The stereoselective synthesis of cis-/trans-fused hexahydropyrano[4,3-b] chromenes via Prins cyclization trapping by a tethered nucleophile

Article abstract of DOI:10.1039/c2ob25771h

A novel intramolecular Prins cyclization of (Z)-2-(5-hydroxypent-2-enyl) phenol with various aldehydes has been achieved using 10 mol% In(OTf) ₃ and 30 mol% TsOH to produce the cis-fused hexahydropyrano[4,3-b] chromene derivatives in good yields, while the coupling of (E)-2-(5-hydroxypent- 2-enyl)phenol with aldehydes under similar conditions affords the corresponding trans-fused hexahydropyrano[4,3-b]chromene derivatives.

Full text of DOI:10.1039/c2ob25771h

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PAPER
The stereoselective synthesis of cis-/trans-fused hexahydropyrano[4,3-b]-
chromenes via Prins cyclization trapping by a tethered nucleophile†
B. V. Subba Reddy,*a Sayed Jalal,a Prashant Borkar,a J. S. Yadav,a P. P. Reddy,b A. C. Kunwarb and
B. Sridharc
Received 23rd April 2012, Accepted 1st June 2012
DOI: 10.1039/c2ob25771h
A novel intramolecular Prins cyclization of (Z)-2-(5-hydroxypent-2-enyl)phenol with various aldehydes
has been achieved using 10 mol% In(OTf)3 and 30 mol% TsOH to produce the cis-fused
hexahydropyrano[4,3-b]chromene derivatives in good yields, while the coupling of (E)-2-(5-hydroxypent-
2-enyl)phenol with aldehydes under similar conditions affords the corresponding trans-fused
hexahydropyrano[4,3-b]chromene derivatives.
Introduction
The Prins cyclization is a powerful method for the stereo-
selective synthesis of a wide range of tetrahydropyran scaf-
folds.1,2 In particular, intramolecular Prins cyclization is an
important tool for the stereoselective construction of fused het-
erobicycles and tricycles.3 Recently, we have successfully
Scheme 1 Representative examples of intramolecular Prins cycli-
explored the intramolecular version of the Prins cyclization by
trapping of the resulting carbenium ion with tethered nucleo-
philes like hydroxyl, N-tosylamide and aryl groups to afford the
corresponding heterobicycles and tricycles respectively
(Scheme 1).4 However, to the best of our knowledge, there are
no reports on the intramolecular version of Prins cyclization with
a tethered phenolic group.
zation.
Furthermore, oxygen containing heterocycles are often found
in various natural products such as flavonoids, catechins and
pterocarpans.5,6 In particular, the hexahydropyrano[4,3-b]chro-
mene moiety is a core structure in some natural flavonoids such
as dependensin 1 (Fig. 1). It is a dimeric flavonoid isolated as a
racemate from the root bark of the Tanzanian medicinal plant
Uvaria dependens.7 Although the biological activity of pure
dependensin has not been investigated due to its scarcity, the
crude extract shows potent antimalarial activity.7 Some
Fig. 1 Structure of dependensin 1.
dependensin analogues are known to exhibit antimalarial activity
against Plasmodium falciparum.8
In continuation of our research on Prins type cyclizations and
their application to the total synthesis of natural products,4,9 we
herein report a facile method for the stereoselective synthesis of
cis- and trans-fused hexahydropyrano[4,3-b]chromenes via an
intramolecular Prins cyclization.
aNatural Product Chemistry, Indian Institute of Chemical Technology,
Uppal Road, Tarnaka, Hyderabad 500607, India.
E-mail: basireddy@iict.res.in; Fax: (+)91 40 27160512
bCentre for Nuclear Magnetic Resonance, Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
cLaboratory of X-ray Crystallography, Indian Institute of Chemical
Technology, Uppal Road, Tarnaka, Hyderabad 500607, India
†Electronic supplementary information (ESI) available: Copies of
1H and 13C NMR spectra of products. CCDC 862191. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25771h
Results and discussion
As a preliminary experiment, we first attempted the cross coup-
ling of p-tolualdehyde (2a) with (Z)-2-(5-hydroxypent-2-enyl)-
phenol (1) in the presence of 10 mol% In(OTf)3 and 30 mol%
TsOH in 1,2-dichloroethane. Interestingly, the reaction proceeded
smoothly at room temperature to furnish the corresponding
6562 | Org. Biomol. Chem., 2012, 10, 6562–6568
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Table 1 Intramolecular Prins cyclization of (Z)-2-(5-hydroxypent-2-
enyl)phenol (1) with p-tolualdehyde using various acid catalystsa
Entry Acid catalyst
mol% Solvent
Time (h) Yieldb (%)
a
b
c
d
e
f
g
h
i
CSA
20
20
10
10
CH2Cl2
CH2Cl2
CH2Cl2
24
24
14
0
10
75
80
88
92
40
65
60
Ts-OH
In(OTf)3
In(OTf)3
Fig. 2 Characteristic nOe’s and energy minimized structure of 3a.
ClCH2CH2Cl 14
In(OTf)3 + Ts-OH 10 + 20 ClCH2CH2Cl 08
In(OTf)3 + Ts-OH 10 + 30 ClCH2CH2Cl 07
Sc(OTf)3
Sc(OTf)3 + Ts-OH 10 + 30 ClCH2CH2Cl 12
InCl3 10 ClCH2CH2Cl 24
10
ClCH2CH2Cl 24
cis-fused hexahydropyrano[4,3-b]chromene 3d in 90% yield
(entry d, Table 2). The structure of 3d was confirmed by X-ray
crystallography (Fig. 3).11
a The reaction was performed at 0.5 mmol scale. b Isolated yield.
Similarly, other aromatic aldehydes such as 4-nitrobenzalde-
hyde, 4-chlorobenzaldehyde, 2-bromobenzaldehyde, thiophene-
2-carbaldehyde and 3-phenylpropionaldehyde reacted well with
(Z)-homoallylic alcohol 1 to furnish the respective cis-fused hexa-
hydropyrano[4,3-b]chromene scaffolds in good yields (entries b,
c, e–g, Table 2). The reaction works not only with aromatic alde-
hydes but also with aliphatic aldehydes such as n-hexanal and 3-
methylbutanal. In the case of aliphatic aldehydes, the corre-
sponding alkyl substituted cis-fused hexahydropyrano[4,3-b]-
chromene derivatives were obtained in good yields (entries h and
i, Table 2). The method is successful not only with aldehydes
but also with ketones. For instance, cyclohexanone gave the cor-
responding cis-fused spiro-dioxatricycle under the reaction con-
ditions (entry j, Table 2).
product 3a in 92% yield with complete cis-selectivity (entry f,
Table 1). Among various Lewis and Brønsted acids tested, the
combination of In(OTf)3 and TsOH (1 : 3) works more effec-
tively than either In(OTf)3 or TsOH alone in terms of reaction
time and yields (Table 1). The high catalytic performance of the
above reagent system may be attributed to cooperative cata-
lysis4d,10 between the Lewis acid In(OTf)3 and Brønsted acid
TsOH. Of various Lewis and Brønsted acids studied for this reac-
tion (Table 1), the combination of In(OTf)3 and TsOH (1 : 3)
was found to give the best results in terms of conversion. Next,
we examined the effect of various solvents such as dichloro-
methane, 1,2-dichloroethane and toluene. Of these, 1,2-dichloro-
ethane appeared to give the best results.
Next, we studied the effect of the geometry of the starting
olefin on the stereoselectivity of the reaction. Accordingly, treat-
ment of (E)-2-(5-hydroxypent-2-enyl)phenol (4) with p-tolualde-
hyde (2a) in the presence of 10 mol% In(OTf)3 and 30 mol%
TsOH in 1,2-dichloroethane gave the respective trans-fused hexa-
hydropyrano[4,3-b]chromene 5a as sole product in 90% yield
(entry a, Table 3). The structure and stereochemistry of 5a were
characterized by extensive NMR experiments including
DQFCOSY and NOESY. The assignments were made with the
help of DQFCOSY experiments. From proton NMR spectra,
The structure and stereochemistry of product 3a were charac-
terized by extensive NMR experiments including 2-D double
quantum filtered correlation spectroscopy (DQFCOSY) and
nuclear Overhauser effect spectroscopy (NOESY). The assign-
ments were made with the help of DQFCOSY experiments.
3
3
From proton NMR spectra J4a-H–4-H′ = 4.8, J4a-H–4-H = 11.9,
3J4a-H–10a-H = 4.8, J4-H′–3-H′ = 3.6, J4-H′–3-H = 5.1, J4-H–3-H′
=
=
3
3
3
3
3
3
3
3
5.3, J4-H–3-H = 11.9, J10a-H–10-H′ = 5.7 and J10a-H–10-H
the coupling constants, J4a-H–4-H′ = 5.0, J4a-H–4-H = 10.4,
3J4a-H–10a-H = 11.0, J4-H′–3-H′ = 1.4, J4-H′–3-H = 2.2, J4-H–3-H′
=
3
3
3
12.4 Hz were obtained for 3a. The nOe correlations 4a-H/3-H,
4a-H/1-H, 3-H/1-H and 4-H/10-H provide emphatic support for
the energy minimized structure shown in Fig. 2. The structure
clearly brings out the cis fusion of the two six membered rings
(cis disposition of protons 4a-H and 10a-H). Large diaxial coup-
lings and the presence of 1,3-nOe interactions in the six-mem-
bered ring containing the p-tolyl group confirm its 4C1 chair
conformation. The structure is additionally supported by the cor-
relations arising from the ω-couplings between 4-H′–10a-H and
4a-H–10-H′ in the DQFCOSY experiment.
Inspired by the above results, we next extended this process
for other aldehydes. The scope of the reaction is illustrated with
respect to various aldehydes and the results are summarized in
Table 2. Interestingly, 3,4-dimethoxybenzaldehyde (2d) under-
went a smooth cyclization with (Z)-2-(5-hydroxypent-2-enyl)-
phenol (1) under similar conditions to afford the corresponding
3
3
3
4.8, J4-H–3-H = 12.2, J1-H–10a-H = 10.0, J10a-H–10-H = 12.2 and
3J10a-H–10-H′ = 5.1 Hz, were derived for 5a. The nOe correlations
4a-H/1-H, 4a-H/10-H, 4-H/10a-H, 3-H/1-H and 1-H/10-H amply
support the energy minimized structure shown in Fig. 4. The
structure clearly brings out the trans disposition of protons 4a-H
and 10a-H, which indicates the trans fusion of the two six-mem-
bered rings. Like 3a, for 5a also the six membered ring bearing
the tolyl group takes a 4C1 chair conformation.
The scope of the stereoselectivity with respect to the E-olefin
is illustrated with respect to various aldehydes and the results are
summarized in Table 3. Interestingly, several aromatic aldehydes
such as 4-nitrobenzaldehyde, 3,4-dimethoxybenzaldehyde, 4-
chlorobenzaldehyde, 2-bromobenzaldehyde, thiophene-2-carbal-
dehyde and 3-phenylpropionaldehyde underwent a smooth intra-
molecular Prins cyclization with (E)-homoallylic alcohol 1 to
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Table 2 Synthesis of cis-fused hexahydropyrano[4,3-b]chromene
scaffoldsa
Entry
a
Aldehyde (2)
Product (3)b
Time (h)
7
% Yieldc
92
b
c
d
e
9
8
7
9
89
85
90
84
Fig. 3 ORTEP diagram of 3d.
furnish the respective trans-fused hexahydropyrano[4,3-b]chro-
mene scaffolds in good to excellent yields (entries b–g, Table 3).
Aliphatic aldehydes such as n-hexanal and 3-methylbutanal also
gave the corresponding alkyl substituted trans-fused hexahydro-
pyrano[4,3-b]chromene derivatives in good yields (entries h and
i, Table 3). Cyclic ketones such as cyclohexanone also gave the
corresponding spiro-dioxatricycles under similar conditions
(entry j, Table 3). From the above study, it is evident that the
geometry of the olefin controls the stereoselectivity of the reac-
tion i.e. a cis-olefin gives the cis-fused product whereas a trans-
olefin provides the trans-fused product exclusively.
This method provides a wide range of octahydropyrano[4,3-b]-
chromene derivatives in good yields with excellent stereoselec-
tivity. Mechanistically, the reaction is expected to proceed via the
formation of an oxocarbenium ion from the hemi-acetal which is
formed in situ from an aldehyde and a homoallylic alcohol,
likely after activation through In(III). This is followed by attack
of an internal olefin resulting in the formation of a carbocation
which is simultaneously trapped by a tethered phenolic group
leading to the formation of the octahydropyrano[4,3-b]pyran as
depicted in Scheme 2.
f
8
8
80
78
g
Conclusions
In summary, we have demonstrated a novel intramolecular Prins
cyclization for the stereoselective synthesis of a novel class of
dioxatricycles with the formation of three stereocenters in a
single step. This is the first report on a Prins cyclization in which
a tethered phenolic group terminates the cyclization. This
method provides an easy access to cis- and trans-fused hexa-
hydropyrano[4,3-b]chromene scaffolds in a single step process.
h
i
7
7
75
78
j
12
70
Experimental
General
a The reactions were performed on a 0.5 mmol scale. b All the products
were characterized by 1H and 13C NMR, IR and mass spectroscopy.
c Yield refers to pure products after column chromatography.
1,2-Dichloroethane and dichloromethane were dried according to
a standard literature procedure. The reactions were performed in
oven-dried round bottom flasks under nitrogen atmosphere.
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Table 3 Synthesis of trans-fused hexahydropyrano[4,3-b]chromene
Table 3 (Contd.)
scaffoldsa
Entry
Aldehyde (2)
Product (5)b
Time (h)
% Yieldc
Entry
a
Aldehyde (2)
Product (5)b
Time (h)
7
% Yieldc
90
a The reactions were performed on a 0.5 mmol scale. b All the products
were characterized by 1H and 13C NMR, IR and mass spectroscopy.
c Yield refers to pure products after column chromatography.
b
9
85
c
d
e
8
7
9
86
88
82
Fig. 4 Characteristic nOe’s and energy minimized structure of 5a.
Glass syringes were used to transfer the solvent. The products
were purified by column chromatography on silica gel of
60–120 mesh. Thin layer chromatography plates were visualized
by ultraviolet light and/or by exposure to iodine vapour and/or
by exposure to an acidic methanolic solution of p-anisaldehyde
followed by heating (<1 min) on a hot plate (∼250 °C). Organic
solutions were concentrated on a rotary evaporator at 35–40 °C.
f
8
8
84
80
1
IR spectra were recorded on an FT-IR spectrometer. H and 13C
g
NMR spectra were recorded in CDCl3 using 300 or 500 MHz
NMR spectrometers. The chemical shifts (δ) were reported in
parts per million (ppm) with respect to TMS as an internal stan-
dard. The coupling constants (J) are quoted in hertz (Hz). Mass
spectra were recorded on a mass spectrometer by electrospray
ionization (ESI) technique.
h
i
7
7
84
78
Typical procedure for the intramolecular Prins cyclization
To a stirred solution of (Z)- or (E)-2-(5-hydroxypent-2-enyl)-
phenol (1 or 3; 0.50 mmol) and aldehyde (2, 0.60 mmol) in dry
1,2-dichloroethane (5 mL) were added In(OTf)3 (10 mol%) and
TsOH (30 mol%). The resulting mixture was stirred at room
temperature under nitrogen atmosphere for the specified time
(Table 2 or Table 3). After completion of the reaction as indi-
cated by TLC, the mixture was quenched with saturated aqueous
NaHCO3 solution (0.5 mL) and extracted with dichloromethane
j
12
72
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127.0, 120.9, 120.2, 120.0, 116.6, 78.8, 73.6, 66.4, 36.9, 26.9,
19.9; IR (KBr): ν 2925, 2855, 1486, 1457, 1243, 1049,
757 cm−1; ESI-MS: m/z 301 (M + H)+; HRMS (ESI) calculated
for C18H18ClO2: 301.0995 (M + H)+, Found 301.1012.
(1R*,4aS*,10aS*)-1-(3,4-Dimethoxyphenyl)-1,3,4,4a,10,10a-
hexahydropyrano[4,3-b]chromene (3d; Table 2; entry d).
Crystals for XRD were obtained by dissolving compound in
4–5 mL methanol, followed by slow evaporation of solvent over
4 days. Yield, 90%; Solid, mp 128–130 °C; 1H NMR (500 MHz,
CDCl3): δ 7.04–6.95 (m, 1H), 6.91–6.66 (m, 6H), 4.64 (broad s,
1H), 4.62 (td, J = 12.0 and 4.7 Hz, 1H), 4.25 (ddd, J = 12.0, 5.1
and 1.2 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.66 (dt, J = 12.0
and 2.0 Hz, 1H), 2.84 (dd, J = 16.8 and 12.3 Hz, 1H), 2.58–2.46
(m, 1H), 2.09 (dd, J = 16.8 and 5.7 Hz, 1H), 1.97 (dq, J = 12.0
and 5.2 Hz, 1H), 1.82–1.69 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ 152.3, 148.7, 147.8, 132.4, 130.0, 127.2, 120.3,
120.1, 117.2, 116.6, 110.9, 108.5, 79.0, 73.8, 66.4, 55.8, 37.3,
27.0, 20.0; IR (KBr): ν 2925, 2854, 1514, 1455, 1230, 1026,
753 cm−1; ESI-MS: m/z 327 (M + H)+; HRMS (ESI) calculated
for C20H23O4: 327.1596 (M + H)+, Found 327.1586.
Scheme 2 A plausible reaction pathway.
(2 × 10 mL). The organic phases were combined, washed with
brine (3 × 2 mL), dried over anhydrous Na2SO4 and concen-
trated in vacuo. The resulting crude product was purified by
silica gel column chromatography (60–120 mesh) using ethyl
acetate/hexane as eluent to afford pure product 3 or 5 (Table 2 or
Table 3).
(1R*,4aS*,10aS*)-1-p-Tolyl-1,3,4,4a,10,10a-hexahydropyrano-
[4,3-b]chromene (3a; Table 2; entry a). Yield, 92%; Solid, mp
112–114 °C; 1H NMR (300 MHz, CDCl3): δ 7.27–7.14 (m, 4H),
7.10–7.01 (m, 1H), 6.94–6.87 (m, 1H), 6.83–6.73 (m, 2H), 4.64
(broad s, 1H), 4.61 (td, J = 11.9 and 4.8 Hz, 1H), 4.25 (ddd, J =
11.9, 5.1 and 1.1 Hz, 1H), 3.67 (dt, J = 11.9 and 2.3 Hz, 1H),
2.88 (dd, J = 16.6 and 12.4 Hz, 1H), 2.58–2.46 (m, 1H), 2.36 (s,
3H), 2.08 (dd, J = 16.6 and 5.5 Hz, 1H), 1.98 (dq, J = 12.1 and
5.3 Hz, 1H), 1.83–1.71 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
152.4, 136.8, 136.6, 130.0, 128.9, 127.2, 125.2, 120.4, 120.1,
116.6, 79.4, 73.9, 66.4, 37.2, 27.1, 21.1, 20.0; IR (KBr): ν 2923,
2858, 1488, 1453, 1231, 1082, 1051, 807, 756 cm−1; ESI-MS:
m/z 281 (M + H)+; HRMS (ESI) calculated for C19H21O2:
281.1538 (M + H)+, Found 281.1565.
(1R*,4aS*,10aS*)-1-(2-Bromophenyl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (3e; Table 2; entry e). Yield, 84%;
Solid, mp 107–109 °C; 1H NMR (300 MHz, CDCl3): δ
7.58–7.48 (m, 2H), 7.42–7.34 (m, 1H), 7.22–7.13 (m, 1H),
7.11–7.03 (m, 1H), 6.94–6.86 (m, 1H), 6.84–6.74 (m, 2H), 4.88
(broad s, 1H), 4.66 (td, J = 12.1 and 4.5 Hz, 1H), 4.25 (ddd, J =
12.1, 5.3 and 1.0 Hz, 1H), 3.73 (dt, J = 12.1 and 2.3 Hz, 1H),
3.02–2.77 (m, 2H), 2.10–1.89 (m, 2H), 1.85–1.73 (m, 1H); 13C
NMR (75 MHz, CDCl3): δ 152.3, 133.8, 132.8, 130.0, 128.8,
128.3, 127.3, 127.1, 122.9, 120.7, 120.1, 116.6, 79.1, 73.3, 66.5,
33.5, 26.9, 20.2; IR (KBr): ν 2927, 2853, 1489, 1461, 1240,
1103, 1059, 753 cm−1; ESI-MS: m/z 345 (M + H)+; HRMS
(ESI) calculated for C18H18BrO2: 345.0485 (M + H)+, Found
345.0491.
(1R*,4aS*,10aS*)-1-(4-Nitrophenyl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (3b; Table 2; entry b). Yield, 89%;
Solid, mp 154–156 °C; 1H NMR (500 MHz, CDCl3): δ
8.31–8.18 (m, 2H), 7.58–7.46 (m, 2H), 7.07–6.97 (m, 1H),
6.86–6.77 (m, 1H), 6.76–6.69 (m, 2H), 4.72 (broad s, 1H), 4.59
(td, J = 11.7 and 4.9 Hz, 1H), 4.27 (ddd, J = 11.7, 4.9 and 1.1 Hz,
1H), 3.68 (dt, J = 11.7 and 2.0 Hz, 1H), 2.81 (dd, J = 16.6 and
12.7 Hz, 1H), 2.64–2.52 (m, 1H), 1.98 (dq, J = 12.7 and 4.9 Hz,
(1R*,4aS*,10aS*)-1-(Thiophen-2-yl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (3f; Table 2; entry f). Yield, 80%;
Solid, mp 108–110 °C; 1H NMR (300 MHz, CDCl3):
δ 7.27–7.17 (m, 1H), 7.11–6.68 (m, 6H), 4.86 (d, J = 1.1 Hz,
1H), 4.54 (td, J = 11.9 and 4.5 Hz, 1H), 4.22 (ddd, J = 12.1, 5.1
and 1.9 Hz, 1H), 3.68 (dt, J = 12.1 and 2.0 Hz, 1H), 2.91 (dd,
J = 16.8 and 12.3 Hz, 1H), 2.64–2.52 (m, 1H), 2.32 (dd, J =
16.8 and 5.5 Hz, 1H), 1.99 (dq, J = 12.5 and 5.0 Hz, 1H),
1.79–1.68 (m, 1H); 13C NMR (75 MHz, CDCl3): δ 152.3, 142.9,
130.1, 127.3, 126.7, 124.0, 122.4, 120.7, 120.2, 116.7, 77.3,
73.2, 66.8, 37.5, 26.9, 20.2; IR (KBr): ν 2924, 2855, 1520,
1343, 1082, 1055, 804, 753 cm−1; ESI-MS: m/z 273 (M + H)+;
HRMS (ESI) calculated for C16H17O2S: 273.0944 (M + H)+,
Found 273.0924.
1H), 1.91 (dd, J = 16.6 and 5.9 Hz, 1H), 1.83–1.75 (m, 1H); 13
C
NMR (75 MHz, CDCl3): δ 152.1, 147.6, 147.1, 129.9, 127.5,
126.1, 123.5, 120.7, 120.3, 116.7, 78.6, 73.4, 66.5, 36.9, 26.8,
19.9; IR (KBr): ν 2924, 2855, 1520, 1343, 1082, 1055, 804,
753 cm−1; ESI-MS: m/z 312 (M + H)+; HRMS (ESI) calculated
for C18H18NO4: 312.1236 (M + H)+, Found 312.1244.
(1R*,4aS*,10aS*)-1-(4-Chlorophenyl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (3c; Table 2; entry c). Yield, 85%;
Solid, mp 152–154 °C; 1H NMR (300 MHz, CDCl3): δ
7.52–7.41 (m, 2H), 7.23–7.15 (m, 2H), 7.05–6.95 (m, 1H),
6.88–6.79 (m, 1H), 6.78–6.66 (m, 2H), 4.59 (broad s, 1H), 4.55
(td, J = 11.7 and 4.5 Hz, 1H), 4.23 (ddd, J = 11.9, 4.5 and 1.3 Hz,
1H), 3.65 (dt, J = 12.0 and 2.1 Hz, 1H), 2.88–2.71 (m, 1H),
2.56–2.43 (m, 1H), 2.08–1.86 (m, 2H), 1.82–1.69 (m, 1H); 13C
NMR (75 MHz, CDCl3): δ 152.3, 138.8, 131.3, 130.0, 127.3,
(1S*,4aS*,10aR*)-1-Phenethyl-1,3,4,4a,10,10a-hexahydropyr-
ano[4,3-b]chromene (3g; Table 2; entry g). Yield, 78%; Solid,
mp 72–74 °C; H NMR (300 MHz, CDCl3): δ 7.35–7.15 (m,
5H), 7.13–7.01 (m, 2H), 6.88–6.75 (m, 2H), 4.36 (td, J = 11.7
and 4.9 Hz, 1H), 4.08 (ddd, J = 11.7, 4.5 and 1.2 Hz, 1H),
3.54–3.39 (m, 2H), 2.98 (dd, J = 16.6 and 12.5 Hz, 1H),
2.88–2.53 (m, 3H), 2.27–2.15 (m, 1H), 2.10–1.63 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 152.6, 141.7, 130.1, 128.4, 128.4,
1
6566 | Org. Biomol. Chem., 2012, 10, 6562–6568
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127.3, 125.9, 120.1, 120.1, 116.7, 77.4, 73.6, 66.2, 34.9, 34.0,
32.1, 27.3, 20.1; IR (KBr): ν 2926, 2857, 1490, 1455, 1235,
1074, 758, 697 cm−1; ESI-MS: m/z 295 (M + H)+; HRMS (ESI)
calculated for C20H23O2: 295.1698 (M + H)+, Found 295.1712.
δ 8.33–8.20 (m, 2H), 7.63–7.50 (m, 2H), 7.16–7.03 (m, 1H),
6.95–6.75 (m, 3H), 4.36–4.24 (m, 1H), 4.15 (d, J = 9.8 Hz, 1H),
4.01 (dt, J = 10.6 and 4.9 Hz, 1H), 3.79 (dt, J = 12.1 and 2.3 Hz,
1H), 2.56–2.43 (m, 1H), 2.37–1.88 (m, 4H); 13C NMR
(75 MHz, CDCl3): δ 153.9, 147.8, 146.4, 129.7, 128.0, 127.6,
123.8, 123.4, 120.7, 116.5, 82.7, 75.8, 66.4, 42.6, 31.9, 27.2; IR
(1S*,4aS*,10aR*)-1-Pentyl-1,3,4,4a,10,10a-hexahydropyrano-
[4,3-b]chromene (3h; Table 2; entry h). Yield, 75%; Viscous
liquid; 1H NMR (300 MHz, CDCl3): δ 7.08–6.92 (m, 2H),
6.82–6.67 (m, 2H), 4.31 (td, J = 11.9 and 4.7 Hz, 1H), 4.00
(ddd, J = 11.7, 4.5 and 1.2 Hz, 1H), 3.49–3.30 (m, 2H), 2.91
(dd, J = 16.6 and 12.3 Hz, 1H), 2.52 (dd, J = 16.6 and 5.8 Hz,
1H), 2.22–2.09 (m, 1H), 1.84 (dq, J = 12.5 and 5.1 Hz, 1H),
1.71–1.54 (m, 2H), 1.51–1.17 (m, 7H), 0.91 (t, J = 6.4 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 152.6, 130.1, 127.3, 120.3,
120.1, 116.7, 78.5, 73.8, 66.3, 34.7, 32.1, 31.8, 27.3, 25.5, 22.6,
20.0, 14.0; IR (Neat): ν 2929, 2854, 1489, 1457, 1239, 1081,
753 cm−1; ESI-MS: m/z 261 (M + H)+; HRMS (ESI) calculated
for C17H25O2: 261.1849 (M + H)+, Found 261.1840.
(KBr): ν 2925, 2854, 1519, 1461, 1352, 1228, 1081, 755 cm−1
;
MS-ESI: m/z 312 (M + H)+; HRMS (ESI) calculated for
C18H18NO4: 312.1236 (M + H)+, Found 312.1251.
(1R*,4aS*,10aR*)-1-(4-Chlorophenyl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (5c; Table 3; entry c). Yield, 86%;
Solid, mp 182–184 °C; 1H NMR (300 MHz, CDCl3): δ
7.42–7.29 (m, 4H), 7.14–7.04 (m, 1H), 6.94–6.87 (m, 1H),
6.86–6.76 (m, 2H), 4.27 (ddd, J = 11.7, 4.7 and 1.5 Hz, 1H),
4.01 (d, J = 10.0 Hz, 1H), 3.99 (dt, J = 10.6 and 4.7 Hz, 1H),
3.77 (dt, J = 11.7 and 2.3 Hz, 1H), 2.51–2.36 (m, 1H),
2.27–1.91 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 154.0, 137.6,
134.0, 129.7, 128.7, 128.5, 127.4, 121.1, 120.5, 116.4, 83.0,
76.0, 66.3, 42.3, 32.3, 27.3; IR (KBr): ν 2925, 2854, 1490,
1238, 1087, 757 cm−1; MS-ESI: m/z 301 (M + H)+; HRMS
(ESI) calculated for C18H18ClO2: 301.0995 (M + H)+, Found
301.1008.
(1S*,4aS*,10aR*)-1-Isobutyl-1,3,4,4a,10,10a-hexahydropyr-
ano[4,3-b]chromene (3i; Table 2; entry i). Yield, 78%; Solid,
1
mp 54–56; H NMR (300 MHz, CDCl3): δ 7.13–7.02 (m, 2H),
6.88–6.76 (m, 2H), 4.40 (td, J = 12.1 and 4.5 Hz, 1H), 4.04
(ddd, J = 11.3, 5.3 and 1.5 Hz, 1H), 3.57–3.42 (m, 2H), 2.95
(dd, J = 16.6 and 12.1 Hz, 1H), 2.58 (dd, J = 16.6 and 6.0 Hz,
1H), 2.23–2.11 (m, 1H), 1.87(dq, J = 12.8 and 5.3 Hz, 1H),
1.80–1.52 (m, 3H), 1.35–1.15 (m, 1H), 0.99–0.91 (m, 6H); 13C
NMR (75 MHz, CDCl3): δ 152.6, 130.1, 127.3, 120.3, 120.1,
116.7, 76.6, 73.9, 66.3, 41.2, 35.1, 27.3, 24.5, 23.1, 22.4, 20.2;
(1R*,4aS*,10aR*)-1-(3,4-Dimethoxyphenyl)-1,3,4,4a,10,10a-
hexahydropyrano[4,3-b]chromene (5d; Table 3; entry d).
Yield, 88%; Solid, mp 134–136 °C; 1H NMR (300 MHz,
CDCl3): δ 7.14–7.04 (m, 1H), 6.99–6.76 (m, 6H), 4.31–4.21 (m,
1H), 4.07–3.92 (m, 1H), 3.97 (d, J = 9.8 Hz, 1H), 3.91 (s, 3H),
3.90 (s, 3H), 3.77 (dt, J = 12.1 and 2.3 Hz, 1H), 2.48–2.33 (m,
1H), 2.29–2.15 (m, 2H), 2.14–1.98 (m, 2H); 13C NMR
(75 MHz, CDCl3): δ 154.1, 149.3, 149.1, 131.6, 129.8, 127.3,
121.5, 120.5, 119.9, 116.4, 110.9, 109.9, 83.7, 76.3, 66.3, 55.9,
42.1, 32.4, 27.4; IR (KBr): ν 2925, 2855, 1516, 1232, 1158,
1088, 1026, 755 cm−1; MS-ESI: m/z 327 (M + H)+; HRMS
(ESI) calculated for C20H23O4: 327.1596 (M + H)+, Found
327.1598.
IR (Neat): ν 2928, 2855, 1490, 1457, 1240, 1080, 754 cm−1
;
ESI-MS: m/z 247 (M + H)+; HRMS (ESI) calculated for
C16H23O2: 247.1683 (M + H)+, Found 247.1678.
(4a′S*,10a′S*)-4′,4a′,10′,10a′-Tetrahydro-3′H-spiro[cyclo-
hexane-1,1′-pyrano[4,3-b]chromene] (3j; Table 2; entry j).
1
Yield, 70%; Solid, mp 80–84 °C; H NMR (300 MHz, CDCl3):
δ 7.08–6.88 (m, 2H), 6.83–6.64 (m, 2H), 4.60–4.43 (m, 1H),
3.86–3.73 (m, 1H), 3.72–3.57 (m, 1H), 2.90–2.75 (m, 1H),
2.74–2.60 (m, 1H), 2.07–1.94 (m, 1H), 1.93–1.62 (m, 3H),
1.61–1.07 (m, 9H); 13C NMR (75 MHz, CDCl3): δ 153.1, 129.8,
127.1, 120.9, 120.1, 116.6, 75.1, 70.5, 58.3, 32.4, 28.3, 25.8,
22.7, 21.5, 21.4; IR (KBr): ν 2928, 2855, 1490, 1453, 1236,
1075, 754 cm−1; ESI-MS: m/z 259 (M + H)+; HRMS (ESI) cal-
culated for C17H23O2: 259.1698 (M + H)+, Found 259.1715.
(1R*,4aS*,10aR*)-1-(2-Bromophenyl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (5e; Table 3; entry e). Yield, 82%;
Solid, mp 118–120 °C; 1H NMR (300 MHz, CDCl3): δ
7.56–7.41 (m, 2H), 7.33–7.24 (m, 1H), 7.16–7.07 (m, 1H),
7.05–6.95 (m, 1H), 6.90–6.80 (m, 1H), 6.78–6.68 (m, 2H), 4.63
(d, J = 9.8 Hz, 1H), 4.19 (ddd, J = 12.1, 5.3 and 1.5 Hz, 1H),
4.01 (dt, J = 10.6 and 4.5 Hz, 1H), 3.75 (dt, J = 12.1 and 2.3 Hz,
1H), 2.70–2.53 (m, 1H) 2.22–2.08 (m, 2H), 2.07–1.88 (m, 2H);
13C NMR (75 MHz, CDCl3): δ 154.0, 138.6, 132.6, 129.7,
129.6, 128.8, 128.0, 127.4, 124.0, 121.4, 120.5, 116.4, 80.6,
76.0, 66.4, 43.1, 32.4, 26.6; IR (KBr): ν 2924, 2853, 1487,
1460, 1249, 1085, 755 cm−1; ESI-MS: m/z 345 (M + H)+;
HRMS (ESI) calculated for C18H18BrO2: 345.0485 (M + H)+,
Found 345.0495.
(1R*,4aS*,10aR*)-1-p-Tolyl-1,3,4,4a,10,10a-hexahydropyrano-
[4,3-b]chromene (5a; Table 3; entry a). Yield, 90%; Solid, mp
122–124 °C; 1H NMR (300 MHz, CDCl3): δ 7.24–7.16 (m, 2H),
7.15–7.07 (m, 2H), 7.05–6.96 (m, 1H), 6.86–6.79 (m, 1H),
6.78–6.67 (m, 2H), 4.23–4.12 (m, 1H), 3.97–3.85 (m, 2H), 3.69
(dt, J = 12.1 and 2.3 Hz, 1H), 2.41–2.31 (m, 1H), 2.29 (s, 3H),
2.18–2.07 (m, 2H), 2.06–1.90 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 154.1, 138.1, 136.0, 129.8, 129.2, 127.3, 127.2,
121.5, 120.4, 116.4, 83.7, 76.4, 66.3, 42.1, 32.4, 27.4, 21.2; IR
(1R*,4aS*,10aR*)-1-(Thiophen-2-yl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (5f; Table 3; entry f). Yield, 84%;
Solid, mp 126–128 °C; 1H NMR (300 MHz, CDCl3):
δ 7.31–7.21 (m, 1H), 7.07–6.82 (m, 4H), 6.80–6.69 (m, 2H),
4.29 (d, J = 9.8 Hz, 1H), 4.19 (ddd, J = 12.1, 5.3 and 1.5 Hz,
1H), 3.90 (dt, J = 10.6 and 5.3 Hz, 1H), 3.71 (dt, J = 12.1 and
2.3 Hz, 1H), 2.44–2.26 (m, 2H), 2.17–1.90 (m, 3H); 13C NMR
(KBr): ν 2922, 2849, 1490, 1235, 1083, 810, 761 cm−1
;
ESI-MS: m/z 281 (M + H)+; HRMS (ESI) calculated for
C19H21O2: 281.1538 (M + H)+, Found 281.1558.
(1R*,4aS*,10aR*)-1-(4-Nitrophenyl)-1,3,4,4a,10,10a-hexahy-
dropyrano[4,3-b]chromene (5b; Table 3; entry b). Yield, 85%;
Solid, mp 184–186 °C; 1H NMR (300 MHz, CDCl3):
This journal is © The Royal Society of Chemistry 2012
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(75 MHz, CDCl3): δ 154.0, 141.9, 129.8, 127.4, 126.3, 125.6,
121.2, 120.5, 116.4, 78.8, 76.0, 66.3, 43.1, 32.1, 27.4; IR (KBr):
ν 2925, 2853, 1228, 1074, 754, 720 cm−1; ESI-MS: m/z 273
(M + H)+; HRMS (ESI) calculated for C16H17O2S: 273.0944
(M + H)+, Found 273.0936.
Acknowledgements
S.J. and P.B. thank CSIR, New Delhi for the award of
fellowships.
(1S*,4aS*,10aS*)-1-Phenethyl-1,3,4,4a,10,10a-hexahydropyr-
ano[4,3-b]chromene (5g; Table 3; entry g). Yield, 80%; Solid,
mp 93–95 °C; H NMR (300 MHz, CDCl3): δ 7.34–7.15 (m,
Notes and references
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hedron Lett., 2007, 48, 7155; (d) S. D. Rychnovsky and C. R. Thomas,
Org. Lett., 2000, 2, 1217; (e) P. O. Miranda, M. A. Ramirez, V. S. Martin
and J. I. Padron, Org. Lett., 2006, 8, 1633; (f) M. L. Bolla, B. Patterson
and S. D. Rychnovsky, J. Am. Chem. Soc., 2005, 127, 16044;
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J. R. Harding and C. L. Willis, Chem. Commun., 2005, 5097.
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(b) M. Suginome, Y. Ohmori and Y. Ito, Chem. Commun., 2001, 1090;
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(d) A. C. Spivey, L. Laraia, A. R. Bayly, H. S. Rzepa and A. J. P. White,
Org. Lett., 2010, 12, 900; (e) Z.-H. Chen, Y.-Q. Tu, S.-Y. Zhang and
F.-M. Zhang, Org. Lett., 2011, 13, 724; (f) A. J. Bunt, C. D. Bailey,
B. D. Cons, S. J. Edwards, J. D. Elsworth, T. Pheko and C. L. Willis,
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1
5H), 7.13–6.98 (m, 2H), 6.89–6.76 (m, 2H), 4.22–4.13 (m, 1H),
3.79 (dt, J = 10.6 and 4.5 Hz, 1H), 3.58 (dt, J = 12.1 and 2.3 Hz,
1H), 3.06 (dt, J = 9.1 and 2.3 Hz, 1H), 2.96–2.83 (m, 1H),
2.76–2.62 (m, 2H), 2.44–2.26 (m, 2H), 2.15–1.67 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 154.2, 142.1, 129.8, 128.5, 128.4,
127.4, 125.8, 121.3, 120.5, 116.4, 79.2, 76.1, 65.7, 40.7, 34.4,
32.4, 31.5, 27.2; IR (KBr): ν 2925, 2855, 1488, 1452, 1230,
1085, 760 cm−1; MS-ESI: m/z 295 (M + H)+; HRMS (ESI) cal-
culated for C20H23O2: 295.1698 (M + H)+, Found 295.1692.
(1S*,4aS*,10aS*)-1-Pentyl-1,3,4,4a,10,10a-hexahydropyrano-
[4,3-b]chromene (5h; Table 3; entry h). Yield, 84%; Viscous
liquid; 1H NMR (300 MHz, CDCl3): δ 7.16–6.01 (m, 2H),
6.90–6.76 (m, 2H), 4.18–4.08 (m, 1H), 3.80 (dt, J = 10.6 and
4.7 Hz, 1H), 3.57 (dt, J = 12.3 and 2.1 Hz, 1H), 3.12–3.01 (m,
1H), 2.78–2.66 (m, 1H), 2.49–2.35 (m, 1H), 2.14–2.03 (m, 1H),
1.98–1.79 (m, 1H), 1.79–1.37 (m, 9H), 0.91 (t, J = 6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 154.2, 129.8, 127.3, 121.4,
120.4, 116.4, 80.3, 76.3, 65.7, 40.6, 32.4, 32.3, 32.0, 27.3, 24.8,
22.6, 14.1; IR (Neat): ν 2926, 2854, 1488, 1457, 1250, 1231,
1100, 753 cm−1; ESI-MS: m/z 261 (M + H)+; HRMS (ESI) cal-
culated for C17H25O2: 261.1849 (M + H)+, Found 261.1855.
4 (a) J. S. Yadav, P. P. Chakravarthy, P. Borkar, B. V. S. Reddy and
A. V. S. Sarma, Tetrahedron Lett., 2009, 50, 5998; (b) J. S. Yadav,
P. Borkar, P. P. Chakravarthy, B. V. S. Reddy, A. V. S. Sarma, B. Sridhar
and R. Grée, J. Org. Chem., 2010, 75, 2081; (c) B. V. S. Reddy,
P. Borkar, P. P. Chakravarthy, J. S. Yadav and R. Grée, Tetrahedron Lett.,
2010, 51, 3412; (d) B. V. S. Reddy, P. Borkar, J. S. Yadav, B. Sridhar and
R. Grée, J. Org. Chem., 2011, 76, 7677.
5 (a) H. U. Wagner and R. Gompper, The Chemistry of Quinonoid Com-
pounds, ed. S. Patai, Wiley, New York, 1974, Part 2, ch. 18, 1145; (b) K.
C. Nicolaou, D. Gray and J. Tae, Angew. Chem., Int. Ed., 2001, 40, 3675;
(c) Y. Nianhuan, S. Aiming, W. Xiaobing, D. Seth and S. L. Kit,
J. Comb. Chem., 2007, 9, 668.
6 (a) F. Fringuelli and A. Taticchi, Dienes in the Diels-Alder Reaction,
Wiley, New York, 1990, ch. 3, 125; (b) Y. Genisson, P. C. Tyler and
R. N. Young, J. Am. Chem. Soc., 1994, 116, 759; (c) S. Inoue, M. Asami,
K. Honda and H. Miyazaki, Chem. Lett., 1996, 889; (d) Y. Genisson and
R. N. Young, Tetrahedron Lett., 1994, 35, 7747; (e) O. L. Chapman,
M. R. Engel, J. P. Spinger and J. C. Clardy, J. Am. Chem. Soc., 1971, 93,
6696.
7 M. H. H. Nkunya, R. Waibel and H. Achenbach, Phytochemistry, 1993,
34, 853.
8 R. Devakaram, D. S. Black, K. T. Andrews, G. M. Fisher, R. A. Davis
and N. Kumar, Bioorg. Med. Chem., 2011, 19, 5199.
9 (a) J. S. Yadav, N. Thrimurtulu, K. U. Gayathri, B. V. S. Reddy and
A. R. Prasad, Tetrahedron Lett., 2008, 49, 6617; (b) J. S. Yadav,
K. L. Lakshmi, N. M. Reddy, A. R. Prasad and B. V. S. Reddy, Tetra-
hedron, 2010, 44, 334; (c) J. S. Yadav, B. Padmavani, B. V. S. Reddy,
Ch. Venugopal and A. B. Rao, Synlett, 2007, 2045.
10 (a) N. Greeves, H. C. Aspinall, J. S. Bissett and D. Levin, Tetrahedron
Lett., 2002, 43, 319; (b) N. Greeves, H. C. Aspinall, J. S. Bissett and
D. Levin, Tetrahedron Lett., 2002, 43, 323.
11 The crystal belongs to the monoclinic crystal system, space group is P21/
c with a = 12.8286(7) Å, b = 12. 1802(7) Å, c = 11.4263(6) Å, β =
111.313(1), V = 1663.31(16) Å3, ρcalc = 1.303 mg m−3, λ = 0.71073 Å,
μ(Mo Kα) = 0.090 mm−1, F000 = 696, T = 294(2) K. Data collection
yielded 15 572 reflections resulting in 2927 unique, averaged reflection,
2641 with I > 2(I), θ range: 1.70–25.00°. Full-matrix least-squares refine-
ment led to a final R = 0.0327, wR = 0.0900 and GOF = 1.047. Intensity
data were measured on Bruker Smart Apex with CCD area detector. The
supplementary crystallographic data (CIF File) for this compound is
available as ESI†
(1S*,4aS*,10aS*)-1-Isobutyl-1,3,4,4a,10,10a-hexahydropyrano-
[4,3-b]chromene (5i; Table 3; entry i). Yield, 78%; Solid, mp
70–72 °C; H NMR (300 MHz, CDCl3): δ 7.08–6.93 (m, 2H),
1
6.83–6.69 (m, 2H), 4.04 (ddd, J = 12.1, 5.3 and 1.5 Hz, 1H),
3.73 (dt, J = 10.6 and 5.3 Hz, 1H), 3.48 (dt, J = 12.1 and 2.3 Hz,
1H), 3.03 (dt, J = 9.8 and 2.3 Hz, 1H), 2.70–2.58 (m, 1H),
2.39–2.25 (m, 1H), 2.07–1.96 (m, 1H), 1.92–1.72 (m, 2H),
1.68–1.28 (m, 3H), 0.92–0.80 (m, 6H); 13C NMR (75 MHz,
CDCl3): δ 154.2, 129.8, 127.3, 121.5, 120.4, 116.4, 78.4, 76.3,
65.7, 41.7, 41.3, 32.3, 27.4, 24.1, 24.0, 21.4; IR (KBr): ν 2926,
2856, 1489, 1460, 1374, 1236, 1091, 1053, 755 cm−1; ESI-MS:
m/z 247 (M + H)+; HRMS (ESI) calculated for C16H23O2:
247.1683 (M + H)+, Found 247.1690.
(4a′S*,10a′R*)-4′,4a′,10′,10a′-Tetrahydro-3′H-spiro[cyclo-
hexane-1,1′-pyrano[4,3-b]chromene] (5j; Table 3; entry j).
Yield, 72%; Solid, mp 106–108 °C; 1H NMR (300 MHz,
CDCl3): δ 7.16–6.97 (m, 2H), 6.89–6.74 (m, 2H), 4.08 (dt, J =
10.8 and 5.1 Hz, 1H), 3.93–3.80 (m, 1H), 3.75–3.60 (m, 1H),
2.74–2.53 (m, 2H), 2.16–2.03 (m, 1H), 2.02–1.39 (m, 9H),
1.37–1.18 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 153.6, 129.5,
127.2, 122.0, 120.1, 116.2, 75.3, 72.5, 58.2, 45.2, 36.7, 32.8,
26.4, 26.0, 24.8, 21.1, 20.1; IR (KBr): ν 2927, 2854, 1489,
1452, 1233, 1079, 1018, 806, 752 cm−1; ESI-MS: m/z 259
(M + H)+; HRMS (ESI) calculated for C17H23O2: 259.1698
(M + H)+, Found 259.1704.
6568 | Org. Biomol. Chem., 2012, 10, 6562–6568
This journal is © The Royal Society of Chemistry 2012