Hydrophilically functionalized pyrazoles from sugars

Article abstract of DOI:10.1016/S0008-6215(98)00137-2

An effective and convenient protocol has been developed for the conversion of D-glucose and 6-O-α-D-glucopyranosyl-D-fructose (palatinose, isomaltulose) into 5-[(1'S)-1','2/-dihydroxyethyl]-1-phenylpyrazole-3-carboxaldehyde (4) and 5-[(1'S)-2-(α-D-glucopyranosyloxy)-1-hydroxethyl])-1-phenylpyrazole-3 -carboxaldehyde (5), key steps being the acetic anhydride-promoted dehydrative cyclization of the respective phenylosazones, and subsequent liberation of the N-acetylphenylhydrazone-blocked aldehyde function. Exploitation of the ensuing chemistry of 4 and 5 led to a variety of pyrazole building blocks with a diverse level of hydrophilic substituents (hydroxymethyl, dihydroxyethyl or glucosyl residues) and useful functional groups, such as chloro, cyano, aminomethyl, vinyl and acryloyl moieties.

Full text of DOI:10.1016/S0008-6215(98)00137-2

Carbohydrate Research 309 (1998) 269±279
Hydrophilically functionalized pyrazoles from
sugars1
Nobuhiro Oikawaa, Christoph Mullera, Markwart Kunzb,
Frieder W. Lichtenthalera,*
a Institut fur Organische Chemie, Technische Universitat Darmstadt, Petersenstraûe 22,
D-64287 Darmstadt, Germany
È
È
b Zentrale Forschung und Entwicklung, Sudzucker AG, D-67283 Obrigheim/Pfalz, Germany
È
Received 26 February 1998; accepted 18 May 1998
Abstract
An e€ective and convenient protocol has been developed for the conversion of d-glucose and 6-
O-ꢀ-d-glucopyranosyl-d-fructose (palatinose1, isomaltulose) into 5-[(10S)-10,20-dihydroxyethyl]-1-
phenylpyrazole-3-carboxaldehyde (4) and 5-[(1S)-2-(ꢀ-d-glucopyranosyloxy)-1-hydroxethyl])-1-
phenylpyrazole-3-carboxaldehyde (5), key steps being the acetic anhydride-promoted dehydrative
cyclization of the respective phenylosazones, and subsequent liberation of the N-acetylphenylhy-
drazone-blocked aldehyde function. Exploitation of the ensuing chemistry of 4 and 5 led to a
variety of pyrazole building blocks with a diverse level of hydrophilic substituents (hydroxymethyl,
dihydroxyethyl or glucosyl residues) and useful functional groups, such as chloro, cyano, amino-
methyl, vinyl and acryloyl moieties. # 1998 Elsevier Science Ltd. All rights reserved
Keywords: Osazone!pyrazole conversions; Hydrophilic pyrazoles; Isomaltulose; Palatinose
1. Introduction
Prototype of such industrially useful building
blocks are the oxygen heterocycles furfural (1) and
its 5-hydroxymethyl analog HMF (2), as they can
be readily produced from wood- or straw-derived
xylans [3], and d-fructose [4±6], respectively, in
processes worked out on a pilot plant level. By
contrast, technically viable reaction channels from
carbohydrates to nitrogen heterocycles, which
would be of similar industrial importance, have not
been systematically exploited. Although the trans-
formation of carbohydrates into N-heterocycles
occurs extensively on the exposure of foodstu€s to
heat (Maillard reaction [7]), the yields obtainable
are so modest as to be of little if any preparative
use. The same holds for various chemically induced
To improve the competitiveness of low mole-
cular weight carbohydrates over petrochemical raw
materials, the development of practical, large-scale
adaptable reaction channels is required leading
from cheap, ton-scale accessible sugars to building
blocks with industrial application pro®les [2].
* Corresponding author. Fax: 00-49-6151-166-674;
e-mail: fwlicht@sugar.oc.chemie.tu-darmstadt.de
1
Enantiopure Building Blocks from Sugars. Part 22. For
Part 21, see Ref. [1].ÐPresented, in part, at the 9th European
Carbohydrate Symposium, Utrecht, The Netherlands, July
1997; Abstract E1.
0008-6215/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00137-2

270
N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
conversions sugar!N-heterocycle [8±10], as only a
few short, simple, and reasonably well elaborated
procedures are available that lead from inexpen-
sive, bulk scale-accessible sugars to N-heterocyclic
building blocks with potential use as industrial
intermediate chemicals. Notable examples are the
generation of pyrrole from galactaric acid by
pyrolysis of its ammonium salt [11], the prepara-
tion of pyrrole derivatives by cyclocondensation of 2-
amino-2-deoxy-d-glucose with dicarbonyl com-
pounds [8], of 4-hydroxymethyl- [12] and 4-tetra-
hydroxybutyl-imidazole [13] from d-fructose by
heating with formamidine acetate in ammonia,
and the recently developed, practical access to
pyrazolecarboxaldehyde 3 from d-xylose [1].
As pyrazoles with a variable level of hydrophilic
substituents o€er the prospect of serving as useful
starting materials for the synthesis of a wide vari-
ety of productsÐbacteriostatics of the sulfaphena-
zol-type [14] with higher bioavailability, or more
readily biodegradable agricultural chemicalsÐthis
report describes the practical elaboration of acetic
anhydride-induced pyrazole cyclizations of the
d-glucose- and isomaltulose-derived phenylosa-
zones, and a ®rst exploitation of the ensuing
chemistry feasible.
conceivably involves three consecutive steps, acet-
ylation of the OH and NH groups, displacement of
the 4-acetoxy function by the 2-phenyl-hydrazono
nitrogen and elimination of acetic acid from the
pyrazoline thus formed. In re-addressing the con-
version of d-glucose phenylosazone 6 into the
respective pyrazole 7Ðno yield had been reported
previously [15]Ðit was found advantageous to add
the osazone to re¯uxing acetic anhydride, thereby
e€ecting quick dissolution and, hence, short reac-
tion times (40 min), allowing the isolation of 7 in
preparatively useful yield (77%). Various attempts
to further improve on the conversion of 6!7, e.g.
by addition of zinc chloride or sodium acetate,
gave inferior results.
The utility of pyrazole 7 as a potential key com-
pound for the generation of versatile building
blocks rests on the eciency with which ensuing
reactions can be performed, particularly with
respect to modi®cations at the phenylhydrazono-
blocked aldehyde group. These can be e€ected in
several ways. Heating with hydroxylamine hydro-
ꢀ
chloride in dimethyl sulfoxide (2 h at 100 C or
ꢀ
45 min at 120 C) e€ectively (70%) converted pyr-
azole 7 or its de-O-acetylated derivative 8 into the
respective nitrils 9 and 10, a reaction sequence
obviously initiated by exchange of the phenylhy-
drazone group by the hydroxylamine function, the
respective aldoxime intermediate thus formed then
undergoing thermal dehydration. The comparative
ease with which this reaction occurred is note-
worthy, as the conditions had only been applied for
the conversion of aromatic aldehydes into their
nitriles, e.g. of furfural into furonitrile [17] and not
for the prior removal of phenylhydrazono residues
which are particularly stable when N-acetylated [1].
Thus, 7 remained unchanged after re¯uxing with
benzaldehyde/acetic acid, i.e. conditions that read-
ily allow the removal of the (non-acetylated) phe-
nylhydrazone residues in osazone 6 to yield the
respective osone [18]. Employing the more reactive
formaldehyde, however, i.e. re¯uxing 7 with 35%
aqueous formaldehyde/acetic acid, eciently liber-
ated the N-acetylphenylhydrazone-blocked alde-
hyde function to give the acetyl derivative 12
(86%). Another means for removing the N-acetyl-
phenylhydrazone moiety in 7 proved to be
exposure to hydrazine in the presence of Raney
2. Results and discussion
Phenylosazones derived from various mono-
saccharides have been shown, upon re¯uxing in
acetic anhydride, to elaborate the pyrazole ring by
spanning C-2 and C-4 of the sugar with an N±N-
bond [15,16]. Although the mechanism of this
complex reaction has not been studied in detail, it
ꢀ
nickel, which induced a smooth (2 h at 25 C) and
ecient catalytic reduction (of the intermediate
hydrazone conceivably) to a€ord the nicely
crystalline amine 11 (91%).
Scheme 1.

N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
271
Scheme 2.
Pyrazole-aldehyde 12 and its deacetylated
derivative 4, were subjected to various further
modi®cations: the aldoxime 13 was readily pre-
pared from 12, and Ð by its conversion into the
nitrile 9 on heating in dimethyl sulfoxide Ð shown
to be the intermediate in the generation of 9 from
the phenylhydrazone 7. Reduction of 12 with
sodium borohydride smoothly a€orded the respec-
tive alcohol 14. Attempts to oxidize the aldehyde
group in 12 to the carboxylic acid with a cheap
oxidant, i.e. sodium hypochlorite, led to chlorina-
tion of the pyrazole ring instead, to give the 4-
chloropyrazole analog 15 (88%). The pyrazole-
aldehyde 12 readily underwent aldol type reaction
without a€ecting the acetate ester functions. Thus,
aluminium oxide-catalyzed [19] Knoevenagel reac-
tion with malononitrile a€orded the dicyanovinyl
derivative 16 (82%), whilst butylammonium acet-
ate-induced [20] addition of nitromethane a€orded
the 2-nitrovinyl analog 17 (70%). Vinyl analogs
with a polymerizable double bond could be gener-
ated by Wittig-type reactions: exposure to methyl-
triphenylphosphonium bromide in THF in the
presence of n-butyl lithium a€orded the corre-
sponding unsubstituted alkene 18, whereas carbonyl
ole®nation with ethoxycarbonylmethylene triphenyl-
phosphorane gave the pyrazole-acrylate 19 in
nearly quantitatively.

272
N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
The methodology developed has been further
extended to 6-O-ꢀ-d-glucopyranosyl-d-fructose
(isomaltulose, palatinose1), a disaccharide avail-
able on an industrial scale from sucrose via
2
6
Protaminobacter rubrum-induced O! O-glycosyl
transfer [21]. Indeed, the ecacy with which the
palatinose phenylosazone 20 responded to the
dehydrative cyclization, when re¯uxed in acetic
anhydride, proved a quite attractive route (79%) to
the glucosylated pyrazoles 21 and 22 (after de-O-
acetylation). Liberation of the carbonyl function in
21 or 22 from its phenylhydrazono protection was
carried out as above by heating with for-
maldehyde/acetic acid to give the carboxaldehydes
5 and 23, respectively, in yields over 90%, or, upon
hydride reduction, the corresponding alcohol 24.
Similarly, the acetylated phenylhydrazone 21
underwent reductive cleavage with Raney-nickel/
hydrazine to deliver the amine 25 (93%), also
characterized as its N-acetate 26.
In conclusion, the varied level of hydrophilic
substituents purposefully introduced into the
pyrazole ring by its generation from inexpensive,
bulk scale-accessible sugars, and the high degree of
functional group diversity achievable by exploiting
the ensuing chemistry of the key pyrazoles 7 and
21, provides a useful array of versatile pyrazole
building blocks with broad application pro®les for
the generation of pharmaceuticals, agrochemicals,
and novel polymers.
3. Experimental
General methods.ÐMelting points were deter-
mined with a Bock hot-stage microscope and are
not corrected. Optical rotations were measured
with a Perkin±Elmer 241 polarimeter. Mass spectra
were recorded with a Varian 311A spectrometer
and NMR spectra with Bruker WM300 and
AC300 instruments at 300 (1H) and 75.5 MHz
(13C). Chemical shifts are given in ppm using
Me4Si as internal standard. TLC on Silica Gel 60
F254 plastic sheets (E. Merck, Darmstadt) was used
to monitor the reactions and ascertain the puritiy
of the products. Eluents employed: toluene-EtOAc
in 1:1±5:1 ratios for acylated products, CHCl3-
MeOH in 2:1±5:1 ratios for the pyrazoles with free
OH groups, and 6:1 EtOH 2.5% aq ammonia for
amines 11 and 25. The spots were visualized by UV
light or by spraying with 50% H2SO4 and charring
Scheme 3.
performed on Silica Gel 60 (Macherey & Nagel;
63±200 nm). Evaporations were conducted under
diminished pressure at bath temperatures below
ꢀ
45 C.
d-arabino-Hexose phenylosazone (6).ÐTo
solution of 18 g (0.1 mmol) of d-glucose in 150 mL
of water, phenylhydrazine (35 mL, 0.35 mol) and
a
ꢀ
at 120 C for 5 min. Column chromatography was

N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
273
glacial HOAc (5 mL )ꢀwere added. The mixture was
stirred for 2 h at 100 C. After cooling, ®nally in a
refrigerator, the voluminous yellow precipitate was
collected and washed with water and n-hexane. The
product (mp 202 ꢀC) was recrystallized from
MeOH tꢀo give 31.2 g (87%) of 6 as yellow needles;
mp 210 C, [ꢀ]2d0 88.2ꢀ (c 0.5, Me2SO); Lit [22].:
no yield given, mp 208±209 ꢀC, [ꢀ]d20 59.5ꢀ (c 0.46,
IR-120, H+ form), ®ltration of the mixture and
removal of the solvent from the ®ltrate under
reduced pressure yielded a syrup, which was crys-
tallized from EtOAc to a€ord 8 (411 mg, quant.) as
colorless needles; mp 176±178 ꢀC, [ꢀ]d20 +9.2ꢀ (c 1,
ꢀ
MeOH); Lit [15].: no yield given, mp 185 C, [ꢀ]d20
+13ꢀ (c 1, EtOH); 1H NMR (Me2SO-d6): ꢁ 2.50 (s,
3H, NAc), 3.59, 3.65 (2 ddd, 1H each, two H-20),
4.53 (ddd, 1H, H-10), 4.91 (t, 1H, OH-20), 5.60 (d,
1H, OH-10), 6.89 (s, 1H, H-4), 7.16 (s, 1H,
1
2-methoxyethanol); H NMR (Me2SO-d6): ꢁ 3.48
(m, 2H, H-4), H-5, 3.62 (m, 2H, two H-6), 4.38 (t,
1H, 6-OH), 4.54 (dd, 1H, H-3), 4.60 (m, 2H, 4-OH,
5-OH), 5.12 (d, 1H, 3-OH), 6.83±7.38 (m, 10 H, 2
C6H5), 7.89 (s, 1H, H-1), 10.70, 12.19 (2 s, 1H each,
2 NH), J3,4 2.6, J3,3-OH 5.2, J6,6-OH 5.5 Hz; 13C
NMR ([D6]DMSO): ꢁ 63.3 (C-6), 71.3 (C-5), 72.1
(C-3), 74.5 (C-4), 111.8±129.5, 144.0, 144.4 (2
C6H5), 134.7 (C-1), 137.8 (C-2); MS (FD): m/z 358
(M+).
0
0
N=CH), 7.23±7.62 (m, 10 H, 2 C6H5), J1 ,2 5.9
and 6.4, J2 ,2 11.5 Hz; 13C NMR ([Me2SO-d6): ꢁ
21.7 (NCOMe), 64.9 (C-20), 65.3 (C-10), 102.4 (C-
4), 124.8±130.1, 146.7, 147.6 (2 C6H5), 135.2 (3-
CH), 135.7, 139.0 (C-3, C-5), 171.2 (COMe); MS
(FD): m/z 364 (M+).
0
0
5-[(10S)-10,20-Diacetoxyethyl]-3-cyano-1-phenyl-
pyrazole
(9).ÐHydroxylamine
hydrochloride
5-[(10S)-10,20-Diacetoxyethyl]-1-phenylpyrazole-
3-carboxaldehyde N-acetylphenyl-hydrazone (7).Ð
To re¯uxing Ac2O (400 mL) was added in por-
tions 28 g (78 mmol) of 6, and the mixture was
re¯uxed (bath temp. 140 ꢀC) for 40 min, then
poured into a mixture of ice (300 g) and satd
NaHCO3 solution (300 mL), and extracted with
300 mL of CH2Cl2. The extract was washed with
satd NaHCO3 solution and water. Drying
(MgSO4) and removal of the solvent gave a syrup,
which crystallized from aq EtOH to give 7 (24.5 g,
(210 mg, 3 mmol) was added to a solution of pyr-
azole 7 (898 mg, 2 mmol) in dry Me2SO (10 mL),
and the mixture was heated to 100 ꢀC for 2 h. After
cooling to ambient temp., the mixture was poured
into ice cold, satd. NaHCO3 solution (50 mL), then
extracted with EtOAc (3Â100 mL), washed with
water (2Â100 mL), and dried (NaSO4). The residue
remaining after removal of the solvent in vacuo
was puri®ed by column (2Â20 cm) chromato-
graphy (1:1 n-hexane-EtOAc) to give 9 (410 mg,
67%) as a syrup; [ꢀ]2d0 +53.3 (c 1.5, CHCl3). H
1
ꢀ
71%) as colorless needles; mp 132±133 C, [ꢀ]d20
NMR (CDCl3): ꢁ 2.01, 2.02 (2 s, 3H each, 2 Ac),
4.26, 4.33 (2 dd, 1H each, two H-20), 5.99 (dd, 1H,
H-10), 6.90 (s, 1H, H-4), 7.45±7.59 (m, 5 H, C6H5),
+60ꢀ (c 1.0, CHCl3). A second crop (1.9 g) was
obtained by working up the mother liquor,
J1 ,2 6.4 and 4.6, J2 ,2 11.9 Hz; 13C NMR (CDCl3):
ꢁ 20.7 (2 COMe), 63.6 (C-20), 65.0 (C-10), 111.4
(C-4), 113.6 (CN), 125.8, 125.9, 129.7, 130.2 (C6H5),
138.0, 141.1 (C-3, C-5), 169.6, 170.2 (2 COMe). MS
(FD): m/z 313 (M+). Anal. Calcd for C16H15N3O4
(313.3): C, 61.33; H, 4.83; N, 13.41. Found: C,
61.30; H, 4.76; N, 13.47.
0
0
0
0
increasing the yield to 77%;ꢀ Lit [13].: no yield
ꢀ
given, mp 131 C, [ꢀ]2d0 +68 (c 1, CHCl3); H
1
NMR (CDCl3): ꢁ 2.02, 2.04 (2 s, 3H each, 2 OAc),
2.62 (s, 3-H, NAc), 4.33 (m, 2 H, two H-20), 6.02 (t,
1H, H-10), 6.91 (s, 1H, H-4), 7.36 (s, 1H, 3-CH),
7.14±7.54 (m, 10 H, 2 C6H5), J1 ,2 5.9 Hz; 13C
NMR (CDCl3): ꢁ 20.7, 20.8 (2 OCOMe), 22.2
(NCOMe), 64.2 (C-20), 65.4 (C-10), 103.5 (C-4),
125.8±130.5, 149.1 (2 C6H5), 135.9 (3-CH), 138.8,
140.7 (C-3, C-5), 169.7, 170.4 (2 OCOMe), 172.8
(NCOMe); MS (FD): m/z 448 (M+). Anal. Calcd
for C24H24N4O5 (448.5): C, 64.28, H, 5.39, N,
12.49. Found: C, 64.25, H, 5.36, N, 12.55.
0
0
3 - Cyano-5 - [(10S) - 10, 20 -dihydroxyethyl] - 1-
phenylpyrazole
chloride (230 mg, 3.3 mol) was added to a solution
(10).ÐHydroxylamine
hydro-
of 8 (1.0 g, 2.7 mmol) in Me2SO (10 mL), and the
ꢀ
mixture was kept for 45 min at 120 C. Processing
of the mixture in a manner analogous to the con-
version of 7!9 gave 10 (440 mg, 70%) as an
amorphous powder; [ꢀ]2d0 +19.5ꢀ (c 1.1, MeOH);
1H NMR (CDCl3): ꢁ 2.75, 3.40 (2 bs, each 1H, 2 OH),
3.73 (d, 2H, two H-20), 4.73 (t, 1H, H-10), 6.87 (s,
1H, H-4), 7.42±7.57 (m, 5H, C6H5), J1 ,2 0 5.0 Hz;
13C NMR (CDCl3): ꢁ 65.2 (C-20), 65.7 (C-1 ), 110.9
(C-4), 114.0 (CN), 125.4, 125.6, 129.7, 139.9 (C6H5),
5-[(10S)-10,20-Dihydroxyethyl]-1-phenylpyrazole-
3-carboxaldehyde N-acetylphenyl-hydrazone (8).Ð
To a solution of 500 mg (1.1 mmol) of pyrazole 7
in dry MeOH (50 mL) was added 20 mg of
NaOMe, and the mixture was stirred at room
temp. for 1.5 h. Neutralization with 500 mg of
strongly acidic ion exchange resin (Amberlite
0
0

274
N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
138.2, 144.6 (C-3, C-5); MS (FD): m/z 229 (M+).
Anal. Calcd for C12H11N3O2 (229.23): C, 62.87; H,
4.84; N, 18.33. Found: C, 62.80; H, 4.78; N, 18.28.
3-Aminomethyl-5-[(10S)-10,20-dihydroxyethyl]-
1-phenylpyrazole (11).ÐTo a solution of pyrazole 7
(5.0 g, 11.1 mmol) in 50 mL of MeOH was added
liquid hydrazine hydrate (50 mL, equivalent to 64
% N2H4), and the mixture was stirred for 2 h at
ambient temperature. Raney-nickel (1 g) was then
added, and stirring was continued until evolution
of gas had ceased (ca. 5 h). Subsequently, the cata-
lyst was ®ltered o€, the solvent was removed uder
reduced pressure from the ®ltrate, and the residue
was puri®ed by crystallization from CH3CN to
give 11 (2.4 g, 91%) as colorless prisms; mp 122 ꢀC;
[ꢀ]2d0 +14ꢀ (c 1.1, MeOH); 1H NMR (Me2SO-d6): ꢁ
3.53, 3.62 (2 dd, 1H each, two H-20), 3.70 (s, 2H, 3-
NCH2), 4.51 (t, 1H, 10-H), 6.43 (s, 1H, H-4), 7.38±
After removal of MeOH under reduced pressure,
water (50 mL) was added, followed by extraction
with EtOAc (3Â50 mL). Drying of the organic
phases (MgSO4), and concentration left a residue,
which was puri®ed by column (3Â25 cm) chroma-
tography (1:1 toluene-EtOAcꢀ) to yield syrupy 4
NMR (Me2SO-d6): ꢁ 3.60 (m, 2H, two H-20), 4.54
(t, 1H, H-10), 4.92 (t, 1H, 20-OH), 5.65 (d, 1H, 10-
OH), 6.97 (s, 1H, H-4), 7.53±7.70 (m, 5H, C6H5),
(510 mg, quant.); [ꢀ]2d0 + 20.3 (c 1.2, MeOH); H
1
9.96 (s, 1H, CHO), J1 ,2 6.3; 13C NMR (Me2SO-
d6): ꢁ 65.1 (C-20), 65.6 (C-10), 104.9 (C-4), 125.7,
129.4, 129.7, 151.1 (C6H5), 139.2, 148.2 (C-3, C-5),
187.3 (CHO); MS (FD): m/z 232 (M+). Anal.
Calcd for C12H12N2O3 (232.2): C, 62.06; H, 5.21;
N, 12.06. Found: C, 62.09; H, 5.18; N, 12.00.
0
0
5-[(10S)-10,20-Diacetoxyethyl]-1-phenylpyrazole-
3-carboxaldehyde oxime (13).ÐAldehyde 12
(316 mg, 1 mmol) in MeOH (40 mL) was added to a
7.60 (m, 5H, C6H5), J1 ,2 6.4, J2 ,2 10.8 Hz; 13C
NMR (Me2SO-d6): ꢁ 39.7 (3-CH2), 65.2 (C-20), 65.4
(C-10), 103.4 (C-4), 124.7, 127.3, 128.9, 139.6 (C6H5),
145.1, 154.7 (C-3, C-5); MS (FD): m/z 233 (M+).
Anal. Calcd for C12H15N3O2 (233.3): C, 61.79; H,
6.48; N, 18.01. Found: C, 61.72; H, 6.45; N, 18.11.
5-[(10S)-10,20-Diacetoxyethyl]-1-phenylpyrazole-
3-carboxaldehyde (12).ÐTo a solution of 7 (10 g,
22 mmol) in 100 mL of EtOH was added 35%
aqueous solution of formaldehyde (120 mL) and
HOAc (5 mL). After stirring the mixture for 5 h at
0
0
0
0
.
solution of 2.2 g (31 mmol) of NH2OH HCl and
2.1 g (25 mmol) of NaOAc in 10 mL of water, and
the mixture was stirred for 1 h at ambient temp.
The solvent was removed in vacuo, and the residue
was puri®ed by elution from a silica gel column
(2Â22 cm) with 4:1 n-hexane-EtOAc to a€ord 13
(280 mg, 84%) as an amorphous powder; 1H NMR
(CDCl3): ꢁ 2.02 (2 s, 3H each, 2 Ac), 4.30, 4.36 (2 dd,
1H each, two H-20), 6.06 (dd, 1H, H-10), 6.88 (s, 1H,
H-4), 7.45±7.54 (m, 5 H, C6H5), 8.29 (s, 1H, 3-CH),
ꢀ
0
0
0
0
100 C, it was made slightly basic by the addition
9.40 (bs, 1H, OH), J1 ,2 7.1 and 4.4, J2 ,2 11.8 Hz;
13C NMR (CDCl3): ꢁ 22.3 (2 COMe), 65.7 (C-20),
66.9 (C-10), 105.6 (C-4), 127.5, 130.9, 131.2, 148.2
(C6H5), 140.3, 142.0 (C-3, C-5), 145.6 (3-CH),
171.5, 172.2 (2 COMe); MS (FD): m/z 331 (M+).
Anal. Calcd for C16H17N3O5 (331.3): C, 58.00; H,
5.17; N, 12.68. Found: C, 57.86; H, 5.10; N, 12.70.
5-[(10S)-10,20-Diacetoxyethyl]-3-hydroxymethyl-
1-phenylpyrazole (14).ÐTo a cooled (0 ꢀC) solution
of aldehyde 12 (158 mg, 0.5 mmol) in MeOH
(10 mL) was added NaBH4 (90 mg, 2.4 mmol) and
of ice cold, satd. NaHCO3 solution. Several
extractions with ether (4Â100 mL), washing with
water (3Â50 mL), drying (Na2SO4), and evapora-
tion of the solvent left a residue, which was puri®ed
by column (4Â30 cm) chromatography (5:1
toluene±EtOAc) to a€ord 12 (6.1 g, 86%) as a
syrup; [ꢀ]2d0 + 52.6ꢀ (c 1.5, CHCl3); H NMR
1
(CDCl3): ꢁ 2.02, 2.03 (2 s, 3H each, 2 Ac), 4.27,
4.34 (2 dd, 1H each, two H-20), 6.01 (dd, 1H, H-10),
7.01 (s, 1H, H-4), 7.50±7.59 (m, 5H, C6H5), 10.01
ꢀ
(s, 1H, CHO), J1 ,2 6.4 and 5.4, J2 ,2 11.9 Hz; 13C
NMR (CDCl3): ꢁ 20.7 (2 COMe), 63.9 (C-20), 65.3
(C-10), 105.6 (C-4), 125.9, 129.7, 130.0, 151.6
(C6H5), 138.6, 141.7 (C-3, C-5), 169.7, 170.3 (2
COMe), 186.6 (CHO); MS (FD): m/z 316 (M+).
Anal. Calcd for C16H16N2N5 (316.3): C, 60.75; H,
5.10; N, 8.86. Found: C, 60.61; H, 5.04; N, 8.80.
5-[(10S)-10,20-Dihydroxyethyl]-1-phenylpyrazole-
3-carboxaldehyde (4).ÐTo a solution of pyrazole
12 (700 mg, 2.2 mmol) in 1:1 MeOH±water
(60 mL), was added K2CO3 (1 g, 7.2 mmol) and the
mixture was stirred for 3 h at ambient temperature.
the mixture was stirred 0 C for 45 min, followed
0
0
0
0
by decomposition of excessive NaBH4 with few
drops of HOAc. Removal of the solvent under
reduced pressure left a syrup which was puri®ed by
column (2Â22 cm) chromatography (1:1 toluene-
EtOAc) to give 14 (145 mg, 91%) as a colorless
1
syrup; H NMR (CDCl3): ꢁ 1.99 (2 s, 3H each, 2
Ac), 3.25 (bs, 1H, OH), 4.25, 4.33 (2 dd, 1H each,
two H-20), 4.66 (s, 2H, 3-CH2), 6.03 (dd, 1H, H-10),
0
0
6.49 (s, 1H, H-4), 7.43±7.51 (m, 5 H, C6H5), J1 ,2
0
7.2 and 4.5, J2 ,2 11.8 Hz; 13C NMR (CDCl3): ꢁ
20.6 (COMe), 58.5 (3-CH2), 64.1 (C-20), 65.3 (C-10),
0

N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
275
104.8 (C-4), 125.8, 128.4, 128.9, 153.0 (C6H5),
138.9, 139.8 (C-3, C-5), 169.7, 170.4 (COMe); MS
(FD): m/z 318 (M+). Anal. Calcd for C16H18O5N2
(318.3): C, 60.37; H, 5.70; N, 8.80. Found: C,
60.34; H, 5.75; N, 8.70.
O4N4 (364.3): C, 62.63; H, 4.43; N, 15.38. Found:
C, 62.43; H, 4.38; N, 15.40.
5-[(10S)-10,20-Diacetoxyethyl]-3-[(E)-200-nitro-100-
vinyl)]-1-phenylpyrazole (17).ÐTo a solution of
aldehyde 12 (500 mg, 1.6 mmol) in CH3NO2 (5 mL)
over freshly desiccated molecular sieve (3 A) was
added n-butylamine and AcOH (one drop each)
and the mixture was stirred for 18 h at ambient
temperature. Evaporation and silica gel column
(2Â22 cm) chromatography (9:1 toluene-EtOAc)
a€orded 17 (400 mg, 70%) as a yellowish syrup; 1H
NMR (CDCl3): ꢁ 2.02, 2.04 (s, 3H each, 2 Ac),
4.27, 4.34 (2 dd, 1H each, two H-20), 6.02 (dd, 1H,
H-10), 6.76 (s, 1H, H-4), 7.48±7.59 (m, 5 H, C6H5),
4-Chloro-[(10S)-10,20-diacetoxyethyl]-1-phenyl-
pyrazole-3-carboxaldehyde (15).ÐTo
a
cooled
ꢀ
(0 C) solution of aldehyde 12 (316 mg, 1 mmol) in
MeOH (4 mL) was added HOAc (0.2 mL) and,
subsequently, a 14% aq NaOCl solution (1 mL,
dropwise), and the mixture was stirred for 1 h at
ꢀ
0 C. After addition of 20 mL of ice water, the
mixture was extracted with CHCl3 (3Â50 mL). The
combined organic phases were washed with sat.
NaHCO3 solution, and water (50 mL each), fol-
lowed by drying (Na2SO4), and removal of the
solvent under reduced pressure. Puri®cation of the
residue by elution from a silica gel column
(2Â25 cm) with 4:1 toluene±EtOAc and evapora-
tion of the solvents yielded syrupy 15 (310 mg,
7.68 (d, 1H, H-100), 7.98 (d, 1H, H-200), J1 ,2 6.8 and
0
0
4.6, J2 ,2 11.8, J1 ,2 13.7 Hz; 13C NMR (CDCl3): ꢁ
20.7 (COMe), 63.9 (C-20), 65.2 (C-10), 107.2 (C-4),
125.8, 129.7, 129.8, 143.9 (C6H5), 130.5 (C-100),
138.4, 141.6 (C-3, C-5), 138.5 (C-200), 169.7, 170.3
(2 COMe); MS (FD): m/z 359 (M+). Anal. Calcd
for C6H17N3O6 (359.3): C, 56,82; H, 4.77; N, 11.70.
Found: C, 56.87; H, 4.70; N, 11.67.
0
0
00 00
1
88%). H NMR (CDCl3): ꢁ 1.97, 2.03 (2 s, 3H
each, 2 Ac), 4.39, 4.46 (2 dd, 1H each, two H-20),
5.87 (dd, 1H, H-10), 7.42±7.54 (m, 5 H, C6H5),
5-[(1S)-10,20-Diacetoxyethyl]-3-vinyl-1-phenylpyr-
azole (18).ÐA suspension of methyltriphenylphos-
phonium bromide (450 mg, 1.3 mmol) and 0.8 mL
(1.3 mmol) of a commercial 1.6 M n-hexane solu-
tion of BuLi in 5 mL of dry THF was cooled at
0
0
0
0
10.00 (s, 1H, CHO), J1 ,2 7.5 and 4.4, J2 ,2 11.7 Hz;
13C NMR (CDCl3): ꢁ 20.4, 20.7 (2 COMe), 62.4
(C-20), 67.0 (C-10), 105.6 (C-4), 126.3, 129.7, 130.4,
145.9 (C6H5), 137.4, 138.5 (C-3, C-5), 169.8, 170.2
(2 COMe), 184.8 (CHO); MS (FD): m/z 350, 352
(M[35Cl]+, M[37Cl]+). Anal. Calcd for C16H15
N2O5Cl (350.7): C, 54.79; H, 4.31; N, 7.99. Found:
C, 54.69; H, 4.33; N, 7.86.
ꢀ
40 C and a solution of aldehyde 12 (200 mg,
0.7 mmol) in THF (1 mL) was added. The mixture
was stirred under N2 for 1 h, then poured into an
ice-cooled 2 n NaHSO4 solution (30 mL), and
extracted with Et2O (2Â50 mL). The combined
organic phases were washed with satd. NaHCO3,
and water (30 mL each), dried, and evaporated to
dryness. The residue was puri®ed by elution from
silica gel (2Â20cm column) with 4:1 toluene±EtOAc
to yield 18 (133 mg, 67%) as a colorless, amorphous
solid; 1H NMR (CDCl3): ꢁ 2.01 (2 s, 3H each, 2 Ac),
4.27, 4.33 (2 dd, 1H each, two H-20), 5.36 (dd, 1H,
H-200trans), 5.78 (dd, 1H, H-200cis), 6.05 (dd, 1H, H-
10), 6.62 (s, 1H, H-4), 6.75 (dd, 1H, H-10), 7.42±7.50
5-[(10S)-10,20-Diacetoxyethyl]-3-[2,2-dicyano-
vinyl)-1-phenylpyrazole (16).ÐTo a solution of
aldehyde 12 (316 mg, 1 mmol), and malono-nitrile
(90 mg, 1.4 mmol) in dry MeOH (50 mL) was
added freshly dried Al2O3 (400 mg) and the mix-
ture was stirred for 18 h at room temp. The solu-
tion was ®ltered through celite, the ®lter washed
thoroughly with MeOH, and the entire ®ltrate
taken to dryness under reduced pressure. Puri®ca-
tion of the resulting syrup by column chromato-
graphy (4:1 toluene±EtOAc) gave 16 (300 mg,
82%) as an amorphous product; 1H NMR
(CDCl3): ꢁ 2.03, 2.05 (2 s, 3H each, 2 Ac), 4.30,
4.35 (2 dd, 1H each, two H-20), 5.99 (dd, 1H, H-10),
7.41 (s, 1H, H-4), 7.48±7.59 (m, 5H, C6H5), 7.91 (s,
0
0
0
0
(m, 5 H, C6H5); J1 ,2 7.2 and 4.6, J1 ,2 11.8,
J1 ,2 trans 11.0 and 7.8, J2 ,2 1.2 Hz; 13C NMR
(CDCl3): ꢁ 20.6, 20.7 (2 COMe), 64.1 (C-20), 65.3
(C-10), 103.0 (C-4), 116.2 (C-200), 125.8, 128.7, 129.3,
151.3 (C6H5), 128.8 (C-100), 139.0 (C-5), 139.8 (C-3),
169.6, 170.3 (2 COMe); MS (FD): m/z 314 (M+).
5-[(10S)-10,20-Diacetoxyethyl]-3-[(E)-2-ethoxy-
00 00
00 00
1H, H-100), J1 ,2 6.1 and 4.1, J2 ,2 11.9 Hz; 13C
NMR (CDCl3): ꢁ 20.7 (2 COMe), 63.9 (C-20), 65.2
(C-10), 83.0 (C-200), 108.4 (C-4), 112.5, 113.4 (2
CN), 125.7, 129.8, 130.2, 145.0 (C6H5), 138.1, 142.5
(C-3, C-5), 152.2 (C-100), 169.7, 170.3 (2 COMe);
MS (FD): m/z 364 (M+). Anal. Calcd for C19H16
0
0
0
0
carbonyl-1-vinyl]-1-phenylpyrazole (19).ÐTo
a
solution of aldehyde 12 (1.0 g, 3.1 mmol) in THF
(30 mL) was added commercial ethoxycarbonyl-
methylene triphenylphosphorane (1.3 g, 3.4 mmol)

276
N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
and the mixture was stirred for 6 h at room temp.
Concentration under reduced pressure, elution of
the residue from a silica gel column (3Â27 cm) with
4:1 toluene±EtOAc and drying under vacuum
(®nally at 0.1 Torr) gave 19 (1.20 g, 98%) as a
syrup; 1H NMR (CDCl3): ꢁ 1.27 (t, 3H, CH2CH3),
1.96, 1.97 (2 s, 3H each, 2 Ac), 4.20 (q, 2H,
CH2CH3), 4.22, 4.29 (2 dd, 1H each, two H-20),
6.00 (dd, 1H, H-10), 6.44 (d, 1H, H-200), 6.68 (s, 1H,
H-4), 7.42±7.50 (m, 5 H, C6H5), 7.64 (d, 1H, H-100),
to ambient temperature, the mixture was poured
into ice-cold satd. NaHCO3 (300 mL) with vigor-
ous stirring, and was then made slightly basic by
the addition of solid NaHCO3. Extraction with
CH2Cl2 (4Â200 mL), washing with satd. NaHCO3
(2Â100 mL), and drying (MgSO4) yielded a solid
residue which was recrystallized from EtOH to
a€ord 21 (25.2 gꢀ, 79%) in two crops as colorless
needles; mp 190 C; [ꢀ]2d0 118ꢀ (c 0.9, CHCl3); Lit.
[24]: 60%, mp 190 ꢀC, [ꢀ]d20 +118ꢀ (c 0.55, CHCl3);
1H NMR (CDCl3): ꢁ 1.86, 2.01, 2.03, 2.04, 2.09 (5
s, 3H each, 5 OAc) 2.63 (s, 3H, NAc), 3.72, 4.01 (2
dd, 1H each, two H-20), 3.95 (ddd, 1H, H-500) 4.08,
4.23 (2 dd, 1H each, two H-600), 4.82 (dd, 1H, H-
200), 5.05 (d, 1H, H-100), 5.06 (t, 1H, H-400), 5.48 (t,
1H, H-300), 5.99 (t, 1H, H-10), 6.93 (s, 1H, 3-CH),
7.36 (s, 1H, H-4), 7.12±7.56 (m, 10 H, 2 C6H5),
0
0
0
0
00 00
J1 ,2 7.0 and 4.5, J2 ,2 11.8, J1 ,2 16.1 Hz; MS
(FD): m/z 386 (M+). Anal. Calcd for C20H22N2O6
(386.4): C, 62.16; H, 5.74; N, 7.25. Found: C,
62.08; H, 5.80; N, 7.21.
6-O-(a-d-Glucopyranosyl)-d-arabino-hexose
phenylosazone (20).ÐA solution of 30 mL
(0.35 mmol) of phenylhydrazine in 100 mL of water
was made slightly acidic by adding 16 mL of
AcOH. A solution of 30.0 g (84 mmol) of iso-
maltulose monohydrate in 100 mL of water was
then added, and the mixture was stirred for 2 h at
100 ꢀC. After addition of water (300 mL) to the hot
solution, it was allowed to come to room tempera-
ture and subsequently placed in a refrigerator
overnight. The voluminous precipitate was ®ltered
o€, and washed with water and n-hexane to give
40.2 g (92%) of crude osazone 20 as yellow needles
0
0
0
0
00 00
00 00
00 00
J1 ,2 6.2, J2 ,2 10.6, J1 ,2 3.7, J2 ,3 10.3, J3 ,4 9.8,
J4 ,5 10.0, J5 ,6 4.3 and 2.2, J6 ,6 12.4 Hz; 13C
NMR (CDCl3): ꢁ 20.5±20.8 (5 OCOMe), 22.2
(NCOMe), 61.7 (C-600), 65.5 (C-10), 67.9 (C-500),
68.3 (C-400), 69.8 (C-300), 68.9 (C-20), 70.6 (C-200),
96.3 (C-100), 103.1 (C-4), 126.1±130.5, 144.7, 149.1
(2 C6H5), 135.8, 138.8 (C-3, C-5), 135.9 (3-CH),
169.5±170.7 (6 COMe); MS (FD): m/z 736
(M+). Anal. Calcd. for C36H40N4O13 (736.7): C,
58.69; H, 5.47; N, 7.60. Found: C, 58.60; H, 5.34;
N, 7.53.
00 00
00 00
00 00
ꢀ
of mp 180±181 C, which was used for the sub-
sequent conversion into pyrazole 21. Recrystalliza-
5-[(1S)-2-(a-d-Glucopyranosyloxy)-1-hydroxy-
ethyl]-1-phenylpyrazole-3-carboxaldehyde N-acetyl-
phenylhydrazone (22).ÐTo a solution of 10 g
(1.3 mmol) of pyrazole 21 in dry MeOH (250 mL)
was added NaOMe (0.5 g, 9.2 mmol), and the mix-
ture was kept for 4 h at room temp. Subsequently,
the solution was neutralized with a strongly acidic
ion exchange resin (Amberlite IR-120, H+ form),
®ltered and the ®ltrate was taken to dryness under
reduced pressure. The residue was crystallized on
trituration with aqueous iPrOH (90%) and was
recrystallized from MeOH to give 22 (6.7 g, 96%)
tion from water or MeOH raised the mp to 192±
ꢀ
194 C; [ꢀ]2d0 +30!47ꢀ (24 h, c 1, 2-methoxy-
ꢀ
ethanol); Lit [23].: mp 177±179 C and [ꢀ]d20
+3346ꢀ (24 h, c 2, 2-methoxyethanol) for a sample
prepared from isomaltose; 1H NMR (Me2SO-d6): ꢁ
3.10±3.22 (m, 2H, two H-60), 3.43±3.63 (m, 6 H, H-
4, H-5, H-20, H-30, H-40, H-50), 3.70±3.80 (m, 2H,
two H-6), 4.42 (t, 1H, OH-60), 4.58 (s, 1H, H-10),
4.69 (d, 1H, H-3), 4.59, 4.60, 4.70, 4.81, 4.88, 5.20
(6 d, 1H each, 6 OH), 6.84±7.34 (m, 10H, 2 C6H5),
7.91 (s, 1H, H-1), 10.71, 12.27 (s, 1H each, 2 NH);
ꢀ
J3,4 3.5, J6 ,6 -OH 5.6 Hz; 13C NMR (Me2SO-d6): ꢁ
60.7 (C-60), 69.3 (C-6), 69.1, 70.0, 71.9, 72.2, 72.4,
73.5, 74.3 (C-3, C-4, C-5, C-20, C-30, C-40, C-50),
98.7 (C-10), 111.8±129.5, 144.0, 144.4 (2 C6H5),
134.9 (C-1), 138.0 (C-2); MS (FD): m/z 520 (M+).
Anal. Calcd. for C24H32N4O9 (520.5): C, 55.38; H,
6.20; N, 10.76. Found: C, 55.31; H, 6.25; N, 10.75.
5-[(10S)-1-Acetoxy-2-(2,3,4,6-tetra-O-acetyl-a-d-
glucopyranosyloxy)ethyl]-1-phenylpyrazole-3-carb-
oxaldehyde N-acetylphenylhydrazone (21).ÐA sus-
pension of osazone 20 (22.2 g, 43 mmol) in Ac2O
(250 mL) was heated for 3 h to 140 ꢀC. After cooling
as colorless needles; mp 207 C; [ꢀ]2d0 +71ꢀ (c 0.9,
0
0
MeOH); 1H NMR (Me2SO-d6): ꢁ 2.51 (s, 3H,
NAc), 3.10 (dt, 1H, H-400), 3.17 (ddd, 1H, H-200),
3.32 (ddd, 1H, H-500), 3.40 (m, 1H, H-300), 3.43,
3.51 (m, dd, 1H each, two H-600), 3.64, 3.89 (2 dd,
1H each, two H-20), 4.45 (t, 1H, OH-600), 4.63 (d,
1H, OH-200), 4.67 (d, 1H, H-100), 4.68 (m, 1H, H-10),
4.81 (d, 1H, OH-300), 4.93 (d, 1H, OH-400), 5.71 (d,
1H, OH-10), 6.97 (s, 1H, N=CH), 7.16 (s, 1H, H-
0
0
0
0
4), 7.24±7.63 (m, 10H, 2 C6H5), J1 ,2 5.7, J2 ,2 10.3,
00 00
J1 ,2 3.5, J2 ,3 9.5, J3 ,4 9.2, J4 ,5 9.8, J5 ,6 4.6
00 00
00 00
00 00
00 00
00 00
0
0
00 00
and < 1.0, J6 ,6 10.5, J1 ,1 -OH 6.6, J2 ,2 -OH 7.2,

N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
277
5.03 (t, 1H, H-400), 5.44 (t, 1H, H-300), 5.89 (t, 1H,
H-10), 7.00 (s, 1H, H-4), 7.13±7.65 (m, 5H, C6H5),
00 00
00 00
00 00
J3 ,3 -OH 4.7, J4 ,4 -OH 4.9, J6 ,6 -OH 5.7 Hz;
13C NMR (Me2SO-d6): ꢁ 22.2 (NCOMe), 60.6 (C-
600), 63.0 (C-10), 69.8 (C-400), 70.7 (C-20), 71.9 (C-
200), 72.9 (C-300), 73.3 (C-500), 99.1 (C-100), 102.7 (C-
4), 124.0-130.1, 145.9, 147.6 (2 C6H5), 135.0 (3-
CH), 135.7, 138.8 (C-3, C-5), 171.3 (COMe); MS
(FD): m/z 526 (M+). Anal. Calcd for C26H30N4O8
(526.6): C, 59.31; H, 5.74; N, 10.64. Found: C,
59.28; H, 5.69; N, 10.58.
0
10.01 (s, 1H, CHO) J1 ,2 7.0, J2 ,2 10.4, J1 ,2 3.7,
0
0
0
00 00
00 00
00 00
00 00
00 00
J2 ,3 10.3, J3 ,4 9.8, J4 ,5 10.0, J5 ,6 4.3 and 2.2,
00 00
J6 ,6 12.4 Hz; 13C NMR (CDCl3): ꢁ 20.5±20.7 (5
COMe), 61.7 (C-600), 65.3 (C-10), 67.9 (C-500), 68.3
(C-400), 68.6 (C-20), 69.8 (C-300), 70.5 (C-200), 96.3
(C-100), 105.1 (C-4), 126.1±130.5, 151.6 (C6H5),
138.6, 142.7 (C-3, C-5), 169.5±170.7 (5 COMe),
186.4 (CHO); MS (FD): m/z 603 (M+). Anal.
Calcd for C28H32N2O13 (604.56): C, 55.63; H, 5.34;
N, 4.63. Found: C, 55.57; H, 5.24; N, 4.60.
5-[(1S)-2-(a-d-Glucopyranosyloxy)-1-hydroxy-
ethyl])-1-phenylpyrazole-3-carboxaldehyde (5).Ð
To a suspension of pyrazole 22 (3.40 g, 6.5 mmol)
in 80 mL of MeOH and 80 mL of a 35% aqueous
formaldehyde solution was added 2.5 mL of
HOAc, and the mixture was re¯uxed for 4 h. Sub-
sequently, the solution was taken to dryness under
reduced pressure and the residue was puri®ed by
column (4Â35 cm) chromatography (5:1 CHCl3-
MeOH) to ꢀa€ord 5 (2.35 g, 92%) as a solid foam;
5-[(10S)-2-(a-d-Glucopyranosyloxy)-1-hydroxy-
ethyl]-3-hydroxymethyl-1-phenylpyrazole (24).ÐTo
a stirred solution of 23 (3.65 g, 6.0 mmol) in MeOH
(150 mL) was added NaBH4 (1.3 g, 34 mmol), and
stirring was continued for 16 h at ambient tem-
perature. Decomposition of excessive NaBH4 by a
few drops of HOAc and removal of the solvent
under reduced pressure left a residue which was
puri®ed by column (5Â39 cm) chromatography
(2:1 CHCl3±MeOH) to ꢀgive 24 (2.06 g, 87%) as a
1
[ꢀ]2d0 +100 (c 1, MeOH); H NMR (Me2SO-d6):
ꢁ 3.06 (t, 1H, H-400), 3.15 (m, 1H, H-200), 3.26 (m,
1H, H-500), 3.31±3.57 (m, 3H, H-300, two H-600), 3.63,
3.85 (2 dd, 1H each, two H-20), 4.42 (bs, 1H, OH-600),
4.63 (bs, 1H, OH-200), 4.65 (d, 1H, H-100), 4.71 (m,
1H, H-10), 4.81 (bs, 1H, OH-300), 4.88 (bs, 1H, OH-
400), 5.73 (d, 1H, OH-10), 7.03 (s, 1H, H-4), 7.55±
solid foam. [ꢀ]2d0 +100 (c 1, MeOH); H NMR
1
(Me2SO-d6): ꢁ 3.07 (t, 1H, H-400), 3.15 (dd, 1H, H-
200), 3.32 (m, 1H, H-500), 3.40, 3.51 (2 dd, 1H each,
two H-600), 3.43 (m, 1H, H-300), 3.58, 3.83 (2 dd, 1H
each, two H-20), 4.46 (s, 2H, 3-CH2), 4.65 (d, 1H,
H-100), 4.68 (m, 1H, H-10), 4.9 (bs, 6 H, 6 OH), 6.49
0
7.72 (m, 5 H, C6H5), 9.95 (s, 1H, CHO), J1 ,2 6.1
and 5.6, J2 ,2 10.4, J1 ,2 3.6, J3 ,4 9.2, J4 ,5 9.2,
0
0
0
00 00
00 00
00 00
J1 ,1 -OH 5.1 Hz; 13C NMR (Me2SO-d6): ꢁ 61.1 (C-
600), 63.4 (C-10), 70.3 (C-400), 70.8 (C-20), 72.2 (C-
200), 73.3 (C-500), 73.6 (C-300), 99.6 (C-100), 105.2 (C-
4), 125.9, 129.5, 129.7, 151.0 (C6H5), 139.2, 147.5
(C-3, C-5), 187.3 (CHO); MS (FD): m/z 394 (M+).
Anal. Calcd for C18H22N2O8 (394.37): C, 54.82; H,
5.62; N, 7.10. Found: C, 54.76; H, 5.58; N, 7.01.
5-[(10S)-Acetoxy-2-(2,3,4,6-tetra-O-acetyl-a-d-
glucopyranosyloxy)ethyl]-1-phenylpyrazole-3-carb-
oxaldehyde (23).ÐTo a solution of 1 g (1.4 mmol)
of pyrazole 21 in EtOH (6 mL) was added 6 mL of
a 35% aq formaldehyde solution and 0.3 mL of
HOAc, and the mixture was stirred for 6 h at
0
0
0
(s, 1H, H-4), 7.40±7.62 (m, 5H, C6H5), J1 ,2 6.4 and
0
0
0
00 00
00 00
00 00
00 00
5.2, J2 ,2 10.3, J1 ,2 3.6, J2 ,3 9.6, J3 ,4 9.2, J4 ,5
9.2, J5 ,6 5.0 and 1.9, J6 ,6 11.7 Hz; 13C NMR
(Me2SO-d6): ꢁ 57.2 (3-CH2), 60.6 (C-600), 63.0 (C-
10), 69.9 (C-400), 70.7 (C-20), 71.9 (C-200), 72.8 (C-
500), 73.1 (C-300), 98.9 (C-100), 104.3 (C-4), 124.8,
127.5, 129.0, 153.2 (C6H5), 139.4, 144.4 (C-3, C-5);
MS (FD): m/z 419 (M+Na+), 396 (M+). Anal.
Calcd for C18H24N2O8 (396.39): C, 54.54; H, 6.10;
N, 7.07. Found: C, 54.55; H, 6.00; N, 7.02.
00 00
00 00
3-Aminomethyl-5-[(10S)-2-(a-d-glucopyranosyloxy)-
1-hydroxyethyl]-1-phenylpyrazole
(25).ÐAcety-
lated phenylhydrazone 21 (1 g, 1.4 mmol) was
added to hydrazine hydrate (80% 50 mL), and the
mixture was heated for 1 h at 100 ꢀC. After cooling
to ambient temperature, 500 mg of Raney-nickel
was added and the mixture was kept at room tem-
perature for about 30 h. Filtration of the catalyst,
washing with water and MeOH, and evaporation
of the ®ltrate to dryness gave a residue, which was
puri®ed by column (3.5Â17 cm) chromatography
(6:1 iPrOH-2.5% aq NH3) to yield 25 (0.52 g, 93%)
ꢀ
100 C. After concentration under reduced pres-
sure to a few mL, 20 mL of an ice-cold satd.
NaHCO3 solution was added, followed by extrac-
tion with CH2Cl2 (4Â30 mL), washing with water
(3Â30 mL), drying (Na2SO4). Puri®cation by column
(2Â20 cm) chromatography (2:3 n-hexane±EtOAc)
gave 23 (600 mg, 73%) of 23 as an amorphous
1
powder; H NMR (CDCl3): ꢁ 1.88, 2.01±2.08 (5 s,
3H each, 5 Ac), 3.69, 3.99 (2 dd, 1H each, two H-
20), 3.90 (ddd, 1H, H-500), 4.06, 4.22 (2 dd, 1H each,
two H-600), 4.81 (dd, 1H, H-200), 5.02 (d, 1H, H-100),
ꢀ
1
as a solid foam; [ꢀ]2d0 +103 (c 1.0, MeOH); H
NMR (Me2SO-d6): ꢁ 3.11 (t, 1H, H-400), 3.19 (dd,

278
N. Oikawa et al./Carbohydrate Research 309 (1998) 269±279
1H, H-200), 3.28 (ddd, 1H, H-500), 3.41±3.52 (m, 3H,
H-300, two H-600), 3.57, 3.81 (2 dd, 1H each, two
H-20), 3.82 (s, 2H, NCH2), 4.60 (bs, 2H, 2 OH), 4.66
(d, 1H, H-100), 4.72 (m, 1H, H-10), 4.94, 5.10, 5.87
(3 bs, 1H each, 3 OH), 6.73 (s, 1H, H-4), 7.46±7.65
Agriculture and Forestry (Grant 94 NR 078-F),
administered by the Fachagentur Nachwachsende
Rohsto€e, Gulzow. The authors thank Dipl.-Ing.
Volker Diehl for repeating key experiments, clarify-
ing inconsistencies, and expert assistance in the pre-
paration of the manuscript.
0
(m, 5H, C6H5), 7.70 (s, 2H, NH2); J1 ,2 6.3 and 5.5,
0
0
0
00 00
00 00
00 00
00 00
J2 ,2 10.6, J1 ,2 3.5, J2 ,3 9.6, J3 ,4 9.3, J4 ,5 9.8,
00 00
J5 ,6 4.5 and 2.0 Hz; 13C NMR (Me2SO-d6): ꢁ 36.3
(3-CH2), 60.6 (C-600), 63.0 (C-10), 69.9 (C-400), 70.5
(C-20), 71.8 (C-200), 72.8 (C-300), 73.2 (C-500), 98.9
(C-100), 104.7 (C-4), 125.1, 128.3, 129.2, 138.9 (C6H5),
145.4, 145.6 (C-3, C-5); MS (FD): m/z 395 (M+).
3-Acetamidomethyl-5-[10S-acetoxy-2-(2,3,4,6-tetra-
O-acetyl-a-d-glucopyranosyloxy)ethyl]-1-phenylpyr-
azole (26).ÐTo a stirred and cooled (0 ꢀC) solution
of 25 (513 mg, 1.3 mmol) in 20 mL of dry pyridine
were added dropwise 5 ml of Ac2O. After 30 min
the ice bath was removed and the solution was
stirred for an additional 15 h at ambient temp. The
resulting mixture was hydrolyzed by the addition
of ice-water (5 mL), then concentrated under
reduced pressure to a syrup, which was extracted
with CH2Cl2 (100 mL). The extract was washed
successively with 2 n HCl (3Â50 mL), NaCl solu-
tion (30 mL), satd. NaHCO3 solution (3Â30 mL),
and again with NaCl solution (30 mL). Column
(4Â25 cm) chromatography (EtOAc) furnished 26
(698 mg, 83%) as a solid foam; [ꢀ]2d0 +109ꢀ (c 1,
CHCl3); 1H NMR (CDCl3): ꢁ 1.88±2.08 (6 s, 3H
each, 6 Ac), 3.68, 3.96 (2 dd, 1H each, two H-20),
3.90 (ddd, 1H, H-500), 4.06, 4.22 (2 dd, 1H each,
two H-600), 4.43, 4.55 (2 dd, 1H each, NCH2), 4.74
(dd, 1H, H-200), 5.02 (d, 1H, H-100), 5.03 (t, 1H, H-
400), 5.46 (t, 1H, H-300), 5.90 (t, 1H, H-10), 6.33 (m,
1H, NH), 6.44 (s, 1H, H-4), 7.47±7.57 (m, 5H,
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È
0
5.0 and 5.6, J1 ,2
3-CH2,NH
0
C6H5); J
) 5.3, J
gem(3-CH2
0
6.6 and 5.9, J2 ,2 10.8, J1 ,2 3.6, J2 ,3 10.3, J3 ,4
0
00 00
00 00
00 00
9.9, J4 ,5 10.2, J5 ,6 4.4 and 2.0, J6 ,6 12.4 Hz; 13
C
00 00
00 00
00 00
NMR (CDCl3): ꢁ 20.5±23.1 (6 COMe), 37.6
(NCH2), 61.7 (C-600), 65.4 (C-10), 67.9 (C-500), 68.2
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139.0, 141.0, (C-3, C-5), 169.5-170.5 (6 OCOMe);
MS (FD): m/z 647 (M+). Anal. Calcd for
C30H37N3O13 (647.6): C, 55.64; H, 5.76; N, 6.49.
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