (3 × 10 ml). The combined organic
extracts were washed with a saturated solution of ammonium
chloride (10 ml), dried (Na2SO4) and concentrated under
reduced pressure. Purification by flash chromatography, eluting
with petroleum ether–ethyl acetate yielded the methylsulfane
as platelets (1.49 g, 92.4%); mp. 83–84.5 ЊC (from dichloro-
methane)(lit.2 89–90 ЊC); νmax(CH2Cl2)/cmϪ1 1588 (Ar), 745
(S–CH3) and 704 (S–CH3); δH(300 MHz; CDCl3) 7.24–7.06
(8 H, m, ArH), 3.02 (4 H, s, ArCH2) and 2.48 (6 H, s, SMe);
δC(75.5 MHz; CDCl3) 139.8 (1 or 2-ArC), 137.3 (1 or 2-ArC),
129.2 (ArC), 126.8 (ArC), 125.7 (ArC), 125.0 (ArC), 34.1
(ArCH2) and 15.9 (SMe); m/z (EI) 274 (Mϩ, 9%), 259.0619
(Mϩ Me. C16H18S2 requires 259.0615), 227 (Mϩ SMe, 4) and
137 (ArCH2, 100).
Scheme 3 S2Im2 has two types of leaving group.
Thus as well as a disulfide, reaction with nucleophiles may
well give sulfides. Indeed, reaction of S2Im2 with PhLi
gave mostly the sulfide (Scheme 4). It should be remembered
that PhSSPh reacts with PhLi to give PhSPh so that even if the
disulfide is made, it may undergo further reaction. Despite all
these pitfalls, reaction of lithiated 3 with S2Im2 did indeed give
the disulfide with an impressive 85% yield (Scheme 5).
Scheme 4 Reaction of PhLi with S2Im2.
Bibenzyl-2,2Ј-dithiol 7
Scheme 5 Route two—using S2Im2.
Methylsulfane 5 (1.00 g, 3.65 mmol) was dissolved in dichloro-
methane (20 ml). Then 57–86% m-CPBA (396 mg) was added
and the solution stirred at room temperature for 0.1 h. Sodium
sulfite (1.00 g) was added and the reaction mixture stirred for
0.1 h. The suspension was filtered and the filtrate concentrated
under reduced pressure. The product was dissolved in tri-
fluoroacetic anhydride (30 ml), heated to reflux and stirred at
this temperature for 0.5 h. The solution was allowed to cool to
room temperature and concentrated under reduced pressure.
The residue was dissolved in a mixture of methanol (20 ml) and
triethylamine (20 ml) and once again concentrated under
reduced pressure. The crude product was dissolved in chloro-
form (20 ml), washed with a saturated ammonium chloride
solution (20 ml), dried (Na2SO4) and concentrated under
reduced pressure. Purification by flash chromatography, eluting
with petroleum ether–ethyl acetate yielded the dithiol as a pow-
der (270 mg, 30.1%); mp 62–63 ЊC (from dichloromethane);
νmax(CH2Cl2)/cmϪ1 2560 (SH), 1589 (Ar) and 1569 (Ar); δH(300
MHz; CDCl3) 7.30–7.04 (8 H, m, ArH), 3.37 (2 H, s, ArSH )
and 2.97 (4 H, s, ArCH2); δC(75.5 MHz; CDCl3) 139.6 (2-ArC),
131.0 (1-ArC), 130.3 (ArC), 129.8 (ArC), 126.9 (ArC), 126.2
(ArC) and 34.8 (ArCH2); m/z (CI) 247.0614 ([MH]ϩ. C14H15S2
requires 247.0615), 246 ([MH] ϩ H, 62%), 213 ([MH] ϩ H2S,
51) and 137 (100).
Conclusions
Although the above two routes start with the same dibromide,
with the first strategy the two sulfur atoms are introduced
independently and the sufur sulfur bond is made later. With the
second strategy the sulfur sulfur bond is already in place. Both
routes gave compounds with identical characterisation data but
these did not agree with the data of Zheltov et al. most notably
their compound melts at a temperature 150 ЊC greater than
ours.2
Experimental
Flash chromatography was performed using Merck 9385
Kieselgel 60 according to Still.9 Thin layer chromatography
(TLC) was performed using commercially available glass plates
coated with Merck silica Kieselgel 60F254. The compounds were
visualised by a Mineralight UV lamp or by dipping into a
potassium permanganate solution in aqueous sodium hydrox-
ide and heating with a hot air gun.
Melting points were determined on a Gallenkemp melting
point apparatus and are uncorrected. Infra red spectra were
recorded on a Perkin Elmer 141 spectrophotometer as liquid
films or as solutions in dichloromethane on sodium chloride
plates. All nuclear magnetic resonance (NMR) spectra were
recorded as solutions using tetramethylsilane as the internal
reference on a Jeol GX270 MHz, GX400 MHz or λ300 MHz
spectrometer. All mass spectra were recorded on a Fisons
Autospec mass spectrometer and were determined by electron
impact (EI), chemical ionisation (CI) or fast atom bombard-
ment (FAB) techniques.
(11,12)-Dihydrodibenzo[c,g][1,2]dithiocine 2 (by route one)
Dithiol 7 (200 mg, 0.813 mmol) was dissolved in chloroform
(10 ml) to which an excess of potassium triiodide was added.
The resulting solution was washed with a saturated solution of
sodium sulfonate (10 ml), dried (Na2SO4) and concentrated
under reduced pressure. Recrystallisation from petroleum ether
yielded the disulfide as a powder (187 mg, 94.3%).
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(11,12)-Dihydrodibenzo[c,g][1,2]dithiocine 2 (by route two)
with dichloromethane (3 × 10 ml). The combined organic
extracts were washed with a saturated solution of ammonium
chloride (10 ml), dried (Na2SO4) and concentrated under
reduced pressure. The crude mixture was dissolved in di-
chloromethane, filtered through a pad of silica and concen-
trated under reduced pressure. 13C NMR indicated a mixture of
diphenylsulfide;10 δC(75.5 MHz; CDCl3) 131.9 (ArC), 130.1
(ArC) and 127.1 (ArC), and diphenyldisulfide;11 δC(75.5 MHz;
CDCl3) 129.9 (ArC), 128.4 (ArC) and 128.1 (ArC). Addition of
Cr(acac)2 (30 mg) to the NMR sample allowed for an accurate
integration of the 13C-NMR signals.12 The ratio of diphenyl-
sulfide to diphenyldisulfide was found to be 5 to 1.
Bibenzyl 4 (3.00 g, 8.82 mmol) was dissolved in dry THF
(30 ml) under an argon atmosphere and cooled to Ϫ78 ЊC. Then
n-BuLi (7.77 ml of a 2.5 M solution, 19.4 mmol) was added
dropwise to the stirred solution. After the addition was com-
plete the reaction solution is stirred for a further 0.5 h at 78 ЊC.
Disulfur diimidazole8 (10.5 g, 52.9 mmol) was then added and
the reaction was stirred for a further 1 h at this temperature
before being allowed to warm to room temperature overnight.
Water (10 ml) was added and the reaction stirred for 0.5 h. The
layers were separated and the aqueous layer extracted with di-
chloromethane (3 × 10 ml). The combined organic extracts
were washed with a saturated solution of ammonium chloride
(10 ml), dried (Na2SO4) and concentrated under reduced pres-
sure. Purification by flash chromatography, eluting with petrol-
eum ether–ethyl acetate yielded the disulfide as a yellow powder
(1.82 g, 84.5%); mp 41–42.5 ЊC (from petroleum ether)(lit.,2
192–193 ЊC);† νmax(CH2Cl2)/cmϪ1 1589 (Ar), 1563 (Ar) and
683 (S–S); δH(300 MHz; CDCl3) 7.44 (2 H, br d, J 7.9,
4-ArH), 7.17–7.04 (6 H, m, ArH) and 3.31 (4 H, s, ArCH);
δC(75.5 MHz; CDCl3) 142.2 (4a-ArC), 134.5 (12a-ArC), 131.2
(4-ArC), 130.3 (ArC), 127.6 (ArC), 126.2 (ArC) and 33.4
(ArCH2); m/z (EI) 244.0377 (Mϩ C14H12S2 requires 244.0380)
and 212 (M ϩ S, 100%).
Acknowledgements
Support of this work by the University of Bristol via a
University Scholarship (to A.H.) and by the School of
Chemistry is gratefully acknowledged.
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† Our data do not match those of Zheltov et al. (ref. 2). Not only is the
melting point out but the chemical shift at 3.31 ppm is reported as
3.15 ppm. Given we have made the compound by two quite separate
methods and obtained identical characterisation data we are confident
we have made the correct material.
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