Domino Knoevenagel-hetero-Diels-Alder reactions: a stereoselective synthesis of sugar-annulated furo[3,2-b] pyrano[4,3-d]pyran derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.02.132

The O-propargyl derivative of a sugar aldehyde derived from d-glucose undergoes smooth intramolecular domino Knoevenagel-hetero-Diels-Alder reactions with 1,3-diketones in the presence of CuI/Et₃N system in refluxing methanol to afford a novel class of carbohydrate analogues, furopyranopyrans in good yields. 1-Aryl-pyrazol-5-ones also undergo smooth coupling with O-propargyl tethered sugar aldehyde under similar conditions to furnish pyrazole-annulated furopyranopyrans. The stereochemistry of the products was assigned by various NMR experiments.

Full text of DOI:10.1016/j.tetlet.2010.02.132

Tetrahedron Letters 51 (2010) 2305–2308
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Tetrahedron Letters
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Domino Knoevenagel–hetero-Diels–Alder reactions: a stereoselective
synthesis of sugar-annulated furo[3,2-b] pyrano[4,3-d]pyran derivatives
a
a
a
a
J. S. Yadav a, , B. V. Subba Reddy , A. V. Hara Gopal , R. Nageshwar Rao , R. Somaiah ,
*
P. Purushotham Reddy b, A. C. Kunwar b
a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Center for Nuclear Magnetic Resonance, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The O-propargyl derivative of a sugar aldehyde derived from D-glucose undergoes smooth intramolecular
Received 18 November 2009
Revised 17 February 2010
Accepted 20 February 2010
Available online 24 February 2010
domino Knoevenagel–hetero-Diels–Alder reactions with 1,3-diketones in the presence of CuI/Et3N sys-
tem in refluxing methanol to afford a novel class of carbohydrate analogues, furopyranopyrans in good
yields. 1-Aryl-pyrazol-5-ones also undergo smooth coupling with O-propargyl tethered sugar aldehyde
under similar conditions to furnish pyrazole-annulated furopyranopyrans. The stereochemistry of the
products was assigned by various NMR experiments.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Domino Knoevenagel–hetero-Diels–Alder
reaction
1,3-Diones
Pyrazolones
Sugar aldehyde
Polycyclic heterocycles
The pyrazole moiety is frequently found in various biologically
active compounds.1 Pyrazole derivatives are known to exhibit a
wide spectrum of biological activities such as anti-hyperglycemic,
analgesic, anti-inflammatory, anti-pyretic, anti-bacterial, hypogly-
cemics, and sedative-hypnotic activity.2 Recently, some arylpyraz-
ole derivatives are reported to have non-nucleoside HIV-1 reverse
transcriptase inhibitory activity.3 The domino Knoevenagel intra-
molecular hetero-Diels–Alder reaction is one of the most powerful
synthetic routes for the synthesis of various heterocycles and
natural products.4,5 Recently, there have been some reports on
domino Knoevenagel–hetero-Diels–Alder reactions to produce
annulated polycyclic heterocycles.6,7 However, to the best of our
knowledge, there are no reports on domino Knoevenagel intramo-
lecular hetero-Diels–Alder reactions using an O-propargyl tethered
The reaction proceeds via a tandem Knoevenagel- and hetero-
Diels–Alder pathway. The structure of product 3a was characterized
by NMR experiments including 2-D nuclear Overhauser effect spec-
troscopy (NOESY) and double quantum filtered correlationspectros-
copy (DQFCOSY) (Fig. 1). From the one dimensional 1H NMR
experiments, JH1-H2 = 3.9 Hz, JH3-H4 = 2.6 Hz, JH4-H5 = 4.8 Hz, and
3JH6-H7(pro-R) = 1.6 Hz were determined. The twist boat conformation
of the oxygen-containing six-membered ring is supported by the
NOESY cross peak H5/H7(pro-S), H6/H7(pro-S), and H3/H7(pro-R).
In addition, thesmallvalues of3JH3-H4 and3JH4-H5 provide furtherevi-
dence for the structure.8
In case of 4-hydroxycoumarin, no other regioisomer was
observed (entry a, Table 1) by 1H NMR. Encouraged by the results
obtained with 4-hydroxycoumarin, we turned our attention to var-
ious 1,3-diketones (Table 1, entries b–d). The cyclic 1,3-diketones
such as cyclohexa-1,3-dione, dimedone, and 1,3-dimethylbarbitu-
ric acid participated effectively in this reaction. In all cases, the cor-
responding furo[3,2-b]pyrano[4,3-d]pyrans were isolated in good
yields. However, acyclic 1,3-ketones such as acetyl acetone and
ethyl acetoacetate did not participate in the reaction. Similarly,
cyclic ketones such as cyclohexanone, cyclopentanone, and tetra-
lone also failed to give the desired products under similar condi-
tions. Furthermore, substituted propargyl ether tethered sugar
aldehyde did not undergo the hetero-Diels–Alder reaction with
1,3-diones. The reaction was successful only with unsubstituted
propargyl ether tethered sugar aldehyde. Next, we have attempted
3
3
3
sugar aldehyde derived from D-glucose.
In this Letter, we describe a novel protocol for the synthesis of
sugar-fused pyrano[4,3-d]pyrans via domino Knoevenagel–het-
ero-Diels–Alder reaction between propargyl ether tethered sugar
aldehyde and 1,3-diketones. Thus, the treatment of 4-hydroxy-
coumarin (1) with O-propargyl tethered sugar aldehyde (2) in the
presence of 0.3 equiv of CuI and a stoichiometric amount of trieth-
ylamine in methanol at 70 °C resulted in the formation of couma-
rin-annulated furo[3,2-b]pyrano[4,3-d]pyran 3a in 75% yield
(Scheme 1).
* Corresponding author. Tel.: +91 40 27193030; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.132

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J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2305–2308
H
O
O
O
O
O
O
O
CuI/Et3N
O
O
O
O
H
+
CH3OH, reflux
O
O
OH
O
3a
1
2
Scheme 1. Reaction of sugar aldehyde with 4-hydroxycoumarin.
H1
CH3
zole-annulated furo[3,2-b]pyrano[4,3-d]pyrans in good yields
(Scheme 2, entries e–h).
Next, we attempted the domino-Knoevenagel–hetero-Diels–Al-
der reaction with O-propargyl tethered sugar aldehyde derived
O
O
O
O
O
H4
H2
CH3
H5
O
from D-ribose. The reaction proceeded well under similar condi-
tions to give the desired product in 80% yield (entry i, Table 1).
As a solvent, methanol appeared to give the best results. In all
cases, the reactions proceeded rapidly in refluxing methanol. The
reactions were clean and the desired products were obtained in
good yields. Only a single product was obtained from each reac-
tion, the structure of which was confirmed by 1H NMR.
We assume that the cycloaddition proceeds in a concerted way
via endo-E-syn transition state. Mechanistically, a 1-oxa-1,3-buta-
diene may be formed from 1,3-diketone and propargyl ether teth-
ered sugar aldehyde which may undergo subsequently an
intramolecular hetero-Diels–Alder reaction leading to tetracyclic
heterocycle (Scheme 3).
H3
O
H7(pro-R)
)
H6 H7(pro-S
H4
H5
H1
The scope and generality of the reaction are illustrated with
respect to various cyclic 1,3-diketones and pyrazolin-5-ones and
the results are presented in Table 1.9
In summary, we have developed a novel method for the synthesis
of poly-oxygenated ring heterocycles via a domino Knoevenagel–
hetero-Diels–Alderreactionbetweenpropargylethertetheredsugar
aldehyde and cyclic 1,3-diketones. This method also works well with
pyrazolin-5-ones. It is entirely a new strategy to construct sugar
annulated tetracyclic- and pentacyclic-heterocycles in a single-step
operation.
H2
H7(pro-S)
H3
H6
H7(pro-R)
Figure 1. Characteristic NOE’s and energy-minimized structure of 3a.
the condensation of propargyl ether tethered sugar aldehyde with
1-aryl-pyrazol-5-ones. Interestingly, various pyrazol-5-ones
underwent smooth coupling with sugar aldehyde to afford pyra-
Table 1
Domino Knoevenagel–hetero-Diels–Alder reaction
Entry
Substrate
Aldehyde
Producta
Time (h)
4.0
Yieldb (%)
O
H
O
O
O
O
O
O
O
O
a
75
OH
H
O
O
O
O
O
O
H
O
O
O
O
O
O
O
H
O
O
b
c
4.0
3.5
90
84
O
O
O
O
H
O
O
H
O
O
O
O
O
O
O
O
O
O
N
O
H
O
O
O
N
O
O
N
O
O
O
d
4.5
85
O
N
O
H
O
O
O
O

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2305–2308
2307
Table 1 (continued)
Entry
Substrate
Aldehyde
Producta
Time (h)
5.0
Yieldb (%)
H
O
O
N
N
N
O
N
O
N
O
e
76
80
H
O
O
O
O
O
O
O
O
H
N
O
N
O
N
O
H
f
O
4.5
5.0
O
O
O
O
O
H
F
O
N
N
O
N
O
N
O
H
O
O
g
O
75
O
O
O
O
O
F
H
O
O
N
N
O
N
N
O
O
Cl
h
5.5
4.5
78
80
H
O
O
O
O
O
Cl
O
O
O
H
O
O
O
H
i
O
O
O
O
O
O
O
a
The products were characterized by NMR, IR, and mass spectroscopy.
Yield refers to pure products after chromatography.
b
References and notes
N
N
H
1. Elguero, J.. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 3, pp 1–75.
2. Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron Lett. 2003, 44, 6737–6740. and
references cited therein.
3. (a) Genin, M. J.; Biles, C.; Keiser, B. J.; Poppe, S. M.; Swaney, S. M.; Tarpley, W. G.;
Yagi, Y.; Romero, D. L. J. Med. Chem. 2000, 43, 1034; (b) Huang, Y. R.;
Katzenellenbogen, J. A. Org. Lett. 2000, 2, 2833; (c) Stauffer, S. R.; Coletta, C. J.;
Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.;
Katzenellenbogen, J. A. J. Med. Chem. 2000, 43, 4934.
O
N
H
O
CuI/Et3N
O
O
O
O
N
O
+
O
CH3OH, reflux
O
O
O
3e
Scheme 2. Reaction of sugar aldehyde with 3-methyl-pyrazol-5-one.
4. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (b) Tietze, L. F.; Zhou, Y. F. Angew.
Chem., Int. Ed. 1999, 38, 2045–2047.
5. (a) Tietze, L. F.; Kettschau, G.; Gewert, J. A.; Schuffenhauer, A. Curr. Org. Chem.
1998, 2, 19–40; (b) Tietze, L. F.; Ott, C.; Haunert, F. Can. J. Chem. 2001, 79, 1511–
1514; (c) Shanmugasundaram, M.; Manikandan, S.; Raghunathan, R. Tetrahedron
2002, 58, 997–1003.
6. (a) Kiamehr, M.; Moghaddam, F. M. Tetrahedron Lett. 2009, 50, 6723–6727; (b)
Yadav, J. S.; Reddy, B. V. S.; Narsimhaswamy, D.; Lakshmi, P. N.; Narsimulu, K.;
Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2004, 45, 3493–3497; (c)
Khoshkholgh, M. J.; Balalaie, S.; Bijanzadeh, H. R.; Rominger, F.; Gross, J. H.
Tetrahedron Lett. 2008, 49, 6965–6968; (d) Majumdar, K. C.; Taher, A.; Ray, K.
Tetrahedron Lett. 2009, 50, 3889–3891.
7. (a) Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 1812–1817; (b)
Matiychuk, V. S.; Lesyk, R. B.; Obushak, M. D.; Gzella, A.; Atamanyuk, D. V.;
Ostapiuk, Y. V.; Kryshchyshyn, A. P. Tetrahedron Lett. 2008, 49, 4648–4651; (c)
Jayashankaran, J.; Manian, R. D. R. S.; Raghunathan, R. Tetrahedron Lett. 2006, 47,
2265–2270; (d) Manian, R. D. R. S.; Jayashankaran, J.; Raghunathan, R.
Tetrahedron Lett. 2007, 48, 1385–1389.
O
O
OHC
O
+
O
O
O
O
O
H
O
O
O
O
O
[4+2]
O
O
O
O
O
8. Molecular mechanics calculations were carried out using Insight-II (97.0/
Discover 1) programme on a silicon graphics O2 workstation.
Scheme 3. A plausible reaction mechanism.
9. Typical procedure:
A mixture of ketone 1 (1 mmol), O-propargylated sugar
Acknowledgment
aldehyde (1.2 mmol) and triethyl amine (1 mmol) was stirred in
2
methanol solution for 30 min. Then CuI (0.3 mmol) was added and the
resulting mixture was allowed to stir under reflux for specified time
(Table 1). After complete conversion, as monitored by TLC, the mixture was
filtered and washed with methanol. The filtrate was concentrated in vacuo
A.V.H.G. and R.S. thank CSIR, New Delhi for the award of
fellowships.

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J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2305–2308
and purified by column chromatography using ethyl acetate/hexane (1:9) as
an eluent to afford pure product. Spectral data for the selected compounds
3b: IR (KBr):
3421, 2925, 2854, 1726, 1658, 1457, 1214, 1078 cmÀ1 1H
NMR (500 MHz, CDCl3): 6.42 (s, 1H), 5.97 (d, J = 3.6 Hz, 1H), 4.39 (d,
3.35 (s, 6H), 1.41 (s, 3H), 1.28 (s, 3H). 13C NMR (75 MHz, CDCl3): d 161.7,
133.0, 114.4, 111.4, 105.8, 87.4, 86.7, 82.6, 79.1, 65.7, 31.7, 29.6, 28.9, 28.2,
26.8, 26.3. LC–MS: m/z: 365 (M+H). HRMS calcd for C17H20N2O7Na (M+Na):
387.1168. Found: 387.1153. Compound 3f: White yellow solid, mp 145–
m
.
d
J = 3.6 Hz, 1H), 4.37 (s, 1H), 4.16 (d, J = 12.6 Hz, 1H), 4.04 (dd, J = 2.7, 4.5 Hz,
1H), 3.95 (d, J = 2.7 Hz, 1H), 3.38 (d, J = 5.4 Hz, 1H), 2.57–2.32 (m, 6H), 1.40
(s, 3H), 1.27 (s, 3H). 13C NMR (75 MHz, CDCl3): d 196.9, 165.8, 134.2, 113.5,
111.2, 105.8, 87.3, 82.7, 79.0, 66.4, 37.0, 30.0, 29.6, 27.4, 26.8, 26.2, 20.0.
LC–MS: m/z: 321 (M+H). HRMS calcd for C17H21O6 (M+H): 321.1338. Found:
148 °C, IR (KBr):
m
3435, 2924, 2854, 1743, 1674, 1607, 1521, 1521, 1457,
.
1220, 1076, 817 cmÀ1
1H NMR (300 MHz, CDCl3): d 7.51 (d, 2H), 7.16 (d,
2H), 6.51 (m, 1H), 5.97 (d, J = 3.7 Hz, 1H), 4.54–4.52 (m, 1H), 4.50–4.47 (m,
1H), 4.36–4.27 (m, 2H), 3.93 (d, J = 3.7 Hz, 1H), 3.58 (d, J = 5.2 Hz, 1H), 2.36
(s, 3H), 2.34 (s, 3H), 1.41 (s, 3H), 1.30 (s, 3H). 13C NMR (75 MHz, CDCl3): d
135.8, 135.5, 134.3, 129.5, 120.7, 111.6, 110.8, 105.8, 97.1, 97.0, 86.6, 83.4,
79.5, 66.2, 32.8, 29.6, 27.0, 26.5, 20.9, 21.0. LC–MS: m/z: 397 (M+H). HRMS
calcd for C22H25N2O5 (M+H): 397.1763. Found: 397.1768. Compound 3i: 1H
NMR (600 MHz, CDCl3): d 6.52 (t, J4 = 0.9 Hz, 1H), 5.85 (d, J3 = 4.0 Hz, 1H),
4.60 (t, J3 = 4.0 Hz, 1H), 4.19 (d, J2 = 12.2 Hz, 1H), 4.02 (dt, J4 = 1.8, 12.2 Hz,
1H), 3.64 (dd, J3 = 9.9, J3 = 8.6 Hz,1H), 3.57 (d, J3 = 9.9 Hz, 1H) 3.44 (dd,
J3 = 4.0, 8.6 Hz,1H), 2.44 (d, J2 = 15.6 Hz, 1H), 2.41 (d, J2 = 17.2 Hz, 1H), 2.24
(d, J2 = 15.6 Hz, 1H), 2.19 (d, J2 = 17.2 Hz, 1H), 1.55 (s, 3H), 1.31 (s, 3H),
1.12 (s, 3H), 1.05 (s, 3H).13C NMR (75 MHz, CDCl3): d 197.0, 164.2, 138.2,
112.9, 112.4, 104.1, 82.4, 78.4, 76.1, 69.4, 50.9, 41.2, 35.0, 32.1, 29.6, 28.8,
27.8, 26.1, 25.9. LC–MS: m/z: 349 (M+H).
321.1349. Compound 3c: IR(KBr):
m
3436, 2954, 1729, 1620, 1448, 1382,
6.42 (s, 1H), 5.97 (d, J = 3.7 Hz,
1214 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d
1H), 4.42–4.36 (m, 2H), 4.16 (d, J = 12.3 Hz,1H), 4.03 (dd, J = 2.8, 4.7 Hz, 1H),
3.96 (d, J = 2.6 Hz, 1 Hz), 3.37 (d, J = 4.7 Hz, 1H), 2.41–2.19 (m, 4H), 1.39 (s,
3H), 1.27 (s, 3H), 1.13 (s, 3H), 1.10 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
216.0, 183.2, 153.5, 132.5, 130.5, 125.0, 106.2, 101.8, 97.9, 85.54, 70.17,
60.32, 51.0, 49.3, 47.5, 47.3, 46.0, 45.4, 20.1. LC–MS: m/z: 349 (M+H).
HRMS calcd for C19H25O6 (M+H): 349.1651. Found: 349.1649. Compound
3d: IR(KBr):
NMR (500 MHz, CDCl3):
(m, 2H), 4.24–4.20 (m, 2H), 3.95 (d, J = 2.9 Hz, 1H), 3.55 (d, J = 3.9 Hz, 1H),
m .
3436, 2926, 1704, 1640, 1453, 1378, 1162, 1073 cmÀ1 1H
d
6.51 (s, 1H), 5.98 (d, J = 2.9 Hz, 1H), 4.48–4.40