An efficient protocol for synthesizing dibenzodithiapentalenes

Article abstract of DOI:10.1016/j.tetlet.2011.05.125

Two new scalable methods for the synthesis of dibenzo[bc,fg]dithiapentalene (2) (DPP) are reported starting from either 1-bromo-3-fluoro-2-iodobenzene over four steps in 57% yield or from THP-protected 3-fluorothiophenol over three steps in 43% yield. Att

Full text of DOI:10.1016/j.tetlet.2011.05.125

Tetrahedron Letters 52 (2011) 4045–4047
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An efficient protocol for synthesizing dibenzodithiapentalenes
Tue Heesgaard Jepsen a,b, Mogens Larsen a, Morten Jørgensen a, Mogens Brøndsted Nielsen b,
⇑
a Discovery Chemistry and DMPK, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
b Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new scalable methods for the synthesis of dibenzo[bc,fg]dithiapentalene (2) (DPP) are reported start-
ing from either 1-bromo-3-fluoro-2-iodobenzene over four steps in 57% yield or from THP-protected 3-
fluorothiophenol over three steps in 43% yield. Attempts to prepare dibenzodioxapentalene (15) using
similar conditions were unsuccessful. Instead, we observed the formation of a macrocyclic dimeric prod-
uct 16. Fluorine–hydrogen bond interactions were observed by NMR in the F/SH- and F/OH-substituted
dibenzothiophene and dibenzofuran intermediates.
Received 16 April 2011
Revised 17 May 2011
Accepted 27 May 2011
Available online 2 June 2011
Keywords:
Dibenzo[bc,fg][1,4]dithiapentalene
Dibenzofuran
Ó 2011 Elsevier Ltd. All rights reserved.
Nucleophilic aromatic substitution
Fluorine–hydrogen bonding
Conjugated scaffolds based on thienothiophenes are interesting
targets for organic charge carrier transport materials.1 Three of the
four isomeric thienothiophenes are stable, isolable compounds,
while the fourth isomer, thieno[3,4-c]thiophene (1, Fig. 1), is itself
very unstable.2 Stability is, however, enhanced by substitution,2
and in 1992 Furukawa and co-workers3 reported the first synthesis
of the stable dibenzo-fused analog dibenzo[bc,fg][1,4]dithiapenta-
lene (2, DDP) from the precursor 3 (Scheme 1) and showed, accord-
ing to X-ray crystallography, that it has a completely planar
structure. The synthesis suffers, however, from relatively modest
yields and we became interested in developing an alternative
route.4
Compound 7 was subjected to a metal–halogen exchange by
treatment with butyllithium; the lithiated species was then trans-
metallated to the diarylcopper species, which furnished the steri-
cally encumbered biphenyl
6 in good yield upon reductive
elimination. In the second step we followed the previously re-
ported sulfur-coupling reaction,5,7 by means of which we obtained
dithioether 5 in near-quantitative yield. The third step in the pro-
tocol was deprotection of thioether 5 with potassium tert-butoxide
(2.5 M equiv) in THF at ambient temperature. Quenching with
MeOH furnished dithiol 49 in a yield of 91%. We note that forma-
tion of the six-membered tricyclic disulfide of 4 was not observed.
The dithiol 4 was converted into the desired DDP (2) by nucleo-
philic aromatic substitution with cesium carbonate in DMSO. The
formation of fluoro-mercaptodibenzothiophene 810 as a result of
the first ring-closure was rather easy since it was formed quantita-
tively at 50 °C after 1 h. Increasing the temperature to 150 °C for
5 h resulted in formation of 2 in 91% yield.11 It should be noted that
attempts at performing the deprotection of 5 and subsequent ring-
closure in a one-pot reaction were not successful.
Based on our recent work on substituted dibenzothiophenes,5
we decided to try to expand the scope of the protocol to dibenzo-
dithiapentalenes. In this Letter, we report a concise and efficient
protocol for synthesizing functionalized DDPs under mild reaction
conditions.
Scheme
2 summarizes our four-step DDP synthesis: (1)
Ullmann-type coupling of a tris-halobenzene6 at low temperature
forming a 2,20,6,60-tetrahalobiphenyl, (2) Pd-catalyzed C–S cou-
pling with ethyl 3-mercaptopropionate,7 (3) deprotection to
form the dithiol, and (4) tandem cyclization via intramolecular
SNAr-reactions5 to give the desired DDP. Initially, we attempted
to prepare the strained 2,20,6,60-tetrahalobiphenyl 6 by using
modifications of the Suzuki–Miyaura coupling,8 but no conversion
of the starting material was observed. Therefore, we turned to
Leroux’s low temperature Ullmann-type coupling6 using the
trihalobenzene 7 as starting material.
The difference in reactivity between the first and the second
SNAr reaction indicates that the formation of the last C–S bond is
associated with a higher energy of activation owing to the flat
S
S
S
S
2
1
⇑
Corresponding author. Tel.: +45 35320210.
E-mail address: mbn@kiku.dk (M.B. Nielsen).
Figure 1. Structures of compounds 1 and 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.125

4046
T. H. Jepsen et al. / Tetrahedron Letters 52 (2011) 4045–4047
H
14
S
S
S
F
O
a
hv, benzene
11%
S
S
2
3
O
hv
benzene
Δ
61%
S
61%
S
O
O
S
S
7.75
7.45
7.15
(ppm)
6.85
6.55
mCPBA
34%
S
b
S
Scheme 1. Previous protocol for synthesizing DDP.3
O
OEt
O
F
F Br
F
S
S
F
BuLi, CuBr2
PhNO2
HS
OEt
I
6.85
6.55
[Pd2dba3], dpephos
K2CO3, toluene
110 oC, 16h
7.75
7.45
7.15
Et2O
Br
5
(ppm)
-78 oC
Br F
74%
94%
7
6
H
8
KOtBu, THF
1 min, rt
F
S
EtO
O
c
H
HS
S
F
F
S
Cs2CO3
S
Cs2CO3
DMSO
150 oC, 5 h
DMSO
50 oC, 1 h
S
2
S
S
F
8
4
91%
H
91%
Scheme 2. Four-step protocol for the synthesis of DDP.
8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 4.1 4.0 3.9 3.8 3.7 3.6
(ppm)
THP
d
H
F
F
S
BuLi, CuBr2
PhNO2
F
S
S
HCl(aq)
MeOH
Et2O
S
-78 oC
S
F
F
9
THP
10
4
THP
H
86%
55%
THP
H
O
8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 4.2
(ppm)
F
4.1 4.0 3.9 3.8 3.7
F
O
BuLi, CuBr
PhNO2
F
HCl(aq)
MeOH
Et2O
Figure 2. NMR spectral evidence of XH–F interactions in compounds 14 (X = O) and
8 (X = S). (a) 1H NMR (500 MHz, CDCl3) of 14 with OH-F resonance at dH 6.52 (d,
J = 19.7 Hz); (b) 19F-decoupled 1H NMR (500 MHz, CDCl3) of 14; (c) 1H NMR
(500 MHz, CDCl3) of 8 with SH-F resonance at dH 3.98 ppm (d, J = 37.5 Hz); (d) 19F-
decoupled 1H NMR (500 MHz) of 8.
O
-78 o
C
O
F
O
F
11
THP
12
13
THP
83%
H
89%
F
HO
O
O
Cs2CO3
O
16
O
O
NMP
and prepared the DDP on gram-scale (2.25 g) in an overall yield of
56% starting from 7.
O
O
220 oC
15
14
70%a
0%a
30%a
(22%)b
(61%)b
The mild conditions of our method should allow for the synthe-
sis of substituted DPPs in the future and the incorporation of DPPs
into larger conjugated scaffolds for materials science. Thus, a slight
modification of our protocol by incorporating a non-symmetric
biphenyl coupling via lithiation as described by Leroux,12 or alter-
natively via the Molander modification13 of the Suzuki-coupling,
may allow access to asymmetrically functionalized DDPs. The
scope of the protocol is currently being investigated.
Scheme 3. Modified protocol for synthesizing the DPP precursor
corresponding oxygen counterpart 13. The product yields of the final SNAr reaction
4 and the
are based on (a) GC/LC and (b) isolated products.
and strained structure of DDP3 and the larger distance between the
fluorine-bearing carbon and the sulfur in the intermediate diben-
zothiophene 8. As a testimony to the robustness of the protocol
we managed to scale up the reactions without lowering the yields
The seleno derivative of DDP was prepared by Furukawa and co-
workers3b in 1994, while the analogous preparation of the oxygen

T. H. Jepsen et al. / Tetrahedron Letters 52 (2011) 4045–4047
4047
derivative failed. To the best of our knowledge, dibenzodioxapen-
talene (15) has not been reported in the literature. Therefore, we
decided to investigate this possibility by using our newly-devel-
oped protocol (Scheme 3). First, we enlarged the scope of Leroux’s
biphenyl synthesis by changing from metal–halogen exchange of
the iodide to ortho-lithiation of the THP-protected 3-fluorothi-
ophenol 9 and 3-fluorophenol 11, whereby the heteroatom was al-
ready installed at the onset of the synthesis. This improved the
synthesis of DDP by reducing the protocol from four to three steps,
and completely avoided the use of palladium catalysis. We synthe-
sized the THP-protected biphenyls 10 and 12 in moderate-to-good
yields. The bis-phenol 13 and bis-thiophenol 4 were obtained by
acid-mediated deprotection of 10 and 12, respectively.
future studies of the electronic and spectroscopic properties of
DDP molecules.
References and notes
1. (a) Savenije, T. J.; Grzegorczyk, W. J.; Heeney, M.; Tierney, S.; McCulloch, I.;
Siebbeles, L. D. A. J. Phys. Chem. C 2010, 114, 15116–15120; (b) Zhang, X.;
Hudson, S. D.; DeLongchamp, D. M.; Gundlach, D. J.; Heeney, M.; McCulloch, I.
Adv. Funct. Mater. 2010, 20, 4098–4106; (c) Kleinhenz, N.; Yang, L.; Zhou, H.;
Price, S. C.; You, W. Macromolecules 2011, 44, 872–877.
2. (a) Cava, M. P.; Husbands, G. E. M. J. Am. Chem. Soc. 1969, 91, 3952–3953; (b)
Cava, M. P.; Lakshmikantham, M. V. Acc. Chem. Res. 1975, 8, 139–144; (c)
Litvinov, V. P. Russ. Chem. Rev. 2005, 74, 217–248.
3. (a) Kimura, T.; Ishikawa, Y.; Ogawa, S.; Nishio, T.; Iida, I.; Furukawa, N.
Tetrahedron Lett. 1992, 33, 6355–6358; (b) Kimura, T.; Ishikawa, Y.; Minoshima,
Y.; Furukawa, N. Heterocycles 1994, 37, 541–552.
From this starting point we studied the ring-closure of the bis-
phenol 13 in an attempt to prepare dibenzodioxapentalene (15),
and as expected it was much less reactive than the analogous
bis-thiophenol 4. We identified formation of the dibenzofuran
product 1414 from reaction with cesium carbonate in DMSO at
150 °C overnight, but only 50% conversion of 13 and no trace of
15 was seen. Using harsher conditions with various bases such as
potassium tert-butoxide and cesium carbonate in NMP at 220 °C,
gave full conversion of 13 into 14 and the intermolecularly cyclized
dimer of 14, that is, the macrocyclic compound 16.14 However, still
no trace of dibenzodioxapentalene (15) was observed. Based on the
typical difficulty of performing intermolecular SNAr reactions on
unactivated substrates, the formation of the dimer 16 revealed
the complexity of forming the desired, and thus far putative diben-
zodioxapentalene (15). On the basis of these results, it seems unli-
kely that 15 can be prepared by the present protocol, reflecting the
remarkably different properties of oxygen compared to sulfur, both
with respect to bond angles, bond lengths, atom size, and
nucleophilicity.
It was possible to isolate the intermediate mercaptofluoro-
dibenzothiophene 8 (Scheme 2). We observed an interesting intra-
molecular F–H interaction in the 1H NMR spectrum recorded in
CDCl3 of compound 8 as well as in that of compound 14, which
we assign to XH–F (X = S, O) hydrogen bonds. Indeed, unambigu-
ous spectroscopic evidence of an interaction between F and H
was obtained from the 19F decoupled 1H NMR spectra ( Fig. 2).
We reasoned that the F–H interaction was possible because of
the rigidity of the tricyclic scaffold, since the hydrogen and the
fluorine atoms are located in close proximity. We note that F–H
bonding in o-fluorobenzanilides corresponding to a six-membered
ring is known in the literature,15 while to our knowledge, it has not
been observed in seven-membered rings fused to a dibenzothio-
phene/furan scaffold.
4. We note that another route to substituted DDPs has been described: Cariou, M.;
Douadi, T.; Simonet, J. New J. Chem. 1996, 20, 1031–1039.
5. Jepsen, T. H.; Larsen, M.; Jørgensen, M.; Solanko, K. A.; Bond, A. D.; Kadziola, A.;
Nielsen, M. B. Eur. J. Org. Chem. 2011, 1, 53–57.
6. Leroux, F. R.; Simon, R.; Nicod, N. Lett. Org. Chem. 2006, 3, 948–954.
7. Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587–4590.
8. (a) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Germany, 2004; pp 41–109. second ed.; (b)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
9. Compound 4: Mp 107–108 °C; 1H NMR (600 MHz, CDCl3) d 7.30 (td, J = 8.1,
5.5 Hz, 2H), 7.26–7.23 (m, 2H), 7.00 (td, J = 8.8, 1.1 Hz, 2H), 3.37 (s, 2H); 13C
NMR (151 MHz, CDCl3) d 160.3 (d, J = 248.8 Hz), 135.1, 130.7 (d, J = 9.4 Hz),
125.1, 120.5 (d, J = 19.9 Hz), 113.0 (d, J = 22.3 Hz); GC–MS: m/z = 254 [M+],
Anal. Calcd for C12H8F2S2: C, 56.67; H, 3.17. Found: C, 56.59; H, 3.26
10. Compound 8: Mp 102–103 °C; 1H NMR (500 MHz, CDCl3) d 7.64 (d, J = 7.9 Hz,
2H), 7.45 (m, 2H), 7.29 (m, J = 7.9 Hz, 1H), 7.18 (dd, J = 12.6, 8.0 Hz, 1H), 3.98 (d,
J = 37.5 Hz, 1H); 13C NMR (151 MHz, CDCl3) d 157.3 (d, J = 246.3 Hz), 141.6,
141.1, 130.1, 130.0, 127.9, 126.9, 122.8, 119.5, 118.6, 111.8, 111.6; GC–MS: m/
z = 234 [M+], Anal. Calcd for C12H7FS2: C, 61.51; H, 3.01. Found: C, 61.42; H,
3.13.
11. Synthesis of 2: Compound 4 (3.08 g, 12.1 mmol) and Cs2CO3 (9.87 g, 30.3 mmol)
were dissolved in DMSO (35 mL). The mixture was stirred in a closed vial under
an argon atmosphere for 5 h at 150 °C. Brine (150 mL) was added, and the
mixture was extracted with EtOAc (3 ꢀ 50 mL). The combined organic layers
were concentrated in vacuo onto Celite and purified by column flash chro-
matography on silica with heptane as eluent to give compound 2 as a white solid
(2.25 g, 87%). The product was recrystallized from MeOH to afford 2 as a white
cotton-like substance. Characterization data was in accordance with Ref. 3.
12. Bonnafoux, L.; Colobet, F.; Leroux, F. R. Synlett 2010, 2953–2955.
13. Molander, G.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286.
14. Synthesis of 14 and 16: Compound 13 (50 mg, 0.2 mmol) and Cs2CO3 (183 mg,
0.56 mmol) were dissolved in NMP (3 mL). The mixture was stirred in a closed
vial under an argon atmosphere for 5 h at 220 °C. Brine (30 mL) was added and
the mixture was extracted with EtOAc (3 ꢀ 15 mL). The combined organic
layers were concentrated in vacuo onto Celite and purified by column
chromatography on silica with heptane as eluent to give compound 14
(10 mg, 22%) and 16 (25 mg, 61%) as white solids. Compound 14: 1H NMR
(500 MHz, CDCl3) d 7.45–7.40 (m, 3H), 7.19–7.08 (m, 2H), 6.94 (d, J = 8.1 Hz,
1H), 6.52 (d, J = 19.7 Hz, 1H); 13C NMR (151 MHz, CDCl3) d 157.0, 155.8 (d,
J = 240.6 Hz), 150.7, 129.5, 127.5 (d, J = 9.0 Hz), 111.47, 111.4 (d, J = 21.2 Hz),
109.6, 108.8, 108.7, 108.3, 103.7; GC–MS: m/z = 202 [M+], Anal. Calcd for
C
12H7FO2: C, 71.29; H, 3.49. Found: C, 71.27; H, 3.51.
Compound 16: 1H NMR (600 MHz, CDCl3) d 7.66 (dd, J = 8.2, 0.6 Hz, 4H), 7.51 (t,
J = 8.2 Hz, 4H), 7.41 (dd, J = 8.2, 0.6 Hz, 4H); 13C NMR (151 MHz, CDCl3) d 157.2,
152.9, 127.9, 116.5, 116.2, 108.3. GC–MS: m/z = 364 [M+]. Anal. Calcd for
In conclusion, we have developed efficient three- and four-step
protocols for the synthesis of DDPs. The use of milder reaction con-
ditions offers a significantly improved scalable protocol with the
potential of preparing functionalized DDPs. We are currently in
the process of exploring the scope of the protocol to facilitate
C
24H12O4: C, 79.12; H, 3.32. Found: C, 79.07; H, 3.30. Calcd exact mass: m/
z = 364.07301 [M+], found: m/z = 364.07301 [M+].
15. Reddy, G. N. M.; Kumar, M. V. V.; Rowb, T. N. G.; Suryaprakash, N. Phys. Chem.
Chem. Phys. 2010, 12, 13232–13237.