Synthesis of 6-cycloalkylcarbonyl-2(3H)-benzothiazolones via 6-tributyltin intermediates

Article abstract of DOI:10.3987/COM-07-11078

6-Cycloalkylcarbonyl-2(3H)-benzothiazolones cannot be prepared by classical Friedel-Crafts acylation with the corresponding cycloalkylcarbonyl chlorides. We have explored new way via stille coupling from the tributyltin intermediates which were synthesised by protection of the NH group with ethylmethyl ether or potassium salt of the corresponding 6-bromo-2-(3H)-benzothiazolone. The stille coupling reaction of these tributyltin intermediates with the desired cycloalkylcarbonyl chlorides followed by deprotection of the NH group, afforded the corresponding 6-cycloalkylcarbonyl-2(3H)-benzothiazolones.

Full text of DOI:10.3987/COM-07-11078

HETEROCYCLES, Vol. 71, No. 9, 2007
2041
HETEROCYCLES, Vol. 71, No. 9, 2007, pp. 2041 - 2047. © The Japan Institute of Heterocyclic Chemistry
Received, 13th April, 2007, Accepted, 25th May, 2007, Published online, 29th May, 2007. COM-07-11078
SYNTHESIS
OF
6-CYCLOALKYLCARBONYL-2(3H)-
BENZOTHIAZOLONES VIA 6-TRIBUTYLTIN INTERMEDIATES
Pascal Carato,* Kallyl Cherry, Nicolas Lebegue, Pascal Berthelot, and Saïd
Yous
Faculty of Pharmacy, EA 1043, 3, rue du Pr. Laguesse, BP 83, 59006 LILLE
cedex France; Fax : 03 20 96 49 13 ; e-mail : pascal.carato@univ-lille2.fr
Abstract – 6-Cycloalkylcarbonyl-2(3H)-benzothiazolones cannot be prepared by
classical Friedel-Crafts acylation with the corresponding cycloalkylcarbonyl
chlorides. We have explored new way via stille coupling from the tributyltin
intermediates which were synthesised by protection of the NH group with
ethylmethyl
ether
or
potassium
salt
of
the
corresponding
6-bromo-2-(3H)-benzothiazolone. The stille coupling reaction of these tributyltin
intermediates with the desired cycloalkylcarbonyl chlorides followed by
deprotection
of
the
NH
group,
afforded
the
corresponding
6-cycloalkylcarbonyl-2(3H)-benzothiazolones.
INTRODUCTION
2(3H)-Benzothiazolone is a pharmacophore who was usually used to build molecules with medicinal
properties or useful as pharmacological tools.1-3 Friedel-Crafts acylation which used drastic acid
conditions as PPA or AlCl3 – DMF complex, was usually employed to give the corresponding products
substituted regioselectively in the C-6 position.4 We showed that introduction of cycloalkylcarbonyl
group in N-methyl-2-(3H)-benzothiazolone cannot be performed in these reaction conditions, the acylium
ion is unstable. 6-Cycloalkylcarbonyl-N-methyl-2(3H)-benzothiazolones were obtained by Stille coupling
using stannic intermediates.5
In this paper, we have focused our attention on the 2(3H)-benzothiazolone ring without substitution on
the NH group which seems to be essential structural requirement for activity and receptor selectivity.6 As
for N-methyl derivatives, the general approach to synthesize the corresponding 6-cycloalkylcarbonyl
compounds with free NH group was explored using stannic intermediates.
RESULTS AND DISCUSSION
Stille coupling reaction with 6-bromo-2(3H)-benzothiazolone (5), Pd(PPh)3 and (Bu3Sn)2 in toluene or

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HETEROCYCLES, Vol. 71, No. 9, 2007
DMF was unsuccessful and all the starting material was recovered (Method A, Scheme 1). As we claimed
in a recent publication, some reactions which are successful in the N-methyl series cannot be applied in
the N-H benzothiazolonic series.7 Stille reaction is sensible to acid media or acid group as the hydrogen
of the thiocarbamate moiety, we have then decided to protect the NH form with ethylmethyl ether group
(Method B, Scheme 1).
O
O
H
N
N
S
N
S
b
a
O
O
O
S
SnBu3
Br
Br
5
7
6
a
c
Method B
Method A
H
N
O
O
H
N
S
SnBu3
N
d
O
O
( )
( )
m
m
S
S
8a-b
2b-c
O
O
Scheme 1. Reagents: (a) : (Bu3Sn)2, Pd(PPh3)4, toluene, argon (b) : ClCH2OCH2CH3, K2CO3, DMF,
85%(c) : cycloalkylcarbonyl chloride (m= 2, 4), PdCl2(PPh3)2, toluene, argon, 61-76% (d) : TFA,
21-28%.
8
The 6-bromo-2(3H)-benzothiazolone (5) in dimethyformamide, in the presence of 2-chloromethylethyl
ether and potassium carbonate afforded the N-protected compound 6. Treatment of bromo derivative 6
with
(Bu3Sn)2
and
Pd(PPh3)4
in
toluene
under
argon
gave
the
3-ethoxymethyl-6-tributyltin-2(3H)-benzothiazolone (7) with satisfactory yield (58%). Reaction of the
stannic intermediate 7 in toluene, under argon, with PdCl2(PPh3)2 and the desired cycloalkylcarbonyl
chlorides gave compounds 8a-b with good yields (61-74%). The last step was the cleavage of the
protecting group ethylmethyl ether in refluxing TFA of the compounds 8a-b to afford the corresponding
products 2b-c with low yields (21 and 28 % respectively). Others protecting groups, as acetyl and
methanesulfonyl, were introduced to give the N-protected-6-bromo-2(3H)-benzothiazolone. These
N-protected products were treated according to Stille coupling reaction, but surprisingly we cannot obtain
the corresponding N-protected-6-tributyltin-2(3H)-benzothiazolones. Considering the weak yields of
deprotection and the observed cycloalkyl opening rings in the hard deprotection conditions, we adopted
another method of protection to inhibit the interaction of the NH acid group in the stille coupling. Yang
have described the introduction of trimethylstannyl group on 5-bromoindole,9 which was first converted
to its potassium salt derivative, subjected to halogen-metal exchange using tert-butyllithium and then
introduction of the trimethylstannyl. We have adopted this methodology (Scheme 2).

HETEROCYCLES, Vol. 71, No. 9, 2007
2043
H
N
H
N
K
N
b
a
O
O
O
S
S
S
Br
Li
SnBu3
5
9
c
( )
O
m
H
N
S
N
S
d
O
O
( )
( )
m
m
2a-d
10a-d
O
O
Scheme 2 Reagents: (a) i : KH, THF ; ii : tert-BuLi (b) Bu3SnCl, 65% (c): KH, cycloalkylcarbonyl
chloride derivatives (m= 1, 2, 3, 4), PdCl2(PPh3)2, THF, 76-89%(d) NaOH, H2O, MeOH, 55-81%.
On the first step 6-bromo-2(3H)-benzothiazolone (5) in THF at 0 °C with KH was converted to the
potassium salt compound, the second step was the introduction at -78 °C of tert-butyl lithium to realise
the halogen-metal exchange, then tributyltin chloride was added to give the desired
6-tributyltin-2(3H)-benzothiazolone (9). The first attempt of Stille coupling of stannic (9) in standard
conditions led to the recovery of 2-(3H)-benzothiazolone. We decided to convert as previously described,
the NH group to its potassium salt for the Stille coupling in presence of KH, PdCl2(PPh3)2 and the
corresponding cycloalkylcarbonyl chlorides in refluxing THF under argon. In these reaction conditions,
the 3,6-diacylated compounds 10a-d were obtained and the cleavage of the N-cycloalkylcarbonyl groups
was easily realised in a mixture of water/MeOH in the presence of sodium hydroxide to give the
corresponding 6-cycloalkylcarbonyl-2(3H)-benzothiazolones (2a-d) with free NH group.
In
conclusion,
in
this
article
we
report
the
synthesis
of
original
6-cycloalkylcarbonyl-2(3H)-benzothiazolones (2a-d) which represent powerfull intermediates for the
synthesis of a great range of biologically active compounds. These compounds were synthesized by stille
coupling via the corresponding 6-tributyltin intermediates. In this article we showed the interaction of the
N-H acid group of the 2(3H)-benzothiazolone in the Stille reaction, and the necessary to protect via the
potassium salt or ethylmethylether group to produce the 6-tributyltin intermediates (7, 9). These
protections allowed leading to original compounds 2a-d, 10a-d, and 8a-b.
EXPERIMENTAL
Melting points were determined on a Büchi SMP-535 apparatus and are uncorrected. IR spectra were
recorded on a Brüker Vector 22 spectrophotometer using KBr pellets. 1H NMR spectra were recorded on
a Brüker AC 300 instrument using TMS as an internal reference.

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HETEROCYCLES, Vol. 71, No. 9, 2007
6-Bromo-3-ethoxymethyl-2(3H)-benzothiazolone (6): To a solution of 6-bromo-2(3H)-benzothiazolone
(5) (3 g, 13 mmol) in DMF (50 mL), K2CO3 (5.4 g, 39 mmol) were refluxed for 30 min and then
chloromethyl ethyl ether (1.8 mL, 19 mmol) was added. The mixture was stirred at 100 °C for 4 h. The
mixture was allowed to cool, and the reaction was quenched with the addition of water (200 mL). The
precipitate was filtered off, dried and recristallised with to give the title compound (2.2 g, 85%). mp
79-80 °C (petroleum ether); IR 1676 (CO); 1H NMR (CDCl3): δ 1.15 (t, 3H, J= 7.0 Hz, CH3), 3.60 (q, 2H,
J= 7.0 Hz, CH2), 5.40 (s, 2H, NCH2O), 7.15 (d, 1H, J= 8.5 Hz, H4), 7.45 (dd, 1H, J= 8.5 Hz, J= 1.7 Hz,
H5), 7.60 (d, 1H, J= 1.7 Hz, H7). M/z= 289.2. Anal. Calcd for C10H10NO2S: C, 41.68; H, 3.50; N, 4.86.
Found: C, 41.89; H, 3.74; N, 4.61.
3-Ethoxymethyl-6-tri-n-butyltin-2(3H)-benzothiazolone (7): To
a
mixture of 6-bromo-3-
ethyoxymethyl-2(3H)-benzothiazolone (6) (5.2 g, 18 mmol) in dry toluene (50 mL) under argon,
tetrakis(triphenylphosphine)palladium (2.1 g, 1.8 mmol) and bis(tributyltin) (13.6 mL, 27 mmol) were
added. The reaction was stirred at 90 °C for 16h. The solution was evaporated under reduced pressure.
The oily residue was purified by flash column chromatography with petroleum ether/EtOAc (9.7/0.3) to
give an oily product. Yield 58%; IR 1677 (CO); 1H NMR (CDCl3): δ 0.90 (t, 9H, J= 6.8 Hz, (CH3)3), 1.10
(t, 6H, J= 6.0 Hz, (CH2)3),1.20 (t, 3H, J= 7.0 Hz, CH3), 1.35 (m, 6H, (CH2)3), 1.55 (m, 6H, (CH2)3), 3.60
(q, 2H, J= 7.0 Hz, OCH2), 5.40 (s, 2H, NCH2), 7.25 (d, 1H, J= 7.9 Hz, H4), 7.40 (dd, 1H, J= 7.9 Hz, J=
0.9 Hz, H5), 7.50 (s, 1H, H7). M/z= 499.1.
General procedure for the preparation of products 8a-b: Compounds 7 (1.15 g, 2.3 mmol) in dry
toluene (10 mL) was placed under argon, PdCl2(PPh3)2 (0.16 g, 0.23 mmol) and the desired
cycloalkylcarbonyle chloride (4.6 mmol) was added. The reaction was refluxed for 4 h. The solution was
evaporated under reduced pressure. The residue was purified by flash column chromatography with
petroleum ether/EtOAc (8/2).
6-Cyclobutylcarbonyl-3-ethoxymethyl-2(3H)-benzothiazolone (8a): Yield 61%; mp 76-77 °C; IR 1673
1
(CO) 1660 (CO); H NMR (CDCl3): δ 1.20 (t, 3H, J= 7.0 Hz, CH3), 1.90 (m, 1H, CH2), 2.10 (m, 1H,
CH2), 2.30 (m, 2H, CH2), 2.45 (m, 2H, CH2), 3.60 (q, 2H, J= 7.0 Hz, OCH2), 4.00 (m, 1H, CH), 5.45 (s,
2H, NCH2), 7.35 (d, 1H, J= 8.5 Hz, H4), 7.90 (dd, 1H, J= 8.5 Hz, J= 1.8 Hz, H5), 8.05 (d, 1H, J= 1.8 Hz,
H7). M/z= 292.1. Anal. Calcd for C15H17NO3S: C, 61.83; H, 5.88; N, 4.81. Found: C, 61.95; H, 5.96; N,
4.67.
6-Cyclohexylcarbonyl-3-ethoxymethyl-2(3H)-benzothiazolone (8b): Yield 76%; mp 115-116 °C; IR
1
1672 (CO); H NMR (CDCl3): δ 1.15 (t, 3H, J= 7.0 Hz, CH3), 1.40 (m, 5H, CH2), 1.85 (m, 5H, CH2),
3.25 (m, 1H, CH), 3.60 (q, 2H, J= 7.0 Hz, CH2), 5.40 (s, 2H, NCH2O), 7.35 (d, 1H, J= 8.5 Hz, H4), 7.95

HETEROCYCLES, Vol. 71, No. 9, 2007
2045
(dd, 1H, J= 8.5 Hz, J= 1.7 Hz, H5), 8.10 (d, 1H, J= 1.7 Hz, H7). M/z= 320.2. Anal. Calcd for C17H21NO3S:
C, 63.92; H, 6.63; N, 4.39. Found: C, 64.15; H, 6.78; N, 4.50.
6-Tributyltin-2(3H)-benzothiazolone (9): In dry THF (40 mL) under argon atmosphere, KH (0.8g, 8.70
mmol) was added dropwise at 0 °C and 6-bromo-2(3H)-benzothiazolone (5) (1 g, 4.35 mmol) in 10 mL of
dry THF. The solution was cooled to -78 °C and a 1.5 M solution of tert-BuLi (5.8 mL, 8.70 mmol) in
pentane was added. After the addition, the solution was strirred for 15 mn and a solution of tributyltin
chloride (3.5 mL, 13.05 mmol) was added dropwise at -7 8°C. The mixture was stirred for 1 h at -78 °C
and then the reaction mixture was allowed to warm to rt. A solution of 10% H3PO4 (100 mL) was added
to the reaction and the mixture was extracted with Et2O. The extracts were washed with water, dried, and
concentrated to give a residue. The resulting crude product was purified by flash column chromatography
eluting with petroleum ether/EtOAc (9.5/0.5) to give an oily product. Yield 65%; IR 1681 (CO); 1H NMR
(CDCl3): δ 0.90 (t, 9H, J= 6.7 Hz, (CH3)3), 1.10 (m, 6H, J= 6.0 Hz, (CH2)3), 1.25 (m, 6H, (CH2)3), 1.50
(m, 6H, (CH2)3), 7.15 (d, 1H, J= 7.6 Hz, H4), 7.35 (dd, 1H, J= 7.6 Hz, J= 0.9, H5), 7.45 (s, 1H, H7), 9.55
(brs, 1H, NH). M/z= 231.2.
General procedure for the preparation of products 10a-d: In dry THF (40 mL) under argon
atmosphere, KH (0.4 g, 4.54 mmol) was added dropwise at 0 °C and 6-tributyltin-2(3H)-benzothiazolone
(7) (1 g, 2.27 mmol) in 10 mL of dry THF. After the addition of dichlorobis(triphenyl phosphine)
palladium (0.08 g, 0.114 mmol), the mixture was stirred for 10 mn and the desired cycloalkylcarbonyl
chloride was added (3.41 mmol). The reaction mixture was refluxed for 3 h. The solution was evaporated.
The resulting crude product was purified by flash column chromatography eluting with petroleum
ether/EtOAc (9.5/0.5) to give the 3,6-dicycloalkylcarbonyl intermediates 10a-d.
3,6-Dicyclobutylcarbonyl-2(3H)-benzothiazolone (10b): Yield (85%), mp 83-84 °C, IR 1713(CO),
1671 (CO); 1H NMR (CDCl3): δ 2.05 (m, 4H, CH2), 2.40 (m, 8H, CH2), 4.00 (m, 1H, CH), 4.20 (m, 1H,
CH), 7.85 (dd, 1H, J= 8.8 Hz, J= 1.9 Hz, H5), 8.00 (d, 1H, J= 1.5 Hz, H7), 8.35 (d, 1H, J= 8.8 Hz, H4).
M/z= 316.3.
3,6-Dicyclopentylcarbonyl-2(3H)-benzothiazolone (10c): Yield (76%), mp 97-98 °C, IR 1702 (CO),
1665 (CO); 1H NMR (CDCl3): δ 1.70 (m, 8H, (CH2)2), 2.05 (m, 8H, CH2), 3.65 (m, 1H, CH), 4.00 (m, 1H,
CH), 7.90 (dd, 1H, J= 8.8 Hz, J= 1.8 Hz, H5), 8.05 (d, 1H, J= 1.8 Hz, H7), 8.20 (d, 1H, J= 8.8 Hz, H4).
M/z= 344.1.
3,6-Dicyclohexylcarbonyl-2(3H)-benzothiazolone (10d): Yield (89%), mp 93-95 °C, IR 1728(CO),
1703 (CO), 1654 (CO); 1H NMR (CDCl3): δ 1.30 (m, 10H, CH2), 1.65 (m, 8H, CH2), 2.00 (m, 2H, CH2),

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HETEROCYCLES, Vol. 71, No. 9, 2007
3.35 (m, 1H, CH), 3.50 (m, 1H, CH), 7.95 (dd, 1H, J= 8.7 Hz, J= 1.6 Hz, H5), 8.05 (d, 1H, J= 8.7 Hz, H4),
8.40 (d, 1H, J= 1.6 Hz, H7). M/z= 372.2.
General procedure for the preparation of products 2a-d: The products 10a-d were dissolved in
MeOH (15mL), and a solution of 5% aqueous NaOH (10 mL) was added. The mixture was refluxed for
1h. MeOH was epavorated under reduced pressure. The basic solution was diluted with water (30 mL),
and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 12N HCl, and extracted with
CH2Cl2. The organic layer was dried, and concentrated to give the corresponding products 2a-d. The
compound was recrystallized with the appropriated solvent.
6-Cyclopropylcarbonyl-2(3H)-benzothiazolone (2a): Yield 75% (EtOH); mp 203-204 °C; IR 1688
1
(CO), 1668 (CO); H NMR (DMSO-d6): δ 1.00 (m, 4H, (CH2)2), 2.90 (m, 1H, CH), 7.20 (d, 1H, J= 8.5
Hz, H4), 8.00 (dd, 1H, J= 8.5 Hz, J= 1.5 Hz, H5), 8.30 (d, 1H, J= 1.5 Hz, H7), 12.30 (brs, 1H, NH). M/z=
220.1. Anal. Calcd for C11H9NO2S: C, 60.26; H, 4.14; N, 6.39. Found: C, 60.49; H, 4.25; N, 6.51.
6-Cyclobutylcarbonyl-2(3H)-benzothiazolone (2b): Yield 55% (EtOH); mp 151-152 °C; IR 3135 (NH),
1
1685 (CO), 1663 (CO); H NMR (DMSO-d6): δ 1.70 (m, 1H, CH2), 2.00 (m, 1H, CH2), 2.20 (m, 4H,
CH2), 4.10 (m, 1H, CH), 7.20 (d, 1H, J= 8.5 Hz, H4), 7.80 (dd, 1H, J= 8.5 Hz, J= 1.8 Hz, H5), 8.15 (d, 1H,
J= 1.8 Hz, H7), 12.30 (brs, 1H, NH). M/z= 234.1. Anal. Calcd for C12H11NO2S: C, 61.78; H, 4.75; N, 6.00.
Found: C, 61.61; H, 4.94; N, 5.85.
6-Cyclopentylcarbonyl-2(3H)-benzothiazolone (2c): Yield 62% (EtOH); mp 137-138 °C; IR 3225 (NH),
1712 (CO), 1653 (CO); 1H NMR (DMSO-d6): δ 1.70-2.00 (m, 8H, CH2), 3.80 (m, 1H, CH), 7.20 (d, 1H,
J= 8.2 Hz, H4), 7.90 (dd, 1H, J= 8.2 Hz, J= 1.8 Hz, H5), 8.30 (d, 1H, J= 1.8 Hz, H7), 12.30 (brs, 1H, NH).
M/z= 248. Anal. Calcd for C13H13NO2S: C, 63.13; H, 5.30; N, 5.66. Found: C, 63.42; H, 5.51; N, 5.41.
6-Cyclohexylcarbonyl-2(3H)-benzothiazolone (2d): Yield 81% (EtOH); mp 195-196 °C; IR 1714 (CO),
1
1648 (CO); H NMR (DMSO-d6): δ 1.30 (m, 5H, CH2), 1.70 (m, 5H, CH2), 3.25 (m, 1H, CH), 7.20 (d,
1H, J= 8.3 Hz, H4), 7.90 (dd, 1H, J= 8.3 Hz, J= 1.6 Hz, H5), 8.30 (d, 1H, J= 1.6 Hz, H7), 12.30 (brs, 1H,
NH). M/z= 262. Anal. Calcd for C14H15NO2S: C, 64.34; H, 5.79; N, 5.36. Found: C, 64.61; H, 5.88; N,
5.51.
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