Reducing disaccharides and their 1,2-dicarbonyl intermediates as building blocks for nitrogen heterocycles

Article abstract of DOI:10.1039/c3ra47349j

The existential importance of a sustainable economy necessitates the utilisation of plant based renewable resources such as lignin and carbohydrates. Carbohydrate utilization as industrial raw materials requires low environmental impact conversions from sugars to high value products. Here we present the conversion of reducing disaccharides into industrially relevant heterocycles of the quinoxaline-, 1,2,4-triazine-, pyrazine- and pyrazolo[3,4-b]quinoxaline- type. Heterocycle formation was facilitated by chemical conversion of reducing sugars into 1,2-dicarbonyl intermediates and their subsequent cyclization with nitrogen bis-nucleophiles. A range of disaccharides was converted into quinoxalines carrying a diverse glycosylation pattern on the polyhydroxy alkyl side chain. All transformations were performed without the need of protecting group chemistry.

Full text of DOI:10.1039/c3ra47349j

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Reducing disaccharides and their 1,2-dicarbonyl
intermediates as building blocks for nitrogen
heterocycles
Cite this: RSC Adv., 2014, 4, 5759
ab
and Eckehard Cunyb
*
Andreas Brust
The existential importance of a sustainable economy necessitates the utilisation of plant based renewable
resources such as lignin and carbohydrates. Carbohydrate utilization as industrial raw materials requires low
environmental impact conversions from sugars to high value products. Here we present the conversion of
reducing disaccharides into industrially relevant heterocycles of the quinoxaline-, 1,2,4-triazine-, pyrazine-
and pyrazolo[3,4-b]quinoxaline-type. Heterocycle formation was facilitated by chemical conversion of
reducing sugars into 1,2-dicarbonyl intermediates and their subsequent cyclization with nitrogen bis-
nucleophiles. A range of disaccharides was converted into quinoxalines carrying a diverse glycosylation
pattern on the polyhydroxy alkyl side chain. All transformations were performed without the need of
protecting group chemistry.
Received 8th November 2013
Accepted 16th December 2013
DOI: 10.1039/c3ra47349j
www.rsc.org/advances
N-heterocycles of the pyrrol-, thiophen-, pyridazine-, dia-
zepinone- and pyridazinone-type was achieved.10,12,13 Other work
Introduction
Peak oil production has been reached,1 but the chemical
industry is still reliant on non renewable oil based hydrocar-
bons. This creates the urgent necessity for a progressive
changeover towards renewable and hence, sustainable feed-
stocks to full the industries' raw material needs.2 Carbohy-
drates are by far the most abundant organic compounds and
represent the major portion of the renewable biomass. Carbo-
hydrate utilization for the production of low cost, sustainable
and eco-friendly chemicals or polymers of versatile industrial
applicability is herewith of central importance for relieving the
reliance of industry on petrochemical raw materials.2–7
The bulk scale sustainable carbohydrate conversion into
building blocks for ne chemical production requires entry
reactions with broad applicability and reaction pathways using
benign reagents and solvents. Aromatic N-heterocycles are key
building blocks of the chemical industry and their renement
leads to solvents, drugs, pesticides, polymers, pigments, ionic
liquids and other high value materials.
has expanded on the utilization of sugar phenylosazones as
building blocks for the synthesis of prrazoles.13–15 Rare exam-
ples of direct single step conversions of natural reducing sugars
into aromatic N-heterocycles, lead to quinoxalines,16,17 pyr-
azines,18 imidazoles,19–21 fused ring pyrazolo[3,4-b]quinoxa-
lines16,22,23 and benzimidazoles.24–26
Here we exploit reducing carbohydrates as a source of 1,2-
dicarbonyl-building blocks (diuloses) and their conversion into
N-heterocycles.
Enzymatic oxidative processes have been developed to
produce monosaccharide dicarbonyl sugars27–29 like 3-ketoglu-
cose,30 5-ketofructose,31 2,5-diketo-D-gluconate32 as well as 2-
keto-D-glucose (D-glucoson) 1.33,34 These biotechnological
produced dicarbonyl sugars show potential as building blocks
for heterocycle synthesis.35–38 In particular, the 1,2-dicarbonyl
sugar, D-glucoson 1 was used to access heterocycles (Scheme 1)
of the quinoxaline type16,17 / 3 the pyrazolo[3,4-b]quinoxaline
type16,22,23 / 2 and 1,2,4 triazine / 4 type.35 The selective bio-
conversion of disaccharides into the related 1,2-dicarbonyl
analogues is only limited realized for the (1 / 6) linked
disaccharides gentiobiose, isomaltose, melibiose and the (1 / 4)
linked lactose.27,39,40 To address the difficult access to 1,2-
dicarbony disaccharide analogues, chemical methods have
been investigated to allow for the general conversion of all
reducing sugars into these important building blocks for
heterocycles.
The key to the utilization of carbohydrates is the ability to
transform the poly-hydroxylated sugar framework and to
introduce reactive moiety's like e.g. carbonyl functions or amino
groups suitable for subsequent chemical modications. The
utilization of sugar derived furfurales8,9 as raw materials was
shown, leading to reactive 1,4-diketo compounds10 or g-keto-
carboxylic acid analogues.11 Their subsequent conversion into
In the pioneering work of Emil Fischer, the oxidation of
reducing sugars during formation of phenyl osazones (1,2-
bishydrazones) has had a groundbreaking impact towards the
elucidation of the conguration of carbohydrates.41 Phenyl
aInstitute of Molecular Bioscience, University of Queensland, Brisbane, Australia.
E-mail: a.brust@imb.uq.edu.au; Tel: +61 7 3346 2985
b
¨
¨
Clemens-Schopf Institut fur Organische Chemie und Biochemie, Technische
¨
Universitat Darmstadt, Darmstadt, Germany 97321
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Outside of the medicinal chemistry area, quinoxalines and
pyrazolo[3,4b]quinoxalines have found applications in organic
optoelectronic applications55 and have been considered as
candidates for the design of dye-sensitized solar cells (DSSCs).56
The application potential and the existing straightforward
synthetic procedures (Scheme 1) provide an interesting gateway
to 1,2-dicarbonyl sugar based N-heterocycles that will still
contain parts of the carbohydrate skeleton. Application to
disaccharides results in products with a tunable glycosylation
pattern on the hydroxylated side chain.
Here we present straightforward procedures allowing the
conversion of generally all reducing disaccharides and mono-
saccharide's into side chain poly-hydroxylated quinoxalines,
pyrazolo[3,4-b]quinoxalines, pyrazines and 1,2,4-triazines with a
diverse glycosylation pattern.
Scheme
1 The key 1,2-dicarbony building block 1 (2-keto-D-
glucose)33,34,42,43 enables access to N-heterocycles of the pyrazolo
[3,4b]quinoxaline- (2),16,21,22 quinoxaline- (3)16,17 and 1,2,4-triazine-
type (4).35
Results
Isomaltulose (palatinose®) is a naturally occurring disaccharide
and is also an industrial bulk sugar enzymatically produced
from sucrose as an intermediate for the production of low
caloric sweetener Isomalt®.57,58 Therefore, Isomaltulose is an
ideal cheap raw material as industrial feedstock.57,58
The focus of initial experiments was on utilizing isomaltulose
(a-D-Glcp-(1 / 6)-D-Fruf) for the conversion of reducing disac-
charides into N-heterocycles.
Isomaltulose was transformed into the osazone 5 with a yield
of 92%.14 Removal of the phenyl hydrazone protection of the
underlying 1,2-diketo-sugar 7 was achieved by treatment with
an excess of benzaldehyde (Scheme 2; method A) according to a
procedure reported by Byne.42 Due to required chromatographic
purication on silica gel was the isomaltosone 7 only obtained
in a yield of 40%. In an alternative process (Scheme 2; method
B) the removal of the hydrazone59 was achieved, via diazotation,
osazone formation follows a reaction cascade of initial phenyl
hydrazon formation, tautomeric rearrangement (Amadori rear-
rangement) and dehydration by excess phenyl hydrazin, thereby
yielding a b-keto hydrazine derivative and nally the formation
of the bis-phenyl hydrazon product. This process is a prototype
entry reaction as D-fructose or D-glucose bis-phenyl hydrazone
can chemically be transformed into the reactive 1,2-diketo sugar
1 (ref. 42 and 43) enabling access to a range of sugar-based
heterocycles (Scheme 1). The oson 1 converts with o-phenylen
diamine to the quinoxalines 3 and with amino guanidine to the
1,2,4 triazole 4.35 In the presence of phenyl hydrazine and
o-phenylen diamine, a direct conversion of D-fructose into a
pyrazolo[3,4-b]quinoxaline 2 has been achieved.22,23,44 In this
reaction the intermediate 1 forms a quinoxaline 3 and the
excess phenyl hydrazine performs the dehydration of the
secondary alcohol adjacent to the aromatic ring under phenyl-
hydrazon formation and cyclization to the pyrazolo-annulation
product 2 (R ¼ Ph). Quinoxaline 3 can also be obtained directly
from the sugars, employing hydrazine for dehydration and
direct cyclization with o-phenylen diamine (glucose/fructose /
3).23 Starting from 3 a pyrazolo annulation to 2 (R ¼ H) has been
performed employing hydrazine in acetic acid in the presence of
catalytic copper.45 These examples show the potential of 1,2-
dicarbonyl sugars as building block for high value products. In
particular this concept is emphasized, as N-heterocyclic scaf-
folds of the quinoxaline-, pyrazolo[3,4-b]quinoxaline- as well as
triazine- and pyrazine-type are found in a range of bioactive
molecules with a variety of pharmaceutical activitvities (for
reviews see e.g. quinoxalines and pyrazolo-quinoxalines,46–50
pyrazines,51 1,2,4-triazines52). Of notable interest are the optical
properties of quinoxalines and pyrazolo[3,4-b]quinoxalines as
they can be used for targeted cancer treatment when irradiated
with light.53 Additionally, by addressing bioactive molecules to a
particular site of action, employing carbohydrate recognition
motives54 suggests potential medicinal chemistry application
for carbohydrate-derived heterocycles.
Scheme 2 Reactive 1,2-dicarbonyl intermediate synthesis (method A
and B employing phenyl osazone intermediate 5 / 7. Method C is
employing a “one pot” hydrazine treatment with in situ formed 7)
allows for the conversion of isomaltulose into N-heterocycles of the
quinoxaline- (8) pyrazolo[3,4b]quinoxaline- (10), 1,2,3-triazine- (9) and
pyrazine-type (11).
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with sodium nitrite in acidic solution delivering a 50% yield of quinoxaline products 8a–c was obtained aer decoloring with
isomaltosone 7 aer chromatographic purication. activated charcoal and chromatographic workup in surprisingly
With the 1,2-dicarbonyl building block 7 obtained, cycliza- good 65, 50 and 30% yield (method C, see Table 1).
tion reactions were investigated towards the production of
N-hetreocycles (Scheme 2).
The transformation of the quinoxaline 3 into the pyrazole-
fused 2 (see Scheme 1) is possible in aqueous acetic acid using
The pure isomaltosone 7 reacts readily with 1,2-diamino hydrazine as dehydrating/cyclization reagent by employing
benzene derivates under formation of quinoxalines 8a (85% copper catalysis.45 When using these conditions for the
yield) and 8b (80% yield). Also the conversion into a 4-amino- conversion of 8a the desired product 10 was not formed due to
1,2,3-triazines 9 was achieved with amino guanidine (76% instability of the glycosidic bond resulting in product 2. Only
yield). While the same reaction with glucosone 1 delivered only when transferring the reaction into water free conditions by
a single product35 was no regio-chemical preference observed, using glacial acetic acid was the transformation (8a / 10) in
resulting in a mixture of isomeric products (9a and b). Dia- 38% yield possible.
minomaleonitrile was cyclized with isomaltosone 7, to the bis-
The “one pot” reaction cascade (method C; sugar / [6 / 7]
nitrile substituted pyrazine product 11 (43% yield). Reduction / heterocycle) of hydrazone formation; tautomerisation reac-
of the nitrile with hydrogen was possible over Pd/C resulting in tion followed by bis-hydrazone formation and nal hydrolysis to
a bis-aminomethyl substituted pyrazine, obtained as the bis- the osone 7 was considered as potentially useful to access
acetyl product 12 (31% yield).
heterocyclic compounds of the type 8–12 directly from any
The difficult purication of glucosone 7 was avoided by reducing sugar.
alternative procedures, the 1,2-dicarbonyl sugar 7 was gener-
Firstly we evaluated the scope of this “one pot” procedure
ated in situ and reacted directly with o-phenylen diamine to the towards quinoxalines of type 3 and 8 by investigating different
respective quinoxaline product 8. Starting from osazone 5, nitrogen donor molecules to give access to ring substitution.
diazotation was performed (Scheme 2, see method B) in acidic Alternative to o-diaminobenzene, 3,4-dichloro-o-diaminobenzene
sodium nitrite solution, removing the phenyl hydrazine groups. as well as 2,3-diaminonaphtaline and unsymmetrical 3,4-diamino
The formed phenyl azide byproduct was removed by extraction benzoic acid as cyclization partner was investigated to introduce
and the residual crude 7 was directly cyclized. This pathway ring substituents into the obtained products. In all cases
(isomaltulose / 5 / 7 / 8) resulted in some yield improve- the envisaged quinoxaline conversions (fructose / 3a–c, iso-
ment but more importantly required only a single chromato- maltulose / 8a–c) were obtained in good to moderate yield (see
graphic purication step for the conversion of 5 to 8a (overall Table 1). When using, the non-symmetric 3,4-diamino benzoic
yield from isomaltulose via 5 to 8a was 60%).
acid with fructose a mixture of the two regio-isomeric products (3c)
A further improvement (Scheme 2; method C) was achieved was obtained.
by employing a procedure developed by Ohle and Hilcher.23
Aer establishing the scope of the in situ hydrazine-dehy-
Instead of using an isolated phenyl osazone 5, with hydrazine dration/quinoxaline “one pot” cyclization with fructose and
an unsubstituted bis-hydrazone 6 was formed in situ as the isomaltulose, this protecting group free entry reaction (per-
dicarbonyl intermediate. The labile bis-hydrazon 6 hydrolyzes formed in water) was expanded towards other bulk scale
in situ to the dicarbonyl sugar 7. This process (isomaltulose / available disaccharides.60
[6 / 7] / 8) is achieved in “one pot” by treatment of the
Our aim was to obtain diverse glycosylation along the
carbohydrate with 3 equivalents of hydrazine in water at pH 7–8; hydrophilic tetrahydroxybutyl side chain of obtained quinoxa-
avoiding the cleavage of the glycosidic linkage, while reuxing line products (see Scheme 3). This glycosylation diversity was
with 1 equivalents of o-phenylene diamine for 18 h. The effectively introduced, based on the disaccharides used. Other
Table 1 Product yields obtained from “one pot” transformation of sugars into quinoxalines. Matrix shows obtained variable glycosylation pattern
and quinoxaline ring substitution
Sugar
DABa X ¼
#
R4
R3
R2
R1
Yield [%]
D-Fructose
D-Fructose
D-Fructose
Isomaltulose
Isomaltulose
Isomaltulose
Melibiose
Leucrose
Maltose
Cellobiose
Lactose/lactulose
Turanose
H
Cl
4-COOH
H
3
H
H
H
H
H
H
H
H
H
H
a-D-Glc
H
H
H
H
H
H
H
H
H
H
H
H
a-D-Glc
b-D-Glc
b-D-Gal
H
H
H
H
H
H
H
H
H
H
H
H
a-D-Glc
75
65
50
65
50
30
55
42
42
40
45/40
5
3b
3c
8a
8b
8c
13
14
15
16
17
18
a-D-Glc
a-D-Glc
a-D-Glc
a-D-Gal
Cl
b
H
H
H
H
H
H
H
H
H
H
a
DAB ¼ 1,2-diamino benzene analogue. b Condensation with 2,3-diamino naphthalene resulting in a benzo-annulated quinoxaline 8c.
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representative disaccharide example. However, the methods
presented are transferable to all reducing disaccharides, as was
shown in detail for the quinoxaline heterocycle class (/ 13–18).
In situ conversion of reducing sugars into 1,2-dicarbonyl
intermediates, employing hydrazine in a “one pot” process was
used to show that a matrix of quinoxalines (see Table 1) can be
produced. Based on the disaccharide starting material, prod-
ucts were obtained that are distinguished by diverse glycosyla-
tion patterns on the tetrahydroxybutyl side chain (see Scheme 3
and Table 1). The developed synthesis procedures can be easily
transferred into large scale production and the produced
N-heterocycles of the quinoxaline- (3, 8, 13–18), pyrazolo[3,4b]
quinoxaline- (10), triazine- (9) and pyrazine- (11 and 12) type can
provide suitable raw materials for novel high value products
with unique properties based on their carbohydrate origin.
Scheme 3 One pot condensation of carbohydrates with diamino
benzene (DAB) analogues into tetrahydroxybutyl substituted qui-
noxalines with
a
variable a/b-D-Glc/Gal-glycosylation sphere
depending on used starting disaccharide.
than the industrial produced disaccharide, isomaltulose (a-D-
Glcp-(1 / 6)-D-Fruf), we investigated the sustainable, in mass
scale produced, low cost carbohydrates60 such as the reducing
dissacharide-pyranoses; melibiose (a-D-Galp-(1 / 6)-D-Glcp),
maltose (a-D-Glcp-(1 / 4)-D-Glcp), cellobiose (b-D-Glcp-(1 / 4)-D-
Glcp) and lactose (b-D-Galp-(1 / 4)-D-Glcp) as well as leucrose
(a-D-Glcp-(1 / 5)-D-Frup). Furthermore, the rare disaccharide
turanose (a-D-Glcp-(1 / 3)-D-Fruf) was used as a model sugar to
also obtain a glycosylation adjacent to the heterocyclic qui-
noxaline ring system.
All reducing disaccharides were transformed into quinoxa-
lines (8 and 13–18) resulting in products with a diverse glyco-
sylation patterns on the tetrahydroxybutyl side chain.
While the yields of mono-saccharide derived quinoxalines
were good, disaccharides delivered the products 13–18 in
moderate yield, most likely due to chromatographic losses of
the highly hydrophilic products on silica gel (see Table 1).
A particular low yield was obtained for the turanose-derived
quinoxaline 18. Even though the reaction was performed at pH
8, partial cleavage of the glycosidic linkage (18 / 2) was
observed. In summary, these results show that the “one pot”
procedure is generally suitable for the conversion of reducing
disaccharides into quinoxalines allowing for the introduction of
heterocyclic ring substituents by selection of suitable 1,2-dia-
mino building blocks.
Experimental
Analytical instrumentation used: melting points (uncorrected
values) recorded on a Bock monoskop instrument. Spectral
measurements were performed on: Perkin Elmer 241 (rota-
tions), Varian MAT 311 A (MS), Bruker WM 300 instruments (1H
at 300 or 500, 13C NMR at 75.5 or 125 MHz, respectively). Perkin-
Elmer 240 elemental analyzer was used for compound micro-
analysis and purity conrmation. TLC on Kieselgel 60 F254
plastic sheets (Merck) was used to monitor the reactions and to
ascertain the purity of the products (single point on TLC plate);
eluents employed and Rf values observed are given in the
appropriate experiment; detection of TLC plates was performed
with UV-light or by charring with sulfuric acid. Column chro-
matography: Kieselgel 60 (63–200 mesh, Macherey-Nagel).
D-Glucopyranosyl-a(1 / 6)-D-arabino-hexos-2-ulose (7)
[isomaltoson (7)]
Method A: from isomaltulose phenylosazon 5 (ref. 14) via
hydrazone transfer to benzaldehyde To a suspension of 12.0 g
(23.1 mmol) isomaltulose-phenylosazone 5 (ref. 14) in 240 mL of
EtOH, 400 mL of water and 6 mL of concentrated acetic acid was
added 16 mL of freshly distilled benzaldehyde. Aer 6 h on
reux a further 4 mL glacial acetic acid was added and reuxed
for an additional 2 h. Solvent was removed in vacuum and the
Conclusion
ꢀ
residual solution was stored over night at 4 C resulting in the
Carbohydrates provide a sustainable source of carbon, which crystallisation of benzaldehyde phenylhydrazone, which was
can potentially replace petrochemical raw materials.2,7 Carbo- removed by vaccum ltration. The residual solution was treated
hydrate transformation into heterocyclic molecules may alle- for 30 min. with activated charcoal at 60 ꢀC, ltered and
viate some of the resource pressure of the chemical industry, concentrated in vacuo. The crude product, 7.44 g of a brown
while delivering novel unique molecular entities. Carbohy- foam, was puried on silica gel (12 ꢁ 25 cm) by elution with
drates can provide molecular features such as their hydrophilic, MeCN–H2O (4 : 1). Evaporation of fractions with Rf 0.24 yield
poly-hydroxylated backbone with resulting enzymatic instability 3.05 g (40%) 7 in form of a yellow hard foam.
(biodegradability) to sugar derived heterocyclic products.
Method B: from isomaltulose phenylosazone 5 (ref. 14) via
Elaboration of facile chemical pathways to 1,2-dicarbonyl diazotation with NaNO2 To as suspension of isomaltulose
intermediates of carbohydrates was presented. The conversion phenylosazone 5 (2.6 g, 5 mmol) in ethanol–water (2 : 1, 30 mL)
of 1,2-dicarbonyl disaccharide building blocks allowed access to 1.2 mL conc. HCl is added adjusting pH to 3. At 30 ꢀC and strong
quinoxalines (8), triazines (9), pyrazol[3,4b] quinoxalines (10) as agitation a solution of NaNO2 (0.7 g, 10 mmol) in water (5 mL)
well as pyrazines (11 and 12). These products were obtained was added within 15 min. The resulting red solution is buffered
from the cheap bulk carbohydrate isomaltulose as
a
by addition of 0.75 g of NaOAc. Ethanol was removed in vacuo
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and the formed red phenyl azide was removed by extraction of Amberlite IR120 acidic ion exchange resin the mixture was
with CHCl3 (5 ꢁ 50 mL). The residual aqueous solution was steered in an argon atmosphere for 18 h at room temp. Aer
evaporated in vacuo resulting in a slightly yellow hard foam. The ltration over diatomite, the solution was concentrated and
crude product was puried on silica gel (4 ꢁ 20 cm) with MeCN– puried on silica gel (2.5 ꢁ 25 cm) using CHCl3–MeOH 2 : 1 as
H2O (4 : 1) as eluent. Evaporation of fractions with Rf 0.24 yield eluent. Combined fractions with Rf 0.46 were evaporated
0.85 g (50%) 7 in form of a yellow hard foam—[a]2D0 + 90ꢀ (c delivered 198.4 mg (43%) o the pyrazine 11 as a light brown
0.99, DMSO).
amorphous residue. (Found: C, 46.66; H, 4.93; N, 13.55%
C
16H20N4O9 requires C, 46.60; H, 4.89; N, 13.59%); 1H NMR (300
1H NMR (300 MHz, [D6]DMSO): d 3.08 (dd, 1H, 40-H), 3.20
(dd, 1H, 20-H), 3.37–3.50 (m, 4H, 4-H, 30-H, 50-H, 60-Ha), 3.55– MHz, [D6]DMSO): d 3.30 (dd, 1H, 400-H), 3.41 (dd, 1H, 200-H),
3.65 (m, 2H, 6-Ha, 60-Hb), 3.78 (dd, 1H, 6-Hb), 4.13 (m, 1H, 5-H), 3.61–3.66 (m, 4H, 40-Ha, 300-H, 400-H, 600-Ha), 3.76 (m, 1H, 600-Hb),
4.32 (m, 1H, 3-H), 4.68 (d, 1H, 10-H), 4.60–4.70 (m, 3H, 20-OH, 30- 3.90 (dd, 1H, 20-H), 3.95 (m, 1H, 30-H), 4.01 (dd, 1H, 40-Hb), 4.84
OH, 40-OH), 4.90 (s, 1H, 1-H)—J5,6b ¼ 5.5, J6,6 ¼ 10.8, J1 ,2 ¼ 3.4, (d, 1H, 100-H), 5.52 (d, 1H, 10-H), 9.16 (s, 1H, 3-H)—J1 ,2 ¼ 3.7,
0
0
00 00
J2 ,3 ¼ 9.6, J3 ,4 ¼ 8.9, J4 ,5 ¼ 8.9 Hz. 13C NMR (75.5 MHz, [D6] J2 ,3 ¼ 9.6, J3 ,4 ¼ 9.1, J4 ,5 ¼ 9.1 Hz, J1 ,2 ¼ 1.5, J2 ,3 ¼ 9.2,
0
0
0
0
0
0
00 00
00 00
00 00
0
0
0
0
DMSO): d 61.1 (C-60), 66.5 (C-6), 70.4 (C-40), 71.2 (C-5), 72.2 (C-20), J3 ,4b ¼ 6.3, J4 ,4 ¼ 10.3 Hz. 13C NMR (75.5 MHz, [D6]DMSO): d
0
0
0
0
72.8 (C-30), 73.4 (C-50), 74.5 (C-4), 76.5 (C-3), 93.9 (C-1), 98.9 62.6 (C-600), 70.3 (C-40), 71.0 (C-500), 71.7 (C-10), 73.3–75.0 (C-30,
(C-10), 201.9 (C-2). MS (FD): m/z ¼ 363 [M+ + Na].
C-200, C-300, C-400), 75.3 (C-20), 100.4 (C-100), 114.7, 114.8 (2 CN),
132.8, 133.6 (C-5, C-6), 148.7 (C-3), 164.9 (C-2).
3-Amino-5-[(10R,20S,30R)-40-(a-D-glucopyranosyloxy)-10,20,30-
trihydroxy-butyl]-1,2,4-triazine (9a) and 3-amino-6-
[(10R,20S,30R)-40-(a-D-glucopyranosyloxy)-10,20,30-trihydroxy-
butyl]-1,2,4-triazine (9b)
5,6-Bis-(N-acetylaminomethyl)-2-[(D-arabino)-40-(a-D-
glucopyranosyloxy)-10,20,30-trihydroxybutyl]-pyrazine (12)
To a solution of dicyano pyrazine 11 (0.8 mmol, 330 mg) in 8 mL
To a solution of 200 mg (0.59 mmol) of isomaltosone 7 in 10 mL of dry methanol and 0.3 mL of acetic anhydride was added
of water was added 100 mg (0.73 mmol) of aminoguanidine- 100 mg of Palladium on activated charcoal. Aer steering in a
ꢀ
hydrogencarbonat and it was steered for 3 h at 30 C. Concen- hydrogen atmosphere over night, the solution was ltered over
tration in vacuo results in a light brown amorphous residue diatomite. The ltrate was concentrated and puried on silica
which was puried on silica gel (3 ꢁ 15 cm) using ethanol–25% gel (2 ꢁ 20 cm) using CHCl3–MeOH (1 : 1) as eluent. Combined
NH3-sol (3 : 1) as eluent. Evaporation of product containing fractions with Rf 0.37 were evaporated and delivered 125 mg
fractions delivered 170 mg (76%) of a 1 : 1 mixture of triazine 9a (31%) of bis-acetylamino pyrazine 12 as a light yellow syrup. 1H
and 9b as a light brown amorphous solid. A second chromato- NMR (300 MHz, [D6]DMSO): d 1.87, 1.88 (2s, 6H 2 COCH3), 3.07
graphic purication on silica gel (2 ꢁ 30 cm) employing the (m, 1H, 200-H), 3.20 (m, 2H, 300-H, 400-H), 3.44–3.46 (m, 4H, 20-H,
same eluent allowed for the separation o the individual regio- 30-H, 500-H, 600-Ha), 3.56 (m, 2H, 40-Ha, 600-Hb), 3.72–3.75 (m, 1H,
isomeric triazines 9a and b allowing their NMR spectroscopic 40-Hb), 4.41–4.48 (m, 4H, 5-CH2, 6-CH2), 4.67 (d, 1H, 100-H), 4.98
00 00
characterisation. (Found: C, 41.15; H, 5.90; N, 14.95% (s, 1H, 10-H), 8.27–8.32 (m, 2H, 2 NH), 8.59 (s, 1H, 3-H)—J1 ,2
¼
00 00
00 00
00 00
0
0
0
0
C
13H22N4O9 requires C, 41.27; H, 5.86; N, 14.81%).
3.7, J2 ,3 ¼ 9.6, J3 ,4 ¼ 9.1, J4 ,5 ¼ 9.1 Hz, J1 ,2 ¼ 1.5, J2 ,3 ¼ 9.2,
9a: Rf 0.20 [ethanol–25% NH3-sol (3 : 1)]. 1H NMR (300 MHz, J3 ,4b ¼ 6.3, J4 ,4 ¼ 10.3 Hz. 13C NMR (75.5 MHz, [D6]DMSO): d
0
0
0
0
D2O): d 3.35–3.48 (m, 1H, 400-H), 3.58–3.61 (m, 1H, 200-H), 3.71– 62.6 (C-600), 70.3 (C-40), 71.0 (C-500), 71.7 (C-10), 73.3–75.0 (C-30,
3.81 (m, 6H, 300-H, 500-H, 600-Ha, 600-Hb, 30-H, 400-H), 3.96–4.03 (m, C-200, C-300, C-400), 75.3 (C-20), 100.4 (C-100), 114.7, 114.8 (2 CN),
3H, 20-H, 40-H2), 4.96 (m, 1H, 100-H), 5.01 (d, 1H, 10-H), 8.78 (s, 132.8, 133.6 (C-5, C-6), 148.7 (C-3), 164.9 (C-2).
1H, 5-H)—J1 ,2 ¼ 2.5 Hz. 13C NMR (75.5 MHz, D2O): d 62.9
(C-600), 70.9 (C-40), 71.5 (C-30), 71.7 (C-400), 72.1 (C-10), 73.4 (C-200),
74.2 (C-500), 75.5 (C-20), 100.6 (C-100), 141.5 (C-6), 165.0 (C-5),
0
0
(2-[(10R,20S,30R)-40-(a-D-glucopyranosyloxy)-10,20,30-
trihydroxybutyl])-quinoxaline (8a)
+
168.3 (C-3). MS (FD): m/z ¼ 362 [M ꢂ NH2 ].
Method A: via cyclisation of pure isomaltosone 7 with
o-phenylen diamin: (7 / 8a). To a solution of 340 mg
(1.0 mmol) isomaltosone 7 in water (10 mL), 120 mg (1.1 mmol)
of o-phenylendiamine was added and 1.5 h steered at 60 ꢀC.
Evaporation in vacuo resulted in a dark brown residue which
was puried on silica gel (3 ꢁ 18 cm) with CHCl3–MeOH (3 : 1)
as eluent. Evaporation of fractions with Rf 0.35 [CHCl3–MeOH
(1 : 1)] yielded 350 mg (85%) of quinoxaline 8a as a light brown
amorphous solid.
9b: Rf 0.14 [ethanol–25% NH3-sol (3 : 1)]. 1H NMR (300 MHz,
D2O): d 3.35–3.48 (m, 1H, 400-H), 3.58–3.61 (m, 1H, 200-H), 3.71–
3.81 (m, 6H, 300-H, 500-H, 600-Ha, 600-Hb, 30-H, 400-H), 3.96–4.03 (m,
3H, 20-H, 40-H2), 4.96 (m, 1H, 100-H), 5.20 (d, 1H, 10-H), 8.54 (s,
1H, 6-H)—J1 ,2 ¼ 2.5 Hz. 13C NMR (75.5 MHz, D2O): d 62.9 (C-
600), 70.9 (C-40), 71.5 (C-30), 71.7 (C-400), 72.1, 72.6 (C-10), 73.4 (C-
200), 74.2 (C-500), 75.5 (C-20), 100.6 (C-100), 141.5 (C-6), 154.1, (C-5),
0
0
+
168.3 (C-3). MS (FD): m/z ¼ 362 [M ꢂ NH2 ].
Method B: from isomaltulose phenylosazone 5 via in situ
generated isomaltosone 7 employing diazotation (5 / 8a). To
as suspension of phenylosazone 5 (ref. 14) (2.6 g, 5 mmol) in
5,6-Dicyano-2-[(D-arabino)-40-(a-D-glucopyranosyloxy)-10,20,30-
trihydroxybutyl]-pyrazine (11)
To a solution of isomaltosone 7 (1.12 mmol, 380.8 mg) in 8 mL ethanol–water (2 : 1, 30 mL) 1.2 mL of conc. HCl is added to
ꢀ
of dry methanol was added 122 mg (1.12 mmol) of diamino adjust the pH to 3. At 30 C and strong agitation a solution of
˚
maleodinitril. Aer addition of molecular sieve (3 A) and 500 mg NaNO2 (0.7 g, 10 mmol) in water (5 mL) is added within 15 min.
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The resulting red solution was buffered with 0.75 g of NaOAc. (m, 1H, 300-H), 4.01 (dd, 1H, 30-Hb), 4.07 (dd, 1H, 600-Ha), 4.28
Ethanol was removed in vacuo and the red phenyl azide was (dd, 1H, 600-Hb), 4.69 (m, 1H, 20-H), 4.77 (d, 1H, 100-H), 5.03 (d,
removed by extraction with CHCl3 (5 ꢁ 50 mL). To the 1H, 10-H), 7.82 (m, 1H, 7-H), 7.91 (m, 1H, 6-H), 8.14 (d, 1H, 5-H),
remaining aqueous solution o-phenylendiamine (0.54 g, 5 8.28 (d, 1H, 8-H), 13.77 (bs, 1H, NH)—J5,6 ¼ 8.5, J6,7 ¼ 7.1, J7,8
¼
ꢀ
0
0
0
0
0
0
0
0
00 00
mmol) was added and 1 h heated to 80 C. Aer decolouring 8.5, J1 ,2 ¼ 9.1, J2 ,3 a ¼ 2.0, J2 ,3 b ¼ 4.5, J3 a,3 b ¼ 9.7, J1 ,2 ¼ 3.6,
with activated charcoal (1.0 g), ltration and concentration in J2 ,3 ¼ 9.5, J4 ,5 ¼ 9.2, J5 ,6 ¼ 5.7 J6 a,6 b ¼ 11.7 Hz. 13C NMR
vacuo, the residual was puried on silica gel (5 ꢁ 20 cm) with (125.75 MHz, [D6]DMSO): d ¼ 63.8 (C-600), 68.3 (C-10), 69.1 (C-30),
CHCl3–MeOH (3 : 1) as eluent. Quinoxaline 8a (1.2 g, 60%) was 69.9 (C-300), 70.5 (C-500), 71.3 (C-20), 72.6 (C-200), 73.9 (C-400), 99.0
00 00
00 00
00 00
00
00
obtained as yellowish hard foam.
(C-100), 128.1 (C-7), 128.7 (C-5), 130.4 (C-8), 131.1 (C-6), 135.5,
Method C: general “one pot” method for the conversion of 140.4 (C-10, C-11), 141.3, 144.3 (C-12, C-13), 147.2 (C-3).
reducing sugars into quinoxalines (3, 3b, 3c, 8a, 8b, 8c, 13–18)
6,7-Dichlor-2-[(10R,20S,30R)-40-(a-D-glucopyranosyloxy)-10,20,30-
trihydroxy-butyl]-quinoxaline (8b)
employing hydrazine hydrate and o-phenylendiamine analogues.
Reducing sugars (10 mmol) were dissolved in 50 mL of water and
1.5 mL (30 mmol) of hydrazine hydrate was added. Using acetic
acid the pH was adjusted to 7–8 and the solution was heated to
100 ꢀC for 18 h. Aer treatment with activated charcoal (1 g),
ltration and evaporation a amorphous residue was obtained and
was puried on silica gel.
(isomaltulose / 8a) The obtained brown residue was eluted
from silica gel (5 ꢁ 25 cm) with CHCl3–MeOH 3 : 1. Quinoxaline
8a (2.65 g, 65%) was obtained as a brown yellow amorphous
foam—[a]2D0 + 13.7 (c 0.98, DMSO). (Found: C, 52.44; H, 5.80; N,
6.75% C18H24N2O9 requires C, 52.42; H, 5.87; N, 6.79%); 1H
NMR (300 MHz, [D6]DMSO): d 3.07 (dd, 1H, 400-H), 3.18 (dd, 1H,
200-H), 3.41–3.47 (m, 3H, 300-H, 500-H, 600-Ha), 3.54 (m, 2H, 40-Ha,
600-Hb), 3.72 (m, 1H, 20-H), 3.76–3.82 (m, 2H, 30-H, 40-Hb), 4.40
(bs, 1H, 600-OH), 4.69 (d, 1H, 100-H), 4.81 (m, 5H, 20-OH, 30-OH,
200-OH, 300-OH, 400-OH), 5.19 (s, 1H, 10-H), 7.79–7.84 (m, 2H, 6-H,
Method A: via cyclisation of pure isomaltosone 7 with 3,4-
dichloro-o-phenylen diamine: (7 / 8b). Similar to conversion
(7 / 8a), isomaltosone 7 (340 mg, 1.0 mmol) in water (50 mL)
was converted with 3,4-dichlor-phenylendiamin (180 mg,
1.1 mmol). Workup as for 8a and chromatographic purication
on silica gel (3 ꢁ 18 cm) with CHCl3–MeOH (3 : 1) as eluent
delivered 380 mg (80%) quinoxaline 8b as a light brown amor-
phous solid—Rf 0.62 [CHCl3–MeOH (1 : 1)].
Method B: from isomaltulose via “one pot” conversion
employing hydrazine hydrate and 3,4-dichlor-o-phenylendi-
amine. Similar to (isomaltulose / 8a), was isomaltulose (3.6 g,
10 mmol) cyclized with 3,4-dichloro-o-phenylendiamine (1.8 g,
10 mmol) and hydrazine hydrate (1.5 mL, 30 mmol) at pH 7–8
(CH3COOH). Workup and chromatographic purication as for
8a delivered 2.4 g (50%) of 8b as light brown solid. (Found: C,
45.01; H, 4.64; N, 5.90% C18H22Cl2N2O9 requires C, 44.92; H,
4.61; N, 5.82%); 1H NMR (300 MHz, CD3OD): d 3.32 (dd, 1H, 400-
H), 3.45 (dd, 1H, 200-H), 3.59–3.64 (m, 5H, 300-H, 400-H, 500-H,
600-Ha, 30-H), 3.67–3.70 (m, 1H, 600-Hb), 4.06–4.07 (m, 3H, 20-H,
40-H2), 4.85 (s, 1H, 100-H), 5.32 (s, 1H, 10-H), 8.20, 8.21 (2 s, je 1H,
00 00
7-H), 8.04–8.10 (m, 2H, 5-H, 8-H), 9.12 (s, 1H, 3-H)—J1 ,2 ¼ 3.3,
00 00
00 00
00 00
J2 ,3 ¼ 9.4, J3 ,4 ¼ 9.1, J4 ,5 ¼ 9.1 Hz.
13C NMR (75.5 MHz, [D6]DMSO): d 61.1 (C-600), 69.3 (C-30),
69.8 (C-40), 70.4 (C-400), 72.6–72.8 (C-10, C-200, C-300), 73.9 (C-500),
74.7 (C-20), 99.2 (C-100), 128.9, 129.2 (C-5, C-8), 129.6, 130.3 (C-6,
1
C-7), 140.7, 140.9 (C-4a, C-8a), 145.7 (C-3), 159.4 (C-2). H NMR
5-H, 8-H), 9.14 (s, 1H, 3-H)—J1 ,2 ¼ 3.5, J2 ,3 ¼ 9.6 Hz. 13C NMR
(75.5 MHz, CD3OD): d 63.0 (C-600), 70.6 (C-40), 71.5 (C-30), 72.0
(C-400), 74.0 (C-200), 74.2 (C-10, C-500),75.5 (C-300), 75.7 (C-20), 100.7
(C-100), 131.0, 131.1 (C-5, C-8), 135.1, 135.6 (C-6, C-7), 141.9 (C-4a,
C-8a), 147.8 (C-3), 161.8 (C-2).
00 00
00 00
(300 MHz, CD3OD): d 3.34 (dd, 1H, 400-H), 3.43 (dd, 1H, 200-H),
3.60–3.73 (m, 5H, 300-H, 500-H, 600-Ha, 600-Hb, 30-H), 4.03–4.07 (m,
3H, 20-H, 40-H2), 4.85 (d, 1H, 100-H), 5.35 (s, 1H, 10-H), 7.76–7.82
(m, 2H, 6-H, 7-H), 8.04–8.09 (m, 2H, 5-H, 8-H), 9.14 (s, 1H, 3-
H)—J1 ,2 ¼ 3.5, J2 ,3 ¼ 9.6 Hz. 13C NMR (75.5 MHz, CD3OD): d
62.5 (C-600), 70.1 (C-40), 71.1 (C-30), 71.6 (C-400), 73.6 (C-10), 73.7
(C-200), 75.0 (C-500), 75.2 (C-20), 100.2 (C-100), 129.5, 129.8 (C-5, C-
8), 130.8, 131.3 (C-6, C-7), 142.5, 142.7 (C-4a, C-8a), 145.9 (C-3),
159.7 (C-2). MS (FD): m/z ¼ 435 [M+ + Na].
00 00
00 00
2-[(10R,20S,30R)-40-(a-D-Glucopyranosyloxy)-10,20,30-
trihydroxybutyl]-benzo[1,2-g]quinoxaline (8c)
From isomaltulose via “one pot” cyclization with hydrazine
hydrate and 2,3-diamino-naphtaline. Similar to (isomaltulose /
8a), isomaltulose (3.6 g, 10 mmol) was cyclized with 2,3-diamino-
naphtalene (0.85 g, 5.4 mmol) and hydrazine hydrate (1.5 mL,
30 mmol) at pH 7–8 (CH3COOH). The reaction was performed in
3-[(10S,20R)-30-(a-D-Glucopyranosyloxy)-10,20, dihydroxy-propyl]-
1-H-pyrazolo-[3,4-b]-quinoxaline (10)
To a solution of 300 mg (0.73 mmol) of quinoxaline 8a in 10 mL 30 mL of water–DMF (1 : 2) for 18 h under reux. Aer dilution
of glacial acetic acid was added 0.25 mL (5 mmol) of hydrazine with water (50 mL) and extraction with chloroform (3 ꢁ 50 mL),
hydrate and 0.5 g of copper powder. Aer reuxing for 4 h it was the aqueous phase was evaporated and chromatographic puri-
ltered and the solvent removed in vacuum. The residual was ed on silica gel (5 ꢁ 25 cm) with CHCl3–MeOH 2 : 1 as eluent.
puried on silica gel (CHCl3–MeOH, 3 : 1) and product fractions Aer evaporation of product containing fractions with Rf 0.32
with Rf 0.41 were combined and evaporated to yield 10 (150 mg, (CHCl3–MeOH 1 : 1) the benzo[1,2-g]quinoxalin 8c (693 mg,
48%) as a yellow amorphous hard foam. (Found: C, 51.22; H, 30%) was obtained as a orange syrup. (Found: C, 57.12; H, 5.25;
1
5.33; N, 13.25% C18H22N4O8 requires C, 51.18; H, 5.25; N, N, 6.13% C22H26N2O9 requires C, 57.14; H, 5.67; N, 6.06%); H
1
13.26%); H NMR (500 MHz, [D6]DMSO): d 3.14 (m, 1H, 500-H), NMR (300 MHz, CD3OD): d 3.33 (m, 1H, 400-H), 3.44 (m, 1H, 200-
3.24 (dd, 1H, 200-H), 3.54 (t, 1H, 400-H), 3.65 (dd, 1H, 30-Ha), 3.81 H), 3.57–3.72 (m, 6H, 300-H, 400-H, 500-H, 600-H2, 30-H), 4.02–4.09
5764 | RSC Adv., 2014, 4, 5759–5767
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(m, 3H, 20-H, 40-H2), 4.82 (d, 1H, 100-H), 5.37 (m, 1H, 10-H), 7.60 the 7- and 6-quinoxaline carboxylic acid making the signal
(m, 2H, 7-H, 8-H), 8.15 (m, 2H, 6-H, 9-H), 8.61 (2 s, je 1H, 5-H, identication in the NMR ambiguous.
10-H), 9.15 (s, 1H, 3-H)—J1 ,2 ¼ 3.8 Hz. 13C NMR (75.5 MHz,
1H NMR (300 MHz, [D6]DMSO): d 3.35 (m, 1H, OH), 3.70 (m,
00 00
CD3OD): d 62.5 (C-600), 70.1 (C-40), 71.3 (C-30), 72.1 (C-400), 74.0 (C- 1H, 40-Ha), 3.85–4.00 (m, 6H, 20-H, 30-H, 40-Hb, 3 OH), 5.33 and
200), 73.8 (C-10), 74.0 (C-500), 75.0 (C-300), 75.2 (C-20), 100.3 (C-100), 5.35 (2 s, combined 1H, 10-H of 6- and 7-carboxylic acid 3c), 7.98
124.7–129.3 (C-5, C-6, C-7, C-8, C-9, C-10), 135.0, 135.3 (C-5a, and 8.01 (2 s, 1H, 5-H in 7-carboxylate, 8-H in 6-carboxylate),
C-9a), 139.0, 139.2 (C-4a, C-10a), 147 (C-3), 161.0 (C-2). MS (FD): 8.30 and 8.33 (2 d, 1H, 6-H in 7-carboxylate, 7-H in 6-carbox-
m/z ¼ 485 [M+ + Na].
ylate), 8.61 (s, 1H, 5-H in 6-isomer, 8-H in 7-isomer), 9.10 and
9.13 (2 s, 1H, 3-H in 6- and 7-isomer). 13C NMR (75.5 MHz, [D6]
DMSO): d 64.9 (C-40), 72.9 (C-30), 73.8 (C-20), 75.5 (C-10), 129.2,
129.4 (C-5 in 7-isomer, C-8 in 6-isomer), 131.1 (C-5 in 6-isomer,
C-8 in 7-isomer), 131.8, 132.3 (C-6 in 7-isomer, C-7 in 6-isomer),
139.8, 142.0, 142.2, 143.6 (C-4a, C-8a), 146.6 (C-3), 160.3 (C-2),
173.3 (COOH). MS (FD): m/z ¼ 317 [M+ + Na].
2-[(10R,20S,30R)-10,20,30,40-Tetrahydroxybutyl]-Quinoxaline (3)
From fructose via “one pot” conversion employing hydrazine
hydrate/o-phenylendiamine. Similar to (isomaltulose / 8a) was
D-fructose (3.6 g, 20 mmol) cyclized with o-phenylendiamine
(2.7 g, 20 mmol) and hydrazine hydrate (3 mL, 60 mmol) at pH
7–8 (CH3COOH). Workup and crystallisation in the cold deliv-
ered quinoxaline 3 in form of light brown crystal needles; 3.7 g 2-[(10R,20S,30R)-40-(a-D-Galactopyranosyloxy)-10,20,30-
(75%)—Mp 190–192 ꢀC—Rf 0.45 (CHCl3–MeOH 1 : 1)—Lit.61: trihydroxybutyl]-quinoxaline (13)
ꢀ
Mp 192 C, 62% Synthesis at pH 6 under addition of boronic
From melibiose monohydrate via “one pot” conversion
acid. 1H NMR (300 MHz, [D6]DMSO): d 3.52 (m, 1H, 40-Ha), 3.68–
employing hydrazine hydrate/o-phenylendiamine. Similar to
3.73 (m, 3H, 20-H, 30-H, 40-Hb), 4.20–4.50 (m, 4H, 10-OH, 20-OH,
(isomaltulose / 8a) was melibiose (3.6 g, 10 mmol) converted
30-OH, 40-OH), 5.19 (s, 1H, 10-H), 7.82–7.86 (m, 2H, 6-H, 7-H),
with o-phenylendiamine (1.1 g, 10 mmol) and hydrazine hydrate
8.04–8.11 (m, 2H, 5-H, 8-H), 9.13 (s, 1H, 3-H). 13C NMR (75.5
(1.5 mL, 30 mmol) at pH 7–8, and reux for 18 h. Workup and
MHz, [D6]DMSO): d 63.4 (C-40), 71.2 (C-30), 72.4 (C-10), 72.3 (C-20),
chromatographic purication as for 8a delivered 2.3 g (55%) of
128.5, 128.2 (C-5, C-8), 129.2, 129.9 (C-6, C-7), 140.8, 140.9 (C-4a,
20
13 as light brown solid—Rf 0.39 (CHCl3–MeOH, 1 : 1)—[a]D
+
C-8a), 145.1 (C-3), 159.4 (C-2). MS (FD): m/z ¼ 250 [M+], 251 [M+ +
15.3ꢀ (c 1.05, MeOH). (Found: C, 52.47; H, 5.89; N, 6.83%
18H24N2O9 requires C, 52.42; H, 5.87; N, 6.79%); 1H NMR (300
H], 252 [M+ + 2H], 273 [M+ + Na].
C
MHz, CD3OD): d 3.31–3.86 (m, 7H, 30-H, 200-H, 300-H, 400-H, 500-H,
600-H2), 4.01–4.06 (m, 3H, 20-H, 40-H2), 4.88 (d, 1H, 100-H), 5.35 (s,
1H, 10-H), 7.76–7.83 (m, 2H, 6-H, 7-H), 8.04–8.08 (m, 2H, 5-H, 8-
6,7-Dichloro-2-[(10R,20S,30R)-10,20,30,40-tetrahydroxy-butyl]-
quinoxaline (3b)
H), 9.14 (s, 1H, 3-H)—J1 ,2 ¼ 3.5 Hz. 13C NMR (75.5 MHz,
00 00
From D-fructose via “one pot” conversion, employing hydra-
zine hydrate and 4,5-dichloro-o-phenylendiamine: D-fructose
(3.6 g, 20 mmol) was cyclized with 4,5-dichloro-o-phenyl-
endiamine (3.6 g, 20 mmol), hydrazine hydrate (3 mL,
60 mmol) at pH 7–8 (CH3COOH). Workup as for 8a and
elution from silica gel (6 ꢁ 25 cm) with CHCl3–MeOH 3 : 1
delivered aer evaporation of fractions Rf 0.64 (CHCl3–MeOH,
1 : 1) quinoxaline 3b (4.7 g, 65%) as a light brown amorphous
CD3OD): d 62.7 (C-600), 70.2 (C-40), 70.5 (C-30), 71.0 (C-400), 71.6 (C-
10), 72.2 (C-300), 73.7 (C-500), 75.2 (C-20),100.5 (C-100), 129.6, 129.8
(C-5, C-8), 130.8, 131.4 (C-6, C-7), 142.5, 142.7 (C-4a, C-8a), 145.9
(C-3), 159.7 (C-2). MS (FD): m/z ¼ 435 [M+ + Na].
2-[(10R,20S,30R)-30-(a-D-Glucopyranosyloxy)-1',2',4'-trihydroxy-
butyl]-quinoxaline (14)
1
solid. —Ref. 22, 43% yield. H NMR (300 MHz, [D6]DMSO): d
From leucrose via “one pot” conversion employing hydrazine
hydrate/o-phenylendiamine. Similar to (isomaltulose / 8a)
was leucrose (3.4 g, 10 mmol) cyclized with o-phenylendiamine
(1.1 g, 10 mmol) and hydrazine hydrate (1.5 mL, 30 mmol) at
pH 7–8, and reux for 18 h. Workup and chromatographic
purication as for 8a (CHCl3–MeOH, 2 : 1) delivered qui-
noxaline 14 (1.72 g, 42%) as a light brown hard foam—Rf 0.42
(CHCl3–MeOH 1 : 1)—[a]2D0 + 35.7 (c 1.00, MeOH). 1H NMR
(300 MHz, CD3OD): d 3.32 (t, 1H, 400-H), 3.51 (dd, 1H, 200-H),
3.70–3.90 (m, 7H, 30-H, 40-H2, 300-H, 500-H, 600-H2), 4.20 (dd, 1H,
3.59 (m, 1H, 40-Ha), 3.86–4.07 (m, 7H, 4 OH, 20-H, 30-H, 40-Hb),
5.25 (s, 1H, 10-H), 8.19, 8.21 (2 s, je 1H, 5-H, 8-H), 9.16 (s, 1H, 3-
13
H). C NMR (75.5 MHz, [D6]DMSO): d 64.6 (C-40), 71.5 (C-30),
73.2 (C-10), 73.7 (C-20), 131.3, 131.5 (C-5, C-8), 135.5, 135.9
(C-6, C-7), 141.9 (C-4a, C-8a), 147.8 (C-3), 162.8 (C-2).
2-[(10R,20S,30R)-10,20,30,40-tetrahydroxybutyl]-quinoxaline-6-
carboxylic acid (3c) and 2-[(10R,20S,30R)-10,20,30,40-
tetrahydroxybutyl]-quinoxaline-7-carboxylic acid (3c)
From D-fructose via “one pot” conversion, employing hydrazine 20-H), 5.18 (d, 1H, 100-H), 5.45 (d, 1H, 10-H), 7.76–7.82 (m,
hydrate and 3,4-diamino benzoic acid: D-fructose (1.8 g, 2H, 6-H, 7-H), 8.03–8.08 (m, 2H, 5-H, 8-H), 9.14 (s, 1H, 3-H)—
0
0
0
0
00 00
00 00
00 00
00 00
10 mmol) was cyclized with 3,4-diamino benzoic acid (1.5 g, J1 ,2 ¼ 1.9, J2 ,3 ¼ 7.9, J1 ,2 ¼ 3.8, J2 ,3 ¼ 9.8, J3 ,4 ¼ J4 ,5
¼
10 mmol), hydrazine hydrate (1.5 mL, 30 mmol) at pH 7–8 under 9.8 Hz. 13C NMR (75.5 MHz, CD3OD): d 62.0 (C-600), 62.5 (C-40),
reux for 18 h. Workup as for 8a and elution from silica gel (4 ꢁ 71.2 (C-400), 72.7 (C-10), 73.1 (C-20), 73.6 (C-200), 74.1 (C-300), 74.4
30 cm) with CHCl3–MeOH (1 : 1) delivered aer evaporation of (C-500), 82.1 (C-30),101.0 (C-100), 128.9 (C-5, C-8), 130.1, 131.7
fractions with Rf 0.15 (CHCl3–MeOH, 1 : 1), quinoxaline 3c (C-6, C-7), 141.8 (C-4a, C-8a), 145.2 (C-3), 158.7 (C-2). MS (FD):
(1.6 g, 50%) as a light brown amorphous solid as a mixture o m/z ¼ 435 [M+ + Na].
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300-H), 3.43 (dd, 1H, 200-H), 3.61 (d, 1H, 400-H), 3.86 (d, 2H, 40-H2),
3.97 (m, 1H, 30-H), 4.19 (d, 1H, 100-H), 4.23 (dd, 1H, 20-H), 5.34 (d,
1H, 10-H), 7.77–7.84 (m, 2H, 6-H, 7-H), 8.04–8.09 (m, 2H, 5-H,
2-[(10R,20S,30R)-20-(a-D-Glucopyranosyloxy)-10,30,40-
trihydroxybutyl]-quinoxaline (15)
From maltose monohydrate via “one pot” conversion
employing hydrazine hydrate/o-phenylendiamine. Similar to
(isomaltulose / 8a) was maltose (3.6 g, 10 mmol) cyclized with
o-phenylendiamine (1.1 g, 10 mmol) and hydrazine hydrate
(1.5 mL, 30 mmol) at pH 7–8, and reux for 18 h. Workup and
chromatographic purication as for 8a (silica gel; 5 ꢁ 30 cm;
CHCl3–MeOH, 2 : 1) delivered quinoxaline 15 (1.73 g, 42%) as a
yellow hard foam—Rf 0.39 (CHCl3–MeOH 1 : 1). 1H NMR
(300 MHz, CD3OD): d 3.27–3.35 (m, 2H, 200-H, 400-H), 3.61–3.79
(m, 7H, 30-H, 300-H, 40-H2, 500-H, 600-H2), 4.39 (t, 1H, 20-H), 4.93 (d,
1H, 100-H), 5.29 (d, 1H, 10-H), 7.78–7.84 (m, 2H, 6-H, 7-H), 8.06–
0
0
0
0
0
0
00 00
8-H), 9.09 (s, 1H, 3-H)—J1 ,2 ¼ 2.6, J2 ,3 ¼ 7.7, J3 ,4 ¼ 4.0, J1 ,2
¼
00 00
00 00
00 00
00 00
7.7, J2 ,3 ¼ 9.6, J3 ,4 ¼ 3.0, J5 ,6 H ¼ 7.5, J5 ,6 H ¼ 5.7,
b
a
Jgem,6 -H ¼ 10.8 Hz. 13C NMR (75.5 MHz, CD3OD): d 58.7 (C-600),
00
2
61.9 (C-40), 67.3 (C-400), 70.7 (C-30), 70.8 (C-200), 70.9 (C-10), 72.8
(C-300), 73.7 (C-500), 81.2 (C-20), 103.1 (C-100), 127.6, 127.8 (C-6,
C-7), 128.9, 129.4 (C-5, C-8), 140.5, 140.6 (C-4a, C-8a), 144.6 (C-3),
157.1 (C-2). MS (FD): m/z ¼ 413 [M+ + H]; 435 [M+ + Na].
2-[(10R,20S,30R)-10-(a-D-Glucopyranosyloxy)-20,30,40-
trihydroxybutyl]-quinoxaline (18)
0
0
0
0
8.11 (m, 2H, 5-H, 8-H), 9.17 (s, 1H, 3-H)—J1 ,2 ¼ 4.8, J2 ,3 ¼ 5.0,
From turanose via “one pot” conversion employing hydra-
zine hydrate/o-phenylendiamine. Similar to (isomaltulose / 8a)
was turanose (1.7 g, 5 mmol) cyclized with o-phenylendiamine
(0.55 g, 5 mmol) and hydrazine hydrate (0.75 mL, 15 mmol) at
pH 7–8, and reux for 18 h. Workup and chromatographic
purication as for 8a (silica gel; 3 ꢁ 25 cm; CHCl3–MeOH, 2 : 1)
delivered quinoxaline 18 (0.1 g, 5%) as a light brown hard
foam—Rf 0.53 (CHCl3–MeOH 1 : 1). 1H NMR (300 MHz,
CD3OD): d 3.20 (d, 1H, 600-Ha), 3.29–3.32 (m, 2H, 500-H, 400-H),
3.40 (dd, 1H, 600-Hb), 3.50 (dd, 1H, 200-H), 3.66–3.70 (m, 2H, 30-H,
40-Ha), 3.82–3.87 (m, 3H, 300-H, 20-H, 40-Hb), 5.23 (d, 1H, 100-H),
5.35 (d, 1H, 10-H), 7.80–7.83 (m, 2H, 6-H, 7-H), 8.04–8.09 (m, 2H,
J1 ,2 ¼ 3.5, J2 ,3 ¼ 9.6 Hz. 13C NMR (75.5 MHz, CD3OD): d 62.6
(C-600), 64.0 (C-40), 71.5 (C-400), 73.4 (C-200), 73.8 (C-500), 74.6 (C-10),
74.8 (C-300), 83.5 (C-20), 101.9 (C-100), 129.3, 129.7 (C-6, C-7),
131.4, 131.6 (C-5, C-8), 142.4, 142.7 (C-4a, C-8a), 146.0 (C-3),
157.9 (C-2). MS (FD): m/z ¼ 435 [M+ + Na].
00 00
00 00
2-[(10R,20S,30R)-20-(b-D-Glucopyranosyloxy)-10,30,40-
trihydroxybutyl]-quinoxaline (16)
From cellobiose via “one pot” conversion employing hydra-
zine hydrate/o-phenylendiamine. Similar to (isomaltulose / 8a)
was cellobiose (3.4 g, 10 mmol) cyclized with o-phenylendiamine
(1.1 g, 10 mmol) and hydrazine hydrate (1.5 mL, 30 mmol) at pH
7–8, and reux for 18 h. Workup and chromatographic purica-
tion as for 8a (silica gel; 5 ꢁ 30 cm; CHCl3–MeOH, 2 : 1) delivered
quinoxaline 16 (1.64 g, 40%) as a yellowish hard foam—Rf 0.30
(CHCl3–MeOH, 1 : 1)—[a]2D0 ꢂ 65.4 (c 1.20, MeOH). (Found: C,
52.51; H, 5.89; N, 6.78% C18H24N2O9 requires C, 52.42; H, 5.87; N,
6.79%); 1H NMR (300 MHz, CD3OD): d 2.70–2.75 (m, 2H, 500-H, 600-
Ha), 2.93–2.96 (m, 2H, 400-H, 600-Hb), 3.07 (dd, 1H, 200-H), 3.19 (dd,
1H, 300-H), 3.85 (d, 2H, 40-H2), 4.23 (d, 1H, 100-H), 4.28 (dd, 1H,
20-H), 5.35 (d, 1H, 10-H), 7.78–7.85 (m, 2H, 6-H, 7-H), 8.05–8.09
0
0
00 00
00 00
5-H, 8-H), 9.12 (s, 1H, 3-H)—J1 ,2 ¼ 2.4, J1 ,2 ¼ 3.9, J2 ,3 ¼ 9.8,
J5 ,6 -H ¼ 3.0, Jgem,6 -H ¼ 12.6 Hz. 13C NMR (75.5 MHz, CD3OD):
00 00
00
b
2
d 61.7 (C-600), 64.7 (C-40), 71.1 (C-400), 72.6 (C-300), 73.9 (C-200), 74.7
(C-500), 75.0 (C-20), 75.7 (C-30), 82.3 (C-10), 102.5 (C-100), 129.7,
129.9 (C-6, C-7), 131.1, 131.5 (C-5, C-8), 142.6 (C-4a, C-8a), 146.6
(C-3), 157.5 (C-2). MS (FD): m/z ¼ 435 [M+ + Na].
Acknowledgements
This work was nancially supported by Grant 94 NR 078-F and
99 NR 063 from the Ministry of Nutrition, Agriculture and
Forestry, Bonn, administered by the Fachagentur Nachwach-
0
0
0
0
0
0
(m, 2H, 5-H, 8-H), 9.11 (s, 1H, 3-H)—J1 ,2 ¼ 2.6, J2 ,3 ¼ 7.7, J3 ,4
¼
4.2, J1 ,2 ¼ 7.6, J2 ,3 ¼ 9.3 Hz. 13C NMR (75.5 MHz, CD3OD): d
62.2 (C-600), 63.9 (C-40), 71.4 (C-400), 72.5 (C-300), 74.2 (C-10), 77.1
(C-500), 77.6 (C-300), 82.5 (C-20), 104.2 (C-100), 129.5, 129.8 (C-6, C-7),
130.9, 131.3 (C-5, C-8), 142.4 (C-4a, C-8a), 146.7 (C-3), 159.0 (C-2).
MS (FD): m/z ¼ 435 [M+ + Na].
00 00
00 00
¨
sende Rohstoffe, Gulzow.
Notes and references
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5766 | RSC Adv., 2014, 4, 5759–5767
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RSC Adv., 2014, 4, 5759–5767 | 5767