Mild and efficient one-pot synthesis of diverse flavanone derivatives via an organocatalyzed Mannich-type reaction

Article abstract of DOI:10.1055/s-0033-1340466

A facile ethylenediamine diacetate (EDDA)-catalyzed one-pot synthesis of biologically interesting flavanone derivatives from 2-hydroxyacetophenones, aromatic aldehydes, and aniline via a Mannich-type reaction is described. This synthetic method provides a rapid access to biologically interesting flavanone derivatives. To demonstrate this method, several biologically interesting natural products bearing a flavanone moiety were synthesized as racemates.

Full text of DOI:10.1055/s-0033-1340466

PAPER
▌465
paper
Mild and Efficient One-Pot Synthesis of Diverse Flavanone Derivatives via an
Organocatalyzed Mannich-Type Reaction
One-Pot Synthesis of Diverse Flavanone Derivatives
Srinivasu V. N. Vuppalapati, Likai Xia, Naushad Edayadulla, Yong Rok Lee*
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, South Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
Received: 26.10.2013; Accepted after revision: 25.11.2013
methylsticum10 and Combretaceae apiculatum,11 Miliusa
Abstract: A facile ethylenediamine diacetate (EDDA)-catalyzed
sinensis,12 Piper porphyrophyllum,13 Chloranthus elati-
one-pot synthesis of biologically interesting flavanone derivatives
or,14 and Otochilus fuscus.15 These compounds exhibited
antimicrobial, antibacterial, antifungal, antiviral, aniplas-
from 2-hydroxyacetophenones, aromatic aldehydes, and aniline via
a Mannich-type reaction is described. This synthetic method pro-
vides a rapid access to biologically interesting flavanone deriva- modial, antioxidant, anticancer, and anti-inflammatory
activities.16
tives. To demonstrate this method, several biologically interesting
natural products bearing a flavanone moiety were synthesized as
racemates.
Pinocembrin (6) was isolated from Penicillium italicum,17
Combretum apiculatum,18 and Boesenbergia pandurata,19
Key words: aldehydes, ketones, Mannich bases, Michael addition,
cycloaddition
and found to exhibit antifungal, antioxidant, antibacterial,
antimicrobial, anti-adhesion, antituberculosis, anti-aggre-
gatory, anti-inflammatory, and antitumor activities.20
Strobopinin (7) and its isomer cryptostrobin (8) were iso-
Flavanones (chroman-4-ones) are an abundant subclass of
lated from Melaleuca quinquenervia,21 and they displayed
flavonoids, which are widely distributed in nature as race-
antioxidant, antimalarial, antifungal, antimycobacterial,
mates and chiral forms (Figure 1).1 Flavanones have re-
anti-inflammatory, antitumoral, and antiplasmodial activ-
ceived considerable attention due to their favorable
ities.22 In addition, they were found to inhibit novel influ-
pharmacological properties, which include antioxidant,
enza A(H1N1)23 and P2Y2 receptor antagonists24 and to
antitumor, antileukemia, anti-allergic, antiproliferative,
have immunomodulatory effects.25
cytoprotective, antifungal, and antibacterial activities.2
The general method used to synthesize flavanones in-
volves the cyclization of the appropriately substituted 2-
hydroxychalcones, prepared by aldol condensation be-
tween 2-hydroxyacetophenones and aldehydes. This cy-
clization has been carried out under several conditions
using acids,26 bases,27 photochemical,28 and electrochem-
ical reactions.29 Other alternative approaches to the syn-
theses of flavanones include the oxidation of flavan-4-
ol,30 the transformation of phenylalkenyl aryl ethers in the
presence of Hg(OCOCF3)2,31 the intramolecular oxa-
Michael addition of activated α,β-unsaturated ketones,32
Julia–Kocienski olefination of 2-(benzo[d]thiazol-2-yl-
sulfonyl)-1-phenylethanones with aldehydes in the pres-
ence of a base,33 intermolecular C–O addition of
They also display important biological activities as
tyrosinase3 and aldose reductase inhibitors,4 and as non-
steroidal inhibitors of human aromatase.5 The flavanones
also serve as important intermediates or precursors in the
syntheses of many biologically active natural products.6
Among these, 7-methoxyflavanone (1) and 4′,7-dimeth-
oxyflavanone (2), isolated from Ixeridium gracile7 and
Terminalia fagifolia,8 respectively, exhibited potent anti-
proliferative, anticarcinogenic, anticancer, antioxidative,
and antituberculosis activities.9 5,7-Dimethoxyflavanone
(3), pinostrobin (4) (5-hydroxy-7-methoxyflavanone),
and 5-hydroxy-4′,7-dimethoxyflavanone (5) (4′,7-di-O-
methylnaringenin)
were
isolated
from
Piper
R1
O
O
OH
O
R1
MeO
HO
O
R2
R2
7-methoxyflavanone (1) R1 = R2 = H
pinocembrin (6) R1 = R2 = H
strobopinin (7) R1 = Me, R2 = H
cryptostrobin (8) R1 = H, R2 = Me
4',7-dimethoxyflavanone (2) R1 = H, R2 = OMe
5,7-dimethoxyflavanone (3) R1 = OMe, R2 = H
pinostrobin (4) R1 = OH, R2 = H
5-hydroxy-4',7-dimethoxyflavanone (5) R1 = OH, R2 = OMe
Figure 1 Selected naturally occurring flavanones 1–8
SYNTHESIS 2014, 46, 0465–0474
Advanced online publication: 16.12.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340466; Art ID: SS-2013-F0705-OP
© Georg Thieme Verlag Stuttgart · New York

466
S. V. Vuppalapati et al.
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O
O
O
CHO
NH2
EDDA
MeOH
R1
+
R1
+
OH
R2
R2
Scheme 1 EDDA-catalyzed synthesis of flavanone derivatives
carboxylic acids to arynes,34 and intramolecular dehydra- tron-donating and electron-withdrawing groups on the
tion of 3-hydroxy-1-(2-hydroxyphenyl)-3-arylpropan-1- benzene ring were conducted under optimized reaction
ones.35
conditions. The results obtained are summarized in Table
2.
Although a number of methods have been reported for the
synthesis of flavanone derivatives, there is still a need for
generally applicable, facile synthetic methods that can
produce various flavanone derivatives using milder cata-
lysts. Recently, Yao et al. reported the synthesis of flava-
none derivatives under mild reaction conditions using an
iodine-catalyzed Mannich-type reaction.36 This reaction is
important for carbon–carbon bond formation, and a valu-
able tool for constructing a diverse array of pharmaceuti-
cally useful natural and synthetic products.37 We report
herein a mild, facile one-pot synthesis of a variety of bio-
logically interesting diverse flavanone derivatives using
ethylenediamine diacetate (EDDA) as a mild organocata-
lyst (Scheme 1).
The reaction of 2-hydroxyacetophenone (9a) with aniline
and 3-methoxybenzaldehyde (10b) or 2,5-dimethylbenz-
Table 1 Catalyst and Solvent Effects for the Synthesis of Flavanone
12a
O
OH
9a
O
+
catalyst
(20 mol%)
CHO
solvent
O
Organocatalysts act as efficient and convenient catalysts
for a variety of synthetically useful reactions.38 In a previ-
ous study, we described a new method for synthesizing a
variety of benzopyrans using EDDA as effective organo-
catalysts.39 As part of our ongoing study into the synthetic
efficiency of EDDA as a catalyst for the development of
novel organic reactions, we have now examined the
EDDA-catalyzed reactions of 2-hydroxyacetophenones
with aldehydes and aniline to afford flavanone derivatives
via a Mannich-type reaction.
10a
+
12a
NH2
11
Entry Catalyst
Solvent
Conditions
Yield
(%)
1
2
3
4
5
6
7
8
9
CAN
MeOH
MeOH
MeOH
MeOH
MeOH
PhF
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
46
35
29
trace
0
Initially, the reaction of 2-hydroxyacetophenone (9a) (1.0
mmol) with benzaldehyde (10a) (1.2 mmol) and aniline
(11) (1.2 mmol) was examined in the presence of several
catalysts (20 mol%), namely, ceric(IV) ammonium nitrate
(CAN), InCl3, In(OTf)3, Yb(OTf)3, RhCl2(PPh3)3, EDDA,
or other ammonium and pyridinium salts in different sol-
vents (Table 1). The best yield (82%) was obtained in the
presence of 20 mol% of EDDA at 40 °C for 12 hours in
MeOH (Table 1, entry 10). Importantly, EDDA showed
superiority to other ammonium and pyridinium salts, such
as ethylenediamine dihydrochloride, ammonium acetate,
piperidine hydrochloride, pyridine hydrochloride, and
InCl3
In(OTf)3
Yb(OTf)3
RhCl2(PPh3)3
EDDA
20
65
48
56
82
60
55
65
trace
30
15
EDDA
1,4-dioxane 40 °C, 12 h
EDDA
EtOH
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
40 °C, 12 h
EDDA
DMSO
MeOH
MeOH
pyridinium p-toluenesulfonate (PPTS) in terms of yields 10
(entries 12–16). The synthesized compound 12a was iden-
EDDA
11
ethylenediamine
tified by analyzing the spectral data in comparison with
the reported data.36 Interestingly, the reaction of 9a and 12
ethylenediamine·2 HCl MeOH
benzaldehyde (10a) in the absence of aniline in 20 mol%
of EDDA at 40 °C for 24 hours did not produce the de-
sired product.
13
NH4OAc
MeOH
MeOH
MeOH
MeOH
14
15
16
piperidine·HCl
pyridine·HCl
PPTS
To explore the generality of this transformation, addition-
al reactions of several 2-hydroxyacetophenones 9a–c with
aniline (11) and aromatic aldehydes 10a–j bearing elec-
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One-Pot Synthesis of Diverse Flavanone Derivatives
467
aldehyde (10c) in the presence of 20 mol% of EDDA at 12f and 12g in 71 and 60% yield, respectively (entries 5,
40 °C for 12 hours in methanol produced the desired prod- 6). Similarly, reactions of 2-hydroxy-5-methylacetophe-
ucts 12b (79%) and 12c (69%), respectively (Table 2, en- none (9b) with aniline and aromatic aldehydes afforded
tries 1, 2). Treatment of 9a with 4-bromobenzaldehyde the products 12h–o in 52–87% yields (entries 7–14). Fi-
(10d) or 4-chlorobenzaldehyde (10e) afforded the cyclo- nally, reactions of 2-hydroxy-4-methoxyacetophenone
adducts 12d and 12e in 74 and 80% yield, respectively (9c) with aromatic aldehydes 10b,d–f produced 12p–s in
(entries 3, 4). Reaction with 2-naphthaldeyde (10f) or 5- 61–72% yields (entries 15–18).
methylfurfural (10g) produced the desired cycloadducts
Table 2 Additional Reactions for the Synthesis of a Variety of Flavanones 12b–sa
Entry
Acetophenone
Arylaldehyde
Time
(h)
Product
Yield
(%)b
O
O
CHO
1
9a
10b
12
12b
79
OMe
O
O
OH
OMe
CHO
2
3
4
5
10c
10d
10e
10f
12
12
12
12
12c
12d
12e
12f
69
74
80
71
O
O
CHO
O
O
Br
Br
Cl
CHO
O
O
Cl
CHO
O
O
6
10g
15
12g
60
CHO
O
O
O
O
O
CHO
7
8
9b
10a
10h
12
12
12h
12i
70
71
O
O
OH
CHO
O
MeO
OMe
© Georg Thieme Verlag Stuttgart · New York
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S. V. Vuppalapati et al.
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Table 2 Additional Reactions for the Synthesis of a Variety of Flavanones 12b–sa (continued)
Entry
Acetophenone
Arylaldehyde
Time
(h)
Product
Yield
(%)b
O
CHO
9
10d
15
12
12j
60
74
O
O
Br
Br
CHO
Cl
Cl
10
11
10i
12k
12l
O
O
CHO
10e
12
68
O
O
Cl
Cl
CHO
12
13
10j
10f
12
15
12m
12n
87
65
O
O
CHO
O
O
14
15
10g
10b
12
12
12o
12p
52
72
CHO
O
O
O
O
O
CHO
O
9c
MeO
OMe
MeO
OH
OMe
O
CHO
CHO
16
17
10d
10e
12
15
12q
12r
61
63
MeO
MeO
O
O
Br
Cl
Br
Cl
O
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Table 2 Additional Reactions for the Synthesis of a Variety of Flavanones 12b–sa (continued)
Entry
18
Acetophenone
Arylaldehyde
Time
(h)
Product
Yield
(%)b
O
O
CHO
10f
12
12s
67
MeO
a The reaction was carried out using 9 (1.0 mmol), 10 (1.2 mmol), aniline (11; 1.2 mmol), and EDDA catalyst (0.2 mmol) in a MeOH (2.0 mL)
at 40 °C.
b Isolated yield.
The formation of 12a can be explained by the mechanism In summary, an efficient one-pot synthesis of biologically
proposed in Scheme 2. The carbonyl group of benzalde- interesting flavanone derivatives from reactions of 2-hy-
hyde (10a) could be protonated by EDDA, which could droxyacetophenones with aromatic aldehydes and aniline
facilitate the formation of an iminium ion 14. The enol using EDDA as an organocatalyst is described. This meth-
form 15, generated from 2-hydroxyacetophenone (9a), in od has the advantages of mild reaction conditions, use of
the presence of EDDA, could attack the iminium ion 14 to an inexpensive nonmetal catalyst, simple experimentation
give intermediate 16, which could undergo cycloaddition requirements, and good yields. Furthermore, this method
to form the flavanone 12a via an intramolecular SN2 reac- was used to synthesize the naturally occurring materials,
tion. Importantly, when aniline was not used, the reaction 7-methoxyflavanone (1), 4′,7-dimethoxyflavanone (2),
did not proceed. This suggests no pathway via a direct al- and 5,7-dimethoxyflavanone (3).
dol reaction followed by next 1,4-Michael-type cycload-
dition of the hydroxyl group to give product 12a.
All the experiments were carried out under N2 atmosphere. Merck
precoated silica gel plates (Art. 5554) with a fluorescent indicator
As an application of this method, one-step synthesis of
naturally occurring 7-methoxyflavanone (1) 4′,7-dimeth-
oxyflavanone (2), and 5,7-dimethoxyflavanone (3) as ra-
cemates was conducted as shown in Scheme 3. Reaction
were used for analytical TLC. Flash column chromatography was
1
performed using silica gel 9385 (Merck). H NMR and 13C NMR
spectra were recorded on a Bruker Model ARX (300 and 75 MHz,
respectively) spectrometer in CDCl3 as the solvent. IR spectra were
of 9c with benzaldehyde (10a) and aniline (11) in the pres-
ence of 20 mol% of EDDA at 40 °C for 12 hours in meth-
anol provided 7-methoxyflavanone (1) in 62% yield,
whereas reaction with 4-methoxybenzaldehyde (10h) af-
forded 4′,7-dimethoxyflavanone (2) in 59% yield. Simi-
larly, treatment of 9d with benzaldehyde (10a) and aniline
(11) in the presence of 20 mol% of EDDA at 40 °C for 12
hours in methanol afforded 5,7-dimethoxyflavanone (3)
in 55% yield. The spectral data of synthesized compounds
1–3 concurred well with the reported values.7,8,11
recorded on a Jasco FTIR 5300 spectrophotometer. Melting point
was measured with a Fisher-Johns melting point apparatus and are
uncorrected. HRMS were carried out at the Korea Basic Science In-
stitute.
Flavanone Derivatives; General Procedure
To a solution of 2-hydroxyacetophenone 9 (1.0 mmol), aldehyde 10
(1.2 mmol), and aniline (11; 112 mg, 1.2 mmol) in MeOH (2 mL)
was added EDDA (20 mol%) and the reaction mixture was heated
at 40 °C for 12–15 h under N2 atmosphere. After completion of the
reaction, solvent was evaporated under reduced pressure, and the
NH2
+OH
O
EDDA
11
+
NH
H
H
O
HN
14
13
10a
O
OH
OH
16
EDDA
intramolecular SN2 reaction
O
EDDA
OH
OH
NH2
9a
15
+
11
O
12a
Scheme 2 Proposed mechanism for the formation of flavanone 12a
© Georg Thieme Verlag Stuttgart · New York
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470
S. V. Vuppalapati et al.
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O
O
H
H
R
O
O
O
O
MeO
10a
10h
MeO
OH
aniline
MeOH
MeO
MeO
O
aniline
MeOH
EDDA
9c R = H
9d R = OMe
EDDA
OMe
40 °C, 12 h
40 °C, 12 h
1
2
7-methoxyflavanone
4',7-dimethoxyflavanone
O
aniline
MeOH
EDDA
40 °C, 12 h
H
10a
OMe
O
MeO
O
3
5,7-dimethoxyflavanone
Scheme 3 Applications in natural product synthesis
residue was purified by column chromatography on silica gel with
EtOAc–hexane gradient as eluent to give the desired pure product.
HRMS (EI): m/z calcd for C17H16O2: 252.1150; found: 252.1149.
2-(4-Bromophenyl)chroman-4-one (12d)
Yield: 223 mg (74%); colorless solid; mp 114–115 °C.
IR (KBr): 2930, 1685, 1566, 1465, 1300, 1230, 1050, 906 cm–1.
2-Phenylchroman-4-one (12a)
Yield: 184 mg (82%); colorless solid; mp 107–108 °C.
IR (KBr): 3064, 2899, 1689, 1605, 1462, 1303, 1225, 1147, 1110,
1064, 974, 904 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (dd, J = 8.1, 1.5 Hz, 1 H),
7.52–7.37 (m, 6 H), 7.06–7.02 (m, 2 H), 5.49 (dd, J = 13.2, 3.0 Hz,
1 H), 3.09 (dd, J = 16.8, 13.2 Hz, 1 H), 2.90 (dd, J = 16.8, 3.0 Hz, 1
H).
1H NMR (300 MHz, CDCl3): δ = 7.80 (dd, J = 8.1, 1.5 Hz, 1 H),
7.43–7.34 (m, 3 H), 7.21 (d, J = 8.4 Hz, 2 H), 6.94–6.90 (m, 2 H),
5.31 (dd, J = 12.6, 3.0 Hz, 1 H), 2.88 (dd, J = 16.5, 12.9 Hz, 1 H),
2.75 (dd, J = 16.8, 3.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 191.5, 161.1, 137.6, 136.0, 131.8,
127.6, 126.9, 122.5, 121.6, 120.7, 117.9, 78.6, 44.3.
13C NMR (75 MHz, CDCl3): δ = 191.9, 161.5, 138.7, 136.1, 128.8,
128.7, 127.0, 126.1, 121.6, 120.9, 118.1, 79.5, 44.6.
HRMS (EI): m/z calcd for C15H11BrO2: 301.9942; found: 301.9940.
2-(4-Cholophenyl)chroman-4-one (12e)
Yield: 206 mg (80%); colorless solid; mp 92–94 °C.
HRMS (EI): m/z calcd for C15H12O2: 224.0837; found: 224.0835.
IR (KBr): 2988, 1685, 1462, 1374, 1241, 1051, 905 cm–1.
2-(3-Methoxyphenyl)chroman-4-one (12b)
Yield: 201 mg (79%); colorless solid; mp 111–113 °C.
1H NMR (300 MHz, CDCl3): δ = 7.92 (dd, J = 7.5, 0.9 Hz, 1 H),
7.53–7.47 (m, 1 H), 7.43–7.37 (m, 4 H), 7.07–7.02 (m, 2 H), 5.46
(dd, J = 12.9, 2.4 Hz, 1 H), 3.04 (dd, J = 17.1, 12.9 Hz, 1 H), 2.88
(dd, J = 16.8, 3.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 191.4, 161.2, 137.2, 136.2, 134.5,
128.9, 127.4, 127.0, 121.7, 120.8, 118.0, 78.7, 44.5.
IR (KBr): 3058, 2891, 1691, 1602, 1576, 1461, 1371, 1303, 1226,
907 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (dd, J = 7.5, 0.9 Hz, 1 H),
7.52–7.46 (m, 1 H), 7.36–7.30 (m, 1 H), 7.06–7.02 (m, 4 H), 6.92–
6.88 (m, 1 H), 5.46 (dd, J = 13.2, 2.7 Hz, 1 H), 3.83 (s, 3 H), 3.07
(dd, J = 16.8, 13.2 Hz, 1 H), 2.84 (dd, J = 16.8, 3.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 192.0, 161.6, 160.1, 140.4, 136.3,
130.1, 127.2, 121.8, 121.1, 118.5, 118.3, 114.2, 112.0, 79.6, 55.4,
44.8.
HRMS (EI): m/z calcd for C15H11ClO2: 258.0448; found: 258.0446.
2-(Naphthalen-2-yl)chroman-4-one (12f)
Yield: 195 mg (71%); colorless solid; mp 121–123 °C.
HRMS (EI): m/z calcd for C16H14O3: 254.0943; found: 254.0942.
IR (KBr): 2893, 1607, 1574, 1462, 1396, 1342, 1300, 1221, 1028,
907 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 7.8 Hz, 1 H), 7.76–
7.70 (m, 4 H), 7.43–7.33 (m, 4 H), 6.95–6.88 (m, 2 H), 5.47 (dd,
J = 12.9, 3.0 Hz, 1 H), 3.01 (dd, J = 17.1, 13.2 Hz, 1 H), 2.84 (dd,
J = 16.5, 2.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 191.5, 161.5, 136.1, 136.0, 133.3,
133.1, 128.6, 128.0, 127.6, 127.0, 126.4, 125.3, 123.6, 121.5, 121.0,
118.0, 115.0, 79.5, 44.5.
2-(2,5-Dimethylphenyl)chroman-4-one (12c)
Yield: 174 mg (69%) ; colorless solid; mp 102–104 °C.
IR (KBr): 3022, 2911, 1696, 1605, 1461, 1374, 1305, 1064, 880
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.83 (dd, J = 8.1, 1.8 Hz, 1 H),
7.35 (td, J = 8.4, 1.8 Hz, 1 H), 7.28 (s, 1 H), 6.98 (s, 2 H), 6.96–6.88
(m, 2 H), 5.52 (dd, J = 13.8, 2.7 Hz, 1 H), 2.92 (dd, J = 17.1, 13.8
Hz, 1 H), 2.69 (dd, J = 17.1, 2.7 Hz, 1 H), 2.24 (s, 3 H), 2.19 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.2, 161.9, 136.6, 136.1, 136.1,
131.9, 130.8, 129.3, 127.2, 126.4, 121.6, 121.0, 118.1, 77.6, 43.7,
21.2, 18.6.
HRMS (EI): m/z calcd for C19H14O2: 274.0994; found: 274.0992.
2-(5-Methylfuran-2-yl)chroman-4-one (12g)
Yield: 137 mg (60%); yellow solid; mp 124–126 °C.
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471
IR (KBr): 2892, 1691, 1605, 1466, 1307, 1226, 1151, 1097, 886
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.84–7.81 (m, 1 H), 7.43–7.36 (m,
1 H), 6.97–6.92 (m, 2 H), 6.24 (d, J = 3.0 Hz, 1 H), 5.90–5.88 (m, 1
H), 5.39 (dd, J = 11.7, 3.3 Hz, 1 H), 3.19 (ddd, J = 16.8, 12.0, 0.6
Hz, 1 H), 2.87 (ddd, J = 17.1, 3.6, 0.9 Hz, 1 H), 2.23 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.60 (s, 1 H), 7.29–7.21 (m, 4 H),
7.19 (d, J = 8.1 Hz, 1 H), 6.82 (d, J = 8.1 Hz, 1 H), 5.28 (dd, J =
12.6, 2.4 Hz, 1 H), 2.88 (dd, J = 16.5, 13.2 Hz, 1 H), 2.70 (dd, J =
16.5, 2.4 Hz, 1 H), 2.21 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 191.5, 159.2, 137.3, 137.2, 134.3,
131.1, 128.8, 127.3, 126.5, 120.3, 117.7, 78.6, 44.4, 20.3.
13C NMR (75 MHz, CDCl3): δ = 191.5, 160.8, 153.4, 148.9, 136.1,
HRMS (EI): m/z calcd for C16H13ClO2: 272.0604; found: 272.0604.
126.8, 121.5, 120.8, 118.1, 110.4, 106.4, 72.3, 40.7, 13.5.
6-Methyl-1-(naphthalen-1-yl)chroman-4-one (12m)
Yield: 251 mg (87%); white solid; mp 138–140 °C.
HRMS (EI): m/z calcd for C14H12O3: 228.0786; found: 228.0787.
IR (KBr): 3050, 2921, 1690, 1612, 1487, 1416, 1287, 1226, 1053,
978, 904 cm–1.
6-Methyl-2-phenylchroman-4-one (12h)
Yield: 167 mg (70%); light yellow solid; mp 106–108 °C.
IR (KBr): 3033, 2916, 1695, 1612, 1489, 1417, 1370, 1289, 1226,
1057, 993, 911 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.55 (s, 1 H), 7.29–7.20 (m, 5 H),
7.11 (d, J = 7.8 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 5.21 (d, J = 12.3
Hz, 1 H), 2.84 (dd, J = 16.8, 13.2 Hz, 1 H), 2.64 (d, J = 16.8 Hz, 1
H), 2.14 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.89–7.86 (m, 1 H), 7.75–7.69 (m,
2 H), 7.65–7.58 (m, 2 H), 7.39–7.34 (m, 3 H), 7.17 (dd, J = 8.4, 2.1
Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.01 (dd, J = 13.2, 3.0 Hz, 1 H),
3.06 (dd, J = 17.1, 13.2 Hz, 1 H), 2.91 (dd, J = 17.1, 3.0 Hz, 1 H),
2.19 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.2, 159.6, 137.1, 134.1, 133.7,
131.0, 130.0, 129.1, 128.9, 126.5, 126.5, 125.8, 125.2, 123.6, 122.7,
120.5, 117.8, 76.5, 43.8, 20.3.
13C NMR (75 MHz, CDCl3): δ = 191.7, 159.3, 138.7, 136.9, 130.7,
128.5, 128.4, 126.3, 125.9, 120.3, 117.6, 79.2, 44.3, 20.1.
HRMS (EI): m/z calcd for C20H16O2: 288.1150; found: 288.1151.
HRMS (EI): m/z calcd for C16H14O2: 238.0994; found: 238.0993.
6-Methyl-2-(naphthalen-2-yl)chroman-4-one (12n)
Yield: 187 mg (65%); colorless solid; mp 129–131 °C.
2-(4-Methoxyphenyl)-6-methylchroman-4-one (12i)
Yield: 190 mg (71%); colorless solid; mp 108–110 °C.
IR (KBr): 3052, 2915, 1691, 1614, 1483, 1416, 1288, 1219, 1128,
1058, 1001, 907 cm–1.
IR (KBr): 2923, 1687, 1611, 1482, 1460, 1286, 1222, 1174, 1120,
1030, 906 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.58 (s, 1 H), 7.25 (d, J = 7.8 Hz,
2 H), 7.15 (d, J = 8.4 Hz, 1 H), 6.83–6.79 (m, 3 H), 5.21 (d, J = 12.9
Hz, 1 H), 3.69 (s, 3 H), 2.92 (dd, J = 16.2, 13.2 Hz, 1 H), 2.66 (d,
J = 16.2 Hz, 1 H), 2.18 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.81–7.75 (m, 4 H), 7.64 (s, 1 H),
7.46 (d, J = 8.7 Hz, 1 H), 7.42–7.39 (m, 2 H), 7.21 (d, J = 8.4 Hz, 1
H), 6.87 (d, J = 8.4 Hz, 1 H), 5.50 (dd, J = 12.9, 2.4 Hz, 1 H), 3.05
(dd, J = 16.8, 12.9 Hz, 1 H), 2.86 (dd, J = 16.8, 2.7 Hz, 1 H), 2.23
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.0, 159.5, 137.2, 136.1, 133.2,
133.1, 131.0, 128.6, 128.0, 127.6, 126.5, 126.4, 125.3, 123.6, 120.5,
117.5, 79.5, 44.6, 20.3.
13C NMR (75 MHz, CDCl3): δ = 192.2, 159.7, 159.5, 137.0, 130.7,
130.7, 127.5, 126.3, 120.3, 117.7, 113.9, 79.0, 55.1, 44.2, 20.2.
HRMS (EI): m/z calcd for C17H16O3: 268.1099; found: 268.1096.
HRMS (EI): m/z calcd for C20H16O2: 288.1150; found: 288.1153.
2-(4-Bromophenyl)-6-methylchroman-4-one (12j)
Yield: 190 mg (60%); brown solid; mp 120–121 °C.
6-Methyl-2-(5-methylfuran-2-yl)chroman-4-one (12o)
Yield: 126 mg (52%); yellow solid; mp 111–113 °C.
IR (KBr): 2913, 1692, 1612, 1488, 1415, 1291, 1225, 1164, 1064,
1005, 905 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.59 (s, 1 H), 7.42 (d, J = 8.1 Hz,
2 H), 7.25–7.19 (m, 3 H), 6.82 (d, J = 8.4 Hz, 1 H), 5.30 (dd, J =
12.9, 2.7 Hz, 1 H), 2.89 (dd, J = 16.8, 13.2 Hz, 1 H), 2.75 (dd, J =
16.5, 3.0 Hz, 1 H), 2.21 (s, 3 H).
IR (KBr): 2916, 1636, 1560, 1489, 1364, 1295, 1183, 1016, 822
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 1.2 Hz, 1 H), 7.22–
7.18 (m, 1 H), 6.81 (d, J = 8.1 Hz, 1 H), 6.23 (d, J = 3.0 Hz, 1 H),
5.89–5.88 (m, 1 H), 5.35 (dd, J = 11.7, 3.3 Hz, 1 H), 3.16 (ddd, J =
16.8, 11.7, 1.2 Hz, 1 H), 2.83 (ddd, J = 16.8, 3.3, 1.2 Hz, 1 H), 2.22
(s, 3 H), 2.21 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 191.5, 159.2, 137.8, 137.2, 131.8,
131.1, 127.6, 126.5, 122.4, 120.3, 117.7, 78.6, 44.4, 20.3.
13C NMR (75 MHz, CDCl3): δ = 191.7, 158.8, 153.3, 149.0, 137.1,
HRMS (EI): m/z calcd for C16H13BrO2: 316.0099; found: 316.0095.
130.9, 126.4, 120.4, 117.8, 110.2, 106.4, 72.2, 40.7, 20.3, 13.5.
2-(2-Chlorophenyl)-6-methylchroman-4-one (12k)
Yield: 201 mg (74%); light yellow solid; mp 94–96 °C.
HRMS (EI): m/z calcd for C15H14O3: 242.0943; found: 242.0944.
IR (KBr): 2920, 1691, 1618, 1489, 1422, 1364, 1290, 1226, 1133,
1061, 1003, 911, 823, 758 cm–1.
7-Methoxy-2-(3-methoxyphenyl)chroman-4-one (12p)
Yield: 205 mg (72%); white solid; mp 101–103 °C.
1H NMR (300 MHz, CDCl3): δ = 7.62 (s, 2 H), 7.28–7.15 (m, 4 H),
6.83 (d, J = 8.1 Hz, 1 H), 5.72 (dd, J = 13.2, 2.7 Hz, 1 H), 2.86 (dd,
J = 16.8, 2.7 Hz, 1 H), 2.72 (dd, J = 17.1, 13.5 Hz, 1 H), 2.21 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ = 191.5, 159.4, 137.1, 136.7, 131.4,
131.1, 129.5, 129.4, 127.2, 127.1, 126.5, 120.4, 117.7, 76.3, 43.3,
20.3.
IR (KBr): 2994, 1697, 1609, 1444, 1251, 1159, 1055 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.74 (dd, J = 8.7, 2.4 Hz, 1 H),
7.20 (td, J = 8.1, 2.1 Hz, 1 H), 6.91 (s, 2 H), 6.79 (d, J = 8.1 Hz, 1
H), 6.48 (dt, J = 8.7, 2.1 Hz, 1 H), 6.36 (s, 1 H), 5.30 (dd, J = 13.2,
3.0 Hz, 1 H), 3.69 (s, 6 H), 2.87 (ddd, J = 16.5, 13.2, 2.7 Hz, 1 H),
2.70 (ddd, J = 16.5, 3.0, 2.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 190.1, 165.9, 163.2, 159.7, 140.2,
129.7, 128.5, 118.1, 114.6, 113.8, 111.7, 110.0, 100.7, 79.6, 55.4,
55.0, 44.1.
HRMS (EI): m/z calcd for C16H13ClO2: 272.0604; found: 272.0602.
2-(4-Chlorophenyl)-6-methylchroman-4-one (12l)
Yield: 185 mg (68%); light yellow solid; mp 129–130 °C.
HRMS (EI): m/z calcd for C17H16O4: 284.1049; found: 284.1053.
IR (KBr): 2903, 1692 1615, 1489, 1416, 1291, 1225, 1165, 1087,
1060, 993, 891 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 465–474

472
S. V. Vuppalapati et al.
PAPER
2-(4-Bromophenyl)-7-methoxychroman-4-one (12q)
Yield: 203 mg (61%); colorless solid; mp 106–107 °C.
IR (KBr): 3062, 2941, 1676, 1609, 1570, 1423, 1217, 1159, 1111,
1067, 823 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.34–7.23 (m, 5 H), 6.03 (s, 1 H),
5.97 (s, 1 H), 5.29 (dd, J = 12.9, 2.4 Hz, 1 H), 3.76 (s, 3 H), 3.68 (s,
3 H), 2.89 (dd, J = 16.5, 14.1 Hz, 1 H), 2.69 (dd, J = 16.5, 2.7 Hz, 1
H).
13C NMR (75 MHz, CDCl3): δ = 188.7, 165.7, 164.7, 162.0, 138.6,
128.5, 128.3, 125.8, 105.7, 93.3, 92.9, 78.9, 55.8, 55.3, 45.3.
IR (KBr): 3063, 2954, 1678, 1604, 1439, 1256, 1118, 1058, 828
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 8.7 Hz, 1 H), 7.44 (d,
J = 7.8 Hz, 2 H), 7.23 (d, J = 7.8 Hz, 2 H), 6.50 (d, J = 8.7 Hz, 1 H),
6.39 (s, 1 H), 5.30 (d, J = 12.5 Hz, 1 H), 3.73 (s, 3 H), 2.86 (dd, J =
16.5, 12.5 Hz, 1 H), 2.67 (d, J = 16.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 189.9, 166.1, 163.1, 137.7, 131.8,
128.6, 127.7, 122.5, 114.6, 110.2, 100.8, 79.0, 55.5, 44.0.
HRMS (EI): m/z calcd for C17H16O4: 284.1049; found: 284.1046.
HRMS (EI): m/z calcd for C16H13BrO3: 332.0048; found: 332.0049.
Acknowledgment
2-(4-Chlorophenyl)-7-methoxychroman-4-one (12r)
This research was supported by the Nano Material Technology De-
velopment Program of the Korean National Research Foundation
(NRF) funded by the Korean Ministry of Education, Science, and
Technology (2012M3A7B4049675).
Yield: 181 mg (63%); light yellow solid; mp 118–120 °C.
IR (KBr): 2963, 1695, 1605, 1594, 1258, 1019, 834 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 9.0 Hz, 1 H), 7.34–
7.31 (m, 4 H), 6.55–6.51 (m, 1 H), 6.40 (s, 1 H), 5.37 (dd, J = 12.9,
2.7 Hz, 1 H), 3.75 (s, 3 H), 2.88 (dd, J = 16.8, 12.9 Hz, 1 H), 2.70
(dd, J = 16.2, 2.7 Hz, 1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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13C NMR (75 MHz, CDCl3): δ = 189.9, 166.2, 163.2, 137.3, 134.5,
128.9, 128.7, 127.4, 114.7, 110.3, 100.9, 79.1, 55.6, 44.1.
References
HRMS (EI): m/z calcd for C16H13ClO3: 288.0553; found: 288.0555.
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HRMS (EI): m/z calcd for C20H16O3: 304.1099; found: 304.1102.
7-Methoxyflavanone (1)
Yield: 158 mg (62%); light yellow solid; mp 88–90 °C.
IR (KBr): 2971, 1681, 1609, 1443, 1366, 1249, 1159, 1057, 841
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 8.7 Hz, 1 H), 7.47–
7.34 (m, 5 H), 6.61 (dd, J = 8.7, 2.4 Hz, 1 H), 6.49 (d, J = 1.8 Hz, 1
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4′,7-Dimethoxyflavanone (2)
Yield: 168 mg (59%); light yellow solid; mp 80–81 °C.
IR (KBr): 2961, 1690, 1610, 1444, 1255, 1159, 1029, 833 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.70 (dd, J = 9.0, 2.7 Hz, 1 H),
7.24–7.21 (m, 2 H), 6.80–6.77 (m, 2 H), 6.45–6.40 (m, 1 H), 6.30
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128.3, 127.4, 114.5, 113.8, 109.7, 100.6, 79.3, 55.2, 54.9, 43.7.
HRMS (EI): m/z calcd for C17H16O4: 284.1049; found: 284.1048.
5,7-Dimethoxyflavanone (3)
Yield: 156 mg (55%); light yellow solid; mp 142–144 °C.
Synthesis 2014, 46, 465–474
© Georg Thieme Verlag Stuttgart · New York

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