Synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole-fused glycosides and nucleosides by an intramolecular 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1039/b716996e

Various 1,2,3-triazole and 1,2,3,4-tetrazole fused multi-cyclic compounds were synthesized from carbohydrate derived azido-alkyne and azido-cyanide substrates. The acid sensitive 1,2-O-isopropylidene group of the furanosyl sugar was utilized for diversifi

Full text of DOI:10.1039/b716996e

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Synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole-fused glycosides and
nucleosides by an intramolecular 1,3-dipolar cycloaddition reaction†‡
Ramakrishna I. Anegundi,a Vedavati G. Puranikb and Srinivas Hotha*a
Received 2nd November 2007, Accepted 7th December 2007
First published as an Advance Article on the web 18th January 2008
DOI: 10.1039/b716996e
Various 1,2,3-triazole and 1,2,3,4-tetrazole fused multi-cyclic compounds were synthesized from
carbohydrate derived azido-alkyne and azido-cyanide substrates. The acid sensitive
1,2-O-isopropylidene group of the furanosyl sugar was utilized for diversification to glycosides and
nucleosides under Fischer glycosidation and Vorbruggen’s conditions, respectively.
In the post-genomic era, small molecules are anticipated to play
interesting roles in elucidating and understanding biosynthetic
pathways.1 Typically, biological screening by high-throughput
techniques involves testing large collections of small molecule
libraries that are arrayed into micro titer plates.2 In this regard,
combinatorial ways of synthesizing small molecules facilitated the
synthesis of large numbers of compounds using either solution or
solid phase methods.3 A recent chemo-informative data mining
study to address lacunae in drug discovery programs showed
drastic differences between compounds from natural sources,
semi-synthetic, combinatorial and drug classes under various
descriptors such as molecular weight, number of chiral centers,
number of oxygen atoms, number of nitrogen atoms etc.4 For
example, several compounds from the natural products class
revealed that natural products have greater numbers of oxygen
atoms and chiral centers than the corresponding combinatorial
products thereby highlighting the significance of synthesizing
small molecules that are chiral, oxygen-rich and multi-cyclic for
Fig. 1 Representative examples of small molecule inhibitors with a
1,2,3-triazole and 1,2,3,4-tetrazole moiety.
enhanced efficiency in the identification of hit molecules.4
We recently hypothesized that structurally, stereochemically and
skeletally diverse small molecules5 can be synthesized from carbo-
tetrazole-fused oxygen-rich small molecules9 can be synthe-
sized by an intramolecular 1,3-dipolar cycloaddition of azido-
alkyne/nitrile bearing monosaccharides.6a As part of a major
research program on utilization of carbohydrate-based scaffolds
for the synthesis of structurally diverse, chiral, oxygen-rich and
polycyclic small molecules,6 we became interested in the synthesis
of 1,2,3-triazole and 1,2,3,4-tetrazole fused glycosides and nucleo-
sides. Thus, forward synthetic analysis revealed an intramolecular
Huisgen reaction7 on carbohydrate-derived azido-alkyne and
azido-nitrile as a key step that would give access to 1,2,3-triazole
and 1,2,3,4-tetrazole-fused scaffolds, respectively, embedded with
an acid sensitive 1,2-O-isopropylidene group that can be further
extrapolated to corresponding glycosides and nucleosides. In this
full Article [preliminary report: ref. 6a], we report the efficient
synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole fused glycosides
and nucleosides via an intramolecular 1,3-dipolar cycloaddition of
carbohydrate derivatives, which are accessible from aldopentoses.
To commence our investigation, the carbohydrate-derived azido
substrate for the intramolecular 1,3-dipolar cycloaddition was
prepared by an SN2 displacement reaction of the corresponding
tosylate with NaN3.6a For example, xylofuranosyl diol 1 was
reacted with p-toluenesulfonyl chloride in the presence of pyridine
hydrate precursors using various metal mediated reactions such as
the Pauson–Khand reaction, enyne metathesis, cycloaddition and
Au-mediated cyclization.6 Our search for efficient and versatile
reactions converged on Huisgen’s 1,3-dipolar cycloaddition7 not
only due to the efficiency but also the enticing presence of 1,2,3-
triazole and 1,2,3,4-tetrazole moieties in various small molecule in-
hibitors (Fig. 1) exhibiting a broad spectrum of biological activity8
including anti-HIV,8a anti-allergic,8b anti-bacterial,8c herbicidal,8d
fungicidal8d and anti-haemagglutination activity.8e
1,2,3-Triazoles can be conveniently synthesized from azido-
alkynes as regioisomeric mixtures of 1,4- and 1,5-substituted
triazoles adopting Huisgen’s 1,3-dipolar cycloaddition reaction
conditions.7 Under this premise, we envisaged that triazole and
aDivision of Organic Chemistry, National Chemical Laboratory, Pune 411
008, India. E-mail: s.hotha@ncl.res.in; Fax: +91 20 2590 2624; Tel: +91 20
2590 2401
bCenter for Materials Characterization, National Chemical Laboratory,
Pune 411 008, India
† Dedicated to Dr A. A. Natu on his 60th birthday.
‡ Electronic supplementary information (ESI) available: General ex-
perimental details and 1H, 13C and DEPT NMR spectra. See DOI:
10.1039/b716996e
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at 0 ◦C for 10 h in order to obtain the 5-OTs derivative (2)◦in
91% yield, which was then treated with NaN3 in DMF at 90 C
to give 1,2-O-isopropylidene-5-azido-5-deoxy-xylofuranose (3) in
95% yield. The lone 3-OH group of azide 3 was converted to azido-
alkyne 4 and azido-cyanide 5 by reacting with propargyl bromide–
NaH and chloroacetonitrile–NaH respectively (Scheme 1).10
Scheme 1 Synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole containing
tetracyclic compounds. Reagents: (a) p-TsCl, pyridine, 0 ◦C–rt, 10 h, 91%;
(b) NaN3, DMF, 90 ◦C, 8 h, 95%; (c) NaH, propargyl bromide, DMF,
0
◦C–rt, 2 h, 93%; (d) NaH, ClCH2CN, DMF, 0 ◦C–rt, 3 h, 65%; (e)
toluene, 120 ◦C, 2 h, 95%; (f) toluene, 140 ◦C, 24 h, 55%.
Fig. 2 ORTEP diagram of compound 7. Ellipsoids are drawn at 50%
probability. ORTEP diagram of compound 12c. Ellipsoids are drawn at
50% probability.
The crucial 1,3-dipolar cycloaddition reaction was performed
by heating a toluene solution of the azido-alkyne 4 to 100 ◦C
for 2 h and the resultant 1,2,3-triazole product (6) precipitated
out as a white solid upon cooling to room temperature. In the
1H NMR spectrum of compound 6, the olefinic proton was
identified at d 7.49 ppm as a singlet and the anomeric proton
was observed at 5.77 (d, J = 3.9 Hz). Furthermore, the 13C
NMR spectrum of 6 revealed two olefinic carbons at d 134.8 and
132.1 ppm and all other resonances were in complete agreement
with the assigned structure.11 During our investigation, formation
of compound 6 was reported by Tripathi et al. starting from a
similar starting material.9d The spectral data of Tripathi et al. did
not correlate with our data. Meanwhile, the tetracyclic compound
6 was crystallized by slow evaporation from light petroleum (60–
80 ◦C) and CH2Cl2.9d The single crystal X-ray structure confirmed
the structural authenticity and relative stereochemistry of the
1,2,3-triazole fused tetracyclic compound 6.6a,11a
for introducing diversity leading to the synthesis of glycosides
and nucleosides. Glycosides can be synthesized stereoselectively
yet we opted for the non-diastereoselective glycosylation in the
presence of mineral acid since the diastereomeric products add to
the stereochemical diversity of the resulting library.12
Accordingly, 1,2,3-triazole- and 1,2,3,4-tetrazole-fused tetra-
cyclic compounds were treated with isopropyl, allyl and homo-
propargyl alcohols in the presence of a catalytic amount of sulfuric
◦
acid at 70–80 C for 4–8 h to obtain a, b-glycosides (8a, 8b, 8c,
9a, 9b and 9c) which were easily separated by simple column
chromatography except for 9c (Scheme 2). The ratio of a, b was
Alternatively, azide 3 was treated with chloroacetonitrile–NaH
to obtain azido-cyanide 5 in 65% yield. In the IR spectrum of
compound 5, the stretches corresponding to –CN and –N3 were
identified at 2254 and 2104 cm−1, respectively, along with all other
NMR spectral data in complete agreement with the assigned
structure. The critical cycloaddition reaction was carried out by
heating a solution of azido-cyanide 5 in toluene at 140 ◦C for 24 h.
1
In the H NMR spectrum of 1,2,3,4-tetrazole fused tetracyclic
compound 7, resonances corresponding to the anomeric proton
were observed at d 5.90 (d, J = 3.61 Hz); the 13C NMR spectrum
revealed an olefinic carbon at d 154.6 ppm and the DEPT spectrum
confirmed that the olefinic carbon was quaternary.10 Tetrazole 7
was crystallized by slow evaporation of a chloroform solution and
was subjected to X-ray structure determination and as evident
from the ORTEP diagram, the structural as well as the relative
stereochemical authenticity was confirmed (Fig. 2).10,11b
Furthermore, we envisioned that the 1,2-O-isopropylidene
group of the tetracyclic compounds 6 and 7 could be utilized
Scheme
glycosides.
2 Synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole fused
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1
calculated by integrating characteristic signals in the H NMR
spectrum and thoroughly confirmed by means of 1H and 13C NMR
spectral data. In the 13C NMR spectrum, anomeric carbons were
observed at d 106–108 ppm for 1,2-trans (b-) glycosides and at d
99–101 ppm for 1,2-cis (a-) glycosides.10
Further stereoselective synthesis of nucleosides from tetracyclic
compounds 6 and 7 was achieved by adopting Vorbru¨ggen’s
protocol.13 Thus, initially, the 1,2-O-isopropylidene group of 6 and
7 was cleaved using a catalytic amount of concentrated sulfuric
acid in the presence of H2O to obtain a diol and subsequently
acetylated in the presence of acetic anhydride and pyridine to
get the diacetate (10 and 11), which was then subjected to
Vorbru¨ggen’s conditions (HMDS–TMSCl–TfOH in CH3CN) by
treating with nucleobases such as uracil, thymine, N6-benzoyl
adenine and 6-chloro-2-amino purine to obtain b-configured
nucleosides (12a, 12b, 12c, 12d and 13a, 13b, 13c, 13d) in moderate
yields (Scheme 3). The structures of all the nucleosides were
1
thoroughly confirmed by H, 13C NMR and other spectroscopic
techniques. Furthermore, an acetonitrile solution of nucleoside
12c was subjected to slow evaporation in order to get single crystals
for X-ray structure analysis. The molecular structure of 12c was
unambiguously confirmed (ORTEP diagram, Fig. 3) as well as the
relative stereochemistry of the C-1 position.9,11c
Fig. 3 ORTEP diagram of compound 12c. Ellipsoids are drawn at 50%
probability.
tetrazole fused glycosides and nucleosides in an efficient manner.
We anticipate that the heterocycle–sugar hybrid molecules will
have interesting biological activities reminiscent of the existing
triazole and tetrazole class of compounds.
Experimental section
General experimental procedure for 1,3-dipolar cycloaddition
A solution of azido-alkyne or azido-nitrile (1 mmol) in 10 mL
of toluene was heated to 100 ◦C for 1,2,3-triazole formation and
◦
140 C for 1,2,3,4-tetrazole formation for an appropriate length
of time and cooled to room temperature. The separated solid was
filtered off and crystallized by a slow evaporation technique.
General experimental procedure for the synthesis of glycosides
To a solution of compound 6 or 7 (2 mmol), anhydrous 1,4-dioxane
(10 mL) and ROH (4 mmol) was added a catalytic amount of conc.
◦
H2SO4 and the solution was heated to 70 C until TLC analysis
confirmed the disappearance of starting material (typically 4–
8 h). The reaction mixture was then neutralized by addition of
saturated aq. NaHCO3 solution, diluted with water and extracted
with ethyl acetate. The organic layer was washed with water
(2 × 25 mL), brine solution (1 × 25 mL), dried over anhydrous
Na2SO4, concentrated in vacuo and subjected to silica gel column
chromatography to afford a- and b-glycosides.
Scheme
3
Synthesis of 1,2,3-triazole and 1,2,3,4-tetrazole fused
nucleosides.
General experimental procedure for the nucleoside synthesis
To a solution of diacetate (2 mmol) and nucleobase (2 mmol) in
anhydrous acetonitrile (15 mL) were added HMDS (2.4 mmol),
chlorotrimethylsilane (2.8 mmol) and triflic acid (2.4 mmol)
consecutively under an argon atmosphere. The reaction mixture
In conclusion, we have investigated the 1,3-dipolar cycload-
dition of azido-alkynes and azido-nitriles in an intramolecular
fashion to develop routes for various 1,2,3-triazole and 1,2,3,4-
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was stirred at room temperature for 30 min and refluxed under
argon for the specified time. The reaction mixture was then cooled
to room temperature, diluted with ethyl acetate (200 mL), washed
with a saturated solution of aq. NaHCO3 (25 mL), water (2 ×
25 mL) and brine solution (25 mL). The aqueous layer was
extracted with ethyl acetate (2 × 25 mL), combined organic
extracts were dried over anhydrous Na2SO4 and concentrated in
vacuo to obtain a crude residue which was purified by silica gel
column chromatography using ethyl acetate and light petroleum
as the mobile phase.
Compound characterization data of compound 7.
◦
◦
1
Mp 208 C; [a]D (CHCl3, c 1.16) = −12.24 ; H NMR (CDCl3,
200.13 MHz): d 1.33, 1.51 (6 H, 2 s), 4.28 (1 H, d, J 2.8 Hz), 4.61
(1 H, dd, J 3.2, 6.2 Hz), 4.65 (1 H, d, J 3.8 Hz), 4.79 (1 H, dd,
J 3.4, 14.6 Hz), 5.03 (1 H, dd, J 14.8, 6.2 Hz), 5.06 (2 H, ABq,
J 15.8 Hz), 5.90 (1 H, d, J 3.6 Hz); 13C NMR [DMSO-d6, 50.32
MHz): d 26.1, 26.6, 46.4, 59.4, 72.9, 83.4, 84.0, 104.1, 111.4, 154.6;
CHN Anal. (Calcd for C10H14N4O4 as C, 47.24; H, 5.55; N, 22.04).
Found C, 47.44; H, 5.74; N, 22.38%.
Compound characterization data of compound 4.
Compound characterization data of compound 8aa.
[a]D (CHCl3, c 1.04) = −44.32◦; IR (cm−1) = 3282, 2102; 1H NMR
(CDCl3, 200.13 MHz): d 1.30, 1.48 (6 H, 2 s), 2.48 (1 H, t, J 2.4 Hz),
3.51 (2 H, dt, J 6.8, 12.6 Hz), 4.07 (1 H, d, J 3.3 Hz), 4.22 (2 H,
t, J 2.7 Hz), 4.30 (1 H, m), 4.62 (1 H, d, J 3.8 Hz), 5.89 (1 H, d, J
3.8 Hz); 13C NMR (CDCl3, 50.32 MHz): d 26.2, 26.7, 49.2, 57.4,
75.4, 78.6, 78.7, 81.2, 82.0, 105.0, 111.9; CHN Anal. (Calcd for
C11H15N3O4 as C, 52.17; H, 5.97; N, 16.59). Found C, 52.57; H,
6.39; N, 16.82%.
Mp = 110 ◦C; [a]D (CHCl3, c 1.09) = +52.84◦; 1H NMR (CDCl3,
200.13 MHz): d 1.11 (3 H, d, J 6.3 Hz), 1.16 (3 H, d, J 6.3 Hz),
2.91 (1 H, bs), 3.92 (1 H, ddd, J 6.2, 12.4, 18.6 Hz), 4.11 (2 H, m),
4.45 (2 H, m), 4.78 (1 H, dd, J 3.8, 13.0 Hz), 4.92 (2 H, ABq, J
16.0 Hz), 5.07 (1 H, d, J 3.9 Hz), 7.39 (1 H, s); 13C NMR (CDCl3,
50.32 MHz): d 21.7, 23.3, 48.5, 64.0, 71.0, 75.1, 76.8, 86.6, 99.3,
130.6, 134.1; CHN Anal. (Calcd for C11H17N3O4 as C, 51.76; H,
6.71; N, 16.46). Found C, 52.09; H, 6.97; N, 16.10%.
Compound characterization data of compound 5.
Compound characterization data of compound 8ab.
◦
Mp 208 C; [a]D (CHCl3, c 1.01) = −83.17◦; IR (cm−1) = 2254,
2104; 1H NMR (CDCl3, 200.13 MHz): d 1.33, 1.51 (6 H, 2 s), 3.54
(2 H, ddd, J 6.7, 12.5, 19.1 Hz), 4.05 (1 H, d, J 3.3), 4.30–4.41 (3 H,
m), 4.65 (1 H, d, J 3.8), 5.93 (1 H, d, J 3.8); 13C NMR (CDCl3,
50.32 MHz): d 26.1, 26.6, 48.7, 55.5, 78.1, 81.4, 83.3, 104.9, 112.3,
127.5; CHN Anal. (Calcd for C10H14N4O4 as C, 47.24; H, 5.55; N,
22.04). Found C, 47.59; H, 6.04; N, 22.28%.
Mp = 92–94 ◦C; [a]D (CHCl3, c 1.22) = −86.39◦; 1H NMR (CDCl3,
200.13 MHz): d 1.12 (3 H, d, J 6.3 Hz), 1.15 (3 H, d, J 6.3 Hz),
2.75 (1 H, bs), 3.88 (1 H, m), 4.08 (1 H, d, J 5.7 Hz), 4.27 (1 H,
s), 4.71 (3 H, m), 4.94 (2 H, Abq, J 16.0 Hz), 5.02 (1 H, bs), 7.38
(1 H, s); 13C NMR (CDCl3, 50.32 MHz): d 21.3, 23.2, 49.6, 64.4,
70.0, 78.7, 80.8, 86.8, 106.5, 130.2, 134.1; CHN Anal. (Calcd for
C11H17N3O4 as C, 51.76; H, 6.71; N, 16.46). Found C, 51.51; H,
6.39; N, 16.25%.
Compound characterization data of compound 6.
Compound characterization data of compound 8ba.
Mp 200 ◦C; [a]D (CHCl3, c 1.28) = −7.31◦; IR (cm−1): 1461, 1379;
1H NMR (CDCl3, 200 MHz): d 1.27, 1.46 (6 H, 2 s), 4.22 (1 H,
d, J 2.1 Hz), 4.39 (1 H, m), 4.49 (1 H, d, J 3.6 Hz), 4.58 (1 H,
d, J 14.7 Hz), 4.69 (1 H, dd, J 15.2, 2.4 Hz), 4.92 (1 H, d, J
14.7 Hz), 5.11 (1 H, dd, J 5.6, 15.5 Hz), 5.77 (1 H, d, J 3.6 Hz),
7.49 (1 H, s); 13C NMR (CDCl3, 50 MHz): d 26.0, 26.6, 48.00, 60.6,
74.2, 83.8, 84.4, 104.7, 111.9, 132.1, 134.8; CHN Anal. (Calcd for
C11H15N3O4 as C, 52.17; H, 5.97; N, 16.59). Found C, 51.97; H,
5.46; N, 16.67%.
[a]D (CHCl3, c 1.11) = +43.24◦; 1H NMR (CDCl3, 200.13 MHz):
d 2.50 (1 H, bs), 3.72 (1 H, m), 4.03–4.35 (4 H, m), 4.35–4.94 (3 H,
m), 5.07 (1 H, d, J 4.4 Hz), 5.15–5.36 (3 H, m), 5.91 (1 H, m), 7.45
(1 H, s); 13C NMR (CDCl3, 50.32 MHz): d 48.4, 63.9, 68.8, 75.1,
76.7, 86.3, 100.0, 117.8, 130.5, 133.2, 134.1; CHN Anal. (Calcd
for C11H15N3O4 as C, 52.17; H, 5.97; N, 16.59). Found C, 52.67; H,
6.08; N, 15.98%.
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Compound characterization data of compound 8bb.
Compound characterization data of compound 9ab.
[a]D (CHCl3, c 1.24) = −100.00◦; 1H NMR (CDCl3, 200.13 MHz):
d 1.15 (3 H, d, J 6.3 Hz), 1.21 (3 H, d, J 6.2 Hz), 3.23 (1 H, bs),
3.95 (1 H, m), 4.23 (1 H, m), 4.37 (1 H, s), 4.72 (2 H, m), 4.82 (1 H,
m), 5.10 (1 H, s), 5.19 (2 H, ABq, J 16.7 Hz); 13C NMR (CDCl3,
50.32 MHz): d 21.4, 23.3, 48.1, 63.4, 70.5, 78.7, 81.1, 87.5, 106.5,
152.7; CHN Anal. (Calcd for C10H16N4O4 as C, 46.87; H, 6.29; N,
21.86). Found C, 47.20; H, 6.50; N, 22.14%.
Mp = 110 ◦C; [a]D (CHCl3, c 1.17) = −79.83◦; 1H NMR (CDCl3,
200.13 MHz): d 3.29 (2 H, m), 3.92–4.28 (3 H, m), 4.40 (1 H, s),
4.52–4.96 (3 H, m), 5.06 (1 H, s), 5.10–5.45 (3 H, m), 5.90 (1 H, m),
7.43 (1 H, s); 13C NMR (CDCl3, 50.32 MHz): d 49.5, 64.5, 68.5,
79.2, 80.8, 86.8, 107.5, 117.6, 130.3, 133.6, 134.0; CHN Anal.
(Calcd for C11H15N3O4 as C, 52.17; H, 5.97; N, 16.59). Found C,
51.94; H, 6.30; N, 16.69%.
Compound characterization data of compound 9ba.
Compound characterization data of compound 8ca.
[a]D (CH3OH, c 1.21) = +71.24◦; 1H NMR (CDCl3, 200.13 MHz):
d 2.98 (1 H, bs), 3.98 (1 H, m), 4.13–4.28 (3 H, m), 4.32–4.57 (2 H,
m), 4.77–4.95 (2 H, m), 5.00 (1 H, m), 5.07–5.45 (3 H, m), 5.65–
5.95 (1 H, m); 13C NMR (CDCl3, 50.32 MHz): d 46.9, 64.9, 68.8,
75.0, 76.7, 86.6, 99.7, 118.1, 133.1, 152.7. CHN Anal. (Calcd for
C10H14N4O4 as C, 47.24; H, 5.55; N, 22.04). Found C, 47.78; H,
5.19; N, 21.65%.
◦
1
[a]D (CHCl3, c 1.02) = +43.53 ; IR (cm−1) = 3292; H NMR
(CDCl3, 200.13 MHz): d 1.95 (1 H, t, J 2.6 Hz), 2.31 (1 H, bs),
2.47 (2 H, dt, J 2.6, 6.5 Hz), 3.64 (1 H, m), 3.85 (1 H, m), 4.20
(2 H, m), 4.48–4.90 (3 H, m), 4.96 (2 H, ABq, J 15.7 Hz), 5.04
(1 H, d, J = 4.2 Hz), 7.42 (1 H, s); 13C NMR (CDCl3, 50.32 MHz):
d 19.8, 48.5, 64.1, 66.4, 69.8, 75.4, 77.0, 80.6, 86.4, 101.0, 130.7,
134.1; CHN Anal. (Calcd for C12H15N3O4 as C, 54.33; H, 5.70; N,
15.84). Found C, 54.57; H, 5.98; N, 15.41%.
Compound characterization data of compound 9bb.
Compound characterization data of compound 8cb.
[a]D (CH3OH, c 1.05) = −86.25◦; 1H NMR (CDCl3, 200.13 MHz):
d 2.63 (1 H, bs), 3.95–4.01 (1 H, m), 4.22 (2 H, m), 4.42 (1 H, s),
4.50–4.82 (2 H, m), 4.79–5.08 (2 H, m), 5.03 (1 H, s), 5.15–5.50
(3 H, m), 5.75–5.98 (1 H, m); 13C NMR (CDCl3, 125.76 MHz): d
47.9, 65.4, 68.6, 79.2, 80.8, 87.4, 107.3, 118.0, 133.2, 152.7. CHN
Anal. (Calcd for C10H14N4O4 as C, 47.24; H, 5.55; N, 22.04). Found
C, 47.66; H, 5.94; N, 22.47%.
◦
1
[a]D (CHCl3, c 1.07) = −67.85 ; IR (cm−1) = 3286; H NMR
(CDCl3, 200.13 MHz): d 1.96 (1 H, t, J 2.6 Hz), 2.45 (2 H, dt, J
2.8, 6.8 Hz), 3.52–3.90 (3 H, m), 4.01–4.25 (1 H, m), 4.37 (1 H,
s), 4.50–4.91 (3 H, m), 4.98 (2 H, ABq, J 15.8 Hz), 5.02 (1 H, s),
7.40 (1 H, s); 13C NMR (CDCl3, 50.32 MHz): d 19.7, 49.5, 64.6,
66.2, 69.7, 75.4, 79.4, 80.8, 86.7, 108.6, 130.4, 134.0; CHN Anal.
(Calcd for C12H15N3O4 as C, 54.33; H, 5.70; N, 15.84). Found C,
52.98; H, 6.18; N, 16.31%.
Compound characterization data of compound 9c (inseparable
mixture of 9ca, 9cb).
Compound characterization data of compound 9aa.
IR (cm−1) = 3306, 3016, 2930; 1H NMR (CDCl3, 200.13 MHz): d
2.01 (1 H, m), 2.43–2.58 (2 H, m), 3.01 (1 H, m), 3.55–3.96 (2 H,
m), 4.20 (1 H, m), 4.41–4.95 (2 H, m), 4.70–5.15 (4 H, m), 5.38–
5.52 (1 H, m); 13C NMR (CDCl3, 125.76 MHz): d 19.6, 19.7, 46.9,
47.8, 64.8, 65.2, 66.2, 66.3, 69.7, 69.8, 75.1, 76.8, 79.1, 80.6, 80.8,
80.9, 86.4, 87.2, 100.7, 108.4, 152.7, 152.8. CHN Anal. (Calcd for
C11H14N4O4 as C, 49.62; H, 5.30; N, 21.04). Found C, 48.96; H,
5.82; N, 21.65%.
[a]D (CHCl3, c 1.05) = +86.28◦; 1H NMR (CDCl3, 200.13 MHz):
d 1.20 (3 H, d, J 6.2 Hz), 1.23 (3 H, d, J 6.3 Hz), 2.31 (1 H, bs),
3.81–4.26 (3 H, m), 4.52 (2 H, m), 4.72–5.02 (1 H, m), 5.15 (1 H,
d, J 3.9 Hz), 5.21 (2 H, ABq, J 16.8 Hz); 13C NMR (CDCl3, 50.32
MHz): d 21.8, 23.4, 47.1, 65.2, 71.4, 75.2, 76.9, 87.2, 99.2, 152.7;
CHN Anal. (Calcd for C10H16N4O4 as C, 46.87; H, 6.29; N, 21.86).
Found C, 46.51; H, 5.98; N, 22.33%.
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Compound characterization data of compound 10.
47.8, 60.9, 76.8, 80.9, 83.0, 87.0, 122.8, 127.9–128.8, 132.5, 132.8,
133.5, 134.6, 141.0, 149.6, 151.5, 152.7, 165.1, 169.2. CHN Anal.
(Calcd for C22H20N8O5 as C, 55.46; H, 4.23; N, 23.52). Found C,
55.96; H, 4.70; N, 23.45%.
Compound characterization data of compound 12c.
1H NMR (CDCl3, 200.13 MHz): d 2.03, 2.05, 2.08, 2.09 (6 H, 4 s),
4.39–5.02 (5 H, m), 5.21–5.34 (2 H, m), 6.10–6.49 (1 H, m), 7.42,
7.44 (1 H, 2 s); 13C NMR (CDCl3, 50.32 MHz): d 20.4, 20.7, 20.9,
21.1, 48.2, 49.0, 64.6, 64.9, 76.2, 76.4, 80.8, 81.5, 82.4, 82.4, 83.5,
93.3, 99.3, 130.7, 133.8, 169.2, 169.3, 169.4, 169.8. CHN Anal.
(Calcd for C12H15N3O6 as C, 48.48; H, 5.09; N, 14.14). Found C,
47.95; H, 5.65; N, 13.86%.
Mp = 225 ◦C; [a]D (CH3OH, c 1.18) = +72.88◦; 1H NMR (CDCl3 +
DMSO-d6 (9 : 1), 200.13 MHz): d 2.50 (3 H, s), 4.76 (2 H, s), 5.24
(2 H, ABq, J 14.9 Hz), 5.27 (1 H, dd, J 1.0, 14.9 Hz), 5.44 (1 H,
s), 5.68 (1 H, m), 5.80 (1 H, d), 6.31 (1 H, d, J 1.3 Hz), 7.04 (1 H,
d, J 8.2 Hz), 8.01 (1 H, s), 11.02 (1 H, s); 13C NMR (CDCl3 +
DMSO-d6 (9 : 1), 50.32 MHz): d 19.4, 46.2, 58.3, 74.5, 79.4, 81.1,
86.5, 100.8, 131.2, 135.0, 137.7, 149.1, 162.1, 167.7. CHN Anal.
(Calcd for C14H15N5O6 as C, 48.14; H, 4.33; N, 20.05). Found C,
48.05; H, 4.38; N, 19.79%.
Compound characterization data for compound 11.
1H NMR (CDCl3, 200.13 MHz): d 2.09, 2.13, 2.14, 2.15 (6 H, 4 s),
4.39 (1 H, m), 4.48–4.75 (2 H, m), 4.78–5.10 (2 H, m), 5.20–5.63
(2 H, m), 6.21–6.52 (1 H, m); 13C NMR (CDCl3, 50.32 MHz):
d 20.3, 20.6, 20.7, 21.0, 46.6, 47.3, 65.3, 65.8, 75.8, 76.1, 80.6,
81.5, 82.6, 84.4, 92.8, 99.2, 152.1, 152.3, 168.9, 169.0, 169.3, 169.7.
CHN Anal. (Calcd for C11H14N4O6 as C, 44.30; H, 4.73; N, 18.79).
Found C, 43.86; H, 5.05; N, 19.16%.
Compound characterization data of compound 12d.
Compound characterization data of compound 12a.
Mp = 180 ◦C; [a]D (CH3OH, c 1.68) = +6.19◦; 1H NMR [DMSO-
d6, 200.13 MHz): d 1.53 (3 H, s), 2.07 (3 H, s), 4.28–4.52 (1 H,
m), 4.65–4.82 (1 H, m), 4.87–5.05 (3 H, m), 5.24 (1 H, dd, J 4.7,
15.9 Hz), 5.75 (1 H, d, J 0.9 Hz), 6.29 (1 H, d, J 1.0 Hz), 7.61 (1 H,
s), 7.85 (1H, s), 11.17 (1 H, s); 13C NMR (CDCl3 + DMSO-d6 (9
: 1), 50.32 MHz): d 12.5, 20.8, 47.4, 59.0, 75.9, 80.7, 82.0, 87.6,
109.2, 132.7, 134.9, 136.6, 150.4, 163.9, 169.5. CHN Anal. (Calcd
for C15H17N5O6 as C, 49.59; H, 4.72; N, 19.28). Found C, 48.97; H,
4.87; N, 18.97%.
Mp = 200 ◦C; [a]D (CHCl3, c 1.13) = +28.14◦; IR (cm−1) = 1741,
1
1755; H NMR (CD3OD + CDCl3 (1 : 9), 200.13 MHz): d 2.19
(3 H, s), 4.52–4.60 (4 H, m), 4.98 (2 H, ABq, J 15.0 Hz), 4.99 (1 H,
dd, J 2.0, 15.5 Hz), 5.27–5.40 (2 H, m), 6.08 (1 H, d, J 1.4 Hz),
7.47 (1 H, s), 7.69 (1 H, s); 13C NMR (CD3OD + CDCl3 (1 : 9),
50.32 MHz): d 20.6, 48.2, 60.5, 76.9, 81.2, 83.3, 87.3, 124.3, 132.7,
136.3, 140.8, 151.3, 153.7, 160.4, 170.2; CHN Anal. (Calcd for
C15H15ClN8O4 as C, 44.29; H, 3.71; Cl, 8.72; N, 27.55). Found C,
43.88; H, 3.53; N, 26.99%.
Compound characterization data of compound 13a.
Compound characterization data of compound 12b.
Mp = 170 ◦C (decomposed); [a]D (CH3OH, c 1.60) = −11.00◦;
1H NMR (CD3OD + CDCl3 (1 : 9), 200.13 MHz): d 2.17 (3 H, s),
4.72 (4 H, m), 5.00 (1 H, m), 5.25 (1 H, dd, J 6.1, 14.5 Hz), 5.28
(2 H, ABq, J 15.8 Hz), 5.80 (1 H, m), 6.08 (1 H, d, J 3.5 Hz), 7.82
(1 H, s); 13C NMR (CD3OD + CDCl3 (1 : 9), 50.32 MHz): d 20.4,
46.3, 63.0, 75.4, 78.2, 82.3, 85.2, 120.0, 127.4, 150.1, 153.6, 159.8,
159.9, 169.2; CHN Anal. (Calcd for C14H14ClN9O4 as C, 41.24; H,
3.46; Cl, 8.69; N, 30.91). Found C, 41.15; H, 3.52; Cl, 7.99;
N, 30.94%.
Mp = 130 ◦C; [a]D (CH3OH, c 1.315) = −3.05◦; 1H NMR (CDCl3,
200.13 MHz): d 2.20 (3 H, s), 4.45 (1 H, dd, J 0.9, 2.5 Hz), 4.56
(2 H, m), 4.89 (1 H, dd, J 2.6, 14.9 Hz), 4.95 (2 H, ABq, J 14.9 Hz),
5.30 (1 H, dd, J 5.8, 15.2 Hz), 5.48 (1 H, t, J 1.3 Hz), 6.34 (1 H, d,
J 1.4 Hz), 7.45–7.62 (3 H, m), 7.65 (1 H, s), 7.80 (1 H, s), 7.96–8.08
(2 H, m), 8.77 (1 H, s); 13C NMR (CDCl3, 50.32 MHz): d 20.7,
784 | Org. Biomol. Chem., 2008, 6, 779–786
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Compound characterization data for compound 13b.
determination and analysis of compound 6. RIA acknowledges
the CSIR, New Delhi for SRF.
Notes and references
1 (a) D. R. Spring, Org. Biomol. Chem., 2003, 1, 3867–3870; (b) D. S.
Tan, Nat. Chem. Biol., 2005, 1, 74–84; (c) S. L. Schreiber, Chem. Eng.
News, 2003, 7, 91–96; (d) P. Arya, S. Quevillon, R. Joseph, C.-Q. Wei, Z.
Gan, M. Parisien, B. Sesmilo, P. T. Reddy, Z.-X. Chen, P. Durieux, D.
Laforce, L. C. Campeau, S. Khadem, S. Couve-Bonnaire, R. Kumar,
U. Sharma, D. M. Leek, M. Daroszewska and M. L. Barnes, Pure
Appl. Chem., 2005, 77, 163–178; (e) S. Shang and D. S. Tan, Curr. Opin.
Chem. Biol., 2005, 9, 1–11.
2 (a) D. P. Walsh and Y.-T. Chang, Chem. Rev., 2006, 106, 2476–2530;
(b) B. Stockwell, Nat. Rev. Genet., 2000, 1, 116–125; (c) S. L. Schreiber,
Bioorg. Med. Chem., 1998, 6, 1127–1152; (d) S. Hotha, J. C. Yarrow, J. G.
Yang, S. Garrett, K. V. Renduchintala, T. U. Mayer and T. M. Kapoor,
Angew. Chem., Int. Ed., 2003, 42, 2379–2382; (e) T. U. Mayer, T. M.
Kapoor, S. J. Haggarty, R. W. King, S. L. Schreiber and T. Mitchison,
Science, 2000, 286, 971–974.
[a]D (CH3OH, c 1.06) = −12.45◦; 1H NMR (CD3OD + CDCl3 (1 :
9), 200.13 MHz): d 2.18 (3 H, s), 4.70 (2 H, m), 5.05 (1 H, dd, J 3.0,
15.0 Hz), 5.28 (2 H, ABq, J 15.7 Hz), 5.29 (1 H, dd, J 6.3, 14.9 Hz),
5.74 (1 H, t, J 2.5 Hz), 6.33 (1 H, d, J 2.7 Hz), 7.50–7.75 (4 H, m),
8.07 (2 H, m), 8.12 (1 H, s), 8.73 (1 H, s); 13C NMR (CD3OD +
CDCl3 (1 : 9), 50.32 MHz): d 18.8, 45.6, 60.9, 75.6, 79.3, 82.4, 85.9,
127.3–127.8, 131.9, 141.2, 151.0, 151.5, 153.2, 169.0. CHN Anal.
(Calcd for C21H19N9O5 as C, 52.83; H, 4.01; N, 26.40). Found C,
52.76; H, 4.10; N, 26.35%.
3 (a) A. W. Czarnik and S. H. DeWitt, A Practical Guide to Combinatorial
Chemistry, ACS Books, Washington, 1997; (b) A. Nefzi, J. M. Ostresh
and R. A. Houghten, Chem. Rev., 1997, 97, 449–472; (c) P. H. Seeberger
and W.-C. Haase, Chem. Rev., 2000, 100, 4349–4394.
Compound characterization data of compound 13c.
4 M. Feher and J. M. Schmidt, J. Chem. Inf. Comput. Sci., 2003, 43,
218–227.
5 M. D. Burke and S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43,
46–58.
6 (a) S. Hotha, R. I. Anegundi and A. A. Natu, Tetrahedron Lett., 2005,
46, 4585–4588; (b) S. Hotha and A. Tripathi, J. Comb. Chem., 2005, 7,
968–976; (c) S. Hotha, S. K. Maurya and M. K. Gurjar, Tetrahedron
Lett., 2005, 46, 5329–5332; (d) S. K. Maurya and S. Hotha, Tetrahedron
Lett., 2006, 47, 3307–3310.
Mp = 126 ◦C; [a]D (CH3OH, c 1.10) = +13.27◦; 1H NMR (CD3OD,
200.13 MHz): d 2.13 (3 H, s), 4.53 (1 H, m), 4.61 (1 H, m), 4.96–
5.08 (2 H, m), 5.14–5.40 (3 H, m), 5.58 (1 H, d, J 8.1 Hz), 5.95
(1 H, d, J 2.8 Hz), 7.10 (1 H, d, J 8.2 Hz); 13C NMR (CD3OD +
CDCl3 (1 : 9), 50.32 MHz): d 18.7, 45.3, 60.3, 74.5, 79.4, 82.1, 87.0,
101.43, 139.2, 149.7, 153.3, 163.4, 169.0; CHN Anal. (Calcd for
C13H14N6O6 as C, 44.68; H, 4.18; N, 23.99). Found C, 44.68; H,
4.18; N, 23.85%.
7 R. Huisgen, in 1,3-Dipolar Cycloaddition Chemistry, ed. A. Padwa,
Wiley, New York, 1984, pp. 1–176.
8 (a) R. Alvarez, S. Velazquez, A. San-Felix, S. Aquaro, E. De Clercq, C.-
F. Perno, A. Karlsson, J. Balzarini and M. J. Camarasa, J. Med. Chem.,
1994, 37, 4185–4194; (b) D. R. Buckle, C. J. M. Rockell, H. Smith and
B. A. Spicer, J. Med. Chem., 1986, 29, 2269–2277; (c) M. J. Genin,
D. A. Allwine, D. J. Anderson, M. R. Barbachyn, D. E. Emmert, S. A.
Garmon, D. R. Graber, D. C. Grega, J. B. Hester, D. K. Hutchinson,
J. Morris, R. J. Reischer, C. W. Ford, G. E. Zurenko, J. C. Hamel,
R. D. Schaadt, D. Stapert and B. H. Yagi, J. Med. Chem., 2000, 43,
953–970; (d) H. Wamhoff, in Comprehensive Heterocyclic Chemistry,
ed. A. R. Katritzky and C. W. Rees, Pergamon, Oxford, 1984, vol. 5,
pp. 669–732; (e) D. Gigue`re, R. Patnam, M.-A. Bellefleur, C. St-Pierre,
S. Sato and R. Roy, Chem. Commun., 2006, 2379–2381; (f) P. von der
Peet, C. T. Gannon, I. Walker, Z. Dinev, M. Angelin, S. Tam, J. E.
Ralton, M. J. McConville and S. J. Willams, ChemBioChem, 2006, 7,
1384–1391; (g) J. Li, M. Zheng, W. Tang, P.-L. He, W. Zhu, T. Li, J.-P.
Zuo, H. Liu and H. Jiang, Bioorg. Med. Chem. Lett., 2006, 16, 5009–
5013; (h) F. Pagliai, T. Pirali, E. D. Grosso, R. D. Brisco, G. C. Tron, G.
Sorba and A. A. Genazzani, J. Med. Chem., 2006, 49, 467–470; (i) R. J.
Herr, Bioorg. Med. Chem., 2002, 10, 3379–3393.
Compound characterization data of compound 13d.
9 Selected references on the use of 1,3-dipolar cycloaddition reactions on
carbohydrates: (a) R. N. de Oliveira, D. Sinou and R. M. Srivastava,
J. Carbohydr. Chem., 2006, 25, 407–425; (b) B. L. Wilkinson, L. F.
Bornaghi, S.-A. Poulsen and T. A. Houston, Tetrahedron, 2006, 62,
8115–8125; (c) F. Dolhem, F. Al Tahli, C. Lie`vre and G. Demailly,
Eur. J. Org. Chem., 2005, 5019–5023; (d) S. Tripathi, K. Singha, B.
Achari and S. B. Mandal, Tetrahedron, 2004, 60, 4959–4965.
10 See ESI‡.
Mp = 123 ◦C; [a]D (CH3OH, c 1.14) = +4.38◦; 1H NMR (CDCl3 +
DMSO-d6 (9 : 1), 200.13 MHz): d 1.73 (3 H, s), 2.14 (3 H, s), 4.30–
4.65 (2 H, m), 4.82–5.45 (5 H, m), 5.97 (1 H, d, J 3.0 Hz), 6.72
(1 H, d, J 1.1 Hz), 11.16 (1 H, m); 13C NMR (CD3OD + CDCl3
(1 : 9), 50.32 MHz): d 12.6, 20.7, 47.4, 61.9, 76.6, 81.4, 84.1, 89.1,
111.8, 136.5, 151.9, 155.5, 165.9, 171.0. CHN Anal. (Calcd for
C14H16N6O6 as C, 46.16; H, 4.43; N, 23.07). Found C, 46.10; H,
4.33; N, 23.15%.
11 (a) Crystallographic data of compound 6 was reported by us6a and is in
the CSD [REFCODE DAQJOV]; (b) crystal data of 7: single crystals
of the complex were grown by slow evaporation of the solution in
chloroform. A colourless needle, of approximate size 0.54 × 0.08 ×
0.07 mm, was used for data collection. Crystal to detector distance
6.05 cm, 512 × 512 pixels per frame, hemisphere data acquisition. Total
scans = 3, total frames = 1271, oscillation per frame −0.3◦, exposure
per frame = 10.0 sec per frame, maximum detector swing angle =
−30.0◦, beam center = (260.2, 252.5), in plane spot width = 1.24,
SAINT integration, h range = 1.92 to 25.0◦, completeness to h of 25.0◦
is 100.0%. SADABS correction applied, C10H14N4O4, M = 254.25.
Crystals belong to orthorhombic, space group P212121, a = 5.6672(5),
Acknowledgements
SH thanks DST, New Delhi (SR/S1/OC-06/2004) for financial
support. The authors thank Dr A A Natu and Dr K. N. Ganesh
for their encouragement. SH and RIA thank Dr V. R. Pedireddi
and Mr Kapil Arora for helping with the crystal structure
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3
˚
˚
Crystals belong to orthorhombic, space group P212121, a = 5.9329(8),
b = 9.8214(9), c = 21.2188(19) A, V = 1181.03(18) A , Z = 4, Dc =
1.430 mg m−3, l(Mo–Ka) = 0.112 mm−1, 5801 reflections measured,
2080 unique [I > 2r(I)], R value 0.0406, wR2 = 0.0900. Largest diff.
3
˚
˚
b = 14.5318(19), c = 18.898(3) A, V = 1629.3(4) A , Z = 4, Dc =
1.434 mg m−3, l(Mo–Ka) = 0.114 mm−1, 8097 reflections measured,
2861 unique [I > 2r(I)], R value 0.0607, wR2 = 0.1060. Largest diff.
peak and hole 0.144 and −0.148 eA−3. Crystallographic data has been
˚
peak and hole 0.189 and −0.179 eA−3. Crystallographic data has been
˚
deposited for compound 7 with the Cambridge Crystallographic Data
Centre [CCDC 637450]; (c) crystal data of 12c: single crystals of the
complex were grown by slow evaporation of the solution mixture in
acetonitrile. A colourless needle, of approximate size 0.20 × 0.07 ×
0.06 mm, was used for data collection. Crystal to detector distance
6.05 cm, 512 × 512 pixels per frame, hemisphere data acquisition.
Total scans = 3, total frames = 1271, oscillation per frame −0.3◦,
exposure per frame = 20.0 sec per frame, maximum detector swing
angle = −30.0◦, beam center = (260.2, 252.5), in plane spot width =
1.24, SAINT integration, h range = 1.77 to 25.00◦, completeness to h of
25.0◦ is 99.9%. SADABS correction applied, C14H15N5O6, M = 351.98.
deposited for compound 12c with the Cambridge Crystallographic
Data Centre [CCDC 637451]§.
12 (a) K. Toshima and K. Tatsuta, Chem. Rev., 1993, 93, 1503–1531;
(b) R. R. Schmidt, Angew. Chem., Int. Ed. Engl., 1986, 25, 212–235;
(c) H. Paulsen, Angew. Chem., Int. Ed. Engl., 1982, 21, 155–173.
13 H. Vorbru¨ggen and B. Bennua, Chem. Ber., 1981, 114, 1279–1286.
§ CCDC reference numbers 637450, 637451 and 666078. For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b716996e
786 | Org. Biomol. Chem., 2008, 6, 779–786
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©