Sulfur-alkyne cyclizations for formation of dihydrothiophenes and annulated thiophenes

Article abstract of DOI:10.1055/s-2000-6294

Cycloisomerization of homopropargylic thiols to dihydrothiophenes is promoted by group VI metal carbonyls. Related thiacyclization transformations under basic and radical conditions are also described, including regioselective formation of benzothiophenes from aryl methyl sulfides and alkynes.

Full text of DOI:10.1055/s-2000-6294

970
PAPER
Sulfur-Alkyne Cyclizations for Formation of Dihydrothiophenes and
Annulated Thiophenes
Frank E. McDonald,*a Svetlana A. Burova,a Larry G. Huffman, Jr.b†
a Department of Chemistry, Emory University, Atlanta, GA 30322, USA
b Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
Fax +1(404)7276586; E-mail: fmcdona@emory.edu
Received 1 February 2000
H
Abstract: Cycloisomerization of homopropargylic thiols to dihy-
drothiophenes is promoted by group VI metal carbonyls. Related
thiacyclization transformations under basic and radical conditions
are also described, including regioselective formation of ben-
zothiophenes from aryl methyl sulfides and alkynes.
10 mol%
(Et3N)Mo(CO)5
O
(ref. 5)
O
3
4 (85%)
Ph3PS
CF3CO2H
C6H6
Key words: alkynes, diazo compounds, sulfur heterocycles, thiacy-
clizations, transition metals
H
H
(THF)Cr(CO)5
Et3N, THF
+
S
Our laboratory has studied transition metal-promoted cy-
clizations of terminal alkynes tethered to various nucleo-
philes. In the course of this work we have discovered
novel cycloisomerization transformations with oxygen,1
nitrogen,2 and carbon3 nucleophiles (Figure 1). Sulfur het-
erocycles have broad utility as isosteric analogs of other
cyclic structures,4 and these substructures are found in a
wide range of pharmaceutically important compounds as
well as conducting organic polymers. This communica-
tion describes our studies on cycloisomerizations of ter-
minal alkynyl thiols to dihydrothiophenes, as well as
related transformations for forming annulated thiophenes
from various alkyne and sulfide reactants.
S
5 (62%)
6 (17%)
7 (36%)
Scheme 1 Cycloisomerization of alkynyl episulfide 5
moted by (THF)W(CO)5 in the absence of an amine base
furnished metal complexes10 of dihydrothiophenes 10/11
as the major products (Table, Entry 2), whereas
(THF)Cr(CO)5 gave mixtures of metal-free and com-
plexed dihydrothiophenes. After finding that decomplex-
ation of 11-W(CO)5 to metal-free dihydrothiophene 11
occurred upon treatment with DBU, we developed a better
preparative procedure in which dihydrothiophenes 10 and
11 were obtained as the major products upon irradiation of
a mixture of the corresponding substrate 8 or 9, Cr(CO)6,
H
R
R
"M(CO)5"
XH
X
H
M = Cr, Mo, W
H
1
2
X = O, ref. 1
X = NR', ref. 2
X = CR'2, ref. 3
X = S, this work
Table Conditions for Alkynylthiol Cycloisomerization
Figure 1 Group VI metal-promoted cycloisomerizations
With our precedent of a particularly efficient cycloi-
somerization of alkynyl epoxide 3 to tetrahydrobenzofu-
ran 4,5 we began our studies by preparing the analogous
alkynyl episulfide 5 (Scheme 1).6 Although compound 5
was thermally sensitive and would extrude sulfur upon
warming to provide enyne 7, reaction of 5 with
En- Sub- Conditions
try strate
Product
Yielda
(%)
1
2
3
4
8
9
8
9
20 mol% (Et3N)Mo(CO)5
Et2O, 5 h
10
15
7
(THF)Cr(CO)5 led to formation of tetrahydroben-
1 equiv (THF)W(CO)5
THF, 17 h
11-W(CO)5 65
zothiophene 6 and the enyne 7.8
We then explored cycloisomerizations of alkynylthiols 8
1 equiv Cr(CO)6, hn (350 nm)
THF, DBU, 3 h
10
11
43
76
7
and 9.9 Catalytic (Et3N)Mo(CO)5 gave a modest yield of
dihydrothiophene 10 from substrate 8 (Table, Entry 1),
but the yield was not significantly improved by increasing
the quantity of molybdenum catalyst. Cyclizations pro-
2 equiv Cr(CO)6, hn (350 nm)
THF, DBU, 3 h
a Yield of isolated product.
Synthesis 2000, No. 7, 970–974 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Sulfur-Alkyne Cyclizations for Formation of Dihydrothiophenes
971
DBU, and THF at 350 nm (Table, Entries 3, 4). For been recently approved for treating bone loss associated
substrate 9 without a chromophoric substituent, di- with postmenopausal osteoporosis.15
hydrothiophene 11 was obtained in 76% yield when
2 equivalents of Cr(CO)6 were used (Table, Entry 4).
In the course of preparing alkynylthiol 9, we discovered
that reaction of mesylate 12 with excess potassium thioac-
OMe
S
MeO
17
O
etate proceeded very slowly at room temperature and re-
quired seven days for nearly complete conversion to the
alkynyl thioacetate 13. An attempt to carry out this dis-
placement reaction at elevated temperatures unexpectedly
furnished a 56% yield of dihydrothiophene 11 (Scheme
2). Formation of compound 11 was also observed when
thioacetate 13 was combined with potassium thioacetate
at higher temperatures, suggesting the intermediacy of 13
and the alkynylthiolate 9-K11 in the single-step formation
of dihydrothiophene 11 from alkynyl mesylate 12.
N
O
18, raloxifene
OH
S
HO
Figure 2 Structures of target compound 17 and raloxifene (18)
The standard published route for preparing 2-arylben-
zothiophenes including compound 17 proceeds in only
two steps from commercial materials, but the ben-
zothiophene-forming step proceeds with modest regiose-
lectivity.14a As a result, several other synthetic approaches
to raloxifene have been reported which are somewhat
longer but highly regioselective.16 We now report that rad-
ical bond-forming methods can be used to effect carbon-
carbon bond formation, sulfur demethylation and cycliza-
tion in a single step, beginning with o-diazonium aryl me-
thyl sulfide 23. We developed two routes for the
preparation of compound 23 from commercial p-anisidine
(19) (Scheme 4). The 2-aminobenzothiazole 21 could be
prepared from 19 by reaction with sodium thiocyanate and
bromine,17 which upon hydrolytic cleavage and selective
S-methylation of intermediate 22 afforded 4-methoxy-2-
thiomethylaniline (20) in excellent yield. Alternatively,
compound 20 could be prepared in a single step by copper
iodide-promoted thiomethylation.18 Diazotization under
standard conditions afforded crystalline diazonium tet-
rafluoroborate 23. Annulation of 23 with phenylacetylene
and 1-ethynyl-4-methoxybenzene19 could be accom-
plished with either FeSO4 in pyridine or DMSO,20 or with
TiCl3 in DMF,21 to effect regioselective formation of
2-arylbenzothiophene products 24 and 17.22
KSAc
(2 equiv)
H
n-C8H17
n-C8H17
S
DMF, 120 °C
(56% yield)
OMs
12
11, (30% yield)
KSAc, DMF
20ºC, 7 d
KSAc
(1 equiv)
H
H
n-C8H17
n-C8H17
DMF, 120 °C
SAc
13, 82% yield
SK
9-K+
Scheme 2 Formation of dihydrothiophene 11 from 12
In order to explore analogous cycloisomerizations of
arylthiol nucleophiles, we sought to prepare o-ethynyl-
thiophenol 15 (Scheme 3). Surprisingly, reaction of com-
pound 1412 with sodium-ammonia (precedented
conditions for demethylation of aryl methyl sulfides)13
produced benzothiophene 16 instead of alkynylthiol 15,
presumably by 5-endo-dig cyclization of the arylthiol rad-
ical generated in the demethylation of 14.
In conclusion, this communication documents a variety of
methods and strategies for construction of sulfur hetero-
cycles by thiacyclizations and annulations of alkynes with
sulfur reactants. We anticipate that these methods will
find considerable use in selective preparations of other
sulfur heterocyclic compounds.
H
H
Nao
NH3
SMe
SH
14
15
S
1H NMR spectra were measured in CDCl3 or DMSO-d6 at 300 MHz
on a Varian Mercury 300 NMR spectrometer and were referenced
with residual CHCl3 (7.26 ppm) or DMSO (2.50 ppm). 13C NMR
spectra were recorded at 75 MHz on the Varian Mercury 300 and
were referenced with the 77.0 ppm resonance of CDCl3 or 39.7 ppm
of DMSO-d6. IR spectra were recorded on Mattson Genesis II FT-
IR. Mass spectra (EI) or high-resolution mass spectra (EI) were
measured at 70 eV on VG-70S instrument. High-resolution FAB
mass spectra were recorded on Jeol SX102 at 6kV-Xe using 3-ni-
trobenzyl alcohol, in some cases with addition of LiI as a matrix.
16
Scheme 3 Thiacyclization of alkyne-aryl methyl sulfide 14
One of our general goals in this area was to develop a nov-
el, short, and regioselective synthetic route to 2-arylben-
zothiophenes. One specific target compound was
structure 17 (Figure 2),14 which is an advanced intermedi-
ate in the preparation of the antiestrogenic drug raloxifene Melting points were determined with a Fisher-Johns melting point
apparatus and are uncorrected. Elemental analyses were performed
(18), a selective estrogen receptor modulator which has
Synthesis 2000, No. 7, 970–974 ISSN 0039-7881 © Thieme Stuttgart · New York

972
F. E. McDonald et al.
PAPER
bined organic layers were washed with 1% HCl and dried (Na2SO4).
Flash chromatography with hexane gave 54 mg (76%) of dihy-
drothiophene 11.
NaSCN
Br2, HOAc
NH2
N
S
NH2
(62%)
MeO
MeO
Method B from Dodeca-1-yn-4-ol Mesylate Ester (12): A solu-
tion of mesylate 12 (4.00 g, 15.3 mmol) and KSAc (5.26 g, 46
mmol) in DMF (60 mL) was stirred overnight at 120 °C. The reac-
tion mixture was diluted with H2O and extracted three times with
Et2O. Combined organic fractions were washed with aq satd
NaHCO3 solution and dried (Na2SO4). Flash chromatography with
hexane gave 1.7 g (56%) of dihydrothiophene 11.
19
21
MeSSMe, CuI
o-xylene, 145°C
(51%)
50 % aq. KOH
NH2
MeI
NH2
SK
Method C from Dodeca-1-yne-4-thioacetate (13): A solution of
thioacetate 13 (150 mg, 0.63 mmol) and KSAc (72 mg, 0.63 mmol)
in DMF (2.5 mL) was stirred at 120 °C over 4 d and additionally for
6 d at r.t. The reaction mixture was diluted with 1% HCl and extract-
ed three times with Et2O. The combined organic fractions were
dried (Na2SO4). Chromatography with pentane gave 36 mg (30%)
of dihydrothiophene 11; bp 73-76°C/0.3 Torr.
1H NMR (CDCl3): d = 6.11 (dt, 1 H, J = 6, 2.4 Hz, olefinic proton),
5.54 (dt, 1 H, J = 6, 2.7 Hz, olefinic proton), 3.77 (m, 1 H, CH of the
thiophene ring), 2.82 (m, 1 H, one of the CH2 protons from the
thiophene ring), 2.43 (m, 1 H, one of the CH2 protons from the
thiophene ring), 1.6-1.71 (br m, 2 H, CH2 next to the thiophene
ring), 1.27 (br s, 12 H, CH2's), 0.88 (t, 3 H, J = 6.6 Hz, CH3).
(92%
SMe
MeO
MeO
from 21)
22
20
NaNO2, aq. HCl
then HBF4 (57%)
BF4
HCCAr
FeSO4, DMSO
(24, 55%; 17, 40%)
N2
R
or
S
MeO
MeO
SMe
HCCAr, TiCl3
DMF, -25°C to rt
23
24 R = H
17 R = OMe
(24, 46%; 17, 60%)
Scheme 4 Concise syntheses of 2-arylbenzothiophenes
13C NMR (CDCl3): d = 125.0, 121.3, 50.5, 41.4, 36.9, 31.9, 29.6,
29.5, 29.3, 28.3, 22.7, 14.2.
IR (neat): n = 2925 (s), 2855 (s), 1940 (w), 1720 (w), 1465 (m)
by Atlantic Microlab, Inc. in Norcross, GA. All reactions were con-
ducted in oven-dried (125°C) or flame-dried glassware under dry
N2. Et2O and THF for reactions were distilled from sodium ben-
zophenone ketyl; CH2Cl2 was distilled from CaH2; DMF, DMSO,
and o-xylene were used without purification from Sure-Seal bottles
(Aldrich). All reagents were purchased from Aldrich Chemical Co.
and used without further purification unless noted. Flash chroma-
tography was performed with silica gel (40 microns; 32-63 m) pur-
chased from Scientific Adsorbent, Inc.
cm-1.
MS (EI): m/z (%) = 198 (M+), 85 (M+ - C8H17).
HRMS (EI): m/z calcd for C12H22S 198.1442, found 198.1441.
Anal. calcd for C12H22S: C 72.73; H 11.11; S 16.16. Found: C 70.24;
H 10.69; S 15.51.
Dodeca-1-yne-4-mesylate (12)
Dodeca-1-yn-4-ol (3.0 g, 10.5 mmol) and Et3N (3.4 mL, 24.8
mmol) were dissolved in CH2Cl2 (100 ml) and then cooled to 0 °C.
MeSO2Cl (2.8 mL, 36 mmol) was then added and the reaction mix-
ture was stirred overnight at r.t.. The mixture was then diluted with
aq sat. NaHCO3 solution, the aqueous layer separated from organ-
ics, and extracted twice with CH2Cl2. The combined organic frac-
tions were washed with H2O and dried (Na2SO4). Chromatography
with hexane/Et2O (5:1) gave 4.0 g (93%) of mesylate 12.
1H NMR (CDCl3): d = 4.73 (m, 1 H, CHOSO2), 3.05 (s, 3 H,
CH3SO2), 2.62 (q, 2 H, J = 2.7, 6 Hz, CH2C≡C), 2.07 (t, 1 H, J = 2.7
Hz, acetylenic H), 1.77 (m, 2 H, CH2CHOSO2CH3), 1.26 (br s, 12
H, CH2's), 0.87 (t, 3 H, J = 6.3 Hz, CH3).
Dodec-1-yne-4-thiol (9)
LiAlH4 (140 mg, 3.6 mmol) was suspended in anhyd Et2O (20 mL),
and a solution of thioacetate 13 (378 mg, 1.6 mmol) in Et2O (10 mL)
was added in small portions. The mixture was stirred for 2 h at r.t.
and then poured into ice-water, diluted with Et2O and shaken. The
layers were separated, and the aqueous layer was extracted twice
with Et2O. The combined organic fractions were dried (Na2SO4).
Chromatography with hexane/ether (1:20) gave 220 mg (70%) of
thiol 9.
1H NMR (CDCl3): d = 2.94 (m, 1 H, CHSH), 2.53 (m, 2 H,
CH2C≡C), 2.09 (t, 1 H, J = 1.8 Hz, acetylenic H), 1.82 (d, 1 H,
J = 5.4 Hz, SH), 1.28 (br s, 14 H, CH2's), 0.89 (t, 3 H, J = 6.6 Hz,
CH3).
13C NMR (CDCl3): d = 80.5, 78.9, 71.5, 38.8, 34.1, 32.0, 29.5, 29.4,
25.1, 22.8, 14.3.
13C NMR (CDCl3): d = 81.5 (C≡CH), 70.9 (C≡CH), 39.3, 37.6,
32.0, 29.6, 29.4, 29.3, 27.4, 22.8, 14.3.
IR (neat): 3290 (m), 2930 (s), 2855 (s), 2125 (w), 1355 (s), 1175 (s),
915 (s) cm-1.
IR (neat): n = 3310 (s), 2920 (s), 2855 (s), 2120 (w), 1465 (m), 1260
HRMS (FAB+): m/z calcd for C12H24O3SLi ([M+Li]+) 267.1606,
found 267.1604.
(m), 1120 (m) cm-1.
Anal. calcd for C12H22S: C 72.73; H 11.11, S 16.16. Found: C 72.14;
H 11.20; S 15.94.
Anal. Calcd for C12H24O3S: C 60.00; H 9.23; S 12.31. Found: C
60.06; H 9.28; S 12.20.
2-Octyl-2,3-dihydrothiophene (11)
Dodeca-1-yne-4-thioacetate (13)
Method A from Dodeca-1-yne-4-thiol (9): Alkynylthiol 9 (70 mg,
0.35 mmol), Cr(CO)6 (154 mg, 0.7 mmol), DBU (5 mL) and THF
(20 mL) were premixed into an air-free Pyrex reaction tube fitted
with a reflux condenser. This solution was irradiated (350 nm, Ray-
onet photoreactor) for 3 h, and an internal fan was used to cool the
reaction vessel. The reaction mixture was then stirred at r.t. for 7 d,
diluted with 1% HCl and extracted three times with Et2O. Com-
A solution of mesylate 12 (500 mg, 1.9 mmol) and KSAc (438 mg,
3.8 mmol) in DMF (7.5 mL) was stirred at r.t. for 4 d. Additional
KSAc (438 mg, 3.8 mmol) was then added to the reaction mixture,
and stirring continued for another 3 d at r.t. The mixture was diluted
with 1% HCl and extracted three times with Et2O. The combined or-
ganic layers were dried (Na2SO4). Chromatography with hexane/
Et2O (12:1) gave 378 mg (82%) of thioacetate 13.
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Sulfur-Alkyne Cyclizations for Formation of Dihydrothiophenes
973
1H NMR (CDCl3): d = 3.63 (m, 1 H, CHSAc), 2.55 (m, 2 H,
CH2C≡C), 2.34 (s, 3 H, COCH3), 2.03 (t, 1 H, J = 2.7 Hz, acetylenic
H), 1.27 (br s, 14 H, CH2’s), 0.88 (t, 3 H, J = 6.6 Hz, CH3).
13C (CDCl3): d = 195.6 (CO), 76.5 (C≡CH), 65.9 (C≡CH), 42.9
(COCH3), 33.0, 32.1, 31.0, 29.7, 29.5, 29.4, 27.1, 25.2, 22.9, 14.4.
13C NMR (CDCl3): d = 152.6, 140.6, 121.8, 117.6, 116.1, 114.8,
56.0 (OCH3), 17.7 (SCH3).
IR (neat): n = 3420 (m, N-H), 3340 (m, N-H), 1595 (s), 1490 (s),
1280 (s), 1240 (s), 1040 (s, C-O) cm-1.
6-Methoxy-2-aminobenzothiazole (21)
IR (neat): n = 3310 (m), 2925 (s), 2855 (s), 2120 (w, C∫C), 1690 (s,
C=O), 1465 (m), 1120 (s), 950 (m) cm-1.
A solution of Br2 (16 ml, 320 mmol) in glacial AcOH (50 mL) was
added dropwise to a mixture of p-anisidine (19; 20 g, 160 mmol),
NaSCN (26 g, 320 mmol) and AcOH (550 mL) at 10-15°C over
3 h. After additional stirring for 45 min at r.t., the precipitate was fil-
tered, dissolved into warm water and basified with concentrated
NaOH to pH 8. The beige precipitate was filtered and recrystallized
from MeOH to give 17.8 g (62%) of 21 with mp 160-166°C.
HRMS (EI): m/z calcd for C14H22OS 240.1548, found 240.1541; for
C12H21S (C14H22OS - acetate) calcd 197.1364, found 197.1389.
Anal. calcd for C14H24OS: C 70.00; H 10.00; S 13.33. Found: C
69.73; H 9.93; S 13.60.
1H NMR (CDCl3): d = 7.29 (d, 1 H, JH7-H5 = 3 Hz, H-5 of benzothi-
azole ring), 7.21 (s, 2 H, NH2), 7.21 (d, 1 H, JH8-H7 = 9 Hz, H-8 of
benzothiazole ring), 6.80 (dd, 1 H, JH8-H7 = 9 Hz, JH7-H5 = 3 Hz, H-7
of benzothiazole ring), 3.72 (s, 3 H, OCH3).
13C NMR (CDCl3): d = 165.0, 154.0, 147.0, 132.0, 118.0, 113.0,
105.0, 58.0 (OCH3).
6-Methoxy-1-(4-methoxyphenyl)benzo[b]thiophene (17)
Diazonium tetrafluoroborate 23 (100 mg, 0.37 mmol) and 1-eth-
ynyl-4-methoxybenzene (0.35 mL, 1.48 mmol) were dissolved in
DMF (0.2 mL), and TiCl3 (57 mg, 0.37 mmol) was added in one
portion at -25 °C. The reaction mixture was stirred at -25 °C for
2.5 h, and then overnight at r.t.. The mixture was diluted with 1%
HCl and extracted with CH2Cl2 and EtOAc. The combined organic
fractions were dried (Na2SO4) and absorbed onto silica gel. After
chromatography with hexane/Et2O (50:1), 201 mg of 1-ethynyl-4-
methoxybenzene was recovered, and 61 mg (60%) of ben-
zothiophene 17 was separated in the form of white crystals; mp
200-204°C.
IR (KBr): n = 3390 (m, N-H), 3290 (m, N-H), 3115 (s), 1640 (s),
1547 (s), 1465 (s), 1400 (s), 1280 (m), 1205 (m), 1055 (m) cm-1.
HRMS (EI): m/z calcd for C8H8N2OS (M+) 180.0357, found
180.0361.
Anal. calcd for C8H8N2OS: C 53.33; H 4.44; N 15.56; S 17.78.
Found: C 51.92; H 4.43; N 15.44; S 17.67.
1H NMR (CDCl3): d = 7.58-7.66 (m, 3 H), 7.35 (s, 1 H), 7.30 (d, 1
H, J = 2.1 Hz), 6.92-7.01 (m, 3 H), 3.89 (s, 3 H, OCH3), 3.86 (s, 3
H, OCH3).
2-Thiomethyl-4-methoxydiazobenzene Tetrafluoroborate (23)
A suspension of aniline 20 (550 mg, 3.2 mmol) in H2O (1 mL) was
mixed with concd HCl (37% in H2O, 8.1 mL, 9.7 mmol). The reac-
tion mixture was stirred at r.t. for 1 h and then cooled to -5 °C. A
solution of NaNO2 (224 mg, 3.2 mmol) in H2O (1 mL) was added
dropwise over 25 min, followed by rapid addition of aq HBF4 (47%,
5.9 mL, 31 mmol), keeping the reaction temperature at or below
0°C. After addition of all components, the temperature was gradu-
ally increased to r.t. Partial evaporation of the aqueous layer, cool-
ing and filtration gave 490 mg (57%) of diazonium salt 23.
13C NMR (CDCl3): d = 159.7, 157.4, 141.7, 140.8, 135.1, 127.6,
124.1, 117.9, 114.5, 105.1, 55.8 (OCH3) 55.6 (OCH3).
IR (KBr): n = 2960 (m), 2925 (m), 2360 (w), 2340 (w), 1600 (s),
1500 (s), 1400 (s), 1250 (s), 1025 (s) cm-1.
HRMS (EI): m/z calcd for C16H14O2S (M+) 270.0711, found
270.0713.
Anal. calcd for C16H14O2S: C 71.11, H 5.19, S 11.85. Found: C
70.82; H 5.79; S 11.05.
1H NMR (DMSO-d6): d = 8.57 (d, 1 H, JH6-H5 = 9.3 Hz, H-6 of aro-
matic ring, meta to SCH3), 7.31 (br s, 1 H, H-3 of aromatic ring,
ortho to SCH3), 7.27 (d, 1 H, JH6-H5 = 9.3 Hz, H-5 of aromatic ring,
para to SCH3), 4.08 (s, 3 H, OCH3), 2.85 (s, 3 H, SCH3).
13C NMR (DMSO-d6): d = 150.4, 168.1, 136.2, 115.3, 113.7, 100.6,
57.7 (OCH3), 15.6 (SCH3).
2-Thiomethyl-4-methoxyaniline (20)
Method A: A mixture of p-anisidine (19; 1.23 g, 10 mmol, recrys-
tallized from a mixture of EtOH/H2O before reaction), CuI (1.9
g, 10 mmol), Me2S2 (2.5 mL, 25 mmol) and o-xylene (5 mL) was
refluxed for 94 h, then cooled to r.t., diluted with 3 N aq NaOH (5
mL) and left overnight with stirring. The liquid was decanted from
the black precipitate, which was washed with Et2O several times.
The combined aqueous and organic fractions were shaken and sep-
arated, and the aqueous layer was then extracted twice with Et2O.
The combined organic fractions were washed twice with 3 N HCl.
The acidic aqueous fractions were filtered, basified with aq 5 N
NaOH and extracted with Et2O, and the ethereal extracts were dried
(Na2SO4). After silica gel chromatography with EtOAc/
hexane (1:2), the product 20 was obtained in 51% yield (865 mg) as
a colorless oil.
IR (KBr): n = 3430 (m), 3395 (m), 3130 (m), 2210 (m, N≡N) 2190
(m, N≡N), 1575 (s), 1400 (m), 1250 (m), 1120 (m) cm-1.
HRMS (FAB+): m/z calcd for C8H9ON2S ([M-BF4]+) 181.0436,
found 181.0432.
6-Methoxy-2-phenylbenzo[b]thiophene (24)
This compound was prepared analogous to 17 from diazonium tet-
rafluoroborate 23 and phenylacetylene in DMF and TiCl3 as a pro-
moter with 46% yield. The similar reaction of 23 with
phenylacetylene in DMSO at r.t. with 1 equiv of FeSO4–7H2O gave
24 in 55% yield; mp 155-158°C.
1H NMR (CDCl3): d = 7.62-7.71 (m, 3 H), 7.37-7.48 (m, 3 H),
7.28-7.35 (m, 2 H), 6.98 (dd, 1 H, J = 2, 6 Hz), 3.88 (s, 3 H, OCH3).
Method B: A suspension of benzothiazole 21 (17.8 g, 99 mmol) in
25% aq KOH (200 g) was refluxed for 17 h. After cooling to r.t.,
MeI (6.2 mL, 99 mmol) was added in one portion. The reaction mix-
ture was stirred for an additional hour at r.t. and extracted with Et2O.
Combined organic fractions were dried (Na2SO4) and concentrated.
Distillation of the crude gave 15.5 g (92%) of aniline 20; bp 95-
110°C/0.5 Torr.
13C NMR (CDCl3): d = 157.6, 141.8, 141.1, 134.9, 134.5, 129.0,
128.0, 126.5, 124.3, 115.1, 114.8, 105.0, 56.0 (OCH3).
1H NMR (CDCl3): d = 6.92 (m, 1 H, aromatic H), 6.68 (m, 2 H, ar-
omatic H), 3.95 (br s, 0-1 H, NH2), 3.75 (s, 3 H, OCH3), 2.38 (s, 3
H, SCH3).
IR (KBr): n = 1595 (m), 1520 (m), 1465 (m), 1400 (s), 1260 (m),
1220 (m), 1120 (m), 1060 (m), 1025 (m), 840 (m), 750 (m) cm-1.
HRMS (EI): m/z calcd for C15H12OS (M+) 240.0690, found
240.0617.
Synthesis 2000, No. 7, 970–974 ISSN 0039-7881 © Thieme Stuttgart · New York

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F. E. McDonald et al.
PAPER
(e) Hanekamp, J. C.; Klusener, P. A. A.; Brandsma, L. Synth.
Commun. 1989, 19, 2691.
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Acknowledgement
This research was partially supported by the National Science Foun-
dation (CHE-9501608 to F. E. M.). L.G.H., Jr. gratefully acknow-
ledges a predoctoral fellowship from the National Science
Foundation. We also thank the Camille and Henry Dreyfus Found-
ation and Novartis Pharmaceutical Corporation for additional finan-
cial support of our research programs.
References
Compound 17 is also a key intermediate for the synthesis of
other biologically active compounds:
†
Current address: Department of Chemistry, University of Illinois, 505
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(7) Prepared by photolysis at 350 nm of the group VI metal
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The published representative procedure does not mention the
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(8) A control experiment in which 5 was stirred with Et3N and
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(19) This compound is commercially available but very expensive.
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(9) Alkynylthiol 8 was prepared in two steps from the known
homopropargylic alcohol: (i) PPh3, DEAD, HSAc, Et2O;
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Article Identifier:
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Synthesis 2000, No. 7, 970–974 ISSN 0039-7881 © Thieme Stuttgart · New York