Sulfonic acid libraries attained through opening of 2-sulfobenzoic acid anhydride

Article abstract of DOI:10.1002/ejoc.200400562

2-Sulfobenzoic acid anhydride opens cleanly with N-Boc-protected α-amino alcohols to afford zwitterionic esters 1,2-C₆H ₄(SO₃^-)(CO₂CH₂CHR ¹NH₃⁺) (R¹

Full text of DOI:10.1002/ejoc.200400562

FULL PAPER
Sulfonic Acid Libraries Attained Through Opening of 2-Sulfobenzoic Acid
Anhydride
Richard I. Robinson,[a] John C. Stephens,[a] Steve M. Worden,[a] Alexander J. Blake,[a]
Claire Wilson,[a] and Simon Woodward*[a]
Keywords: Molecular diversity / Amino alcohols / Sulfonic acids / S ligands / N,O ligands / Hydrogen bonding
2-Sulfobenzoic acid anhydride opens cleanly with N-Boc-
protected α-amino alcohols to afford zwitterionic esters 1,2-
C6H4(SO3Ϫ)(CO2CH2CHR1NH3+) (R1 = H, alkyl), the species
R1 = iPr is crystallographically characterised. Dehydration of
the crystallographically characterised complexes MIIL2 (L =
anion of the iPr-oxazolinesulfonic acid). Heating either the
zwitterionic esters or oxazolines with R2NH2 [R2 = CH2Ph,
CH2(1-C10H7), R-CH(Me)Ph] leads to SN2 attack at the ox-
these species affords zwitterionic oxazoline sulfonic acid de- azoline methylene group leading to the amido sulfonic acids
rivatives 1,2-C6H4(SO3Ϫ)(CA=NH+CHR1CH2OA) (CA and OA 1,2-C6H4(CONHCHRCH2NHR2)(SO3H) based on crystallo-
are bonded CϪO) for R1 = iPr (X-ray), iBu, tBu, CH2Ph. Reac- graphic studies on R1 = iPr, R2 = CH2(1-C10H7).
tion with water regenerates the zwitterionic esters while
exposure to M(OAc)2 (M = Cu, Pd) leads to the formation of
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
One major theme of early 21st century synthesis has be-
come the preparation, through simple chemistry, of com-
pound libraries. Such libraries find application in drug
screening, catalysis and materials chemistry.[1] Sulfonic ac-
ids, and their derived sulfonamides, are interesting com-
pound classes to target in this arena as both potent phar-
maceutical and catalytic ligand lead structures abound.[2,3]
We envisaged that the interesting sulfonic acid oxazolines 1
could be attained from either the esters 2 or the amides 3,
and potentially functionalised further to sulfonamides.
Either 2 or 3 should be available from suitable ‘‘click-reac-
tion’’[4] opening of commercial 2-sulfobenzoic acid anhy-
dride (4) with amino alcohols or suitable derivatives
(Scheme 1). Under appropriate conditions it should be pos-
sible to attain a one-step synthesis. While this chemistry is
unprecedented there are limited suggestions in patent, and
related, literature that the equivalent transformations with
diamines have been attained.[5]
Scheme 1. Preparative routes to oxazoline sulfonic acids.
Results and Discussion
dride 4 under DeanϪStark conditions in PhCl pleasingly
led to direct formation of an oxazoline formulated as tau-
tomer 1a (R ϭ iPr) in 50Ϫ60% recrystallised yield after an
overnight reflux. Purification of 1a is complicated by its
polar nature and by the presence of two additional species.
Proton NMR and IR spectroscopy confirmed these as re-
Oxazoline Synthesis
Initial investigations were carried out using valinol as a
representative α-amino alcohol. Reaction with the anhy-
sidual ester 2a (νCO ϭ 1736 cmϪ1) and amide 3a (νCO
ϭ
[a]
School of Chemistry, The University of Nottingham,
University Park, Nottingham, United Kingdom
Fax: (internat.) ϩ44-115-9513564
1653 cmϪ1). The sulfonic acid 1a could not be chromato-
graphed but crystallised readily from the reaction residue
using hot ethanol. Other derivatives of 1 (R ϭ alkyl) were
not as crystalline and could not be separated from the ester/
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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DOI: 10.1002/ejoc.200400562
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Sulfonic Acid Libraries
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amide mixtures. Even under prolonged heating complete
conversion of any amino alcohol and 4 into 1 could not
be attained, some 2 and 3 always remained (amoung other
products). The origin of this observation was revealed by
monitoring the reaction of valinol with 4 by 1H NMR spec-
troscopy in CDCl3. At room temperature 2a and 3a are
formed in a 1:1 ratio from 4 and valinol, although the reac-
tion is not clean. We reasoned that the amine function is
more nucleophilic and opens 4 quickly, but subsequent de-
protonation of the resulting ammonium species by more va-
linol is rapid leading to an eqimolar mixture of ester 2a and
amide 3a. Addition of valinol to 4 in the presence of NEt3
allowed greater formation of 3a (based on 1H NMR spectra
of the crude product) but it’s high water solubility, and the
presence of NHEt3Cl, prevented its isolation. Importantly,
heating the crude amide mixture containing 3a did not fa-
shion any oxazoline indicating that it is the formation of 3
that limits the conversion of 4. Reaction of O-TMS pro-
tected valinol with 4 was also attempted to provided a route Scheme 2. Preparation of esters 2 and oxazolines 1 via N-Boc-am-
ino alcohols.
to 1a (via 3a). However, subsequent heating, under DeanϪ
Stark conditions in PhCl, of the O-TMS analogue of 3a
also afforded no oxazoline 1a. In contrast, we could readily
confirm that the ester 2a (R ϭ iPr) was cleanly converted
to oxazoline 1a in quantitative yield under identical dehy-
drating conditions. These observations show that ester 2a is
hydrolysis.[6] In our cases the proximity of the sulfonic acid
moiety leads to the protonation of the amine functionality,
making it a more suitable leaving group than the alcohol-
derived substituent. The macroscopic reverse of this chemis-
the key intermediate in the preparation of 1a and that a
general approach to 1 should be attainable by such a route.
try accounts for the formation of 1 from 2.
To overcome the problems associated with co-formation of
3 in the reaction mixtures we utilised N-Boc-protected am-
ino alcohols and realised excellent yields of 2 for a range
of substituents (Scheme 2). The Boc group ensures clean
formation of the desired ester and is subsequently spon-
taneously deprotected by the unmasked sulfonic acid, pre-
sumably via 5. Because of these features no added acid is
required for the transformation. When anhydrous MeCN is
used as the solvent at 60 °C, 2 precipitates from the reaction
mixture as a white solid, and this has been found to be
analytically pure in all the cases we have tried. Reactions
carrried out at Ͼ5 g gave out large quantities of heat and
Crystallographic Studies
gas, so precautionary steps should be employed regarding
Because of the unusual features observed in the prep-
the rate of addition of the N-Boc-amino alcohol in such aration and hydrolysis of the oxazolines 1 we were anxious
cases. Species 2 are extremely stable and were unchanged to confirm our structural assignments crystallographically.
after storage for Ͼ1 year under standard laboratory con- Fortunately, both the ester 2a and its derived oxazoline 1a
ditions.
could be obtained as single crystals from MeCN and EtOH
DeanϪStark dehydration of the esters 2 to 1 proceeds respectively. Views of 1 and 2a are presented in Figure 1
well in PhCl (135 °C, 16 h), except in the cases where R ϭ and 2, respectively, which also give selected bond angles and
H, Me, where no product is isolated. This appears to be due distances, including hydrogen bonded H-atoms. The struc-
solely to the insolubility of 2eϪf in the PhCl but attempts ture of 1a confirms that the sulfonic acid oxazoline has been
to ovecome this by changing the solvent were not success- isolated in its zwitterionic form consistent with the observed
ful. Lack of reactivity is not an issue as 2eϪf take part in reactivity for its formation and subsequent hydrolysis, al-
other reactions, for example, 2e reacts with salicylaldehyde though the bond lengths around C(7) suggest some residual
to provide the novel ligand 6 [Equation (1)]. The final ox- double bond character to both the O and N atoms. The
azolines 1 are suseptible to slow hydrolysis on storage under acidic H was located from difference Fourier synthesis and
˚
non anhydrous conditions. Heating samples of 1 in water then refined as a part of a riding model 0.88 A from the
˚
facilitates this degradation. For example, 1a is completely oxazoline nitrogen, 1.83 A from the nearest SO3 oxygen.
hydrolysed within 1 h in warm (45Ϫ55 °C) D2O. The for- Relatively few chelating amino sulfonic acids have been sub-
mation of 2 by the hydrolysis of 1 is somewhat surprising, as jected to crystallographic studies but these indicate similar
amides are typically produced by acid-catalysed oxazoline zwitterionic structures with NϪH distances in the range
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[7]
˚
˚
0.785Ϫ1.015 A. The O···H distances (2.05Ϫ2.511 A) in results indicated identical behaviour for 8, but in this case
these structures are longer than those in 1a, while the no molecular ion could be observed.
O···HϪN angles (100.3Ϫ139.4°) are smaller than that of 1a
(153.7°). Overall the placement of the NH proton in 1a is
still, however, consistent with normal hydrogen bonding. In
addition to confirming the atom connectivity of ester 2a
is correctly assigned, Figure 2 shows (in contrast to purely
intramolecular H-bonding in 1a), an extensive highly or-
dered hydrogen bonding network is present in 2.
Scheme 3. Preparation of metal complexes of 1a.
X-ray crystallographic analysis confirmed the formation
of ML2 complexes. The molecular structures of 7 and 8 are
shown in Figure 3Ϫ4, respectively, together with selected
bond lengths and angle data. The palladium complex 7 ad-
opts an essencially perfect d8 square planar configuration
and crystallised as an acetonitrile solvate. The PdϪO dis-
tances and PdϪOϪS are similar to those reported by Tul-
˚
loch and co-workers for a PdϪOTs complex 2.123 A and
122.81°, respectively.[8] The two ligands in 7 are inequivalent
Figure 1. Molecular structure of 1a. Selected interatomic distances
˚
(A) and angles (°): S(1)ϪO(1) 1.446(3), S(1)ϪO(2) 1.449(3),
both in the solid state and in solution. For example, four
S(1)ϪO(3) 1.471(3), O(1)ϪC(7) 1.312(4), O(1)ϪC(9) 1.478(4),
N(1)ϪC(7) 1.270(5), N(1)ϪC(8) 1.471(4), N(1)ϪH(1A)···O(3) 1.83,
N(1)···O(3) 2.649(4), N(1)ϪH(1A)ϪO(3) 153.7.
methyl doublets at δH ϭ 1.06, 1.38, 1.39 and 1.62 are ob-
served for the diastereotopic iPr groups. The copper()
complex adopts a distorted tetrahedral geometry. Again,
the coordination of the sulfonic acids mimics those of
known copper() tosylate species.[9]
Figure 2. Packing diagram showing five molecules of 2a showing
hydrogen bonding network, the two independent molecules in the
˚
structure are labelled. Selected H-bonding distances (A):
N(1)ϪH(1A)···O(3) 1.93, N(1)···O(3) 2.824(3); N(1)ϪH(1C)···O(3A)
1.92,
N(1)···O(3a)
2.815(3);
N(1A)ϪH(1A1)···O(4)
1.90,
2.03,
N(1A)···O(4A)
2.799(3);
N(1)ϪH(1B)···O(5)(carbonyl)
N(1)···O(5)i 2.779(3); N(1A)ϪH(1a1)···O(5A)ii 1.98, N(1a)···O(5A)ii
2.887(3); i ϭ 1 Ϫ x, y Ϫ 1/2, Ϫz; ii ϭ x Ϫ 1, y, z.
Figure 3. Molecular structure of 7. Selected interatomic distances
˚
(A) and angles (°): Pd(1)ϪO(2) 2.016(13), Pd(1)ϪO(4a) 2.0334(11),
One potential use for the oxazoline ligands 1a is in asym-
metric catalysis, therefore we were keen to confirm that this
class of ligands can bind metal centres. Acetonitrile solu-
tions of 1a were reacted with M(OAc)2 (M ϭ Pd, Cu) at 90
°C and in the presence of 2,6-lutidine for copper() acetate.
On cooling, yellow or dark blue crystals of 7 or 8 respec-
tively formed. Mass spectrometry suggested that metathesis
of the acetates had taken place to provide the bis-complex
Pd(1)ϪN(1) 1.9952(14), Pd(1)ϪN(1A) 1.9908(15), O(2)Ϫ
PdϪO(4A) 83.22(6), O(2)ϪPdϪN(1) 93.25(6), O(4A)ϪPdϪN(1A)
94.52(6), N(1)ϪPdϪN(1A) 89.03(6), O(2)ϪPdϪN(1) vs.
O(4A)ϪPdϪN(1A) interplanar twist angle 1.1 °. An acetonitrile of
crystallisation is also shown in the plot.
Reaction of Oxazolines 1 with Primary Amines
Because of the versatility of sulfonamide units we wished
7 in the case of palladium (Scheme 3). Elemental analysis to establish a simple derivatisation of the sulfonic acids 1
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Figure 4. Molecular structure of 8. Selected interatomic distances
˚
(A) and angles(°) Cu(1)ϪO(2) 1.940(3), Cu(1)ϪO(2a) 1.946(3),
Scheme 5. Formation of compounds 10
Cu(1)ϪN(1) 1.947(4), Cu(1)ϪN(1A) 1.942(3), O(2)ϪCuϪO(2A)
86.80(12),
O(2)ϪCuϪN(1)
96.03(13),
O(2A)ϪCuϪN(1A)
94.18(13), N(1)ϪCuϪN(1A) 92.13(14), O(2)ϪCuϪN(1) vs.
O(2A)ϪCuϪN(1A) interplanar twist angle 31.4 °.
gel. Infra-red spectroscopic studies of 10 suggested the pres-
ence of an amide group (1650Ϫ1620 cmϪ1) and this is sup-
ported by the observation of an amido-like 13C NMR res-
onance (δC ϭ 169.3Ϫ172.2) in each case. Proton NMR
spectra of 10 clearly indicated the presence of three ex-
changable X-H protons (where X ϭ N or O) in each case.
Reaction of the esters 2, under identical conditions also
produced 10 (albeit in slightly lower yields of 50Ϫ60%). In-
itial attempts at recrystallisation of 10a produced only fine
needles unsuitable for X-ray analysis. Therefore compound
10a was subjected to extensive NMR studies in an attempt
to define its structure. Exposure of a CDCl3 solution of 10a
to D2O led to immediate replacement of two broad 1H sig-
nals at δH ϭ 8.92 and 8.90 (subsequently assigned to the
SO3H and NHR2 resonances) and commensurate forma-
tion of an HOD signal at ca. 4.8 ppm. Further shaking with
D2O led to replacement of a 1H doublet (J ϭ 9.5 Hz) at
δH ϭ 7.75 (assigned to CONH) over a 10 minute period.
to increase the diversity of our library. Perhaps the most
simple method for sulfonamide formation is direct reaction
with amines under thermal conditions leading to elimin-
ation of water.[10] Reaction of 1a with PhCH2NH2 under
DeanϪStark conditions (PhCl, 130 °C, 16 h), however, did
not fashion the expected product 9 (Scheme 4). It was clear
that a single new species is formed containing the reaction
components and rearrangement chemistry seemed to have
occurred.
1
The H:1H COSY spectrum links the latter signal with a
broad CH, revealed through the COSY to be itself part of
a NHCH(iPr)CH2OH derived side chain. This led us to
speculate initially that 10a was the hydrolysis product of the
desired 9a (i.e. 11). The 1H:13C COSY spectrum of 10a
showed a cross peak from the amido NH to the carbonyl
signal at δC ϭ 172.2 strongly suggesting that a carbonyl
bound amide is formed. However, the proposed structure
(11) could be discounted as it had already been prepared in
complimentary studies by an independent route.[11] Despite
our best efforts we could not initially pin down the point
of attachment of the R2NH2 derived amine unit.[12] Fortu-
nately, we were finally able to crystallise compound 10c
from methanol and confirm the connectivity by an X-ray
study (Figure 5).
The slow exchange of the sulfonamide NHSO2 with D2O
and the fact that all examples of 10 may be isolated by
chromatography on silica gel suggests strong hydrogen
Scheme 4. Attempted preparation of sulfonamides via 1 or 2.
Both combustion analyses and mass spectra of the prod- bonding in this class of compound. This is confirmed in
ucts indicated empirical formulas with no loss of H2O. Con- the structure of 10c were the presence of intramolecular H-
fusingly, despite their proposed polar constitution these bonding contacts between the amido NH and the sulfato
compounds could be isolated by chromatography on silica group and also between the distal amine and the amide car-
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˚
dried appropriately and stored over 4-A molecular sieves. Light
petroleum refers to the fraction boiling in the range 40Ϫ60 °C.
Infrared spectra were recorded using a PerkinϪElmer 983G (KBr
disc), PerkinϪElmer 882 or a Nicolet Avatar 360 FT-IR infrared
spectrophotometer. The term ‘‘solid state’’ refers to direct analysis
of the oil/solid, using a Nicolet Avatar 360 FT-IR reflecting probe.
Proton and 13C NMR spectra were recorded on either JEOL (GX
270) or Bruker (AM400, AV400 and DRX500) spectrometers at
ambient temperature unless otherwise noted. Tetramethylsilane was
used as an internal standard and J values are given in Hz. Mass
spectra were obtained on a Micromass 70E (electron-impact ionis-
ation, EIϩ), Micromass LCT (electrospray ionization, ESϩ) and
VG AutoSpec (fast-atom bomdardment, FABϩ) machines. Specific
rotations were measured using a Jasco DIP370 Digital polarimeter
Figure 5. Molecular structure of 10c showing intramolecular hy-
at ambient conditions and are given in units of 10Ϫ1°cm2gϪ1; (c in
g/100 mL). Boc-amino alcohols were prepared by literature
routes.[13] Commercially supplied 2-sulfobenzoic acid anhydride
proved unsatisfactory; it was sublimed (170 °C, 0.1 Torr) before use.
˚
drogen bonding. Selected H-bond lengths (A) and angles (°):
N(1)ϪH(1)N···O(4), H(1)N···O(4) 2.45, N(1)···O(4) 2.965(4),
N(2)ϪH(2)N···O(1), H(2)N···O1 2.34, N(2)···O(1) 3.077(4),
N(1)ϪH(1)N···O(4) 118, N(2)ϪH(2)N···O(1) 141.
Representative Procedure. 2-[(S)-4-Isopropyl-4,5-dihydrooxazol-2-
yl]benzenesulfonic Acid (1a): Chlorobenzene (15 mL) was added to
2a (180 mg, 0.63 mmol) and the reaction mixture refluxed with stir-
ring using a DeanϪStark trap (5 mL capacity) for 16 h. Upon com-
pletion the reaction was concentrated under vacuum to give 1a
(168 mg; 100%) as a white solid, with no further purification re-
quired.[14] M.p. 226Ϫ227 °C (EtOH). [α]D ϭ Ϫ44.2 (c ϭ 3.89,
MeOH). 1H NMR (400 MHz, CD3OD): δ ϭ 8.20 (dd, 1 H, J ϭ
8.0, 1.0; Ar), 7.98 (dd, 1 H, J ϭ 8.0, 1.0; Ar), 7.91 (dt, 1 H, J ϭ
8.0, 1.0; Ar), 7.76 (dt, 1 H, J ϭ 8.0, 1.0; Ar), 5.26 (apparent t, 1
H, J ϭ 9.8), 5.04 (dd, 1 H, J ϭ 9.8, 7.4), 4.54 (m, 1 H), 2.17 (m, 1
H, CHMe2), 1.17 (d, 3 H, J ϭ 6.7; Me), 1.11 (d, 3 H, J ϭ 6.7; Me)
ppm, H/D exchange in SO3H group with D from solvent. 13C
NMR (67.8 MHz, CD3OD): δ ϭ 174.8 (Cox), 146.9, 136.3, 132.2,
131.9, 129.7, 119.2, 77.8, 66.6, 32.9, 18.2 (Me), 18.0 (Me) ppm. IR
(solid state): ν˜ ϭ 1659 s (CϭNox), 1501 m, 1456 w, 1340 w, 1254
vs, 1185 vs, 1145 m, 1128 m, 1078 m, 1044 w, 1016 s, 935 m, 800
m, 759 m, 736 s, 691 m cmϪ1. MS: m/z (ESϩ): 846 (M3Hϩ(MeCN),
60%), 270 (MHϩ, 100). C12H15NO4S (269.32): calcd. C 53.5, H 5.6,
N 5.2; found C 53.6, H 5.6, N 5.1.
bonyl. Additionally, the unit cell of 10c contains methanol
crystallisation solvent but this could not be modelled in
terms of atomic sites. In CD3OD exchange of all the OH
and NH protons in 10 is attained within minutes and spec-
tra run in this solvent are devoid of signals due to these
hydrogens. Hydrogen bonding effects also engenders com-
pounds 10 to occlude other polar solvents unless strict an-
hydrous conditions are attained. For example, 10a, d and f
readily crystallise as mono or hemi hydrates; a reproducible
H2O signal at 1.9Ϫ2.0 ppm integrating to 1 or 2 H can be
1
detected in the H (dried CDCl3) NMR spectra of these
compounds in support of the analytical data. The forma-
tion of 10 can be most simply rationalised as an SN2 attack
of the amine R2NH2 on the methylene of the oxazoline
ring; the resulting fragmentation leading directly to the ob-
served products (Scheme 5). Attempted sulfonamide forma-
tion from 10 by its exposure to further equivalents of
R2NH2 (PhCl, 130 °C, 16 h) led only to the recovery of 10.
Compound 1a could also be prepared by direct reaction of 2-sul-
fobenzoic acid anhydride (1.50 g, 8.14 mmol) and -valinol (0.84 g,
8.14 mmol) in PhCl (50 mL) (DeanϪStark apparatus, reflux 17 h).
Evaporation of the PhCl under vacuum followed by recrystalli-
sation of the residue from anhydrous ethanol afforded 1.25Ϫ1.32 g
(55Ϫ60%). This alternative procedure was, however, ineffective for
compounds 1bϪe.
Conclusion
The rapid synthesis of oxazolinesulfonic acids 1 has been
demonstrated either through esters 2 or directly from 2-sul-
fobenzoic acid anhydride and N-Boc-protected amino al-
cohols. A useful displacement reaction of 1 or 2 has been
discovered allowing simple access into diverse 2-amido-di-
amine benzenesulfonicacids 10. The method is eminently
suitable for high throughput library synthesis, and investi-
gations into the usefulness and application of such com-
pounds in asymmetric catalysis is currently being under-
taken both in our group and in collaboration with others.
2-((S)-4-Isobutyl-4,5-dihydrooxazol-2-yl)benzenesulfonic Acid (1b):
Prepared from 2b (238 mg, 0.79 mmol), recrystallisation from
EtOH gave 1b (220 mg, 98%) as white crystals. M.p. 201Ϫ202 °C
(EtOH). [α]D ϭ Ϫ13.8 (c ϭ 1.0, EtOH). 1H NMR (400 MHz,
CD3OD): δ ϭ 8.18 (dd, 1 H, J ϭ 8.0, 1.0; Ar), 7.94 (dd, 1 H, J ϭ
8.0, 1.0; Ar), 7.88 (dt, 1 H, J ϭ 8.0, 1.0; Ar), 7.76 (dt, 1 H, J ϭ
8.0, 1.0; Ar), 5.33 (dd, 1 H, J ϭ 8.8, 7.8; OCH2α), 4.88 (dd, 1 H,
J ϭ 8.8, 7.0; OCH2β), 4.86Ϫ4.79 (m, 1 H, CHN), 1.99 (ddd, 1 H,
J ϭ 13.5, 7.6, 6.0), 1.88 (m, 1 H, CHMe2), 1.75 (ddd, 1 H, J ϭ
13.5, 7.9, 6.0), 1.07 (d, 3 H, J ϭ 6.5; Me), 1.06 (d, 3 H, J ϭ 6.5;
Me) ppm, H/D exchange in SO3H group with D from solvent. 13C
NMR (100 MHz, CD3OD): δ ϭ 174.8 (Cox), 147.1 (C), 136.2,
132.0, 131.8, 129.7, 119.4 (C), 80.0, 59.7, 43.6, 26.2, 23.0 (Me), 22.1
Experimental Section
General: Procedures involving moisture sensitive reagents or inter-
mediates were performed under atmospheres of argon or nitrogen (Me) ppm. IR (solid state): ν˜ ϭ 1651 s (CϭNox), 1497 w, 1451 w,
using standard Schlenk techniques. Tetrahydrofuran and Et2O were
distilled from sodium benzophenone ketyl. Other solvents were
1356 w, 1246 vs, 1190 vs, 1172 s, 1133 m, 1078 w, 1018 s, 939 m,
837 w, 792 m, 751 m, 737 s, 697 cmϪ1. MS: m/z (ESϩ): 284 (MHϩ,
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100%); found (HRMS): MHϩ 284.0982, C13H18NO4S requires quires 288.0906. Other compounds were formed in an analogous
FULL PAPER
284.0957.
manner. C12H17NO5S (287.33): calcd. C 50.2, H 6.0, N 4.9; found
C 50.3, H 6.0, N 4.8.
2-((S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl)benzenesulfonic Acid (1c):
Prepared from 2c (301 mg, 1.00 mmol), recrystallisation from
EtOH gave 1c (260 mg, 92%) as white crystals. M.p. Ͼ 240 °C (dec.,
EtOH). [α]D ϭ Ϫ23.1 (c ϭ 1.0, EtOH). 1H NMR (400 MHz,
CD3OD): δ ϭ 8.24 (dd, 1 H, J ϭ 7.7, 1.0; Ar), 8.07 (dd, 1 H, J ϭ
7.7, 1.0; Ar), 7.93 (dt, 1 H, J ϭ 7.7, 1.0; Ar), 7.78 (dt, 1 H, J ϭ
7.7, 1.0; Ar), 5.19 (dd, 1 H, J ϭ 10.4, 9.9; OCH2α), overlapped by
5.15 (dd, 1 H, J ϭ 9.9, 7.5; CHN), 4.60 (dd, 1 H, J ϭ 10.4, 7.5;
OCH2β), 1.14 (s, 9 H, tBu) ppm, H/D exchange in SO3H group
with D from solvent. 13C NMR (100 MHz, CD3OD): δ ϭ 174.4
(Cox), 147.1 (C), 136.9, 132.9, 132.1, 130.0, 118.8 (C), 76.0, 70.0,
35.1 (Bu), 25.2 (Bu) ppm. IR (solid state): ν˜ ϭ 1655 s (CϭNox),
1497 m, 1452 w, 1379 w, 1255 vs, 1180 vs, 1131 m, 1082 w, 1017 s,
928 w, 901 w, 749 s, 736 s, 687 cmϪ1. MS: m/z (ESϩ): 284 (MHϩ,
100%); found (HRMS): MHϩ 284.0967, C13H18NO4S requires
284.0957. C13H17NO4S (283.34): calcd. C 55.1, H 6.05, N 4.9;
found C 55.2, H 6.1, N 4.8.
(S)-2-Amino-4-methylpentyl 2-Sulfobenzoate (2b): Prepared from N-
Boc--leucinol (500 mg, 2.30 mmol), and 4 (422 mg, 2.30 mmol).
Purification by recrystallisation from MeCN gave 2b (470 mg, 68%)
as a white solid. M.p. 231Ϫ232 °C (MeCN). [α]D ϭ ϩ22.2 (c ϭ
1.0, EtOH). 1H NMR (400 MHz, CD3OD): δ ϭ 8.05 (dd, 1 H, J ϭ
7.0, 1.0; Ar), 7.67Ϫ7.57 (m, 3 H, Ar), 4.74 (dd, 1 H, J ϭ 12.2, 3.0;
OCH2α), 4.19 (dd, 1 H, J ϭ 12.2, 9.0; OCH2β), 3.75 (ddd, 1 H, J ϭ
9.0, 7.0, 3.0; CHN), 1.81 (sept, 1 H, J ϭ 7.0; CHMe2), 1.67Ϫ1.52
(m, 2 H, CHCH2iPr), 1.04 (d, 3 H, J ϭ 7.0; Me), 1.03 (d, 3 H, J ϭ
7.0; Me) ppm, H/D exchange in OH and NH2 groups with D from
solvent. 13C NMR (100 MHz, CD3OD): δ ϭ 169.8 (CO), 143.9,
132.2, 132.1, 131.7, 130.0, 129.0, 65.9 (CH2), 50.1 (CH), 39.2
(CH2), 25.6 (CH), 22.9 (CH3), 22.5 (CH3) ppm. IR (solid state):
ν˜ ϭ 1736 m (CϭOester), 1693 m, 1523 m, 1327 m, 1216 m, 1293 m,
1242 vs, 1228 s, 1188 s, 1175 vs, 1142 s, 1118 w, 1081s, 1017 vs, 754
vs cmϪ1. MS: m/z (ESϩ): 904 (M3Hϩ, 100%), 603 (M2Hϩ, 30), 302
(MHϩ, 30); found (HRMS): MHϩ 302.0994, C13H20NO5S requires
302.0984. C13H19NO5S (301.36): calcd. C 51.8, H 6.4, N 4.65;
found C 51.5, H 6.4, N 4.3.
2-((S)-4-Benzyl-4,5-dihydrooxazol-2-yl)benzenesulfonic Acid (1d):
Prepared from 2d (0.99 g, 2.96 mmol), recrystallisation from di-
chloromethane/light petroleum ether gave 1d (807 mg, 86%) as
white crystals. M.p. 190Ϫ191 °C (EtOH). [α]D ϭ Ϫ53.2 (c ϭ 1.0,
(S)-2-Amino-3,3-dimethylbutyl 2-Sulfobenzoate (2c): Prepared from
N-Boc--tert-leucinol (588 mg, 2.70 mmol), and
4 (496 mg,
1
EtOH). H NMR (400 MHz, CD3OD): δ ϭ 8.16 (d, 1 H, J ϭ 7.8,
2.70 mmol). Purification by recrystallisation from cold MeCN gave
2c (700 mg, 87%) as a white crystalline solid. M.p. 225Ϫ226 °C
(MeCN). [α]D ϭ Ϫ25.6 (c ϭ 1.0, CHCl3). 1H NMR (400 MHz,
CD3OD): δ ϭ 8.05 (dd, 1 H, J ϭ 7.0, 1.0; Ar), 7.65Ϫ7.59 (m, 3 H,
Ar), 4.89 (dd, 1 H, J ϭ 12.0, 3.0; OCH2α), 4.26 (dd, 1 H, J ϭ 12.0,
10.6; OCH2β), 3.49 (dd, 1 H, J ϭ 10.6, 3.0; CHN), 1.14 (s, 9 H,
tBu) ppm, H/D exchange in OH and NH2 groups with D from
solvent. 13C NMR (100 MHz, CD3OD): δ ϭ 169.8 (CO), 144.0,
132.1, 132.0, 131.6, 130.0, 129.0, 64.1 (CH2), 60.2 (CH), 33.1 (C),
26.6 (CH3) ppm. IR (solid state): ν˜ ϭ 2970 w, 1728s (CϭOester),
1633 w, 1528 m, 1303 w, 1280 s, 1245 vs, 1229 s, 1180 vs, 1171 vs,
1.0; Ar), 7.88 (dt, 1 H, J ϭ 7.8, 1.2; Ar), 7.79 (dd, 1 H, J ϭ 7.8,
1.0; Ar), 7.71 (dt, 1 H, J ϭ 7.8, 1.2; Ar), 7.42Ϫ7.34 (m, 5 H, Ar),
5.27 (apparent t, 1 H, J ϭ 12.1; OCH2α), 5.08Ϫ5.02 (m, 2 H,
OCH2β and CHN), 3.29 (dd, 1 H, J ϭ 13.9, 5.3; CH2αPh), 3.22
(dd, 1 H, J ϭ 13.9, 6.8; CH2βPh) ppm, H/D exchange in SO3H
group with D from solvent. 13C NMR (100 MHz, CD3OD): δ ϭ
175.4 (Cox), 146.7 (C), 136.3, 135.9, 131.7, 131.6, 130.7, 130.6,
129.6, 128.6, 119.4 (C), 79.0, 62.2, 40.0 ppm. IR (solid state): ν˜ ϭ
1653 s (CϭNox), 1574 w, 1499 s, 1454 m, 1345 w, 1255 vs, 1184 vs,
1146 m, 1130 m, 1020 s, 934 m, 786 m, 733 s, 699 s cmϪ1. MS:
m/z (ESϩ): 318 (MHϩ, 100%); found (HRMS): MHϩ 318.0746,
C16H15NSO4 requires 318.0742. C16H17NO5S (317.36): calcd. C
60.55, H 4.8, N 4.4; found C 60.15, H 4.65, N 4.3.
1147 s, 1118 w, 1109 s, 1082 vs, 1020 vs, 780 m, 758 s, 739 m cmϪ1
.
MS: m/z (ESϩ): 904 (M3Hϩ, 100%), 603 (M2Hϩ, 30), 302 (MHϩ,
30); found (FABϩ, HRMS): MHϩ 302.1081, C13H20NO5S requires
302.1062. C13H19NO5S (301.36): calcd. C 51.8, H 6.4, N 4.7; found
C 51.6, H 6.4, N 4.7.
Representative Procedure. (S)-2-Amino-3-methylbutyl 2-Sulfobenzo-
ate (2a): To a stirred solution of 2-sulfobenzoic acid cyclic anhy-
dride 4 (3.73 g, 20.3 mmol) in dry MeCN (40 mL) under inert at-
mosphere, was added N-Boc--valinol (4.12 g, 20.3 mmol) as a
solution in dry MeCN (10 mL). The reaction mixture was refluxed
for 8 h, a white insoluble precipitate being formed during the co-
urse of the reaction. The reaction mixture was allowed to cool to
room temperature and stirred overnight. The reaction was cooled
to 0 °C in the freezer for 12 h, the white insoluble product was
filtered off, washed with light petroleum ether then dried under
high vacuum to give 2a (3.91 g, 67%) as a white solid. An ad-
ditional experiment gave (1.68 g, 87%). M.p. 208Ϫ209 °C (EtOH).
[α]D ϭ ϩ36.3 (c ϭ 1.0, EtOH). 1H NMR (400 MHz, CD3OD): δ ϭ
8.05 (dt, 1 H, J ϭ 7.5, 1.0), 7.67Ϫ7.57 (m, 3 H), 4.80 (dd, 1 H, J ϭ
12.1, 3.0; OCH2α), 4.28 (dd, 1 H, J ϭ 12.1, 9.5; OCH2β), 3.47 (ddd,
1 H, J ϭ 9.5, 7.1, 3.0; CHN), 2.08 (d sept, 1 H, J ϭ 7.1, 6.9,
CHMe2), 1.33 (d, 3 H, J ϭ 6.9; Me), 1.14 (d, 3 H, J ϭ 6.9; Me)
ppm, H/D exchange in OH and NH2 groups with D from solvent.
13C NMR (100 MHz, CD3OD): δ ϭ 169.8 (CO), 144.0, 132.1,
132.0, 131.6, 130.0, 129.0, 64.7 (CH2), 57.1 (CH), 29.6 (CH), 19.1
(CH3), 18.8 (CH3) ppm. IR (KBr disc): ν˜ ϭ 3449 m, 3157 m, 2966
m, 1736 vs (CϭOester), 1618 m, 1519 s, 1300 s, 1243 s, 1226 s, 1198
m, 1179 s, 1122 m, 1082 s, 1017 s, 782 m, 762 m, 740 m, 662 m,
(S)-2-Amino-3-phenylpropyl 2-Sulfobenzoate (2d): Prepared from N-
Boc--phenylalaninol (2.01 g, 8.0 mmol), and 4 (1.47 g, 8.0 mmol).
Purification by recrystallisation from cold MeCN gave 2d (2.57 g,
96%) as a white powder. Subsequent recrystallisation from EtOH/
H2O gave 2d (1.69 g, 63%) as off-white crystals. M.p. 174Ϫ175 °C
(EtOH). [α]D ϭ ϩ40.0 (c ϭ 1.0, EtOH). 1H NMR (400 MHz,
CD3OD): δ ϭ 8.06 (d, 1 H, J ϭ 7.5; Ar), 7.66Ϫ7.56 (m, 3 H, Ar),
7.40Ϫ7.30 (m, 5 H, Ar), 4.63 (dd, 1 H, J ϭ 12.1, 2.9; OCH2α), 4.22
(dd, 1 H, J ϭ 12.1, 7.8; OCH2β), 3.94Ϫ3.88 (m, 1 H, CHN), 3.08
(apparent dd, 2 H, J ϭ 8.5, 4.5; CH2Ph) ppm, H/D exchange in
OH and NH2 groups with D from solvent. 13C NMR (67.8 MHz,
CD3OD): δ ϭ 169.6 (CO), 143.9, 136.4, 132.0, 131.9, 131.6, 130.3,
130.1, 130.0, 129.0, 128.6, 65.0 (CH2), 53.0 (CH), 36.3 (CH2) ppm.
IR (solid state): ν˜ ϭ 3489 w, 3288 w, 1751s (CϭOester), 1618 w,
1524 m, 1291 s, 1255 s, 1239 m, 1217 s, 1190 vs, 1145 m, 1124 s,
1081 s, 1018 s, 981 m, 788 m, 759 s, 788 m, 740 m, 720 w, 706 s
cmϪ1. MS: m/z (ESϩ): 671 (M2Hϩ, 40%), 336 (MHϩ, 100); found
(ESϩ, HRMS): MHϩ 336.0881, C16H18NO5S requires 336.0906].
C16H17NO5S·H2O (335.38): calcd. C 54.4, H 5.4, N 4.0; found C
54.0, H 5.3, N 3.8.
617 s cmϪ1. MS: m/z (ESϩ): 862 (M3Hϩ, 100%), 575 (M2Hϩ, 50), 2-Aminoethyl 2-Sulfobenzoate (2e): Prepared from N-Boc-ethanol-
288 (MHϩ, 10); found (HRMS): MHϩ 288.0923, C12H18NO5S re- amine (4.61 g, 28.6 mmol), and 4 (5.26 g, 28.6 mmol). Precipitated
Eur. J. Org. Chem. 2004, 4596Ϫ4605
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4601

R. I. Robinson, J. C. Stephens, S. M. Worden, A. J. Blake, C. Wilson, S. Woodward
FULL PAPER
directly from MeCN to give 2e (6.60 g, 94%) as a white solid. M.p.
Ͼ 250 °C (dec., MeCN). IR (solid state): ν˜ ϭ 3179 w, 1728s (Cϭ
CHN), 3.98 (ddd, 1 H, J ϭ 9.9, 7.5, 6.0; CHN), 2.82 (m, 1 H,
CHMe2), 2.22 (m, 1 H, CHMe2), 1.62 (d, 3 H, J ϭ 7.0; Me), 1.42
Oester), 1485 w, 1455 w, 1372 w, 1292 s, 1256 s, 1218 s, 1184 vs, 1143 (d, 3 H, J ϭ 7.0; Me), 1.38 (d, 3 H, J ϭ 7.0; Me), 1.08 (d, 3 H,
s, 1127 s, 1082 s, 1019 s, 985 m, 961 m, 790 m, 759 s, 743 s, 714 m
J ϭ 7.0; Me) ppm. IR (KBr disc): ν˜ ϭ 3462.6 m, 2964 m, 1624 vs
cmϪ1. MS: m/z (ESϩ): 246 (MHϩ, 100%). This compound was too (CϭN), 1487 m, 1388 s, 1290 vs, 1250 s, 1168 vs, 1131 s, 1066 m,
insoluble to give acceptable NMR spectra. C9H11NO5S (245.25):
calcd. C 44.1, H 4.5, N 5.7; found C 44.0, H 4.6, N 5.5.
1040 w, 1022 w, 974 vs, 771 s, 746 s, 697 m, 668 m, 627 m cmϪ1
MS: m/z 685 100%).
(ESϩ): (MHϩ(MeCN),
.
C24H28N2O8S2Pd·MeCN (684.09): calcd. C 45.7, H 4.6, N 6.1;
found C 45.5, H 4.5, N 6.1.
(S)-2-Aminopropyl 2-Sulfobenzoate (2f): Prepared from N-Boc--al-
aninol (1.05 g, 6.0 mmol), purification by recrystallisation from
MeCN gave 2f (930 mg, 60%) as a white solid. M.p. Ͼ 250 °C
(dec., MeCN). [α]D ϭ Ϫ22.7 (c ϭ 0.3, EtOH). 1H NMR (400 MHz,
CD3OD): δ ϭ 8.06 (dd, 1 H, J ϭ 7.0, 1.0; Ar), 7.65Ϫ7.59 (m, 3 H,
Ar), 4.68 (dd, 1 H, J ϭ 12.0, 3.0; OCH2α), 4.20 (dd, 1 H, J ϭ 12.0,
8.8; OCH2β), 3.79 (ddq, 1 H, J ϭ 8.8, 6.8, 3.0; CHN), 1.14 (d, 3
H, J ϭ 6.8; Me) ppm, H/D exchange in OH and NH2 groups with
D from solvent. 13C NMR (100 MHz, [D6]DMSO): δ ϭ 170.2
(CO), 140.3, 132.1, 132.0, 130.0, 129.2, 127.8, 66.9 (CH2), 46.9
(CH), 14.4 (CH3) ppm. IR (KBr disc): ν˜ ϭ 1733 s (CϭOester), 1626
w, 1506 w, 1390 w, 1320 m, 1286 m, 1255 s, 1227 vs, 1211 vs, 1197
vs, 1181 vs, 1146 s, 1110 s, 1081 vs, 1024 s, 1014 s, 977 m, 951 w,
843 w, 780 m, 767 s, 739 m cmϪ1. MS: m/z (ESϩ): 541 (M2Naϩ,
60%), 519 (M2Hϩ, 100), 260 (MHϩ, 10); found (HRMS): MHϩ
260.0604, C10H14NO5S requires 260.0593. C10H13NO5S (259.28):
calcd. C 46.3, H 5.05, N 5.4; found C 46.4, H 4.9; N 5.2.
Bis[2-{(4ЈS)-4Ј,5Ј-dihydro-4Ј-isopropyloxazolyl]phenylsulfonato]-
copper(II) (8): Copper() acetate (20 mg, 0.1 mmol) and 1a (30 mg,
0.1 mmol) were stirred in dry MeCN (3 mL) followed by the ad-
dition of distilled 2,6-lutidine (12.8 µL, 0.1 mmol). The reaction
mixture was refluxed at 90 °C for 2 h under an inert atmosphere.
The solvent was concentrated in vacuo, taken up into dichloro-
methane (2 mL) and carefully layered with light petroleum ether
(4 mL). Large dark blue crystals formed upon standing for 24 h.
The crystals were filtered, dried under high vacuum, to give 8
(46 mg; 80% yield). M.p. Ͼ 205 °C (dec., dichloromethane). IR
(solid state): ν˜ ϭ 1634 m (CϭN), 1385 m, 1288 s, 1250 m, 1170 vs,
1142 s, 1129 s, 1068 m, 1017 w, 987 s, 929 w, 772 m, 761 m, 746 s,
698 m cmϪ1. MS: m/z (ESϩ): 884 (L3Naϩ, 40%), 597 (L2Naϩ, 100),
288 (Lϩ, 70), Cu coordination not observed. C24H28N2O8S2Cu
(600.17): calcd. C 48.0, H 4.7, N 4.7; found C 48.4, H 4.9, N 4.4.
Sodium
2-[(2-{[(1E)-(2-Hydroxyphenyl)methylene]amino}ethoxy)-
Representative Preparation. 2-[(1S)-(Benzylaminomethyl)-2-methyl-
propylcarbamoyl]benzenesulfonic Acid (10a). Method A: To a solu-
tion of (S)-4-isopropyl-4,5-dihydrooxazol-2-yl)benzenesulfonic acid
(1a) (0.25 g, 0.93 mmol) in chlorobenzene (45 mL) was added ben-
zylamine (0.1 mL, 0.93 mmol). The reaction mixture was refluxed
using a DeanϪStark trap (10 mL capacity) at 130 °C for 16 h. The
reaction mixture was allowed to cool to room temperature and was
concentrated under vacuum to yield a crude off-white solid. Purifi-
cation by flash chromatography (dichloromethane/MeOH 5%) gave
10a (217 mg; 65%) as white microcrystalline solid with no further
purification required; data as Method B.
Method B: To a solution of 2a (0.16 g, 0.54 mmol) in chlorobenzene
(45 mL) was added benzylamine (59 µL, 0.54 mmol). The reaction
mixture was refluxed using a DeanϪStark trap (10 mL capacity) at
130 °C for 16 h. The reaction mixture was allowed to cool to room
temperature and was concentrated under reduced pressure to yield
an off-white crude solid. Purification by flash chromatography (di-
chloromethane/MeOH 5%) gave 10a (99 mg, 50%) as a white solid.
Rf ϭ 0.33 (dichloromethane/MeOH 5%). M.p. 156Ϫ158 °C (di-
chloromethane/MeOH). [α]D ϭ Ϫ32.7 (c ϭ 0.4, CHCl3). These
data were attained under rigorously anhydrous conditions, nor-
mally the hemi hydrate was isolated. 1H NMR (400 MHz, CDCl3):
δ ϭ 8.92 (br. signal, 1 H, SO3H or NHamine), 8.60 (br. signal, 1 H,
SO3H or NHamine), 8.09 (dd, 1 H, J ϭ 6.8, 2.3; Ar), 7.75 (d, 1 H,
J ϭ 9.5; CONH), 7.56Ϫ7.47 (m, 3 H, Ar), 7.40Ϫ7.37 (m, 2 H, Ar),
7.29Ϫ7.20 (m, 3 H, Ar), 4.30 (br. signal, 1 H, CHNH), 4.17 (appar-
ent s, 2 H, CH2Ph), 3.11 (apparent t, 1 H, J ϭ 12.6; CHCH2α), 2.98
carbonyl]benzenesulfonate (6): To a stirred suspension of NaH
(82 mg, 2.04 mmol) in anhydrous THF (5 mL) under an inert at-
mosphere was added 2e (500 mg; 2.04 mmol) at room temperature,
resulting in immediate H2 evolution. The reaction was stirred for a
further 20 min then salicylaldehyde (0.21 mL, 2.04 mmol) was ad-
ded in one portion. The reaction mixture turned yellow immedi-
ately, and was stirred for 48 h. The reaction was quenched by the
addition of MeOH ( 0.5 mL), and then concentrated under vacuum
to give a pale yellow solid. The crude material was taken up in hot
EtOAc ( 10 mL) and hot filtered to give 6 (680 mg, 90%) as a pale
yellow solid. M.p. 209 °C (EtOAc). 1H NMR (400 MHz, CD3OD):
δ ϭ 8.59 (s, 1 H, NCH), 8.02 (dd, 1 H, J ϭ 6.1, 0.8; Ar), 7.56 (dt,
1 H, J ϭ 6.9, 1.1; Ar), 7.48Ϫ7.29 (m, 5 H, Ar), 6.89Ϫ6.86 (m, 2
H, Ar), 4.65 (dt, 2 H, J ϭ 5.3, 3.0; CH2), 4.04 (dt, 2 H, J ϭ 5.9,
1.0; CH2) ppm, OH proton signal was not observed due to H/D
exchange with CD3OD. 13C NMR (100 MHz, CD3OD): δ ϭ 170.7
(COester), 169.2 (CHimine), 144.1 (C), 133.9, 133.2, 132.8 (C), 131.3,
131.2, 131.1, 129.1, 129.0, 120.0 (C), 119.4, 118.2, 66.1, 57.8 ppm.
IR (solid state): ν˜ ϭ 1739 s (CϭO), 1632 s (CϭN), 1500 w, 1461
w, 1286 s, 1230 s, 1197 vs, 1137 s, 1119 w, 1085 m, 1026 vs, 922 w,
757 vs, 735 m cmϪ1. MS: m/z (FABϩ): 394 (MNaϩ, 10%), 372
(MHϩ, 25), 329 (15), 307 (30), 289 (15), 176 (30), 154 (100), 137
(65), 107 (20), 91 (15), 77 (15), 57 (20); found (HRMS): MHϩ
372.0508, C16H15NO6SNa requires 372.0518.
Bis[2-{(4ЈS)-4Ј,5Ј-dihydro-4Ј-isopropyloxazolyl]phenylsulfonato]-
palladium(II) (7): Palladium() acetate (83.5 mg, 0.37 mmol) and 1a
(100 mg, 0.37 mmol) were refluxed at 90 °C in MeCN (7 mL) with
(dd, 1 H, J ϭ 12.6, 2.5; CHCH2β), 1.72 (oct, 1 H, J ϭ 6.7; CHMe2),
1
stirring. After 20 min the reaction mixture was allowed to cool to 0.83 (d, 3 H, J ϭ 6.7; Me), 0.80 (d, 3 H, J ϭ 6.7; Me). H NMR
room temperature slowly, followed by cooling to 0 °C for 12 h, The
resulting small yellow crystals were filtered to give 7 (150 mg, 7.64Ϫ7.60 (m, 4 H, Ar), 7.55 (m, 1 H, Ar), 7.47Ϫ7.45 (m, 3 H,
100%). M.p. Ͼ184 °C (dec., MeCN). 1H NMR (400 MHz, [D6]ace-
Ar), 4.34Ϫ4.29 (m, 1 H, NHCH), 4.33 (d, 2 H, J ϭ 2.0; CH2Ph),
tone): δ ϭ 8.29 (dd, 1 H, J ϭ 8.0, 1.0; Ar), 8.13Ϫ8.04 (m, 3 H, 3.37 (dd, 1 H, J ϭ 11.5, 2.5; CHCH2α), 3.21 (dd, 1 H, J ϭ 11.5,
Ar), 8.00 (dt, 1 H, J ϭ 8.0, 1.0; Ar), 7.93 (dd, 1 H, J ϭ 8.0, 1.0; 12.5; CHCH2β), 1.89 (oct, 1 H, J ϭ 7.0: CHMe2), 1.03 (d, 3 H,
Ar), 7.88 (dt, 1 H, J ϭ 8.0, 1.0; Ar), 7.81 (dt, 1 H, J ϭ 8.0, 1.0; J ϭ 7.0; Me), 1.02 (d, 3 H, J ϭ 7.0; Me) ppm, OH and NH proton
Ar), 5.08 (apparent t, 1 H, J ϭ 9.5 OCH2α), 4.97 (dd, 1 H, J ϭ
signals not observed due to H/D exchange with CD3OD. 13C NMR
10.4, 9.1; OCH2α), 4.92 (dd, 1 H, J ϭ 9.3, 6.0; OCH2β), 4.81 (dd, (100 MHz, CD3OD): δ ϭ 172.2 (COam), 142.8 (C), 135.7 (C), 132.3
1 H, J ϭ 9.1, 7.5; OCH2β), 4.37 (ddd, 1 H, J ϭ 10.4, 7.5, 6.0; (C), 132.0, 131.5, 131.4, 131.2, 130.7, 130.2, 130.1, 129.6, 128.5,
(400 MHz, CD3OD): δ ϭ 8.03 (dd, 1 H, J ϭ 7.0, 1.0; Ar),
4602
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4596Ϫ4605

Sulfonic Acid Libraries
FULL PAPER
53.2, 52.8, 51.5, 32.0 (CH), 19.8 (Me), 18.6 (Me) ppm. IR (solid
(400 MHz, CDCl3): δ ϭ 8.80 (br. d, 2 H, SO3H and NH), 8.06 (dd,
state): ν˜ ϭ 2966 w, 1653 s (CϭOam), 1594 w, 1557 m, 1458 m, 1319 1 H, J ϭ 6.0, 1.0; Ar), 7.65 (d, 1 H, J ϭ 9.0; SO2NH), 7.50 (dt, 1
w, 1241 s, 1172 vs, 1140 vs, 1081 s, 1056 w, 1033 m, 1017 vs, 830 H, J ϭ 1.5, 7.5; Ar) overlapped by 7.46 (dt, 1 H, J ϭ 1.4, 7.4; Ar),
w, 753 vs, 741 vs, 729 vs, 699 vs cmϪ1. MS: m/z (FABϩ): 399
7.32 (dd, 1 H, J ϭ 7.4, 1.4; Ar), 7.26Ϫ7.12 (m, 7 H, Ar), 7.04Ϫ7.02
(MNaϩ, 15%), 377 (MHϩ, 90%), 307 (20), 154 (100), 136 (75), 120 (m, 2 H, J ϭ 6.0, 1.0; Ar), 4.67 (br. signal, 1 H, CONHCH), 4.05
(25), 107 (30), 91 (55), 83 (40), 69 (95), 57 (90); found (HRMS): (apparent s, 2 H, NHCH2Ph), 3.07 (br. t, 1H J 11.8; CHCH2αNH),
MHϩ 377.1519, C19H25N2O4S requires 377.1535. C19H24N2O4S 2.89 (br. d, 1 H, J 11.8; CHCH2βNH), 2.76 (dd, 1 H, J ϭ 13.8,
(376.47): calcd. C 60.6, H 6.4, N 7.4; found C 60.2, H 6.4, N 7.1.
7.9; CHCH2αPh), 2.70 (dd, 1 H, J ϭ 13.8, 7.4; CHCH2βPh) ppm.
13C NMR (67.8 MHz, CD3OD): δ ϭ 171.9 (COam), 142.8, 138.3,
135.7, 132.2, 131.8, 131.5 (2C), 131.1, 130.6 (2C), 130.3 (2C), 130.1
(2C), 129.7, 129.1, 128.5, 128.0, 52.6 (CH2), 52.3 (CH2), 49.6 (CH),
39.2 (CH2) ppm. The DEPT spectrum confirms the overlap of the
CH resonance with the solvent. IR (solid state): ν˜ ϭ 2359 w, 1651s
(CϭOam), 1627 m, 1593 w, 1546 s, 1497 w, 1454 m, 1312 w, 1250
vs, 1211 s, 1162 vs, 1138 s, 1081 m, 1018 vs, 869 w, 753 s, 744 vs,
727 m, 699 vs cmϪ1. MS: m/z (FABϩ): 425 (MHϩ, 30%), 307 (25),
289 (15), 154 (100), 136 (75), 107 (25), 91 (30), 77 (25), 69 (25),
57 (35); found (HRMS): MHϩ 425.1544, C23H25N2O4S requires
425.1535. C23H24N2O4S·1/2H2O (433.52): calcd. C 63.7, H 5.8, N
6.5; found C 63.5, H 5.55, N 6.3.
2-[(1S)-(Benzylaminomethyl)-3-methylbutylcarbamoyl]-
benzenesulfonic Acid (10b): Procedure as for 10a, method A. Purifi-
cation by flash chromatography (dichloromethane/MeOH 5%) gave
10b (164 mg, 78%) as a viscous oil (which solidified on prolonged
drying) from 1b (153 mg, 0.54 mmol) and benzylamine (59 µL,
0.54 mmol). Rf
ϭ 0.35 (dichloromethane/MeOH 5%). M.p.
267Ϫ269 °C (dichloromethane/MeOH 5%). [α]D ϭ Ϫ27.6 (c ϭ 1.0,
CHCl3). 1H NMR (500 MHz, CD3OD): δ ϭ 7.96Ϫ7.99 (m, 1 H,
Ar), 7.53Ϫ7.58 (m, 4 H, Ar), 7.39Ϫ7.45 (m, 5 H, Ar), 4.55 (m, 1
H, CHNH), 4.28 (apparent s, 2 H, CH2Ph), 3.18 (dd, 1 H, J ϭ
12.7, 2.9; CHCH2αNH), 3.11 (dd,
1 H, J ϭ 10.9, 12.7;
CHCH2βNH), 1.70 (m, 1 H, CHMe2), 1.51 (m, 1 H, CHCH2αCH),
1.28 (m, 1 H, CHCH2βCH), 0.98 (d, 3 H, J ϭ 6.7; Me), 0.94 (d, 3
H, J ϭ 6.7; Me) ppm, OH and NH proton signals not observed
due to H/D exchange with CD3OD. 13C NMR (100 MHz,
CD3OD): δ ϭ 172.2 (COam), 142.8 (C), 135.8 (C), 132.2 (C), 131.8
(2C), 131.4, 130.9, 130.5 (2C), 130.1, 129.1, 128.5, 53.6, 52.7, 46.2,
41.9, 26.0 (CH), 23.4 (Me), 22.0 (Me) ppm. IR (solid state): ν˜ ϭ
2957 w, 1662 w, 1631s (CϭOam), 1537 m, 1453 m, 1252 s, 1168 s,
1142 s, 1080 m, 1017 s, 747 s, 756 s, 700 s cmϪ1. MS: m/z (FABϩ):
391 (MHϩ, 16%), 176 (29), 155 (25), 154 (86), 136 (70), 97 (40),
69 (76), 57 (100); found (HRMS): MHϩ 391.1704, C20H27N2O4S
requires 391.1692. C20H26N2O4S (390.50): calcd. C 61.5, H 6.7, N
7.2; found C 61.4, H 6.8, N 7.2.
2-{2-Methyl-(1S)-[((1R)-phenylethylamino)methyl]propylcarb-
amoyl}benzenesulfonic Acid (10e): Procedure as in 10a, method A.
Purification by flash chromatography (dichloromethane/MeOH
5%) gave 10e (156 mg, 73%) from 1a (148 mg, 0.55 mmol) and
(1R)-phenylethylamine (71 µL, 0.55 mmol) as a viscous oil. Rf ϭ
0.40 (dichloromethane/MeOH 5%). [α]D ϭ Ϫ42.0 (c ϭ 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ ϭ 9.18 (br. s, 1 H, SO3H or
NHamine), 8.89 (br. s, 1 H, SO3H or NHamine), 8.17Ϫ8.14 (m, 1 H,
Ar), 8.04 (d, 1 H, J ϭ 9.0; CONH), 7.72Ϫ7.70 (m, 1 H, Ar),
7.75Ϫ7.55 (m, 4 H, Ar), 7.44Ϫ7.39 (m, 3 H, Ar), 4.62 (br. q, J 6.5,
1 H, NHCHPh), 4.43 (br. s, 1 H, NHCHiPr), 3.13 (br. t, J 12.4, 1
H, CHCH2α), 2.86 (br. d, J 12.4, 1 H, CHCH2β), 1.73 (d, 3 H, J ϭ
6.8; CH(Ph)Me] 1.66 (oct, 1 H, J ϭ 6.8; CHMe2), 0.82 (d, 3 H,
J ϭ 6.8; Me), 0.77 (d, 3 H, J ϭ 6.8; Me) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 169.5 (COam), 141.3 (C), 135.6 (C), 133.9 (C), 130.9,
130.4, 129.8, 129.6, 129.5, 127.9, 127.5, 57.8, 50.4, 46.9, 31.0, 20.7,
19.1 (Me), 18.2 (Me) ppm. IR (solid state): ν˜ ϭ 2969 w, 1652 m
(CϭOam), 1594 w, 1556 m, 1456 m, 1318 w, 1241 s, 1174 vs, 1140
s, 1080 s, 1016 vs, 782 w, 762 s, 735 s, 702 vs cmϪ1. MS: m/z (ESϩ):
781 (M2Hϩ, 100%), 391 (MHϩ, 50); found (HRMS): MHϩ
391.1656, C20H27N2SO4 requires 391.1691.
2-(2-Methyl-(1S)-{[(naphthalen-2-ylmethyl)amino]methyl}-
propylcarbamoyl)benzenesulfonic Acid (10c): Procedure as for 10a,
method A. Purification by flash chromatography (dichlorometh-
ane/MeOH 5%) gave 10c (134 mg, 82%) as a viscous oil from 1a
(102 mg, 0.38 mmol) and 1-naphthylenemethylamine (56 µL,
0.38 mmol). Rf
ϭ 0.37 (dichloromethane/MeOH 5%). M.p.
1
286Ϫ288 °C (MeOH). [α]D ϭ Ϫ34.3 (c ϭ 0.5, CHCl3). H NMR
(400 MHz, CD3OD): δ ϭ 8.26 (dd, 1 H, J ϭ 8.5, 1.0; Ar),
8.06Ϫ7.98 (m, 3 H, Ar), 7.69 (dd, 1 H, J ϭ 7.0, 1.0; Ar), 7.69 (dt,
1 H, J ϭ 7.0, 1.0; Ar), 7.63Ϫ7.54 (m, 5 H, Ar), 4.89 (s, 2 H,
CH2Ph), 4.39 (m, 1 H, CHNH), 3.47 (dd, 1 H, J ϭ 13.0, 2.5;
CHCH2α), 3.32 (dd, 1 H, J ϭ 13.0, 11.5; CHCH2β), 1.90 (oct, 1 H,
J ϭ 7.0; CHMe2), 1.03 (d, 3 H, J ϭ 7.0; Me), 1.01 (d, 3 H, J ϭ
7.0; Me) ppm, OH and NH proton signals not observed due to H/
D exchange with CD3OD. 13C NMR (100 MHz, CD3OD): δ ϭ
172.2 (COam), 142.7 (C), 135.7 (C), 135.3, 132.8, 132.0, 131.4,
131.1, 130.7, 130.0, 129.6, 128.5, 128.3, 128.1, 127.4, 126.5, 124.1,
54.8, 53.0, 32.0, 19.7 (CH3), 18.5 (CH3) ppm. IR (solid state): ν˜ ϭ
2967 w, 1655 m (CϭOam), 1595 m, 1560 m, 1459 m, 1229 m, 1164
2-{3-Methyl-(1S)-[((1R)-1-phenylethylamino)methyl]butyl-
carbamoyl}benzenesulfonic Acid (10f): Procedure as in 10a, method
A. Purification by flash chromatography (dichloromethane/MeOH
5%) gave 10f (189 mg, 75%) as a viscous oil from 1b (0.81 g,
2.85 mmol) and (1R)-phenylethylamine (367 µL, 2.85 mmol). Rf ϭ
0.40 (dichloromethane/MeOH 5%). [α]D ϭ Ϫ40.0 (c ϭ 0.1, CHCl3).
1H NMR (400 MHz, CDCl3): δ ϭ 9.23 (br. s, 1 H, SO3H or
NHamine), 8.91 (br. s, 1 H, SO3H or NHamine), 8.14 (dd, 1 H, J ϭ
7.0, 1.5; Ar), 7.89 (d, 1 H, J ϭ 9.0; CONH), 7.67 (dd, 1 H, J ϭ
7.0, 1.5; Ar), 7.58Ϫ7.53 (m, 4 H, Ar), 7.43Ϫ7.41 (m, 3 H, Ar), 4.66
(br. q, J 7, 1 H, CH(Ph)Me]; overlapped by (br. s, 1 H, CONHCH),
3.08 (t, 1 H, J ϭ 12.0; CHCH2αNH), 2.79 (d, 1 H, J ϭ 12.0;
CHCH2βNH), 1.75 (d, 3 H, J ϭ 7.0; CH(Ph)Me]; 1.57Ϫ1.48 (m,
1 H, CHMe2), 1.44Ϫ1.34 (m, 1 H, CHCH2αCH), 1.10 (m, 1 H,
CHCH2βCH), 0.87 (d, 3 H, J ϭ 6.9; Me), 0.80 (d, 3 H, J ϭ 6.9;
Me) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 169.3 (COam), 141.3
(C), 135.7 (C), 134.0 (C), 130.8, 130.2, 130.1, 129.6, 129.5, 127.8,
s, 1141 m, 1082 m, 1018 s, 802 m, 799 s, 790 s, 774 s, 738 s cmϪ1
.
MS: m/z (FABϩ): 427 (MHϩ, 5%), 391 (5), 329 9 (7), 307 (40), 289
(15), 176 (10), 154 (100), 137 (65), 120 (10), 107 (20), 91 (12), 77
(15), 57 (20); found (HRMS): MHϩ 427.1719, C23H27N2O4S re-
quires 427.1692.
2-[(1S)-Benzyl-2-benzylaminoethylcarbamoyl]benzenesulfonic Acid
(10d): Procedure as in 10a, method A. Purification by flash chro-
matography (dichloromethane/MeOH 5%) gave 10d (125 mg, 74%) 127.5, 58.2, 49.1, 44.0, 41.9, 24.8, 22.7 (CH3), 22.0 (CH3), 20.7
as a white solid from 1d (127 mg, 0.40 mmol) and benzylamine (59 (CH3) ppm. IR (solid state): ν˜ ϭ 2959 w, 1653 m (COam), 1595 w,
µL, 0.40 mmol). Rf ϭ 0.3 (dichloromethane/MeOH 5%). M.p. 1548 m, 1457 m, 1387 w, 1305 w, 1235 s, 1174 vs, 1140 s, 1082 s,
1
107Ϫ109 °C (MeOH). [α]D ϭ Ϫ44.0 (c ϭ 0.35, CHCl3). H NMR
1017 vs, 850 w, 758 vs, 743 s, 702 vs, 692 s cmϪ1. MS: m/z (FABϩ):
Eur. J. Org. Chem. 2004, 4596Ϫ4605
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4603

R. I. Robinson, J. C. Stephens, S. M. Worden, A. J. Blake, C. Wilson, S. Woodward
FULL PAPER
427 (MNaϩ, 55%), 405 (MHϩ, 100), 307 (25), 169 (25), 154 (95), Geometrically refined hydrogen atoms were refined as part of a
136 (75), 120 (20), 105 (55), 89 (20), 77 (25), 69 (20), 57 (35), 55 riding model, with the hydrogen atoms assigned isotropic displace-
(30); found (HRMS): MHϩ 405.1852, C21H29N2O4S requires ment parameters 1.2 times the parent atom Ueq, except the methyl
405.1848. C21H28N2O4S·H2O (422.54): calcd. C 59.7, H 7.2, N 6.6;
found C 60.15, H 6.8, N 6.8.
atoms where it was 1.5 times. Suitable geometric constraints were
applied to all disorder models. In both 8 and 10c a solvent region
could not be satisfactorily modelled in terms of atomic sites and
the electron density in this region was calculated and accounted for
using the SQUEEZE procedure.[19] Neutral atom scattering factors
and anomalous dispersion corrections were taken from the Inter-
national Tables for Crystallography.[20] Crystallographic data are
summarised in Table 1.
X-ray Crystallographic Studies: Crystals of 1a and 2a, were grown
from EtOH, those of 7 and 8 from MeCN, that of 10c from
[D4]MeOH. X-ray diffraction data were collected on SMART[15]
area detector diffractometers (APEX and SMART1000), using
˚
graphite-monochromated Mo-Kα radiation (λ ϭ 0.71073 A).
SAINT[15] software was used to integrate the data sets and apply
the Lorentz and polarisation corrections. An absorption and inci-
dent beam decay correction was performed using SADABS for
complexes 7 and 8.[16] No absorption or decay correction was made
for species 1a, 2a and 10c. The structures were solved by direct
methods using SHELXS-97.[17] The structures were refined on F2
using full-matrix least-squares (SHELXL-97).[18] Unless otherwise
stated, all fully occupied non-hydrogen atoms were refined with
anisotropic displacement parameters. Hydrogen atoms were placed
in geometrically calculated positions except those of the MeCN
molecules in 7 and the NH3 and methyl hydrogens in compounds
2a and 1a, which were all located by difference Fourier synthesis.
CCDC-246699 to -246703 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from
the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: ϩ44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgments
We acknowledge generous support of the European Commission
through project FP6Ϫ505267Ϫ1 (LIGBANK) and the COST-D24
Table 1. Crystal structure data of compounds 1a, 2a, 7, 8, 10c
1a
2a
7
8
10c
formula
Mw
C12H15NO4S
269.31
C12H17NO5S
287.33
monoclinic
P21
8.7089(12)
12.666(2)
12.559(2)
90
107.374(2)
90
1322.2(6)
4
1.443
0.26
608
C26H31N3O8PdS2
684.06
monoclinic
P21
8.1006(5)
16.6538(10)
10.9452(7)
90
104.939(1)
90
1426.79(3)
2
1.592
0.85
700
C26H32Cl4CuN2O8S2 C24H29N2O5S
770.00
hexagonal
P61
19.2656(14)
457.55
orthorhombic
P212121
10.520(3)
12.047(4)
20.267(6)
90
crystal system
space group
orthorhombic
P212121
8.1800(9)
10.575(1)
14.683(2)
90
90
90
1270.2(4)
4
1.408
˚
a (A)
˚
b (A)
Ϫ
˚
c (A)
15.1909(16)
90
α (°)
β (°)
γ (°)
90
90
120
90
3
˚
V (A )
4882.9(7)
6
2568(2)
4
Z
ρcalcd. [g cmϪ3
absorption coefficient [mmϪ1
F(000)
]
1.571
1.183
]
0.261
568
1.18
0.16
2370
972
crystal size (mm)
Data collection
T [K]
0.31ϫ0.20ϫ0.18
0.52ϫ0.24ϫ0.12
0.54ϫ0.32ϫ0.24
0.40ϫ0.12ϫ0.10
0.58ϫ0.30ϫ0.19
150(2)
2.4Ϫ28.8
ω
150(2)
2.3 Ϫ28.8
ω
150(2)
1.9 Ϫ28.6
ω
150(2)
2.4 Ϫ28.9
ω
150(2)
2.2Ϫ26.4
ω
θminϪθmax (°)
scan type
h, k, l ranges
Ϫ10 to 7, Ϫ10 to 14, Ϫ11 to 11, Ϫ17 to 14, Ϫ10 to 10, Ϫ21 to 22, Ϫ25 to 7, Ϫ21 to 22, Ϫ13 to 13, Ϫ15 to 14,
Ϫ19 to 12
8010
Ϫ7 to 16
7361
Ϫ14 to 12
11281
Ϫ20 to 19
14314
Ϫ25 to 25
19909
total reflections collected
independent reflections
reflections with I Ͼ 2σ(I)
absorption correction
2803 (Rint ϭ 0.0635) 5306 (Rint ϭ 0.038)
6231 (Rint ϭ 0.014)
6149
Tmin. ϭ 0.653
Tmax. ϭ 0.801
7458 (Rint ϭ 0.052)
4693
Tmin. ϭ 0.716
Tmax. ϭ 1.000
5264 (Rint ϭ 0.039)
4802
none
2327
none
4500
none
Refinement
data/restraints/parameters
final R indices [I Ͼ 2σ(I)]
2803/0/164
R1 ϭ 0.064,
wR2 ϭ 0.156
R1 ϭ 0.0751,
wR2 ϭ 0.01624
1.01
0.03(13)
0.001
0.86 /Ϫ0.97
5293/1/349
R1 ϭ 0.036,
wR2 ϭ 0.082
R1 ϭ 0.0443,
wR2 ϭ 0.0852
0.96
Ϫ0.03(7)
0.001
0.33 /Ϫ0.43
6231/1/363
R1 ϭ 0.018,
wR2 ϭ 0.047
R1 ϭ 0.0179,
wR2 ϭ 0.0471
1.05
0.005(12)
0.001
0.35 /Ϫ0.29
7458/14/342
R1 ϭ 0.051
wR2 ϭ 0.091
R1 ϭ 0.089
wR2 ϭ 0.100
1.02
0.020(15)
0.001
0.33/Ϫ0.41
5227/0/272
R1 ϭ 0.057
wR2 ϭ 0.150
R1 ϭ 0.061
wR2 ϭ 0.152
1.11
0.03(11)
0.001
0.29/Ϫ0.29
final R indices (all data)
goodness-of-fit on F2
absolute structure parameter
final (∆/σ)max
Ϫ3
˚
largest diff. peak and hole (e·A
)
4604
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4596Ϫ4605

Sulfonic Acid Libraries
FULL PAPER
Inspection of the CSD database (www.ccdc.cam.ac.uk) reveals
the structures BEYZIO, BEYZIO01/02, OTANAC and RAT-
BOD to be of relevance.
A. A. D. Tulloch, S. Winston, A. A. Danopoulos, G. Eastham,
M. B. Hursthouse, Dalton Trans. 2003, 699Ϫ708.
For example, structures ADUREW, WABXUS and XABPEN
from the CSD database (www.ccdc.cam.ac.uk) show CuϪO
distances in the range 2.386Ϫ2.471, and CuϪOϪS angles
covering 126.33Ϫ173.04°.
Alternative preparations relying on activation of ArSO3H
groups through SOCl2, (COCl)2/DMF or POCl3 were not suc-
cessful in our case due to the presence of the wrong tautomeric
form of the oxazolinesulfonic acid 1.
R. I. Robinson, S. Woodward, unpublished work, see sup-
plementary data for this paper (13C NMR spectra for com-
pounds 1, 2, 6Ϫ11).
R. I. Robinson, Ph. D. Thesis, The University of Not-
tingham, 2003.
D. A. Quagliato, P. M. Andrae, E. M. Matelan, J. Org. Chem.
2000, 65, 5037Ϫ5042.
All oxazolinesulfonic acids could be recrystallised using anhy-
drous ethanol, apart from 2-((S)-4-benzyl-4,5-dihydrooxazol-2-
yl)benzenesulfonic acid (1d).
[7]
programme. One of us (RIR) is grateful to the EPSRC for the
award of a studentship.
[8]
[9]
[1]
[2]
[3]
[1a]
Overviews of library preparations:
Handbook of Combina-
torial Chemistry (Eds.: K. C. Nicolaou, R. Hanko, W. Hart-
wig), vol. 1Ϫ2, Wiley-VCH, Weinheim, 2002. [1b]C. Gennari,
U. Piarulli, Chem. Rev. 2003, 103, 3071Ϫ3100. [1c] A. Lee, J. G.
Breitenbucher, Current Opinion in Drug Discovery and Develop-
ment 2003, 6, 494Ϫ508.
Pharmaceutical applications of sulfonamides:
[10]
[11]
[2a]
C. T. Supu-
ran, A. Innocenti, A. Mastrolorenzo, A. Scozzafava, Mini-Re-
views in Medicinal Chemistry 2004, 4, 189Ϫ200. [2b] C. T. Supu-
ran, A. Casini, A. Scozzafava, Med. Res. Rev. 2003, 23,
[2c]
535Ϫ558.
A. Scozzafava, T. Owa, A. Mastrolorenzo, C. T.
Supuran, Cur. Med. Chem. 2003, 10, 925Ϫ953.
Sulfonamides in selective catalysis:
[3a]
[12]
[13]
[14]
F. Lake, C. Moberg,
[3b]
Russ. J. Org. Chem. 2003, 39, 436Ϫ452.
P. J. Walsh, Acc.
[3c]
Chem. Res. 2003, 36, 739Ϫ749.
J. Zhang, H.-B. Zhou, R.-
G. Xie, Cur. Org. Chem. 2002, 6, 865Ϫ890.
[4] [4a]
H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003,
8, 1128Ϫ1137. [4b]H. C. Kolb, M. G. Finn, K. B. Sharpless,
Angew. Chem. Int. Ed. 2001, 40, 2004Ϫ2021; H. C. Kolb, M.
G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113, 2056Ϫ2075.
[15]
[16]
[17]
[18]
[19]
[20]
SMART and SAINT Area-Detector Control and Integration
Software, Bruker AXS, Madison, 1997.
[5] [5a]
H. Moehrke, H. Koch, H. von Freyberg, German Patent
1953, DE 865305 (Farberke Hoechst AG, Meister Lucius and
G. M. Sheldrick, SADABS: Program for Scaling and Correction
of Area Detector Data, University of Göttingen, 1996.
G. M. Sheldrick, SHELXS-97: Program for the Solution of
Crystal Structures, University of Göttingen, 1997.
G. M. Sheldrick, SHELXL-97: Program for the Refinement of
Crystal Structures, University of Göttingen, 1997.
P. v.d. Sluis, A. L. Spek, Acta Crystallogr., Sect. A 1990, 46,
194Ϫ201.
Bruning) [Chem. Abstr. 1958, 52, 113808]. [5b]J. R. Ashby, E.
M. Ramage, J. Heterocycl. Chem. 1978, 15, 1501Ϫ1502.
[5c]
A.
D. Wolf, M. P. Rorer, Eur. Pat. Appl. 1983, EP 83975 A2
19830720 (du Pont de Nemours) [Chem. Abstr. 1983, 99,
175812].
For example, 2-phenyl-4,5-dihydrooxazole in the presence of
concentrated aqueous HCl reportedly undergoes ring opening
to form N-(2-chloroethyl)benzamide. See: R. Gabriel, M. Hey-
mann, Ber. Dtsch. Chem. Ges. 1890, 23, 2502; B. Goldberg, F.
Kelly, J. Chem. Soc. 1948, 1919Ϫ1925.
[6]
International Tables for Crystallography, vol. C (Ed.: A. J. C.
Wilson), Kluwer Academic, Dordrecht, 1992.
Received August 6, 2004
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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