Aromatic ring opening of fused thiophenes via organolithium addition to sulfur

Article abstract of DOI:10.1055/s-1998-1674

Organolithium reagents can add to the sulfur atom of thiophenes that are substituted by a chlorine atom and fused to another aromatic system, at -78°C, to give ortho-substituted aryl sulfides.

Full text of DOI:10.1055/s-1998-1674

April 1998
SYNLETT
407
Aromatic Ring Opening of Fused Thiophenes via Organolithium Addition to Sulfur
B. Hill, M. De Vleeschauwer, K. Houde, M. Belley*
Merck Frosst Centre for Therapeutic Research, Department of Medicinal Chemistry, 16711 Route Transcanadienne, Kirkland, Québec,
H9H 3L1, Canada
Fax (514) 428-4936; E-Mail: belley@merck.com
Received 10 November 1997
Abstract: Organolithium reagents can add to the sulfur atom of
thiophenes that are substituted by a chlorine atom and fused to another
aromatic system, at -78°C, to give ortho-substituted aryl sulfides.
most cases, side reactions such as proton abstraction (thiophenes 5-9,
12, 14 and 15) and lithium-chlorine exchange (10, 16) compete
effectively with the ring opening. In the absence of a chlorine
substituent or an “acidic” proton, as in compounds 13 and 17, there is no
reaction at all, even in ether at room temperature. 2,5-Dichloro-3,4-
dinitrothiophene 18 gave only decomposition products and the acid 11
is attacked to give the butyl ketone at -78°C.
1
While working on thieno[3,2-d]thiazole 1 , we encountered an
unexpected reaction. Treatment of 1 with butyllithium at -100°C and
addition of N-chlorosuccinimide yielded a product containing a butyl
group and an extra chlorine atom. This unknown compound was then
oxidized to the sulfone 4, which was identified by X-ray crystallography
(scheme 1 and figure 1). This addition product could be explained by the
addition reaction of the butyl group to the sulfur atom of the thiophene,
with subsequent ring opening and trapping of the vinylic anion 2 with
N-chlorosuccinimide.
Scheme 2
Scheme 1
The only thiophenes we have found that react with BuLi by addition to
the sulfur are represented by the two 2-chlorothieno[3,2-d]thiazoles 1
9
and 19 (scheme 1 and table 1) and the fused thiophenes substituted by a
chlorine atom in position 3 (table 2). In the case of the two
2-chlorothieno[3,2-d]thiazoles 1 and 19, the intermediate anion 2
obtained after addition of an organolithium salt can be trapped with the
more reactive electrophiles to yield substituted (E)-chloroalkenes 20
with retention of configuration. As shown in table 1, this anion is not
nucleophilic enough to react with ethyl iodide and benzyl bromide.
2
3
Although addition of alkyllithiums to sulfur in thioethers , disulfides
4
and dithioketals is known, there are few reports on addition to a sulfur
atom included in an aromatic heterocycle with subsequent ring
cleavage;
known
heterocycles
reacting
this
way
are
5
6
7
imidazo[2,1-b]benzothiazoles , 1,4-dithiins
and isothiazoles .
Evidences for the addition of butyl- and phenyllithium to thiophenes
were reported for 3,4-dichloro-2,5-dimethoxythiophene at room
temperature, but the only products of the reaction were dibutyl and
8
diphenyl sulfides respectively . We wish to report in this paper
examples of this addition reaction of organolithiums to thiophenes, at
-78°C or below, and evidence supporting the proposed mechanism.
We first tried to determine what are the structural features that can
promote such ring cleavage on a thiophene. Scheme 2 lists all the
heterocycles that failed to give any addition of BuLi to the sulfur. In

408
LETTERS
SYNLETT
For the thiophenes of table 2, a slightly different pathway is followed by
the reaction. The electron withdrawing effect of the 3-chloro
substituent, along with its easy elimination, probably facilitates the
addition of butyllithium to the sulfur to give the chloroalkyne 30
(scheme 3). Then lithium-chlorine exchange gives the alkyne anion 31
which adds to the electrophile. Addition of BuLi to the
thieno[3,2-d]thiazole 21 and lithium-chlorine exchange with the
chloroalkyne intermediate 30 compete with each other. In the presence
of 2.2 equivalents of BuLi, the ratio of products 25:26 is 1:2, while use
of 3.3 equivalents gave a ratio of 2:1. In the last three entries of table 1,
the chloroalkyne was not detected when an excess of BuLi was added. It
should also be noted that the benzylic alcohols 25, 27 and 28 are slowly
oxidized by air to give the corresponding phenyl ketones.
the thiophene ring vary with the structure of the substrate (tables 3 and
4).
Scheme 3
20
Ring opening of thiophenes
heterocycles
and other sulfur containing
7a,21
was reported to occur via another route (scheme 4).
3-Bromothiophene 36 can be metallated in position 3 and cleavage of
the thiophene ring can then occur at room temperature in ether. The
thiolate anion 38 can add to an electrophile such as butyl bromide
(generated in the first step or added later during the reaction). Product
29 (table 2) was obtained by this method from 3-bromo-2-
20b
phenylbenzo[b]thiophene
(the bromo analog of 24). We do not
believe that this mechanism is operating here for the following reasons:
1) the ring opening reported in this paper occurs at -78°C or below while
ring opening of 3-lithiothiophenes happens at room temperature, 2) the
products 3 and 20a-g (scheme 1 and table 1), along with the addition
products obtained with t-BuLi (32c, table 3) and PhLi (34c, table 4),
cannot be rationalized using this mechanism, 3) addition of sec-BuLi to
24 and hydrolysis with NH Cl produced the sec-butyl thioether 40
4
(scheme 5) which cannot arise from the attack of the thiolate 38 on
We then tried to determine which organometallic species can give rise
to this attack on the sulfur atom of thiophenes and found that this is
specific to aryl- and alkyllithium salts; Grignard, cuprate, organozinc
reagents, as well as cyanide, lithium enolates, lithium
triethylborohydride (Super-Hydride) and diisobutylaluminum hydride
did not react at all. The reaction with organolithiums is not general: the
more basic sec-BuLi affords preferentially products arising from
hydrogen abstraction while the behavior of tert-BuLi and PhLi toward
Scheme 4

April 1998
SYNLETT
409
22
sec-butyl chloride at -78°C and 4) lithium chlorine exchange on a
2,3-dichlorothiophene would occur preferentially with the 2-chloro
substituent.
Rohrbaugh, D. K.; Ferguson, C. P. J. Fluorine Chem. 1995, 73, 7,
f) Kitazumi, T.; Otaka, T.; Takei, R.; Ishikawa, N. Bull. Chem.
Soc. Jpn. 1976, 49, 2491.
3.
4.
a) Gilman, J.; Webb, F. J. J. Am. Chem Soc. 1949, 71, 4062.
b) Seebach, D.; Teschner, M. Chem. Ber., 1976, 109, 1601.
a) Krief, A.; Konda, B.; Barbeaux, P. Tetrahedron Lett. 1991, 32,
2509, b) Crowley, P. J.; Leach, M. R.; Meth-Cohn, O.; Wakefield,
B. J. J. Chem. Res. 1992, Synop. 4, 128.
5.
6.
7.
Mase, T.; Murase, K. Heterocycles 1984, 22, 1013.
Scheme 5
Parham, W. E.; Kneller, M. J. J. Org. Chem. 1958, 23, 1702.
a) Micetich, R. G. Can. J. Chem. 1970, 48, 2006, b) Carrington,
D. E. L.; Clarke, K.; Scrowston, R. M. J. Chem. Soc. (C), 1971,
3903, c) Caton, M. P. L.; Jones, D. H.; Slack, R.; Wooldridge, K.
R. H. J. Chem. Soc., 1964, 446.
In summary, fused thiophenes substituted by at least one chlorine can
react with organolithium reagents, at -78°C, by addition to the sulfur.
The anion generated after ring opening can then add to electrophiles or
give elimination products when there is a leaving group in position 3 of
the thiophene ring. The reaction is not general and is highly dependent
on the substitution pattern of the thiophene and the nature of the
organolithium species. Side reactions, such as proton abstraction and
lithium-chlorine exchange, compete with the ring opening. Thiophenes
that are not fused to another aromatic ring do not give rise to this
reaction, the only known exception being 3,4-dichloro-
8.
9.
Hallberg, A.; Frejd, T.; Gronowitz, S. Chem. Scr., 1979, 13, 186
13,24
Obtained by chlorination of 2-acetamidothieno[3,2-d]thiazole
with trichloroisocyanuric acid (0.5 equiv., CH Cl , 0°C then r.t.
2
2
2h; 51% yield).
13
10. Prepared from 19 (HCl, dioxane, reflux ).
25
11. Prepared from 5-bromothieno[3,2-d]thiazole (4-FC H B(OH) ,
8
6
4
2
2,5-dimethoxythiophene at room temperature .
26
Pd(Ph P) , aq. Na CO , toluene / ethanol, 100°C 3h ).
3
4
2
3
13,25
12. Prepared as 6 from 2-methylthieno[3,2-d]thiazole 8
13. Paulmier, C. Bull. Soc. Chim. Fr. 1980, II-151.
.
23
Typical experimental procedure
4-(Butylthio)-5-(2,2-dichloroethenyl)- 2-methylthiazole 3:
14. Prepared from 9 (BuLi, -100°C 5 min., PhCHO; 77% yield).
Butyllithium 1.6 M in hexane (2.4 ml, 3.36 mmol) was added dropwise
to a solution of 5-chloro-2-methylthieno[3,2-d]thiazole 1 (544 mg, 2.87
mmol) in THF (8 ml) at -100°C under nitrogen. The mixture was stirred
at -100°C for 5 min and a solution of N-chlorosuccinimide (795 mg,
5.95 mmol) in THF (8 ml) was then added slowly. The mixture was
.
15. Prepared from 3-acetylbenzo[b]thiophene (1, NH OH HCl,
2
BaCO ; 2, PCl , ether; 3, Br , NH SCN; 4, 170°C, Dowtherm
3
).
5
2
4
13,27
A
9
16. Obtained as a side product in the synthesis of 19 (13% yield).
stirred at -78°C for 15 min and was quenched with saturated NH Cl.
4
17. Young, R. N.; Labelle, M.; Leblanc, Y.; Xiang, Y. B.; Lau, C. K.;
Dufresne, C.; Gareau, Y. U.S.P. 5,472,964, Dec. 5, 1995 (Chem.
Abstr. 1996, 124, 232429d).
The product was extracted in ethyl acetate, dried over Na SO and
2
4
concentrated under reduced pressure. The crude residue was purified by
flash chromatography with 2.5% EtOAc/hexane to yield 673 mg (84 %)
18. Prepared from benzo[b]thiophene (trichloroisocyanuric acid (1.0
1
of 3 as an oil. H NMR (400 MHz, CDCl ) δ 7.08 (s, 1H), 2.74 (t, J=7.3
3
equiv., CH Cl , 0°C then r.t. 2h; 36% yield).
2
2
Hz, 2H), 2.69 (s, 3H), 1.55 (m, 2H), 1.40 (m, 2H), 0.90 (t, J=7.3 Hz,
13
19. Prepared from benzo[b]thiophene (1, BuLi, DME, -78°C; 2,
B(OiPr) , -78°C to r. t.; 3, PhI, (Ph P) Pd, 2 M Na CO , reflux,
3H); C NMR (400 MHz, CDCl ) δ 167.2 (C), 150.5 (C), 129.8 (C),
3
3
3
4
2
3
124.3 (C), 120.2 (CH), 38.5 (CH ), 31.2 (CH ), 21.5, 19.9, 13.5 (CH );
2
2
3
68% yield; 4, trichloroisocyanuric acid (0.4 equiv.), CH Cl , 0°C
2
2
IR (KBr) 3030, 2980, 2920, 2860, 1735, 1605, 1490, 1460, 1430, 1270,
-1
then r. t. 2h, 88% yield).
1170, 1050, 900, 720 cm ; MS (+CI, CH ) m/z 282 (M+1, 100), 284
4
20. a) Karlsson, J. O.; Svensson, A.; Gronowitz, S. J. Org. Chem.
1984, 49, 2018, and references cited, b) Iddon, B. Heterocycles
1983, 20, 1127 and references cited.
(M+3, 78). Anal. Calcd for C
S, 22.72; Cl, 25.12. Found: C, 42.85; H, 4.79; N, 4.94; S, 22.60; Cl,
24.92.
H Cl NS : C, 42.56; H, 4.64; N, 4.96;
10 13 2 2
21. a) Schoufs, M.; Meyer, J.; Vermeer, P.; Brandsma, L. Recl. Trav.
Chim. Pays-Bas 1977, 96, 259, b) Wilson, S. R.; Georgiadis, G.
M.; Khatri, H. N.; Bartmess, J. E. J. Am. Chem. Soc. 1980, 102,
3577.
Acknowledgment
The authors are grateful to Dr R. G. Ball for the determination of the
crystal
structure
of
4-(butylsulfonyl)-5-(2,2-dichloroethenyl)-
22. Ring opening of 3-lithiobenzothiophene occurs only at room
2-methylthiazole 4.
20b
temperature
and lithium thiophenolate doesn’t react with sec-
butyl chloride, even after 10 min. at room temperature in THF.
References and notes
23. All new compounds gave satisfactory analytical and spectroscopic
13
1.
Prepared by chlorination of 2-methylthieno[3,2-d]thiazole 8
data. Selected data: 4-(butylsulfonyl)-5-(2,2-dichloroethenyl)-2-
1
with trichloroisocyanuric acid (0.4 equiv., CH Cl , 0°C then r.t.
2h; 73% yield).
2
2
methylthiazole 4; m.p. 74.5-75.5°C; H NMR (400 MHz, CDCl )
3
δ 7.39 (s, 1H), 3.15 (m, 2H), 2.75 (s, 3H), 1.72 (m, 2H), 1.42 (m,
13
2.
For examples, see: a) Wildschut, G. A.; Bos, H. J. T.; Brandsma,
L.; Arens, J. F. Monatsh. Chem. 1967, 98, 1043, b) Biellmann, J.
F.; Ducep, J. B.; Schmitt, J. L.; Vicens, J. J. Tetrahedron 1976, 32,
1061, and references cited, c) Tamura, Y.; Kawasaki, T.; Gohda,
N.; Kita, Y. Tetrahedron Lett. 1979, 20, 1129, d) Braga, A. L.;
Comasseto, J. V.; Petragnani, N. Tetrahedron Lett. 1984, 25,
1111, e) Munavalli, S.; Hassner, A.; Rossman, D. I.; Singh, S.;
2H), 0.91 (t, J=7.3 Hz, 3H); C NMR (400 MHz, CDCl ) δ 170.4
3
(C), 150.7 (C), 132.1 (C), 129.1 (C), 118.7 (CH), 57.9, 24.7, 21.4,
19.9, 13.4 (CH ); IR (KBr) 3080, 2970, 2950, 2880, 1610, 1490,
3
1470, 1440, 1340, 1300, 1290, 1240, 1180, 1140, 1080, 910, 860,
-1
790, 770, 730, 670 cm ; MS (+CI, CH ) m/e 316 (M+3), 314
4
(M+1), 279, 157; anal. calcd for C
H S O Cl N: C, 38.22; H,
10 13 2 2 2
4.17; N, 4.46; S, 20.40; Cl, 22.56; found: C, 38.55; H, 4.18; N,

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LETTERS
SYNLETT
13
4.46; S, 20.20; Cl, 22.35; (E)-2-(acetylamino)-4-butylthio-5-(3-
C NMR (400 MHz, CDCl ) δ 155.5, 140.2, 140.0, 136.4, 135.3,
3
hydroxy-3-phenyl-2-chloropropen-1-yl)thiazole 20d; m.p. 141-
128.5 (2C), 128.3, 127.0 (2C), 121.2, 98.6, 95.1, 83.7, 69.2, 64.9,
1
142°C; H NMR (400 MHz, CDCl ) δ 10.68 (s, 1H), 7.40-7.37
62.3, 32.1, 30.7, 30.5, 25.3, 21.9, 19.4, 13.6; IR (KBr) 3200, 2950,
3
1
(m, 2H), 7.20-7.16 (m, 3H), 7.10 (s, 1H), 6.06 (s, 1H), 2.72 (t,
2220 cm- ; MS (+CI, CH ) m/e 452 (M-C H ), 440 (M-C H ),
4
3
5
2 5
J=7.3 Hz, 2H), 2.22 (s, 3H), 1.55-1.50 (m, 2H), 1.42-1.36 (m, 2H),
412 (M+1), 394 (M-OH); 3-(2-(methylthio)phenyl)-1-
13
1
0.88 (t, J=7.3 Hz, 3H); C NMR (500 MHz, CDCl ) δ 168.6,
phenylprop-2-yn-1-ol 34a; H NMR (400 MHz, CDCl ) δ 7.67 (d,
3
3
158.2, 145.9, 140.2, 139.2, 128.2, 127.7, 126.2, 123.7, 120.2,
75.9, 38.3, 31.3, 22.9, 21.5, 13.5; IR (KBr) 3500, 3240, 3190,
3060, 2960, 2930, 1680, 1535, 1370, 1325, 1310, 1280, 1260,
2H), 7.40 (m, 3H), 7.30 (m, 2H), 7.14 (d, 1H), 7.08 (t, 1H), 5.76
13
(s, 1H); C NMR (400 MHz, CDCl ) δ 141.6, 140.3, 132.4,
3
128.9, 128.4 (2C), 128.2, 126.7 (2C), 124.1, 124.0, 120.4, 94.9,
-1
1
1060, 1040, 700 cm ; MS (FAB+, NBA) m/z 396 (M+, 44), 397
84.0, 65.1, 14.9; IR (NaCl) 3390, 3060, 2920, 2220 cm- ; MS
(M+1, 34), 398 (M+2, 24), 399 (M+3, 13), 379 (100), 303 (98);
(+CI, CH ) m/e 295 (M+C H ), 283 (M+C H ), 237 (M-OH).
4 3 5 2 5
anal. calcd for C
16.15; Cl, 8.93; found: C, 54.53; H, 5.47; N, 7.12; S, 16.25; Cl,
H N S O Cl: C, 54.46; H, 5.33; N, 7.06; S,
21 18 2 2 2
24. Paulmier, C. Tetrahedron Lett. 1978, 21, 1797.
25. Grehn, L. J. Heterocyclic Chem. 1978, 15, 81.
8.74;
3-(butylthio)-2-(3-hydroxy-3-phenylprop-1-yn-1-yl)-6-
1
26. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
((2H)-tetrahydropyran-2-yloxymethyl)pyridine 27; H NMR (400
513.
MHz, CDCl ) δ 7.68 (d, 2H), 7.56 (d, 1H), 7.38 (m, 4H), 5.75 (s,
3
1H), 4.82 (d, 1H), 4.71 (t, 1H), 4.58 (d, 1H), 3.87 (m, 1H), 3.51
(m, 1H), 2.89 (t, 2H), 1.62 (m, 8H), 1.44 (m, 2H), 0.91 (t, 3H);
27. Fieser, L. F.; Fieser, M. Reagents For Organic Synthesis, Vol 1;
Wiley: New York, 1967; p 353.