Synthesis of novel 1,2,5-benzothiadiazepine 1,1-dioxides

Article abstract of DOI:10.1016/S0040-4020(01)00658-5

3-Methoxycarbonyl-2-N-methyl-1,2,5-benzothiadiazepine 1,1-dioxide 2b can be obtained in seven unambiguous steps starting from commercially available L-serine methyl ester. The crucial step in the synthesis of 2b is the intramolecular Michael addition of dehydroalanine derivative 17, which can be achieved using sodium tert-butoxide as a non-nucleophilic base. An initial attempt to construct the same scaffold via an alternative strategy, which was based on a nucleophilic aromatic substitution as the key ring-closing step, proofed to be unsuccessful.

Full text of DOI:10.1016/S0040-4020(01)00658-5

TETRAHEDRON
Pergamon
Tetrahedron 57 62001) 7021±7026
Synthesis of novel 1,2,5-benzothiadiazepine 1,1-dioxides
Thomas M. KruÈlle and Jac C. H. M. Wijkmansp
Department of Medicinal Chemistry, British Biotech Pharmaceuticals Ltd., Watlington Road, Oxford OX46LY, UK
Received 29 March 2001; revised 24May 2001; accepted 14June 2001
AbstractÐ3-Methoxycarbonyl-2-N-methyl-1,2,5-benzothiadiazepine 1,1-dioxide 2b can be obtained in seven unambiguous steps starting
from commercially available l-serine methyl ester. The crucial step in the synthesis of 2b is the intramolecular Michael addition of
dehydroalanine derivative 17, which can be achieved using sodium tert-butoxide as a non-nucleophilic base. An initial attempt to construct
the same scaffold via an alternative strategy, which was based on a nucleophilic aromatic substitution as the key ring-closing step, proofed to
be unsuccessful. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
strated that the seven-membered ring system could readily
be obtained via ring-expansion of a 3-chloromethyl-1,2,4-
benzothiadiazine 1,1-dioxide derivative.11 In the present
paper we report a route into the novel 3-substituted 1,2,5-
benzothiadiazepine 1,1-dioxides 2 following an alkoxide-
catalysed intramolecular Michael addition.
Over the past three decades, 1,4-benzodiazepines have
elicited extensive pharmacological interest and numerous
derivatives have been identi®ed that display selective
activities against a diverse array of biological targets.1
Interestingly, the 1,2,5-benzothiadiazepine 1,1-dioxides
61), a subset of the 1,4-benzodiazepines, have received
relatively little attention. Reported biological activities
associated with the thiadioxobenzodiazepine ring system
include inhibition of metalloproteinases2 and farnesyl
protein transferase3 as well as hypolipidemic activity.4
Tricyclic members of this class of compounds containing
a pyrrole moiety have shown promise as antidepressants5
and, notably, as inhibitors of HIV-1 replication.6
2. Results and discussion
Retrosynthetic disconnection of target molecule 2 6Scheme
1) suggested the possibility of using 2,3-diaminopropionate
3 or 2-aminoacrylate 4 as key intermediates, both of which
can readily be accessed from serine derivative 5. Formation
of the seven-membered core structure would be achieved
either via an aromatic nucleophilic displacement 6route A)
or an intramolecular Michael addition 6route B). Since
literature precedent5,6d supported the former strategy, our
initial focus was directed towards the preparation of the
appropriate sulfonamide derivative 3 and ensuing cyclisa-
tion.
As shown in Scheme 2, target intermediate 10 could be
obtained in four steps starting from the commercially
available hydrochloric salt of l-serine methyl ester 5.
Thus, base-mediated sulfonylation of amine 5 with 2-¯uoro-
benzenesulfonyl chloride furnished serine derivative 6 in
quantitative yield. Selective N-alkylation of compound 6
with methyl iodide proceeded cleanly in the presence of
sodium hydride to give tertiary sulfonamide 7. Subsequent
dehydration was carried out in a straightforward manner via
base-induced b-elimination of the in situ formed tri¯ate 8 to
afford dehydroalanine derivative 9 in 80% overall yield.
Finally, conjugate addition of benzylamine to acrylate 9
provided the desired diaminopropionate 10, which was
isolated in excellent yield.
Cyclisation strategies that have been described for the
construction of the 1,2,5-benzothiadiazepine 1,1-dioxide
framework involve either an intramolecular amide bond
formation,7 reductive cyclisation,8 intramolecular SNAr
reaction,5,6d aza-Wittig reaction9 or a Pictet±Spengler type
condensation.10 In addition, Field and co-workers demon-
Keywords: Michael addition; benzodiazepines.
Corresponding author. Tel.: 144-1865-780829; fax: 144-1865-780814;
e-mail: wijkmanj@britbio.co.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020601) 00658-5

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T. M. Krulle, J. C. H. M. Wijkmans / Tetrahedron 57 02001) 7021±7026
7022
Scheme 1.
Scheme 2. 6i) 2-Fluorobenzenesulfonyl chloride 60.5 equiv.), DIEA 61 equiv.), CH2Cl2, 12 h 6quant.); 6ii) MeI 63 equiv.), NaH 61.1 equiv.), DMF, 0!208C,
4h 674%); 6 iii) Tf2O 61.5 equiv.), DIEA 64equiv.), CH 2Cl2, 0!208C, 2 h 680%); 6iv) benzylamine 62.8 equiv.), K2CO3, CH3CN, 18 h 688%).
dioxide framework. First, thermal cyclisation of 10 was
attempted in re¯uxing toluene or THF, however, no reaction
was observed. Interestingly, heating in toluene at re¯ux for
three days in the presence of N,N-diisopropylethylamine
6DIEA) led to partial reformation of the a,b-unsaturated
ester 9 which was isolated in 20% yield. The same observa-
tion was made when, for instance, THF and sodium tert-
butoxide were used while utilisation of Ag2O as a base
furnished a mixture of starting material, ole®n 9 and dimeric
Michael adduct 11 in a 20:12:1 ratio. On the other hand,
treatment of precursor 10 with DIEA in DMSO at 1108C for
24h afforded only compound 9 in 35% yield and decom-
posed material. Furthermore, exposure of 10 to typical SNAr
reaction conditions using DMF or DMSO and an inorganic
base 6e.g. NaHCO3 or Na2CO3) at elevated temperature led
to rapid decomposition of starting material with no trace of
either 9 or the desired cyclised product 2a.
With intermediate 10 in hand we next set out to explore
cyclisation conditions to construct the 1,2,5-thiadiazepine

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T. M. Krulle, J. C. H. M. Wijkmans / Tetrahedron 57 02001) 7021±7026
7023
Scheme 3. 6i) 2-Nitrobenzenesulfonyl chloride 61 equiv.), DIEA 62 equiv.), CH2Cl2, 12 h 671%); 6ii) MeI 63 equiv.), NaH 61.1 equiv.), DMF, 0!208C, 4h
682%); 6iii) 1/1 6v/v) cyclohexene/ethanol, 10% Pd/C, re¯ux, 48 h 686%); 6iv) Fmoc-Cl 62.1 equiv.), NaHCO3 62.1 equiv.), CH2Cl2, 12 h 652%); 6v) Tf2O
61.5 equiv.), DIEA 64equiv.), CH 2Cl2, 0!208C, 2 h 673%); 6vi) 1/1 6v/v) DIEA/CH2Cl2, re¯ux, 48 h 670%); 6vii) NaOtBu 60.5 equiv.), THF, 08C, 30 min
660%); 6viii) benzyl bromide 65 equiv.), Na2CO3 65 equiv.), Bu4NI 60.5 equiv.), THF, re¯ux, 72 h 692%).
It is apparent from these results that the intramolecular
cyclisation of 10, despite being a favoured seven-endo/
exo-trig process12 is problematic. Furthermore, the intrinsic
tendency of diaminopropionate derivative 10 to eliminate
benzylamine precludes the intramolecular cyclisation by
this approach.
On the basis of the latter result it was considered that in
order for the ring closure to take place a base would be
required that is able to deprotonate the aniline moiety. A
suitable base that meets this criterion is sodium tert-
butoxide. However, a possible complication that was
envisaged was that cyclisation onto the ester functionality
could take place under strong basic conditions giving
benzothiadiazepin-3-one 1,1-dioxide 18. Indeed, Mayer et
al.13 previously showed that sodium tert-butoxide could
successfully be used to affect the cyclisation of solid-
supported amino acid anthranilate derivatives to form and
simultaneously release 1,4-benzodiazepine-2,5-diones.
Nonetheless, when precursor 17 was treated with sodium
tert-butoxide in THF, rapid formation of desired benzo-
thiadiazepine dioxide 2b as the sole product took place.
This observation likely re¯ects the high reactivity of
acrylate 17 towards Michael additions. Optimal results
were obtained by using a half an equivalent of sodium
tert-butoxide in THF at 08C for 30 min, which furnished
2b in 60% yield.
At this stage, we turned our efforts to investigate the
synthesis of target molecule 2 via route B. Requisite
sulfonamide derivative 12 was obtained in a straightforward
manner, analogous to the synthesis of serine derivative 6
6vide supra), by treatment of l-serine methyl ester hydro-
chloride 65´HCl) with 2-nitrobenzenesulfonyl chloride
under basic conditions. Similarly, selective alkylation of
the secondary sulfonamide moiety with methyl iodide 6cf.
synthesis of 7) was uneventful, yielding compound 13.
Subsequent reduction of the nitro group was achieved via
hydrogen-transfer hydrogenolysis to give amine 14 which
was then treated with 9-¯uorenylmethyl chloroformate in
the presence of tertiary base to afford the Fmoc-protected
compound 15 in 45% overall yield. Dehydroalanine deriva-
tive 16 was subsequently obtained, as described for the
preparation of 9, by treatment with tri¯ic anhydride under
the agency of a tertiary base.
The obtained benzothiadiazepine dioxide 2b can be further
functionalised at the 5-position by, for instance, alkylation
using benzylbromide in the presence of sodium carbonate
and tetrabutylammonium iodide to give tertiary aniline 2a in
excellent yield. Interestingly, compound 2a is completely
stable towards treatment with DIEA in toluene under re¯ux
for 24h.
In the next step, it was anticipated that removal of the Fmoc-
group using standard conditions, i.e. piperidine/DMF,
would rapidly lead to the formation of the corresponding
piperidyl adduct 6cf. synthesis of 10). Therefore, alternative
conditions for the deprotection of Fmoc-derivative 16 were
studied. It was found that clean reaction could be achieved
using a 1:1 mixture of dichloromethane and DIEA.
However, the reaction was extremely slow. Fortunately,
heating the mixture at re¯ux for 48 h afforded aniline
derivative 17 in 70% yield. It is important to note that
no cyclisation was observed under these conditions
6Scheme 3).
In summary, we have developed an expedient route for the
synthesis of novel 3-substituted 1,2,5-benzothiadiazepine
1,1-dioxides. Construction of the core structure follows a
favourable seven-endo-trig Michael addition employing
suitably protected aniline derivative 17. Application of
this methodology should provide an entry into the synthesis
of a diverse range of 1,2,5-benzothiadiazepine 1,1-dioxides
showing interesting biological activities.

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T. M. Krulle, J. C. H. M. Wijkmans / Tetrahedron 57 02001) 7021±7026
7024
22
[a]D ˆ216.0 62.4, CHCl3); MS 6ESI1, m/z): 292
3. Experimental
1
6M1H1); H NMR 6250 MHz, CDCl3): dˆ2.10 6t, 1H,
Jˆ6.6 Hz, OH), 2.98, 2.99 62£s, 3H, NMe), 3.61 6s, 3H,
OMe), 3.88±4.08 6m, 2H, Hb), 4.78 6dd, 1H, J1ˆ5.3 Hz,
J2ˆ7.0 Hz, Ha), 7.16±7.30 6m, 2H, H-arom.), 7.57 6m, 1H,
H-arom.), 7.90 6dt, 1H, J1ˆ1.7 Hz, J2ˆ7.5 Hz, H-arom.);
13C NMR 662.5 MHz, CDCl3): dˆ31.7 6NMe), 52.7
6OMe), 61.2 6Cb), 61.46C a), 117.3 6d, JC,Fˆ21.6 Hz, CH-
arom.), 124.6 6d, JC,Fˆ3.8 Hz, CH-arom.), 127.46d,
JC,Fˆ14.3 Hz, CSO2), 131.2 6CH-arom.), 135.5 6d,
JC,Fˆ8.5 Hz, CH-arom.), 159.46d, JC,Fˆ253 Hz, CF),
169.8 6CvO). Anal. Calcd for C11H14FNO5S: C 45.36; H
4.84; N 4.81; Found: C 45.22; H 4.92; N 4.71.
3.1. General
Commercially available reagents and solvents were used as
received. Flash column chromatography was performed
using silica gel 60 60.040±0.063 mm, Merck). Melting
points were measured using a Gallenkamp apparatus and
are uncorrected. Infrared spectra were recorded on a
Perkin±Elmer 1600 FTIR. Optical rotations were measured
using a Perkin±Elmer 241 polarimeter with a path length of
1 dm; concentrations are expressed in g/100 mL. Mass
spectra were recorded using an API 165 Perkin±Elmer
workstation with TIS interface. 1H NMR spectra were
3.1.3. Methyl 2-[N-*2-¯uorobenzenesulfonyl)methyl-
amino]acrylate *9). Compound 7 60.35 g, 1.2 mmol) was
dissolved in dry dichloromethane 615 mL) under argon and
cooled to 08C. Then, DIEA 60.85 mL, 4.9 mmol) and
tri¯uoromethanesulfonic anhydride 60.30 mL, 1.8 mmol)
were added successively before the ice bath was removed.
After additional stirring for 2 h at room temperature, the
mixture was concentrated and puri®ed by silica gel ¯ash
chromatography 6eluent: 2/1 hexane/ethyl acetate) to give
a,b-unsaturated ester 9 60.27 g, 80%) as a colourless oil. IR
6neat): nmax 1732 6s, CvO), 1632 6w, CvC), 1356 6s, SO2),
1223 6s), 1173 6s, SO2) cm21; MS 6ESI1, m/z): 296
6M1Na1); 1H NMR 6250 MHz, CDCl3): dˆ3.16, 3.17
62£s, 3H, NMe), 3.66 6s, 3H, OMe), 5.85, 6.3462 £s, 2H,
Hb), 7.17±7.28 6m, 2H, H-arom.), 7.57 6m, 1H, H-arom.),
7.83 6dt, 1H, J1ˆ1.8 Hz, J2ˆ7.8 Hz, H-arom.); 13C NMR
662.5 MHz, CDCl3): dˆ37.6 6NMe), 52.8 6OMe), 117.4
6d, JC,Fˆ21.6 Hz, CH-arom.), 124.5 6d, JC,Fˆ3.8 Hz, CH-
arom.), 127.1 6d, JC,Fˆ14.3 Hz, CSO2), 127.46C b), 131.4
6CH-arom.), 135.6 6d, JC,Fˆ8.4Hz, CH-arom.), 137.9 6C a),
159.6 6d, JC,Fˆ255 Hz, CF), 164.1 6CvO). Anal. Calcd for
C11H12FNO4S: C 48.35; H 4.43; N 5.13; Found: C 48.54; H
4.50; N 5.08.
recorded on
a Bruker DPX 250 spectrometer at
250.1 MHz in CDCl3 and are referenced to internal tetra-
methylsilane. 13C NMR spectra were recorded on a Bruker
DPX 250 or a Bruker AMX 500 spectrometer using the
Attached Proton Test 6APT) technique at 62.5 or
125 MHz, respectively, and referenced to the corresponding
deuterated solvent peaks. Microanalyses were performed by
Elemental Microanalysis Ltd. 6Okehampton, UK).
3.1.1. N-*2-Fluorobenzenesulfonyl)-l-serine methyl ester
*6). l-Serine methyl ester hydrochloride 63.5 g, 23 mmol)
and DIEA 66.0 mL, 35 mmol) were added to a solution of
2-¯uorobenzenesulfonyl chloride 62.2 g, 11 mmol) in
dichloromethane 650 mL) and stirred for 12 h at room
temperature. Then, the mixture was diluted with dichloro-
methane 6200 mL) and washed with water 650 mL), satu-
rated aq. NaCl 650 mL), dried 6MgSO4) and ®ltered.
Concentration in vacuo yielded sulfonamide 6 63.1 g,
100%) as a colourless oil. IR 6neat): nmax 32746br), 1744
22
6s, CvO), 1342 6s, SO2), 1169 6s, SO2) cm21; [a]D ˆ19.7
64.4, CHCl3); MS 6ESI1, m/z): 300 6M1Na1); MS 6ESI2,
m/z): 276 6M2H1); H NMR 6250 MHz, CDCl3): dˆ2.49
1
6t, 1H, Jˆ6.3 Hz, OH), 3.63 6s, 3H, OMe), 3.86±4.02 6m,
2H, Hb), 4.16 6m, 1H, Ha), 5.96 6bd, 1H, Jˆ7.0 Hz, NH),
7.18±7.30 6m, 2H, H-arom.), 7.58 6m, 1H, H-arom.), 7.87
6dt, 1H, J1ˆ1.7 Hz, J2ˆ7.5 Hz, 1H-arom.); 13C NMR
662.5 MHz, CDCl3): dˆ53.2 6OMe), 58.3 6Ca), 64.1
3.1.4. Methyl 3-benzylamino-2-[N-*2-¯uorobenzene-
sulfonyl)methylamino]propionate *10). Potassium car-
bonate 60.14g, 1.0 mmol) and benzylamine 60.20 mL,
1.8 mmol) were added to a solution of acrylate 9 60.18 g,
0.64mmol) in acetonitrile 68 mL). The mixture was stirred
for 15 h at room temperature, ®ltered and evaporated to
dryness. Puri®cation by silica gel ¯ash chromatography
6eluent: 1/1 hexane/ethyl acetate) gave diaminopropionate
10 60.22 g, 88%) as a colourless oil. IR 6neat): nmax 1742 6s,
CvO), 1344 6s, SO2), 1171 6m, SO2) cm21; MS 6ESI1,
6Cb), 117.46d,
JC,Fˆ21.1 Hz, CH-arom.), 124.7 6d,
JC,Fˆ3.8 Hz, CH-arom.), 128.46d, JC,Fˆ13.8 Hz, CSO2),
130.3 6CH-arom.), 135.5 6d, JC,Fˆ8.5 Hz, CH-arom.),
159.46d, JC,Fˆ254Hz, CF), 170.5 6C vO). Anal. Calcd
for C10H12FNO5S: C 43.32; H 4.36; N 5.05; Found: C
43.03; H 4.51; N 4.90.
1
m/z): 381 6M1H1); H NMR 6250 MHz, CDCl3): dˆ2.91,
3.1.2. N-*2-Fluorobenzenesulfonyl)-N-methyl-l-serine
methyl ester *7). Serine derivative 6 63.1 g, 11 mmol)
was dissolved in anhydrous DMF 650 mL) and cooled to
08C. Next, methyl iodide 62.0 mL, 32 mmol) and sodium
hydride 60.5 g, 60% dispersion in mineral oil) were added
and the mixture was stirred for 3 h at 08C. After removal of
the ice bath and additional stirring for 1 h, the solution was
poured into saturated aq. NaCl 6300 mL) and extracted with
ethyl acetate 64£50 mL). The combined extracts were
washed with saturated aq. NaCl 650 mL), dried 6MgSO4),
®ltered and evaporated to dryness. Puri®cation of the
residue by silica gel ¯ash chromatography 6eluent: 1/1
hexane/ethyl acetate) afforded tertiary sulfonamide 7
62.4g, 74%) as a colourless oil. IR 6neat): nmax 3526 6br),
2.92 62£s, 3H, NMe), 2.946dd, 1H, J1ˆ9.1 Hz, J2ˆ13.1 Hz,
Hb), 3.11 6dd, 1H, J1ˆ5.4Hz, J2ˆ13.1 Hz, Hb), 3.53 6s,
3H, OMe), 3.74, 3.89 62£d, 2H, Jgemˆ13.2 Hz, CH2Ph),
4.85 6dd, 1H, J1ˆ5.4Hz, J2ˆ9.1 Hz, Ha), 7.10±7.36 6m,
7H, CH-arom.), 7.53 6m, 1H, CH-arom.), 7.88 6dt, 1H,
J1ˆ1.7 Hz, J2ˆ7.7 Hz, CH-arom.); 13C NMR 662.5 MHz,
CDCl3): dˆ30.9 6NMe), 47.6, 53.2 62£NCH2), 52.5
6OMe), 117.46d, JC,Fˆ21.7 Hz, CH-arom.), 124.6 6d,
JC,Fˆ3.8 Hz, CH-arom.), 127.5, 128.6, 128.8 6CH-arom.),
127.7 6d, JC,Fˆ14.4 Hz, CSO2), 131.3 6CH-arom.), 135.4
6d, JC,Fˆ8.5 Hz, CH-arom.), 140.2 6ipso C-phenyl), 159.5
6d, JC,Fˆ253.6 Hz, CF), 170.46C vO). Anal. Calcd for
C18H21FN2O4S: C 56.83; H 5.56; N 7.36; Found: C 56.58;
H 5.57; N 7.29.
1744 6s, CvO), 1342 6s, SO2), 1172 6s, SO2) cm21
;

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T. M. Krulle, J. C. H. M. Wijkmans / Tetrahedron 57 02001) 7021±7026
7025
3.1.5. N-*2-Nitrobenzenesulfonyl)-l-serine methyl ester
*12). DIEA 623.5 mL, 0.14mol) was added dropwise to a
suspension of l-serine methyl ester hydrochloride 610.5 g,
0.68 mol) and 2-nitrobenzenesulfonyl chloride 615.0 g,
0.68 mol) in dichloromethane 6250 mL). After stirring for
12 h at room temperature, the solution was further diluted
with dichloromethane 6250 mL), successively washed with
water 63£100 mL) and saturated aq. NaCl 6100 mL), dried
6MgSO4), ®ltered and evaporated to dryness. Crystallisation
of the crude product from ethyl acetate afforded sulfon-
amide 12 614.5 g, 71%) as off-white crystals. Mp: 125±
1278C 6ethyl acetate); IR 6neat): nmax 3488 6br), 1752 6s,
CvO), 1539 6s, NO2), 13546s, SO 2), 1156 6s, SO2), 10746s)
6Ca), 115.6, 117.7, 129.9, 134.3 6CH-arom.), 118.8 6CSO2),
147.3 6CNH2), 169.9 6CvO). Anal. Calcd for C11H16N2O7S:
C 45.82; H 5.59; N 9.72; Found: C 45.69; H 5.63; N 9.52.
3.1.8. N-[2-N0-*9-Fluorenylmethylcarbonyl)aminobenzene-
sulfonyl]-N-methyl-l-serine methyl ester *15). Sodium
hydrogen carbonate 62.4g, 28 mmol) and 9-¯uorenylmethyl
chloroformate 67.0 g, 27 mmol) were added to a solution of
compound 14 63.7 g, 12.7 mmol) in dichloromethane
6100 mL). After stirring for 12 h at room temperature, the
mixture was distributed between dichloromethane 6200 mL)
and water 6100 mL). The organic layer was washed with
water 6100 mL) and saturated aq. NaCl 6100 mL), dried
6MgSO4), ®ltered and concentrated. Silica gel ¯ash chroma-
tography 6eluent: 1/1 hexane/ethyl acetate) of the resulting
oil gave carbamate 15 63.4g, 52%) as a colourless foam. IR
6neat): nmax 3350 6br), 1732 6br, CvO), 1525 6s), 1437 6s),
cm21; [a]D ˆ296.5 62.3, MeOH), lit.14 [a]D ˆ2103
22
24
63.0, MeOH); MS 6ESI1, m/z): 327 6M1Na1); MS
1
6ESI2, m/z): 303 6M2H1); H NMR 6250 MHz, CDCl3):
dˆ2.12 6t, 1H, OH), 3.60 6s, 3H, OMe), 3.92±4.08 6m, 2H,
Hb), 4.27 6m, 1H, Ha), 6.46 6bd, 1H, Jˆ7.7 Hz, NH), 7.71±
8.13 63 m, 4H, H-arom.); 13C NMR 6125 MHz, DMSO-d6):
dˆ52.3 6OMe), 58.7 6Ca), 62.3 6Cb), 124.6, 130.2, 132.8,
133.7 6CH-arom.), 134.4 6CSO2), 147.6 6CNO2), 170.46s,
CvO). Anal. Calcd for C10H12N2O7S: C 39.47; H 3.98; N
9.21; Found: C 39.40; H 3.93; N 9.12.
22
1326 6s, SO2), 1210 6s), 1145 6s, SO2) cm21; [a]D ˆ215.5
1
61.1, CHCl3); MS 6ESI1, m/z): 383 6M1Na1); H NMR
6250 MHz, CDCl3): dˆ2.09 6t, 1H, Jˆ6.4Hz, OH), 2.81
6s, 3H, NMe), 3.52 6s, 3H, OMe), 3.78±4.00 6m, 2H, Hb),
4.27 6t, 1H, Jˆ6.7 Hz, CH-Fmoc), 4.49 6dd, 1H, J1ˆ6.6, Hz
J2ˆ10.6 Hz, CH2-Fmoc), 4.56 6dd, 1H, J1ˆ6.9 Hz,
J2ˆ10.6 Hz, CH2-Fmoc), 4.64 6dd, 1H, J1ˆ5.2 Hz,
J2ˆ7.5 Hz, Ha), 7.13±7.79 6m, 10H, CH-arom.), 7.85 6dd,
1H, J1ˆ1.5 Hz, J2ˆ8.0 Hz, CH-arom.), 8.13 6d, 1H,
Jˆ8.3 Hz, CH-arom.), 8.76 6bs, 1H, NH); 13C NMR
6125 MHz, CDCl3): dˆ31.6 6NMe), 47.4 6CH-Fmoc),
53.0 6OMe), 60.9 6Cb), 61.1 6Ca), 67.8 6CH2-Fmoc),
120.5, 122.6, 123.6, 125.4, 127.6, 128.3, 130.5, 134.7
6CH-arom.), 126.7 6CSO2), 136.9, 141.8, 144.0 6C-arom.),
153.6 6CONH), 169.5 6CvO).
3.1.6.
N-Methyl-N-*2-nitrobenzenesulfonyl)-l-serine
methyl ester *13). Compound 12 611.0 g, 36.2 mmol) was
N-methylated as described for the synthesis of 7 using
methyl iodide 66.8 mL, 0.11 mol) and sodium hydride
61.5 g, 60% dispersion in mineral oil) in anhydrous DMF
6100 mL). Puri®cation by silica gel ¯ash chromatography
6eluent: 1/3 hexane/ethyl acetate) gave tertiary sulfonamide
13 69.5 g, 82%) as a colourless oil. IR 6neat): nmax 3529 6br),
1740 6s, CvO), 1541 6s, NO2), 1372 6s), 1344 6s), 1171 6s,
SO2) cm21; [a]D ˆ224.8 60.25, CHCl3); MS 6ESI1, m/z):
3.1.9. Methyl 2-N-[[2-N0-*9-¯uorenylmethylcarbonyl)-
aminobenzenesulfonyl]methyl-amino]acrylate *16). In
situ O-tri¯ation and b-elimination of compound 15
60.55 g, 1.1 mmol) was carried out as described for the
preparation of acrylate 9 using DIEA 60.75 mL, 4.3 mmol)
22
1
341 6M1Na1); H NMR 6250 MHz, CDCl3): dˆ2.26 6t,
1H, OH), 3.046s, 3H, NMe), 3.68 6s, 3H, OMe), 3.86±
4.12 6m, 2H, Hb), 4.81 6dd, 1H, J1ˆ4.8 Hz, J2ˆ7.5 Hz,
Ha), 7.61±7.76 6m, 3H, H-arom.), 8.09 6m, 1H, H-arom.);
13C NMR 662.5 MHz, CDCl3): dˆ32.0 6NMe), 53.0 6OMe),
61.1 6Cb), 61.6 6Cb), 124.7, 131.8, 132.3, 134.2 6CH-
arom.), 132.7 6CSO2), 148.3 6CNO2), 169.7 6CvO). Anal.
Calcd for C11H14N2O7S: C 41.51; H 4.43; N 8.80; Found: C
41.34; H 4.46; N 8.63.
and
tri¯uoromethanesulfonic
anhydride
60.25 mL,
1.5 mmol) in dichloromethane 610 mL). Puri®cation by
silica gel ¯ash chromatography 6eluent: 5/2 hexane/ethyl
acetate) gave a,b-unsaturated ester 15 60.39 g, 73%) as a
colourless oil. IR 6neat): nmax 3346 6br), 1728 6br, CvO),
1585 6s), 1526 6s), 1437 6s), 1321 6s, SO2), 1210 6s), 1149
6m, SO2) cm21; MS 6ESI1, m/z): 515 6M1Na1); 1H NMR
6250 MHz, CDCl3): dˆ3.00 6s, 3H, NMe), 3.59 6s, 3H,
OMe), 4.28 6t, 1H, Jˆ7.0 Hz, CH-Fmoc), 4.48 6d, 2H,
Jˆ7.0 Hz, CH2-Fmoc), 5.84, 6.60 62£s, 2H, Hb), 7.12±
7.79 6m, 10H, CH-arom.), 7.82 6dd, 1H, J1ˆ1.6 Hz,
J2ˆ8.0 Hz, CH-arom.), 8.23 6d, 1H, Jˆ8.3 Hz, CH-
arom.), 8.88 6bs, 1H, NH); 13C NMR 6125 MHz, DMSO-
d6): dˆ37.6 6NMe), 47.4 6CH-Fmoc), 53.0 6OMe), 67.9
6CH2-Fmoc), 120.5, 121.8, 123.1, 125.6, 127.6, 128.3,
130.6, 134.9 6CH-arom.), 125.3, 127.7 6CSO2, Cb), 137.4,
138.0, 141.8, 144.1 6Ca, C-arom.), 153.46CONH), 164.0
6CvO). Anal. Calcd for C26H24N2O6S.H2O: C 61.16; H
5.13; N 5.49; Found: C 61.26; H 4.85; N 5.40.
3.1.7. N-*2-Aminobenzenesulfonyl)-N-methyl-l-serine
methyl ester *14). A suspension of compound 13 69.5 g,
30 mmol) and 10% palladium on activated carbon 60.99 g)
in a mixture of ethanol 6200 mL) and cyclohexene 620 mL)
was stirred under re¯ux. After 48 h, mass spectroscopic
analysis revealed that all starting material had disappeared.
The mixture was ®ltered over Celite, evaporated to dryness
and puri®ed by silica gel ¯ash chromatography 6eluent: 1/2
hexane/ethyl acetate) to furnish aniline 14 67.3 g, 86%) as a
colourless oil. IR 6neat): nmax 3471 6br), 1736 6s, CvO),
22
1619 6s), 1320 6s, SO2), 1136 6s, SO2) cm21; [a]D ˆ27.5
1
62.8, CHCl3); MS 6ESI1, m/z): 311 6M1Na1); H NMR
6250 MHz, CDCl3): dˆ2.76 6s, 1H, OH), 2.846s, 3H,
NMe), 3.67 6s, 3H, OMe), 3.83 6m, 1H, Hb), 4.00 6m, 1H,
Hb), 4.83 6dd, 1H, J1ˆ5.3 Hz, J2ˆ8.4Hz, H a), 4.95 6bs,
2H, NH2), 6.746dd, 1H, J1ˆ,1.0 Hz, J2ˆ8.1 Hz, H-arom.),
6.81 6t, 1H, H-arom.), 7.31 6m, 1H, H-arom.), 7.70 6dd, 1H,
J1ˆ1.5 Hz, J2ˆ8.0 Hz, H-arom.); 13C NMR 6125 MHz,
DMSO-d6): dˆ31.2 6NMe), 52.2 6OMe), 60.1 6Cb), 60.7
3.1.10. Methyl 2-N-[*2-aminobenzenesulfonyl)methyl-
amino]acrylate *17). Compound 16 60.30 g, 0.62 mmol)
was dissolved in a mixture of dichloromethane 65 mL) and
DIEA 65 mL) and stirred under re¯ux for 48 h. The solution
was then concentrated and the residue puri®ed by silica gel

È
T. M. Krulle, J. C. H. M. Wijkmans / Tetrahedron 57 02001) 7021±7026
7026
¯ash chromatography 6eluent: 5/2!1/1 hexane/ethyl
acetate) to give amine 17 60.12 mg, 70%) as a yellow oil.
IR 6neat): nmax 3476 6br), 1727 6s, CvO), 1616 6s, CvC),
1317 6s, SO2), 1211 6s), 1138 6s, SO2) cm21; MS 6ESI1,
m/z): 293 6M1Na1); 1H NMR 6250 MHz, CDCl3): dˆ3.00
6s, 3H, NMe), 3.746s, 3H, OMe), 5.12 6bs, 2H, NH 2), 5.74,
6.26 62£s, 2H, Hb), 6.68±6.75 6m, 2H, CH-arom.), 7.30 6m,
1H, CH-arom.), 7.646d, 1H, J1ˆ1.4Hz, J2ˆ8.0 Hz, CH-
arom.); 13C NMR 6125 MHz, CDCl3): dˆ37.2 6NMe),
53.0 6OMe), 116.2, 118.2, 131.1, 135.1 6CH-arom.), 118.3
6CSO2), 124.6 6Cb), 139.2 6Ca), 147.1 6CNH2), 165.1
6CvO). Anal. Calcd for C11H14N2O4S: C 48.88; H 5.22;
N 10.36; Found: C 48.90; H 5.24; N 10.26.
C18H20N2O4S: C 59.98; H 5.59; N 7.77; Found: C 59.74; H
5.65; N 7.24.
References
Â
1. See, for instance: 6a) Liegeois, J.-F. F.; Bruhwyler, J.; Damas,
J.; Nguyen, T. P.; Chleide, E. M. G.; Mercier, M. G. A.;
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2107. 6b) Hsu, M. C.; Schutt, A. D.; Holly, M.; Slice, L. W.;
Sherman, M. I.; Richman, D. D.; Potash, M. J.; Volsky, D. J.
Science 1991, 254, 1799. 6c) Pauwels, R.; Andries, K.;
Desmyter, J.; Schols, D.; Kukla, M. J.; Breslin, H. J.;
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V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.;
Springer, J. P.; Hirsh®eld, J. J. Med. Chem. 1988, 31, 2235.
6e) Roemer, D.; Buescher, H. H.; Hill, R. C.; Maurer, R.;
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6f) Sternbach, L. H. J. Med. Chem. 1979, 22, 2.
3.1.11. *^)-3-Methoxycarbonyl-2-N-methyl-1,2,5-benzo-
thiadiazepine 1,1-dioxide *2b). Sodium tert-butoxide
615 mg, 0.15 mmol) was added to a solution of compound
17 677 mg, 0.29 mmol) in anhydrous THF 610 mL) at 08C
under argon. After stirring for 30 min, the mixture was
diluted with ethyl acetate 6100 mL) and successively
washed with water 620 mL) and saturated aq. NaCl
620 mL), dried 6MgSO4), ®ltered and concentrated in
vacuo. The residue was puri®ed by silica gel ¯ash chromato-
graphy 6eluent: 1/1 hexane/ethyl acetate) to give benzothia-
diazepine 2b 646 mg, 60%) as a white solid. Mp: 112±
1148C 6hexane/ethyl acetate); IR 6neat): nmax 33846s),
1736 6br, CvO), 1481 6s), 1318 6s, SO2), 1261 6s), 1147
2. Duan, J.; Chen, L.; Cherney, R. J.; Decicco, C. P.; Voss, M. E.
PCT Int. Appl. WO 99/41246.
3. Ding, C. Z. PCT Int. Appl. WO 98/02436.
4. Handlon, A. L.; Hodgson, G. L.; Hyman, C. E. PCT Int. Appl.
WO 98/38182.
1
6s, SO2) cm21; MS 6ESI1, m/z): 293 6M1Na1); H NMR
5. Giannotti, D.; Viti, G.; Sbraci, P.; Pestellini, V.; Volterra, G.;
Borsini, F.; Lecci, A.; Meli, A.; Dapporto, P.; Paoli, P. J. Med.
Chem. 1991, 34, 1356.
6250 MHz, CDCl3): dˆ2.97 6s, 3H, NMe), 3.75 6ddd, 1H,
J1ˆ4.8 Hz, J2ˆ7.7 Hz, Jgemˆ14.8 Hz, H-4), 3.80 6s, 3H,
OMe), 4.10 6m, 1H, H-4), 4.32 6dd, 1H, J1ˆ4.8 Hz,
J2ˆ10.6 Hz, H-3), 4.47 6bd, 1H, NH), 6.77 6dd, 1H,
J1,1.0 Hz, J2ˆ8.1 Hz, CH-arom.), 6.93 6dt, 1H, J1,
1.0 Hz, J2ˆ7.6 Hz, CH-arom.), 7.30 6dt, 1H, J1,1.0 Hz,
J2ˆ7.6 Hz, CH-arom.), 7.77 6dd, 1H, J1ˆ1.5 Hz, J2ˆ
8.1 Hz, CH-arom.); 13C NMR 6125 MHz, DMSO-d6):
dˆ38.1 6NMe), 46.0 6C-4), 52.4 6OMe), 64.9 6C-3),
118.6, 119.4, 128.8, 133.3 6CH-arom.), 124.4 6C-7), 147.4
6C-6), 169.8 6CvO). Anal. Calcd for C11H14N2O4S: C
48.88; H 5.22; N 10.36; Found: C 48.89; H 5.31; N 10.29.
6. 6a) Di Santo, R.; Costi, R.; Artico, M.; Massa, S.; Marongin,
M. E.; Loi, A. G.; De Montis, A.; La Colla, P. Antiviral Chem.
Chemotherapy 1998, 9, 127. 6b) Bellarosa, D.; Antonelli, G.;
Bambacioni, F.; Giannotti, D.; Viti, G.; Nannicini, R.;
Giachetti, A.; Dianzani, F.; Witvrouw, M.; Pauwels, R.;
Desmyter, J.; De Clercq, E. Antiviral Res. 1996, 30, 109.
6c) Artico, M.; Silvestri, R.; Pagnozzi, E.; Stefancich, G.;
Massa, S.; Loi, A. G.; Putzolu, M.; Corrias, S.; Spiga, M. G.;
La Colla, P. Bioorg. Med. Chem. 1996, 4, 837. 6d) Giannotti,
D.; Viti, G.; Nannicini, R.; Pestellini, V.; Bellarosa, D. Bioorg.
Med. Chem. Lett. 1995, 5, 1461.
3.1.12. *^)-5-N-Benzyl-3-methoxycarbonyl-2-N-methyl-
1,2,5-benzothiadiazepine 1,1-dioxide *2a). Benzyl-
bromide 60.70 mL, 5.9 mmol), sodium carbonate 60.60 g,
5.7 mmol) and tetrabutylammonium iodide 60.20 g,
0.54mmol) were added to a solution of compound 2b
60.30 g, 1.1 mmol) in anhydrous THF 610 mL). The mixture
was stirred under re¯ux for 72 h, ®ltered and evaporated to
dryness. Puri®cation by silica gel ¯ash chromatography
6eluent: 2/1!1/1 hexane/ethyl acetate) furnished tertiary
amine 2a 60.37 g, 92%) as a colourless wax. IR 6neat):
nmax 1750 6s, CvO), 1492 6s), 1322 6s, SO2), 1206 6s),
7. 6a) Ogawa, K.; Matsushita, Y. Chem. Pharm. Bull. 1992, 40,
2442. 6b) Artico, M.; Silvestri, R.; Stefancich, G. Synth.
Commun. 1992, 22, 1433.
8. 6a) Silvestri, R.; Artico, M.; Pagnozzi, E. J. Heterocycl. Chem.
1994, 31, 1033. 6b) Langlois, N.; Andriamialisoa, R. Z.
Heterocycles 1989, 29, 1529. 6c) Migliara, O.; Petruso, S.;
Sprio, V. J. Heterocycl. Chem. 1979, 16, 835.
9. Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.;
Loukou, C. Tetrahedron Lett. 2000, 41, 10107.
10. 6a) Silvestri, R.; Pagnozzi, E.; Stefancich, G.; Artico, M.
Synth. Commun. 1994, 24, 2685. 6b) Stefancich, G.; Silvestri,
R.; Pagnozzi, E.; Artico, M. J. Heterocycl. Chem. 1994, 31,
867.
1
1144 6s, SO2) cm21; MS 6ESI1, m/z): 383 6M1Na1); H
NMR 6250 MHz, CDCl3): dˆ2.89 6s, 3H, NMe), 3.65 6dd,
J1ˆ3.8 Hz, Jgemˆ15.2 Hz, H-4), 3.72 6s, 3H, OMe), 4.05
6m, 1H, H-4), 4.20 6dd, 1H, J1ˆ3.8 Hz, J2ˆ10.5 Hz, H-3),
4.52, 4.70 62£d, 2H, Jgemˆ15.4Hz, CH 2Ph), 6.97±7.03 6m,
2H, CH-arom.), 7.25±7.41 6m, 6H, CH-arom.), 7.86 6dd,
1H, J1ˆ1.7 Hz, J2ˆ8.1 Hz, CH-arom.); 13C NMR
6125 MHz, CDCl3): dˆ36.9 6NMe), 51.1 6C-4), 52.9
6OMe), 58.0 6CH2Ph), 63.3 6C-3), 119.5, 121.4, 128.0,
128.1, 129.3, 130.3, 133.7 6CH-arom.), 129.7 6C-7), 137.6
6ipso C-phenyl), 148.1 6C-6), 169.7 6CvO). Anal. Calcd for
11. Field, G. F.; Zally, W. J.; Sternbach, L. H. J. Org. Chem. 1971,
36, 2968.
12. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
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J. J. Tetrahedron Lett. 1996, 37, 8081.
14. Bowman, W. R.; Coghlan, D. R. Tetrahedron 1997, 53,
15787.