Cyclization in situ of enose-/ynose-nitrilimines: An expedient approach to the synthesis of chiral glycopyrazoles and pyrazolonucleosides

Article abstract of DOI:10.1016/j.tet.2004.10.096

Intramolecular [3+2] nitrilimine cycloaddition reactions on carbohydrate-derived substrates proceed in a regioselective fashion, affording structurally novel chiral glycopyrazoles (4-6 and 10a-c) in good yields. The products can be subsequently transformed to bicyclic pyrazoles (viz. 11 from 4) or nucleoside analogues (viz. 12 from 4).

Full text of DOI:10.1016/j.tet.2004.10.096

Tetrahedron 61 (2005) 365–371
Cyclization in situ of enose-/ynose-nitrilimines:
an expedient approach to the synthesis of chiral
glycopyrazoles and pyrazolonucleosides
*
Ashim Roy, Sk. Sahabuddin, Basudeb Achari and Sukhendu B. Mandal
Division of Medicinal Chemistry, Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Kolkata 700 032, India
Received 25 August 2004; revised 7 October 2004; accepted 29 October 2004
Abstract—Intramolecular [3C2] nitrilimine cycloaddition reactions on carbohydrate-derived substrates proceed in a regioselective fashion,
affording structurally novel chiral glycopyrazoles (4–6 and 10a–c) in good yields. The products can be subsequently transformed to bicyclic
pyrazoles (viz. 11 from 4) or nucleoside analogues (viz. 12 from 4).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
in achieving the target structure. Although the synthesis of
enantiomerically pure pyrazole derivatives employing
chiral dipolarophiles and homochiral nitrilimines has been
reported,10 reports on the intramolecular version of this
methodology on a carbohydrate backbone are rare.11 For our
research programme directed towards the synthesis of
enantiomerically pure pyrazole derivatives, we opted to
use this reaction on appropriately designed carbohydrate-
derived precursors. We realized that introduction of a
C-/O-allyl or propargyl group at C-3 of the glucose ring and
generation of an aldehyde group at C-5 through simple
functional group manipulations followed by conversion of
the aldehyde to nitrilimine could lead to spontaneous [3C2]
cycloaddition, furnishing optically active and structurally
unique pyrazoles or pyrazolines (Fig. 1). Opening of the
furanose ring in the addition products was expected to
furnish fused pyrazoles/pyrazolines. Besides, introduction
of various nucleobases directly onto the anomeric center of
the furanose ring could lead to nucleoside analogues with
The pyrazole moiety is present in a large number of
biologically active compounds,1 which find wide appli-
cation in the pharmaceutical2 and agrochemical industries.3
Numerous synthetic routes to pyrazole heterocycles have
been developed based on (i) the condensation of hydrazines
with b-dicarbonyl compounds4 or with a, b-unsaturated
carbonyl compounds followed by appropriate transform-
ations,5 and (ii) inter-, intra-, or sequential inter-intra-
molecular [3C2] cycloaddition reaction of diazo
compounds6 or nitrilimines7 to alkynes or alkenes followed
by oxidation. The 1,3-dipolar cycloaddition reactions of
nitrilimines to obtain pyrazoles appears to have tremendous
potential for the development of structurally novel synthetic
entities, particularly when the nitrilimine is generated8,9
through oxidation of aldehyde hydrazones with chloramine
T or lead tetraacetate; judicious manipulation of the
aldehyde and the olefin moieties allows a lot of flexibility
Figure 1. A general method for the synthesis of glycopyrazoles.
Keywords: Nitrilimine cycloaddition reaction; Synthesis; Glycopyrazoles; Pyrazolonucleosides; D-Glucose.
* Corresponding author. Tel.: C91 332473 3491; fax: C91 3324735197; e-mail: sbmandal@iicb.res.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.096

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A. Roy et al. / Tetrahedron 61 (2005) 365–371
Scheme 1. Synthesis of pyrazoline 3 and pyrazoles 4–6 through INIC reaction.
pyrazole/pyrazoline ring in the structures. The present
communication deals with the scope of this reaction for
developing functionalized chiral glycopyrazoles and
pyrazolonucleosides.
the 1H NMR spectrum. This was confirmed by the presence
of three quaternary (d 112.6, 145.6 and 147.0) and two
methylene (d 49.9 and 71.5) carbon signals in its 13C NMR
spectrum. The absence of similar proton signals in the NMR
of 4 and the appearance instead of a 1H singlet at d 7.63
confirmed its formation through the oxidation of 3.
Regarding the identification of the other products, the
appearance of a double doublet for H-5a at d 4.54 (JZ5.3,
10.2 Hz) in the 1H NMR spectrum of 5 and of five
quaternary carbon signals in its 13C NMR spectrum
indicated its formation. Similarly, the absence of signals
in the olefinic proton region (d 5.18–6.03) coupled with the
presence of two singlets at d 5.09 and 7.63 in the 1H NMR
spectrum and of five quaternary carbons in the 13C NMR
spectrum of 6 indicated the structure shown. The trans
relationship of H-3a (d 3.59) with H-9a (d 4.98) (and hence
with H-5a at d 4.02) in 3 was borne out by the absence of
correlation in the NOESY spectrum. However, the presence
of distinct cross-peaks between the signals for the H-6a (d
4.36) and the H-5a (d 4.54) in the NOESY spectrum of 5
signified their cis relationship.
2. Results and discussion
Selective opening of the 5,6-O-isopropylidene group of the
D-glucose-derived precursors 1a–c12 by acid treatment
followed by vicinal diol cleavage with sodium periodate
and reaction with phenyl hydrazine furnished the corre-
sponding hydrazones 2a–c (as a mixture of cis and trans
1
isomers as evident from the duplicity of peaks in the H
NMR). Oxidation with chloramine T thereafter was
expected to furnish the respective pyrazolines as the
intramolecular nitrilimine cycloaddition (INIC) products.
However, the initially formed pyrazolines appear to have
undergone in situ oxidation to form the pyrazoles
(Scheme 1); only 2a yielded the pyrazoline 3 (40%) as the
major product along with the pyrazole 4 (15%), while 2b
and 2c gave 5 and 6, respectively. Formation of 3 was
indicated by the disappearance of vinylic proton signals of
1a in the d 5.20–5.30 and 5.80–6.00 regions along with
appearance of peaks for methylene protons at d 3.25–3.34
(m, 2H) and for a methine proton at d 3.55–3.62 (m, 1H) in
The INIC reaction was also attempted on the substrates
carrying an O-propargyl or substituted propargyl group at
C-3 of the carbohydrate precursor. Starting with 7
(Scheme 2), the 3-O-propargyl-a-D-glucofuranose
Scheme 2. Preparation of 3-O-alkynyl-1,2:5,6-diacetone-D-glucose derivatives 8, 9a–c.

A. Roy et al. / Tetrahedron 61 (2005) 365–371
367
derivative 8 was prepared through propargylation (propar-
gyl bromide, CH2Cl2, 50% aq NaOH, n-Bu4NCBrK, rt,
12 h) of C-3–OH group. Compounds 9a–c were, however,
synthesized by incorporating phenyl, 2,4-dimethoxyuracil-
5-yl and thiophen-2-yl groups at the terminal carbon of the
triple bond of 8 though Sonogashira coupling13 with the
corresponding iodides in the presence of a catalytic amount
of bis(triphenylphosphine)dichloro palladium(II) and
copper (I) iodide. The formation of the desired product in
each case was tested by NMR spectroscopy. Thus, the
1
acetylenic proton signal at d 2.48 in the H NMR of 8 was
found absent in those of the products 9a–c. Instead the
characteristic signals for protons of the substituent were
observed.
When the acetylenic compounds 8 and 9a–c were subjected
to dil acetic acid treatment, they afforded the respective 5,6-
dihydroxy derivatives. The products were subjected to
vicinal diol cleavage with NaIO4 and reaction with phenyl
hydrazine to furnish the corresponding hydrazones.
Oxidation of these hydrazones with chloramine T followed
by cycloaddition reactions of the generated nitrilimines
furnished the corresponding pyrazoles 4 and 10a–c in
32–38% overall yields (Scheme 3). The structures of the
products were deduced from spectral analyses.
Scheme 4. Conversion of 4 to bicyclic pyrazole 11 and modified nucleoside
12.
by the neighbouring acetoxy group directs the incoming
nucleobase to the b-face.
The formation of 11 was deduced from the appearance of an
acetoxy peak at d 2.11 (s, 6H) and of two methylene carbon
1
signals at d 62.8 and 63.1 in its H and 13C NMR spectra.
The presence of a 3H singlet at d 2.19 (OAc) and two
doublets at d 5.63 and 7.70 (olefin protons of uracil) in the
1H NMR of 12 confirmed the presence of the nucleoside
base at the anomeric carbon of the ribose ring.
In summary, it appears that intramolecular [3C2]
nitrilimine cycloaddition reaction could be applied to
D-glucose derived substrates to synthesize chiral pyrazoles
of diverse structures and also pyrazolonucleoside analogues.
The method is very simple and capable of extension to many
other carbohydrate based precursors.
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded on a Bruker AM
300 L spectrometer using CDCl3 as solvent and TMS as
internal standard. Mass spectra were obtained using either
JEOL AX-500 or Micromass Q-Tof microe spectrometers.
IR spectra were measured on a JASCO 700 spectro-
photometer. Elemental analyses were carried out with a C,
H, N-analyzer. Specific rotations were measured at 589 nm
on a JASCO P-1020 polarimeter. TLC was performed on
pre-coated plates (0.25 mm, silica gel 60 F254).
Scheme 3. Conversion of 8 and 9a–c to pyrazoles 4 and 10a–c.
The derived INIC products could be further transformed
into new varieties of bicyclic pyrazoles and nucleoside
analogues (Scheme 4). Thus, 4 was converted to pyrano-
pyrazole 11 through a sequence of reactions involving
removal of the 1,2-O-isopropylidene group with 4% H2SO4
in CH3CN–H2O (3:1), NaIO4 cleavage of the masked
aldehyde, NaBH4 reduction, and acetylation of the diol with
acetic anhydride in pyridine. Besides, nucleobases could be
successfully installed on 4 by cleavage of the acetonide
group, acetylation to form a mixture of the diacetates and
reaction with 2,4-bis-(trimethylsilyloxy)pyramidine in
presence of TMS–OTf in CH3CN at room temperature to
furnish the nucleoside derivative 12. Anchimeric assistance
3.1.1. 1,2-O-Isopropylidene-3-O-allyl-5-aldoglucofuran-
ose phenylhydrazones (2a cis/trans mixture). Typical
procedure. Compound 1a (3.0 g, 10.0 mmol) was dissolved
in dil HOAc (75%, 50 mL) and stirred at rt for 18 h. The
solvent was evaporated in vacuo and the last trace of HOAc
was removed through coevaporation with toluene (3!
50 mL) to afford a crude residue, which was purified by
column chromatography over silica gel using CHCl3–
MeOH (49:1) to afford the corresponding 5,6-dihydroxy
glucose derivative (2.08 g). The material was dissolved in
EtOH (40 mL); the solution was cooled to 10 8C and treated

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A. Roy et al. / Tetrahedron 61 (2005) 365–371
1
with an aqueous solution (40 mL) of NaIO4 (2.05 g,
9.6 mmol) dropwise while stirring (45 min). The reaction
mixture was filtered, the filtrate was concentrated and the
product was extracted with CHCl3 (2!40 mL). The CHCl3
solution was washed with H2O (2!50 mL), dried (Na2SO4)
and evaporated to give a crude aldehyde (1.37 g). Without
further purification, it was treated with phenylhydrazine
hydrochloride (900 mg, 6.18 mmol) and pyridine (1.0 mL),
and the mixture was stirred at rt for 5 h. The solvent
was evaporated and the product was extracted with CHCl3
(3!25 mL). The CHCl3 solution was washed with H2O
(2!25 mL), dried (Na2SO4) and the solvent was evaporated
to yield the hydrazone mixture 2a (1.62 g, 51%) as a sticky
mass; [found: C, 64.02; H, 6.82; N, 8.58. C17H22N2O4
requires C, 64.13; H, 6.97; N, 8.80]; IR (KBr): nmax 3305,
1500, 1377, 1214, 1161, 1093, 1013, 752 cmK1; H NMR
(CDCl3, 300 MHz): d 1.35 (s, 3H), 1.56 (s, 3H), 3.25–3.34
(m, 2H), 3.54–3.66 (m, 1H), 3.98 (dd, 1H, JZ10.1,
11.5 Hz), 4.02 (d, 1H, JZ1.9 Hz), 4.21 (dd, 1H, JZ6.3,
10.5 Hz), 4.58 (d, 1H, JZ3.5 Hz), 4.98 (d, 1H, JZ1.9 Hz),
6.01 (d, 1H, JZ3.5 Hz), 6.85 (dt, 1H, JZ0.6, 7.3 Hz), 6.99
(dd, 2H, JZ0.6, 7.8 Hz), 7.25–7.30 (m, 2H); 13C NMR
(CDCl3, 75 MHz): d 26.7 (CH3), 27.2 (CH3), 41.7 (CH),
49.9 (CH2), 71.5 (CH2), 74.1 (CH), 83.6 (CH), 84.0 (CH),
106.4 (CH), 112.6 (C), 113.2 (2!CH), 120.0 (CH), 129.6
(2!CH), 145.6 (C), 147.0 (C); EIMS, m/z: 316 (MC).
3.1.6. Compound 4. Sticky material; [found: C, 64.95; H,
5.73; N, 8.72. C17H18N2O4 requires C, 64.96; H, 5.77; N,
8.91]; [a]2D5ZC23.1 (c 0.4, CHCl3); IR (neat): nmax 1597,
1
1648, 1601, 1585, 1318, 1257, 1100, 1004, 753 cmK1; H
1
1503, 1389, 1213, 1162, 1084, 1015, 756 cmK1; H NMR
NMR (CDCl3, 300 MHz): d 1.35 (s), 1.49 (s), 1.51 (s), 1.55
(s), 3.97–4.14 (m), 4.30 (br s), 4.59 (m), 4.85 (br s), 5.18–5.30
(m), 5.97–6.07 (m), 6.87 (m), 7.01 (d), 7.06 (d), 7.23 (m), 7.46
(br s); ESIMS, m/z: 319 (MCCH), 341 (MCCNa).
(CDCl3, 300 MHz): d 1.38 (s, 3H), 1.59 (s, 3H), 4.17 (d, 1H,
JZ2.0 Hz), 4.65 (d, 1H, JZ13.9 Hz), 4.71 (d, 1H, JZ
3.6 Hz), 4.92 (d, 1H, JZ13.9 Hz), 5.20 (d, 1H, JZ2.1 Hz),
6.05 (d, 1H, JZ3.6 Hz), 7.30 (t, 1H, JZ7.3 Hz), 7.43 (t, 2H,
JZ8.1 Hz), 7.67 (d, 2H, JZ7.2 Hz), 7.69 (s, 1H); 13C NMR
(CDCl3, 75 MHz): d 26.8 (CH3), 27.3 (CH3), 62.7 (CH2),
70.8 (CH), 81.2 (CH), 84.3 (CH), 106.4 (CH), 112.5 (C),
117.1 (C), 119.8 (2!CH), 121.6 (CH), 127.2 (CH), 129.8
(2!CH), 140.4 (C), 145.1 (C); FABMS, m/z: 315 (MCC1).
3.1.2. 1,2-O-Isopropylidene-3-O-cyclohex-2-enyl-5-aldo-
glucofuranose phenylhydrazone (2b cis/trans mixture).
Sticky mass; [found: C, 66.88; H, 7.08; N, 7.59.
C20H26N2O4 requires C, 67.02; H, 7.31; N, 7.82]; IR
(KBr): nmax 3330, 1645, 1601, 1321, 1262, 1072, 998,
761 cmK1; 1H NMR (CDCl3, 300 MHz): d 1.34 (s), 1.50 (s),
1.55 (s), 1.63-2.10 (m), 3.96–4.39 (m), 4.58 (d), 4.85
(t-like), 5.70–6.06 (m, merged with a d at d 5.97), 6.82–6.91
(m), 6.99–7.11 (m), 7.21 (t-like), 7.61 (br s); ESIMS, m/z:
359 (MCCH), 381 (MCCNa).
3.1.7. (5aS,6aS,7R,8R,9aR)-7,8-Isopropylidene-dioxy-
3,4,5,5a,6a,7,8,9a-octahydro-2H-6,9-dioxa-1,2-diaza-
cyclopenta[d]acenaphthalene (5). Foam; [found: C, 67.69;
H, 6.18; N, 7.63. C20H22N2O4 requires C, 67.78; H, 6.26; N,
7.90]; [a]2D5ZK7.1 (c 0.33, CHCl3); IR (KBr): nmax 1597,
1
1503, 1380, 1217, 1162, 1077, 1017, 756 cmK1; H NMR
3.1.3. 1,2-O-Isopropylidene-3-C-allyl-5-aldoallofuran-
ose-phenylhydrazone (2c cis/trans mixture). Gum;
[found: C, 63.90; H, 6.77; N, 8.60. C17H22N2O4 requires
C, 64.13; H, 6.97; N, 8.80]; IR (neat): nmax 3472, 3312,
1640, 1600, 1256, 1079, 1007, 756 cmK1; 1H NMR (CDCl3,
300 MHz): d 1.37 (s), 1.40 (s), 1.63 (s), 2.14–2.29 (m),
2.39–2.48 (m), 3.60 (br s), 4.36 (d), 4.39 (d), 4.48 (d), 4.75
(d), 5.12–5.21 (m), 5.78–5.93 (m), 6.47 (d), 6.86 (t), 6.94
(d), 7.03 (t-like), 7.22 (d), 7.27 (d), 7.65 (s), 9.12 (s);
ESIMS, m/z: 319 (MCCH), 341 (MCCNa).
(CDCl3, 300 MHz): d 1.37 (s, 3H), 1.58 (s, 3H), 1.81–1.90
(m, 2H), 2.15–2.24 (m, 2H), 2.68 (m, 1H), 3.00 (dd, 1H, JZ
6.0, 16.8 Hz), 4.36 (d, 1H, JZ2.2 Hz), 4.54 (dd, 1H, JZ5.3,
10.2 Hz), 4.69 (d, 1H, JZ3.6 Hz), 5.28 (d, 1H, JZ2.2 Hz),
6.02 (d, 1H, JZ3.6 Hz), 7.30 (t, 1H, JZ7.4 Hz), 7.42 (t, 2H,
JZ7.9 Hz), 7.62 (d, 2H, JZ7.8 Hz); 13C NMR (CDCl3,
75 MHz): d 21.7 (CH2), 24.2 (CH2), 26.8 (CH3), 27.4 (CH3),
29.2 (CH2), 71.4 (CH), 72.3 (CH), 82.7 (CH), 84.1 (CH),
106.5 (CH), 112.2 (C), 120.7 (C), 122.3 (2!CH), 127.1
(CH), 129.5 (2!CH), 136.9 (C), 140.7 (C), 143.8 (C);
FABMS, m/z: 355 (MCCH).
3.1.4. (3aR,5aS,5bR,8aR,9aR)-7,7-Dimethyl-2-phenyl-
2,3,3a,4,5a,5b,8a,9a-octahydro-5,6,8,9-tetraoxa-1,2-
diaza-cyclopenta[b]-as-indacene (3); (5aS,5bR,8aR,9aR)-
7,7-dimethyl-2-phenyl-2,4,5a,5b,8a,9a-hexahydro-5,6,
8,9-tetraoxa-1,2-diaza-cyclopenta[b]-as-indacene (4).
Typical procedure. To the hydrazone 2a (636 mg,
2.0 mmol) dissolved in ethanol (40 mL) was added
chloramine T (843 mg, 3.0 mmol) and the mixture was
heated at reflux under N2 for 6 h. The solvent was
evaporated in vacuo and the residual mass was extracted
with CHCl3 (2!30 mL). The CHCl3 solution was washed
successivelywithwater(2!25 mL),1 MNaOH(20 mL),and
brine (2!20 mL), and then dried (Na2SO4). Evaporation of
the solvent furnished a reddish gummy material, which was
purified by chromatography on silica gel using CHCl3 as
eluent to afford 3 (253 mg, 40%) and 4 (94 mg, 15%).
3.1.8. (3aR,3bR,4aR,7bR)-2,2-Dimethyl-6-phenyl-3a,6,
7b,8a-tetrahydro-4H-1,3,8-trioxa-6,7-diaza-dicyclo-
penta[a,e]pentalen-3b-ol (6). Foamy mass; [found: C,
64.79; H, 5.65; N, 8.87. C17H18N2O4 requires C, 64.96; H,
5.77; N, 8.91]; [a]2D5ZC112.7 (c 0.25, CHCl3); IR (neat):
nmax 3449, 1598, 1504, 1380, 1218, 1162, 1080, 1030, 999,
1
756 cmK1; H NMR (CDCl3, 300 MHz): d 1.44 (s, 3H),
1.67 (s, 3H), 2.93 (d, 1H, JZ16.2 Hz), 3.01 (d, 1H, JZ
16.2 Hz), 4.51 (d, 1H, JZ3.6 Hz), 5.09 (s, 1H), 6.01 (d, 1H,
JZ3.6 Hz), 7.29 (1H merged signal), 7.42 (t, 2H, JZ
7.8 Hz), 7.63 (s, 1H), 7.64 (d, 2H, JZ7.8 Hz); 13C NMR
(CDCl3, 75 MHz): d 27.4 (CH3), 27.8 (CH3), 34.7 (CH2),
82.6 (CH), 83.5 (CH), 94.6 (C), 107.2 (CH), 113.7 (C),
119.9 (2!CH), 122.4 (CH), 125.9 (C), 126.9 (CH), 129.8
(2!CH), 141.1 (C), 158.6 (C); EIMS, m/z: 314 (MC).
3.1.5. Compound 3. Gummy mass; [found: C, 64.34; H,
6.18; N, 8.58. C17H20N2O4 requires C, 64.54; H, 6.37; N,
8.86]; [a]2D5ZC117.4 (c 0.56, CHCl3); IR (neat): nmax 1598,
3.1.9. (3aR,4S,5R,6aR)-5-(2,2-Dimethyl-[1,3]dioxolan-
4R-yl)-2,2-dimethyl-6-prop-2-ynyloxy-tetrahydro-
furo[2,3-d][1,3]dioxole (8). To a stirred heterogeneous

A. Roy et al. / Tetrahedron 61 (2005) 365–371
369
solution of 7 (1.30 g, 5.0 mmol) in dichloromethane
(70 mL) and 50% NaOH (70 mL) containing n-tetrabutyl-
ammonium bromide (160 mg), was added propargyl
bromide (893 mg, 7.5 mmol) and the mixture was stirred
at rt for 12 h. The organic layer was taken out, washed with
H2O until neutral and then dried (Na2SO4). The solvent was
evaporated and the resulting product was purified by silica
gel column chromatography using CHCl3–pet. ether (1:9) as
the eluent to obtain 8 (1.25 g, 83%) as a thick liquid; [found:
C, 60.37; H, 7.28. C15H22O6 requires C, 60.39; H, 7.43]; IR
3.1.12. (3aR,4S,5R,6aR)-5-(2,2-Dimethyl-[1,3] dioxolan-
4R-yl)-2,2-dimethyl-6-(3-thiophen-2-yl-prop-2-ynyloxy)-
tetrahydro-furo[2,3-d][1,3]dioxole (9c). Gum; [found: C,
59.67; H, 6.38. C19H24O6S requires C, 59.98; H, 6.36];
[a]2D5ZK5.53 (c 0.75, CHCl3); IR (neat): nmax 2222, 1375,
1
1253, 1214, 1163, 1077, 1024, 847, 706 cmK1; H NMR
(CDCl3, 300 MHz): d 1.32 (s, 3H), 1.35 (s, 3H), 1.42 (s, 3H),
1.50 (s, 3H), 4.01 (dd, 1H, JZ5.4, 8.5 Hz), 4.10 (dd, 1H,
JZ6.1, 8.4 Hz), 4.15 (m, 2H), 4.29–4.35 (m, 1H), 4.51 (s,
2H), 4.67 (d, 1H, JZ3.6 Hz), 5.90 (d, 1H, JZ3.6 Hz), 6.98
(dd, 1H, JZ3.7, 4.9 Hz), 7.23 (d,1H, JZ3.4 Hz), 7.27 (d,
1H, JZ4.7 Hz); 13C NMR (CDCl3, 75 MHz): d 25.8 (CH3),
26.6 (CH3), 27.2 (2!CH3), 59.3 (CH2), 67.6 (CH2), 72.9
(CH), 80.2 (C), 81.5 (CH), 81.9 (CH), 83.2 (CH), 89.0 (C),
105.6 (CH), 109.4 (C), 112.2 (C), 122.7 (C), 127.3 (CH),
127.9 (CH), 132.9 (CH). FABMS, m/z: 381 (MCCH), 403
(MCCNa).
(neat): nmax 3275, 2117, 1378, 1216, 1076, 1022, 849 cmK1
;
1H NMR (CDCl3, 300 MHz): d 1.32 (s, 3H), 1.35 (s, 3H),
1.43 (s, 3H), 1.50 (s, 3H), 2.48 (t, 1H, JZ2.3 Hz), 3.99 (dd,
1H, JZ5.4, 8.6 Hz), 4.07–4.11 (m, 2H), 4.14 (dd, 1H, JZ
3.0, 7.6 Hz), 4.25–4.31 (m, 3H), 4.63 (d, 1H, JZ3.6 Hz),
5.88 (d, 1H, JZ3.6 Hz); EIMS, m/z: 298 (MC).
3.1.10. (3aR,4S,5R,6aR)-5-(2,2-Dimethyl-[1,3]dioxolan-
4R-yl)-2,2-dimethyl-6-(3-phenyl-prop-2-ynyloxy)-tetra-
hydro-furo[2,3-d][1,3]dioxole (9a). Typical procedure. To
a solution of 8 (2.00 g, 6.71 mmol) in dry benzene (50 mL)
was added bis(triphenylphosphine)palladium dichloride
(93 mg, 0.13 mmol), cuprous iodide (13 mg, 0.06 mmol),
triethyl amine (4.6 mL) and iodobenzene (1.63 g, 0.9 mL),
and the mixture was stirred under N2 for 20 h at rt. After
removal of the solvent under reduced pressure, the residue
obtained was extracted with CHCl3 (3!30 mL). The CHCl3
solution was washed with water (2!20 mL), dried
(Na2SO4) and evaporated to give a crude product, which
was purified by column chromatography on silica gel.
Elution with pet. ether–CHCl3 (1:1) furnished 9a (1.91 g,
76%) as a light yellowish oil; [found: C, 67.15; H, 6.90.
C21H26O6 requires C, 67.36; H, 7.00]; [a]2D5ZK10.5 (c
0.43, CHCl3); IR (neat): nmax 2237, 1498, 1448, 1375, 1254,
3.1.13. (5aS,5bR,8aR,9aR)-7,7-Dimethyl-2,3-diphenyl-
2,4,5a,5b,8a,9a-hexahydro-5,6,8,9-tetraoxa-1,2-diaza-
cyclopenta[b]-as-indacene (10a). The reaction was carried
out according to the method adopted for 3. Thus, the
hydrazone (392 mg, 1.0 mmol) derived from 9a as
described was dissolved in ethanol (40 mL), treated with
chloramine T (418 mg, 1.5 mmol) and heated at reflux for
6 h under N2. Usual work-up followed by purification using
silica gel column chromatography and CHCl3–MeOH
(99.5:0.5) as eluent afforded 10a (273 mg, 70%) as a thick
gum; [found: C, 70.69; H, 5.55; N, 6.91. C23H22N2O4
requires C, 70.75; H, 5.68; N, 7.17]; [a]2D5ZK4.0 (c 0.5,
CHCl3); IR (neat): nmax 1596, 1498, 1448, 1373, 1216,
1162, 1081, 1015, 756 cmK1; 1H NMR (CDCl3, 300 MHz):
d 1.38 (s, 3H), 1.59 (s, 3H), 4.24 (d, 1H, JZ1.8 Hz), 4.72 (d,
1H, JZ3.6 Hz), 4.77 (s, 2H), 5.24 (d, 1H, JZ1.9 Hz), 6.08
(d, 1H, JZ3.6 Hz), 7.07 (m, 2H), 7.31 (br s, 8H); 13C NMR
(CDCl3, 75 MHz): d 26.9 (CH3), 27.3 (CH3), 63.1 (CH2),
71.1 (CH), 81.3 (CH), 84.3 (CH), 106.5 (CH), 112.5 (C),
115.7 (C), 125.5 (2!CH), 127.9 (CH), 128.9 (CH), 129.1
(2!CH), 129.3 (4!CH), 129.9 (C), 137.2 (C), 140.1 (C),
144.2 (C); ESIMS, m/z: 413 (MCCNa), 803 (2MCCNa).
1
1215, 1163, 1077, 1026, 847, 758, 692 cmK1; H NMR
(CDCl3, 300 MHz): d 1.32 (s, 3H), 1.35 (s, 3H). 1.42 (s, 3H),
1.51 (s, 3H), 4.02 (dd, 1H, JZ5.6, 8.4 Hz), 4.11 (dd, 1H,
JZ6.1, 8.4 Hz), 4.18 (m, 2H), 4.34 (dd, 1H, JZ5.8,
11.8 Hz), 4.50 (s, 2H), 4.69 (d, 1H, JZ3.4 Hz), 5.90 (d,
1H, JZ3.4 Hz), 7.32 (m, 3H), 7.45 (m, 2H). 13C NMR
(CDCl3): d 25.2 (CH3), 26.1 (CH3), 26.7 (2!CH3), 58.6
(CH2), 67.0 (CH2), 72.4 (CH), 80.9 (CH), 81.2 (CH), 82.6
(CH), 84.4 (C), 86.4 (C), 105.1 (CH), 108.9 (C), 111.7 (C),
128.1 (2!CH), 128.4 (CH), 130.1 (C), 131.6 (2!CH);
FABMS, m/z: 375 (MCCH).
3.1.14. (5aS,5bR,8aR,9aR)-3-(2,4-Dimethoxypyrimidin-
5-yl)-7,7-dimethyl-2-phenyl-2,4,5a,5b,8a,9a-hexahydro-
5,6,8,9-tetraoxa-1,2-diaza-cyclopenta[b]-as-indacene
(10b). Foamy solid; [found: C, 60.88; H, 5.32; N, 12.19.
C23H24N4O6 requires C, 61.05; H, 5.35; N, 12.38];
[a]2D5ZC3.5 (c 1.38, CHCl3); IR (KBr): nmax 1735, 1613,
3.1.11. (3aR,4S,5R,6aR)-5-{3-[5-(2,2-Dimethyl-[1,3]
dioxolan-4R-yl)-2,2-dimethyl-tetrahydro-furo[2,3-d]
[1,3]dioxol-6-yloxy]-prop-1-ynyl}-2,4-dimethoxy-pyri-
midine (9b). Gummy material; [found: C, 57.68; H, 6.33; N,
6.19. C21H28N2O8 requires C, 57.79; H, 6.47; N, 6.42];
[a]2D5ZK5.5 (c 1.5, CHCl3); IR (neat): nmax 2226, 1594,
1572, 1552, 1480, 1455, 1391, 1082, 1015, 758, 696 cmK1
;
1H NMR (CDCl3, 300 MHz): d 1.38 (s, 3H), 1.58 (s, 3H),
3.78 (s, 3H), 3.99 (s, 3H), 4.23 (d, 1H, JZ2.0 Hz), 4.66–
4.72 (m, 3H), 5.23 (d, 1H, JZ2.1 Hz), 6.07 (d, 1H, JZ
3.5 Hz), 7.28–7.36 (m, 5H), 7.94 (s, 1H); 13C NMR (CDCl3,
75 MHz): d 26.8 (CH3), 27.3 (CH3), 54.4 (CH3), 55.5 (CH3),
62.9 (CH2), 70.9 (CH), 81.3 (CH), 84.3 (CH), 105.6 (C),
106.5 (CH), 112.5 (C), 117.2 (C), 124.7 (2!CH), 128.2
(CH), 129.2 (C), 129.4 (2!CH), 140.3 (C), 144.2 (C), 159.4
(CH), 165.9 (C), 168.3 (C); ESIMS, m/z: 475 (MCCNa).
1
1551, 1472, 1388, 1077, 1017, 848, 756 cmK1; H NMR
(CDCl3, 300 MHz): d 1.32 (s, 3H), 1.36 (s, 3H), 1.46 (s, 3H),
1.51 (s, 3H), 4.02 (s, 3H), 4.05 (s, 3H), 4.09–4.18 (m, 4H),
4.32 (m, 1H), 4.53 (s, 2H), 4.70 (d, 1H, JZ3.6 Hz), 5.90 (d,
1H, JZ3.6 Hz), 8.34 (br s, 1H); 13C NMR (CDCl3,
75 MHz): d 25.8 (CH3), 26.6 (CH3), 27.2 (2!CH3), 54.9
(CH3), 55.5 (CH3), 59.3 (CH2), 67.6 (CH2), 73.0 (CH), 78.5
(C), 81.4 (CH), 82.0 (CH), 83.2 (CH), 91.5 (C), 105.6 (CH),
109.4 (C), 112.2 (C), 162.0 (CH), 164.7 (C), 2 quaternary C
signals not observed; FABMS, m/z: 437 (MCCH), 459
(MCCNa).
3.1.15. (5aS,5bR,8aR,9aR)-7,7-Dimethyl-2-phenyl-3-
thiophen-2-yl-2,4,5a,5b,8a,9a-hexahydro-5,6,8,9-tetra-
oxa-1,2-diaza-cyclopenta[b]-as-indacene (10c). Foamy
solid; [found: C, 63.68; H, 5.05; N, 6.94. C21H20N2O4S
requires C, 63.62; H, 5.08; N, 7.07]; [a]2D5ZC5.27 (c 0.56,

370
A. Roy et al. / Tetrahedron 61 (2005) 365–371
CHCl3); IR (KBr): nmax 1736, 1596, 1498, 1455, 1376,
1219, 1162, 1085, 1016, 759, 698 cmK1; 1H NMR (CDCl3,
300 MHz): d 1.38 (s, 3H), 1.58 (s, 3H), 4.22 (d, 1H, JZ
1.6 Hz), 4.72 (d, 1H, JZ3.8 Hz), 4.73 (d, 1H, JZ13.4 Hz),
4.90 (d, 1H, JZ14.1 Hz), 5.21 (d, 1H, JZ1.9 Hz), 6.07 (d,
1H, JZ3.5 Hz), 6.72 (dd, 1H, JZ0.9, 3.5 Hz), 6.97 (dd, 1H,
JZ3.7, 5.0 Hz), 7.31–7.37 (m, 6H); 13C NMR (CDCl3,
75 MHz): d 26.9 (CH3), 27.3 (CH3), 63.1 (CH2), 70.9 (CH),
81.1 (CH), 84.2 (CH), 106.5 (CH), 112.5 (C), 115.9 (C),
126.3 (2!CH), 127.6 (CH), 127.9 (CH), 128.2 (CH), 128.7
(CH), 129.3 (CH), 129.5 (CH), 130.4 (C), 131.5 (C),
140.0 (C), 144.1 (C); ESIMS, m/z: 419 (MCCNa), 815
(2MCCNa).
CHCl3–MeOH mixture (49.5:0.5) to afford 12 (193 mg,
47%) as a foamy solid; [found C, 58.60; H, 4.38; N, 13.40.
C20H18N4O6 requires C, 58.53; H, 4.42; N, 13.65];
[a]2D5ZC73.7 (c 0.95, CHCl3); IR (KBr): nmax 3408,
1
1747, 1688, 1503, 1459, 1391, 1221, 1060, 756 cmK1; H
NMR (CDCl3, 300 MHz): d 2.19 (s, 3H), 4.20 (d, 1H, JZ
2.2 Hz), 4.71 (d, 1H, JZ14.1 Hz), 4.98 (d, 1H, JZ14.1 Hz),
5.18 (d, 1H, JZ2.2 Hz), 5.27 (br s, 1H), 5.63 (d, 1H, JZ
8.0 Hz), 6.21 (d, 1H, JZ1.1 Hz), 7.33 (t, 1H, JZ7.4 Hz),
7.44–7.49 (m, 3H), 7.70 (d, 2H, JZ7.8 Hz), 7.77 (s, 1H),
8.96 (s, 1H); 13C NMR (CDCl3, 75 MHz): d 21.2 (CH3),
62.9 (CH2), 72.9 (CH), 79.9 (CH), 81.5 (CH), 90.5 (CH),
102.7 (CH), 116.7 (C), 119.8 (2!CH), 121.9 (CH),
127.6 (CH), 129.9 (2!CH), 140.2 (C), 141.0 (CH), 143.5
(C), 150.3 (C), 163.2 (C), 169.7 (C); ESIMS, m/z: 433
(MCCNa), 843 (2MCCNa).
3.1.16. (6R,7R)-Acetic acid-6-acetoxymethyl-2-phenyl-
2,4,6,7-tetrahydro-pyrano [4,3-c] pyrazol-7-yl ester
(11). Compound 4 (314 mg, 1.0 mmol) was dissolved in
4% H2SO4 in CH3CN–H2O (3:1) (25 mL) and kept at rt for
24 h. The acidic solution was neutralized with solid CaCO3,
filtered, and the filtrate was evaporated in vacuo. The
residue was dissolved in EtOH (20 mL) and treated
dropwise at 10 8C with an aqueous solution (20 mL) of
NaIO4 (314 mg, 1.0 mmol) with stirring for 45 min. Usual
work-up followed by NaBH4 reduction in MeOH (30 mL)
afforded an alcohol, which was acetylated with Ac2O
(0.5 mL) in pyridine (1.5 mL) at rt for 12 h to furnish a
crude product. The product was purified by silica gel
column chromatography using pure CHCl3 as an eluent to
afford 11 (119 mg, 36%) as a thick gum; [found: C, 61.68;
H, 5.28; N, 8.30. C17H18N2O5 requires C, 61.81; H, 5.49; N,
8.48]; [a]2D5ZK74.5 (c 0.52, CHCl3); IR (neat): nmax 1743,
Acknowledgements
The work was supported by a grant from the Department of
Science and Technology (Govt. of India). One of the authors
(A. R.) gratefully acknowledges the Council of Scientific
and Industrial Research for providing him a Senior Research
Fellowship.
References and notes
1
1598, 1503, 1371, 1225, 1049, 958, 758, 690 cmK1; H
1. (a) Elguero, J. In Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Comprehensive Heterocyclic Chemistry;
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NMR (CDCl3, 300 MHz): d 2.11 (s, 6H), 4.01–4.06 (m, 1H),
4.27 (dd, 1H, JZ7.2, 11.5 Hz), 4.36 (dd, 1H, JZ5.3,
11.5 Hz), 4.75 (d, 1H, JZ14.0 Hz), 5.05 (d, 1H, JZ
14.0 Hz), 6.16 (d, 1H, JZ1.9 Hz), 7.29 (t, 1H, JZ7.6 Hz),
7.44 (t, 2H, JZ8.1 Hz), 7.66 (d, 2H, JZ7.9 Hz), 7.69 (s,
1H); 13C NMR (CDCl3, 75 MHz): d 20.6 (CH3), 20.8 (CH3),
62.6 (CH), 62.8 (CH2), 63.1 (CH2), 75.6 (CH), 116.9 (C),
119.3 (2!CH), 121.2 (CH), 126.8 (CH), 129.3 (2!CH),
139.8 (C), 145.5 (C), 169.9 (C), 170.5 (C); ESIMS, m/z: 353
(MCCNa).
3.1.17. (5aS,6R,7R,8aR)-Acetic acid-7-(2,4-dioxo-3,4-
dihydro-2H-pyrimidin-1-yl)-2-phenyl-2,4,5a,6,7,8a-
hexahydro-5,8-dioxa-1,2-diaza-as-indacen-6-yl ester
(12). 2,4-Bis-(trimethyl silyloxy)pyramidine was prepared
by refluxing a mixture of uracil (336 mg, 3.0 mmol) and
trimethylsilyl chloride (2 drops) dissolved in hexamethyl
disilazane (7 mL) under N2 for 10 h. The residue obtained
after evaporation of the solvent in vacuo was dissolved in
acetonitrile (5 mL) and added to a solution of the diacetate
mixture (358 mg, 1.0 mmol) in acetonitrile (5 mL) [gener-
ated from 4 through opening of 1,2-O-isopropylidene group
followed by acetylation] and TMS–OTf (0.5 mL). The
mixture was stirred for 6 h at rt under N2. TLC showed
complete disappearance of the starting material. The
solution was neutralized with solid NaHCO3, treated with
water (3 drops), and the solvent was evaporated in rotary
evaporator. The gummy material was extracted with CHCl3
(2!25 mL), the CHCl3 solution was washed with brine,
dried (Na2SO4), and concentrated. The crude product was
purified by silica gel column chromatography eluting with
4. Barber, G. N.; Olofson, R. A. J. Org. Chem. 1978, 43, 3015.
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A. Roy et al. / Tetrahedron 61 (2005) 365–371
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`
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