Facile synthesis of furowarfarins via hetero-diels-alder cycloaddition reaction

Article abstract of DOI:10.1080/00397911.2011.609302

Synthesis of new furowarfarins has been carried out via tandem Knoevenagel-hetero-Diels-Alder cycloaddition reaction. One-pot, multicomponent reaction involving, heating a mixture of hydroxy chromenone, aldehyde, and 2-methoxy propene afforded pyranochromenone with good diastereoselectivity, favoring the exo (trans) cycloadduct, in contrast to previous literature reports. The pyran ring exists in a half-chair conformation with C9-OMe in-axial and C7-phenyl ring in-equatorial positions. Single-crystal X-ray analysis conclusively confirms the structure.

Full text of DOI:10.1080/00397911.2011.609302

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Facile Synthesis of Furowarfarins
via Hetero-Diels–Alder Cycloaddition
Reaction
Shubhangi S. Soman a & Jagdish M. Patel a
a Department of Chemistry, Faculty of Science, Maharaja Sayajirao
University of Baroda, Vadodara, India
Accepted author version posted online: 27 Feb 2012.Version of
record first published: 21 Dec 2012.
To cite this article: Shubhangi S. Soman & Jagdish M. Patel (2013): Facile Synthesis of Furowarfarins
via Hetero-Diels–Alder Cycloaddition Reaction, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 43:6, 775-783
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Synthetic Communications1, 43: 775–783, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.609302
FACILE SYNTHESIS OF FUROWARFARINS VIA
HETERO-DIELS–ALDER CYCLOADDITION REACTION
Shubhangi S. Soman and Jagdish M. Patel
Department of Chemistry, Faculty of Science, Maharaja Sayajirao
University of Baroda, Vadodara, India
GRAPHICAL ABSTRACT
Abstract Synthesis of new furowarfarins has been carried out via tandem Knoevenagel–
hetero-Diels–Alder cycloaddition reaction. One-pot, multicomponent reaction involving,
heating a mixture of hydroxy chromenone, aldehyde, and 2-methoxy propene afforded pyr-
anochromenone with good diastereoselectivity, favoring the exo (trans) cycloadduct, in con-
trast to previous literature reports. The pyran ring exists in a half-chair conformation with
C9-OMe in w-axial and C7-phenyl ring in w-equatorial positions. Single-crystal x-ray
analysis conclusively confirms the structure.
Keywords Exo (trans); furowarfarin; half-chair conformation; Knoevenagel–
hetero-Diels–Alder cycloaddition; x-ray crystallography
INTRODUCTION
Warfarins today dominate coumarin anticoagulants because of their excellent
potency and good pharmacokinetic profile.[1] Coumadin, a sodium salt of warfarin,
is available on the market. Coumachlor and acenocoumarol are other well-known
derivatives that belong to the same class. 3-Substituted 4-hydroxy coumarin deriva-
tives[2] and tricomarol[3] have been found to possess nonpeptidic HIV inhibitory
Received July 4, 2011.
Address correspondence to Shubhangi S. Soman, Department of Chemistry, Faculty of Science,
Maharaja Sayajirao University of BarodaVadodara 390 002, India. E-mail: shubhangiss@rediffmail.com
775

776
S. S. SOMAN AND J. M. PATEL
potency.[4] Some common clinical uses of warfarin are fibrillation, artificial heart
valves, treatment for deep venous thrombosis pulmonary embolism,[5] and probe
for cytochrome P 450.[6] Warfarins have also been used as rodenticides.
Most studies show the synthesis of warfarins by Michael condensation of
4-hydroxy coumarins with a,b-unsaturated ketones.[7–9] Depending the conditions
used, the product obtained is a mixture of normal condensation product and cyclic
ketal.[10] A number of modifications using catalyst have been reported.[11]
Literature reveals not much work has been documented for the synthesis of
warfarins via hetero-Diels–Alder (HDA) cycloaddition. Moreover, no reports have
been found for the synthesis of furowarfarins. Benzo[c]furans are susceptible to
Diels–Alder reaction, so it was of interest to start with benzo[b]furan, in continu-
ation of our earlier work.[10,12]
Multicomponent reactions have emerged as an efficient tool in organic syn-
thesis because of their valued features such as atom economy, straightforward reac-
tion design, simple purification, and the opportunity to construct target compounds
by the introduction of several diversety elements in a single chemical event, which
stimulated us to synthesize and investigate structures of new furowarfarins. The
present investigation reports on the synthesis of a new class of furowarfarins via a
tandem Knoevenagel–hetero-Diels–Alder cycloaddition reaction, in which the con-
figuration and conformation of the intermediate exo (trans) HDA cycloadduct
has been established on the basis of x-ray crystallography. These furowarfarins are
expected to show anticoagulant properties.
RESULTS AND DISCUSSION
1-(6-Hydroxy-7-methyl-3-phenyl-benzofuran-5-yl)-ethanone[13] 1 reacted with
diethyl carbonate and pulverized sodium to give 5-hydroxy-9-methyl-
1
3-phenyl-furo[3,2-g]chromen-7-one 2. The H NMR of this compound showed sing-
lets at d 5.74 ppm and d 11.84 ppm for C6-H and C5-OH (enolic) protons respectively,
which confirmed the structure. The O-H stretching vibration in the infrared (IR) spec-
trum was observed at 3430 cmꢀ1 (m), whereas a band at 1664 cmꢀ1 (s) contributed to
=
the >C O stretching of the lactone ring. In liquid chromatography–mass spec-
trometry (LCMS), the molecular ion peak was observed at 293.1 m=z, amu with
maximum abundance.
5-Hydroxy-9-methyl-3-phenyl-furo[3,2-g]chromen-7-one 2, when subjected to a
one-pot, multicomponent reaction with benzaldehyde and 2-methoxy propene in dry
dioxane (85–90 ꢁC, 6h, screw-cappressuretube)inthepresenceofcatalyticethylenediam-
˚
monium diacetate (Tietze base) and powdered oven-dried 5-A molecular sieves,
gave
2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-dihydro-2H-1,6,8-trioxa-cyclopenta
[b]phenanthren-5-one 3a (Scheme 1). The in situ generated 3-arylidene-2,4-chromane-
dione, derived from the Knoevenagel condensation of 5-hydroxy-9-methyl-3-phenyl-
furo[3,2-g]chromen-7-one 2 with benzaldehyde, underwent inverse-electron-demand
Diels–Alder cycloaddition with 2-methoxy propene to give 2-methoxy-2,7-dimethyl-4,
10-diphenyl-3,4-dihydro-2H-1,6,8-trioxacyclopenta[b]phenanthren-5-one 3a. The actual
results showed that the reaction proceeds with good exo-selectivity. The product was pur-
ified by column chromatography using neutral alumina powder because the cyclic ketals

SYNTHESIS OF FUROWARFARINS
777
Scheme 1. Synthesis of furowarfarins.
1
are susceptible to hydrolysis in acidic silica. The H NMR of 3a showed a singlet at d
1.71 ppm for C2-CH3 and a singlet at d 3.33ppm for C2-OCH3. Double doublets at d
1.96–2.03ppm (Jvicinal ¼ 11.7 Hz, Jgeminal ¼ 13.9Hz), and d 2.47–2.52 ppm (Jvici-
¼ 7.0 Hz, Jgeminal ¼ 14.0 Hz), both corresponding to one proton each, indicated
nal
C3-HA and C3-HB diastereotopic protons respectively. A double doublet at d
4.08–4.12ppm (Jvicinal ¼ 7.0 Hz, Jvicinal ¼ 11.7 Hz) again corresponding to one proton
indicated C4-H proton, thus forming an ABX system. The 1H NMR obtained was of
the pure compound, but it could not be concluded whether the cycloadduct formed
was endo (cis) or exo (trans) isomer.
However, when the single-crystal x-ray analysis of compound 3a was carried
out, it was observed that the cycloadduct exists in exo (trans) configuration, which
is in accordance with the anomeric effect. Thus it can be concluded that the reaction
proceeds with good diastereoselectivity, favoring the exo (trans) isomer as major pro-
duct. This can be explained on the basis of anomeric effect or Edward–Lemieux
effect, which is a stereoelectronic effect that describes the tendency of heteroatomic
substituents (here methoxy) adjacent to a heteroatom (here oxygen) within a cyclo-
hexane ring (here pyran ring) to prefer the axial orientation instead of the less hin-
dered equatorial orientation that would be expected from steric considerations. Here
the C2-OMe group is w-axial in a half-chair conformation and the C4-phenyl ring is
w-equatorial, which is stereoelectronically the more stable isomer (3a) in all cases.
Moreover, this anomeric effect was further confirmed by facile acidhydrolysis of
3a to 4a, in which the axially orientated lone pair of pyran oxygen pushes away
the axially orientated C2-OMe group, to get the desired hydrolyzed product 4a.
The results of the single-crystal x-ray diffraction analysis are discussed later.
The ratio of isomers in the crude product could not be concluded because the
difference in rf values for both the isomers was very little and moreover, other isomer
being minor, separation by column chromatography was extremely difficult.
Higher-performance liquid chromatography (HPLC) of the crude product could
1
not be done because of limitations. The H NMR of the crude compound 3a also
could not reflect much on the isomer ratios.

778
S. S. SOMAN AND J. M. PATEL
Figure 1. ORTEP diagram of 2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-dihydro-2H-1,6,8-trioxa-
cyclopenta[b]phenanthren-5-one 3a with atom numbering scheme (40% probability factor for the thermal
ellipsoids). (Figure is provided in color online.)
The unmasking of the carbonyl function in 3a was carried out using trifluoroa-
cetic acid = water, which gave 5-hydroxy-9-methyl-6-(3-oxo-1-phenyl-butyl)-
3-phenyl-furo[3,2-g]chromen-7-one 4a. The 1H NMR of 4a was obtained as a highly
complicated spectrum because of their existence in solution as an equilibrium mixture
of open-chain keto tautomer and two diastereomeric cyclic hemiketal tautomers.[14]
The hydrolysis product is a d-hydroxy ketone and can therefore undergo ring
closure to cyclic hemiketal. The LCMS of 4a showed a molecular ion peak at m=z
439.2 with maximum abundance, which was consistent with the product structure.
Similar observations were recorded using p-anisaldehyde, p-chloro benzal-
dehyde, and p-nitro benzaldehyde. Cycloadducts 3b, 3c, and 3d were subjected to
hydrolysis without any purification. The reaction sequence for different title com-
pounds is outlined in Scheme 1. The structures of all the compounds have been
established on the basis of their elemental analyses and spectral data (IR, NMR,
and LCMS).
Compound 3a crystallizes in a centrosymmetric monoclinic space group P21=n.
Figure 1 shows the ORTEP diagram with atom numbering scheme (40% probability
factor for the thermal ellipsoids), and Fig. 2 shows the crystal structure of 3a
Figure 2. Crystal structure of 2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-dihydro-2H-1,6,8-trioxa-
cyclopenta[b]phenanthren-5-one 3a. (Figure is provided in color online.)

SYNTHESIS OF FUROWARFARINS
779
Table 1. Crystal data and structure refinement of 2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-dihydro-2H-
1,6,8-trioxacyclopenta[b]phenanthren-5-one 3a
Parameter
Value
Empirical formula
Formula weight
Temperature
C29 H24 O5
452.48
293(2) K
˚
Wavelength
0.71073 A
Monoclinic
P21=n
Crystal system
Space group
Unit cell dimensions
ꢁ
˚
a ¼ 9.9765(13) A, a ¼ 90
ꢁ
˚
b ¼ 21.684(3) A, b ¼ 106.461(2)
ꢁ
˚
c ¼ 11.0838(15) A, c ¼ 90
3
˚
Volume
Z
2299.5(5) A
4
Density (calculated)
Absorption coefficient
F(000)
1.307 mg=m3
0.089 mmꢀ1
952
Crystal size
Theta range for data collection
Index ranges
0.80 ꢂ 0.30 ꢂ 0.05 mm
1.88ꢁ to 27.50ꢁ
ꢀ12 ꢃ ¼ hꢃ ¼ 12, ꢀ24 ꢃ ¼ kꢃ ¼ 28, ꢀ10 ꢃ ¼ lꢃ ¼ 14
13548
Reflections collected
Independent reflections
Absorption correction
Max. and min. transmission
Refinement method
Data=restraints=parameters
Goodness of fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
Largest diff. peak and hole
[R(int) ¼ 0.0300]
Semi-empirical from equivalents
0.9956 and 0.9323
Full-matrix least-squares on F2
5197=0=310
1.221
R1 ¼ 0.0800, wR2 ¼ 0.1670
R1 ¼ 0.0963, wR2 ¼ 0.1747
ꢀ3
˚
0.254 and ꢀ0.250 e.A
Crystallographic data (excluding structural factors) for the structure in this article have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 698274.
generated using Mercury 1.4.2 software.[15] The asymmetric unit consists of a single
molecule at a normal position. As can be seen from these figures, the C9-OMe group
is w-axial in a half-chair conformation with respect to C7-phenyl ring, which is w-
equatorial. This configuration corresponds to exo (trans) isomer of the cycloadduct
3a. The crystal structure shows the (S)-configuration at C-7 and C-9 for the mol-
ecule. All the atoms apart from C-9 are coplanar. Crystal data for the compound
are given in Table 1.
CONCLUSION
Single crystal x-ray analysis of 2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-
dihydro-2H-1,6,8-trioxa- cyclopenta[b]phenanthren-5-one 3a shows that the HDA
cycloadduct exists in exo (trans) configuration. Thus it can be concluded that the
hetero-Diels–Alder reaction proceeds with good diastereoselectivity, favoring the
exo (trans) isomer in this case. The pyran ring of the molecule adopts the half-chair
conformation. The process can be explored for asymmetric synthesis of furowarfarin

780
S. S. SOMAN AND J. M. PATEL
derivatives using various chiral auxiliaries. The compounds can be explored for
possible anticoagulant properties.
EXPERIMENTAL
All the chemicals used were of the LR grade procured from Merck, except
ethylenediammonium diacetate, which was from Fluka. Melting points (uncor-
rected) were determined using a scientific capillary melting-point apparatus. Purity
of the compounds was checked by thin-layer chromatography (TLC) on Acme’s
silica-gel G plates using UV=iodine vapor as visualizing agent. Acme’s silica gel
(60–120 mesh) and neutral alumina powder was used for column chromatographic
purification. Elemental analyses were carried out on Perkin-Elmer C, H, N, S ana-
lyzer (model 2400). IR spectra were recorded on Perkin-Elmer Fourier transform
(FT)–IR spectrometer (spectrum RX1) using potassium bromide optics. The mass
spectrum was obtained on Perkin-Elmer Sciex Triple Quadrupole LC=MS=MS
mass spectrometer (EI, 70 eV) (model 016932) using ion spray source. NMR spec-
tra were recorded on Bruker 400-MHz spectrophotometer. Chemical shifts are
relative to tetramethylsilane on a d-scale in parts per million (ppm). Coupling con-
stants are given in hertz (Hz) and relative peak areas were in agreement with all
˚
assignments. X-ray diffraction data were collected using Mo Ka (k ¼ 0.71073 A)
radiation on a Smart Apex diffractometer equipped with a charge coupled device
(CCD) area detector. Data collection, data reduction, and structure solution=
refinement were carried out using the software package of Smart Apex. Graphics
were generated using Mercury 1.4.1.[15]
Preparation of 5-Hydroxy-9-methyl-3-phenyl-furo[3,2-g]chromen-7-
one (2)
A solution of 1-(6-hydroxy-7-methyl-3-phenyl-benzofuran-5-yl)-ethanone[13]
(1 g, 3.75 mmol) in diethyl carbonate (25 mL) was added to pulverized sodium
(0.21 g, 9.38 mmol) (Caution: moisture sensitive and pyrophoric) and stirred for
15 min under anhydrous conditions. It was then gradually heated to reflux and main-
tained for 30 min (Caution: exothermic). The reaction mixture was cooled to room
temperature, and methanol (10 mL) was added to decompose unreacted sodium.
The reaction mass was poured into water (50 mL). The aqueous solution was then
washed twice with toluene (25 mL) and acidified with concentrated hydrochloric acid
until pH 2. The product obtained was filtered and crystallized from ethanol to get
cream-colored crystals (0.5 g, 45.55%), mp 255 ꢁC of 5-hydroxy-9-methyl-
3-phenyl-furo[3,2-g]chromen-7-one. IR (KBr) (nmax=cmꢀ1): 3430, 3071, 1664, 1589,
1
1501, 1375, 1353, 1285, 1228, 1120. H NMR [(CD3)2SO]: d 2.60 (s, 3H, C9-CH3),
5.74 (s, 1H, C6-H), 7.38–7.42 (m, 1H, C40-H), 7.48–7.52 (m, 2H, C30-H and
C50-H), 7.65–7.68 (m, 2H, C20-H and C60-H), 7.92 (s, 1H, C2-H), 8.15 (s, 1H,
C4-H), 11.84 (s, 1H, C5-OH). LCMS (EI) m=z (%): 315.1 (37.03, M þ Na), 293.1
(100, M þ 1), 279.2 (11.11), 269.3 (7.40). Anal. calcd. for C18H12O4: C, 73.97; H,
4.14. Found: C, 73.81; H, 4.03%.

SYNTHESIS OF FUROWARFARINS
781
Preparation of 2-Methoxy-2,7-dimethyl-4,10-diphenyl-3,4-
dihydro-2h-1,6,8-trioxacyclopenta[b]phenanthren-5-one (3a)
To a solution of 5-hydroxy-9-methyl-3-phenyl-furo[3,2-g]chromen-7-one 2
(0.5 g, 1.71 mmol), freshly distilled benzaldehyde (0.18 g, 1.71 mmol) and 2-methoxy
˚
propene 97% (0.28 g, 3.76 mmol) in dry dioxane (25 mL), powdered oven-dried 5-A
molecular sieves, and a catalytic amount of ethylenediammonium diacetate
(2 mol %) were added, and the reaction mixture was heated to 85–90 ꢁC for 6 h in
a screw-cap pressure tube. It was then filtered and washed with dioxane. The filtrate
was poured into ice water, and the solid obtained was collected by filtration. The
crude product was purified by column chromatography using neutral alumina pow-
der and petroleum ether–ethyl acetate (9:1) mixture at 60–80 ꢁC, which gave light yel-
low crystals (0.35 g, 45.21%), mp 225 ꢁC, of 2-methoxy-2,7-dimethyl-4,10-
diphenyl-3,4-dihydro-2H-1,6,8-trioxa-cyclopenta[b]phenanthren-5-one 3a. IR (KBr)
(nmax=cmꢀ1): 3057, 1718, 1633, 1602, 1454, 1383, 1357, 1237, 1194, 1119, 1082,
1069.1H NMR [(CD3)2SO]: d 1.71 (s, 3H, C2-CH3), 1.96–2.03 (dd, Jvicinal ¼ 11.7
and Jgeminal ¼ 13.9 Hz, 1H, C3-HA), 2.47–2.52 (dd, Jvicinal ¼ 7.0 and Jgeminal ¼ 14.0 Hz,
Hz, 1H, C3-HB), 2.60 (s, 3H, C7-CH3), 3.33 (s, 3H, C2-OCH3), 4.08–4.12 (dd,
Jvicinal ¼ 7.0 and Jvicinal ¼ 11.7 Hz, 1H, C4-H), 7.19–7.22 (m, 3H, C30-H, C40-H and
C50-H), 7.26–7.29 (m, 2H, C20-H and C60-H), 7.42–7.46 (m, 1H, C400-H), 7.53–7.57
(m, 2H, C300-H and C500-H), 7.67–7.70 (m, 2H, C200-H and C600-H), 7.94 (s, 1H,
C2-H), 8.12 (s, 1H, C4-H). Anal. calcd. for C29H24O5: C, 76.98; H, 5.35. Found:
C, 76.78; H, 5.11%.
Single Crystal X-Ray Diffraction
X-ray-quality single crystals of 2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-
dihydro-2H-1,6,8-trioxa-cyclopenta[b]phenanthren-5-one 3a were grown by a slow
evaporation condition at room temperature. Crystals were obtained from a mixture
of ethanol and toluene. The structure was solved by direct methods and refined in a
routine manner. All hydrogen atoms were geometrically fixed and refined.
Preparation of 5-Hydroxy-9-methyl-6-(3-oxo-1-phenyl-butyl)-
3-phenyl-furo[3,2-g]chromen-7-one (4a)
A
solution
of
2-methoxy-2,7-dimethyl-4,10-diphenyl-3,4-dihydro-2H-
1,6,8-trioxacyclopenta[b]phenanthren-5-one 3a (0.5 g, 1.10 mmol) in trifluoroacetic
acid–water (9.5:0.5) (10 mL) was stirred at room temperature for 6 h. The reaction
mass was then poured into ice water and the solid thus obtained was collected by
filtration. The crude product was purified by column chromatography using silica
gel and chloroform–methanol (9:1) eluent, which yielded white crystals 0.4 g
(82.55%), mp 198 ꢁC of 5-hydroxy-9-methyl-6-(3-oxo-1-phenyl-butyl)-3-phenyl-
furo[3,2-g]chromen-7-one 4a. IR (KBr): 3422, 2926, 1682, 1632, 1598, 1453, 1385,
1361, 1246, 1121, 1072 cmꢀ1. LCMS (EI) m=z (%): 477.2 (4.76, M þ K), 461.3
(21.42, M þ Na), 439.2 (100, M þ 1). Anal. calcd. for C28H22O5: C, 76.70; H, 5.06.
Found: C, 76.58; H, 4.91%.

782
S. S. SOMAN AND J. M. PATEL
5-Hydroxy-6-[1-(4-methoxy-phenyl)-3-oxo-butyl]-9-methyl-3-phenyl-
furo[3,2-g]chromen-7-one (4b)
Cream-colored crystals (81%), mp 180 ꢁC. IR (KBr): 3428, 2928, 1686, 1638,
1600, 1458, 1390, 1366, 1282, 1252, 1131, 1080 cmꢀ1 Anal. calcd. for C29H24O6: C,
74.35; H, 5.16. Found: C, 74.55; H, 5.31%.
6-[1-(4-Chloro-phenyl)-3-oxo-butyl]-5-hydroxy-9-methyl-3-phenyl-
furo[3,2-g] chromen-7-one (4c)
Off-white crystals (75%), mp 212–214 ꢁC. IR (KBr): 3432, 2946, 1692, 1642,
1594, 1458, 1388, 1369, 1248, 1132, 1092 cmꢀ1. Anal. calcd. for C28H21ClO5: C,
71.11; H, 4.48. Found: C, 70.98; H, 4.21%.
5-Hydroxy-9-methyl-6-[1-(4-nitro-phenyl)-3-oxo-butyl]-3-phenyl-
furo[3,2-g]chromen-7-one (4d)
Cream-colored crystals (88%), mp 230–232 ꢁC. IR (KBr): 3426, 2932, 1684,
1630, 1594, 1450, 1378, 1364, 1242, 1120, 1068 cmꢀ1. Anal. calcd. for C28H21NO7:
C, 69.56; H, 4.38; N, 2.90. Found: C, 69.38; H, 4.11; N, 2.74%.
ACKNOWLEDGMENTS
The authors are thankful to the head, Department of Chemistry, Maharaja
Sayajirao University of Baroda, for providing the necessary facilities. One of the
authors (J. M. P.) is thankful to AICTE, New Delhi, for providing financial assistance.
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