Facile synthesis of disubstituted and spiro five-membered benzosultams mediated by TMSCL-NaI-MeCN reagent

Article abstract of DOI:10.1039/b109832b

Facile synthesis of distributed and spiro five-membered benzosultams mediated by TMSCI-NaI-MeCN reagent was presented. o-Lithiation of N-tert-butylbenzenesulfonamide followed by reaction with ketones gave carbinol sulfonamides. Spiro five-membered benzosu

Full text of DOI:10.1039/b109832b

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Facile synthesis of disubstituted and spiro five-membered
benzosultams mediated by TMSCl–NaI–MeCN reagent
Zhaopeng Liu, Norio Shibata* and Yoshio Takeuchi
1
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University,
Sugitani 2630, Toyama 930-0194, Japan. E-mail: nozshiba@ms.toyama-mpu.ac.jp
Received (in Cambridge, UK) 29th October 2001, Accepted 21st December 2001
First published as an Advance Article on the web 10th January 2002
Table
1
Synthesis of 3,3-disubstituted and spiro-five-membered
benzosultams
o-Lithiation of N-tert-butylbenzenesulfonamide followed
by reaction with ketones gave carbinol sulfonamides,
which underwent TMSCl–NaI–MeCN reagent mediated
cyclization to afford 3,3-disubstituted and spiro-2,3-
dihydrobenzo[d]isothiazole-1,1-diones in high yields.
Yields (%)
6a–g
Yields (%)
7a–g
Entry
R1
R2
a
b
c
d
e
f
Me
Me
Me
Me
Me
Ph
85
86
84
55
76
70
83
95
99
92
98
96
92
96
Oppolzer’s saccharine derived benzosultams 1, 21,2 are an
important class of chiral auxiliaries that have many appli-
cations in asymmetric reactions such as alkylation,1c acyl-
ation,1c aldolization,1c Diels–Alder reactions1b,d and azidation.2b
However, the existence of acidic benzyl protons in 1, and 2
sometimes makes them unsuitable as templates for enantio-
selective fluorinating reagents,3 see for example ref. 3f. As a part
of our continuing studies on the development of novel
fluorinating reagents 3 based on sultam templates,3e–3i we are
interested in 3,3-disubstituted 5-membered benzosultams and
spirobenzosultams. These sultams have also received attention
as potent HIV-1 inhibitors.4
4-Methylphenyl
1-Naphthyl
–CH2CH2CH2CH2–
–CH2CH2CH2CH2CH2–
g
Scheme 1
3,3-Disubstituted 2,3-dihydrobenzo[d]isothiazole-1,1-diones
are usually prepared by addition of organolithium compounds
or Grignard reagents to the N-sulfonylimine 4.1b,d,2a,3e,5,6
However, these methods have limitations owning to the
unavailability or poor reactivity of some hindered organometal-
lic species. In fact, only a limited number of such compounds
have been prepared in this way. Watanabe et al. have reported
cyclization methods for the preparation of N-methyl or phenyl
3,3-disubstituted five-membered benzosultams under acidic or
thermal conditions,7a however, the difficulty in removing the
methyl or phenyl protective group made the method impossible
for general use. Moreover, there are no reported methods
for the synthesis of spiro-2,3-dihydrobenzo[d]isothiazole-1,1-
diones. Recently we have developed a novel cyclization
mediated by TMSCl–NaI–MeCN reagent for the construction
of 3,3-disubstituted and spiro six-membered benzosultams.3g
In this paper, we show a new method for the facile preparation
of 3,3-disubstituted and spiro-2,3-dihydrobenzo[d]isothiazole-
1,1-diones (Scheme 1).
ortho-Lithiation of N-substituted benzenesulfonamides is a
well established method for the preparation of their o-function-
alized derivatives and heterocycles.6,7 We first attempted the
ortho-lithiation using N-Boc-benzenesulfonamide. N-Boc-benz-
enesulfonamide was treated with excess tert-BuLi (2.5 equiv.)
followed by the addition of 1.1 equivalent of anhydrous
acetone, however, there was no expected carbinol sulfonamide
formed, only the removal of the Boc protecting group was
observed which yielded benzenesulfonamide. N-tert-Butyl-
benzenesulfonamide (5) was next used for the reaction. The
ortho-lithiation of 5 proceeded smoothly to furnish an anion,
which reacted with acetone to give the carbinol sulfonamide 6a
in 85%, isolated yield (Table 1, entry a). The sulfonamide 6a was
subjected to TMSCl–NaI–MeCN reagent (2 equiv.) under
refluxing conditions to form benzosultam 7a in 95% yield.8 The
sultam 7a is a known template for a fluorinating reagent.9 To
examine the scope and generality of this method, we examined
the reactions using various ketones ranging from alkyl and aryl
ketones to cyclic ketones. In all cases, the corresponding
carbinol sulfonamides 6 were obtained in good yields, and the
sultams 7 including spiro sultams 7e–g were formed nearly
quantitatively (Table 1). This method provided a general
synthesis of 3,3-disubstituted five-membered benzosultams 7.
As far as we know, this is the first example of a synthesis of
spiro-2,3-dihydrobenzo[d]isothiazole-1,1-diones.
The 3D structure of spirosultam 7g would be interesting,
since the two flat benzo[d]isothiazole and indan rings in 7g are
orthogonalized on the spiro carbon. We finally obtained the
optically pure 7g to form a new chiral auxiliary. Racemic 7g was
treated with NaH (2 equiv.) in THF and it was reacted with (ϩ)-
10-camphorsulfonyl chloride (1.5 equiv.) overnight to form two
diastereomers, the less polar (ϩ)-8 and the more polar (Ϫ)-8, in
22% and 24% isolated yields, respectively. The unreacted
racemic 7g was recovered (44%). Removing the chiral auxiliary
of (ϩ)-8 and (Ϫ)-8 under Oppolzer’s conditions (conc.
H2SO4),1d to our surprise, gave racemic 7g.10 However, when
aq. LiOH (2 M) was used for the hydrolysis, the reaction
went slowly at room temperature to furnish the optically pure
(Ϫ)-7g11 and (ϩ)-7g11 in high yields without racemization.
302
J. Chem. Soc., Perkin Trans. 1, 2002, 302–303
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b109832b

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In summary, we have developed a facile synthesis of 3,3-
disubstituted and spiro-2,3-dihydrobenzo[d]isothiazole-1,1-
diones mediated by the TMSCl–NaI–MeCN reagent. It is
worth noting that spiro five-membered benzosultams such as
7e–g were obtained for the first time. Optically pure benzo-
sultams (ϩ)-7g and (Ϫ)-7g would be useful as chiral auxiliaries
for asymmetric synthesis. Considering the diverse biological
profiles of sulfonamide derivatives, these benzosultams may
also be used for biological evaluations and as possible sub-
strates for developing sulfonamide peptidomimetics.12
8 Typical experimental procedure: A. To a stirred solution of N-tert-
butylbenzenesulfonamide (1.07 g, 5 mmol) in THF (25 mL) was
added a 1.50 M solution of tert-BuLi in hexane (10 mL, 15 mmol)
under nitrogen at Ϫ78 ЊC. The reaction mixture was stirred for 15
min at Ϫ78 ЊC, warmed to 0 ЊC, stirred for an additional 1 h, and
cooled to Ϫ78 ЊC. A solution of anhydrous acetone (0.29 g, 5 mmol)
in THF (5 mL) was added. After 2 h, saturated aqueous NH4Cl was
added. The mixture was extracted with EtOAc, the combined
organic layers were washed with brine, dried (MgSO4) and concen-
trated in vacuo. The residue was chromatographed (30% EtOAc
in hexane) to give the carbinol sulfonamide 6a (1.15 g, 85%) as
colorless prisms: mp 124–126 ЊC; IR (KBr) 3460, 3241 cmϪ1 1H
;
Acknowledgements
NMR δ 1.24 (s, 9H), 1.68 (s, 6H), 4.45 (s, 1H), 6.24 (s, 1H), 7.30–7.36
(m, 2H), 7.45–7.51 (m, 1H), 8.18 (m, 1H); 13C NMR δ 30.7, 33.3,
55.4, 74.9, 127.0, 129.3, 129.8, 132.0, 140.4, 147.2; MS m/z 271 (Mϩ),
256 (Mϩ Ϫ Me). Anal. Calcd for C13H21NO3S: C, 57.54; H, 7.80; N,
5.16. Found: C, 57.59; H, 7.75; N, 5.06%. B. To a stirred solution of
6a (0.55 g, 2 mmol) in MeCN (10 mL) was added under nitrogen,
sodium iodide (0.60 g, 4 mmol) and chlorotrimethylsilane (0.51 mL,
4 mmol). The reaction mixture was refluxed for 1 h. It was cooled
to room temperature and 10% sodium thiosulfate aqueous solution
was added. The mixture was extracted with EtOAc, and the com-
bined organic layers were washed with water, brine, dried (MgSO4)
and concentrated in vacuo. The residue was chromatographed
(30% EtOAc in hexane) to give sultam 7a (0.37 g, 95%) as colorless
prisms.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports and Culture, Japan.
Notes and references
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1
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3.27 (dt, J = 16.1, 7.8 Hz, 1H), 4.65 (s, 1H), 7.04 (d, J = 7.8 Hz, 1H),
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