Synthesis of Diverse Oxa-Carbocycle-Annulated Flavones Using the Combined Claisen Rearrangement and Ring-Closing Metathesis

Article abstract of DOI:10.1002/hlca.201600028

A simple and efficient route for the synthesis of oxepine-, oxocine-, oxepinone-, and dioxocine-angularly annulated flavone skeletons has been developed. The combined Claisen rearrangement and the ring-closing metathesis are used as key steps for the construction of C₇/C₈–C₆–C₆tricyclic core structures.

Full text of DOI:10.1002/hlca.201600028

Helv. Chim. Acta 2016, 99, 1 – 11
1
201600028
FULL PAPER
Synthesis of Diverse Oxa-Carbocycle-Annulated Flavones Using the Combined
Claisen Rearrangement and Ring-Closing Metathesis
by Thirupathi Gogulaa) and Jayaprakash Rao Yerrabelly*a)b)
a) Department of Chemistry, Osmania University, Hyderabad, Telangana 500007, India (phone: +91-9849814236;
e-mail: yjpr_19@yahoo.com)
b) Department of Chemistry, Telangana University, Nizamabad 503322, India (phone: +91-9849814236;
e-mail: yjpr_19@yahoo.com)
A simple and efficient route for the synthesis of oxepine-, oxocine-, oxepinone-, and dioxocine-angularly annulated
flavone skeletons has been developed. The combined Claisen rearrangement and the ring-closing metathesis are used as key
steps for the construction of C7/C8–C6–C6 tricyclic core structures.
Keywords: Hydroxyflavones, Claisen rearrangement, Ring-closing metathesis, Grubbs’ I and II catalysts, Oxa-carbocycle-
annulated flavones.
heterocyclic ring systems especially for medium to large
rings from diene and ene-yne precursors [31][32]. The
Introduction
Flavonoids are the prominent polyphenolic group of sec-
medium-size rings are difficult to prepare due to enthalpic
ondary metabolites found through the plant kingdom [1].
(increasing strain in transition state) and entropic influ-
These compounds naturally occur in fruits, vegetables, ences (probability of chain ends meeting). However, to
seeds, nuts, and flowers [2][3][4], and play significant role
in many biological processes [5][6]. Flavonoids exhibit
diverse type of properties that are useful for human
health by interacting with a wide variety of cellular tar-
gets involved in cell signatory pathway in the body. Sev-
date there is no report of this methodology being
employed for the synthesis of angularly heterocycles ring-
fused flavones. Several methodologies have been reported
for the synthesis of various heterocyclic ring-fused fla-
vones [33], but medium-size oxa-carbocycle-annulated fla-
eral therapeutically interesting biological, pharmaceutical vones are unknown, probably due to lack of general
activities of certain flavones have been reported, including methods. It appeared to us that a combination of the
anticancer [7], anti-HIV [8], antioxidant [9], antimicrobial
[10], antiarthritic [11], DNA cleaving [12], antianginous
Claisen rearrangement and the RCM could be useful to
prepare diverse oxa-unknown medium-sized heterocycle-
[13], antihepatotoxic [14], anti-inflammatory [15], antimu- annulated flavone system of interest. Here, we report a
tagenic [16], antiosteoporotic [17], antidiabetic [18],
diversity-oriented approach for the synthesis of skeletally
antiulcer [19], antifungal [20], antiallergic [21], vasodilat- different oxa-carbocycle-annulated flavone molecular
ing [22], analgesic [23], antidiarrheal [24], antiviral [25],
and various enzyme-inhibitory effects [26]. The benzox-
epines and benzoxocines are privileged structural scaf-
folds in medicinal chemistry because of their presence in
several bioactive natural products [27]. The structural fea-
tures and wide range of biological activity attracted
organic chemists for the synthesis of these heterocycles
fused to other bioactive heterocycles. Some of the phar-
frameworks (from more readily available starting materi-
als) through the application of the combined Claisen rear-
rangement and RCM. Moreover, the construction of rings
is an important strategy of natural product synthesis.
Results and Discussion
7-Hydroxyflavones 1a,b on treating with allylbromide in
macologically important heterocyclic ring-fused flavones acetone/K2CO3 medium gave 7-allyloxyflavones 2a,b; sub-
[28] (cyclomorusin and artoflavone A) and oxepine ring
sequently, the thermal Claisen rearrangement of 2a,b in
containing biologically active natural products [29][30] diphenyl ether solvent under refluxing conditions exclu-
(ptaeroxylin, heliannuols A) are shown in Fig. 1. The sively produced C(8) regioisomers of 3a,b. Earlier the
ring-closing metathesis (RCM) using Grubbs’ catalysts Claisen rearrangement was reported in N,N-diethylaniline
(I and II) is a highly powerful and reliable tool for the
construction of wide range of carbocyclic and
solvent, but we observed that the isolation of the products
is simpler in diphenyl ether as compared to the reported
a
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DOI: 10.1002/hlca.201600028

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Helv. Chim. Acta 2016, 99, 1 – 11
Fig. 1. Some pharmacologically active natural products.
procedure [34]. The rearrangement products 3a,b on fur-
ther alkylation with allyl bromide in refluxing acetone/
selectively angularly fused oxepinoflavones 10a,b by leav-
ing some unreacted 9a,b. However, the RCM of 9a,b with
K2CO3 gave the diene precursors of RCM, 7-allyloxy- 12 mol-% of Grubbs’ I catalyst under refluxing CH2Cl2
8-allylflavones 4a,b, as colorless crystalline solids with (2 h) gave unequal amounts of compounds 10a,b
82 – 86% of yields. Similarly, butenyl ethers 5a,b were (62 – 65%) and linearly fused oxepinoflavones 11a,b
prepared by treating 8-allyl-7-hydroxyflavones 3a,b with (35 – 38%) (Scheme 2); exclusive formation of linearly
but-3-en-1-yl bromide in acetone/K2CO3 medium. The fused 6,7-oxipinoflavones 11a,b was not observed. In
RCM approach is very useful for the synthesis of med- order to obtain exclusive compounds, either 10a,b or 11a,b,
ium-sized oxacycles; these cyclic ethers are present in
many bioactive natural products such as brevetoxins [35].
the RCM was carried out with 12 mol-% of Grubbs’ II
catalyst, but as in Grubbs’ I catalyst, the RCM gave the
Treatment of the precursors 4a,b with bis(tricyclo- mixture of 10a,b and 11a,b. Attempts to achieve cross-
hexylphosphine)benzylidene ruthenium(IV) dichloride metathesis of compounds 10a,b in refluxing CH2Cl2 using
(Grubbs’ I catalyst) (0.01M or 10 mol-%) under refluxing
CH2Cl2 for 1.5 h resulted in the formation of the desired
10 mol-% of Grubbs’ II catalyst were also unsuccessful.
In the 1H-NMR spectra of 10b, two doublets at d 3.49
oxepinoflavones 6a,b in good yields (68 – 75%) (d, J = 6.5 Hz, 2 H); d 3.74 (d, J = 5.3 Hz, 2 H); a doublet
(Scheme 1). However, when same reaction was carried at d 4.63 (d, J = 2.5 Hz, 2 H); a multiplet at d 5.08 – 5.10
out at room temperature with varied concentrations of
Ru-catalyst, no conversion was observed. Similarly, the d 5.85 – 5.90 (m, 2 H) were assigned to oxepine ring
RCM of butenyl ethers 5a,b using Grubbs’ I catalyst H-atoms and allyl group H-atoms. The structures of 10a,b
(m, 2 H) and two multiplets at d 5.52 – 5.58 (m, 1 H);
under refluxing CH2Cl2 afforded oxocine derivatives 7a,b and 11a,b were further confirmed by NOESY spectra. In
with 58 – 64% of yields, but the RCM of compounds 5a,b the NOESY spectrum of 10b, the strong correlations are
proved sluggish (12 h). It is known that eight-membered observed between d 3.49 (C(1″)–CH2) and d 7.98 (H–C
cycloalkenes proved to reverse process, i.e., ring-opening (5)), weak correlations are observed between d 3.49 (C
metathesis (ROM), which is not observed in our synthe-
sis. In the 1H-NMR spectra of 6b, the characteristic
signals of newly formed oxepino-ring protons appeared at
(1″)–CH2) and d 4.64 (C(8)–OCH2), d 3.49 (C(1″)–CH2)
and d 5.09 (C(3″)–CH2) (Fig. 2). It was also supported by
DQFCOSY and HMBC spectrum of 10b. The HMBC of
d 3.77 (d, J = 3.5 Hz, 2 H); d 4.67 (d, J = 3.0 Hz, 2 H); H–C(1″) correlates with C(6a), C(5), C(2″), C(6), and C
d 5.61 – 5.64 (m, 1 H) and d 5.91 – 5.93 (m, 1 H).
In order to investigate regioselectivity in the RCM,
the 8-allyl-7-allyloxyflavones 4a,b, subjected to Claisen
(3″), of H–C(8) correlates with C(6a), C(9), and C(10), of
H–C(11) correlates with C(12), C(12a), C(9), and C(10).
However, in the H-NMR spectra of 11b, two doublets at
1
rearrangement in N,N-diethylaniline as solvent under d 3.58 (d, J = 6.5 Hz, 2 H) and d 3.64 (d, J = 5.3 Hz, 2 H)
reflux conditions, afforded compounds 8a,b, whereas in were assigned to sixth and eighth position of ArCH2–, a
diphenyl ether under reflux conditions no conversion was
observed. The rearrangement products 8a,b on further
doublet at d 4.64 (d, J = 2.5 Hz, 2 H) was assigned to
OCH2–, two multiplets at 4.99 – 5.04 (m, H);
d
2
alkylation with allyl bromide in refluxing acetone/K2CO3 d 5.97 – 6.01 (m, 1 H) were assigned to allyl H-atoms and
gave the unknown highly substituted 6,8-diallyl-7-allyloxy- two multiplets at d 5.44 – 5.47 (m, 1 H); d 5.89 – 5.92
flavones 9a,b as pale red colored solids, ring-closing
metathesis of 9a,b with Grubbs’ I catalyst (0.005M (or)
5 mol-%, 6 h) in CH2Cl2 under reflux conditions afforded
(m, 1 H) were assigned to oxepine C=O. In the NOESY
spectrum of 11b, the strong correlations are observed
between d 3.58 (C(6)–CH2) and d 7.88 (H–C(5)), d 3.58
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Helv. Chim. Acta 2016, 99, 1 – 11
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Scheme 1.
a) Allyl bromide (1 equiv.), K2CO3, acetone, reflux,4 h. b) Diphenyl ether, reflux, 3 h. c) Allyl bromide (1 equiv.) or but-3-en-1-yl bromide (1
equiv.), K2CO3, acetone, reflux, 6 – 16 h. d) Grubbs’ I, CH2Cl2, reflux, 1.5 – 12 h.
(C(6)–CH2), and d 5.91 (H–C(7)). It was also supported 2-oxooxepine ring protons appeared at
d
3.56
by the DQFCOSY and HMBC spectrum of 11b. The (d, J = 2.3 Hz, 2 H); d 5.79 (d, J = 4.9 Hz, 1 H), and
HMBC of H–C(1″) correlates with C(2″), C(3″), C(10a),
C(11), and C(11a), of H–C(6) correlates with C(5a), C(7),
d 6.40 – 6.44 (m, 1 H).
We next turned our attention to the synthesis of diox-
C(8), and C(10a), and of H–C(9) correlates with C(10a) ocineflavones 18a – 18c from 7,8-dihydroxyflavones
and C(8).
With a view to develop ene-yne metathesis, flavones
16a – 16c, which were prepared by Baker–Venkataraman
rearrangement of 2,3,4-trihydroxyacetophenone and ben-
3a,b on treating with propargyl bromide in K2CO3/ace- zoyl chloride under refluxing acetone in the presence of
tone under reflux conditions afforded compounds 12a,b. K2CO3. These on alkylation with two equivalents of allyl
Initially, we tried the RCM of 12a,b with varied concen- bromide in refluxing acetone/K2CO3 medium provided
trations of Grubbs’ I catalyst, but the formation of
cyclized product was not observed. Thus, the RCM of
7,8-diallyloxyflavones 17a – 17c. The RCM of 17a – 17c
with 10 mol-% of Grubbs’ I catalyst under refluxing
12a,b attempted with Grubbs’ II catalyst (10 mol-%) in CH2Cl2 afforded dioxicine derivatives 18a – 18c with
CH2Cl2 under reflux conditions, underwent the ene-yne
66 – 76% yields; the formation of 18a – 18c is much faster
RCM and furnished 13a,b with 45 – 52% of yields than oxipine derivatives 6a,b (1.5 h) (Scheme 5). In the 1H-
1
(Scheme 3). In the H-NMR spectra of 13b, the H-atoms NMR spectra of 18b, two doublets at d 4.91 (d, J = 1.6 Hz,
of newly formed vinyl oxepine resonated at d 3.84 (d, 2 H) and d 5.16 (d, J = 7.0 Hz, 2 H) were assigned to –
J = 5.8 Hz, 2 H); d 4.91 (s, 2 H); d 5.01 (dd, J = 14.5 Hz,
OCH2- H-atoms and a multiplet at d 5.92 – 5.96 (m, 2 H)
18.1 Hz, 2 H), d 6.01 (t, J = 5.8 Hz, 1 H), and d 6.25 (dd, was assigned to dioxocino C=O H-atoms.
J = 11.3 Hz, 17.9 Hz, 1 H).
Subsequently, we concentrated our efforts on the con-
struction of cross-coupling products. The rearrangement
To further expand the scope of the RCM approach
and to develop oxipinoneflavones, the compound 8-allyl-
7-hydroxyflavones 3a,b treated with acryloyl chloride in room-temperature conditions afforded compounds 19a,b,
products 3a,b on treating with MeI in K2CO3/acetone at
CH2Cl2 under cooling conditions gave 7-acryloxy-8-allyl-
flavones 14a,b as white colored solids. Upon the RCM of
14a,b with Grubbs’ I catalyst (0.01M or 10 mol-%, 2.5 h)
under refluxing CH2Cl2 provided the exclusive formation
of angular oxepinoneflavone derivatives 15a,b with
which on treating with Grubbs’ I catalyst did not furnish
cross-coupled products. But in the presence of Grubbs’ II
catalyst (10 mol-%, 6 h) under refluxing CH2Cl2 exclu-
sively gave compounds 20a,b with 52 – 56% yields
1
(Scheme 6). In the H-NMR spectra of 20b the character-
62 – 66% of yields (Scheme 4). In the 1H-NMR spectra istic signals of newly formed olefinic C=O H-atoms
of 15b, absence of allylic (=CH2) and acrylic (=CH2) was
observed, the characteristic signals of newly formed
appeared at d 3.50 (d, J = 3.3 Hz, 4 H) and d 5.55
(t, J = 3.3 Hz, 2 H).
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Helv. Chim. Acta 2016, 99, 1 – 11
Scheme 2.
a) N,N-Diethylaniline, reflux, 3 h. b) Allyl bromide (1.1 equiv.), K2CO3, acetone, reflux, 8 h. c) Grubbs’ I (5 mol-%), CH2Cl2, reflux, 6 h. d)
Grubbs’ I (12 mol-%), CH2Cl2, reflux, 2 h.
Experimental Part
General
All the experiments were carried out under a N2 atmo-
sphere. Thin-layer chromatography (TLC): precoated
silica gel plates GF254 (SiO2; Merck, India). Column
chromatography (CC): SiO2 (60 – 120 mesh). IR Spectra:
PerkinElmer 120-000 apparatus (PerkinElmer, Germany)
in KBr discs; m in cmꢀ1. H- and 13C-NMR spectra: Bru-
1
~
Fig. 2. Important NOESY (H ↔ H) correlations of 10b and 11b.
ker DPX-400 spectrometer (Bruker, Switzerland) in
CDCl3; d in ppm rel. to Me4Si as internal standard, J in
Hz. NOESY Spectra: AVENUE II 500 spectrometer.
We have successfully used the combined Claisen rear- Elemental analysis: Thermo Finnigan CHNS analyzer
Conclusion
rangement and RCM strategy for the synthesis of some
potentially bioactive oxepin-, oxepinone-, dioxocin-annu-
lated flavones, and also bisflavones.
(Thermo Finnigan, Italy).
General Procedure for the Preparation of 7-Hydroxy-
2-phenyl-4H-chromen-4-one 1a,b [33]: To the solution of
resacetophenone/propiophenones (1 mmol) and K2CO3
(4 mmol) in acetone, benzoyl chloride (2 mmol) was
We thank CSIR, New Delhi, India, for fellowships to
G.T. and also Head, Department of Chemistry, UCS, added dropwise for about 5 min. The resulting reaction
O.U. for providing facilities.
mixture was refluxed for 8 h, acetone was evaporated,
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Helv. Chim. Acta 2016, 99, 1 – 11
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Scheme 3.
a) Propargyl bromide (1.1 equiv.), K2CO3, acetone, reflux, 4 h. b) Grubbs’ II, CH2Cl2, reflux, 16 h.
Scheme 4.
a) Acryloyl chloride (1 equiv.), Et3N, CH2Cl2, 0°, 2 h. b) Grubbs’ I, CH2Cl2, reflux, 2.5 h.
Scheme 5.
a) Allyl bromide (2.2 equiv.), K2CO3, acetone, reflux, 4 h. b) Grubbs’ I, CH2Cl2, reflux, 2 h.
Scheme 6.
a) MeI (1.1 equiv.), K2CO3, acetone, r.t., 2.5 h. b) Grubbs’ II, CH2Cl2, reflux, 6 h.
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Helv. Chim. Acta 2016, 99, 1 – 11
and 100 ml of MeOH/H2O (1:1) was added. Then, the cold water was added. The precipitate was filtered and
solution was refluxed for 2 h, cooled to r.t., poured into
crushed ice, and acidified with 2N HCl. The precipitate was
filtered, dried, and recrystallized from MeOH to get com-
pounds 1a,b.
dried to give compounds 5a,b as off-white solid.
7-(But-3-en-1-yloxy)-2-phenyl-8-(prop-2-en-1-yl)-4H-1-
benzopyran-4-one (5a). Yield: 54%. M.p. 142 – 144°. IR
1
(KBr): 1628 (C=O). H-NMR (400 MHz, CDCl3): 2.62 (q,
General Procedure for the Preparation of 7-(Allyloxy)-
J = 6.3, 2 H); 3.68 (d, J = 5.1, 2 H); 4.18 (d, J = 6.2, 2 H);
2-phenyl-4H-chromen-4-ones 2a,b [33]: To the solution of 5.05 (dd, J = 1.2, 13.4, 2 H); 5.39 (dd, J = 1.9, 17.5, 2 H);
compounds 1a,b (1 mmol) in acetone, allyl bromide 5.96 – 6.04 (m, 2 H); 6.87 (s, 1 H); 7.04 (d, J = 8.8, 1 H);
(1.2 mmol) and anh. K2CO3 (2 mmol) was added. The
resulting mixture was refluxed for 4 h, the acetone was
evaporated, and ice-cold water was added. The precipitate
was filtered and dried to afford compounds 2a,b.
7.53 – 7.56 (m, 3 H); 7.68 – 7.73 (m, 2 H); 7.99 (d,
J = 9.0, 1 H). 13C-NMR (100 MHz, CDCl3): 28.2; 34.6;
68.3; 106.4; 110.4; 115.8; 117.1; 117.6; 118.2; 125.4; 128.4;
129.3; 130.2; 133.1; 134.3; 135.9; 156.2; 161.4; 162.8; 178.8.
General Procedure for the Preparation of 8-Allyl-7- ESI-MS: 333 ([M + H]+). Anal. calc. for C22H20O3
hydroxy-2-phenyl-4H-chromen-4-ones 3a,b [33]: Com- (332.39): C 79.50, H 6.06; found: C 79.46, H 6.01.
pounds 2a,b (1 mmol) were dissolved in 30 ml of diphenyl
ether, the reaction mixture was refluxed for 3 h, and
cooled to r.t. Then, 60 ml of petroleum ether (PE) was
7-(But-3-en-1-yloxy)-3-methyl-2-phenyl-8-(prop-2-en-1-
yl)-4H-1-benzopyran-4-one (5b). Yield: 58%. M.p.
133 – 135°. IR (KBr): 1625 (C=O). 1H-NMR (400 MHz,
added, the precipitate was filtered, and dried to afford CDCl3): 2.17 (s, 3 H); 2.59 (q, J = 6.1, 2 H); 3.60 (d, J = 5.5,
compounds 3a,b as off-white solids. 2 H); 4.16 (d, J = 6.8, 2 H); 5.01 (dd, J = 0.9, 12.4, 2 H);
General Procedure for the Preparation of 8-Allyl-7- 5.37 (dd, J = 1.5, 17.3, 2 H); 5.90 – 6.01 (m, 2 H); 6.99
(allyloxy)-2-phenyl-4H-chromen-4-ones 4a,b: To the solu- (d, J = 8.8, 1 H); 7.50 – 7.55 (m, 3 H); 7.64 – 7.69 (m, 2 H);
tion of compounds 3a,b (1 mmol) in acetone was added 8.12 (d, J = 8.5, 1 H). 13C-NMR (100 MHz, CDCl3): 11.6;
anh. K2CO3 (2 mmol) and allyl bromide (1.2 mmol) at
r.t. The reaction mixture was refluxed for 6 h, acetone
was evaporated, and ice-cold water was added. The pre-
27.3; 33.7; 68.0; 107.1; 109.8; 115.2; 115.6; 116.5; 117.4; 125.1;
128.3; 129.0; 130.0; 133.7; 134.1; 135.5; 155.1; 160.2; 160.6;
178.9. ESI-MS: 347 ([M + H]+). Anal. calc. for C23H22O3
cipitate was filtered and dried to give compounds 4a,b as (346.42): C 79.74, H 6.40; found: C 79.70, H 6.32.
General Procedure for the Preparation of 2-Phenyl-
8,11-dihydro-4H-oxepino[2,3-h]chromen-4-ones and (Z)-2-
off-white solids.
2-Phenyl-8-(prop-2-en-1-yl)-7-(prop-2-en-1-yloxy)-4H-
1-benzopyran-4-one (4a). Yield: 82%. M.p. 109 – 110°. IR Phenyl-8,9-dihydrooxocino[2,3-h]chromen-4(12H)-ones
(KBr): 1626 (C=O). 1H-NMR (400 MHz, CDCl3): 3.72 (6a,b and 7a,b): To a solution of the substrates 4a,b
(d, J = 6.8, 2 H); 4.66 (d, J = 5.6, 2 H); 5.03 (dd, J = 1.3, (1 mmol) in dry, degassed CH2Cl2 (8 ml) was added
13.6, 2 H); 5.44 (dd, J = 1.0, 16.3, 2 H); 5.99 – 6.11 (m, 2 Grubbs’ I catalyst (5 mol-%) under N2 atmosphere and
H); 6.86 (s, 1 H); 7.04 (d, J = 8.8, 1 H); 7.50 – 7.55 (m, 3
H); 7.66 – 7.69 (m, 2 H); 8.16 (d, J = 8.8, 1 H). 13C-NMR
the resulting solution was stirred at ambient temp. for
1.5 h. The solvent was evaporated in vacuo, the residue
(100 MHz, CDCl3): 28.4; 70.2; 110.4; 115.9; 116.9; 117.4; was loaded on a pad of silica gel and eluted with 15%
118.2; 125.4; 126.8; 128.4; 129.1; 130.4; 132.9; 133.8; 136.1; AcOEt/hexane to afford 6a,b as colorless solids. The reac-
155.9; 159.1; 161.2; 178.9. ESI-MS: 319 ([M + H]+). Anal. tion of 5a,b (1 mmol) with Grubbs’ I catalyst under iden-
calc. for C21H18O3 (318.37): C 79.22, H 5.70; found:
C 79.18, H 5.66.
tical conditions led to 7a,b after 12 h. The
chromatography on silica gel using 20% AcOEt/hexane as
eluent provided pure 7a,b as colorless solids.
8,11-Dihydro-2-phenyl-4H-pyrano[2,3-g][1]benzoxepin-
4-one (6a). Yield: 68%. M.p. 139 – 140°. IR (KBr): 1629
3-Methyl-2-phenyl-8-(prop-2-en-1-yl)-7-(prop-2-en-1-
yloxy)-4H-1-benzopyran-4-one (4b). Yield: 86%. M.p.
99 – 101°. IR (KBr): 1629 (C=O). 1H-NMR (400 MHz,
CDCl3): 2.17 (s, 3 H); 3.63 (d, J = 6.3, 2 H); 4.68 (d, (C=O). 1H-NMR (400 MHz, CDCl3): 3.91 (d, J = 3.5, 2
J = 5.3, 2 H); 5.01 (dd, J = 0.9, 12.4, 2 H); 5.38 (dd, H); 4.70 (d, J = 3.0,
2 H); 5.63 – 5.68 (m, 1 H);
J = 1.5, 17.3, 2 H); 5.90 – 6.10 (m, 2 H); 6.99 (d, J = 8.8, 1 5.94 – 6.03 (m, 1 H); 6.78 (s, 1 H); 7.12 (d, J = 8.0, 1 H);
H); 7.50 – 7.55 (m, 3 H); 7.66 – 7.71 (m, 2 H); 8.12 (d, 7.55 – 7.59 (m, 3 H); 7.89 – 7.92 (m, 2 H); 8.08 (d,
J = 9.0, 1 H). 13C-NMR (100 MHz, CDCl3): 11.6; 27.3; J = 8.5, 1 H). 13C-NMR (100 MHz, CDCl3): 23.0; 70.5;
69.3; 109.9; 115.2; 115.8; 115.9; 116.6; 117.6; 125.1; 128.4; 107.2; 119.6; 120.4; 123.5; 124.9; 125.8; 126.2; 127.9;
129.0; 130.0; 132.6; 133.7; 135.4; 155.1; 159.9; 160.5; 178.8. 129.2; 131.5; 132.0; 153.7; 163.0; 163.3; 178.3. ESI-MS:
ESI-MS: 333 ([M + H]+). Anal. calc. for C22H22O3 291 ([M + H]+). Anal. calc. for C19H14O3 (290.31):
(332.39): C 79.50, H 6.06; found: C 79.56, H 6.01.
General Procedure for the Preparation of 8-Allyl-7-
(but-3-en-1-yloxy)-2-phenyl-4H-chromen-4-ones 5a,b: To
C 78.61, H 4.86; found: C 78.58, H 4.81.
8,11-Dihydro-3-methyl-2-phenyl-4H-pyrano[2,3-g][1]
benzoxepin-4-one (6b). Yield: 74%. M.p.: 134 – 138°. IR
1
a stirred solution of compounds 3a,b (1 mmol) in ace- (KBr): 1628 (C=O). H-NMR (400 MHz, CDCl3): 2.16 (s,
tone was added anh. K2CO3 (2 mmol) and 1-bromo-3-
butene (1.2 mmol) at r.t. The resulting reaction mixture
was refluxed for 16 h, acetone was evaporated, and ice-
3 H); 3.77 (d, J = 3.5, 2 H); 4.67 (d, J = 3.0, 2 H);
5.61 – 5.64 (m, 1 H); 5.91 – 5.93 (m, 1 H); 7.08 (d, J = 8.8,
1 H); 7.53 – 7.66 (m, 5 H); 8.11 (d, J = 8.5, 1 H). 13C-NMR
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Helv. Chim. Acta 2016, 99, 1 – 11
7
(100 MHz, CDCl3): 11.6; 22.7; 70.4; 116.9; 118.9; 119.2; ([M + H]+). Anal. calc. for C22H20O3 (332.39): C 79.50, H
122.8; 125.1; 126.0; 127.7; 128.5; 128.9; 130.1; 133.6; 153.7; 6.06; found: C 79.45, H 6.09.
160.6; 162.9; 178.7. ESI-MS: 305 ([M + H]+). Anal. calc.
General Procedure for the Preparation of 6,8-Diallyl-7-
for C20H16O3 (304.34): C 78.93, H 5.30; found: C 78.96, (allyloxy)-2-phenyl-4H-chromen-4-ones 9a,b: To the solu-
H 5.27.
(10Z)-9,12-Dihydro-2-phenyl-4H,8H-pyrano[2,3-h][1]
tion of compounds 8a,b (1 mmol) in acetone was added
anh. K2CO3 (2 mmol) and allyl bromide (1.2 mmol) at
benzoxocin-4-one (7a). Yield: 58%. M.p.: 92 – 96°. IR r.t. The reaction mixture was refluxed for 8 h under N2
(KBr): 1622 (C=O). 1H-NMR (400 MHz, CDCl3): 2.54 atmosphere, acetone was evaporated, and ice-cold water
(q, J = 6.8, 2 H); 3.71 (d, J = 7.1, 2 H); 4.24 (t, J = 4.9, 2
H); 5.74 – 5.76 (m, 1 H); 6.08 – 6.11 (m, 1 H); 6.80 (s, 1
H); 7.14 (d, J = 8.8, 1 H); 7.56 – 7.71 (m, 5 H); 8.14
was added. The precipitate was filtered and dried to give
compounds 9a,b as off-white solids.
2-Phenyl-6,8-di(prop-2-en-1-yl)-7-(prop-2-en-1-yloxy)-
(d, J = 8.5, 1 H).). 13C-NMR (100 MHz, CDCl3): 24.1; 4H-1-benzopyran-4-one (9a). Yield: 55%. M.p. 136 – 139°.
1
30.2; 70.3; 108.4; 115.6; 117.4; 118.2; 125.1; 125.9; 128.2;
IR (KBr): 1644 (C=O). H-NMR (400 MHz, CDCl3): 3.61
129.0; 129.6; 130.1; 133.5; 134.2; 154.7; 158.4; 160.9; 176.8. (d, J = 5.8, 2 H); 3.72 (d, J = 5.9, 2 H); 4.48 (d, J = 5.1, 2
ESI-MS: 305 ([M + H]+). Anal. calc. for C20H16O3
(304.11): C 78.93, H 5.30; found: C 78.89, H 5.78.
(10Z)-9,12-Dihydro-3-methyl-2-phenyl-4H,8H-pyrano
H); 4.99 – 5.52 (m, 4 H); 6.01 – 6.13 (m, 3 H); 6.89 (s, 1
H); 7.52 – 7.56 (m, 3 H); 7.66 – 7.71 (m, 2 H); 8.00 (s, 1
H). 13C-NMR (100 MHz, CDCl3): 26.7; 28.5; 68.9; 109.2;
[2,3-h][1]benzoxocin-4-one (7b). Yield: 64%. M.p.: 114.4; 115.6; 115.8; 115.9; 116.2; 117.9; 122.9; 128.3; 129.3;
82 – 84°. IR (KBr): 1622 (C=O). 1H-NMR (400 MHz, 131.8; 132.5; 134.6; 134.8; 135.6; 153.9; 157.1; 160.2; 177.9.
CDCl3): 2.20 (s, 3 H); 2.51 (q, J = 6.5, 2 H); 3.70 (d, ESI-MS: 359 ([M + H]+). Anal. calc. for C24H22O3
J = 7.1, 2 H); 4.18 (t, J = 5.0, 2 H); 5.71 – 5.76 (m, 1 H); (358.43): C 80.42, H 6.19; found: C 80.34, H 6.23.
6.00 – 6.06 (m, 1 H); 7.12 (d, J = 8.8, 1 H); 7.56 – 7.71 (m,
3-Methyl-2-phenyl-6,8-di(prop-2-en-1-yl)-7-(prop-2-en-
5 H); 8.11 (d, J = 8.5, 1 H). 13C-NMR (100 MHz, CDCl3): 1-yloxy)-4H-1-benzopyran-4-one (9b). Yield: 55%. M.p.
11.6; 23.4; 29.6; 73.9; 109.6; 117.0; 118.0; 118.7; 119.2; 124.9; 132 – 134°. IR (KBr): 1630 (C=O). 1H-NMR (400 MHz,
125.6; 127.9; 128.3; 129.0; 130.2; 132.4; 154.3; 160.8; 161.9; CDCl3): 2.19 (s, 3 H); 3.54 (d, J = 5.9, 2 H); 3.66 (d, J = 5.9,
178.9. ESI-MS: 319 ([M + H]+). Anal. calc. for C21H18O3 2 H); 4.43 (d, J = 4.9, 2 H); 4.98 – 5.49 (m, 6 H);
(318.37): C 79.22, H 5.70; found: C 79.18, H 5.73.
General Procedure for the Preparation of 6,8-Diallyl- H); 8.03 (s, 1 H). 13C-NMR (100 MHz, CDCl3): 10.9; 26.4;
7-hydroxy-2-phenyl-4H-chromen-4-ones 8a,b: The com- 28.6; 68.3; 110.9; 114.2; 115.6; 115.9; 116.3; 116.6; 117.6;
pounds 4a,b (1 mmol) were dissolved in 20 ml of N,N- 123.9; 127.9; 128.6; 130.2; 131.5; 134.1; 134.4; 135.8; 153.3;
5.99 – 6.14 (m, 3 H); 7.51 – 7.55 (m, 3 H); 7.65 – 7.69 (m, 2
diethylaniline, refluxed in the reaction mixture for 3 h,
and cooled to r.t. Then, the solution was acidified with
50 ml of 2N HCl and extracted twice with AcOEt
(2 9 40 ml). The organic layer was combined, dried
(Na2SO4), and evaporated in rota evaporator. The resi-
due was loaded on silica gel and eluted with 20%
AcOEt/hexane to afford 8a,b as colorless solids.
156.3; 159.3; 177.7. ESI-MS: 373 ([M + H]+). Anal. calc. for
C25H24O3 (372.46): C 80.62, H 6.49; found: C 80.56, H 6.51.
General Procedure for the Preparation of 6-Allyl-2-
phenyl-8,11-dihydro-4H-oxepino[2,3-h]chromen-4-ones
and 11-Allyl-2-phenyl-6,9-dihydro-4H-oxepino[3,2-g]chro-
men-4-ones (10a,b and 11a,b): To the solution of com-
pounds 9a,b (1 mmol) in 8 ml of dry and degassed
CH2Cl2, 12 mol-% of Grubbs’ I catalyst was added under
7-Hydroxy-2-phenyl-6,8-di(prop-2-en-1-yl)-4H-1-benzo-
pyran-4-one (8a). Yield: 55%. M.p. 158 – 160°. IR (KBr): N2 atmosphere and the solution was refluxed for 2 h. The
1
1628 (C=O). H-NMR (400 MHz, CDCl3): 3.62 (d, J = 6.1, solvent was evaporated in vacuo, the residue was loaded
2 H); 3.71 (d, J = 5.9, 2 H); 5.08 – 5.19 (m, 4 H); on silica gel and eluted with 12% AcOEt/hexane to
5.99 – 6.10 (m, 2 H); 6.88 (s, 1 H); 7.02 (d, J = 8.8, 1 H); afford 10a,b as colorless solids; further elution with 14%
7.53 – 7.58 (m, 3 H); 7.69 (m, 2 H); 8.01 (s, 1 H). AcOEt/hexane afforded 11a,b as colorless solids.
13C-NMR (100 MHz, CDCl3): 26.9; 29.4; 110.4; 115.3;
8,11-Dihydro-2-phenyl-6-(2-propen-1-yl)-4H-pyrano[2,3-
115.8; 116.2; 117.8; 121.9; 124.2; 127.8; 128.9; 129.4; 131.4; g][1]benzoxepin-4-one (10a). Yield: 62%. M.p.: 191 – 193°.
1
133.1; 133.8; 153.6; 160.1; 161.2; 177.9. ESI-MS: 319 IR (KBr): 1629 (C=O). H-NMR (500 MHz, CDCl3): 3.43
([M + H]+). Anal. calc. for C21H18O3 (318.37): C 79.22, H (d, J = 6.5, 2 H); 3.84 (d, J = 5.3, 2 H); 4.61 (d, J = 2.5, 2
5.70; found: C 79.15, H 5.74.
7-Hydroxy-3-methyl-2-phenyl-6,8-di(prop-2-en-1-yl)-4H-
H); 5.01 – 5.05 (m, 2 H); 5.51 – 5.55 (m, 1 H); 5.87 – 5.98
(m, 2 H); 6.72 (s, 1 H); 7.46 – 7.51 (m, 3 H); 7.88 – 7.91
1-benzopyran-4-one (8b). Yield: 55%. M.p.: 145 – 147°. IR (m, 2 H); 7.91 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 11.8;
(KBr): 1626 (C=O). 1H-NMR (400 MHz, CDCl3): 2.19
29.4; 34.6; 71.1; 116.6; 117.0; 118.1; 124.1; 124.8; 125.6; 127.3;
(s, 3 H); 3.55 (d, J = 5.9, 2 H); 3.67 (d, J = 5.9, 2 H); 128.6; 129.1; 130.1; 130.8; 133.5; 136.9; 153.1; 160.2; 160.8;
5.13 – 5.24 (m, 4 H); 5.97 – 6.11 (m, 2 H); 6.99 (d, J = 8.8, 178.8. ESI-MS: 331 ([M + H]+). Anal. calc. for C22H18O3
1 H); 7.51 – 7.55 (m, 3 H); 7.66 – 7.70 (m, 2 H); 7.97 (s, 1
(330.38): C 79.98, H 5.49; found: C 79.94, H 5.46.
8,11-Dihydro-3-methyl-2-phenyl-6-(2-propen-1-yl)-4H-
H). 13C-NMR (100 MHz, CDCl3): 10.6; 26.5; 28.6; 108.9;
115.0; 115.6; 116.1; 118.2; 121.3; 123.7; 127.9; 129.0; 131.5; pyrano[2,3-g][1]benzoxepin-4-one (10b). Yield: 65%.
132.7; 134.1; 134.4; 153.8; 159.1; 160.0; 178.1. ESI-MS: 333 M.p.: 186 – 188°. IR (KBr): 1631 (C=O). 1H-NMR
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Helv. Chim. Acta 2016, 99, 1 – 11
(500 MHz, CDCl3,): 2.17 (s, 3 H); 3.49 (d, J = 6.5, 2 H); 2 H); 4.85 (s, 2 H); 5.01 (dd, J = 0.9, 12.4, 2 H); 5.99 – 6.10
3.74 (d, J = 5.3, 2 H); 4.63 (d, J = 2.5, 2 H); 5.08 – 5.10 (m, 1 H); 7.13 (d, J = 8.8, 1 H); 7.50 – 7.66 (m, 5 H); 8.12
(m, 2 H); 5.52 – 5.58 (m, 1 H); 5.85 – 5.90 (m, 2 H); (d, J = 8.8, 1 H). 13C-NMR (100 MHz, CDCl3): 11.2; 27.2;
7.51 – 7.55 (m, 3 H); 7.63 – 7.65 (m, 2 H); 7.98 (s, 1 H). 56.5; 110.1; 115.3; 116.4; 116.6; 117.2; 117.3; 124.9; 128.3;
13C-NMR (125 MHz, CDCl3): 11.7; 29.6; 34.1; 70.2; 116.2; 128.9; 130.0; 133.5; 135.5; 155.5; 158.8; 160.6; 178.7. ESI-MS:
116.9; 118.9; 123.9; 124.6; 125.2; 127.6; 128.4; 128.9; 130.0; 331 ([M + H]+). Anal. calc. for C22H18O3 (330.38): C 79.98,
133.6; 136.6; 152.2; 160.5; 160.9; 178.7. ESI-MS: 345 H 5.48; found: C 79.92, H 5.45.
([M + H]+). Anal. calc. for C23H20O3 (344.41): C 80.21,
H 5.85; found: C 80.24, H 5.79.
6,9-Dihydro-2-phenyl-11-(2-propen-1-yl)-4H-pyrano[3,2-
General Procedure for the Preparation of 2-Phenyl-9-
vinyl-8,11-dihydro-4H-oxepino[2,3-h]chromen-4-ones 13a,
b: To a solution of the substrates 12a,b (1 mmol) in dry,
h][1]benzoxepin-4-one (11a). Yield: 38%. M.p.: 215 – 218°. degassed CH2Cl2 (8 ml) was added Grubbs’ II catalyst
1
IR (KBr): 1629 (C=O). H-NMR (400 MHz, CDCl3): 3.51 (10 mol-%) under N2 atmosphere and the resulting solu-
(d, J = 5.3, 2 H); 3.72 (d, J = 7.8, 2 H); 4.61 (d, J = 2.6, 2
tion was stirred at ambient temp. for 16 h. The solvent
H); 5.00 – 5.04 (m, 2 H); 5.39 – 5.46 (m, 1 H); 5.84 – 5.89 was evaporated in vacuo, the residue was loaded on a pad
(m, 1 H); 6.01 – 6.06 (m, 1 H); 6.71 (s, 1 H); 7.48 – 7.52 of silica gel and eluted with 20% AcOEt/hexane to afford
(m, 3 H); 7.51 (s, 1 H); 7.86 – 7.89 (m, 2 H). 13C-NMR 13a,b as colorless solids.
(100 MHz, CDCl3): 11.8; 28.1; 31.3; 71.1; 115.8; 117.4;
9-Ethenyl-8,11-dihydro-2-phenyl-4H-pyrano[2,3-g][1]
118.9; 121.3; 123.1; 125.6; 126.8; 128.9; 128.9; 129.6; 129.6; benzoxepin-4-one (13a). Yield: 52%. M.p.: 63 – 66°. IR
130.4; 133.9; 134.6; 135.7; 154.5; 160.8; 161.1; 178.6. (KBr): 1628 (C=O). 1H-NMR (400 MHz, CDCl3): 3.76
ESI-MS: 331 ([M + H]+). Anal. calc. for C22H18O3 (d, J = 5.0, 2 H); 4.86 (s, 2 H); 5.11 (dd, J = 11.5, 17.1, 2
(330.38): C 79.98, H 5.49; found: C 79.91, H 5.52.
H); 5.89 (t, J = 6.1, 1 H); 6.19 (dd, J = 10.3, 17.5, 1 H);
6.82 (s, 1 H); 7.04 (d, J = 8.8, 1 H); 7.53 – 7.67 (m, 5 H);
8.18 (d, J = 9.0, 1 H). 13C-NMR (100 MHz, CDCl3):
23.2; 71.1; 109.6; 117.1; 118.2; 119.2; 121.4; 123.4; 124.8;
6,9-Dihydro-3-methyl-2-phenyl-11-(2-propen-1-yl)-4H-
pyrano[3,2-h][1]benzoxepin-4-one (11b). Yield: 35%.
M.p.: 195 – 196°. IR (KBr): 1629 (C=O). 1H-NMR
(500 MHz, CDCl3): 2.17 (s, 3 H); 3.58 (d, J = 6.5, 2 H); 125.2; 127.3; 128.0; 128.9; 130.4; 132.6; 135.8; 137.0; 154.3;
3.64 (d, J = 5.3, 2 H); 4.64 (d, J = 2.5, 2 H); 4.99 – 5.04 161.2; 162.8; 178.8. ESI-MS: 317 ([M + H]+). Anal. calc.
(m, 2 H); 5.44 – 5.47 (m, 1 H); 5.89 – 5.92 (m, 1 H); for C21H16O3 (317.38): C 79.73, H 5.10; found: C 79.70,
5.97 – 6.01 (m, 1 H); 7.50 – 7.53 (m, 3 H); 7.63 – 7.65 (m, H 5.55.
2 H); 7.88 (s, 1 H). 13C-NMR (125 MHz, CDCl3): 11.7;
27.8; 31.4; 71.4; 115.5; 117.0; 118.6; 121.1; 122.7; 125.8;
126.6; 128.6; 128.6; 129.0; 129.0; 130.0; 133.6; 134.2; 135.8; 68 – 69°. IR (KBr): 1623 (C=O). 1H-NMR (400 MHz,
154.2; 160.5; 160.7; 178.8. ESI-MS: 345 ([M + H]+). Anal. CDCl3): 2.17 (s, 3 H); 3.84 (d, J = 5.8, 2 H); 4.91 (s, 2
9-Ethenyl-8,11-dihydro-3-methyl-2-phenyl-4H-pyrano
[2,3-g][1]benzoxepin-4-one (13b). Yield: 46%. M.p.:
calc. for C23H20O3 (344.41): C 80.21, H, 5.85; found:
C 80.26, H 5.81.
H); 5.01 (dd, J = 14.5, 18.1, 2 H); 6.01 (t, J = 5.8, 1 H);
6.25 (dd, J = 11.3, 17.9, 1 H); 7.09 (d, J = 8.8, 1 H);
General Procedure for the Preparation of 8-Allyl-2- 7.53 – 7.67 (m, 5 H); 8.10 (d, J = 8.5, 1 H). 13C-NMR
phenyl-7-(prop-2-yn-1-yloxy)-4H-chromen-4-ones
12a,b: (100 MHz, CDCl3): 11.6; 22.3; 69.3; 111.6; 117.0; 118.8;
To the solution of compounds 3a,b (1 mmol) in acetone 118.9; 121.0; 128.1; 128.5; 128.9; 130.2; 133.5; 136.8; 137.0;
was added anh. K2CO3 (2 mmol) and propargyl bromide 153.7; 160.5; 162.6; 178.7. ESI-MS: 331 ([M + H]+). Anal.
(1.2 mmol) at r.t. The reaction mixture was refluxed for
4 h, acetone was evaporated, and added ice-cold water.
The precipitate was filtered and dried to give compounds
12a,b as off-white solids.
calc. for C22H18O3 (330.38): C 79.98, H 5.49; found:
C 79.92, H, 5.53.
General Procedure for the Preparation of 8-Allyl-4-
oxo-2-phenyl-4H-chromen-7-yl Acrylates 14a,b: To the
solution of compounds 3a,b (1 mmol) in 25 ml of dry
2-Phenyl-8-(prop-2-en-1-yl)-7-(prop-2-yn-1-yloxy)-4H-
1-benzopyran-4-one (12a). Yield: 82%. M.p. 151 – 153°. CH2Cl2 was added Et3N (2 mmol) and acryloyl chloride
IR (KBr): 1630 (C=O). 1H-NMR (400 MHz, CDCl3): (1 mmol) at 0 °C. Then the solution was stirred for 2 h,
2.56 (t, J = 1.9, 1 H); 3.68 (d, J = 5.8, 2 H); 4.89 (s, 2 H); the solvent was evaporated. To the obtained residue
5.03 (dd, J = 1.1, 12.7, 2 H); 5.99 – 6.11 (m, 1 H); 6.86 (s, 50 ml of ice-cold water was added and extracted twice
1 H); 7.14 (d, J = 8.5, 1 H); 7.50 – 7.66 (m, 5 H); 8.14 (d, with AcOEt (2 9 50 ml). The organic layer was washed
J = 9.0, 1 H). 13C-NMR (100 MHz, CDCl3): 27.6; 57.1; with water and dried (Na2SO4), filtered and evaporated
110.4; 115.8; 116.9; 117.1; 117.3; 117.8; 126.5; 128.5; 129.2;
129.3; 130.3; 133.9; 134.9; 155.6; 159.3; 165.9; 178.3. ESI-
under vacuo to give residue, which was purified by col-
umn chromatography to afford compounds 14a,b as off -
MS: 317 ([M + H]+). Anal. calc. for C21H16O3 (316.35): white solids.
C 79.73, H 5.10; found: C 79.66, H 5.16.
4-Oxo-2-phenyl-8-(prop-2-en-1-yl)-4H-1-benzopyran-7-
yl Prop-2-enoate (14a). Yield: 71%. M.p.: 164 – 166°. IR
(KBr): 1634 (C=O). H-NMR (400 MHz, CDCl3): 3.61 (d,
3-Methyl-2-phenyl-8-(prop-2-en-1-yl)-7-(prop-2-yn-1-
yloxy)-4H-1-benzopyran-4-one (12b). Yield: 82%. M.p.
146 – 148°. IR (KBr): 1627 (C=O). 1H-NMR (400 MHz,
1
J = 6.6, 2 H); 4.99 – 5.08 (m, 2 H); 5.86 – 5.96 (m, 1 H);
CDCl3): 2.17 (s, 3 H); 2.58 (t, J = 1.8, 1 H); 3.61 (d, J = 5.3, 6.13 (d, J = 11.1, 1 H); 6.38 (dd, J = 11.1, 18.1, 1 H); 6.66
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Helv. Chim. Acta 2016, 99, 1 – 11
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(d, J = 17.9, 1 H); 6.94 (s, 1 H); 7.21 (d, J = 2.5, 1 H);
7.51 – 7.64 (m, 5 H); 8.25 (d, J = 7.6, 1 H). 13C-NMR
to r.t., and poured into crushed ice, acidified with 2N
HCl. The precipitate was filtered, dried, and recrystal-
(100 MHz, CDCl3): 32.1; 116.9; 118.4; 120.4; 121.6; 121.9; lized in MeOH to yield compounds 16a – 16c as light
123.6; 125.2; 127.8; 129.1; 129.8; 133.6; 134.3; 134.8; 153.1; red solids.
155.9; 162.5; 166.1; 180.1. ESI-MS: 333 ([M + H]+). Anal.
calc. for C21H16O4 (332.35): C 75.89, H 4.85; found: C
75.83, H 4.80.
3-Methyl-4-oxo-2-phenyl-8-(prop-2-en-1-yl)-4H-1-
benzopyran-7-yl Prop-2-enoate (14b). Yield: 76%. M.p.:
159 – 161°. IR (KBr): 1630 (C=O). 1H-NMR (400 MHz,
General Procedure for the Preparation of 7,8-Bis(allyl-
oxy)-3-methyl-2-phenyl-4H-chromen-4-ones 17a – 17c: To
the solution of compounds 16a – 16c (1 mmol) in acetone
was added anh. K2CO3 (5 mmol) and allyl bromide
(2.0 mmol). The reaction mixture was refluxed for 4 h,
acetone was evaporated, and ice-cold water was added.
CDCl3): 2.22 (s, 3 H); 3.56 (d, J = 6.1, 2 H); 4.98 – 5.04 The precipitate was filtered and dried to give compounds
(m, 2 H); 5.82 – 5.93 (m, 1 H); 6.09 (d, J = 10.6, 1 H); 17a – 17c as off-white solids.
6.36 (dd, J = 10.6, 17.3, 1 H); 6.67 (d, J = 17.3, 1 H); 7.18
(d, J = 2.3, 1 H); 7.50 – 7.66 (m, 5 H); 8.23 (d, J = 7.5, 1
2-Phenyl-7,8-bis(prop-2-en-1-yloxy)-4H-1-benzopyran-
4-one (17a). Yield: 78%. M.p. 198 – 199°. IR (KBr):
H). 13C-NMR (100 MHz, CDCl3): 13.3; 31.8; 116.8; 118.2; 1641 (C=O). 1H-NMR (400 MHz, CDCl3): 4.65 (d,
119.9; 121.4; 122.0; 125.0; 127.6; 128.8; 129.0; 130.3; 133.1; J = 5.9, 2 H); 4.79 (d, J = 5.1, 2 H); 5.19 – 5.23 (m, 4 H);
134.1; 134.2; 152.8; 155.6; 161.9; 165.8; 179.2. ESI-MS: 347 6.02 – 6.14 (m, 2 H); 6.84 (s, 1 H); 7.09 (d, J = 8.5, 1 H);
([M + H]+). Anal. calc. for C22H18O4 (346.38): C 76.29, H 7.52 – 7.56 (m, 3 H); 7.67 – 7.69 (m, 2 H); 8.01 (d,
5.24; found: C 76.22, H 5.21.
General Procedure for the Preparation of 2-Phenyl-
J = 8.8, 1 H). 13C-NMR (100 MHz, CDCl3): 70.2; 74.9;
108.3; 115.8; 117.2; 118.4; 118.9; 122.1; 128.5; 129.2; 130.3;
4H-oxepino[2,3-h]chromene-4,8(11H)-diones 15a,b: To a 132.6; 133.2; 134.0; 136.1; 151.3; 155.8; 161.1; 178.8. ESI-
solution of the substrates 14a,b (1 mmol) in dry, degassed
MS: 335 ([M + H]+). Anal. calc. for C22H20O4 (334.37):
CH2Cl2 (8 ml) was added Grubbs’ I catalyst (5 mol-%) C 75.43, H 5.43; found: C 75.38, H 5.46.
under N2 atmosphere and the resulting solution was stir-
3-Methyl-2-phenyl-7,8-bis(prop-2-en-1-yloxy)-4H-1-
red at ambient temp. for 2.5 h. The solvent was evapo- benzopyran-4-one (17b). Yield: 89%. M.p.: 189 – 191°.
rated in vacuo, the residue was loaded on a pad of silica
gel, and eluted with 15% AcOEt/hexane to afford 15a,b 2.17 (s, 3 H); 4.63 (d, J = 5.8, 2 H); 4.73 (d, J = 5.0, 2
as colorless solids. H); 5.18 – 5.24 (m, 4 H); 6.03 – 6.13 (m, 2 H); 7.02
IR (KBr): 1637 (C=O). 1H-NMR (400 MHz, CDCl3):
2-Phenyl-4H-pyrano[2,3-g][1]benzoxepin-4,8(11H)-dione (d, J = 9.03, 1 H); 7.51 – 7.54 (m, 3 H); 7.66 – 7.69 (m,
(15a). Yield: 62%. M.p.: 128 – 130°. IR (KBr): 1628 (C=O). 2 H); 7.94 (d, J = 8.8, 1 H). 13C-NMR (100 MHz,
1H-NMR (400 MHz, CDCl3): 3.56 (d, J = 3.1, 2 H); 5.88
(d, J = 5.7, 1 H); 6.38 – 6.41 (m, 1 H); 6.78 (s, 1 H); 7.16
CDCl3): 11.6; 69.9; 74.6; 111.3; 116.7; 117.5; 118.1; 118.3;
121.0; 128.3; 129.0; 130.3; 132.5; 133.6; 133.8; 135.6;
(d, J = 8.6, 1 H); 7.48 – 7.59 (m, 5 H); 8.08 (d, J = 8.8, 150.8; 155.4; 160.4; 178.4. ESI-MS: 349 ([M + H]+). Anal.
1 H). 13C-NMR (100 MHz, CDCl3): 29.4; 114.3; 115.1; calc. for C22H20O4 (348.39): C 75.84, H 5.79; found: C
118.8; 120.4; 121.2; 120.9; 124.9; 127.2; 128.1; 128.4; 129.4; 75.81, H 5.76.
130.6; 132.6; 135.2; 153.4; 159.6; 162.8; 179.8. ESI-MS: 305
([M + H]+). Anal. calc. for C19H12O4 (304.30): C 74.99,
H 3.97; found: C 74.94, H 3.93.
2,3-Diphenyl-7,8-bis(prop-2-en-1-yloxy)-4H-1-benzopyran-
4-one (17c). Yield: 89%. M.p. 181 – 183°. IR (KBr): 1644
(C=O). 1H-NMR (400 MHz, CDCl3): 4.60 (d, J = 5.9, 2
3-Methyl-2-phenyl-4H-pyrano[2,3-g][1]benzoxepin-4,8
(11H)-dione (15b). Yield: 66%. M.p.: 121 – 123°. IR
H); 4.71 (d, J = 5.8,
2 H); 5.21 – 5.26 (m, 4 H);
6.06 – 6.15 (m, 2 H); 7.14 (d, J = 9.1, 1 H); 7.21 – 7.46
(KBr): 1631 (C=O). 1H-NMR (400 MHz, CDCl3): 2.21 (m, 10 H); 8.14 (d, J = 8.6, 1 H). 13C-NMR (100 MHz,
(s, 3 H); 3.56 (d, J = 2.3, 2 H); 5.79 (d, J = 4.9, 1 H);
6.40 – 6.44 (m, 1 H); 7.10 (d, J = 8.6, 1 H); 7.51 – 7.57
(m, 5 H); 8.14 (d, J = 9.0, 1 H). 13C-NMR (100 MHz,
CDCl3): 11.8; 28.3; 116.3; 117.8; 119.7; 120.6; 121.2; 124.8;
127.2; 128.5; 129.0; 130.3; 133.3; 133.6; 134.2; 152.4; 154.9;
160.9; 163.8; 178.6. ESI-MS: 319 ([M + H]+). Anal. calc.
for C20H14O4 (318.32): C 75.46, H 4.43; found: C 75.48,
H 4.41.
CDCl3): 69.8; 72.8; 112.6; 116.9; 117.4; 119.8; 121.6; 123.0;
125.6; 127.7; 128.0; 128.6; 128.8; 129.5; 130.4; 131.0; 132.6;
133.6; 134.1; 154.5; 161.0; 162.8; 178.1. ESI-MS: 411
([M + H]+). Anal. calc. for C27H22O4 (410.46): C 79.01,
H 5.40; found: C 79.98, H 5.42.
General Procedure for the Preparation of (Z)-10-
Methyl-11-phenyl-2H-[1,4]dioxocino[2,3-h]chromen-9(5H)-
ones 18a – 18c: The diallyloxy compounds 17a – 17c
General Procedure for the Preparation of 7,8-Dihy- (1 mmol) in dry CH2Cl2 was degassed for 10 min, then
droxy-3-methyl-2-phenyl-4H-chromen-4-ones 16a – 16c: To the Grubbs’ I catalyst (10 mol-%) was added, and the reac-
solution of 1,2,3-trihydroxyacetophenone(1 mmol) and
K2CO3 (8 mmol) in acetone, benzoyl chloride
(3.3 mmol) was added dropwise about 10 min. The
resulting reaction mixture was refluxed for 12 h, acetone
was evaporated, and 250 ml of MeOH/H2O (1:1) was
added. Then the solution was refluxed for 3 h, cooled
tion mixture was refluxed for 2 h. The resulting reaction
mixture was concentrated under reduced pressure and
the crude product was purified by silica gel flash chro-
matography. The elution of the column with 20%
AcOEt and PE mixture gave compounds 18a – 18c as
colorless solids.
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com

10
Helv. Chim. Acta 2016, 99, 1 – 11
(3Z)-2,5-Dihydro-11-phenyl-9H-pyrano[2,3-h]-1,6-
H); 7.47 – 7.56 (m, 3 H); 7.67 (s, 1 H); 8.16 (d, J = 9.0, 1
benzodioxocin-9-one (18a). Yield: 72%. M.p. 186 – 188°. H). 13C-NMR (100 MHz, CDCl3): 11.5; 27.2; 56.1; 108.9;
1
IR (KBr): 1634 (C=O). H-NMR (400 MHz, CDCl3): 4.81 115.2; 115.4; 116.8; 118.4; 125.3; 127.1; 128.8; 129.0; 129.7;
(d, J = 2.6, 2 H); 5.21 (d, J = 6.7, 2 H); 5.80 – 5.83 130.1; 130.9; 135.3; 155.0; 158.9; 161.0; 178.6. ESI-MS: 307
(m, 2 H); 6.88 (s, 1 H); 7.11 (d, J = 8.78, 1 H); 7.52 – 7.56 ([M + H]+). Anal. calc. for C20H18O3 (306.36): C 78.41, H
(m, 3 H); 7.77 – 7.81 (m, 2 H); 7.98 (d, J = 8.9, 1 H). 5.92; found: C 78.36, H 5.88.
13C-NMR (100 MHz, CDCl3): 28.1; 68.2; 68.1; 109.9;
General Procedure for the Preparation of (2E)-8,80-
115.8; 116.2; 116.9; 120.4; 124.6; 128.4; 128.8; 132.2; 133.0; (But-2-ene-1,4-diyl)bis(7-methoxy-2-phenyl-4H-chromen-4-
134.6; 135.2; 155.2; 156.8; 160.3; 178.4. ESI-MS: 307 one) (20a,b): To a solution of the substrates 19a,b
([M + H]+). Anal. calc. for C19H14O4 (306.31): C 74.50, H (1 mmol) in dry, degassed CH2Cl2 (8 ml) was added
4.61; found: C 74.54, H 4.55.
Grubbs’ II catalyst (10 mol-%) under N2 atmosphere, and
the resulting solution was stirred at ambient temp. for
6 h. The solvent was evaporated in vacuo, the residue was
loaded on a pad of silica gel and eluted with 40%
(3Z)-2,5-Dihydro-10-methyl-11-phenyl-9H-pyrano[2,3-
h]-1,6-benzodioxocin-9-one (18b). Yield: 76%. M.p.
172 – 173°. IR (KBr): 1630 (C=O). 1H-NMR (400 MHz,
CDCl3): 2.16 (s, 3 H); 4.91 (d, J = 1.6, 2 H); 5.16 AcOEt/hexane to afford 20a,b as off -white solids.
(d, J = 7.0, 2 H); 5.92 – 5.96 (m, 2 H); 6.92 (d, J = 9.0, 1
8,80-(2E)-But-2-ene-1,4-diylbis(7-methoxy-2-phenyl-4H-
H); 7.52 – 7.56 (m, 3 H); 7.64 – 7.68 (m, 2 H); 7.88 1-benzopyran-4-one) (20a). Yield: 52%. M.p.: 225 – 228°.
1
(d, J = 9.03, 1 H). 13C-NMR (100 MHz, CDCl3): 11.7; IR (KBr): 1626 (C=O); 1634 (C=O). H-NMR (400 MHz,
66.3; 73.1; 117.3; 117.6; 117.8; 118.0; 121.6; 124.8; 128.4;
CDCl3): 3.61 (d, J = 2.9, 4 H); 3.94 (s, 6 H); 5.42
128.5; 128.9; 130.1; 133.5; 133.7; 134.0; 151.7; 152.9; 160.1; (t, J = 3.5, 2 H); 6.82 (s, 2 H); 7.08 (d, J = 9.1, 2 H);
178.19. ESI-MS: 321 ([M + H]+). Anal. calc. for C20H16O4 7.34 – 7.54 (m, 10 H); 8.08 (d, J = 8.8, 2 H). 13C-NMR
(320.34): C 74.99, H 5.03; found: C 74.96, H 5.07.
(3Z)-2,5-Dihydro-10,11-diphenyl-9H-pyrano[2,3-h]-1,6-
(100 MHz, CDCl3): 24.1; 60.6; 110.5; 114.6; 119.2; 119.8;
123.9; 127.2; 129.1; 130.1; 130.6; 131.1; 135.2; 135.9; 153.8;
benzodioxocin-9-one (18c). Yield: 66%. M.p.: 156 – 158°. 160.6; 161.4; 179.6. ESI-MS: 580 ([M + Na]+). Anal. calc.
1
IR (KBr): 1644 (C=O). H-NMR (400 MHz, CDCl3): 3.83 for C36H28O6 (557.01): C 77.68, H 5.07; found: C 77.62,
(d, J = 5.3, 2 H); 4.72 (d, J = 6.8, 2 H); 5.63 – 5.66 (m, 1
H); 5.94 – 5.98 (m, H); 7.12 (d, J = 9.1, H);
7.19 – 7.42 (m, 10 H); 8.14 (d, J = 8.3, 1 H). 13C-NMR
H 5.09.
8,80-(2E)-But-2-ene-1,4-diylbis(7-methoxy-3-methyl-2-
phenyl-4H-1-benzopyran-4-one) (20b). Yield: 56%. M.p.:
1
1
1
(100 MHz, CDCl3): 69.4; 70.8; 118.4; 119.6; 119.9; 122.4; 204 – 206°. IR (KBr): 1632 (C=O); 1636 (C=O). H NMR
123.0; 125.7; 127.6; 128.0; 128.3; 129.5; 130.4; 131.2; 132.7; (400 MHz, CDCl3): 2.13 (s, 6 H); 3.50 (d, J = 3.3, 4 H);
133.3; 133.7; 153.6; 161.1; 163.3; 177.3. MS-ES+: 383 3.86 (s, 6 H); 5.55 (t, J = 3.3, 2 H); 6.98 (d, J = 9.0, 2 H);
([M + H]+). Anal. calc. for C25H18O4 (382.41): C 78.52, 7.29 – 7.47 (m, 10 H); 8.12 (d, J = 8.8, 2 H). 13C-NMR
H 4.74; found: C 78.56, H 4.70.
(100 MHz, CDCl3): 11.8; 29.8; 57.6; 111.1; 116.5; 116.8;
General Procedure for the Preparation of 8-Allyl-7- 118.4; 126.5; 128.5; 128.6; 131.4; 131.9; 132.5; 135.0; 136.9;
methoxy-2-phenyl-4H-chromen-4-ones 19a,b: To the solu- 156.8; 161.2; 163.8; 181.8. ESI- MS: 585 ([M + H]+). Anal.
tion of compounds 3a,b (1 mmol) in acetone was added calc. for C38H32O6 (584.66): C 78.06, H 5.52; found:
anh. K2CO3 (2 mmol) and MeI (1.1 mmol). The reaction
mixture was stirred at r.t. for 2.5 h, acetone was evapo-
rated, and ice-cold water was added. The precipitate was
filtered and dried to give compounds 19a,b as colorless
solids.
C 78.04, H 5.57.
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[22] F. Perez-Vizcaıno, M. Ibarra, A. L. Cogolludo, J. Duarte,
ꢀ
Received January 30, 2016
Accepted March 29, 2016
ꢀ
F. Zaragoza-Arnaez, L. Moreno, G. Lopez-Lopez, J. Tamargo,
J. Pharmacol. Exp. Ther. 2002, 301, 66.
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ꢀ
ꢀ
€
© 2016 Verlag Helvetica Chimica Acta AG, Zurich
www.helv.wiley.com