Tandem one-pot synthesis of flavans by recyclable silica-HClO4 catalyzed Knoevenagel condensation and [4 + 2]-Diels-Alder cycloaddition

Article abstract of DOI:10.1039/c2ob25376c

An efficient one-pot multi-component synthesis of flavans using perchloric acid supported on silica as a recyclable heterogeneous catalyst has been described. This is the first report of direct one-step construction of a flavan skeleton from a phenolic precursor. The method involves a Knoevenagel-type condensation leading to in situ formation of transient O-quinone methide which further undergoes [4 + 2]-Diels-Alder cycloaddition with styrene to yield a flavan skeleton. The method provides easy access to a wide range of bio-active natural products viz. flavonoids, anthocyanins and catechins.

Full text of DOI:10.1039/c2ob25376c

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Tandem One-Pot Synthesis of Flavans by Recyclable Silica-HClO4
catalyzed Knoevenagel Condensation and [4+2]-Diels-Alder
Cycloaddition#¤
Sandip B. Bharate,†* Ramesh Mudududdla,† Jaideep B. Bharate,† Narsaiah Battini,† Satyanarayana
5
Battula,† Rammohan R. Yadav,† Baldev Singh‡ and Ram A. Vishwakarma†*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient one-pot multi-component synthesis of flavans using perchloric acid supported on
silica as a recyclable heterogeneous catalyst has been described. This is the first report of
10 direct one-step construction of flavan skeleton from phenolic precursor. The method involves
Knoevenagel-type condensation leading to in-situ formation of transient O-quinone methide
which further undergoes [4+2]-Diels-Alder cycloaddition with styrene to yield flavan
skeleton. The method provides easy access to wide range of bio-active natural products viz.
flavonoids, anthocyanins and catechins.
OH
OHC
HO
15
OH
CHO
OH
Introduction
CHO
2
HO
O
HO
R1
Flavans are a set of naturally occurring flavonoids possessing a 2-
phenyl-3,4-dihydro-2H-chromene nucleus. They are widely
distributed in the plant kingdom1 with >17000 natural flavans
20 isolated so far2 and many exhibit interesting and useful biological
O
3
OH
OH
OH
OH R2
O
(+)-Catechin (1): 2R, 3S
(-)-Catechin (2): 2S, 3R
(-)-Epicatechin (3): 2R,3R
(+)-Epicatechin (4): 2S,3S
3
Sideroxylonal B (5): R1 = H, R2 = isobutyl
Grandinal (6): R1 = isobutyl, R2 = H
activities.1, Amongst different flavans, flavan-3-ols are most
abundant and occur in monomeric, oligomeric and polymeric
forms, which are also known as condensed tannins or
proanthocyanidins. They exhibit high degree of structural
25 diversity varying according to the type of constitutive units, type
of interflavan linkages, and degree of polymerization. Most
widely known flavans are catechins (1-2, 2R,3S and 2S,3R) and
epicatechins (3-4, 2R,3R and 2S,3S), which occur in plants such
as catechu, tea cocoa etc. and are known to possess various
30 biological properties such as anticarcinogenic, anti-inflammatory,
antioxidant, immunomodulatory, inhibition of bone resorption
etc.4 Fully substituted monomeric flavans sideroxylonal B (5) and
grandinal (6) have been reported from Eucalyptus sideroxylon
and E. grandis which exhibited antibacterial activities against
35 gram-positive bacteria and inhibition of aldose reductase.5
Recently benzodipyran and benzotripyran type of compounds
have been reported to posses potent angiogenic activities.6
Structures of flavans 1-6 are shown in Figure 1.1
40
Figure 1 Examples of naturally occurring biologically active flavans
Flavans have received considerable amount of attention in last
few decades because of their numerous bioactivities. However,
45 due to their structural complexity, very little synthetic work has
been reported. Currently available protocols for synthesis of
flavan skeleton include Heck-arylation of chromene intermediate
with arenediazonium salt,7 reaction of tris-O-boc formyl
phloroglucinol with styrene in presence of magnesium bromide
50 dietherate and lithium aluminum hydride,8
reduction of
dihydroflavones or dihydroflavonols,9 and cinnamylation of
phenolic compounds with cinnamyl alcohol in presence of
H3PO4.10 Synthesis of polyfunctional flavans sideroxylonals 511
and grandinal 612 have been reported via cycloaddition reaction
55 between in situ generated O-quinone methide from ortho-alkyl
substituted phloroglucinols (using DDQ) and substituted styrene
type compound. Most of the reported protocols require multiple
steps to construct flavan skeleton; many of them require
†
Medicinal Chemistry Division, Indian Institute of Integrative Medicine
(CSIR), Canal Road, Jammu-180001, India
‡
National Products Chemistry Division, Indian Institute of Integrative
Medicine (CSIR), Canal Road, Jammu-180001, India
E-mail: ram@iiim.ac.in; sbharate@iiim.ac.in
Fax: +91-191-2569333; Tel: +91-191-2569111
#
Electronic supplementary information (ESI) available: NMR spectra of
¤ IIIM Publication number IIIM/1474/2012
all new compounds. See DOI: 10.1039/xxxx
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expensive, hazardous chemicals and require anhydrous
conditions. Several protocols comprise protection/ deprotection
we determined total acidity of fresh and used catalyst (after first
use) by ammonia-TPD experiment. The total acidity of the fresh
steps and uses homogeneous catalytic systems. Direct one-step 55 catalyst was found to be 10.95 mmol NH3/g, however it was
construction of a flavan skeleton is not known in the literature.
decreased to 7.6 mmol NH3/g after first use. This decreased
acidity is a clear indication of the catalyst leaching after its use,
which justifies the reason for decrease in the product yield from
84% (fresh catalyst) to 65% (first recycle). However, the catalyst
60 could be recycled upto three times producing >50% yield of
desired flavan.
5
In recent years, great number of short and efficient strategies have
been discovered by chemists to facilitate synthesis of complex
natural products.13 In this regard, several domino ‘one-pot’
strategies which consist of merging compatible single bond
forming processes so as to allow multiple bond forming events
10 between several substrates, a concept generally termed as multi-
component reactions (MCRs) are coming up.14 In the present
communication, we report synthesis of flavans directly from
We also performed control experiment with neat HClO4 instead
of Silica-HClO4 catalyst. When 100 mol% of HClO4 in ACN as a
solvent was used, 20% product was formed after 3 h reflux (entry
phloroglucinol or mono- or di-substituted phloroglucinols 7 using 65 16), however after reflux for 10 h, 60% of the desired flavan 10c
one-pot MCR between phloroglucinol 7, formaldehyde 8 and
15 styrene 9 in presence of recyclable heterogeneous solid acid
catalyst in excellent yields. This one-pot protocol involves
was formed (entry 17). The reaction when performed in neat
HClO4 (excess) without ACN, reaction did not proceed (entry
18). These results indicated that apart from ease of product
isolation and its recyclable nature; Silica-HClO4 catalyst is much
Knoevenagel type condensation of formaldehyde
8 with
phloroglucinol 7 leading to in situ formation of transient O- 70 more efficient in comparison to neat HClO4.
quinone methide which further undergoes [4+2]-Diels-Alder
20 cycloaddition with styrene 9 to yield flavan 10 (Scheme 1).
Table 1 Solvent and catalyst optimization studiesa
O
O
R3
R3
HO
O
OH
+
HO
O
O
R1
R1
Catalyst
Solvent
+
HO
R2
OH
+
HO
R2
O
Silica-HClO4
ACN, 80 o
HCHO
+
OH
10c
OH
C
R4
R4
HCHO
8
9a
7c
OH
OH
7
8
9
10
Entry Catalyst (% w/w)
Solvent
ACN
Temp. Time
Yieldb
(%)
50
50
50
20
30
0
(h)
3
(C)
80
Scheme 1 One-pot MCR approach to flavan synthesis
1
Amberlyst-15 (50)
25
2
Amberlite-IR-50 (50) ACN
Amberlite-IR-140 (50) ACN
80
3
Results and discussion
3
80
3
4
Amberlyst-15 (50)
Amberlyst-15 (50)
Silica gel (50)
H2O
100
100
80
3
Initially, an experimental exploration on reaction parameters,
including catalyst, solvent, temperature and reaction time, was
conducted using the model MCR between 2,4-diacetyl
5
Dioxane
ACN
ACN
ACN
ACN
H2O
6
6
6
7
Silica-I2 (50)
80
3
55
60
84
50
50
70
50
80
35
20
60
0
30 phloroglucinol (7c), formaldehyde (8) and styrene (9a) (Table 1).
Catalyst-free MCR was first attempted by varying solvent,
reaction temperature and time; however no product was formed.
Catalytic effect of various cation-exchange resins and silica based
acid catalysts15-17 was investigated. Amberlyst-15 and amberlite
35 catalysts led to formation of flavan 10c in 50% yield. A brief
examination of solvents showed ACN as a suitable solvent
(entries 1 vs. 4 and 5), which was selected for further
optimization studies. After numerous trials, we eventually found
that all three silica based catalysts, silica-I2, silica-FeCl3 and
40 silica-HClO4 are competent, affording the flavan 10c in >55%
yield (entries 7-9). Further optimization revealed that the reaction
could proceed smoothly by decreasing the catalyst loading as low
as 10 %w/w (entry 14); however, 50% w/w silica-HClO4
appeared to be superior in terms of efficiency and reaction time.
8
Silica-FeCl3 (50)
Silica-HClO4 (50)
Silica-HClO4 (50)
Silica-HClO4 (50)
Silica-HClO4 (20)
Silica-HClO4 (10)
Silica-HClO4 (10)
Silica-HClO4 (5)
HClO4 (100)
80
3
9
80
3
10
11
12
13
14
15
16
17
18
100
100
80
3
Dioxane
ACN
ACN
ACN
ACN
ACN
ACN
HClO4
3
3
80
3
80
12
3
80
70
3
HClO4 (100)
70
10
3
HClO4
70
a
Reagents and conditions: 7c (1 mmol), 8 (3 mmol), 9a (1.5 mmol) and
75 catalyst; b Isolated yields.
Next, we studied scope of the MCR. Phloroglucinol (7a) and its
mono- 7b and di-substituted analogs 7c-7e,18, 19 styrenes (9a), 4-
methyl styrene (9b), 4-tert-butyl styrene (9c), 2-vinyl napthalene
80 (9d) and isosaffrol (9e) were investigated (Table 2). Under
optimized reaction conditions, MCR of phloroglucinol (7a) with
8 and 9a led to formation of hexahydrobenzotripyran 10a in 35%
yield (entry 1). Similarly, mono-substituted phloroglucinol 7b
(entry 2) produced tetrahydrodipyran 10b in 52% yield. Like 2,4-
85 diacetyl phloroglucinol 7c (entry 3), other disubstituted
45 Recyclability of the catalyst was checked to prove the
heterogeneous nature and its repeated use. The MCR between 7c,
8 and 9a in presence of silica-HClO4 (50 %w/w) led to formation
of flavan 10c in 84, 65, 58 and 48% in 3 h reaction time over four
cycles respectively. However, when reaction time was increased
50 to 8, 12, 16 h for cycles 2-4, product yields were improved to 78,
70 and 65% respectively. In order to understand the reason for
decreased catalytic activity of Silica-HClO4 catalyst after its use,
2
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7c
phloroglucinols 7d and 7e also produced desired flavans 10d and
CHO
CHO
OH
10e in excellent yields (entries 4 and 5). 4-Methyl styrene 9b, 4-
tert-butyl styrene 9c as well as 2-vinyl naphthalene 9d
participated well in this reaction producing desired flavans in
good yields (entries 6-10). The MCR protocol also worked well
with -substituted styrene isosaffrol (9e). Reaction of 7c with
isosaffrol (9e) produced 3-methyl substituted flavan 10k in 88%
yield (entry 11). It is evident from the Table 2 that disubstituted
phloroglucinols showed better reactivity in MCR compared with
10 mono-substituted followed by non-substituted phloroglucinol.
Amongst different styrenes used, 4-methyl 9b and t-butyl 9c
styrenes produced higher yields compared with unsubstituted
styrene 9a.
HO
OH
7
8
3.0
87
HO
O
OHC
OHC
OH
10g
9b
9b
5
7d
O
O
O
1.0
92
HO
OH
HO
O
O
OH
OH
O
10h
7e
O
O
9
1.0
94
92
88
HO
O
OH
HO
O
10i
OH
OH
9c
All synthesized flavans have been fully characterized using
7c
1
15 melting point, H NMR, 13C NMR, MS, IR and HRMS data. The
O
O
O
10
11
1.0
1.5
CH proton at C2 position shows typical ‘dd (J = 2-6 and 8-15
Hz)’ in 1H NMR spectrum, which is in consistence with literature
values.20 The H2 proton of flavan 10k showed J2-3 = 9.9 Hz
indicating 2,3-trans relative stereochemistry. 2,3-Trans relative
20 stereochemistry was further confirmed by NOESY experiment.
The applicability of MCR protocol for substituted flavan 10k,
indicates its promise in total synthesis of variety of biologically
important 3-substituted flavans (e.g. grandinal, catechins).
HO
O
OH
OH
HO
O
O
10j
OH
O
OH
9d
9e
7c
O
O
O
O
HO
O
O
HO
O
CH3
10k
OH
OH
7c
a
Reagents and conditions: 7 (1 mmol), 8 (3 mmol), 9 (1.5 mmol) and
catalyst silica-HClO4 (50 %w/w) in ACN at 80 C; b Isolated yields.
25 Table 2 One-pot synthesis of flavans 10 from phloroglucinols 7
Entry Phloroglu-
Styrene
Flavan 10
Time Yieldb
cinol, 7
9
(h)
(%)
Further, the utility of this protocol was explored for flavonoid
30 synthesis. Flavan 10c on treatment with DDQ in dioxane (1%
water) led to formation of corresponding flavone 11 in 75% yield.
Next, we attempted one-pot conversion of disubstituted
phloroglucinol 7c to flavone 11. The mixture of 7c, 8, 9a and
silica-HClO4 in acetonitrile was refluxed for 1.5 h, followed by
35 addition of a DDQ (4 equiv). Reaction was continued to reflux
for 6 h, which led to formation of desired flavone 11, but only in
10% yield. After further optimization studies, we found that
flavan 10 synthesis works well in ACN solvent; however
oxidation/dehydrogenation reaction requires dioxane solvent.
40 Thus an optimized one-pot protocol for flavone synthesis directly
from phloroglucinols 7 include, evaporation of ACN after flavan
10c formation followed by addition of DDQ and dioxane (1%
water) in the same pot, which leads to formation of flavone 11 in
65% yield (Figure 2).
HO
OH
1
6.0
35
O
O
O
OH
9a
9a
7a
10a
O
O
HO
O
OH
HO
2
3
6.0
52
84
OH
O
7b
10b
O
O
1.5
HO
O
OH
HO
O
O
OH
10c
OH
9a
9a
7c
CHO
45 The formation of flavone 11 via one-pot protocol from
phoroglucinol precursor 7c involves cascade of 4 reactions
namely, Knoevenagel-type condensation, [4+2] Diels-Alder
cycloaddition, DDQ-mediated oxidation and DDQ-mediated
dehydrogenation. The plausible mechanism for this one-pot MCR
50 is depicted in Figure 3. Under acidic conditions, formaldehyde
gets protonated (structure I) which enhances its electrophilicity.
2,4-Disubstituted phloroglucinol being an active hydrogen
species, it undergoes Knoevenagel-type condensation with
protonated formaldehyde, producing transient O-quinone methide
55 III. This O-quinone methide III quickly undergoes [4+2]-Diels-
Alder cycloaddition reaction with dienophile 9a to produce flavan
10c. Further DDQ-mediated oxidation of the benzylic CH2,
CHO
HO
OH
4
5
4.0
1.5
76
86
HO
O
OHC
OHC
OH
OH
10d
7d
O
O
HO
OH
HO
O
O
O
OH
9a
9b
OH
10e
7e
O
O
6
1.0
92
HO
O
OH
HO
O
O
OH
10f
OH
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features of our developed methodology are (a). no
protection/deprotection steps required; (b). inexpensive, easy to
prepare, non-hazardous, easy to separate from reaction mixture,
15 reusable catalyst and (c). diversity-oriented synthesis. The
developed protocol provides shorter route to access variety of
flavan natural products such as catechins, flavonoids,
anthocyanins, grandinal etc. using appropriate dienophile,
aldehyde and phloroglucinol precursor.
produces 2,3-dihydro flavone VIII. Here, activation of benzylic
CH2 of flavan 10c occurs via hydride ion abstraction by DDQ.21,
2,3-Dihydroflavone VIII further undergoes DDQ-mediated
dehydrogenation leading to formation of flavone 11 (Figure 3).
22
O
HO
O
OH
+
HCHO
+
20
OH
7c
8
9a
Experimental Section
(i). Silica-HClO4
(50% w/w)
General
ACN, 80 oC, 1.5 h
"One-pot"
All chemicals were obtained from Sigma-Aldrich Company and
used as received. 1H, 13C and DEPT NMR spectra were recorded
25 on Brucker-Avance DPX FT-NMR 500 and 400 MHz
instruments. Chemical data for protons are reported in parts per
million (ppm) downfield from tetramethylsilane and are
referenced to the residual proton in the NMR solvent (CDCl3,
7.26 ppm). Carbon nuclear magnetic resonance spectra (13C
30 NMR) were recorded at 125 MHz or 100 MHz: chemical data for
carbons are reported in parts per million (ppm, δ scale) downfield
from tetramethylsilane and are referenced to the carbon resonance
of the solvent (CDCl3, 77 ppm). ESI-MS and HRMS spectra were
recorded on Agilent 1100 LC-Q-TOF and HRMS-6540-UHD
35 machines. IR spectra were recorded on Perkin-Elmer IR
spectrophotometer. Melting points were recorded on digital
melting point apparatus.
(ii). Dioxane (1% H2O)
DDQ (6 equiv.)
O
HO
O
O
OH
O
11
5
Figure 2 One-pot synthesis of flavone 11 from phloroglucinol 7c
Conclusion
In summary, we have developed a very simple and economical
10 tandem one-pot protocol for synthesis of flavans 10 and flavones
11 directly from substituted phloroglucinol precursors. Key
O
O
O
O
O
HO
O
O
Ph
H2O
Cl
Cl
CN
CN
H
H
HO
O
OH
HO
O
Ph
CH2
H
H
HO
O
O
H
Silica-HClO4
O
OH
H
H
H
OH
OH
10c
CH2
OH
H
O
I
OH
7c
O
OH
II
OH
III
DDQ
[4+2] Diel's-Alder
Cycloaddition
8
H
Protonated
formaldehyde
H transfer
DDQH
Knoevenagel-type
condensation
DDQ
O
O
O
O
O
O
HO
O
Ph
HO
O
O
O
Ph
HO
Ph
HO
O
O
Ph
HO
O
O
H
Ph
CN
H2O
-2DDQ-2H
DDQ
NC
O
OH
CN
CN
DDQH
CN
OH
Cl
O
O
O
OH
O
O
OH
VIII
O
HO
Cl
Cl
Cl
CN
CN
O
OH
CN
Cl
CN
CN
OH
Cl
Cl
Cl
CN
Cl
VI
OH
VII
OH
CN
V
Cl
O
IV
DDQ
Cl
Cl
OH
OH
DDQH
DDQH
DDQ-mediated oxidation
DDQH
CN
Cl
Cl
Cl
NC
Cl
Cl
Cl
O
O
OH
O
O
OH
HO
O
HO
O
O
O
Ph
HO
NC
O
HO
O
O
Ph
Cl
Cl
CN
CN
O
DDQ-2H
O
O
HO
O
Cl
CN
DDQ-2H
Ph
H
NC
Cl
CN
DDQH
CN
NC
DDQ
OH
11
O
OH
OH
OH
DDQH
IX
X
DDQ-mediated dehydrogenation
40 Figure 3 Plausible mechanism of one-pot multi-component synthesis of flavan 10c and flavone 11
Procedures for preparation of silica catalysts. (a). Silica-I2:16
Commercial iodine (1 g) and silica gel (#230–400) (1 g) were
taken in a culture tube and mixed thoroughly for 30 min. The
added silica gel (10 g, #230–400) at room temperature. The
solvent was evaporated under the reduced pressure and the
resulting yellow powder was kept in a closed container. (c).
45 prepared catalyst was kept in the closed tube. (b). Silica-FeCl3:17 50 Silica-HClO4:15 Perchloric acid (1.25 g, as a 70% aqueous
To a solution of FeCl3 6.H2O (1.2 g) in acetone (20 mL) was
solution) was added to the suspension of silica gel (23.75 g,
4
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#230–400) in Et2O. The mixture was concentrated and the residue
heated at 100 °C for 72 h under vacuum to afford HClO4–SiO2 as
a free flowing powder.
in dioxane (5 mL) at room temperature, under a nitrogen
atmosphere. This solution was then stirred at room temperature
for 12 hours, whereupon it turned into a yellow amorphous solid.
60 This solid mixture was cooled to 0 °C before being added to ice-
water slurry (~40 mL). The solution was allowed to slowly warm
to room temperature and stirring was continued for a further 4
hours, during which time a cream precipitate formed. This
precipitate was then filtered off and washed with more water, to
65 get 2,4-diformyl phloroglucinol 7d (1.22 g). Yield: 85%; cream
Procedure for determination of acidity of Silica-HClO4
catalyst. Acidity of the catalyst before and after use was
determined by CHEMBET-3000 TPD/TPR/TPO instrument,
containing a quartz reactor and TCD detector. Prior to TPD
studies, samples were pretreated at 250 oC for 2 h with
continuous flow of pure nitrogen (99.9%), then cooled to room
5
1
colored solid; mp. 218-220 °C; H NMR (CDCl3, 400 MHz): 
10 temperature. After pre-treatment, samples were saturated with
NH3 gas until saturated adsorption. Temperature increased to 80
oC and kept there for 2 h, while a helium flow of 20 cm3/min to
remove the physisorbed ammonia. Finally the system was heated
10.09 (s, 2H), 5.83 (s, 1H); ESI-MS: m/z 183 [M+1]+.20
General procedure for one-pot multi-component synthesis of
flavans 10a-k. To a solution of substituted phloroglucinol (7, 100
o
o
from 80 C to 1000 oC at the rate of 10 C/min and desorbed gas 70 mg) in acetonitrile were added formaldehyde (8, 3 equiv.),
15 monitored with TCD detector. All the flow rates were maintained
at normal temperature and pressure.
substituted styrene (9, 1.5 mmol) and Silica-HClO4 (50 %w/w).
The mixture was then refluxed at 80 °C for 1-6 h. Completion of
the reaction was monitored by TLC. After completion of reaction,
reaction mixture was cooled to room temperature and was filtered
75 through Whatman filter paper. Filtrate was concentrated on vacuo
rotavapor to get crude product. Crude products were purified by
silica gel (#100-200) column chromatography to get flavans 10a-
k in 35-92% yield.
Procedure for preparation of 1-acetylphloroglucinol (7b). A
solution of phloroglucinol (7a, 10 g, 79.36 mmol) and anhydrous
aluminum chloride (21.7 g, 237.9 mmol) in carbon disulphide
20 (100 mL) was stirred at room temperature for 20 min.
Nitrobenzene (150 mL) was added and temperature of the
reaction mixture was allowed to increase up to 50 °C. Acyl
chloride (18.6 mL, 237.9 mmol) was added and reaction mixture
Tris-(2-phenyl-2,3-dihydro benzopyran) (10a, Table 2, entry
was stirred further for 30 min. On cooling, reaction mixture was 80 1): 131 mg; Yield: 35%; white sticky solid; 1H NMR (CDCl3, 400
25 diluted with ethyl acetate. Water was added to the resultant
mixture leading to formation of white precipitate in aqueous
layer. Organic layer was decanted out and the remaining solid
residue was washed 5-6 times with ethyl acetate. The combined
MHz): δ 7.46-7.31 (m, 15H), 5.07-5.00 (m, 3H), 2.85 (m, 3H),
2.74 (m, 3H), 2.23 (m, 3H), 2.05 (m, 3H); 13C NMR (CDCl3, 100
MHz): δ 151.28, 151.18, 142.39, 142.32, 142.29, 128.38, 127.51,
125.79, 125.76, 102.17, 102.15, 77.42, 29.81, 29.79, 29.67,
ethyl acetate layer was evaporated under reduced pressure and the 85 19.45, 19.44, 19.36; IR (CHCl3): max 3451, 3030, 3064, 2925,
30 remaining viscous oil was purified by silica gel column
chromatography using hexane-EtOAc as eluent to yield
monoacetyl phloroglucinol 7b (9.5 g). Yield: 72%; cream colored
2852, 1732, 1614, 1496, 1443, 1310, 1218, 1126, 1085 cm-1; ESI-
MS: m/z 475 [M+1]+; HRMS: m/z 475.2266 calcd for
C33H30O3+H+ (475.2268).
1
solid; mp. 134-136 °C; H NMR (CD3OD, 400 MHz): δ 5.80 (s,
8-Acetyl-bis-(2-phenyl-2,3-dihydro benzopyran) (10b, Table 2,
90 entry 2): 123 mg; Yield: 52%; white sticky mass; 1H NMR
(CDCl3, 500 MHz): δ 14.23 (s, 1H), 7.39 (m, 10H), 5.09 (m, 2H),
2.80-2.69 (m, 4H), 2.57 (s, 3H), 2.32 (m, 2H), 2.02 (m, 2H); 13C
NMR (CDCl3, 125 MHz): δ 203.44, 162.37, 159.08, 155.99,
141.22, 141.12, 128.60, 128.55, 126.02, 125.71, 105.25, 102.20,
2H), 2.60 (s, 3H); ESI-MS: m/z 169 [M+1]+.19
35 General procedure for preparation of diacylphloroglucinols
7c and 7e. A solution of phloroglucinol (7a, 10 g, 79.36 mmol)
and acetic acid or isovaleric acid (3 equiv.) in BF3-etherate (100
mL) were refluxed at 100 C for 2.5 h. Reaction mixture was
cooled to room temperature, poured into crushed ice and 95 101.14, 78.78, 78.72, 33.47, 29.31, 29.12, 19.27, 18.59; IR
40 extracted with ethyl acetate (100 mL x 3). Combined organic
layers were evaporated on rotary evaporator. Crude product was
purified by silica gel (#100-200) column chromatography to get
diacyl phloroglucinols 7c (11.6 g) and 7e (17.2 g). 1,3-Diacetyl-
2,4,6-trihydroxy benzene (7c): Yield: 70%; cream colored solid;
(CHCl3): max 3450, 2927, 1615, 1424, 1369, 1276, 1131, 1105
cm-1; ESI-MS: m/z 401 [M+1]+; HRMS: m/z 401.1732 calcd for
C26H24O4+H+ (401.1753).
6,8-Diacetyl-5,7-dihydroxyflavan (10c, Table 2, entry 3): 130
100 mg; Yield: 84%; white crystalline solid; m.p. 101-103 °C; 1H
NMR (CDCl3, 500 MHz): δ 16.15 (s, 1H), 15.18 (s, 1H), 7.40 (m,
5H), 5.15 (dd, J = 2.3, 10.4 Hz, 1H), 2.76 (m, 1H), 2.72 (s, 3H),
2.66 (m, 1H), 2.53 (s, 3H), 2.24 (m, 1H), 2.02 (m, 1H); 13C NMR
(CDCl3, 125 MHz): δ 204.5, 203.4, 171.6, 170.9, 162.6, 140.0,
105 128.8, 128.5, 127.8, 125.8, 104.6, 103.9, 101.1, 79.99, 33.34,
33.10, 28.54, 18.49; IR (CHCl3): max 3400, 2924, 1615, 1423,
1364, 1169, 1105, 1024 cm-1; ESI-MS: m/z 327 [M+1]+; HRMS:
m/z 349.1045 calcd for C19H18O5+Na+ (349.1015).
1
45 mp. 172-174 ºC; H NMR (CD3OD, 400 MHz):  5.84 (s, 1H),
2.65 (s, 6H); ESI-MS: m/z 211 [M+1]+. 1,3-Di-(3-methyl-
butanoyl)-2,4,6-trihydroxy benzene (7e): Yield: 75%; yellow
1
solid; mp. 114-116 ºC; H NMR (CDCl3, 200 MHz):  5.85 (s,
1H), 2.99 (d, J = 6.7 Hz, 4H), 2.26 (m, 2H), 0.99 (d, J = 6.7 Hz,
50 12H); ESI-MS: m/z 295 [M+1]+.23
Procedure for preparation of 2,4-diformyl phloroglucinol
(7d). Phosphoryl chloride (1.6 mL, 16.7 mmol) was added drop-
wise to DMF (1.3 mL, 16.7 mmol) with strong stirring, at room
temperature under a nitrogen atmosphere. Stirring was continued
55 for 30 minutes. This Vilsmeier reagent was then slowly added to
a stirred solution of anhydrous phloroglucinol (7a, 1 g, 7.9 mmol)
6,8-Diformyl-5,7-dihydroxyflavan (10d, Table 2, entry 4): 124
1
110 mg; Yield: 76%; light yellow solid; m.p. 236-238 °C; H NMR
(CDCl3, 500 MHz): δ 13.51 (s, 1H), 13.30 (s, 1H), 10.19 (s, 1H),
10.07 (s, 1H), 7.39 (m, 5H), 5.22 (dd, J = 6.0, 15 Hz, 1H), 2.76
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(m, 1H), 2.66 (m, 1H), 2.31 (m, 1H), 2.04 (m, 1H); 13C NMR
(CDCl3, 125 MHz): δ 192.0, 191.9, 169.0, 168.0, 164.0, 139.6,
128.8, 128.5, 125.8, 104.1, 103.9, 101.2, 79.7, 28.3, 17.6; IR
(s, 1H), 7.44 (d, J = 6.8 Hz, 2H), 7.32 (d, J = 6.8 Hz, 2H), 5.16
(dd, J = 2.0, 10.0 Hz, 1H), 2.80 (m, 1H), 2.76 (s, 3H), 2.64 (m,
1H), 2.52 (s, 3H), 2.27 (m, 1H), 2.08 (m, 1H), 1.35 (s, 9H); 13C
(CHCl3): max 2924, 1640, 1442, 1305, 1154 cm-1; ESI-MS: m/z 60 NMR (CDCl3, 125 MHz): δ 204.4, 203.5, 170.0, 169.5, 162.7,
5
299 [M+1]+; HRMS: m/z 299.0888 calcd for C17H14O5+H+
(299.0918).
151.4, 136.9, 125.7, 125.6, 104.5, 103.9, 101.1, 79.8, 34.6, 33.4,
33.0, 31.3, 28.5, 18.5; IR (CHCl3): max 3401, 2961, 1615, 1424,
1364, 1292, 1169, 1104 cm-1; ESI-MS: m/z 383 [M+1]+, 405
[M+Na]+; HRMS: m/z 383.1882 calcd for C23H26O5+H+
65 (383.1853).
6,8-Di-(3-methylbutyryl)-5,7-dihydroxyflavan (10e, Table 2,
entry 5): 119 mg; Yield: 86%; light yellow solid; m.p. 117-119
1
°C; H NMR (CDCl3, 400 MHz): δ 16.39 (s, 1H), 15.37 (s, 1H),
10 7.42 (m, 5H), 5.09 (dd, J = 2.3, 10.7 Hz, 1H), 3.03 (d, J = 6.8 Hz,
2H), 2.82 (d, J = 6.7 Hz, 2H), 2.62 (m, 2H), 2.28 (m, 2H), 2.04
(m, 2H), 1.00 (d, J = 6.7 Hz, 6H), 0.72 (m, 6H); 13C NMR
(CDCl3, 100 MHz): δ 207.0, 206,0, 170.1, 169.7, 162.3, 139.8,
6,8-Diacetyl-3,4-dihydro-2-(naphthalen-1-yl)-2H-chromene-
5,7-diol (10j, Table 2, entry 10): 164 mg; Yield: 92%; white
1
crystalline solid; m.p. 161-163 °C; H NMR (CDCl3, 500 MHz):
δ 16.20 (s, 1H), 15.22 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.94 (d, J
128.7, 128.6, 126.4, 104.7, 103.8, 101.1, 80.2, 53.1, 53.0, 28.2, 70 = 6.6 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.0 Hz, 1H),
15 25.6, 25.1, 22.8, 22.7, 22.4, 22.3, 18.8; IR (CHCl3): max 3400,
2956, 2926, 1614, 1417, 1294, 1192, 1161, 1023 cm-1; ESI-MS:
m/z 411 [M+1]+; HRMS: m/z 411.2139 calcd for C25H30O5+H+
(411.2166).
7.58 (m, 3H), 5.91 (d, J = 10.4 Hz, 1H), 2.44 (m, 1H), 2.38 (m,
1H), 2.36 (s, 3H), 2.22 (s, 3H), 2.14 (m, 2H); 13C NMR (CDCl3,
100 MHz): δ 204.6, 203.5, 170.1, 169.6, 162.8, 135.2, 133.9,
130.3, 129.2, 129.1, 126.6, 125.9, 125.4, 123.6, 122.7, 104.7,
75 104.0, 101.3, 77.2, 33.2, 33.1, 27.5, 18.9; IR (CHCl3): max 3400,
2923, 2852, 1615, 1423, 1364, 1293, 1172, 1105 cm-1; ESI-MS:
m/z 377 [M+1]+, 399 [M+Na]+; HRMS: m/z 377.1384 calcd for
C23H20O5+H+ (377.1384).
6,8-Diacetyl-5,7-dihydroxy-4'-methyl-flavan (10f, Table 2,
20 entry 6): 148 mg; Yield: 92%; white crystalline solid; m.p. 157-
1
159 °C; H NMR (CDCl3, 400 MHz): δ 16.15 (s, 1H), 15.16 (s,
1H), 7.29-7.20 (m, 4H), 5.13 (dd, J = 2.0, 10.4 Hz, 1H), 2.81 (m,
1H), 2.78 (m, 1H), 2.64 (m, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.26
6,8-Diacetyl-3,4-dihydro-2-(3,4-methylene-dioxy-phenyl)-3-
(m, 1H), 2.07 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 204.5, 80 methyl-2H-chromene-5,7-diol (10k, Table 2, entry 11): 160 mg;
1
25 203.5, 170.0, 169.5, 162.7, 138.3, 137.0, 129.4, 126.1, 104.5,
103.9, 101.1, 79.9, 33.3, 33.1, 29.7, 28.5, 21.2, 18.6; IR (CHCl3):
Yield: 88%; white sticky solid; H NMR (CDCl3, 500 MHz): δ
16.12 (s, 1H), 15.16 (s, 1H), 6.85 (m, 3H), 6.01 (s, 2H), 4.59 (d, J
= 9.9 Hz, 1H), 2.93 (dd, J = 5.0, 14.5 Hz, 1H), 2.73 (s, 3H), 2.45
(s, 3H), 2.25 (dd, J = 11.2, 16.5 Hz, 1H), 2.08 (m, 1H), 0.89 (d, J
85 = 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 204.5 (-CO),
203.5 (-CO), 170.0 (C7), 169.2 (C5), 162.4 (C8a), 148.1 (C4’),
147.9 (C4'), 147.8 (C5'), 133.5 (C5'), 133.5 (C1'), 133.3 (C1'),
121.2 (C6'), 121.1 (C6'), 108.2 (C2'), 108.0 (C2'), 107.6 (C3'),
107.0 (C4a), 104.5 (C6), 103.7 (C8), 101.3 (O-CH2-O), 101.2
90 (O-CH2-O), 86.0 (C2), 85.8 (C2), 33.2 (COCH3), 33.1 (COCH3),
32.0 (C3), 27.2 (C4), 17.5 (CH-CH3); IR (CHCl3): max 2927,
1618, 1505, 1445, 1425, 1381, 1364, 1247, 1175, 1039 cm-1; ESI-
MS: m/z 385 [M+1]+; HRMS: m/z 385.1255 calcd for
C21H20O7+H+ (385.1282).

max 3400, 2921, 2851, 1620, 1591, 1422, 1365, 1169, 1109 cm-1;
ESI-MS: m/z 341 [M+1]+, 363 [M+Na]+; HRMS: m/z 341.1385
calcd for C20H20O5+H+ (341.1389).
30 6,8-Diformyl-5,7-dihydroxy-4'-methyl-flavan (10g, Table 2,
entry 7): 149 mg; Yield: 87%; white crystalline solid; m.p. 115-
1
117 °C; H NMR (CDCl3, 400 MHz): δ 13.49 (s, 1H), 13.30 (s,
1H), 10.19 (s, 1H), 10.06 (s, 1H), 7.28-7.22 (m, 4H), 5.18 (d, J =
10 Hz, 1H), 2.76 (m, 1H), 2.64 (m, 1H), 2.40 (s, 3H), 2.30 (m,
35 1H), 2.04 (m, 1H); 13C NMR (CDCl3, 125 MHz): δ 192.0, 191.8,
168.9, 168.0, 164.1, 138.4, 136.6, 129.4, 129.1, 125.8, 125.7,
104.0, 103.9, 101.2, 79.7, 28.2, 21.2, 17.6; IR (CHCl3): max
2924, 1643, 1443, 1306, 1272, 1182, 1154 cm-1; ESI-MS: m/z
313 [M+1]+, 335 [M+Na]+; HRMS: m/z 313.1072 calcd for 95 Synthesis of flavone 11 from flavan 10c. To the solution of 5,7-
40 C18H16O5+H+ (313.1076).
dihydroxy-6,8-diacetyl-flavan (10c, 100 mg, 0.306 mmol) in
dioxane (1% H2O) was added DDQ (0.278 mg, 1.2 mmol).
Resulting mixture was refluxed at 100 C for 16 h. Reaction
mixture was allowed to cool to room temperature and then
100 filtered through Whatman filter paper. Filtrate was concentrated
on vacuo rotavapor to get crude product, which on silica gel
(#100-200) column chromatography gave flavone 11 (78 mg) in
75% yield. 6,8-Diacetyl-5,7-dihydroxyflavone (11, Figure 2):
6,8-Di-(3-methyl-butyryl)-5,7-dihydroxy-4'-methyl-flavan
(10h, Table 2, entry 8): 132 mg; Yield: 92%; light greyish
1
crystalline solid; m.p. 100-102 °C; H NMR (CDCl3, 400 MHz):
δ 16.38 (s, 1H), 15.36 (s, 1H), 7.30 (d, J = 7.7 Hz, 2H), 7.23 (d, J
45 = 7.7 Hz, 2H), 5.07 (d, J = 10.5 Hz, 1H), 3.03 (d, J = 6.7 Hz, 2H),
2.84 (m, 2H), 2.68 (m, 2H), 2.38 (s, 3H), 2.16 (m, 2H), 2.06 (m,
2H), 0.99 (d, J = 6.2 Hz, 6H), 0.74 (d, J = 6.3 Hz, 3H), 0.70 (d, J
= 6.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 206.9, 206.0,
170.1, 169.6, 162.3, 138.4, 136.8, 129.3, 126.3, 104.6, 103.8,
50 101.1, 80.0, 53.1, 53.0, 28.2, 25.6, 25.0, 22.4, 22.3, 21.2, 18.8; IR
(CHCl3): max 2957, 2929, 2870, 1614, 1435, 1367, 1294, 1193,
1161, 1126 cm-1; ESI-MS: m/z 425 [M+1]+, 447 [M+Na]+;
HRMS: m/z 425.2323 calcd for C26H32O5+H+ (425.2323).
1
White sticky solid; H NMR (CDCl3, 400 MHz): δ 16.04 (s, 1H),
105 15.72 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.67 (m, 2H), 7.64 (t, J =
7.8 Hz, 2H), 2.94 (s, 3H), 2.82 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 205.9, 201.3, 182.6, 171.4, 167.9, 159.5, 151.4, 137.0,
133.0, 129.1, 128.7, 115.5, 110.9, 107.0, 100.6, 32.8, 30.9; IR
(CHCl3): max 3400, 2923, 2852, 1614, 1611, 1455, 1372, 1304,
110 1172 cm-1; ESI-MS: m/z 339 [M+1]+, 361 [M+Na]+; HRMS: m/z
339.0878 calcd for C19H14O6+H+ (339.0863).
6,8-Diacetyl-5,7-dihydroxy-4'-tert-butyl-flavan (10i, Table 2,
55 entry 9): 170 mg; Yield: 92%; light yellow crystalline solid; m.p.
119-121 °C; 1H NMR (CDCl3, 400 MHz): δ 16.15 (s, 1H), 15.16
6
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Procedure for one-pot synthesis of 6,8-diacetyl-5,7-
dihydroxyflavone (11) from phloroglucinol precursor 7. To
the solution of 2,4-diacetylphloroglucinol (7c, 100 mg, 0.476
mmol) in acetonitrile were added formaldehyde (8, 3 equiv.),
styrene (9a, 0.074 g, 0.714 mmol) and Silica-HClO4 (0.05 g, 50
%w/w). The mixture was then refluxed at 80 °C for 1.5 h.
Completion of the reaction was monitored by TLC. After
completion of reaction, acetonitrile was evaporated on vacuo
rotavapor to dryness. Dioxane (5 mL), water (10 L, 5% of
10 dioxane) and DDQ (0.649 g, 2.856 mmol) was then added to the
dry reaction mixture and was refluxed at 100 °C for 16 h.
Reaction mixture was allowed to cool to room temperature and
then filtered through whatman filter paper. Filtrate was
concentrated on vacuo rotavapor to get crude product, which on
15 silica gel (#100-200) column chromatography gave flavone 11
(104 mg) in 65% yield.
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acetonitrile (10 mL) were added formaldehyde (8, 3 equiv.),
20 styrene (9, 3.57 mmol) and Silica-HClO4 (250 mg, 50 %w/w).
The mixture was then refluxed at 80 °C for 1.5 h. After
completion of reaction, catalyst was recovered by filtration
followed by washing with acetonitrile. Recovered catalyst was
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25 3 times and the amount of catalyst recovered and percentage yield
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Acknowledgements
RM, SB and RRY thanks CSIR and NB thanks UGC for award of
Junior Research Fellowship. Authors are thankful to analytical
30 department, IIIM for NMR, MS and IR analysis of our
compounds.
17. M. Nasrollahzadeh, Y. Bayat, D. Habibi and S. Moshaee,
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