Sulfonamide ligands attained through opening of saccharin derivatives

Article abstract of DOI:10.1002/ejoc.200600508

Literature N-alkylsaccharins (saccharin-R²) have been shown in some cases to be O-alkylated regioisomers by crystallography (3 structures). The genuine former species react with (S)-H₂NCHR¹CH ₂OH at 101°C in dio

Full text of DOI:10.1002/ejoc.200600508

FULL PAPER
DOI: 10.1002/ejoc.200600508
Sulfonamide Ligands Attained Through Opening of Saccharin Derivatives
Richard I. Robinson,[a] Ross Fryatt,[a] Claire Wilson,[a] and Simon Woodward*[a]
Keywords: Molecular diversity / Amino alcohols / Sulfonamides / Sulfonic acids / N,O ligands / X-ray analysis
Literature N-alkylsaccharins (saccharin-R2) have been
shown in some cases to be O-alkylated regioisomers by crys-
tallography (3 structures). The genuine former species react
with (S)-H2NCHR1CH2OH at 101 °C in dioxane to provide
1,2-C6H4(CONHCHR1CH2OH)(SO2NHR2) [R1 = H, Me, iPr,
Bn, (CH2)2SMe; R2 = Bn, iPr, CHPh2, CHMePh]. The (iPr,Bn)
compound is crystallographically characterised. If both R1
and R2 are sterically congested then reaction of the amino
alcohol with the saccharin surrogate 1,2-C6H4(CO2Me)-
(SO2NHR2) is required. The saccharin-derived alcohols are
converted into the oxazolines 1,2-C6H4(R1-oxazoline)-
(SO2NHR2) (R1 = H, Bn, Me, iPr; R2 = Bn, CHPh2, nPr, iPr,
tBu, CHMePh). The dibenzyl compound is crystallographi-
cally characterised.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
best of our knowledge, studies of the reactions of N-substi-
tuted saccharins with 1,2-amino alcohols have never been
carried out viz. the route we aimed to employ.
Introduction
Recently we proposed that, by unusual rearrangement
chemistry, the amides 2 formed when the oxazolines 1 are
heated with primary amines (Scheme 1).[1] Our initial as-
signment of structure 2 was based on extensive NMR stud-
ies as, at first, no example of this compound class could be
crystallised. On the basis of NMR spectroscopic data alone,
the structural assignment of 2 could not completely exclude
the alternative possible structures 3 (the originally desired
product of the reaction of 1 and R2NH2) and its hydrolysis
product 4. Thus, prior to successful crystallisation of 2, an
independent synthesis of 3 and 4 was sought. We had ob-
tained the sulfonic acids 1 by opening of the anhydride 5
with amino alcohol derivatives. We envisaged that an alter-
native approach to the desired motif 3 would be opening of
the saccharin 6 with similar α-amino acid derivatives afford-
ing the amide intermediate 4, which could be cyclised to the
oxazoline 3. Surprisingly, despite the enormous abundance
of saccharin literature, its opening (and opening of its deriv-
atives) with amino acids (or their derivatives) is very poorly
represented. Romani and co-workers opened compound 6
Scheme 1. Preparative routes to oxazoline sulfonic acids.
(R2
C6H4(SO2NHBz)[CONHCH(R1)CO2H] (R1
=
CO2Bn) with α-amino acids, to afford 1,2-
Results and Discussion
=
various
amino acids) in good yields.[2] Whereas this has led to a
widely used peptide-coupling procedure using a related
compound 6 (R2 = S-2-NO2Ph) the intermediate amido sul-
fonamides were never isolated. In a single example,
Proudfoot demonstrated that the saccharin 6 (R2 = allyl)
opened cleanly with HNMe2 in dioxane.[3] However, to the
Opening of Saccharins with 1,2-Amino Alcohols
The saccharin starting materials 6 were prepared by
either routine alkylation of saccharin 6a (R2 = H) in DMF
with RX (Method A) or by Mitsonobu chemistry (Method
B) on the equivalent alcohol. Alkylation methods led to the
desired N-alkylation products 6b–g; however, Mitsonobu
chemistry tended to favour the corresponding O-alkylation
7b and 7f (Scheme 2), a fact not noted in the literature be-
fore.
[a] School of Chemistry, The University of Nottingham,
University Park, Nottingham, United Kingdom
Fax: +44-115-9513564
E-mail: simon.woodward@nottingham.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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R. I. Robinson, R. Fryatt, C. Wilson, S. Woodward
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Figure 2. Crystallographic confirmation of the presence of an O–
C linkage in O-alkylated saccharin 7f. Displacement ellipsoids
drawn at 50% probability level.
Scheme 2. Preparation of substituted saccharins.
1
Analysis of the H NMR and IR spectra for the com-
pounds 6f and 7f, did not afford explicit assignment of the
connectivity. The structures were confirmed by X-ray crys-
tallography on both compounds (Figures 1 and 2). It could
be confirmed that the OCH2 resonance (δ Ϸ 5 ppm) ap-
peared at higher frequency than the equivalent NCH2 signal
1
(δ Ϸ 4 ppm) in the H NMR spectra.
Figure 3. Crystallographic confirmation of the presence of an O–
C linkage in the bis(sulfonamide) 8a of Reid. Only one of two crys-
tallographically independent molecules shown, displacement ellip-
soids drawn at 50% probability level.
Figure 1. Crystallographic confirmation of the presence of an N–
C linkage in N-alkylated saccharin 6f. Displacement ellipsoids
drawn at 50% probability level.
Attempts to prepare a methylene-spaced bis(saccharin)
by the chemistry of Reid[4] were not successful. The report
of this compound is in error; attempted alkylation of sac-
charin (method A) leads instead to a mixture of species. 4 in good yield (Scheme 3). The extremely polar nature of
The major product is the O-alkylated compound 8a, whose the primary sulfonamide 4aa made it impossible to isolate
structure was determined crystallographically (Figure 3). it cleanly, so our attention was applied to N-substituted sul-
The origin of this one example of O-alkylation by method fonamides. The results of Scheme 3 were obtained using
A is the steric hindrance that bis(N-alkylation) would gen- equimolar quantities of amino alcohol with 6b, on scales
erate. This can be seen as the equivalent propyl derivative Ͼ1 g to facilitate product separation. Alternatively, reac-
8b and all other species 6 were attained in good yield by tions could be driven to completion by using a higher load-
simple alkylation.
ing of amino alcohol (1.5 equiv.) in refluxing dioxane for
The relatively unhindered saccharin 6a opened in re- extended periods. It was noticeable that some amino
fluxing dioxane, b.p. 101 °C (or THF, b.p. 67 °C) with 1,2- alcohols were very much slower to react. This was exem-
amino alcohols to provide the required sulfonamide amides plified by 4eb, where after heating in dioxane for 16 h, only
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Sulfonamide Ligands Attained Through Opening of Saccharin Derivatives
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a 52% yield was achieved, whereas hardly any ring opening Whereas all the substituted saccharins 6b–e could be ring-
was observed in THF. All of the sulfonamides 4 are isolated opened by 2-ethanolamine under the standard conditions,
as viscous oils, extensive drying under high vacuum is re- when L-valinol was employed as a nucleophile, the saccha-
quired to remove hydrogen-bonded solvents from these ma- rins 6c–6e were very sluggish to react, requiring large ex-
terials.
cesses of valinol and elevated temperatures in some cases.
It was noticeable that the isopropyl derivative 6c was also
slower to react than the diphenyl derivative 6d as monitored
by TLC analysis and 1H NMR spectroscopy. In the case of
6e no product formation was observed at all even under
sealed-tube conditions. A number of additives were at-
tempted to see if ring opening of hindered saccharin 6e
could be induced. Catalytic DMAP (10 mol-%) or Lewis-
acidic La(OTf)3·9H2O or Sc(OTf)3 (both at 5 mol-%) had
no effect; neither did pre-treatment of 6e with (Me3O)BF4
in an attempt to improve its reactivity by O-alkylation.
The path of the sterically encumbered amine nucleophile
into the exocyclic carbonyl group of the saccharin ring 6e
appears completely blocked. The presence of the sulfonyl
functionality in the ring enforces the alkyl group to adopt
the conformation shown in structure 9. The resulting transi-
tion state after nucleophilic attack is very cluttered, and in-
teraction with -valinol seems especially disfavoured. This
lack of reactivity led us to develop an alternative method
to such hindered species.
Scheme 3. Opening of saccharins 6 with 1,2-amino alcohols.
Due to oil formation only one example could be crystal-
lised. The structure of 4cb (Figure 4) shows the extensive
hydrogen-bonding network of intramolecular H bonds be-
tween the carbonyl amide O1 (as an H-bond acceptor), and
the sulfonamide proton on N2 (as an H-bond donor). The
hydroxy proton on O4 is also H-bonded with the sulfonyl
oxygen atom O2. The amide proton at N1 forms an inter-
molecular H-bond to the O4 atom of another molecule,
forming a dimeric lattice. This structure also explains the
experimental observation of why removal of hydrogen-
bonding solvents was often so difficult. Prolonged high-vac-
uum drying at 40 °C for several days (a few weeks in some
cases) is required to produce solids. Both EtOH and MeOH
bond very strongly in the H-bonding pocket produced by
these molecules.
In an attempt to determine the scope of this steric effect,
the synthesis of sterically more encumbered saccharin deriv-
atives was carried out. Previous reports on the synthesis of
saccharin derivatives that cannot be prepared by simple SN2
chemistry generally utilise the cyclisation of species 11
(Scheme 4). The sulfonyl chloride 10 makes an excellent
precursor to the sulfonamides 11 and, in fact, these latter
compounds serve as a source of N-alkylsaccharins 6.
Base-catalysed cyclisation via the methoxy ester 11 is
usually very slow, and this often depends on the nature of
group R2, both from a steric and electronic perspective.
Preparation of 6e and the tert-butyl derivative 6h by this
methodology proved difficult, with a very poor yield of the
saccharin produced allowing direct synthesis of 4ch
(Scheme 4). By comparison, phenylsaccharin 6i readily
cyclised in high yield (Scheme 5).
The formation of amides from esters at high tempera-
tures has been previously demonstrated for a variety of sub-
strates.[5] Utilising the methoxy ester 11 as a saccharin sur-
rogate, we could prepare the hindered saccharin substrates
(Scheme 4). The amides could be easily separated from the
saccharin by-product using chromatography. The preferred
Figure 4. Molecular structure of 4cb showing intramolecular hy-
drogen bonding (solid dotted lines). Selected H-bonding contacts
[Å; °]: O(4)···O(2) 2.894(2), O(4)–H(4)–O(2) 163.9, N(2)···O(1)
2.864(2), N(2)–H(2)–O(1) 149(2). Displacement ellipsoids drawn at
50% probability level.
The direct ring opening of hindered alkyl saccharins (6c– procedure was the use of dioxane or toluene in a sealed
e) under dioxane reflux proved challenging. Varying suc- tube at 130 °C, as dioxane reflux was not as effective in this
cess, depending on the steric requirements of the alkyl case. A tertiary sulfonamide derivative 12 was also at-
group (R1) in the incoming amino alcohol, was attained. tempted to see if amide formation was possible without the
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R. I. Robinson, R. Fryatt, C. Wilson, S. Woodward
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Scheme 4. Synthesis of sulfonamides 4 via methoxy ester 11.
Scheme 6. Conversion of amino alcohols 4 to chlorides 13.
Purification only required the removal of triphenylphos-
phane oxide by flash chromatography. Initially, the reac-
tions were run in CH2Cl2 and were only complete after a
48–72 h period; however, when MeCN was used, the reac-
tion was much faster taking just 5 h. Previous reports have
shown that MeCN has a dramatic rate-accelerating effect
on the dissociation of a chlorine atom from CCl4,[7] often
the rate-determining step in this reaction. Two reactions
were run using a 50:50 mixture of CH2Cl2/MeCN in order
to aid solubility (Entries 13ad and 13cd).
Scheme 5. Synthesis of sterically encumbered saccharin derivatives.
Cyclisation of the chlorides 13ab–db was achieved by
treatment with 5% ethanolic KOH, producing near quanti-
tative yields of the corresponding oxazolines 3ab–db
(Scheme 7) in all cases. Recrystallisation of the oxazolines
proved somewhat difficult, although it was not required for
purification in many cases. However, suitable crystals of 3db
for X-ray analysis were produced when a CH2Cl2 solution
was slowly concentrated (Figure 5). This confirmed that we
had synthesised the desired architecture of the ligand. In
this case the oxazoline is not in a protonated state, unlike
the sulfonic acids previously synthesised by us,[1] although
presence of an acidic proton. No sign of reaction was ob-
served, indicating that the presence of the acidic sulfon-
amide proton was critical to the reaction.
Upon completion of the amide series 4ab–4eb, the amide hydrogen bonding between the oxazoline nitrogen atom and
was cyclised to the desired oxazoline ring using established the sulfonamide proton is evident.
literature procedures. Denmark[6] et al. have established a
These ligands, and their precursors, were subsequently
reliable procedure whereby the alcohol functionality is mes- tested for activity in the copper-catalysed 1,4-conjugate ad-
ylated, and subsequent treatment with base forms the oxaz- dition of organometallic reagents to enones. It was found
oline ring. This and other one-pot procedures for oxazoline that in the addition of diethylzinc to cyclohexenone, the li-
formation proved ineffective in our hands. A two-step pro- gands gave very strong rate acceleration but led to poor
cedure via the chloride was thus adopted. Chlorination of enantioselectivity, less than 10%. However, subsequent bio-
alcohols using PPh3/CCl4 was found to be optimal for pro- logical screening revealed significant antibacterial activity
ducing 13 very cleanly in high yields (54–84%, Scheme 6).
for some of the compound library prepared.
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Sulfonamide Ligands Attained Through Opening of Saccharin Derivatives
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amino alcohol. The alcohols 4 are converted into the oxaz-
olines 3 via the intermediate chlorides 13 followed by base-
induced cyclisation. Whereas the final oxazoline sulfon-
amides were not of utility in copper-catalysed conjugate ad-
dition, this class of compounds and their precursors consti-
tutes an interesting scaffold for biological studies and pre-
liminary research is now focused in this area.
Experimental Section
General: Representative general experimental procedures are listed
below. Full experimental procedures and data for compounds 3ab–
db, 4ab–4eb, 6b–6g, 7b, 7f, 8a–b, 11e, 11h, 11i, 13ab–13db is avail-
able in the Supporting Information. Procedures involving moisture-
sensitive reagents or intermediates were performed under argon or
nitrogen using standard Schlenk techniques. Tetrahydrofuran and
Et2O were distilled from sodium/benzophenone ketyl. Other sol-
vents were dried appropriately and stored over molecular sieves
(4 Å). Light petroleum refers to the fraction boiling in the range
40–60 °C. IR spectra were recorded with a Perkin–Elmer 983G
(KBr disc), Perkin–Elmer 882 or a Nicolet Avatar 360 FT-IR infra-
red spectrophotometer. The term “solid state” refers to direct
analysis of the oil/solid, using a Nicolet Avatar 360 FT-IR re-
flecting probe. 1H and 13C NMR spectra were recorded with either
JEOL (GX 270) or Bruker (AM400, AV400 and DRX500) spec-
trometers at ambient temperature unless otherwise noted. Tet-
ramethylsilane was used as an internal standard and J values are
given in Hz. Mass spectra were obtained with a Micromass 70E
(electron impact ionisation, EI+), Micromass LCT (electrospray
ionisation, ES+) and VG AutoSpec (fast-atom bomdardment,
FAB+) machines. Specific rotations were measured with a Jasco
DIP370 Digital polarimeter at ambient conditions and are given in
units of 10–1°cm2 g–1; (c in g/100 mL). Appropriate N-substituted
saccharins were prepared according to literature routes.[8]
Scheme 7. Base cyclisation of chlorides 13 using ethanolic KOH.
Crystallographic Data: Colourless crystals of 6f, 8a were grown
from isopropyl alcohol, 7f from ethanol, 3db from CH2Cl2 and 4cb
from CH2Cl2. All single-crystal diffraction data were collected
using graphite-monochromated Mo-Kα X-ray radiation with a
Bruker SMART APEX, except for 7f which was collected with a
SMART1000 CCD area detector diffractometer, each equipped
with an Oxford Cryostream cooling device. All data were collected
at 150 K. Details of the individual data collections and refinements
are given in Table 1. All structures were solved by direct methods
using SHELXS-97 or SIR-92 (7f). All structures were refined by
least-squares full-matrix refinement against F2 using SHELXL-97
and all non-H atoms refined with anisotropic atomic displacement
parameters (adps). Hydrogen atoms were geometrically placed and
refined as part of a riding model, except for those bound to N and
O in 4cb and N in 3db which were located from difference Fourier
maps and the OH group was refined as a rigid rotor and the NH
atoms were refined freely in both structures. Crystallographic data
for all compounds are summarised in Table 1. CCDC-604476 to
-604480 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Figure 5. Crystal structure of ligand 3db. Displacement ellipsoids
drawn at 50% probability level.
Conclusions
Crystallographic studies of alkylation products of sac-
charin have revealed O-alkylated imides instead of the N-
alkyl species suggested in the parent literature in some
cases. Care must be taken in distinguishing these as their
NMR and IR spectra are often surprisingly similar. Mit-
sonobu approaches favour O-alkylation. Ring opening of
N-alkylsaccharins with 1,2-amino alcohols leads to direct
formation of the sulfonamides 4 if the alkyl substituent in
the saccharin is not too large. In the latter case 4 can still be
attained by the use of 1,2-C6H4(CO2Me)(SO2Cl) through
General Procedure for the Preparation of Oxazolinesulfonamides 3:
Compound 13 (4.8 mmol) was added to a stirred solution of 5%
ethanolic KOH (20 mL). The reaction mixture was stirred at room
temperature for the stated amount of time, followed by the addition
stepwise treatment with RlargeNH2 and subsequently the of CH2Cl2 (50 mL). The reaction mixture was then acidified by the
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R. I. Robinson, R. Fryatt, C. Wilson, S. Woodward
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Table 1. Crystallographic data for 3eb, 4cb, 6f, 7f and 8a.
3eb
4cb
6f
7f
8a
Empirical formula
Mr
Cell setting, space group
Temperature [K]
C23H22N2O3S
406.49
triclinic, P1
150(2)
C19H24N2O4S
376.46
orthorhombic, P212121 monoclinic, P21/n
C9H8BrNO3S
290.13
C9H8BrNO3S
290.13
monoclinic, P21/c
150(2)
C16H12N2O6S2
392.40
triclinic, P1
¯
150(2)
150(2)
150(2)
a [Å]
b [Å]
c [Å]
α [°]
β [°]
γ [°]
5.8503(15)
7.736(2)
22.170(6)
87.995(4)
85.686(4)
89.818(4)
1000.0(8)
2
8.5173(10)
12.5191(14)
18.195(2)
90
90
90
1940.1(4)
4
10.3122(9)
18.944(2)
11.5524(10)
90
109.501(1)
90
2127.4(3)
8
1.812
7.5511(12)
17.164(3)
8.0984(13)
90
92.108(3)
90
1048.9(3)
4
1.837
6.194(2)
10.840(4)
12.625(4)
86.406(5)
80.673(5)
79.499(6)
821.9(5)
2
V [Å3]
Z
Dcalcd. [Mg·m–3
]
1.350
0.19
1.289
0.19
1.586
0.36
µ [mm–1
]
4.05
4.10
Crystal form, colour
Crystal size [mm]
Absorption correction
Tmin. [°]
tablet, colourless
0.41×0.33×0.03
none
block, colourless
0.33×0.18×0.14
none
–
lath, colourless
0.24×0.12×0.07
multi-scan
0.564
plate, colourless
0.40×0.19×0.02
multi-scan
0.091
column, colourless
0.27×0.07×0.04
none
–
–
Tmax. [°]
–
–
0.753
0.164
–
No. of measured/indepen-
dent/observed reflections
[IϾ2σ(I)]
8314/7675/5077
16999/4563/4446
18343/4922/3995
6360/2385/1585
7082/3592/2567
Rint
0.100
0.075, 0.188, 0.94
0.001
0.89, –0.36
0.05(12)
0.034
0.035, 0.099, 1.10
0.002
0.25, –0.23
0.01(7)
0.030
0.037, 0.094, 1.02
Ͻ0.0001
0.071
0.036, 0.078, 0.87
0.001
0.056
0.048, 0.098, 0.93
0.001
R [F2 Ͼ 2σ(F2)], wR(F2), S
(∆/σ)max
∆ρmax, ∆ρmin [e·Å–3
Flack parameter
]
2.06, –1.06
0.56, –0.57
0.44, –0.40
addition of an aqueous 2.0  HCl solution, the organic phase was
extracted, washed with H2O (40 mL), brine (30 mL), dried
(Na2SO4) and concentrated in vacuo to give a pale yellow oil. Puri-
fication by flash chromatography (CH2Cl2) gave 3 as a colourless
oil.
lowed by CH2Cl2/MeOH 5%) gave 4, which was isolated as a vis-
cous oil. After several days of drying and standing under high vac-
uum (0.1 Torr, 20–40 °C), in most cases the oils solidified to white
solids (yields 52–95%).
2-[(Benzylamino)sulfonyl]-N-[(1S)-1-hydroxymethyl-2-methyl-
N-Benzyl-2-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]benzene- propyl]benzamide (4cb): Prepared from L-valinol (3.96 g,
sulfonamide (3db): Prepared from 13db (1.30 g, 2.93 mmol), stirring
for 3 h. Purification by flash chromatography (CH2Cl2) gave 3db
(1.14 g, 95%) as a white solid. Rf = 0.35 (CH2Cl2). M.p. 90–93 °C
38.4 mmol) and 6b (10.5 g, 38.4 mmol) in dioxane (60 mL), re-
fluxing for 72 h. Purification by flash chromatography gave 4cb as
a viscous oil. After several days of drying and standing under high
(dec., CH2Cl2). [α]D = –25.8 (c = 1.2, CHCl3). 1H NMR (400 MHz, vacuum, the oil solidified to a white solid (10.0 g, 69%). Rf = 0.36
CDCl3): δ = 8.22 (br. s, 1 H, SO2NH, exchanges with H2O), 8.04
(dd, J = 7.2, 1.7 Hz, 1 H, Ar), 7.77 (dd, J = 7.2, 1.7 Hz, 1 H, Ar),
7.54 (m, 2 H, Ar), 7.19–7.10 (m, 10 H, Ar), 4.68–4.63 (m, 1 H,
CHN), 4.47 (dd, J = 9.5, 8.5 Hz, 1 H, OCH2α), 4.17 (dd, J = 9.5,
8.5 Hz, 1 H, OCH2β), 4.11 (d, J = 14.0 Hz, 1 H, NHCH2αPh), 4.04
(d, J = 14.0 Hz, 1 H, NHCH2βPh), 3.06 (dd, J = 14.0, 7.2 Hz, 1
H, CHCH2αPh), 2.84 (dd, J = 14.0, 7.2 Hz, 1 H, CHCH2βPh) ppm.
(5% MeOH/CH2Cl2). M.p. 136–137 °C (CH2Cl2). [α]D = –28.9 (c
= 1.0, EtOH). H NMR (400 MHz, CDCl3): δ = 7.90 (dd, J = 7.9,
1
1.0 Hz, 1 H, Ar), 7.60–7.46 (m, 3 H, Ar), 7.22–7.18 (m, 5 H, Ar),
6.72 (t, J = 7.0 Hz, 1 H, SO2NH), 6.39 (d, J = 8.9 Hz, 1 H,
CONH), 4.18 (dd, J = 13.8, 7.0 Hz, 1 H, PhCH2α), 4.00 (dd, J =
13.8, 5.2 Hz, 1 H, PhCH2β), 3.88–3.82 (m, 1 H, NCH), 3.78 (dd, J
= 12.2, 6.3 Hz, 1 H, CH2αOH), 3.65 (dd, J = 12.2, 3.0 Hz, 1 H,
13C NMR (100 MHz, CDCl3): δ = 163.0, 139.7, 137.7, 136.8, 131.9, CH2βOH), 2.95 (br. s, 1 H, OH), 1.80 (oct, J = 6.9 Hz, 1 H,
131.1, 131.0, 129.8, 129.2, 128.7, 128.4, 127.9, 127.5, 126.7, 126.0,
CHMe2), 1.00 (d, J = 6.9 Hz, 3 H, Me), 0.99 (d, J = 6.9 Hz, 3 H,
Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.8, 137.7, 136.2,
135.6, 132.7, 130.1, 129.3, 128.5, 128.4, 128.1, 127.7, 63.0, 58.1,
72.2, 68.6, 47.5, 41.4 ppm. IR (solid state): ν = 1644, 1452, 1438,
˜
1370, 1327, 1310, 1252, 1165, 1137, 1103, 1059, 1026, 963, 781,
770, 732, 699 cm–1. MS (EI+): calcd. for C23H22N2O3S 406.1351, 47.6, 29.1, 19.7, 19.1 ppm. IR (solid state): ν = 3512, 3232, 1640,
˜
found 406.1353 [M]+.
1565, 1431, 1330, 1215, 1166, 1015, 749, 736, 701 cm–1. MS
(FAB+): calcd. for C19H24N2O4S 377.1535, found 377.1352 [M +
H]+. C19H24N2O4S (376.47): calcd. C 60.62, H 6.43, N 7.44; found
C 60.65, H 6.41, N 7.40.
General Procedure for the Reaction of Saccharin 6 with 1,2-Amino
Alcohols. Preparation of 4: The required 1,2-amino alcohol
(40.0 mmol, see Scheme 3 for range employed) was added to a
stirred solution of the appropriate N-alkylsaccharin 6 (40.0 mmol)
in dioxane (60 mL). The reaction mixture was refluxed for 8–96 h,
until no further saccharin was consumed according to TLC analy-
sis. For the preparation of 4ab and 4db the reactions were carried
out in THF (b.p. 67 °C). For 4ad, 4cd, 4ce and 4ch the reaction
was performed in dioxane or toluene in a sealed tube at 130 °C (6–
20 h). The solvent was evaporated in vacuo to yield a colourless
viscous oil. Purification by gradient chromatography (CH2Cl2 fol-
General Procedure for the Preparation of N-Alkylated Saccharin De-
rivatives 6: The appropriate alkyl halide (10.0 mmol) was added to
a stirred solution of sodium saccharin dihydrate (10.0 mmol) in
DMF (20 mL). The reaction mixture was refluxed at 90 °C for 24–
48 h, after which time a white precipitate had formed. The reaction
mixture was cooled and CH2Cl2 (10 mL) and water (10 mL) were
added. The reaction mixture was transferred to a separating funnel
and 2  HCl (10 mL) was added. The layers were separated and
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Eur. J. Org. Chem. 2006, 4483–4489

Sulfonamide Ligands Attained Through Opening of Saccharin Derivatives
FULL PAPER
the aqueous layer washed with more CH2Cl2 (2×10 mL). The com-
bined organic layers were washed with brine (2×10 mL), dried with
MgSO4 and concentrated in vacuo to yield a colourless viscous oil.
Purification was carried out by either flash silica column
chromatography or by recrystallisation as stated for each com-
pound.
6.2 Hz, 2 H, NCH2), 4.27 (t, J = 6.2 Hz, 2 H, CH2O) ppm. 13C
NMR (67.8 MHz, CDCl3): δ = 169.2, 158.9, 143.5, 137.7, 135.2,
134.6, 134.2, 133.6, 127.5, 127.4, 125.5, 124.0, 121.8, 121.2, 67.9,
38.0 ppm. IR (solid state): ν = 1739, 1616, 1556, 1462, 1403, 1322,
˜
1258, 1179, 1159, 1122, 1058, 1040, 953, 930, 788, 755 cm–1. MS
(FAB+): calcd. for C16H13N2O6S2 393.0215, found 393.0206 [M +
H]+. C16H12N2O6S2 (392.41): calcd: C 48.97, H 3.08, N 7.14; found
C 48.80, H 3.00, N 7.1.
2-(2-Bromoethyl)-1,2-benzisothiazol-3(2H)-one 1,1-Dioxide (6f):
Prepared from sodium saccharin dihydrate (5.00 g, 20.7 mmol) and
1,2-dibromoethane (1.80 mL, 20.9 mmol) in DMF (20 mL). Purifi-
cation by flash silica chromatography followed by recrystallisation
from iPrOH gave 6f (2.67 g, 44%) as white crystals. Rf = 0.58 (50%
EtOAc/light petroleum). M.p. 96–98 °C (iPrOH; ref.[9] 99 °C, aq.
General Procedure for the Preparation of Sulfonamide Methyl Ester
11: Triethylamine (5.1 mmol) was added in one portion to a stirred
solution of methyl 2-(chlorosulfonyl)benzoate (4.3 mmol) in dry
CH2Cl2 (20 mL) (inert gas, room temperature). The reaction was
quenched by the addition of 2.0  HCl (5 mL). The organic frac-
tion was extracted and washed with 2.0  HCl (2×50 mL), brine
(50 mL), and then dried (Na2SO4) and concentrated in vacuo. Puri-
fication by flash chromatography (CH2Cl2) gave 11 as either a vis-
cous colourless oil or a foamy white solid.
1
EtOH). H NMR (400 MHz, CDCl3): δ = 8.10–8.08 (m, 1 H, Ar),
7.96–7.84 (m, 3 H, Ar), 4.17 (t, J = 7.6 Hz, 2 H, NCH2), 3.67 (t, J
= 7.6 Hz, 2 H, CH2Br) ppm. 13C NMR (100 MHz, CDCl3): δ =
158.5, 137.4, 135.0, 134.4, 126.9, 125.3, 121.0, 39.8, 26.8 ppm. IR
(solid state): ν = 2360, 2340, 1732, 1462, 1446, 1335, 1296, 1257,
˜
1229, 1176, 1162, 1033, 960, 752 cm–1. MS (EI+): calcd. for
C9H8BrNO3S 290.9388, found 290.9383 [M]+. C9H8BrNO3S
(290.13): calcd. C 37.26, H 2.78, N 4.83; found C 37.38, H 2.81, N
4.78.
General Procedure for the Preparation of Chloro Sulfonamides 13:
Triphenylphosphane (1.30 mmol) and carbon tetrachloride (5 mL,
51.7 mmol) were added to a stirred solution of 4 (1.30 mmol) in
the stated solvent (5 mL) at room temperature for the stated time,
until complete conversion according to TLC was noted. The reac-
tion mixture was concentrated in vacuo, to give a crude colourless
oil. Purification by flash chromatography gave 13 as either a vis-
cous colourless oil or a foamy white solid.
General Procedure for the Preparation of O-Alkylated Saccharin De-
rivatives 7: Anhydrous benzyl alcohol (5.5 mmol) was added to a
stirred solution of saccharin 6a (5.5 mmol) and triphenylphosphane
(6.8 mmol) in dry THF (20 mL) under an inert gas. The reaction
mixture was cooled to 0 °C and diethyl azodicarboxylate
(6.8 mmol) was added dropwise. The reaction mixture was warmed
to room temperature and stirred for 16 h, after which time the sol-
vent was concentrated in vacuo. Purification by flash silica
chromatography and subsequent recrystallisation from cold EtOH
gave the desired O-alkylated product.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and data for compounds 3ab–
db, 4ab–4eb, 6b–6i, 7b, 7f, 8a–b, 11e, 11h, 11i, 13ab–13db together
with graphical images of their 13C NMR spectra.
Acknowledgments
3-(2-Bromoethoxy)benzo[d]isothiazole 1,1-Dioxide (7f): Prepared
from saccharin 6a (2.00 g, 10.9 mmol), triphenylphosphane (3.59 g,
13.7 mmol), anhydrous 2-bromoethanol (0.78 mL, 10.9 mmol), di-
ethyl azodicarboxylate (2.15 mL, 13.7 mmol) and dry THF
(20 mL). Purification by flash silica chromatography (25–100%
CH2Cl2/light petroleum) and subsequent recrystallisation from cold
EtOH gave 7f (1.23 g, 37%) as colourless crystals. Also isolated
from the reaction mixture was compound 6f (0.74 g). Rf = 0.40.
We thank Dr. John Stephens for preparing some samples of these
compounds for The European Ligand Bank [European Commis-
sion Project FP6-505267-1 (LIGBANK)]. One of us (R. I. R.) is
grateful to the EPSRC for the award of a studentship and to the
COST-D24 programme.
1
M.p. 172–174 °C. H NMR (400 MHz, CDCl3): δ = 7.91–7.89 (m,
[1] R. I. Robinson, J. C. Stephens, S. M. Worden, A. J. Blake, C.
Wilson, S. Woodward, Eur. J. Org. Chem. 2004, 4596–4605.
[2] S. Romani, G. Bovermann, L. Moroder, E. Wuensch, Synthesis
1985, 512–513.
1 H, Ar), 7.82–7.71 (m, 3 H, Ar), 4.89 (t, J = 6.0 Hz, 2 H,
OCH2CH2Br), 3.74 (t, J = 6.0 Hz, 2 H, OCH2CH2Br) ppm. 13C
NMR (100 MHz, CDCl3): δ = 168.9, 143.5, 134.4, 133.6, 126.4,
[3] J. R. Proudfoot, U. R. Patel, A. B. Dyatkin, J. Org. Chem.
1997, 62, 1851–1853.
123.5, 122.0, 70.5, 27.1 ppm. IR (solid state): ν = 2361, 1615, 1556,
˜
1457, 1414, 1357, 1327, 1273, 1175, 1273, 1175, 1166, 957, 819,
788, 771, 752 cm–1. MS (EI+): calcd. for C9H8BrNO3S 290.9418,
found 290.9405 [M]+. C9H8BrNO3S (290.13): calcd: C 37.26, H
2.78, N 4.83; found C 37.14, H 2.74, N 4.84.
[4] E. E. Reid, L. M. Rice, C. H. Grogan, J. Am. Chem. Soc. 1955,
77, 5628–5630.
[5] For example, benzoic acid ethyl ester has been shown to yield
2-(benzoylamino)ethanol (77%), when refluxed at 150 °C in 2-
aminoethanol as reported by: A. P. Phillips, R. Baltzly, J. Am.
Chem. Soc. 1947, 69, 200–203.
[6] S. E. Denmark, R. A. Stavenger, A.-M. Faucher, J. P. Edwards,
J. Org. Chem. 1997, 62, 3375–3389.
[7] R. Apple, Angew. Chem. Int. Ed. Engl. 1975, 14, 801–811.
[8] See Supporting Information.
[9] L. L. Meritt, S. Levey, H. B. Cutter, J. Am. Chem. Soc. 1939,
61, 15–16.
2-{2-[(1,1-Dioxo-1,2-benzisothiazol-3-yl)oxy]ethyl}-1,2-benziso-
thiazol-3(2H)-one 1,1-Dioxide (8a): Prepared according to the gene-
ral procedure for the synthesis of 6. Prepared from sodium saccha-
rin dihydrate (1.44 g, 7.02 mmol) and 1,2-dibromoethane (0.3 mL,
3.51 mmol) in DMF (25 mL). Purification by recrystallisation from
CH2Cl2 gave 8a (0.77 g, 56%). Rf = 0.75 (CH2Cl2). M.p. Ͼ 260 °C
(dec., CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 8.10 (dd, J =
6.5, 1.5 Hz, 1 H, Ar), 7.94–7.85 (m, 5 H, Ar), 7.76 (dt, J = 7.5,
1.0 Hz, 1 H, Ar), 7.71 (dt, J = 7.5, 1.0 Hz, 1 H, Ar), 4.91 (t, J =
Received: June 12, 2006
Published Online: August 2, 2006
Eur. J. Org. Chem. 2006, 4483–4489
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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