An efficient process for the synthesis of trans-2,3-disubstituted-2,3- dihydro-4H-1-benzopyran-4-ones (Chroman-4-ones)

Article abstract of DOI:10.1016/S0040-4020(00)00101-0

The piperidine catalyzed Knoevenagel condensation of 2'-aryl/alkyl-2- hydroxyacetophenones 7 and aryl/alkylaldehydes 8 in refluxing isopropyl alcohol with azeotropic removal of water affords, in high yield, equilibrium mixtures of E- and Z-chalcones 9 and

Full text of DOI:10.1016/S0040-4020(00)00101-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1811–1817
An Efficient Process for the Synthesis of trans-2,3-Disubstituted-
2,3-dihydro-4H-1-benzopyran-4-ones (Chroman-4-ones)
*
Richard W. Draper, Bin Hu, Radha V. Iyer, Xun Li, Yuelie Lu, Mohammad Rahman
and Eugene J. Vater
Chemical Process Research and Development Department, Schering-Plough Research Institute, Union, NJ 07083, USA
Received 5 October 1999; accepted 1 February 2000
Abstract—The piperidine catalyzed Knoevenagel condensation of 20-aryl/alkyl-2-hydroxyacetophenones 7 and aryl/alkylaldehydes 8 in
refluxing isopropyl alcohol with azeotropic removal of water affords, in high yield, equilibrium mixtures of E- and Z-chalcones 9 and cis- and
trans-chroman-4-ones 10 which are effectively isomerized in situ to the trans-2,3-diaryl/alkylchroman-4-ones, following the addition of 1,8-
diazabicyclo[5,4,0]undec-7-ene (DBU) to the cooled reaction mixture and may be isolated in high purities (91–99%) by simple filtration,
with good to excellent yields (70–95%). ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Chroman-4-ones are also important synthetic intermediates
for chromans, chromenes and chromanols which themselves
possess diverse pharmacological properties such as
b-blockade, anticonvulsant, antiestrogen and antimicro-
bial.7 More recently, complex 2,3-diarylchroman-4-ones
have been prepared as valuable precursors to 2,3-diaryl-
2H-1-benzopyrans, a class of compounds which exhibits
potent antiestrogenic activity.8–12 Our own interest has
been focused on the synthesis of trans-2,3-dihydro-2-
[400-[2000-(1-piperidinyl)ethoxy]phenyl]-7-[4-tetrahydro-2H-
pyran-2-yl)oxy]-3-[(40-[(tetrahydro-2H-pyran-2-yl)oxy]-
phenyl]-4H-1-benzopyran-4-one, trans-5, which is a par-
ticularly convenient precursor to (S)-3-(400-hydroxy)phenyl-
4-methyl-2-[400-[2-(1-piperidinyl)ethoxy]phenyl]-7-hydroxy-
2H-1-benzopyran 400,7-bistrimethylacetate 6 (Sch 57050,
EM-800), a new anti-estrogenic compound, known to possess
2,3-Dihydro-4H-1-benzopyran-4-ones (chroman-4-ones)
are widely distributed in nature.1 2-Arylchroman-4-ones
(flavanones) and 3-arylchroman-4-ones (isoflavanones) are
ubiquitous in the plant kingdom and many exhibit inter-
esting and useful biological activities.1 Although less
common, natural 2,3-disubstituted chroman-4-ones also
occur, for example, papuanic acid 1,2 isolated from the
bark of Calophyllum papuanum Lauterb., trans-(ϩ)-
inophyllolide 2,3 a constituent of the tree Calophyllum
inophyllum Linn., BE-14348B 3,4 a bacterial metabolite
produced by Streptomyces graminofaciens and the rote-
noids, such as munduserone 4.5 The 2,3-diarylchroman-4-
one substructure also appears commonly in the more elabo-
rate biflavonoids (Fig. 1).6
Figure 1.
Keywords: benzopyrans; chalcones; isomerization; rearrangements.
* Corresponding author. Tel.: ϩ1-908-820-3503; fax: ϩ1-908-820-6620; e-mail: richard.draper@spcorp.com
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00101-0

1812
R. W. Draper et al. / Tetrahedron 56 (2000) 1811–1817
Scheme 1.
Scheme 2.
very strong affinity for the estrogen receptor site in human
breast cancer cell cytosol and noted for its high oral bio-
availability and lack of agonist activity (Scheme 1).13
compounds, chromatography11,12 or fractional crystalli-
zation8 is required, along with the attendant loss in
efficiency and yield. This paper describes our efforts to
identify a practical high yielding method for the preparation
and isolation of chromanone trans-5 without using chroma-
tography and its application to the synthesis of other trans-
2,3-disubstituted chroman-4-ones.
Because of their widespread occurrence and valuable prop-
erties, numerous syntheses have been developed for the
construction of chroman-4-ones.14 Perhaps the most con-
venient and practical method is the base catalyzed Knoeve-
nagel condensation between a 2-hydroxyacetophenone 7
and an aldehyde 8 (Kabbe reaction, Scheme 2).15 In turn,
the requisite acetophenones 7 are usually readily available16
via a Fries rearrangement of the adduct obtained from an
appropriate acid (or derivative thereof) and a substituted
phenol. This route is saddled, however, with a major handi-
cap, in that the product of the Knoevenagel reaction is
normally an equilibrium mixture composed of E and Z-chal-
cones 9 and chroman-4-ones 10.17 If neither R1 nor R2 are
hydrogen, the prospect of forming both cis- and trans-chro-
man-4-ones 10 also exists, generating a total of four
isomers. The equilibrium position between the four poten-
tial products in Scheme 3 depends on several factors such as
the catalyst and solvent employed, and the steric and
electronic characteristics of X, R1 and R2 and the pendant
substituents within the latter.18 It is rare to find examples in
which the chromanones 10 are the sole products of the
reaction and thus to isolate pure samples of these
Results and Discussion
Our first sortie in attacking this synthetic problem was a
study of the effect of a combination of various bases and
solvents on the equilibrium between the a-arylchalcones 13
and the 2,3-diaryl-chromanones 5 (Scheme 3). The piperi-
dine catalyzed Knoevenagel condensation of ketone 1110
and aldehyde 12,19 conveniently run in toluene with azeo-
tropic distillation of water, permitted efficient construction
of the carbon–carbon bond. Of the various cyclic and
acyclic secondary amines, which were examined, only
piperidine catalyzed the reaction. This base specificity in
the Knoevenagel reaction has been noted previously.15
After 24 h one equivalent of water had been produced and
the reaction was complete. The molar ratio of cis-5: trans-5:
E-13: Z-13 in the crude product, as determined by HPLC,20
was about 2.6:7:4.3:1 (chromanones/chalcones ϳ1.8:1).
Scheme 3.

R. W. Draper et al. / Tetrahedron 56 (2000) 1811–1817
Table 1. Effect of base and solvent on the ratio of 5/13
1813
C-2 proton appeared as a pair of doublets each with the
same coupling constant and together integrating for one
proton. This pattern appeared in several of the trans-2,3-
disubstituted chromanones 10, which we later prepared
(vide infra) with, in some cases, similar doubling of the
signal for the C-3 proton. COSY experiments on 10b failed
to reveal any additional coupling (other than to the C-3
proton). We initially thought the pair of doublets might be
caused by the existence of more than one conformation of
the 4H-1-pyran-4-one ring. However, one of the reviewers
suggested the duplicity of these signals was more likely to
arise from the additional stereogenic centers in the tetra-
hydopyranyl ethers and indeed this appears to be the case,
as removal of the THP groups (acetic acid/water/rt) from
compounds 10f, 10g and 10j provided the corresponding
phenols in which the pairs of doublets for the C-2 and C-3
protons had, in each compound, collapsed to solitary doublets,
each integrating for one proton.
Entry
Isomerization conditionsa
Ratio of 5/13b
Yield of 5c
1
2
3
4
5
6
7
8
NaOAc/MeOH/reflux/20 h
KOAc/MeOH/reflux/20 h
DBU/toluene/reflux/20 h
DBU/DMF/rt/20 h
DBU/DMF/rt/6 h
DBU/CH3CN/rt/6 h
DBU/MeOH/rt/8 h
DBU/THF/rt/16 h
DBN/DMF/rt/8 h
DBN/CH3CN/rt/8 h
CsF/DMF/rt/8h
CsF/DMF/4ЊC/20h
CsF/CH3CN/rt/24h
CsF/IPA/rt/8h
TMG/DMF/4ЊC/48h
TMG/CH3CN/rt/54 h
5.9:1
5.9:1
1.6:1
5.4:1
5.9:1
5.3:1
5.0:1
3.1:1
7.0:1
7.7:1
6.2:1
6.0:1
8.5:1
2.0:1
10.8:1
11.8:1
43
47
58
nm
72
71
nm
nm
85
85
81
80
87
nm
79
76
9
10
11
12
13
14
15
16
a NaOAC or KOAc (4 equiv.), other catalysts (0.3 equiv.).
b Approximate molar ratio of (cis-5ϩtrans-5) to (E-13ϩZ-13) by
HPLC.20
Subsequently the polar solvent, isopropyl alcohol, also
fortuitously proved to be a superior medium for the crystalli-
zation of trans-5 and thus was chosen for the isomerization.
Indeed, when the toluene was removed from the crude
product of the Knoevenagel reaction and the residue stirred
at room temperature in isopropyl alcohol with DBU for
24 h, an excellent yield of pure crystalline chromanone
trans-5, essentially free of its isomers, was isolated. DBU
remained in the mother liquors, providing an advantage over
fluoride, which would have been separated with the product.
Further optimization indicated that highest yields of trans-5
were obtained when about 0.3 equiv. of DBU was used and
the concentration of products in the cyclization/crystalli-
zation was adjusted to about 30%. These observations
thus provided the basis of a facile and efficient method for
the construction of the trans-2,3-diarylchroman-4-one
system in high yield.
c (%) in solution by HPLC; nmˆnot measured.
This crude material was then dissolved in various solvents
and treated with a variety of catalysts. Table 1 reports the
results of these experiments.
The use of sodium or potassium acetates in methanol
resulted in substantial deprotection of the phenolic groups
leading to low solution yields of 5 and 13 (entries 1 and 2).
Fluoride has been used previously to catalyze this isomeri-
zation21 and gave a high ratio of 5–13 in acetonitrile and
DMF (entries 11–13) although in isopropyl alcohol (IPA),
where its solubility is less, the ratio was lower (entry 14).
The hindered bases DBU, DBN and tetramethylguanidine
(TMG) also gave high ratios of 5–13 especially in solvents
of high polarity. Several other bases were examined such as
triethylamine, imidazole, dimethylaminopyridine and 1,8-
bis-(dimethylamino)naphthalene, with IPA as solvent, but
all of these led to a chromanone/chalcone ratio of the order
of 1.6:1. Two acid catalysts which were tested (PTSA and
BF3·OEt2) almost completely converted the chromanones to
chalcones and, not unexpectedly, caused substantial
removal of the THP groups. No catalyst was found which
effected complete cyclization of the a-arylchalcones 13 to
give chromanones 5.
A suspension of the ketone 11 and aldehyde 12 (1.05 equiv.)
in toluene was refluxed with azeotropic removal of water in
the presence of piperidine (0.3 equiv.) until the starting
ketone was consumed. At the conclusion of the Knoeve-
nagel reaction, toluene was removed by distillation under
vacuum and replaced with isopropyl alcohol. DBU
(0.3 equiv.) was added and the mixture stirred at ambient
temperature for two days during which time crystallization
of the product occurred. Filtration and washing with iso-
propyl alcohol afforded trans-5 in 89% yield with 98%
purity containing Ͻ1% of the other isomers.
It was felt that of the two chromanones, cis-5 would be the
least stable due to the steric compression of the adjacent aryl
groups. If conditions were identified under which trans-5
could be induced to crystallize during isomerization, then
perturbation of the chalcone/chromanone equilibrium
would occur and the remaining components of the quater-
nary mixture, namely E and Z 13 and cis-5, would
ultimately cycle over to the desired compound. The crude
heterogeneous material from the Knoevenagel reaction,
after removal of toluene, was partially purified by column
chromatography on silica gel (mobile phase, ethyl acetate/
hexane 3:2) and the chromanone trans-5 eventually crys-
tallized from ethyl acetate/hexane. The trans relationship of
the vicinal aryl groups in 5 was established by the large
coupling constant between the C-2 and C-3 protons
(J(2,3)ˆ12 Hz), consistent with that in other trans-2,3-disub-
stituted chroman-4-ones.2,4,22 In trans-5 the signal for the
To improve the manufacturing efficiency of this process it
would be desirable to conduct both the Knoevenagel reac-
tion and the cyclization in the same solvent. As chromanone
trans-5 was too soluble to crystallize from toluene, we
examined the Knoevenagel reaction in isopropyl alcohol.
Since water is miscible with isopropyl alcohol, the reaction
was driven to completion by drying the reflux condensate
˚
via passage through 4 A molecular sieves before returning
to the reaction. Cooling the solution and addition of DBU as
before led to trans-5 in excellent yield. DBU could be added
to the reaction at the start or the finish of the Knoevenagel
condensation without affecting the final yield but this base,
in the absence of piperidine, also failed to catalyze the latter
process.

1814
R. W. Draper et al. / Tetrahedron 56 (2000) 1811–1817
Table 2. Chroman-4-ones [trans-5 and trans-10a–l (Xˆ7-THPO)] prepared by this procedure
Compound
R1
R2
Reflux time (h)
Ratio of 9/10a
mp ЊC
Chemical purity (%)b
Isolated yield (%)c
trans-5
10a
10b
10c
10d
10e
10f
10g
10h
10i
4-THPO-Ph
4-THPO-Ph
4-THPO-Ph
4-THPO-Ph
4-THPO-Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
Af
Ph
24
24
8
24
7
24
24
24
16
24
48
30
72
1/1.6
90–92
164–166
169–171
162–164
160–162
–
136–138
130–132
149–150
126–128
121–123
100–102
–
95
92
98
91
98
99
98
96
97
95
98
99
92
89
92
94
95
94
78e
88
92
84
81
70
81
80e
1/2.0
d
4-CH3-Ph
4-CH3O-Ph
2-naphthyl
n-heptyl
Ph
4-CH3O-Ph
3,4-di-CH3O-Ph
Af
1/2.0
d
1/20.1
1/2.7
1/2.5
1/5.0
1/2.3
1/0.9
1/8.4
1/11.1
10j
10k
10l
Ph
4-CH3O-Ph
n-heptyl
a In solution after Knoevenagel condensation and prior to adding DBU. HPLC area ratios.
b By HPLC area %.
c By filtration of product.
d Not measured. Chromanone crystallized during Knoevenagel condensation.
e Not crystalline—isolated by chromatography.
f Aˆ4-[2-(1-piperidino)ethoxy]phenyl.
This procedure was then applied to the synthesis of other
trans-2,3-disubstituted chroman-4-ones with generally
excellent results (see Table 2). Some adjustment of concen-
tration may be required in order to achieve efficient
crystallization during the isomerization step. An obvious
limitation of the method is a requirement that the desired
chroman-4-one crystallizes, so that isomerization is driven
beyond the point of equilibrium. In two cases (10e and 10l),
the products failed to solidify and were isolated by chroma-
tography. Compound 10h formed as a gum and some ethyl
acetate was added during the isomerization step to promote
crystallization, while 10d crystallized during the Knoeve-
nagel reaction prior to adding DBU.
hydropyranyloxy-2,3-dihydro-4H-1-benzopyran-4-one trans-
5 was filtered off, washed with IPA (2×500 mL) and dried
under vacuum. Yield 1.414 kg (89%, corrected for purity of
95%). 1H NMR; d 1.30–1.95 (18H, m, –CH2–); d 2.38 (4H,
m, –CH2N–); d 2.59 (2H, m, –CH2N–); d 3.55 (2H, m,
–CH2O–); d 3.72 (2H, m, –CH2O–); d 3.98 (2H, t –CH2O–);
d 4.53 (1H, d, JH2,H3ˆ12 Hz, H3); d 5.36 (1H, t, –OCHO–);
d
5.61 (1H, t, –OCHO–); d 5.78, 5.81 (1H, 2d,
JH2,H3ˆ12 Hz, H2); d 6.67 (1H, d, Jˆ2 Hz, H8); d 6.75
(1H, dd, Jˆ2 Hz, Jˆ9 Hz, H6); d 6.82 (4H, d, Jˆ9 Hz,
H30, H300, H50, H500); d 7.00 (2H, d, Jˆ9 Hz, H20, H60); d
7.31 (2H, d, Jˆ9 Hz, H200, H600); d 7.75 (1H, d, Jˆ9 Hz,
H5). 13C NMR; d 18.37; d 18.74; d 23.91; d 24.48; d 24.67;
d 25.54; d 29.46; d 29.88; d 54.38; d 56.13; d 57.34; d
61.65; d 65.44; d 83.42; d 95.63; d 103.38; d 111.22; d
113.98; d 114.99; d 115.82; d 128.43; d 128.77; d 129.34;
d 129.92; d 130.63; d 155.18; d 158.36; d 162.43; d 162.73;
d 191.64. IR; nmax 2950, 1675, 1615, 1580, 1520,
1250 cmϪ1. HR–MS: calcd for C38H46NO7, (MϩH)ϩ
628.3274, found 628.3262.
Experimental
All reactions were carried out under nitrogen. Melting
points were determined with a Mel-temp melting point
1
apparatus and are uncorrected. H and 13C NMR spectra
were recorded in DMSO-d6 (unless indicated otherwise)
using either a Varian Associates XL-300 or Gemini 300
spectrometer operating at 300 MHz and internally locked
to the deuterium frequency (15.4 MHz) of the solvent.
Chemical shifts are in ppm downfield from TMS. IR spectra
(in CHCl3 unless noted otherwise) were obtained on a
Mattson Galaxy Series FTIR 7000.
General procedure for the preparation of trans-2,3-
disubstituted-2,3-dihydro-4H-1-benzopyran-4-ones 10
(Xˆ7-OTHP). A mixture of the ketone 7 (8.0 mmol) and
aldehyde 8 (8.4 mmol) in IPA (8 mL) containing piperidine
(2.67 mL, 2.7 mmol) was heated at reflux until the starting
ketone was consumed (monitored by HPLC or TLC). The
˚
condensate was returned to the reaction through a bed of 4 A
(^)-trans-2-(400-[2000-piperidinoethoxy]phenyl)-3-(40-tetra-
hydropyranyloxyphenyl)-7-tetrahydropyranyloxy-2,3-
dihydro-4H-1-benzopyran-4-one trans-5. A suspension of
20-hydroxy-40-tetrahydropyranyloxy-(4-tetrahydropyranyl-
oxyphenyl)acetophenone (1 kg, 2.424 mol), 4-(20-piperi-
dinoethoxy)benzaldehyde (0.593 kg, 2.545 mol) and
piperidine (62 g, 0.73 mol) in IPA (5.21 L) was heated at
reflux while returning the condensate to the reaction through
molecular sieves (2 g). The reaction mixture was cooled,
DBU (2.7 mmol) was added and the solution agitated for
48 h. The product 2,3-trans-disubstituted chroman-4-one 10
was filtered off, washed with IPA and dried under vacuum.
Yield 80–92%.
10a. Anal. calcd for C31H32O6: C, 74.38%; H, 6.44%, found:
1
C, 74.09%; H, 6.56%; H NMR d 1.34–1.93 (12H, m,
˚
–CH2–); d 3.36–3.80 (4H, m, –CH2O–); d 4.52 (1H, d,
JH2,H3ˆ12 Hz, H3); d 5.33 (1H, t, –OCHO–); d 5.60 (1H,
t, –OCHO); d 5.83, d 5.87 (1H, 2d, JH2,H3ˆ12 Hz, H2); d
6.67 (1H, d, Jˆ2 Hz, H8); d 6.72 (1H, dd, Jˆ2 Hz,
Jˆ10 Hz, H6); d 6.79 (2H, d, Jˆ10 Hz, H300, H500); d
6.98 (2H, d, Jˆ10 Hz, H20, H60); d 7.13–7.33 (3H, m,
a bed of 4 A molecular sieves (beads 8–12 mesh, 0.582 kg)
and monitoring the reaction by HPLC.20 After 24 h the
mixture was cooled to 21ЊC, DBU (110.8 g, 0.73 mol) was
added and the mixture stirred for 48 h during which time the
product crystallized. The (^)-trans-2-(400-[2000-piperidino-
ethoxy]phenyl)-3-(40-tetrahydropyranyloxyphenyl)-7-tetra-

R. W. Draper et al. / Tetrahedron 56 (2000) 1811–1817
1815
H30, H40, H50); d 7.38 (2H, d, Jˆ10 Hz, H200, H600); d 7.74
(1H, d, Jˆ10 Hz, H5). 13C NMR; d 18.37; d 18.73; d 24.49;
d 24.66; d 29.46; d 29.77; d 29.87; d 56.21; d 61.65; d
83.75; d 95.64; d 103.42; d 103.52; d 111.33; d 115.02; d
115.86; d 116.15; d 125.85; d 127.92; d 128.13; d 128.40;
d 128.46; d 129.99; d 130.67; d 137.89; d 155.24; d
162.35; d 162.73; d 162.79; d 191.38. IR; nmax 2950,
1680, 1615, 1580, 1520, 1450, 1250, 1175, 1115, 1035,
d 85.24; d 85.31; d 94.74; d 96.17; d 96.20; d 96.26; d
96.43; d 103.24; d 103.67; d 110.98; d 111.07; d 111.71;
d 111.78; d 111.86; d 114.54; d 114.59; d 115.35; d
115.64; d 116.46; d 116.59; d 124.39; d 126.13; d 126.16;
d 126.29; d 126.59; d 126.65; d 126.75; d 127.58; d
127.90; d 128.02; d 128.11; d 129.29; d 129.80; d 130.42;
d 130.48; d 130.63; d 132.84; d 133.12; d 135.24; d
135.26; d 135.31; d 155.02; d 156.15; d 156.21; d 162.88;
d 163.06; d 163.23; d 163.76; d 163.95; d 191.90; d 192.58.
IR; nmax 2950, 1680, 1610, 1580, 1510, 1440, 1250, 1170,
1110, 1040, 970 cmϪ1. HR–MS: calcd for C35H35O6,
(MϩH)ϩ 551.2434, found 551.2446.
970 cmϪ1
.
HR–MS: calcd for C31H33O6, (MϩH)ϩ
501.2277, found 501.2275.
10b. Anal. calcd for C32H34O6: C, 74.69%; H, 6.66%, found:
1
C, 74.23%; H, 6.68%. H NMR; d 1.35–1.95 (12H, m,
–CH2–); d 2.24 (3H, s, –CH3); d 3.46–3.64 (2H, m,
–CH2O–); d 3.64–3.82 (2H, m, –CH2O–); d 4.53 (1H, d,
JH2,H3ˆ12 Hz, H3); d 5.35 (1H, t, –OCHO–); d 5.61 (1H, t,
–OCHO–); d 5.81, d 5.86 (1H, 2d, JH2,H3ˆ12 Hz, H2); d
6.67 (1H, d, Jˆ2 Hz, H8); d 6.76 (1H, dd, Jˆ2 Hz,
Jˆ10 Hz, H6); d 6.80 (2H, d, Jˆ9 Hz, H300, H500); d 7.01
(2H, d, Jˆ10 Hz, H20, H60); d 7.07 (2H, d, Jˆ10 Hz, H30,
H50); d 7.28 (2H, d, Jˆ9 Hz, H200, H600); d 7.75 (1H, d,
Jˆ10 Hz, H5). 13C NMR; d 18.33; d 18.76; d 20.73; d
24.49; d 24.67; d 29.44; d 29.89; d 56.05; d 61.68; d
83.52; d 95.54; d 95.63; d 103.39; d 103.50; d 111.19; d
114.99; d 115.85; d 127.93; d 128.45; d 128.71; d 130.66;
d 134.97; d 137.64; d 155.21; d 159.84; d 162.38; d
162.69; d 191.53. IR; nmax 2950, 1680, 1615, 1580, 1515,
1445, 1250, 1170, 1110, 1035, 970 cmϪ1. HR–MS: calcd
for C32H35O6, (MϩH)ϩ 515.2434, found 515.2442.
10e. 1H NMR; d 0.81 (3H, dt, –CH3); d 1.04–1.92 (12H, m,
–CH2–); d 3.59 (1H, m, –CH2O–); d 3.69 (1H, m, –CH2O);
d 3.93 (1H, d, JH2,H3ˆ12 Hz, H3); d 4.74 (1H, d,
JH2,H3ˆ12 Hz, H2); d 5.62 (1H, t, –OCHO–); d 6.66 (1H,
d, Jˆ2 Hz, H8); d 6.70 (1H, dd, Jˆ2 Hz, Jˆ9 Hz, H6); d
7.08 (5H, m, 3-Ph); d 7.68 (1H, d, Jˆ9 Hz, H5). 13C NMR;
d 13.88; d 18.23; d 22.01; d 23.99; d 24.52; d 28.40; d
28.48; d 28.58; d 28.70; d 29.46; d 31.06; d 32.56; d 56.43;
d 56.49; d 61.58; d 81.33; d 95.48 d 95.56; d 103.28; d
111.06; d 114.91; d 127.06; d 128.38; d 128.61; d 129.00;
d 129.36; d 162.19; d 162.73; d 191.22. IR (neat on KBr);
nmax 2950, 1680, 1610, 1575, 1445, 1250, 1170, 1110, 1035,
950 cmϪ1
.
HR–MS: calcd for C27H35O4, (MϩH)ϩ
423.2535, found 423.2545.
10f. Anal. calcd for C26H24O4: C, 77.98%; H, 6.04%, found
C, 77.56%; H, 6.35%, 1H NMR; 1.42–1.93 (6H, m, –CH2);
d 3.57 (1H, m, –CH2O–); d 3.69 (1H, m, –CH2O–); d 4.59
(1H, d, JH2,H3ˆ12 Hz, H3); d 5.60 (1H, t, –OCHO–); d
5.88, 5.92 (1H, 2d, JH2,H3ˆ12 Hz, H2); d 6.68 (1H, s,
H8); d 6.75 (1H, d, Jˆ9 Hz, H6); d 7.37 (2H, d, Jˆ9 Hz,
H200H600); d 6.97–7.30 (8H, m, H20, H30, H40, H300, H500); d
7.75 (1H, d, Jˆ9 Hz, H5). 13C NMR; d 18.34; d 24.47; d
29.42; d 57.08; d 61.67; d 83.69; d 95.55; d 103.53; d
111.29; d 115.02; d 125.81; d 126.70; d 127.93; d
128.08; d 128.24; d 128.44; d 129.04; d 129.81; d
135.66; d 137.74; d 162.38; d 162.73; d 191.15. IR; nmax
2950, 1680, 1610, 1580, 1450, 1250, 1170, 1115, 1035,
10c. Anal. calcd for C32H34O7: C, 72.44%; H, 6.46%, found:
1
C, 72.30%; H, 6.57%; H NMR; d 1.37–1.90 (12H, m,
–CH2–); d 3.44-3.62 (2H, m, –CH2O–); d 3.64–3.75
(2H, m, –CH2O–); d 3.67 (3H, s, –OCH3); d 4.52 (1H, d,
JH2,H3ˆ12 Hz, H3); d 5.33 (1H, t, –OCHO–); d 5.59 (1H, t,
–OCHO–); d 5.77, d 5.80 (1H, 2d, JH2,H3ˆ12 Hz, H2); d
6.64 (1H, d, Jˆ2 Hz, H8); d 6.73 (1H, dd, Jˆ2 Hz,
Jˆ10 Hz, H6); d 6.80 (4H, d, Jˆ9 Hz, H30, H300, H50,
H500); d 6.98 (2H, d, Jˆ10 Hz, H20, H60); d 7.32 (2H, d,
Jˆ10 Hz, H200, H600); d 7.72 (1H, d, Jˆ10 Hz, H5). 13C
NMR; d 18.38; d 18.76; d 24.49; d 24.67; d 29.46; d
29.90; d 54.97; d 56.14; d 61.68; d 83.41; d 93.58; d
95.65; d 103.40; d 111.24; d 113.45; d 115.01; d 115.87;
d 128.44; d 128.78; d 129.37; d 129.97; d 130.64; d
155.18; d 159.08; d 162.43; d 162.74; d 191.62. IR; nmax
2950, 1680, 1615, 1580, 1515, 1450, 1250, 1180, 1110,
1035, 970 cmϪ1. HR–MS: calcd for C32H35O7, (MϩH)ϩ
531.2383, found 531.2384.
950 cmϪ1
.
HR–MS: calcd for C26H25O4, (MϩH)ϩ
401.1753, found 401.1761.
10g. Anal. calcd for C27H26O5: C, 75.33%; H, 6.09%, found
C, 75.07%; H, 6.24%, 1H NMR; 1.42–1.93 (6H, m, –CH2);
d 3.59 (1H, m –CH2O–); d 3.68 (3H, s, –OCH3); d 3.72
(1H, m, –CH2O–); d 4.57 (1H, d, JH2,H3ˆ12 Hz, H3); d 5.60
(1H, t, –OCHO–); d 5.81, 5.86 (1H, 2d, JH2,H3ˆ12 Hz, H2);
d 6.68 (1H, d, Jˆ2 Hz, H8); d 6.75 (1H, dd, Jˆ2 Hz,
Jˆ9 Hz, H6); d 6.78 (2H, d, Jˆ9 Hz, H30, H50); d
7.00–7.20 (5H, m, 3-Ph); d 7.32 (2H, d, Jˆ9 Hz, H20,
H60); d 7.75 (1H, d, Jˆ9 Hz, H5). 13C NMR; d 18.35; d
24.46; d 29.44; d 54.95; d 57.00; d 61.71; d 83.39; d 95.64;
d 103.41; d 111.27; d 113.41; d 115.01; d 126.63; d
127.95; d 128.43; d 129.34; d 129.81; d 135.93; d
159.08; d 162.47; d 162.76; d 191.39. IR; nmax 3020,
2950, 1680, 1615, 1580, 1450, 1250, 1170, 1110, 1040,
950, 910 cmϪ1. HR–MS: calcd for C27H27O5 (MϩH)ϩ
431.1858, found 431.1855.
10d. Anal. calcd for C35H34O6: C, 76.34%; H, 6.22%, found
1
C, 76.11%; H, 6.33%, H NMR; d 1.40–1.97 (12H, m,
–CH2–); d 3.30–3.53 (2H, m, –CH2O–); 3.53–3.77 (2H,
m, –CH2O–); d 4.68 (1H, d, JH2,H3ˆ12 Hz, H3); d 5.30 (1H,
t, –OCHO–); d 5.62 (1H, t, –OCHO–); d 6.01, 6.05 (1H,
2d, JH2,H3ˆ12 Hz, H2); d 6.70 (1H, d, Jˆ2 Hz, H8); d 6.77
(1H, dd, Jˆ2 Hz, Jˆ9 Hz, H6); d 6.77 (2H, d, Jˆ9 Hz, H300,
H500); d 7.03 (2H, d, Jˆ9 Hz, H200, H600); d 7.49 (2H, m,
2-Naphth); d 7.64 (1H, d, Jˆ9 Hz, 2-Naphth); d 7.78 (1H,
d, Jˆ9 Hz, H5); d 7.75–7.90 (5H, m, 2-Naphth). 13C NMR;
d 18.45; d 18.49; d 18.69 d 18.74; d 24.92; d 25.09; d
25.23; d 25.36; d 29.94; d 30.25; d 30.29; d 30.62;
d 30.90; d 57.93; d 58.04; d 58.12; d 58.21; d 62.01; d
62.24; d 62.42; d 62.99; d 63.42; d 84.94; d 85.07; d 85.13;
10h. Anal. calcd for C28H28O6: C, 73.03%; H, 6.13%. Found
1
C, 73.32%; H, 6.19%, H NMR; d 1.44–1.95 (6H, m,

1816
R. W. Draper et al. / Tetrahedron 56 (2000) 1811–1817
–CH2–); d 3.60 (1H, m, –CH2O–); d 3.68 (6H, s, –OCH3);
d 3.71 (1H, m, –CH2O–); d 4.65 (1H, d, JH2,H3ˆ12 Hz, H3);
d 5.63 (1H, t, –OCHO–); d 5.79, d 5.83 (1H, 2d,
JH2,H3ˆ12 Hz, H2); d 6.70 (1H, d, Jˆ2 Hz, H8); d 6.76
(1H, d, H50); d 6.76 (1H, q, H6); d 6.85 (1H, q, H20);d
7.08 (1H, d, Jˆ9 Hz, H60); d 7.10–7.26 (5H, 3-Ph); d
7.77 (1H, d, Jˆ9 Hz, H5). 13C NMR; d 18.35; d 24.49; d
29.45; d 55.28; d 55.48; d 57.07; d 61.70; d 83.77; d 95.52;
d 95.64; d 103.46; d 103.52; d 110.87; d 111.31; d 115.02;
d 120.74; d 126.62; d 127.92; d 128.43; d 129.85; d
130.08; d 136.00; d 148.25; d 148.68; d 162.47; d
162.76; d 191.44. IR; nmax 2950, 1685, 1615, 1580, 1520,
1440, 1250, 1170, 1110, 1030, 960 cmϪ1. HR–MS: calcd
for C28H29O6, (MϩH)ϩ 461.1964, found 461.1956.
10l. 1H NMR; d 0.82 (6H, m, –CH3); d 1.04–1.90 (18H, m,
–CH2–); d 2.59 (1H, m, JH2,H3ˆ12 Hz, H3); d 3.56 (1H, m,
–CH2O–); d 3.67 (1H, m, –CH2O–); d 4.17 (1H, d,
JH2,H3ˆ12 Hz, H2); d 5.57 (1H, bt, –OCHO–); d 6.56
(1H, d, Jˆ2 Hz, H8); d 6.66 (1H, dd, Jˆ2 Hz, 9 Hz, H6);
d 7.64 (1H, d, Jˆ9 Hz, H5). 13C NMR; d 10.23; d 13.92; d
18.25; d 22.06; d 23.98; d 24.50; d 28.62; d 28.86; d 29.46;
d 31.22; d 32.13; d 43.77; d 61.57; d 82.07; d 95.42; d
95.53; d 103.16 d 103.27; d 110.88; d 114.17; d 128.12; d
128.37; d 129.35; d 162.11; d 162.51; d 192.80. IR (neat on
KBr); IR; nmax 2950, 1680, 1615, 1575, 1445, 1355, 1250,
1175, 1105, 1040, 955, 910 cmϪ1. HR–MS: calcd for
C22H33O4, (MϩH)ϩ 361.2379, found 361.2393.
trans-7-Hydroxy-2,3-diphenyl-2,3-dihydro-4H-1-benzo-
pyran-4-one (10f, Xˆ7-OH). A suspension of trans-7-
tetrahydropyranyloxy-2,3-diphenyl-2,3-dihydro-4H-1-benzo-
pyran-4-one (400 mg, 1.0 mmol) in acetic acid (6 mL) and
water (0.2 mL) was warmed gently to effect solution then
maintained at room temperature for 18 h. The crystals which
formed on standing were filtered off, washed with water and
dried, 180 mg (57%), mp 221–222ЊC. Anal. calcd for
C21H16O3: C, 79.33%; H, 5.10%. Found C, 79.46%; H,
1
10i. H NMR; d 1.26–1.92 (12H, m, –CH2–); d 2.37 (4H,
m, –CH2N–); d 2.57 (2H, m, –CH2N–); d 3.51–3.80 (2H,
m, –CH2O–); d 3.96 (2H, m, –CH2O–); d 4.57 (1H, d,
JH2,H3ˆ12 Hz, H3); d 5.59 (1H, t, –OCHO–); d 5.81,
5.83 (1H, 2d, JH2,H3ˆ12 Hz, H2); d 6.66 (1H, d, Jˆ2 Hz,
H8); d 6.72 (1H, dd, Jˆ2, 9 Hz, H6); d 6.78 (2H, d, Jˆ9 Hz,
H30, H50); d 7.02–7.20 (5H, m, 3-Ph); d 7.28 (2H, d,
Jˆ9 Hz, H20, H60); d 7.75 (1H, d, Jˆ9 Hz, H5). 13C
NMR; d 18.35; d 23.90; d 24.48; d 25.54; d 29.48; d
54.41; d 56.98; d 57.34; d 61.70; d 65.43; d 83.39; d
95.64; d 103.50; d 103.82; d 112.93; d 113.95; d 115.00;
d 126.63; d 127.95; d 128.43; d 129.33; d 129.79; d
135.93; d 158.37; d 162.47; d 162.76; d 191.39. IR; nmax
2950, 1680, 1615, 1580, 1520, 1450, 1250, 1170, 1110,
1040, 960 cmϪ1. HR–MS: calcd for C33H38NO5, (MϩH)ϩ
528.2750 found 528.2753.
1
5.02%, H NMR; d 4.51 (1H, d, JH2,H3ˆ12 Hz, H3); d
5.82 (1H, d, JH2,H3ˆ12 Hz, H2); d 6.37 (1H, d, Jˆ2 Hz,
H8); d 6.54 (1H, dd, Jˆ2, 9 Hz, H6); d 7.01–7.39 (10H,
m, Ph); d 7.68 (1H, d, Jˆ9 Hz, H5); d 10.65 (1H, s, OH).
13C NMR; d 57.09; d 83.60; d 102.47; d 110.81; d 113.51;
d 126.70; d 127.89; d 127.93; d 128.12; d 128.24; d
128.36; d 128.98; d 129.12; d 129.81; d 135.98; d
137.96; d 162.72; d 164.80; d 190.79; IR; nmax 2950,
1680, 1615, 1580, 1520, 1450, 1250, 1170, 1110, 1035,
10j. Anal. calcd for C21H22O4: C, 74.54%; H, 6.55%. Found
970 cmϪ1
.
HR–MS: calcd for C21H17O3, (MϩH)ϩ
1
C, 74.30%; H, 6.91%, H NMR; d 0.82 (3H, d, Jˆ7 Hz,
317.1178, found 317.1177.
–CH3); d 1.43–1.92 (6H, m, –CH2–); d 3.17 (1H, dq, Jˆ7,
12 Hz, H3); d 3.54 (1H, m, –CH2O–); d 3.67 (1H, m,
–CH2O–); d 5.22, d 5.26 (1H, 2d, JH2,H3ˆ12 Hz, H2); d
5.56 (1H, t, –OCHO–); d 6.60 (1H, d, Jˆ2 Hz, H8); d 6.71
(1H, dd, Jˆ2, 9 Hz, H6); d 7.35–7.56 (5H, m, 2-Ph); d 7.71
(1H, d, Jˆ9 Hz, H5). 13C NMR; d 10.00; d 10.06; d 18.32;
d 24.46; d 29.46; d 44.61; d 61.65; d 84.65 d 84.71; d
95.51 d 95.66; d 103.39; d 111.21; d 114.39; d 127.73;
d 128.22; d 128.52; d 128.81; d 138.10; d 162.42; d
162.52 d 162.62; d 192.42. IR; nmax 2950, 1680, 1610,
1580, 1445, 1250, 1220, 1170, 1120, 1035, 970,
trans-7-Hydroxy-3-phenyl-2-(40-methoxyphenyl)-2,3-di-
hydro-4H-1-benzopyran-4-one (10 g, Xˆ7-OH).
A
suspension of trans-7-tetrahydropyranyloxy-3-phenyl-2-
(40-methoxyphenyl)-2,3-dihydro-4H-1-benzopyran-4-one
(215 mg, 0.5 mmol) in acetic acid (3 mL) and water
(0.1 mL) was warmed gently to effect solution then main-
tained at room temperature for 18 h. The reaction mixture
was then added dropwise to aqueous NaHCO3 solution
(30 mL) and the precipitated solid filtered off, washed
with water and dried, 138 mg (80%), mp 213–215ЊC.
Anal. calcd for C22H18O4: C, 76.29%; H, 5.24%. Found C,
75.76%; H, 5.24%, 1H NMR; d 3.67 (3H, s, –OCH3); d 4.45
(1H, d, JH2,H3ˆ12 Hz, H3); d 5.74 (1H, d, JH2,H3ˆ12 Hz,
H2); d 6.27 (1H, d, Jˆ2 Hz, H8); d 6.48 (1H, dd, Jˆ2,
9 Hz, H6); d 6.78 (2H, d, Jˆ9 Hz, H30, H50); d 7.02–7.20
(5H, m, 3-Ph); d 7.29 (2H, d, Jˆ9 Hz, H20, H60); d 7.63
(1H, d, Jˆ9 Hz, H5). d 10.60 (1H, s, OH). 13C NMR; d
54.99; d 57.03; d 83.24; d 102.46; d 110.78; d 113.22; d
113.44; d 126.61; d 127.32; d 127.96; d 128.25; d 128.94;
d 129.35; d 129.80; d 130.07; d 136.24; d 159.07; d
162.80; d 164.91; d 190.99. IR; nmax 3890, 3340, 1680,
1620, 1590, 1465, 1250, 1180, 1120, 1035 cmϪ1. HR–
MS: calcd for C22H19O4, (MϩH)ϩ 347.1283, found
347.1286.
905 cmϪ1
.
HR–MS: calcd for C21H23O4, (MϩH)ϩ
339.1596, found 339.1607.
10k. Anal. calcd for C22H24O5: C, 71.72%; H, 6.57%. Found
1
C, 71.50%; H, 6.64%, H NMR; d 0.81 (3H, d, Jˆ7 Hz,
–CH3); d 1.42–1.91 (6H, m, –CH2–); d 3.15 (1H, dq, Jˆ7,
12 Hz, H3); d 3.54 (1H, m, –CH2O–); d 3.67 (1H, m,
–CH2O–); d 3.76 (3H, s, –OCH3); d 5.15, d 5.18 (1H,
2d, JH2,H3ˆ12 Hz, H2); d 5.55 (1H, t, –OCHO–); d 6.59
(1H, d, Jˆ2 Hz, H8); d 6.70 (1H, dd, Jˆ2, 9 Hz, H6); d 6.95
(2H, d, Jˆ8.6, H30, H50); d 7.44 (2H, d, Jˆ8.6, H20, H60); d
7.71 (1H, d, Jˆ9 Hz, H5). 13C NMR; d 10.10; d 18.37; d
24.47; d 29.46; d 44.60; d 55.13; d 61.64; d 84.37; d 95.49
d 95.64; d 103.38; d 111.11; d 113.83; d 114.39; d 128.20;
d 129.12; d 130.16; d 159.49; d 162.48; d 192.66. IR; nmax
2950, 1680, 1610, 1580, 1450, 1250, 1170, 1120, 1040,
trans-7-Hydroxy-3-methyl-2-phenyl-2,3-dihydro-4H-1-
benzopyran-4-one (10j, Xˆ7-OH). A solution of trans-7-
tetrahydropyranyloxy-3-methyl-2-phenyl-2,3-dihydro-4H-
970 cmϪ1
.
HR–MS: calcd for C22H25O5, (MϩH)ϩ
369.1702, found 369.1692.

R. W. Draper et al. / Tetrahedron 56 (2000) 1811–1817
1817
Chromans, and Tocopherols; Ellis, G. P., Lockhart, I. M., Eds.;
Wiley: New York, NY, 1977.
8. Saeed, A.; Sharma, A. P.; Durani, N.; Jain, R.; Durani, S.; Kapil,
R. S. J. Med. Chem. 1990, 33, 3210.
9. Sharma, A. P.; Saeed, A.; Durani, S.; Kapil, R. S. J. Med. Chem.
1990, 33, 3216.
10. Sharma, A. P.; Saeed, A.; Durani, S.; Kapil, R. S. J. Med.
Chem. 1990, 33, 3222.
1-benzopyran-4-one (110 mg, 0.295 mmol) in acetic acid
(3 mL) and water (0.1 mL) was maintained at room
temperature for 18 h and then added slowly to aqueous
NaHCO3 solution (30 mL). The precipitated solid was
filtered off, washed with water and dried, 72 mg (87%).
The product was recrystallized from diethylether, mp
173–174ЊC. Anal. calcd for C16H14O3: C, 75.58%; H,
1
5.55%. Found C, 75.34%; H, 5.60%, H NMR; d 0.81
11. Verma, B. S.; Dhindsa, K. S.; Sangwan, N. K. Ind. J. Chem.
1993, 32B, 239.
12. Hajela, K.; Kapil, R. S. Eur. J. Med. Chem. 1997, 32, 135.
13. Gauthier, S.; Caron, B.; Cloutier, J.; Dory, Y. L.; Favre, A.;
Larouche, D.; Mailhot, J.; Ouellet, C.; Schwerdtfeger, A.; Leblanc,
(3H, d, Jˆ7 Hz, –CH3); d 3.09 (1H, dq, Jˆ7, 12 Hz, H3);
d 5.18 (1H, d, JH2,H3ˆ12 Hz, H2) d 6.29 (1H, d, Jˆ2 Hz,
H8); d 6.50 (1H, dd, Jˆ2, 9 Hz, H6); d 7.31–7.58 (5H, m,
Ph); d 7.64 (1H, d, Jˆ9 Hz, H5); d 10.60 (1H, s, OH). 13
C
NMR; d 10.20; d 44.60; d 84.56; d 102.35; d 110.64; d
112.84; d 127.70; d 128.50; d 128.69; d 128.72; d 138.29;
d 162.72; d 164.56; d 192.04; IR; nmax 3590, 1680, 1620,
´
´
G.; Martel, C.; Simard, J.; Merand, Y.; Belanger, A.; Labrie, C.;
Labrie, F. J. Med. Chem. 1997, 40, 2117.
1585, 1470, 1330, 1250, 1180, 1130, 1095, 1015 cmϪ1
.
14. Hepworth, J. D. In Comprehensive Heterocyclic Chemistry;
Boulton, A. J., McKillop, A., Eds.; Pergamon Press: Oxford,
UK, 1984; Vol 3, Part 2B , pp 848–857. Hepworth, J. D.; Gabutt,
C. D.; Heron, B. M. In Comprehensive Heterocyclic Chemistry II,
McKillop, A., Ed.; Pergamon Press: Oxford, UK, 1996; Vol. 5, pp
454–460.
HR–MS: calcd for C16H15O3, (MϩH)ϩ 255.1021, found
255.1023.
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¨ ¨ ¨
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20. YMC Basic S-5 column (4.6 mm×25 cm), mobile phase
MeOH/H2O (8:2), 10 mM NH4OAc, flow rate 1.0 mL/min, inj.
vol. 10mL, conc. ϳ1.0 mg/mL, UV detection at 240 nm. Molar
ratios determined from HPLC area ratios and relative absorbtion
coefficients.
21. Harwood, L. M.; Loftus, G. C.; Oxford, A.; Thomson, C.
Synth. Commun. 1990, 20, 649.
22. Antus, S.; Gottsegen, A.; Nogradi, M. Synthesis 1981, 574.
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In Chemistry of Heterocyclic Compounds, Vol. 31, Chromenes,
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York, NY, 1977. Livingston, R.; Parkhurst, R. M.; Skinner,
W. A. In Chemistry of Heterocyclic Compounds, Vol. 36,