On the Reaction of Some Saccharin Derivatives with Hydrazine and Other Nucleophils

Article abstract of DOI:10.1007/s00706-002-0531-6

The reaction of methyl saccharin-2-acetate with hydrazine gave no 3-hydrazino derivative of saccharin as reported in literature, but yielded with ring opening the benzohydrazide derivative. The analogue reaction was observed when saccharin-2-(2-propionate) was reacted with hydrazine. Furthermore, using an excess of hydrazine, the ester group was transformed into the carbohydrazide too. All hydrazides were fully characterized as hydrazones by reactions with different ketones. The 3-thioxo compounds were prepared by reactions with P ₂S₅, but the yield was improved by using Lawesson's reagent. No attack at the ester group was observed. Finally, reactions of the saccharin-2-carboxylate with some amino acids gave substituted benzamides by attack at position 3 and ring opening. In none of the reactions of the saccharin derivatives with nitrogen nucleophiles a formal substitution of the 3-oxo group was observed.

Full text of DOI:10.1007/s00706-002-0531-6

Monatshefte f€ur Chemie 134, 901–908 (2003)
DOI 10.1007/s00706-002-0531-6
On the Reaction of Some Saccharin
Derivatives with Hydrazine
and Other Nucleophils
ꢀ
Danuta Jarecka, Anita Besch, and Hans-Hartwig Otto
Pharmaceutical=Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, D-17487
Greifswald, Germany
Received July 4, 2002; accepted August 1, 2002
Published online February 20, 2003 # Springer-Verlag 2003
Summary. The reaction of methyl saccharin-2-acetate with hydrazine gave no 3-hydrazino derivative of
saccharin as reported in literature, but yielded with ring opening the benzohydrazide derivative. The
analogue reaction was observed when saccharin-2-(2-propionate) was reacted with hydrazine. Further-
more, using an excess of hydrazine, the ester group was transformed into the carbohydrazide too. All
hydrazides were fully characterized as hydrazones by reactions with different ketones. The 3-thioxo
compounds were prepared by reactions with P2S5, but the yield was improved by using Lawesson’s
reagent. No attack at the ester group was observed. Finally, reactions of the saccharin-2-carboxylate with
some amino acids gave substituted benzamides by attack at position 3 and ring opening. In none of the
reactions of the saccharin derivatives with nitrogen nucleophiles a formal substitution of the 3-oxo group
was observed.
Keywords. Saccharin derivatives; Hydrazine; Lawesson’s reagent; Amino acids.
Introduction
3-Oxo-2,3-dihydrobenz[d]isothiazole 1,1,dioxide (1, saccharin), first prepared by
Remsen and Fahlberg in 1879 [1] is not only used as a sweetener [2]. As a reactive
bicyclic system it is intensely modified and transformed [3]. Furthermore, some of
its derivatives show interesting pharmacological properties [4]. The reaction of the
saccharin derivative 2a with hydrazine hydrate is described in literature [5], result-
ing in the replacement of the oxygen in position 3 of the saccharin ring by the
hydrazino group. As we could not confirm this reaction, we decided to study the
reaction between saccharin derivatives 2a and 2b and nucleophils, especially
hydrazine hydrate, more in detail.
ꢀ
Corresponding author. E-mail: ottohh@pharmazie.uni-greifswald.de

902
D. Jarecka et al.
Results and Discussion
The derivative 2a was prepared from saccharin sodium and methyl chloroacetate [6],
and the propionate 2b was obtained by an analogue reaction with methyl (RS)-2-
chloropropionate [7]. When 2a was reacted with hydrazine hydrate in EtOH at room
temperature as described in [5] we indeed obtained a viscous mass showing a single
spot on TLC, which could not be crystallized from any solvent. An analogous result
was obtained from 2b. But, confirmed by all spectral and analytical data, these
compounds do not show the structure 3 of a 3-hydrazino saccharin but the benzohy-
drazide structure 4. MS spectra show molecular peaks at m=z ¼ 287 (4a) and 301
(4b). The calculated values for structure 3 are 269 and 283.
The IR spectra of 2 show carbonyl absorptions around ꢀꢀ ¼ 1760 and
1738 cmÀ 1, caused by C¼O (position 3) and the ester group, while structures 4
even show two carbonyl absorptions each, one around ꢀꢀ ¼ 1740 cmÀ1 from the ester
group, and the other around ꢀꢀ ¼ 1650 cmÀ1 characterizing the carbohydrazide
structure. 1H NMR data and UV spectra support this structure 4.
Furthermore, when compounds 2 were refluxed with the double amount of
hydrazine hydrate in EtOH the bishydrazides 5a and 5b were isolated. Identical
compounds were obtained from 4a and 4b by refluxing with an excess of hydrazine
hydrate. The bishydrazone 6 was obtained from the reaction between 5a and ace-
tone. This reaction clearly supports the structure of 5a. Analogous results were
obtained when we reacted 4a with a number of ketones. The IR spectra of all isolated
compounds 7 show strong carbonyl absorptions of the ester groups at
ꢀꢀ¼ 1747–1753 cmÀ 1, the amide group gives a strong band at ꢀꢀ¼ 1651–
1665 cmÀ 1, and the imine structure (C¼N) is detected even by a strong absorption
1
band at ꢀꢀ¼ 1630–1634 cmÀ 1. H NMR spectra and HPLC experiments demon-
strate that 7b and 7c were obtained as mixtures of (E)- and (Z)-isomer. From the
1H NMR spectrum of 7c we deduce a ratio (Z) : (E) ¼ 1 : 1.3.
In accordance with Ref. [5] we prepared the thioxo compound 8a from 2a by
the reaction with phosphorous pentasulfide [8] in 1,4-dioxane. Compound 8b was
obtained by an analogous synthesis, but we found that the transformation into the
thioxo compound is much better done and giving higher yields using Lawesson’s
reagent. Derivatives 8a and 8b are nice yellow crystals, and their IR spectra show
that only in the saccharin moiety the carbonyl group has reacted with the sulfur
reagent. The ester group was not attacked. In the 13C NMR spectrum we find the
expected signal of the C¼S group at ꢁ ¼ 184.6 ppm, and the signal of the ester
carbonyl group at ꢁ ¼ 167.9 ppm.
Finally, we prepared methyl saccharin-2-carboxylate 9 [4], and reacted it with
some amino acids in a saturated solution of sodium hydrogen carbonate yielding
the N-acylated amino acids 10a–10d.
From HPLC experiments with a Chiracel OJ-R column it could be deduced that
in all reactions only one defined product was formed and that racemization did not
occur. All compounds 10 show an optical rotation in MeOH solution. The IR
spectra are characterized by a broad absorption of the carboxylic group
ꢀꢀ>3000 cmÀ1, the absorption band of the ester carbonyl group around
ꢀꢀ ¼ 1750 cmÀ1, the strong amide band at ca. ꢀꢀ ¼ 1650 cmÀ1, and the SO2 bands
at ca. ꢀꢀ ¼ 1355 and 1170 cmÀ 1, thus confirming the proposed structure.

Reaction of Saccharin Derivatives
903
Scheme 1
Scheme 2

904
D. Jarecka et al.
Experimental
General
Melting points: PHMX 80=2778 apparatus (uncorrected); IR spectra (KBr): Perkin-Elmer FTIR 1600;
NMR spectra: Bruker DPX 200 (1H: 200 MHz, 13C: 50MHz), room temperature, internal TMS, CDCl3,
if not noted otherwise; mass spectra: Intectra AMD 402=3; UV spectra: Uvikon 930, in MeOH; optical
rotation: Polartronic D (Schmidt Haensch GmbH); elemental analyses: Perkin-Elmer Elementar Ana-
lyzer 2400 CHN: the results agreed with the calculated values within experimental error. TLC: Merck
DC-Alufolia, Silica Gel 60 F254, Nr. 5554; HPLC: LaChrom apparatus series 7000 Merck Hitachi;
columns: LiChrospher 250-4, RP-18, 5 mm, t0 (min) with uracil or thiourea, and Chiralcel OJ-R 250-4,
5 mm, t0 (min) with 1,3,5-tri(tert-butyl)benzene: values from RP-18, acetonitrile=water 7:3, if not noted
otherwise.
Saccharin sodium was obtained from Merck (Nr. 8.141.14), and Lawesson’s Reagent was pur-
chased from Fluka (Nr. 61750). Tetrahydrofuran (THF) was stored with CaCl2, then refluxed with Na
and benzophenone, and distilled prior to use. Dimethylformamide (DMF) was distilled from P4O10 and
˚
stored with molecular sieve 4 A. Other solvents were dried=purified according to literature procedures.
Abbreviations: CC ¼ Column chromatography; DCC ¼ Dicyclohexyl Carbodiimide; EtOAc¼
Ethyl acetate; MeCN ¼ acetonitrile; NHS ¼ N-Hydroxysuccinimide; TEA ¼Triethylamine; TFA ¼
Trifluoroacetic acid.
Methyl 3-Oxo-2,3-dihydrobenzo[d][1,2]thiazol-2-acetate 1,1-Dioxide (2a)
See Ref. [6].
Methyl (RS)-2-(3-Oxo-2,3-dihydrobenzo[d][1,2]thiazol-2-yl)-propionate 1,1-Dioxide (2b)
See Ref. [7].
Methyl (2-Hydrazinocarbonylbenzenesulfonylamino)-acetate (4a, C10H13N3O5S)
2a (1.28 g, 5 mmol) was suspended in 10cm3 EtOH, and 0.25g hydrazine hydrate (5mmol) dissolved
in 10 cm3 EtOH was added dropwise with stirring. When the mixture became clear, the solvent was
evaporated in vacuo. Yield 0.74 g (51%); IR: ꢀꢀ ¼ 3335, 1569 (NH2), 1748, 1652 (CO), 1522 (amide
II), 1330, 1162 (SO2) cmÀ 1; 1H NMR (DMSO-d6): ꢁ ¼ 3.51 (s, OCH3), 3.80 (d, CH2), 4.53 (s, NH2),
7.47–7.88 (m, 5H, arom. H, NH), 9.80 (s, NH) ppm; UV: ꢂmax ¼ 205, 269 nm, lg " ¼ 4.31, 3.34; MS
[EI, 70 eV]: m=z ¼ 287 (2.08%); HPLC: k0 ¼ 0.34, t0 ¼ 2.52 (RP-18, acetonitrile=H2O 1:1).
Methyl (RS)-(2-Hydrazinocarbonylbenzenesulfonylamino)-propionate (4b, C11H15N3O5S)
From 2b (1.35 g, 5 mmol) as described for 4a: Yield 0.54g (38%); IR: ꢀꢀ ¼ 3335, 1570 (NH2), 1742,
1651 (CO), 1524 (amide II), 1337, 1159 (SO2) cmÀ 1; 1H NMR (DMSO-d6): ꢁ ¼ 1.18 (d, CH3), 3.33 (s,
OCH3), 4.05 (m, CH), 4.54 (s, NH2), 7.48–7.89 (m, 5H, arom. H, NH), 9.83 (s, NH) ppm; UV:
ꢂmax ¼ 206, 281 nm, lg " ¼ 4.40, 3.31; MS [EI, 70eV): m=z ¼ 301 (1.9%); HPLC: k0 ¼ 0.44,
t0 ¼ 2.52 (RP-18, acetonitrile=H2O 1:1).
2-(Hydrazinocarbonylmethylsulfamoyl)-benzohydrazide (5a, C9H13N5O4S)
a) From 2a (1.28 g, 5 mmol) and 0.5 g hydrazine hydrate (10 mmol) in 12 cm3 EtOH by refluxing for
2 h. After cooling to room temp., the precipitate was separated. b) From 4a (0.5g, 1.7mmol) and 0.09 g
hydrazine hydrate (1.7mmol) in 2.5 cm3 EtOH as a): Yield: a) 0.8 g (54%), b) 0.2g (14%); colorless
crystals; mp 139–143ꢁC (MeOH); IR: ꢀꢀ ¼ 3336, 1590 (NH2), 1670, 1615 (CO), 1517 (amide II),

Reaction of Saccharin Derivatives
905
1338, 1159 (SO2) cmÀ 1; 1H NMR (DMSO-d6): ꢁ ¼ 3.45 (s, CH2), 4.14 (d, NH2), 4.56 (d, NH2), 7.35
(s, NH), 7.50–7.88 (m, 4H, arom. H), 9.12 (s, NH), 9.89 (s, NH) ppm; UV: ꢂmax ¼ 205, 269 nm, lg
" ¼ 4.33, 3.34; MS [EI, 70eV]: m=z ¼ 255 [Mþ –NH–NH2] (11.01%); HPLC: k0 ¼ 0.17, t0 ¼ 2.00
(RP-18, acetonitrile=H2O 7:3).
2-(Hydrazinocarbonylethylsulfamoyl)-benzohydrazide (5b, C10H15N5O4S)
a) From 2b (1.35 g, 5 mmol) or b) from 4b (0.36 g, 1.2 mmol) as 5a: Yield: a) 1.0 g (60%), b) 0.06g
(16%); colorless crystals; mp 185ꢁC (MeOH); IR: ꢀꢀ ¼ 3317, 1590 (NH2), 1627, 1648 (CO), 1519
1
(amide II), 1333, 1169 (SO2) cmÀ 1; H NMR (DMSO-d6): ꢁ ¼ 1.06 (d, CH3), 3.81 (m, CH), 4.07 (d,
NH2), 4.57 (d, NH2), 7.35–7.45 (s, NH), 7.48–7.89 (m, 4H, arom. H), 9.16 (s, NH), 9.90 (s, NH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 19.4 (CH3), 51.0 (CH), 128.2, 129.7, 130.3, 132.8, 133.9, 138.5 (arom. C),
167.3, 170.2 (CO)ppm; UV: ꢂmax ¼ 205, 268nm, lg " ¼ 4.34, 3.35; MS [EI, 70eV]: m=z ¼ 301
(6.32%); HPLC: k0 ¼ 0.25, t0 ¼ 2.00 (RP-18, acetonitrile=H2O 7:3).
N0-Isopropylidene-2-[(N0-isopropylidenehydrazinocarbonylmethyl)-sulfamoyl]-
benzohydrazide (6a, C15H21N5O4S)
Compound 5a (1.44 g, 5 mmol) and 1.8 g acetone (20 mmol) were refluxed for 1 h in 10cm3 EtOH, and
then stirred at room temperature for 1 h: Yield 0.76 g (42%); colorless crystals; mp 180–182ꢁC
1
(EtOH); IR: ꢀꢀ ¼ 3319, 1539 (NH), 1712 (CO), 1658 (C¼N), 1338, 1170 (SO2) cmÀ 1; H NMR
(CDCl3): ꢁ ¼ 2.51 (m, 4 CH3), 3.91 (m, CH2), 6.60 (s, NH), 7.52–7.95 (m, 4H, arom. H), 8.28 (s,
NH), 9.22 (s, NH) ppm; HPLC: k0 ¼ 0.13, t0 ¼ 1.77 (RP-18, acetonitrile=H2O 7:3).
N0-(ꢃ,4-Dimethylbenzylidene)-2-{N-[N0-(ꢃ,4-dimethylbenzylidene)-
hydrazinocarbonylmethyl]-sulfamoyl}-benzohydrazide (6b, C27H29N5O4S)
From 5a and 4-methylacetophenone analogous to 6a: Yield 1.80g (69%); colorless crystals; mp 207–
212ꢁC (EtOH).
N0-(4-Methoxy-ꢃ-methylbenzylidene)-2-{N-[N0-(4-methoxy-ꢃ-methylbenzylidene)-hydrazino-
carbonylmethyl]-sulfamoyl}-benzohydrazide (6c, C27H29N5O6S)
From 5a and 4-methoxyacetophenone analogous to 6a: Yield 1.94 g (70%); colorless crystals; mp
182–186ꢁC (EtOH).
(RS)-N0-Isopropylidene-2-{[1-(isopropylidenehydrazinocarbonyl)-1-ethyl]-sulfamoyl}-
benzohydrazide (6d, C16H23N5O4S)
From 5b and acetone analogous to 6a: Yield 1.20g (63%); colorless crystals; mp 212–214ꢁC (EtOH).
(RS)-N0-(ꢃ,4-Dimethylbenzylidene)-2-{[1-(ꢃ,4-dimethylbenzylidenehydrazinocarbonyl)-
1-ethyl]-sulfamoyl}-benzohydrazide (6e, C28H31N5O4S)
From 5b and 4-methylacetophenone analogous to 6a: Yield 1.50 g (56%); colorless crystals; mp 185–
188ꢁC (EtOH).
(RS)-N0-(4-Methoxy-ꢃ-methylbenzylidene)-2-{[1-(4-methoxy-ꢃ-methylbenzylidenehydra-
zinocarbonyl)-1-ethyl]-sulfamoyl}-benzohydrazide (6f, C28H31N5O6S)
From 5b and 4-methoxyacetophenone analogous to 6a: Yield 2.04g (72%); colorless crystals;
mp 204–208ꢁC (EtOH).

906
D. Jarecka et al.
Synthesis of 7 (General Procedure)
Compound 4a (1.43 g, 5 mmol) and 10mmol ketone dissolved in 15cm3 EtOH were refluxed for 1 h.
After cooling to room temperature for 12h, the solution was evaporated in vacuo, and a few drops of
EtOH were added to the residue. The colorless crystals were recrystallized from EtOH.
Methyl [2-(Isopropylidenehydrazinocarbonyl)-benzenesulfonylamino]-
acetate (7a, C13H17N3O5S)
From acetone: Yield 1.36 g (85%); mp 184–185ꢁC; IR: ꢀꢀ ¼ 3221, 1547 (NH), 1747, 1651 (CO,
1
amide), 1632 (C¼N), 1359, 1173 (SO2) cmÀ 1; H NMR (CDCl3): ꢁ ¼ 1.99 (s, CH3), 2.15 (s, CH3),
3.58 (s, OCH3), 3.77 (d, CH2), 6.60 (s, NH), 7.53–7.77 (m, 4H, arom. H), 9.05 (s, NH) ppm; HPLC:
k0 ¼ 0.25, t0 ¼ 2.53 (RP-18, acetonitrile=H2O 7:3).
Methyl (E=Z)-[2-(1-Methylpropylidenehydrazinocarbonyl)-benzenesulfonylamino]-
acetate (7b, C14H19N3O5S)
From ethyl methyl ketone: Yield 0.77g (46%); colorless crystals; mp 155ꢁC.
Methyl (E=Z)-[2-(ꢃ-Methylbenzylidenehydrazinocarbonyl)-benzenesulfonylamino]-
acetate (7c, C18H19N3O5S)
From acetophenone: Yield 1.1 g (57%); colorless crystals; mp 158ꢁC.
Methyl [2-(1-Ethylpropylidenehydrazinocarbonyl)-benzenesulfonylamino]-
acetate (7d, C15H21N3O5S)
From diethyl ketone: Yield 0.9 g (51%); colorless crystals; mp 113ꢁC.
Methyl [2-(Cyclohexylidenehydrazinocarbonyl)-benzenesulfonylamino]-acetate
(7e, C16H21N3O5S)
From cyclohexanone: Yield 1.32 g (73%); colorless crystals; mp 170ꢁC.
Methyl [2-(ꢃ,4-Dimethylbenzylidenehydrazinocarbonyl)-benzenesulfonylamino]-acetate
(7f, C19H21N3O5S)
From 4-methylacetophenone: Yield 1.35 g (67%); colorless crystals; mp 165–168ꢁC.
Methyl 3-Thioxo-2,3-dihydrobenzo[d][1,2]thiazol-2-acetate 1,1-dioxide (8a, C10H9NO4S2)
From 2a (1.02 g, 4 mmol) and 1.18g P2S5 (8mmol) as described in [5]: Yield 0.8 g (74%); yellow
crystals; mp 128–130ꢁC (EtOH; Ref. [5]: 114–115ꢁC); IR: ꢀꢀ¼ 3084–2956(CH), 1760 (CO), 1458
(CS), 1308, 1182 (SO2) cmÀ 1; 1H NMR (DMSO-d6): ꢁ ¼ 3.70 (s, OCH3), 4.95 (s, CH2), 8.03–8.38 (m,
4H, arom. H)ppm; HPLC: k0 ¼ 2.94, t0 ¼ 2.71 (RP-18, acetonitrile=0.002 m KH2PO4, pH ¼ 6.57, 1:1).
Methyl (RS)-2-(3-Thioxo-2,3-dihydrobenzo[d][1,2]thiazol-2-yl)-propionate
1,1-dioxide (8b, C11H11NO4S2)
a) From 2b (1.08 g, 4 mmol) and 1.76g P2S5 (8mmol) according to 8a. b) From 2b (1.08 g, 4 mol) and
0.81g Lawesson’s reagent (2mmol) by stirring and refluxing in 10 cm3 dioxane for 2 h. Workup as a):

Reaction of Saccharin Derivatives
907
Yield: a) 0.85 g (75%); b) 1.02 g (90%); yellow crystals; mp 153ꢁC (EtOH); IR: ꢀꢀ ¼ 3088À
3004 ðCHÞ, 1742 (CO), 1454 (CS), 1299, 1189 (SO2) cmÀ 1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.75 (d,
CH3), 3.64 (s, OCH3), 5.53 (q, CH), 7.98–8.35 (m, 4H, arom. H)ppm; 13C NMR (CDCl3): ꢁ ¼ 14.7
(CH3), 51.7 (CH), 52.6 (OCH3), 121.6, 126.4, 128.9, 135.6 (arom C), 167.9 (CO), 184.6 (CS); HPLC:
k0 ¼ 6.12, t0 ¼ 2.52 (RP-18, acetonitrile=H2O 1:1).
Methyl 3-Oxo-2,3-dihydrobenzo[d][1,2]thiazol-2-carboxylate 1,1-dioxide (9)
See Ref. [4].
Synthesis of 10 (General Procedure)
With stirring, the amino acid and an equimolar amount of 9 were dissolved in 15 cm3 satd. solution of
NaHCO3, cooled to 0ꢁC, and 29cm3 THF was added. The mixture was stirred at 40ꢁC for 2 h, and then
adjusted with sulfuric acid to pH¼ 6–7, concentrated in vacuo to half of the volume, and acidified to
pH¼ 1–2. Then it was extracted with EtOAc, the organic layer was washed with a satd. solution of
NaCl, dried (Na2SO4), and evaporated. The residue was purified from excess of 9 by extraction with
diethyl ether (Soxhlet).
N-[2-(N-Methoxycarbonylsulfamoyl)-benzoyl]-L-leucine (10a, C15H20N2O7S)
20
From L-leucine (0.38 g, 2.9 mmol): Yield 0.93g (89%); colorless crystals; mp 75–78ꢁC; ½ꢃꢂD ¼ þ17:8
(c ¼ 2, MeOH); IR: ꢀꢀ ¼ 3359, 1539 (NH), 2961 (CH), 1749, 1651 (CO, amide), 1357, 1165
1
(SO2) cmÀ 1; H NMR (MeOH-d4): ꢁ ¼ 0.97 (d, J ¼ 6.2 Hz, CH3), 1.00 (d, J ¼ 6.3 Hz, CH3), 1.66–
1.82 (m, 3H, CHCH2), 3.64 (s, OCH3), 4.65 (t, J ¼ 7.3 Hz, CH), 7.60–8.11 (m, 4H, arom. H)ppm;
HPLC: k0 ¼ 0.79, t0 ¼ 1.75 (RP-18, acetonitrile=50mmol KH2PO4, pH¼ 3.6; 1:1); k0 ¼ 1.15, t0 ¼ 2.13
(Chiralcel OJ-R, acetonitrile=50 mmol KH2PO4, pH ¼ 3.33; 15:85).
N-[2-(N-Methoxycarbonylsulfamoyl)-benzoyl]-L-valine (10b, C14H18N2O7S)
20
From L-valine (0.34 g, 2.9 mmol): Yield 0.93g (92%); colorless crystals; mp 141–145ꢁC; ½ꢃꢂD
¼
þ30:0 (c ¼ 2, MeOH); IR: ꢀꢀ ¼ 3343, 1540 (NH), 2971–2884 (CH), 1736, 1716 (CO), 1651 (CO
amide), 1359, 1171 (SO2) cmÀ 1
;
1H NMR (DMSO-d6): ꢁ ¼ 0.94 (d, J ¼ 6.7 Hz, CH3), 0.96 (d,
J ¼ 6.7 Hz, CH3), 1.98 (m, CH), 3.56 (s, OCH3). 4.35 (dd, J ¼ 7.3 Hz, CH), 7.47–8.04 (m, 4H, arom.
H), 8.66 (d, NH) ppm; HPLC: k0 ¼ 0.50, t0 ¼ 1.75 (RP-18, acetonitrile=50mmol KH2PO4, pH¼ 3.6;
1:1); k0 ¼ 0.54, t0 ¼ 2.13 (Chiralcel OJ–R, acetonitrile=50mmol KH2PO4, pH¼ 3.33; 15:85).
N-[2-(N-Methoxycarbonylsulfamoyl)-benzoyl]-L-tyrosine (10c, C18H20N2O9S)
20
From L-tyrosine (0.37 g, 2.0 mmol): Yield 0.7 g (80%); viscous solid; ½ꢃꢂD ¼ þ20:2 (c ¼ 2, MeOH);
IR: ꢀꢀ ¼ 3290, 1516 (NH), 3290–2875 (OH), 1732, 1650 (CO, amide), 1354, 1163 (SO2) cmÀ 1
;
1H NMR (MeOH-d4): ꢁ ¼ 2.91–3.31 (m, CH2), 3.64 (s, OCH3), 4.08 (q, J ¼ 7.2 Hz, CH), 6.70–7.32,
7.59–8.13 (2 m, each 4H, arom. H)ppm; HPLC: k0 ¼ 0.30, t0 ¼ 1.75 (RP-18, acetonitrile=50 mmol
KH2PO4, pH ¼ 3.6; 1:1); k0 ¼ 0.59, t0 ¼ 2.13 (Chiralcel OJ–R, acetonitrile=50mmol KH2PO4,
pH¼ 3.33; 15:85).
N-[2-(N-Methoxycarbonylsulfamoyl)benzoyl]-L-aspartic acid (10d, C13H14N2O9S)
20
From L-aspartic acid (0.77 g, 5.8 mmol): Yield 1.3 g (60%); viscous solid; ½ꢃꢂD ¼ þ10:3 (c ¼ 2,
MeOH); IR: ꢀꢀ ¼ 3351, 1540 (NH), 3351–2880 (OH), 1736, 1648 (CO, amide), 1355, 1163

908
D. Jarecka et al.: Reaction of Saccharin Derivatives
1
(SO2) cmÀ 1; H NMR (MeOH-d4): ꢁ ¼ 2.97 (dd, J ¼ 2.2, 2.7 Hz, CH2), 3.64 (s, OCH3), 4.09 (q,
J ¼ 7.1 Hz, CH), 7.59–8.11 (m, 4H, arom. H)ppm; HPLC: k0 ¼ 0.01, t0 ¼ 2.45 (RP-18, acetoni-
trile=50 mmol KH2PO4, pH¼ 3.6; 1:1); k0 ¼ 0.02, t0 ¼ 2.61 (Chiralcel OJ–R, acetonitrile=50 mmol
KH2PO4, pH¼ 3.33; 15:85).
Acknowledgments
We thank E. Merck KGaG, Darmstadt, for generous support with chemicals and with chromatography
materials, and the ‘‘Fonds der Chemischen Industrie’’, Frankfurt=Main, for financial support. D.J.
thanks the Erasmus program for support.
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