Synthesis of 1,3-diaryl benzo[c]thiophenes

Article abstract of DOI:10.1016/j.tetlet.2005.04.048

An array of 1,3-diarylbenzo[c]thiophenes has been synthesized via the ring opening of lactones followed by thionation using Lawesson's reagent.

Full text of DOI:10.1016/j.tetlet.2005.04.048

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4225–4229
Synthesis of 1,3-diaryl benzo[c]thiophenes
Arasambattu K. Mohanakrishnan* and P. Amaladass
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
Received 9 March 2005; revised 7 April 2005; accepted 12 April 2005
Available online 3 May 2005
Abstract—An array of 1,3-diarylbenzo[c]thiophenes has been synthesized via the ring opening of lactones followed by thionation
using LawessonÕs reagent.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The electronic properties of linear p-conjugated oligo-
mers have acquired a growing importance in many areas
of modern chemistry. In recent years, there has been tre-
mendous interest in organic molecules that can be fur-
ther elaborated into materials exhibiting promising
electrochemical, optical and electronic effects that are
desirable for the fabrication of electroluminescent
devices.1–3 Among these, the contribution of aryl-
vinylenes and heteroarylvinylenes in the fabrication of
electroluminescent devices is noteworthy.4 In particular
thiophene oligomers are frequently applied as semicon-
ducting materials in molecular electronic devices5 or
optical devices.6 The thiophene oligomers are the most
widely investigated model compounds for electrically
conducting polymers.7
The nucleosides of this type are useful as potential
probes for understanding the structure and dynamics
of nucleic acids and can also be used as fluorescent la-
bels. Finally, the enhanced photoluminescence behavior
of a dithienylbenzo[c]thiophene derivative during a
photobleaching process has been observed.12
S
S
S
1
The intriguing photophysical properties of thienyl oligo-
mers prompted us to explore further the synthesis of
benzo[c]thiophene derivatives. Our focus was centered
on the synthesis of derivatives, which are reasonably sta-
ble and easily processable. Having targeted the synthesis
of benzo[c]thiophenes, we turned our attention to the
synthesis of the intermediate lactones.13 Since the con-
ventional Friedel–Crafts phthaloylation was successful
only with thiophene, it was decided to explore other
methods, which can deliver highly substituted lactones
in reasonable yields.
The synthesis and characterization of a benzannelated
terthiophene, namely 1,3-dithienylbenzo[c]thiophene 1,
has been reported independently by four groups.8 Cava
and co-workers reported a detailed synthesis of several
1,3-dithienylbenzo[c]thiophenes and their analogs.9
A
Vilsmeier formylation of 1,3-dithienylbenzo[c]thiophene
followed by condensation with active methylene
compounds led to the synthesis of several dithienyl-
benzo[c]thiophene based vinylenes. Oxidative oligomeriz-
ation studies of 1,3-dithienylbenzo[c]thiophene have also
been carried out. Roncali et al. reported the synthesis
and electropolymerization studies of 1,3-(bis-3,4-ethy-
lenedioxythienyl)benzo[c]thiophene.10 The synthesis of
a novel nucleoside analog replacing a DNA base with
1,3-dithienylbenzo[c]thiophene has also been reported.11
A survey of the literature revealed that the synthesis of
several phthalides could be easily achieved via a three-
component coupling reaction using Ni(dppe)Br2–Zn as
the catalyst.14 However, as a model study, the prepara-
tion of known lactone 3a using this procedure was found
to be sluggish and gave only a 20% yield, Scheme 1.
Repetition of the experiment with other aldehydes such
as anthracene-9-carboxaldehyde and veratraldehyde was
found to be futile.
Keywords: Lactone; Grignard reagents; Thionation; Benzo[c]-
thiophene.
*
Corresponding author. Tel.: +91 44 24451108; fax: +91 44
22352494; e-mail: mohan_67@hotmail.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.048

4226
A. K. Mohanakrishnan, P. Amaladass / Tetrahedron Letters 46 (2005) 4225–4229
i) Ar1MgBr/THF
Br
CHO
S
ii) NH4Cl
OMe
iii) Lawesson's reagent
(0.5 eq.)
Ar1
O
Ni(dppe)Br2/Zn, N2
Ar
O
Ar
O
S
O
S
O
THF, Reflux
3a-j
4a-l
2a
Scheme 1.
20%
3a
DCM, rt, 10 h
Scheme 5.
reagents with 2-carboxybenzaldehyde,17 Scheme 4. It is
noteworthy that these lactones 3f–j could not be pre-
pared with the lithiation procedure mentioned above.
The preparation of lactones 3b, c was achieved using an
exchange reaction15 of ethyl 2-iodobenzoate with iso-
propylmagnesium bromide, Scheme 2.
Next, the magnesio protocol published by Kato and co-
workers was explored.16 Notably, the synthesis of differ-
ent types of lactone was achieved through metalation of
2-bromobenzoic acid using combinations of Bu2Mg and
n-BuLi under noncryogenic condition. By adopting
this procedure, the synthesis of several multifunctional
lactones 3a–e was realized in relatively better yields,
Scheme 3.
Having prepared lactones 3a–j in reasonable yields,
conversion of these lactones into the respective 1,3-diaryl-
benzo[c]thiophenes was undertaken. The ring opening of
lactones 3a–j with aryl Grignard reagents followed by
thionation with 0.5 equiv of LawessonÕs reagent and col-
umn chromatographic purification afforded several
benzo[c]thiophene analogs, Scheme 5. Ring opening of
the lactones followed by workup using aq NH4Cl led
to the intermediate keto-alcohols,9 which on thionation
followed by cyclization afforded respective products
4a–l.
The synthesis of other lactones 3f–j was achieved
through the reaction of freshly prepared aryl Grignard
Details such as the nature of the lactones, Grignard
reagents and the products along with their yields are
summarized in Table 1. The reaction of various lactones
with freshly prepared Grignard reagents and a subse-
quent thionation reaction led to the synthesis of 1,3-bis-
aryl benzo[c]thiophenes 4a–l in 40–65% overall yields
(entries 1–14). The structure of 4i was confirmed by
X-ray analysis18 (Fig. 1).
Me
i)
BrMg
I
Me
-40 0C, 1 h
OEt
O
ii) ArCHO
-40 0C to rt, 1 h
25-40%
Ar
O
O
2b
3b Ar = 9-anthracenyl (35%)
3c Ar = 3,4-dimethoxyphenyl (30%)
Most of these benzo[c]thiophenes have at least one
position which can be used for further electrophilic
substitution. Benzo[c]thiophene 4h containing the elec-
tron-withdrawing NO2 function was synthesized in
42% yield. The UV spectrum of benzo[c]thiophenes
4a–l exhibited kmax values between 412 and 470 nm,
Table 2.
Scheme 2.
i) 0.5eq. Bu2Mg/THF
ii) 1eq.n-BuLi/THF
Br
-20 0C, 1 h
OH
O
Ar
O
iii) ArCHO
-20 0C, 1 h
iv) HCl
Finally, the attempted ring opening of lactone 3a with
commercially available ethynyl or propynyl Grignard
reagents followed by thionation did not afford the ex-
pected products, only starting material was recovered,
Scheme 6. The failure of the lactone ring opening in
3a may be due to the basic character of acetylenic
Grignards.
O
2c
3a Ar = 2-thienyl (62%)
3b Ar = 9-anthracenyl (55%)
3c Ar = 3,4-dimethoxyphenyl (52%)
3d Ar = 4-hexyloxyphenyl (60%)
3e Ar = 4-nitrophenyl (40%)
Scheme 3.
CHO
OH
O
i)
Mg/THF
ArMgBr
N2, reflux
ArBr
O
Ar
O
ii) dil. HCl
3f Ar = 4-methoxyphenyl (55%)
3g Ar = 1-naphthyl (58%)
3h Ar = 4-methylphenyl (60%)
3i Ar = 2,4,6-trimethylphenyl (57%)
3j Ar = 3-hexyl-2-thienyl (30%)
Scheme 4.

A. K. Mohanakrishnan, P. Amaladass / Tetrahedron Letters 46 (2005) 4225–4229
Table 1. Synthesis of benzo[c]thiophene analogs
4227
Entry
Lactones
Ar1MgBr19
Products20
Yield (%)a mp
MgBr
1
3a
40 (170 ꢁC)
43 (Semi-solid)
45 (170 ꢁC)
55 (85 ꢁC)
H3CO
S
S
4a
OMe
MgBr
2
3
4
5
6
7
3a
3b
3c
3c
3c
3d
S
S
S
4b
MgBr
S
S
4c
MgBr
S
H3CO
H3CO
S
S
4d
MgBr
51 (88 ꢁC)
H3CO
H3CO
S
4e
MgBr
Me
58 (138 ꢁC)
H3CO
H3CO
CH3
S
4f
65 (80 ꢁC)
MgBr
S
C6H13
O
S
4g
S
8
3e
42 (116 ꢁC)
MgBr
S
O2N
S
4h
S
MgBr
OMe
9
3f
3f
3g
66 (122 ꢁC)
OMe
MeO
S
4i
10
11
4a
62 (107 ꢁC)
MgBr
S
4b
53 (Semi-solid)
MgBr
S
(continued on next page)

4228
A. K. Mohanakrishnan, P. Amaladass / Tetrahedron Letters 46 (2005) 4225–4229
Table 1 (continued)
Entry
Lactones
Ar1MgBr19
Products20
Yield (%)a mp
MgBr
12
13
14
3h
62 (118 ꢁC)
H3C
CH3
S
CH3
4j
3h
60 (106 ꢁC)
MgBr
S
H3C
H3C
S
S
S
4k
CH3
3i
57 (Thick liquid)
S
MgBr
S
CH3
4l
a Isolated yield after column chromatography.
Acknowledgement
A.K.M. thanks DST (SR/FTP/CS-65/2001), New Delhi
and UGC-Potential for Excellence for the financial
support. P.A. thanks UGC for a fellowship. Financial
support to the Department from DST-FIST is also
acknowledged.
References and notes
1. Wegner, G.; Mullen, K. Electronic Materials. The Oligo-
mer Approach; John Wiley: New York, 1996.
2. Goldoni, F.; Iarossi, D.; Mucci, A.; Schenetti, L. Chem.
Commun. 1997, 2175–2176.
Figure 1. ORTEP style plot of compound 4i in Thermal ellipsoids are
drawn at the 50% probability level.
3. Tasaka, S.; Katz, H. E.; Hutton, R. S.; Orenstein, J.;
Frederickson, G. H.; Wang, T. T. Synth. Met. 1986, 16,
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4. Hide, F.; Diaz-Garcia, M. A.; Schwartz, B. J.; Heeger, A.
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Mater. 1991, 3, 51–54; (b) Tour, J. M. Acc. Chem. Res.
2000, 33, 791–804.
i)
BrMg
R
X
O
S
R
O
3a
ii) Thionation
S
S
R = H, Me
Scheme 6.
6. (a) Geiger, F.; Stoldt, M.; Schweizer, H.; Ba¨uerle, P.;
Umbach, E. Adv. Mater. 1993, 5, 922–925; (b) Horowitz,
G.; Delannoy, P.; Bouchriha, H.; Deloffre, F.; Fave, J. L.;
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In summary, syntheses of several lactones have been
achieved involving two methods. All the lactones were
smoothly converted into benzo[c]thiophene analogs in
two steps. The UV spectra of benzo[c]thiophene deriva-
tives are presented. The highly fluorescent nature of
these heterocycles may be suitable for the fabrication
of LED devices. Further synthetic studies in this area
are currently in progress.
Table 2. UV spectral data for 4a–l
Products
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
kmax (nm) (DCM)
412
414
423
445
422
425
416
470
418
424
420
416

A. K. Mohanakrishnan, P. Amaladass / Tetrahedron Letters 46 (2005) 4225–4229
4229
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1.71 mL, 17.72 mmol) and Mg (0.510 g, 21.27 mmol) were
added to a solution of phthalide 3d (5 g, 16.12 mmol) at
0 ꢁC. After the addition was complete, the reaction
mixture was poured into an ice-cooled NH4Cl solution,
and extracted with CH2Cl2 (100 mL) and dried (Na2SO4).
The solution was treated with LawessonÕs reagent (3.26 g,
8.05 mmol) and stirred at room temperature overnight.
The solvent was removed and the residue was gently
heated on a steam bath with ethanol. The crude product
was purified by column chromatography (neutral alumina,
hexane) to afford benzo[c]thiophene 4g as a yellow solid
(4.1 g, 65%).
Spectral data of some selected benzo[c]thiophenes: For 4a:
1
mp 107 ꢁC; H NMR (400 MHz, CDCl3): d 3.91 (s, 3H),
7.03 (d, J = 8.8 Hz, 2H), 7.05–7.16 (m, 3H), 7.33–7.36 (m,
2H), 7.59 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H),
7.95 (d, J = 8.76 Hz, 1H). 13C NMR (75 MHz, CDCl3): d
55.64, 114.80, 121.54, 124.30, 124.79, 125.34, 125.42,
126.20, 128.04, 130.70, 132.21, 134.37, 135.15, 136.24,
159.63. MS(EI) m/z (%): 322(M+, 100), 307(93), 279(32),
195(43), 161(45), 77(14). Elemental Anal. Calcd for
C19H14OS2: C, 70.77; H, 4.38; S, 19.89%. Found: C,
70.60; H, 4.36; S, 19.80%.
1
For 4c: mp 170 ꢁC; H NMR (400 MHz, CDCl3): d 6.92–
7.01 (m, 3H), 7.12 (dd, J = 3.68 Hz, J = 1.44 Hz, 1H), 7.29
(d, J = 3.88 Hz, 1H), 7.42–7.56 (m, 5H), 7.85 (d,
J = 9.28 Hz, 1H), 8.00 (d, J = 8.8 Hz, 2H), 8.06 (d,
J = 8.32 Hz, 2H), 8.62 (s, 1H). MS(EI) m/z (%): 392(M+,
5), 375(100), 351(26), 301(15), 264(29), 233(42), 154(27).
Elemental Anal. Calcd for C26H16S2: C, 79.55; H, 4.11; S,
16.34%. Found: C, 79.46; H, 4.18; S, 16.36%.
15. Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.;
Au, V. A.; Knochel, P. Synthesis 2002, 4, 565–569.
16. Kato, S.; Nonoyama, N.; Tomimoto, K.; Mase, T.
Tetrahedron Lett. 2002, 43, 7315–7317.
17. Wheeler, D. D.; Young, D. C.; Erley, D. S. J. Org. Chem.
1956, 22, 547–556.
18. X-ray data for the X-ray data for compound 4i: X-ray
data were collected at 293(2) K on a ENRAF NONIUS-
CAD4 diffractometer with graphite monochromated
For 4g: mp 80 ꢁC; 1H NMR (300 MHz, CDCl3): d 0.90 (t,
J = 6.1 Hz, 3H), 1.32–1.51 (m, 6H), 1.77 (quin, J = 7.1 Hz,
2H), 3.94 (t, J = 6.25 Hz, 2H), 6.94–7.09 (m, 5H), 7.28 (d,
J = 4.04 Hz, 2H), 7.52 (d, J = 8.24 Hz, 2H), 7.72 (d,
J = 8.45 Hz, 1H), 7.92 (d, J = 8.45 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d 14.04, 22.58, 25.69, 29.18, 31.55,
68.05,114.98, 121.27, 123.93, 124.94, 125.01, 126.61,
127.01, 127.71, 130.30, 134.20, 135.15, 135.81, 136.24,
158. 87. MS(EI) m/z (%): 392 (M+, 49), 346(14), 281(100),
239(55), 223(43), 137(62), 104(59). Elemental Anal. Calcd
for C24H24OS2: C, 73.43; H, 6.16; S, 16.34%. Found: C,
73.35; H, 6.14; S, 16.29%.
˚
Mo-Ka radiation (k = 0.71073 A). The structure was
solved by direct methods (SHELX-97). Refinement was
done by full-matrix least-squares procedures on F2 using
SHELX-97. All non-hydrogen atoms were refined aniso-
tropically. C22H18O2S, MW = 346, yellow crystal of size:
0.30 · 0.22 · 0.28 mm3, crystal system: orthorhombic,
˚
cell parameters: a = 7.508(6) A,
space group: Pcab
,
3
˚
˚
˚
b = 16.493(9) A, C = 27.952(9) A, V = 3461(4) A , Z = 8,
Dc = 1.330 mg/m3, T = 293(2) K, l(Mo-Ka) = 0.199
mmÀ1, F000 = 1456, total number of l.s. parameters = 228,
R1 = 0.0580 for 3579 I > 2r(I) and 0.0955 for all 5044
data. WR2 = 0.1716, GOF = 1.043 for all data. Crystallo-
graphic data (excluding structure factors) for 4i have been
deposited with the Cambridge Crystallographic Data
Center as supplementary publication number CCDC
268130. Copies of the data may be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK (fax: +44(0)-1223-33603 or
e-mail: deposit@ccdc.cam.ac.uk).
1
For 4h: mp 116 ꢁC; H NMR (400 MHz, CDCl3): d 7.17–
7.24 (m, 4H), 7.40 (dd, J = 2.44 Hz, J = 1.22 Hz, 1H), 7.44
(d, J = 4.88 Hz, 1H), 7.83 (d, J = 9.28 Hz, 2H), 8.02 (d,
J = 2.44 Hz, 1H), 8.34 (d, J = 8.8 Hz, 2H). MS(EI) m/z
(%): 338 (M+1+, 100), 292(69), 228(42), 123(36), 82(29).
Elemental Anal. Calcd for C18H11NO2S2: C, 64.07; H,
3.29; N, 4.15; S, 19.01%. Found: C, 64.03; H, 3.33; N,
4.12; S, 18.95%.
For 4j: mp 118 ꢁC; 1H NMR (400 MHz, CDCl3): d 2.42 (s,
6H), 7.05 (dd, J = 3.44 Hz, J = 3.4 Hz, 2H), 7.29 (d,
J = 7.8 Hz, 4H), 7.57 (d, J = 7.8 Hz, 4H), 7.80 (dd,
J = 3.92 Hz, J = 2.92 Hz, 2H). 13C NMR (75 MHz,
CDCl3): d 21.22, 121.20, 123.93, 129.08, 129.70, 131.46,
133.83, 134.99, 137.29. MS(EI) m/z (%): 314(M+,100),
298(18), 283(20), 208(17), 157(35), 77(12). Elemental Anal.
Calcd for C22H18S: C, 84.03; H, 5.77; S, 10.20%. Found:
C, 83.83; H, 5.83; S, 10.34%.
19. The aryl Grignards reagents were prepared from the
corresponding bromo compounds by refluxing with
magnesium in dry THF under N2 atmosphere.
20. All benzo[c]thiophene analogs 4a–l gave satisfactory
spectral and analytical data.
A representative procedure for 4g: Freshly prepared thienyl
magnesium bromide (from 2-bromothiophene, 2.89 g