Benzo[b]thiophene as a template for substituted quinolines and tetrahydroquinolines

Article abstract of DOI:10.1016/j.tetlet.2005.11.108

An original methodology starting from 3-aroyl-2-(2′-nitro-4′- methoxyphenyl)-benzo[b]thiophene allows the synthesis of unusual fused heterocycles. Direct hydrogenation with nickel catalysts followed by desulfurisation led to 2,3-diarylquinolines or 2,3-di

Full text of DOI:10.1016/j.tetlet.2005.11.108

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1015–1018
Benzo[b]thiophene as a template for substituted
quinolines and tetrahydroquinolines
a
a
a
´ ´
´
´
Jeremie Fournier Dit Chabert, Gregory Chatelain, Stephane Pellet-Rostaing,
Denis Bouchub and Marc Lemairea,*
a
` ˆ
Laboratoire de Catalyse et Synthese Organique, UMR 5181, Bat. 308 CPE Lyon, 43 Bd. du 11 Novembre 1918,
69616 Villeurbanne cedex, France
bCentre de Spectroscopie de Masse, UMR 5181, 69616 Villeurbanne cedex, France
Received 9 September 2005; revised 21 November 2005; accepted 22 November 2005
Available online 20 December 2005
Abstract—An original methodology starting from 3-aroyl-2-(20-nitro-40-methoxyphenyl)-benzo[b]thiophene allows the synthesis of
unusual fused heterocycles. Direct hydrogenation with nickel catalysts followed by desulfurisation led to 2,3-diarylquinolines or 2,3-
diaryltetrahydroquinolines.
Ó 2005 Published by Elsevier Ltd.
1. Introduction
one compound functionalised at the alpha position of
the nitrogen was synthesised in four steps.9
The development of new methods for the synthesis of
nitrogen or sulfur-containing heterocycles is of impor-
tance in medicinal chemistry. Among these structures,
quinolines,1 tetrahydroquinolines2 and their derivatives
are excellent precursors of potential drugs.3 Quinolines
are usually synthesised by cyclisation reactions4 and,
to our knowledge, methods that allow the direct synthe-
sis of 2,3-diarylated quinolines are rare.4b,c Little work
has addressed the synthesis of 2,3-disubstituted tetrahy-
droquinolines by intermolecular5 or intramolecular6
cyclisation. Usually, the methods involve the hydroge-
nation of the quinoline precursors, either by PtO2,7
Pd/C8 or nickel complexes.5a
2. Results and discussion
We have recently reported the direct arylation at posi-
tion 2 of the benzo[b]thiophene core by palladium cou-
pling.10 In the presence of a Pd(OAc)2/PPh3 system
and potassium carbonate as a base, 2-(20-nitro-40-meth-
oxyphenyl)-benzo[b]thiophene 1 was obtained in 62%
yield. Acylation at position 3 yielded 3-aroyl-2-(20-nitro-
40-methoxyphenyl)-benzo[b]thiophenes 2a–c in good
yields (74–91% yield). Hydrogenation of the nitro group
afforded an amine, which condensed on the ketone
group and cyclised into the corresponding benzothi-
eno[3,2-c]quinolines 4a–c.
In this letter, we present a simple and efficient synthetic
methodology starting from the benzo[b]thiophene scaf-
fold to form, in a few steps, a number of various hetero-
cyclic structures. We investigated the synthesis of rare
polycyclic compounds such as 11-thia-5-aza-benzo[a]-
fluorenes 4a–c (or benzothieno[3,2-c]quinolines) and
their N-oxide derivatives 3a–c. As far as we know, only
Although no biological evaluation was performed on
these structures, their nitrogen bioisosteres, indolo[3,2-c]-
quinolines proved to possess potent antimalarial activity
and were generally synthesised in 5–7 steps.11 Finally,
desulfurisation of benzothieno[3,2-c]quinolines 4a–c,
followed by hydrogenation led to 2,3-diarylated quino-
lines or tetrahydroquinolines 5a–c (Scheme 1).
The reduction of the nitro group was performed with
Raney nickel under an inert or hydrogen atmosphere
(Table 1). It was found that, at room temperature and
under an atmosphere of argon, partial hydrogenation
Keywords: Nickel hydrogenation; Diarylquinolines; Diaryltetrahydro-
quinolines.
*
Corresponding author. Tel.: +33 4 72 44 82 09; fax: +33 4 72 43 14
08; e-mail: marc.lemaire@univ-lyon1.fr
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.11.108

1016
J. Fournier Dit Chabert et al. / Tetrahedron Letters 47 (2006) 1015–1018
a hydroxylamine, which as in our case, is reactive
enough to condense on the ketone group.
Pd(OAc)2, PPh3
K2CO3, DMF
OMe
S
S
+
1: 62%
140˚C, 5 h
Br
O2N
Under 1 bar of hydrogen, a 30:1 ratio of Raney nickel/
substrate was required for the synthesis of benzo[b]thi-
eno[3,2-c]quinolines 4a–c, which were obtained in mod-
erate yields (entries 2, 5 and 8). However, the reaction
afforded improved yields at higher temperature and
higher hydrogen pressure (30 atm) with 1.5 equiv of
Raney nickel (Table 1, entries 3, 6 and 9). Under these
conditions, a large excess of Raney nickel yielded partial
degradation of the product into the corresponding
desulfurised compounds. Indeed, Jones reported that
Raney nickel could be used to desulfurise 2-aryl-
benzo[b]thiophenes.13 However, the drawbacks of Raney
nickel are numerous as they are tedious to prepare,
difficult to weigh accurately and require a large Ni/S
ratio.14a We turned our attention to other nickel sys-
tems, NiCRAꢀs14 and Ni2B15 (Table 2), which are
known for their high efficiency and chemoselectivity in
the desulfurisation of polyaromatic sulfur-containing
compounds.
ArCOCl, AlCl3
t. a., 1-5 h
O2N
OMe
MeO
O
X
OMe
OMe
H2
N
- H2O
OMe
S
S
O2N
2a: p-OMe: 91%
2b: m-OMe: 74%
2c: o-OMe: 74%
X = O: 3a-c
X = Ø: 4a-c
desulfurisation
MeO
MeO
H
N
N
H2
OMe
OMe
6a-c
5a-c
Scheme 1.
No cyclisation was observed when performed with
NiCRA catalyst on compounds 2a–c (Table 2, entries
1, 4 and 7). Indeed NiCRA catalysts have never been
reported as good reducing agents. In addition, this type
of catalyst is known for its high selectivity towards
desulfurisation, preventing any further hydrogena-
occurred, yielding benzothieno[3,2-c]quinolines-N-oxides
3a–c isolated in moderate yields (Table 1, entries 1, 4
and 7). This phenomenon was described recently for
the hydrogenation/cyclisation of a nitro group.12 The
authors speculated that partial hydrogenation yielded
Table 1. Hydrogenation of compounds 2a–c with Raney nickel
Entry
Substrate 2
Atm
Temperature (°C)
Time (h)
Product 3 (%)
Product 4 (%)
1
2
3
a
Ar
1 atm H2
30 atm H2
20
20
100
2
24
2
51
—
—
17
74
88
4
5
6
b
c
Ar
1 atm H2
30 atm H2
20
20
100
2
24
4
49
—
—
23
59
90
7
8
9
Ar
1 atm H2
30 atm H2
20
20
100
24
48
6
27
—
—
<10
74
78
Table 2. Desulfurisation study of compounds 2a–c and 4a–c
2a-c
+
"Ni"
MeO
N
H
MeO
N
or
4a-c
5a-c
+
-
( )-6a-c
MeO
MeO
Entry
Substrate
Catalyst
Time (h)
Product 5 (%)
Product 6 (%)
1
2
3
2a
2a
4a
Ni Raney
Ni2B
NiCRAꢀs
24
24
15
—
—
5a 66
6a 60
6a 56
—
4
5
6
2b
2b
4b
Ni Raney
Ni2B
NiCRAꢀs
24
48
15
—
—
5b 52
6b 19
6b 38
6b 6
7
8
9
10
2c
2c
4c
4c
Ni Raney
Ni2B
Ni2B
24
24
5
5c 12
—
—
6c 26
6c 38
6c 35
—
NiCRAꢀs
60
5c 48

J. Fournier Dit Chabert et al. / Tetrahedron Letters 47 (2006) 1015–1018
1017
tion.14a To our delight, desulfurisation of compounds
4a–c afforded the corresponding quinolines 5a–c in good
yields and with very little quantities of by-products
(Table 2, entries 3, 6 and 10).
J. J. Med. Chem. 2005, 48, 2243–2247; (b) Maguire, M. P.;
Sheets, K. R.; McVety, K.; Spada, A. P.; Zilberstein, A.
J. Med. Chem. 1994, 37, 2129–2137.
2. (a) Witherup, K. M.; Ransom, R. W.; Graham, A. C.;
Bernard, A. M.; Salvatore, M. J.; Lumma, W. C.;
Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J.
Am. Chem. Soc. 1995, 117, 6682–6685; (b) Carling, R. W.;
Leeson, P. D.; Moseley, A. M.; Smith, J. D.; Saywell, K.;
Tricklebank, M. D.; Kemp, J. A.; Marshall, G. R.; Foster,
A. C.; Grimwood, S. Bioorg. Med. Chem. Lett. 1993, 3,
65–70.
3. Michael, J. P. Nat. Prod. Rep. 2001, 18, 543–559.
4. (a) Holter, S. N.; Kirk-Othmer. Encyclopedia of Chemical
Technology, Quinoline and Isoquinoline, 3rd ed.; John
Wiley & Sons, 1982; Vol.19, pp 532–572; and recent
syntheses: (b) Igarashi, T.; Inada, T.; Sekioka, T.; Naka-
jima, T.; Shimizu, I. Chem. Lett. 2005, 34, 106–107; (c)
Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.;
Defeo-Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J.
R.; Huber, H. E.; Duggan, M. E.; Lindsley, C. W. Bioorg.
Med. Chem. Lett. 2005, 15, 905–909; (d) Chelucci, G.;
Manca, I.; Pinna, G. A. Tetrahedron Lett. 2005, 46, 767–
770; (e) Sangu, K.; Fuchibe, K.; Akiyama, T. Org. Lett.
2004, 6, 353–355; (f) McNuaghton, B. R.; Miller, B. L.
Org. Lett. 2003, 5, 4257–4259; (g) Huma, H. Z. S.; Halder,
R.; Kalra, S. S.; Das, J.; Iqbal, J. Tetrahedron Lett. 2002,
43, 6485–6488; (h) Cacchi, S.; Fabrizi, G.; Goggiamani,
On the other hand, the Ni2B system was reported as an
efficient reagent for the reduction of nitro compounds,
desulfurisation and hydrogenation of the quinoline ring.
However, hydrogenation of the benzo[b]thieno-quino-
line 4c to the corresponding tetrahydroquinoline 6c gave
only a moderate yield of 35% (Table 2, entry 9). When
the synthesis of tetrahydroquinolines 6a–c was investi-
gated from the non-cyclised compounds 2a–c, similar
results were obtained either with Raney nickel (Table 2,
entries 1, 4 and 7) or with Ni2B (Table 2, entries 2, 5
and 8).
A yield of 38–60% appeared to be quite satisfactory con-
sidering the number of steps involved in this one-pot
synthesis (reduction, cyclisation, desulfurisation then
hydrogenation). In addition, the tetrahydroquinolines
were isolated as only one pair of enantiomers. The cis
or trans configuration at C2 and C3 was determined by
1H NMR on compound 6a. It was found that H-2 was
correlated with H-3 in a coupling constant JH2H3 of
4 Hz in agreement with 2,3-cis-disubstituted tetrahydro-
quinolines H-2/H-3 coupling constants previously
reported.8 This low value prevents the protons from
adopting an axial–axial conformation as described in a
recent paper where a 2,3,4-(trans,trans)-trifunctionalised
tetrahydroquinoline gave a 10 Hz H-2/H-3 coupling
constant.5b Based on a 2D NOESY experiment, the
comparative study of the interproton distances from
cross peak amplitudes16 confirmed the cis configuration
of 6a with a distance H2–H3 of 230 pm.
A.; Moreno-Manas, M.; Vallribera, A. Tetrahedron Lett.
˜
2002, 43, 5537–5540; (i) Arcadi, A.; Chiarini, M.; Di
Guiseppe, S.; Marinelli, F. Synlett 2003, 2, 203–206.
5. For a general review about 1,2,3,4-tetrahydroquinolines,
see: (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B.
Tetrahedron 1996, 52, 15031–15070; And recent syntheses:
(b) Fadel, F.; Titouani, S. L.; Soufiaoui, M.; Ajamay, H.;
Mazzah, A. Tetrahedron Lett. 2004, 45, 5905–5908; (c)
Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org. Lett. 2002,
4, 4411–4414; (d) Larock, R. C.; Yang, H.; Pace, P.;
Cacchi, S.; Fabrizi, G. Tetrahedron Lett. 1998, 39, 1885–
1888.
6. (a) Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi,
S. V. J. Org. Chem. 2001, 66, 2822–2827; (b) Gogte, V. N.;
El-Namaky, H. M.; Salama, M. A.; Tilak, B. D. Tetra-
hedron Lett. 1969, 39, 3319–3322.
7. (a) Vecchietti, V.; Clarke, G. D.; Colle, R.; Giardina, G.;
Petrone, G.; Sbacchi, M. J. Med. Chem. 1991, 34, 2624–
2633; (b) Nagata, R.; Tanno, N.; Kodo, T.; Ae, N.;
Yamagushi, H.; Nishimura, T.; Antoku, F.; Tatsuno, T.;
Kato, T.; Tanaka, Y.; Nakamura, M. J. Med. Chem. 1994,
37, 3956–3968.
8. Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C.
Tetrahedron 2003, 59, 9887–9893.
9. Liu, J.; Diwu, Z.; Leung, W.-Y.; Lu, Y.; Patch, B.;
Haugland, R. P. Tetrahedron Lett. 2003, 44, 4355–
4359.
3. Conclusion
In conclusion, we have developed a rapid and efficient
methodology for the synthesis of unusual fused
heterocycles.17 A one-pot hydrogenation/desulfurisation
afforded the corresponding quinolines and tetrahydro-
quinolines. The latter are the first cis-2,3-diarylated
tetrahydroquinolines described by NMR so far. Recent
experiments confirmed that this original methodology
can be extended to a wide variety of sulfur-containing
substrates as well as functional groups. Considerable
efforts along these lines are currently in progress.
10. Fournier Dit Chabert, J.; Joucla, L.; David, E.; Lemaire,
M. Tetrahedron 2004, 60, 3221–3230.
11. (a) Werbel, L. M.; Kersten, S. J.; Turner, W. R. Eur. J.
Med. Chem. 1993, 28, 837–852; (b) Mouaddib, A.; Joseph,
Acknowledgements
´
B.; Hasnaoui, A.; Merour, J.-Y. Synthesis 2000, 4, 549–
556.
The authors thank Dr. Sylvie Ducki for spelling correc-
tions, Dr. Bernard Fenet for 2D NMR studies, Lionel
Joucla and Dr. Jurgen Schulz for useful discussions.
12. Wong, A.; Kuethe, J. T.; Davies, I. W.; Hughes, D. L.
J. Org. Chem. 2004, 69, 7761–7764.
13. Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.;
Black, L. J.; Thompson, A. R.; Falcone, J. F.; Clemens, J.
A. J. Med. Chem. 1984, 27, 1057–1066.
References and notes
`
14. (a) Becker, S.; Fort, Y.; Caubere, P. J. Org. Chem. 1990,
1. (a) Hoekstra, W. J.; Patel, H. S.; Liang, X.; Blanc, J.-B. E.;
Heyer, D. O.; Willson, T. M.; Iannone, M. A.; Kadwell, S.
H.; Miller, L. A.; Pearce, K. H.; Simmons, C. A.; Shearin,
`
55, 6194–6198; (b) Kuehm-Caubere, C.; Guilmart, A.;
Adach-Becker, S.; Fort, Y.; Caubert, P. Tetrahedron Lett.
1998, 39, 8987–8990; With Schiff bases: (c) Adams, H.;

1018
J. Fournier Dit Chabert et al. / Tetrahedron Letters 47 (2006) 1015–1018
Fenton, D. E.; McHugh, P. E. Inorg. Chem. Commun.
2004, 7, 147–150.
7-Methoxy-2-(3-methoxy-phenyl)-3-phenyl-quinoline 5b: 3-
Hydroxy-1-methylpiperidine (2 mmol) in 2 mL dried THF
was added dropwise to a suspension of NaH (7 mmol) and
Ni(OAc)2 (1 mmol) in hot THF (6 mL). After 1 h of reflux,
the substrate 4b (74 mg; 0.2 mmol) was added dropwise in
THF (2 mL). After 15 h stirring at 65 °C, the crude
mixture was cooled to 20 °C and ethanol (1 mL) and water
(15 mL) were added. The mixture was extracted three
times with dichloromethane (20 mL), and the combined
organic phases were dried over MgSO4, filtered and
evaporated. The crude products were purified by flash
chromatography (silica, heptane/ethyl acetate 98:2) to
afford compound 5b (35 mg; 52%) as a pale beige solid; mp
113–114 °C. Anal. Found: C 80.51, H 5.66, N 3.89, O 8.95.
Calcd for C23H19NO2: C 80.92, H 5.61, N 4.10, O 9.37; dH
(300 MHz, CDCl3) 3.67 (s, 3H, OCH3), 3.99 (s, 3H,
OCH3), 6.87 (ddd, 1H, J 0.9; 2.6; 8.2 Hz), 7.02 (dd, 1H, J
1.5; 2.6 Hz), 7.06 (ddd, 1H, J 0.9; 1.5; 7.7 Hz), 7.20 (dd,
1H, J 7.7; 8.2 Hz), 7.24 (dd, 1H, J 2.4; 9.0 Hz), 7.25–7.32
(m, 5H), 7.47 (d, 1H, J 2.4 Hz), 7.76 (d, 1H, J 9.0 Hz), 8.11
(s, 1H); dC (75 MHz, CDCl3) 55.2 (CH3), 55.7 (CH3),
107.4 (CH), 114.6 (CH), 115.0 (CH), 120.2 (CH), 122.6
(C), 122.7 (CH), 127.0 (CH), 128.3 (2CH), 128.6 (CH),
129.1 (CH), 129.8 (2CH), 132.5 (C), 137.4 (CH), 140.3 (C),
141.9 (C), 149.0 (C), 158.3 (C), 159.2 (C), 161.0 (C) ppm;
m/z 341 (M+, 40), 340 (100), 325(20), 297 (30), 254 (20);
HRMS CI found: 342.1496, calcd for C23H19NO2H+:
342.1494.
7-Methoxy-2-(4-methoxy-phenyl)-3-phenyl-1,2,3,4-tetra-
hydro-quinoline 6a: Compound 2a (1 mmol) and
NiCl2Æ6H2O (15 mmol) were dissolved in methanol
(35 mL) and THF (15 mL) in an opened flask cooled in
an ice bath. The solution was stirred while NaBH4
(45 mmol) was added in small portions. After stirring
under 30 bar hydrogen pressure at 100 °C for the time
indicated, the crude mixture was filtered over a short pad
of silica. The metallic residue was treated with a 1 M
solution of HCl (50 mL) and extracted with dichloro-
methane (50 mL). The aqueous solution was basified with
a 1 M KOH solution and then extracted with dichloro-
methane (50 mL). The combined organic phases were
dried over MgSO4, filtered and added to the first filtrate
prior to evaporation. The crude product was purified by
flash chromatography (silica, heptane/ethyl acetate
99.5:0.5) to afford compound 6a (193 mg; 56%) as an
amorphous white solid; mp 132–134 °C. Anal. Found: C
79.76, H 6.77, N 3.91, O 9.60. Calcd for C23H23NO2: C
79.97, H 6.71, N 4.05, O 9.26; dH (500 MHz, CDCl3) 3.00
(d, 2H, J 7.5 Hz), 3.49 (dt, 1H, J 4.0; 7.5 Hz), 3.75 (s, 3H,
OCH3), 3.81 (s, 3H, OCH3), 4.32 (br s, 1H, NH), 4.66 (d,
1H, J 4.0 Hz), 6.20 (d, 1H, J 2.5 Hz), 6.33 (dd, 1H, J 2.5;
8.3 Hz), 6.66 (d, 2H, J 8.9 Hz), 6.72 (d, 2H, J 8.9 Hz),
6.84–6.89 (m, 2H), 6.99 (d, 1H, J 8.3 Hz), 7.15–7.20 (m,
3H); dC (75 MHz, CDCl3) 29.2 (CH2), 44.1 (CH), 55.6
(CH3), 55.6 (CH3), 60.1 (CH), 99.3 (CH), 103.5 (CH),
113.3 (2CH), 113.6 (C), 126.8 (CH), 128.2 (2CH), 129.1
(2CH), 129.2 (2CH), 130.5 (CH), 134.2 (C), 141.9 (C),
145.6 (C), 159.0 (C), 159.6 (C) ppm; m/z 345 (M+, 40), 254
(100), 224 (30); HRMS CI found: 346.1805, calcd for
C23H23NO2H+: 346.1807.
15. (a) Schlesinger, H. I.; Brown, H. C.; Finholt, A. E.;
Gilbreath, J. R.; Hoekstra, H. R.; Hyde, E. K. J. Am.
Chem. Soc. 1953, 75, 215–219; (b) Back, T. G.; Yang, K.;
Krouse, H. R. J. Org. Chem. 1992, 57, 1986–1990; (c)
Back, T. G.; Baron, D. L.; Yang, K. J. Org. Chem. 1993,
58, 2407–2413.
16. Reggeli, M.; Hoffman, H.; Ko¨ck, M.; Mierke, D. F. J. Am.
Chem. Soc. 1992, 114, 3272–3277.
17. 3-Methoxy-6-(4-methoxy-phenyl)-11-thia-5-aza-benzo[a]-
fluorene-5-oxide 3a: In a round bottom flask filled with
Raney nickel (15 mmol) in ethanol (5 mL) was added
compound 2a (210 mg; 0.5 mmol) and the mixture was
stirred at room temperature for 2 h. Dichloromethane
(10 mL) was added to dissolve the yellow precipitate and
the mixture was filtered prior to evaporation. The resulting
solid was purified by flash chromatography (silica, cyclo-
hexane/AcOEt 90:10) to afford compound 3a (98 mg;
51%) as a pale yellow powder; mp >270 °C. Anal. Found:
C 71.10, H 4.47, N 3.61, O 12.51. Calcd for C23H17NO3S:
C 71.30, H 4.42, N 3.61, O 12.39; dH (300 MHz, CDCl3)
3.96 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.83 (d, 1H, J
8.3 Hz), 7.15 (ddd, 1H, J 1.1; 7.3; 8.1 Hz), 7.19 (d, 2H, J
8.7 Hz), 7.33 (dd, 1H, J 2.5; 8.9 Hz), 7.36 (ddd, 1H, J 1.1;
7.3; 8.3 Hz), 7.50 (d, 2H, J 8.7 Hz), 7.84 (d, 1H, J 8.1 Hz),
7.96 (d, 1H, J 8.9 Hz), 8.30 (d, 1H, J 2.5 Hz); dC (75 MHz,
CDCl3) 55.5 (CH3), 56.0 (CH3), 100.7 (CH), 115.1 (2CH),
119.0 (C), 121.5 (CH), 122.8 (CH), 124.5 (CH), 125.0 (C),
125.1 (CH), 126.0 (CH), 126.4 (C), 126.7 (CH), 130.7
(2CH), 134.7 (C), 136.1 (C), 138.9 (C), 140.8 (C), 143.7
(C), 160.6 (C), 161.9 (C) ppm; m/z 389 (20), 388 (MH+,
100), 370 (50), 327 (10); HRMS EI found: 387.0924, calcd
for C23H17NO3S+Å: 387.0929.
3-Methoxy-6-(2-methoxy-phenyl)-11-thia-5-aza-benzo[a]-
fluorene 4c: To Raney nickel (0.75 mmol) in ethanol was
added compound 2c (210 mg; 0.5 mmol) and the mixture
was stirred in a hydrogen pressurised (30 atm) reactor at
100 °C for 2 h. Dichloromethane (10 mL) was added to
dissolve the white precipitate and the mixture was filtered
prior to evaporation. The resulting solid was purified by
flash chromatography (silica, cyclohexane/AcOEt 95:5) to
afford compound 4c (145 mg; 78%) as an amorphous
white powder; mp 149–150 °C. Anal. Found: C 74.37, H
4.71, N 3.70, O 8.67. Calcd for C23H17NO2S: C 74.37, H
4.61, N 3.77, O 8.61; dH (300 MHz, CDCl3) 3.63 (s, 3H,
OCH3), 3.98 (s, 3H, OCH3), 7.06 (ddd, 1H, J 0.7; 1.2;
8.1 Hz), 7.11 (d, 1H, J 8.3 Hz), 7.19 (ddd, 1H, J 1.1; 7.2;
8.3 Hz), 7.20 (ddd, 1H, J 1.1; 7.4; 7.5 Hz), 7.30 (dd, 1H,
J2.5; 9.0 Hz), 7.38 (ddd, 1H, J 1.1; 7.2; 8.2 Hz), 7.47 (dd,
1H, J 1.8; 7.5 Hz), 7.56 (ddd, 1H, J 1.8; 7.4; 8.1 Hz), 7.69
(d, 1H, J 2.5 Hz), 7.91 (ddd, 1H, J 0.7; 1.1; 8.1 Hz), 8.04
(d, 1H, J 9.0 Hz); dC (75 MHz, CDCl3) 55.7 (CH3), 55.7
(CH3), 108.9 (CH), 111.3 (CH), 118.4 (C), 119.6 (CH),
121.5 (CH), 122.7 (CH), 123.8 (CH), 125.0 (CH), 125.1
(CH), 126.0 (CH), 126.9 (C), 130.1 (C), 130.1 (CH), 130.5
(CH), 135.8 (C), 138.5 (C), 146.5 (C), 147.1 (C), 154.5 (C),
157.3 (C), 160.8 (C) ppm; m/z 371 (M+, 60), 340 (50), 297
(60), 266 (100), 207 (10); HRMS CI found: 372.1054, calcd
for C23H17NO2SH+: 372.1058.