Synthesis and tautomerization of hydroxylated isoflavones bearing heterocyclic hemi-aminals

Article abstract of DOI:10.1039/c4ob02137a

The aminomethylation of hydroxylated isoflavones with 2-aminoethanol, 3-amino-1-propanol, 4-amino-1-butanol, and 5-amino-1-pentanol in the presence of excess formaldehyde led principally to 9-(2-hydroalkyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]-oxazin-4-ones 4 and/or the tautomeric 7-hydroxy-8-(1,3-oxazepan-3-ylmethyl)-4H-chromen-4-ones 5. The ratio of these tautomers was dependent on solvent polarity, electronic effects of aryl substituents in the isoflavone and the structure of the amino alcohol. NMR studies confirmed the interconversion of tautomeric forms.

Full text of DOI:10.1039/c4ob02137a

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Synthesis and tautomerization of hydroxylated
isoflavones bearing heterocyclic hemi-aminals†
Cite this: DOI: 10.1039/c4ob02137a
Mykhaylo S. Frasinyuk,a,b,c Svitlana P. Bondarenko,d Volodymyr P. Khilya,d
Chunming Liu,a,e David S. Watta,b,e and Vitaliy M. Sviripa*a,b
The aminomethylation of hydroxylated isoflavones with 2-aminoethanol, 3-amino-1-propanol, 4-amino-
1-butanol, and 5-amino-1-pentanol in the presence of excess formaldehyde led principally to 9-(2-
Received 7th October 2014,
Accepted 13th November 2014
hydroalkyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]-oxazin-4-ones
4
and/or the tautomeric
7-hydroxy-8-(1,3-oxazepan-3-ylmethyl)-4H-chromen-4-ones 5. The ratio of these tautomers was
dependent on solvent polarity, electronic effects of aryl substituents in the isoflavone and the structure of
the amino alcohol. NMR studies confirmed the interconversion of tautomeric forms.
DOI: 10.1039/c4ob02137a
www.rsc.org/obc
inhibit CDKs1–4 and possess a skeleton that couples two,
different structural subunits: a 5,7-dihydroxy-2-methylchro-
Introduction
In connection with our interest in developing antineoplastic mone characteristic of the isoflavonoids and a 3-hydroxypiperi-
agents targeting cyclin-dependent kinases (CDKs), we sought dine ring found in various alkaloids. Chrotacumine A (2)
antagonists that mimicked natural products in the chromone- possesses an interesting hemi-aminal (O/N-acetal) linkage con-
based alkaloid family such as rohitukine (1a) and chrotacu- necting the chromone and piperidine rings. Our interest in
mines A–D1 (1b–d and 2) (Fig. 1). These natural products developing hydroxylated isoflavones with O/N-acetal subunits,
as in chrotacumine A (2), led to an investigation of synthetic
pathways to these targets and led to questions regarding tauto-
merization of hydroxylated isoflavones bearing hemi-aminals.
We required the hemi-aminal functionality as a mimic of
the basic heterocycles found in 2, and we required the hydroxyl
group as a functional handle to which we would ultimately
attach D-(+)-biotin. These biotinylated chromones would provide
a means of identifying the biological targets of these analogs,
just as we have recently done in other systems.5 We now report
the synthesis of various hydroxylated isoflavones bearing hetero-
cyclic hemi-aminals in which we address this tautomerization
issue as a necessary prelude to biological studies.
Results and discussion
Fig. 1 Chemical structures of chromone alkaloids.
The Mannich reaction affects the aminomethylation of carbo-
aDepartment of Molecular and Cellular Biochemistry, College of Medicine, University
of Kentucky, Lexington, KY 40536-0509, USA. E-mail: vitaliy.sviripa@uky.edu
bCenter for Pharmaceutical Research and Innovation, College of Pharmacy,
University of Kentucky, Lexington, KY 40536-0509, USA
nyl and activated aromatic compounds6,7 and accommodates a
range of amines including amino alcohols, N-benzylamino
alcohols,8,9 N,N-dibenzylamino alcohols,10–12 3,4-dihydro-2H-
1,3-benzoxazines,13–15 (1,3-oxazolidin-3-yl)methylphenols and
(1,3-morpholin-3-yl)methyl phenols.15,16 Despite this pre-
cedent and our understanding of the Mannich reaction, we
could not predict the outcome and preference for tautomeric
forms in Mannich reactions using isoflavones and various
ω-amino-1-alcohols. As carbonyl components for our study, we
selected isoflavones that included natural products, such as
cInstitute of Bioorganic and Petrochemistry, National Academy of Science of Ukraine,
Kyiv 02094, Ukraine
dTaras Shevchenko Kyiv National University, Kyiv 01033, Ukraine
eLucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536-
0509, USA
†Electronic supplementary information (ESI) available: Copies of NMR data for
all synthesized compounds and 2D NOESY spectra are available online. See DOI:
10.1039/c4ob02137a
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chromeno[8,7-e][1,3]oxazin-4-ones25 4a–4f as well as the tauto-
meric isomers, 7-hydroxy-3-aryl-8-(1,3-oxazinan-3-ylmethyl)-4H-
chromen-4-ones 5a–5f (Scheme 1).
These latter isomers 5a–5f were minor products relative to
4a–4f (Table 1). Schmidt15 recently demonstrated a similar
outcome with resorcarene condensations with formaldehyde
and ω-amino-1-alcohols but did not report the equilibration of
the tautomeric forms. Mass spectral and 1H NMR data for 4
and 5 unambiguously supported these structural assignments
in which the following features were most important: [1] an
ion with m/z [MH − 12]+, which resulted from the loss of the
hemi-aminal methylene group from either tautomer 4 or 5; [2]
3J(H,H) values of 8.3–9.2 Hz within the isoflavone ring that
confirmed the aminomethylation at position C-8 and excluded
Fig. 2 Structures of isoflavones 3 studied in Mannich reactions.
formonotetin (3a) and cladrin (3b), and that also included syn-
thetic isoflavones 3c–3i (Fig. 2) as starting materials for syn-
thesis of aminoalkylated isoflavone derivatives. Since many
recent drugs contain one or more fluorine atoms,17–19 we
included isoflavones bearing either fluoroaryl rings as in 3c
and 3f and/or trifluoromethyl groups as in 3g–3i.
The synthesis of the required 7-hydroxyisoflavones 3 uti-
lized 2,4-hydroxylated deoxybenzoins under Vilsmeier–Haack
conditions using boron trifluoride in N,N-dimethylformamide
to afford the desired isoflavones 3a–3c. The use of N,N-
dimethylacetamide in place of N,N-dimethylformamide led to
aminomethylation at C-5 or C-6; and [3]
a singlet at
4.99–5.03 ppm that was assigned to the hemi-aminal methyl-
ene group of 4a–4f or a singlet at 4.43–4.49 ppm that was
assigned to the hemi-aminal methylene group of 5a–5f.
Because 1,3-oxazolidines are chemically equivalent to
a
mixture of 2-aminoethanol and formaldehyde and useful for
the aminomethylation of heterocycles,37–40 we also utilized
either 3-butoxymethyl-1,3-oxazolidine (Method B, Table 1,
entries 3, 9) or bis(oxazolidin-3-yl)methane (Method C,
Table 1, entries 5, 7, 10, 12) in the aminomethylation of isofla-
vones. In all cases using Methods B and C, we observed the
formation of a mixture of 4 and 5 in a ratio comparable to that
seen with 2-aminoethanol and formaldehyde under conditions
described in Method A.
In addition to the mass spectral and NMR data in support
of the structural assignments of these tautomers, acid-cata-
lyzed hydrolysis of these isomers afforded the amino diols 6
(Scheme 2). The amino diols 6 were a presumed intermediate
in route from the isoflavones 3 to the tautomers 4 and 5. A
combination of solvent polarity and acidity of the C-7 phenolic
group in 3 dictated the balance between the formation of the
tautomers 4 and 5 versus the amino diols 6. For example, the
isoflavones 3g and 3i possessed an electron-withdrawing tri-
fluoromethyl group that increased the acidity of the C-7 pheno-
lic hydroxyl group. Condensation of these isoflavones with
formaldehyde and 2-aminoethanol (Method A) provided exclu-
sively the amino diols 6g and 6i (n = 1), respectively. Introduc-
tion of two electron-donating methoxy groups, as in isoflavone
3h, counterbalanced the effect of the trifluoromethyl group
the formation of 7-hydroxy-2-methylisoflavones 3d–3f.
A
similar condensation of deoxybenzoins with trifluoroacetic
anhydride in pyridine led to the 7-hydroxy-2-trifluoromethyl-
isoflavones 3g–3i. With this range of isoflavones available to
us, we were in a position to evaluate the influence of different
C-2 substituents (e.g., hydrogen, methyl and trifluoromethyl)
in isoflavones on the outcome of Mannich reactions using
ω-amino-1-alcohols. In the absence of a specific procedure for
the synthesis of chromones20–25 bearing heterocyclic substitu-
ents, we evaluated published options including the reductive
amination of formyl-substituted chromones26–29 or the N-alkyl-
ation
of
amines
with
chloromethyl-substituted
chromones.30–36 These reports, although encouraging, were
limited in scope and led us to develop an alternate, general
procedure.
The aminomethylation of isoflavones 3a–f using ω-amino-1-
alcohols and an excess of aqueous formaldehyde in isopro-
panol (Method A) gave mixtures of 3-aryl-9,10-dihydro-4H,8H-
Scheme 1 Mannich reactions of isoflavones 3 with formaldehyde and amino alcohols. (a) HOCH2(CH2)nNH2, where n = 1 to 4, CH2O, EtOH or i-
PrOH, DMAP, 80 °C, 4–6 h; (b) bis(1,3-oxazolidin-3-yl)methane, dioxane, 100 °C, 2–4 h; (c) 3-butoxymethyl-1,3-oxazolidine, dioxane, 100 °C,
2–4 h.
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Table 1 Ratio of tautomeric isomers 4 and 5 obtained from isoflavones 3 and amino alcohols HOCH2(CH2)nNH2 using Method A as the general pro-
cedure, unless otherwise noted
Amino alcohol HOCH2(CH2)nNH2
or equivalent
Ratio of
Entry
Isoflavone
4 to 5a (%)
Solvent
Yield (%)
1
2
3a
3a
n = 1
n = 1
95
91
5
9
EtOH
i-PrOH
68
50
3b
3a
93
7
1,4-Dioxane
63
4
3b
3b
n = 1
n = 1
n = 1
88
90
12
10
EtOH
49
45
5c
1,4-Dioxane
6
3c
3c
87
89
13
11
i-PrOH
81
67
7c
1,4-Dioxane
8
3d
3d
88
87
12
13
EtOH
47
42
9b
1,4-Dioxane
10c
3d
87
13
THF
37
11
3d
3d
n = 1
91
89
9
EtOH
54
43
12c
11
1,4-Dioxane
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
3f
n = 1
n = 1
n = 2
n = 2
n = 2
n = 2
n = 2
n = 2
n = 2
n = 2
n = 3
n = 3
n = 3
n = 3
n = 3
n = 3
n = 3
n = 3
n = 4
n = 4
n = 4
n = 4
n = 4
n = 4
n = 4
n = 4
n = 4
92
79
3
0
0
0
3
3
3
8
21
97
100
100
100
97
97
97
98
6
i-PrOH
i-PrOH
EtOH
EtOH
EtOH
i-PrOH
EtOH
65
60
75
78
65
58
52
67
48
83
82
83
78
48
66
93
36
53
65
73
52
66
77
87
41
83
57
3h
3a
3b
3c
3d
3e
3f
3g
3h
3a
3b
3c
3d
3d
3f
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
2
94
94
95
94
94
94
90
85
100
100
100
100
100
100
100
100
100
6
5
6
6
6
3h
3i
10
15
0
0
0
0
0
0
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
0
0
a Determined in CDCl3. b Used Method B (see Experimental section). c Used Method C (see Experimental section).
and led to the formation of oxazolidyl-substituted isoflavone propanol led to the isoflavone 5g bearing the 2-(1,3-oxazina-
4h. Solvent also had a dramatic effect on outcomes. For nyl)methyl group. Finally, the aminomethylation of
example, aminomethylation of isoflavone 3g with formal- isoflavones 3 with 4-amino-1-butanol or 5-amino-1-pentanol
dehyde and 3-amino-1-propanol in ethanol led to the gave predominately the fused tautomer 4 and little or none of
amino diol 6g but this same combination of reagents in iso- the isomeric 5.
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CD3OD (Fig. 3, Panel D). The addition of DMSO-d6 to a CDCl3
solution of containing a 9 : 1 ratio of 4b and 5b also led to an
increase in 4b. This increase was best followed by monitoring
the hemi-aminal methylene protons (labeled A in Fig. 3, Panel
A). On the other hand, if CCl4 were added to a CDCl3 solution
of 4b and 5b in DMSO-d6, the ratio changed in favor of 5b.
These outcomes were consistent with a hydrogen-bonded
complex between the amino group and the C-7 phenolic group
in 5b in non-polar solvents such as CCl4 and the disruption of
this hydrogen bonding and an equilibrium shift toward 4b in
polar solvents such as DMSO-d6 or CD3OD. Preference for the
formation N-AlkOH-Solv (for 4) with ArOH-Solv (for 5) was best
explained by Pearson’s acid base concepts. Additional confir-
mation of this point was obtained using a non-polar NMR
solvent, C6D6, which showed a similar ratio of 4b to 5b found
using CDCl3. Applying polar base solvent Py-d5 showed
increased amounts of 4b form, consistent with the expected
shift of equilibrium toward 5b due to interaction with ArOH as
stronger acid than AlkOH. It should also be noted that the
equilibrium between tautomers was rapidly established and
remained unchanged after 24 hours.
Scheme 2 Hydrolysis of tautomers 4 and 5 to amino diols 6. (a) HCl,
EtOH, 80 °C, 0.5–1 h.
Unlike the cases where we used either 2-aminoethanol or
3-amino-1-propanol, the trifluoromethyl groups in isoflavones
3g–3i had no influence on the outcome, and these isoflavones
led to the oxazines 4 as the principal product. In general, we
concluded that polar solvents and electron-withdrawing substi-
tuents on the isoflavone led to the formation of the amino diols
6 whereas less polar solvents and electron-donating groups on
the isoflavone led to the tautomeric isomers 4 and 5.
NMR techniques allowed us to confirm the equilibration of
the isomers 4 and 5 in a manner similar to related tautomeri-
zations reported for 1,3-oxazolidines and 1,3-terahydrooxa-
zines that contain NH proton and could exhibit ring-chain
isomerization involving Schiff’s base.41–48 For example, the
ratio of 4b to 5b was 9 : 1 in CDCl3 (Fig. 3, Panel B), but this
ratio changed to 19 : 1 in either DMSO-d6 (Fig. 3, Panel C) or
The 2D NOESY spectrum of tautomers 4b and 5b displayed
chemical exchange cross-peaks between pairs of methylene
Fig. 3 1H NMR analysis of isoflavone tautomers. Panel A: structures of
isoflavones 4b, n = 1 and 5b, n = 1. Panel B: 1H NMR spectra (400 MHz)
in CDCl3. Panel C: 1H NMR spectra (400 MHz) in DMSO-d6. Panel D: 1H
NMR spectra (400 MHz) in CD3OD.
Fig. 4 2D NOESY spectrum of 4b, n = 1 and 5b, n = 1. Measured at
400 MHz, CDCl3, 25 °C. Black peaks are normal NOE, red peaks are
chemical exchange NOE. Arrows show cross-peaks between pairs of
exchanging protons.
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groups, the hemi-aminal methylene groups and the 2-ami- 60 °C led to minimal change other than the sharpening of
noethanol fragments. These chemical exchange cross-peaks some peaks (Fig. 5, Panel C). Cooling below 20 °C led, as
had the same phase as the diagonal peaks in contrast to the expected, to the broadening of signals for aliphatic protons
opposite-phased normal cross-peaks of aromatic protons and linked to nitrogen.
methylene groups of the amine fragment for 4b and 5b
In summary, a combination of chemical and spectroscopic
(Fig. 4). These correlations are the unambiguous evidence of studies established that isoflavones 3 underwent Mannich
dynamic reversible conversion of tautomers, which is inter- reactions with amino alcohols and an excess of formaldehyde
mediate or slow on the NMR time scale, and these cross-peaks to afford principally two tautomeric isomers 4 and 5 that
confirm the equilibration between 4b and 5b.
incorporate two molecules of formaldehyde for each amino
Similar results were obtained for tautomers using 3-amino- alcohol. A combination of solvent polarity, electronic effects
propan-1-ol and 4-aminobutan-1-ol. It was unexpected that dictated by aryl substituents in the isoflavone, and the struc-
this tautomerism was observed for 4- aminobutan-1-ol deriva- ture of the amino alcohol determined the ratio of these tauto-
tives 4, n = 3 and was not observed for 5-aminopentan-1-ol mers. In some circumstances, such as in the presence of polar
derivatives 4, n = 4 despite the expected, increased stability of solvents and electron-withdrawing groups on the isoflavone 3,
1,3-benzoxazine ring for 4, n = 3 or 4 in comparison with 1,3- the reaction provided an amino diol 6, a presumed intermedi-
axazepane (5, n = 3) or 1,3-oxazocane (5, n = 4) rings. Probably, ate in the conversion of isoflavones 3 to the tautomers 4 and 5.
ring-ring tautomerism of 4, n = 1…3 and 5, n = 1…3 is possible Spectroscopic studies established the dynamic nature of the
due to steric proximity of AlkO–H⋯N and ArO–H⋯N frag- equilibrium between these tautomeric forms which presum-
ments together with ring-chain tautomerism in 1,3-diaza and ably occurs through a transitory immonium salt as well as the
1,3-oxaza heterocycles.49 We also observed that the 1H NMR steric interactions of AlkO(H)⋯N⋯(H)OAr fragments.
spectra of either 4b or 5g in DMSO-d6 did not change when
either of these compounds was heated. Finally, we noted that
the interconversion of tautomeric forms occurred rapidly in
presence of trifluoroacetic acid (TFA) at 20 °C (Fig. 5, Panels A
and B). Addition of TFA at room temperature and heating to
Experimental
1H and 13C NMR spectra were recorded on a Bruker 500
(500 MHz/125 MHz), Bruker 400 (400 MHz/100 MHz) spectro-
meter in CDCl3, DMSO-d6, and D2O. 19F NMR spectra were
recorded on a Bruker 400 (376 MHz) relative to CFCl3. CDCl3
was stored over K2CO3 to prevent possible formation of HCl.
Chemical shifts of compounds 4, n = 1,3,4 and 5, n = 2 are
given for the major tautomeric form in the solvents in which
the content of the major form was the highest. IR spectra were
recorded on a Nicolet Nexus 470 ESP FT/IR spectrometer.
Melting points were determined in open capillarity tubes with
an Buchi B-535 apparatus and uncorrected. Mass spectra were
obtained with an Agilent 1100 using chemical ionization. TLC
was conducted on Merck silica gel 60 F254 plates.
General procedure for synthesis of 7-hydroxyisoflavones 3a–3f
To a solution of benzoin (0.1 mol) in 70 mL of N,N-dimethyl-
formamide or N,N-dimethylacetamide at 30–40 °C was added
boron trifluoride (38 mL, 0.3 mol). The mixture was stirred for
0.5 h and phosphorous oxytrichloride (18.6 mL, 0.2 mol) was
added at the same temperature. The mixture was heated at
55–60 °C for 2 h (in the case of 3a–3c) or 6–8 h (in the case of
3d–3f). The mixture was poured into 500 mL of hot water with
vigorous stirring and then cooled. A precipitate was collected
and washed with water. Recrystallization from methanol gave
isoflavones 3a–3f as white or pale yellow powders.
7-Hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one (3a). Pale
yellow solid (20.9 g, 78%); mp 259–261 °C (lit.50 mp
1
256–258 °C); H NMR (400 MHz, DMSO-d6): δ 3.79 (s, 3H, 4′-
4
3
OCH3), 6.87 (d, 1H, J = 2.2 Hz, 8-H), 6.94 (dd, 1H, J = 9 Hz,
4J = 2.2 Hz, 6-H), 6.99 (d, 2H, J = 8.8 Hz, 3′, 5′-H), 7.52 (d, 2H,
3
Fig. 5 1H NMR spectra of tautomers 4b, n = 1 and 5b, n = 1. Panel A:
DMSO-d6, 20 °C; Panel B: DMSO-d6 and TFA, 20 °C; Panel C: DMSO-d6
and TFA, 60 °C.
3J = 8.8 Hz, 2′, 6′-H), 7.98 (d, 1H, J = 9 Hz, 5-H), 8.31 (s, 1H,
3
2-H), 10.73 ppm (s, 1H, 7-OH); 13C NMR (100 MHz, DMSO-d6):
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δ 55.09 (4′-OCH3), 102.09 (8-C), 113.55 (3′, 5′-C), 115.13 (6-C), 1H, 3J = 7.8 Hz, 4J = 1.5 Hz, 6′-H), 6.83 (d, 1H, 4J = 2.4 Hz, 8-H),
116.61 (4a-C), 123.14 (1′-C), 124.23 (3-C), 127.24 (5-C), 130.02 6.85 (d, 1H, 4J = 1.5 Hz, 2′-H), 6.90 (dd, 1H, 3J = 8.8 Hz, 4J = 2.4
(2′, 6′-C), 153.03 (2-C), 157.41 (8a-C), 158.92 (4′-C), 162.53 (7-C), Hz, 6-H), 6.99 (d, 1H, 3J = 7.8 Hz, 5′-H), 7.87 (d, 1H, 3J = 8.8 Hz,
174.56 ppm (4-C); IR (KBr): νmax 3131, 2979, 1639, 1624, 1568, 5-H), 10.74 ppm (s, 1H, 7-OH); 13C NMR (100 MHz, DMSO-d6):
1513, 1453, 1246 cm−1; MS (CI): m/z (%) 269.1 (100, MH+). δ 19.20 (2-CH3), 55.46, 55.52 (3′, 4′-OCH3), 101.89 (8-C), 111.38
Anal. Calcd for C16H12O4: C, 71.64; H, 4.51. Found: C, 71.71; (5′-C), 114.35 (2′-C), 114.72 (6-C), 115.62 (4a-C), 122.00 (1′-C),
H, 4.56.
122.84 (6′-C), 125.74 (3-C), 127.11 (5-C), 148.14, 148.26 (3′, 4′-
3-(3,4-Dimethoxyphenyl)-7-hydroxy-4H-chromen-4-one (3b). C), 157.03 (8a-C), 162.40 (2-C), 162.57 (7-C), 174.95 ppm (4-C);
White solid (24.8g, 83%); mp 254–256 °C (lit.51 mp IR (KBr): νmax 3151, 2953, 1630, 1593, 1516, 1453, 1269,
1
233–234 °C); H NMR (400 MHz, DMSO-d6): δ 3.79 (s, 6H, 3′, 1160 cm−1; MS (CI): m/z (%) 313.1 (100, MH+). Anal. Calcd for
4
3
4′-OCH3), 6.88 (d, 1H, J = 2.4 Hz, 8-H), 6.96 (dd, 1H, J = 8.8 C18H16O5: C, 69.22; H, 5.16. Found: C, 68.95; H, 5.27.
4
3
Hz, J = 2.4 Hz, 6-H), 7.01 (d, 1H, J = 8.3 Hz, 5′-H), 7.13 (dd,
3-(4-Fluorophenyl)-7-hydroxy-2-methyl-4H-chromen-4-one (3f).
1H, 3J = 8.3 Hz, 4J = 2.0 Hz, 6′-H), 7.20 (d, 1H, 4J = 2.0 Hz, 2′-H), Pale yellow solid (19.5 g, 72%); mp 284–285 °C; 1H NMR
7.99 (d, 1H, J = 8.8 Hz, 5-H), 8.38 (s, 1H, 2-H), 10.82 ppm (s, (400 MHz, DMSO-d6): δ 2.23 (s, 3H, 2-CH3), 6.83 (d, 1H, 4J = 1.7
3
1H, 7-OH); 13C NMR (100 MHz, DMSO-d6): δ 55.52 (3′, 4′- Hz, 8-H), 6.90 (dd, 1H, 3J = 8.8 Hz, 4J = 1.7 Hz, 6-H), 7.24 (t, 2H,
OCH3), 102.16 (8-C), 111.48 (5′-C), 112.79 (2′-C), 115.21 (6-C), 3J(H,H) = 8.8 Hz, J(C,F) = 8.8 Hz, 3′, 5′-H), 7.31 (dd, 2H, J(H,
3
3
4
3
116.68 (4a-C), 121.24 (6′-C), 123.30 (1′-C), 124.60 (3-C), 127.33 H) = 8.8 Hz, J(C,F) = 5.8 Hz, 2′, 6′-H), 7.87 (d, 1H, J = 8.8 Hz,
(5-C), 148.29, 148.61 (3′, 4′-C), 153.31 (2-C), 157.42 (8a-C), 5-H), 10.75 ppm (s, 1H, 7-OH); 13C NMR (100 MHz, DMSO-d6):
2
162.60 (7-C), 174.62 ppm (4-C); IR (KBr): νmax 3200, 3066, 2951, δ 19.16 (2-CH3), 101.93 (8-C), 114.84 (6-C), 114.90 (d, J(C,F) =
1625, 1586, 1515, 1214, 1175, 1136 cm−1; MS (CI): m/z (%) 21.5 Hz, 3′, 5′-C), 115.48 (4a-C), 121.16 (3-C), 127.10 (5-C),
299.2 (100, MH+). Anal. Calcd for C17H14O5: C, 68.45; H, 4.73. 129.61 (d, 4J(C,F) = 3.5 Hz, 1′-C), 132.61 (d, 3J(C,F) = 8.8 Hz, 2′,
1
Found: C, 68.32; H, 5.01.
6′-C), 157.07 (8a-C), 161.51 (d, J(C,F) = 244.2 Hz, 4′-C), 162.54
3-(4-Fluorophenyl)-7-hydroxy-4H-chromen-4-one (3c). Pale (7-C), 162.73 (2-C), 174.75 ppm (4-C); 19F NMR (376 MHz,
yellow solid (18.5 g, 72%); mp 233–235 °C (lit. mp52 DMSO-d6): δ −115.24 ppm; IR (KBr): νmax 3272, 3074, 1632,
202–203 °C; lit.53 235–236 °C); H NMR (400 MHz, DMSO-d6): 1585, 1511, 1452, 1227,1159 cm−1; MS (CI): m/z (%) 271.1 (100,
1
δ 6.88 (d, 1H, J = 2.2 Hz, 8-H), 6.95 (dd, 1H, J = 8.8 Hz, J = MH+ − 12). Anal. Calcd for C16H11FO3: C, 71.11; H, 4.10.
4
3
4
3
3
2.2 Hz, 6-H), 7.25 (t, 2H, J(H,H) = 8.8 Hz, J(C,F) = 8.8 Hz, 3′, Found: C, 71.02; H, 4.39.
5′-H), 7.61 (dd, 2H, J(H,H) = 8.8 Hz, 4J(C,F) = 5.6 Hz, 2′, 6′-H),
3
3
General procedure for synthesis of 7-hydroxy-2-
(trifluoromethyl)isoflavones 3g–3i
7.98 (d, 1H, J = 8.8 Hz, 5-H), 8.39 (s, 1H, 2-H), 10.81 ppm (s,
1H, 7-OH); 13C NMR (100 MHz, DMSO-d6): δ 102.22 (8-C),
2
114.99 (d, J(C,F) = 21.1 Hz, 3′, 5′-C), 115.31 (6-C), 116.58 (4a- To a solution of 10 mmol of the appropriate deoxybenzoin in
C), 122.59 (3-C), 127.32 (5-C), 128.46 (d, J(C,F) = 3.5 Hz, 1′-C), 20 mL of pyridine was added 30 mmol of trifluoroacetic anhy-
4
130.96 (d, 3J(C,F) = 8.1 Hz, 2′, 6′-C), 153.80 (2-C), 157.50 (8a-C), dride dropwise with cooling in an ice bath. After standing at
161.85 (d, 1J(C,F) = 244.6 Hz, 4′-C), 162.74 (7-C), 174.38 ppm 25 °C for 48 h, the mixture was poured into 100 mL of ice
(4-C); 19F NMR (376 MHz, DMSO-d6): δ −114.73 ppm; IR (KBr): water, and the precipitate was collected and recrystallized from
νmax 3421, 3072, 2906, 1635, 1595, 1510, 1332, 1227, 1145, methanol.
795 cm−1; MS (CI): m/z (%) 257.1 (100, MH+). Anal. Calcd for
C15H9FO3: C, 70.31; H, 3.54. Found: C, 70.60; H, 3.68.
7-Hydroxy-3-(4-methoxyphenyl)-2-(trifluoromethyl)-4H-
chromen-4-one (3g). Pale yellow solid (2.8 g, 67%); mp
149–151 °C; 1H NMR (400 MHz, DMSO-d6): δ 3.81 (s, 3H, 4′-
7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one
(3d). White solid (19.2 g, 68%); mp 286–288 °C; 1H NMR OCH3), 6.93 (d, 1H, 4J = 2.2 Hz, 8-H), 6.97–7.04 (m, 3H, 6, 3′, 5′-
3
3
(400 MHz, DMSO-d6): δ 2.23 (s, 3H, 2-CH3), 3.79 (s, 3H, 4′- H), 7.19 (d, 2H, J = 8.8 Hz, 2′, 6′-H), 7.93 (d, 1H, J = 9.0 Hz,
4
3
OCH3), 6.82 (d, 1H, J = 2 Hz, 8-H), 6.90 (dd, 1H, J = 8.8 Hz, 5-H), 11.06 ppm (s, 1H, 7-OH); 13C NMR (100 MHz, DMSO-d6):
4J = 2 Hz, 6-H), 6.98 (d, 2H, J = 8.8 Hz, 3′, 5′-H), 7.19 (d, 2H, δ 55.10 (4′-OCH3), 102.18 (8-C), 113.39 (3′, 5′-C), 115.41 (4a-C),
3
3J = 8.8 Hz, 2′, 6′-H), 7.87 (d, 1H, J = 8.8 Hz, 5-H), 10.74 ppm 116.26 (6-C), 119.45 (q, 1J(C,F) = 276.0 Hz, 2-CF3), 121.32 (1′-C),
3
(s, 1H, 7-OH); 13C NMR (100 MHz, DMSO-d6): δ 19.17 (2-CH3), 124.71 (3-C), 127.46 (5-C), 131.20 (2′, 6′-C), 146.49 (q, J(C,F) =
2
55.05 (4′-OCH3), 101.90 (8-C), 113.45 (3′, 5′-C), 114.72 (6-C), 34.8 Hz, 2-C), 156.44 (8a-C), 159.43 (4′-C), 163.84 (7-C),
115.79 (4a-C), 121.70 (1′-C), 125.34 (3-C), 127.12 (5-C), 131.71 175.21 ppm (4-C); 19F NMR (376 MHz, DMSO-d6):
δ
(2′, 6′-C), 157.05 (2-C), 158.51 (8a-C), 162.42, 162.44 (7, 4′-C), −63.07 ppm; IR (KBr): νmax 3296, 2971, 1638, 1604, 1455, 1274,
174.99 ppm (4-C); IR (KBr): νmax 3249, 2962, 1624, 1608, 1511, 1191 cm−1; MS (CI): m/z (%) 337.2 (100, MH+). Anal. Calcd for
1450, 1291, 1159 cm−1; MS (CI): m/z (%) 283.1 (100, MH+). C17H11F3O4: C, 60.72; H, 3.30. Found: C, 60.95; H, 3.48.
Anal. Calcd for C17H14O4: C, 72.33; H, 5.00. Found: C, 72.54;
H, 4.86.
3-(3,4-Dimethoxyphenyl)-7-hydroxy-2-(trifluoromethyl)-4H-
chromen-4-one (3h). Pale yellow solid (2.6 g, 71%); mp
232–233 °C; 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H, 3′-
3-(3,4-Dimethoxyphenyl)-7-hydroxy-2-methyl-4H-chromen-4-
one (3e). White solid (20g, 64%); mp 227–228 °C (lit.54 mp OCH3), 3.80 (s, 3H, 4′-OCH3), 6.79 (dd, 1H, 3J = 8.3 Hz, 4J =
226–228 °C); 1H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H, 2 Hz, 6′-H), 6.88 (d, 1H, J = 2 Hz, 2′-H), 6.94 (d, 1H, J = 2 Hz,
4
4
3
2-CH3), 3.74 (s, 3H, 3′-OCH3), 3.79 (s, 3H, 4′-OCH3), 6.78 (dd, 8-H), 6.99–7.04 (m, 2H, 6, 5′-H), 7.94 (d, 1H, J = 8.3 Hz, 5-H),
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11.13 ppm (s, 1H, 7-OH); 13C NMR (100 MHz, DMSO-d6): Hz, 2″-CH2), 3.92 (s, 3H, 3′-OCH3), 3.94 (s, 3H, 4′-OCH3), 4.23
δ 55.44 (3′-OCH3), 55.54 (4′-OCH3), 102.18 (8-C), 111.12 (5′-C), (s, 2H, 10-CH2), 5.00 (s, 2H, 8-CH2), 6.90 (d, 1H, 3J = 9 Hz,
113.71 (2′-C), 115.42 (4a-C), 116.29 (6-C), 119.44 (q, 1J(C,F) = 6-H), 6.93 (d, 1H, 3J = 8.3 Hz, 5′-H), 7.05 (dd, 1H, 4J = 2.1 Hz, 3J
4
276.0 Hz, 2-CF3), 121.55 (1′-C), 122.41 (6′-C), 124.89 (3-C), = 8.3 Hz, 6′-H), 7.21 (d, 1H, J = 2.1 Hz, 2′-H), 7.96 (s, 1H, 2-H),
2
127.49 (5-C), 146.49 (q, J(C,F) = 34.9 Hz, 2-C), 148.08, 148.98 8.10 ppm (d, 1H, 3J = 9 Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ
(3′, 4′-C), 156.40 (8a-C), 163.78 (7-C), 175.17 ppm (4-C); 19F 44.89 (1″-C), 53.78 (10-C), 55.94 (3′-OCH3), 55.96 (4′-OCH3),
NMR (376 MHz, DMSO-d6): δ −63.07 ppm; IR (KBr): νmax 3378, 59.33 (2″-C), 83.42 (8-C), 107.31 (10a-C), 111.19 (5′-C), 112.54
2942, 1650, 1611, 1516, 1270, 1214, 1140 cm−1; MS (CI): m/z (2′-C), 115.35 (6-C), 118.09 (4a-C), 121.03 (6′-C), 124.46 (1′-C),
(%) 367.2 (100, MH+). Anal. Calcd for C18H13F3O5: C, 59.02; H, 125.07 (3-C), 125.48 (5-C), 148.79, 149.18 (3′, 4′-C), 151.74 (2-C),
3.58. Found: C, 58.76; H, 3.45.
154.52 (10b-C), 158.41 (6a-C), 175.86 ppm (4-C); IR (KBr): νmax
3-(4-Fluorophenyl)-7-hydroxy-2-(trifluoromethyl)-4H-chromen- 3264, 2980, 2880, 1644, 1602, 1442, 1284, 1156 cm−1; MS (CI):
4-one (3i). Pale yellow solid (2.4 g, 75%); mp 212–213 °C; 1H m/z (%) 372.2 (100, MH+ − 12). Anal. Calcd for C21H21NO6: C,
4
NMR (400 MHz, DMSO-d6): δ 6.94 (d, 1H, J = 2 Hz, 8-H), 7.02 65.79; H, 5.52; N, 3.65. Found: C, 65.49; H, 5.41; N, 3.88.
(dd, 1H, 3J = 8.8 Hz, 4J = 2 Hz, 6-H), 7.21–7.36 (m, 4H, 3-
3-(4-Fluorophenyl)-9-(2-hydroxyethyl)-9,10-dihydro-4H,8H-
C6H4F), 7.92 (d, 1H, 3J = 8.8 Hz, 5-H), 11.07 ppm (s, 1H, 7-OH); chromeno[8,7-e][1,3]oxazin-4-one (4c, n = 1). White solid
13C NMR (100 MHz, DMSO-d6): δ 102.24 (8-C), 114.95 (d, J(C, (550 mg, 81%); mp 149–151 °C; H NMR (400 MHz, CDCl3): δ
2
1
F) = 21.1 Hz, 3′, 5′-C), 115.38 (4a-C), 116.37 (6-C), 119.33 (q, 2.98 (t, 2H, 3J = 5.1 Hz, 1″-CH2), 3.77 (t, 2H, 3J = 5.1 Hz, 2″-
1J(C,F) = 276.2 Hz, 2-CF3), 124.05 (3-C), 125.82 (d, J(C,F) = 3.5 CH2), 4.23 (s, 2H, 10-CH2), 5.01 (s, 2H, 8-CH2), 6.91 (d, 1H, 3J =
4
Hz, 1′-C), 127.48 (5-C), 132.12 (d, 3J(C,F) = 8.4 Hz, 2′, 6′-C), 8.8 Hz, 6-H), 7.13 (t, 2H, J(H,H) = 8.8 Hz, J(H,F) = 8.8 Hz, 3′,
3
3
146.64 (q, 2J(C,F) = 35.2 Hz, 2-C), 156.47 (8a-C), 162.27 (d, 1J(C, 5′-H), 7.53 (dd, 2H, 3J(H,H) = 8.8 Hz, 4J(H,F) = 5.5 Hz, 2′, 6′-H),
F) = 245.8 Hz, 4′-C), 163.92 (7-C), 175.02 ppm (4-C); 19F NMR 7.94 (s, 1H, 2-H), 8.10 ppm (d, 1H, J = 8.8 Hz, 5-H); 13C NMR
3
(376 MHz, DMSO-d6): δ −113.83, −63.24 ppm; IR (KBr): νmax (125 MHz, CDCl3): δ 44.89 (1″-C), 53.77 (10-C), 59.38 (2″-C),
2
3185, 1639, 1602, 1459, 1272, 1197, 1151 cm−1; MS (CI): m/z 83.45 (8-C), 107.40 (10a-C), 115.38 (d, J(C,F) = 21.9 Hz, 3′, 5′-
(%):325.1 (100, MH+). Anal. Calcd for C16H8F4O3: C, 59.27; H, C), 115.43 (6-C), 117.96 (4a-C), 124.48 (3-C), 125.41 (5-C),
2.49. Found: C, 59.53; H, 2.30.
127.68 (d, 4J(C,F) = 3.5 Hz, 1′-C), 130.64 (d, 3J(C,F) = 8.0 Hz, 2′,
1
6′-C), 151.93 (2-C), 154.54 (10b-C), 158.55 (6a-C), 162.70 (d, J
General procedures for the aminomethylation of
7-hydroxyisoflavones 3 with 2-aminoethanol
Method A. A solution of 2.5 mmol of isoflavones 3a–3i, 3 mmol 1600, 1442, 1250 cm−1; MS (CI): m/z (%) 330.2 (100, MH+
(C,F) = 247.8 Hz, 4′-C), 175.50 ppm (4-C); 19F NMR (376 MHz,
CDCl3): δ −114.14 ppm; IR (KBr): νmax 3434, 2950, 2860, 1632,
−
of 2-aminoethanol, 6 mmol of aqueous 37% formaldehyde, 12). Anal. Calcd for C19H16FNO4: C, 66.86; H, 4.72; N, 4.10.
and 1–2 mg of 4-(N,N-dimethylamino)pyridine in 10 mL of Found: C, 67.03; H, 4.61; N, 4.12.
solvent (see Table 1) was refluxed for 4–6 h. The mixture was
9-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-2-methyl-9,10-
cooled, and the precipitate was collected. If precipitation did dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4d,
n
=
not occur, the mixture was diluted with 10 mL of hexane or 1). White solid (342 mg, 47%); mp 151–153 °C; 1H NMR
the solution was concentrated. The products were recrystal- (400 MHz, CDCl3): δ 2.31 (s, 3H, 2-CH3), 2.99 (t, 2H, 3J = 5.2
lized from a mixture of isopropanol and hexane.
9-(2-Hydroxyethyl)-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H- OCH3), 4.23 (s, 2H, 10-CH2), 4.99 (s, 2H, 8-CH2), 6.85 (d, 1H,
Hz, 1″-CH2), 3.77 (t, 2H, 3J = 5.2 Hz, 2″-CH2), 3.85 (s, 3H, 4′-
3
chromeno[8,7-e][1,3]oxazin-4-one (4a,
n =
1). White solid 3J = 8.9 Hz, 6-H), 6.97 (d, 2H, J = 8.7 Hz, 3′, 5′-H), 7.20 (d, 2H,
(480 mg, 68%); mp 114–116 °C; H NMR (400 MHz, CDCl3): δ 3J = 8.7 Hz, 2′, 6′-H), 8.02 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C
2.98 (t, 2H, 3J = 5.2 Hz, 1″-CH2), 3.77 (t, 2H, 3J = 5.2 Hz, 2″- NMR (125 MHz, CDCl3): δ 19.36 (2-CH3), 44.97 (1″-C), 53.75
CH2), 3.85 (s, 3H, 4′-OCH3), 4.23 (s, 2H, 10-CH2), 5.00 (s, 2H, (10-C), 55.25 (4′-OCH3), 59.30 (2″-C), 83.32 (8-C), 106.95 (10a-
1
3
3
8-CH2), 6.89 (d, 1H, J = 8.9 Hz, 6-H), 6.98 (d, 2H, J = 9 Hz, 3′, C), 113.87 (3′, 5′-C), 114.82 (6-C), 116.99 (4a-C), 123.08 (1′-C),
5′-H), 7.49 (d, 2H, 3J = 9 Hz, 2′, 6′-H), 7.93 (s, 1H, 2-H), 125.10 (3-C), 125.40 (5-C), 131.49 (2′, 6′-C), 154.17 (10b-C),
8.10 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3): 158.16 (2-C), 159.10 (4′-C), 162.23 (6a-C), 176.48 ppm (4-C);
δ 44.83 (1″-C), 53.70 (10-C), 55.23 (4′-OCH3), 59.35 (2″-C), 83.38 IR (KBr): νmax 3434, 2925, 2833, 1630, 1606, 1437, 1246 cm−1
;
(8-C), 107.32 (10a-C), 113.85 (3′, 5′-C), 115.17 (6-C), 117.93 (4a- MS (CI): m/z (%) 356.3 (100, MH+ − 12). Anal. Calcd for
C), 123.94 (1′-C), 124.83 (3-C), 125.30 (5-C), 130.00 (2′, 6′-C), C21H21NO5: C, 68.65; H, 5.76; N, 3.81. Found: C, 68.77; H, 5.51;
151.53 (2-C), 154.45 (10b-C), 158.31 (4′-C), 159.50 (6a-C), N, 3.94.
175.76 ppm (4-C); IR (KBr): νmax 3410, 2958, 2846, 1632, 1592,
1434, 1250 cm−1; MS (CI): m/z (%) 342.2 (100, MH+ − 12). Anal. dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4e,
Calcd for C20H19NO5: C, 67.98; H, 5.42; N, 3.96. Found: C, 1). White solid (431 mg, 54%); mp 168–170 °C (decomp); H
3-(3,4-Dimethoxyphenyl)-9-(2-hydroxyethyl)-2-methyl-9,10-
n
=
1
3
68.25; H, 5.31; N, 4.15.
NMR (400 MHz, CDCl3): δ 2.31 (s, 3H, 2-CH3), 2.98 (t, 2H, J =
3-(3,4-Dimethoxyphenyl)-9-(2-hydroxyethyl)-9,10-dihydro- 5.2 Hz, 1″-CH2), 3.76 (t, 2H, 3J = 5.2 Hz, 2″-CH2), 3.88 (s, 3H, 3′-
4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4b, n = 1). White OCH3), 3.91 (s, 3H, 4′-OCH3), 4.22 (s, 2H, 10-CH2), 4.99 (s, 2H,
solid (375 mg, 49%); mp 126–128 °C; 1H NMR (400 MHz, 8-CH2), 6.78–6.83 (m, 2H, 2′, 5′-H), 6.85 (d, 1H, 3J = 8.8 Hz,
CDCl3): δ 2.98 (t, 2H, J = 5.2 Hz, 1″-CH2), 3.77 (t, 2H, J = 5.2 6-H), 6.91–6.69 (m, 1H, 6′-H), 8.01 ppm (d, 1H, 3J = 8.8 Hz,
3
3
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5-H); 13C NMR (125 MHz, CDCl3): δ 19.34 (2-CH3), 44.92 (1″-C), 276.0 Hz, 2-CF3), 121.60 (3-C), 124.01 (1′-C), 125.65 (5-C),
2
53.69 (10-C), 55.81 (3′, 4′-OCH3), 59.30 (2″-C), 83.29 (8-CH2), 131.01 (2′, 6′-C), 145.05 (q, J(C,F) = 34.8 Hz, 2-C), 154.48 (8a-
106.95 (10a-C), 111.13 (5′-C), 113.60 (2′-C), 114.78 (6-C), 116.88 C), 159.07 (4-C), 171.42 (7-C), 174.12 ppm (4′-C); 19F NMR
(4a-C), 122.70 (6′-C), 123.19 (1′-C), 125.25 (5-C), 125.48 (3-C), (376 MHz, DMSO-d6): δ −61.96 ppm; IR (KBr): νmax 3427, 2912,
148.55, 148.70 (3′, 4′-C), 154.09 (10b-C), 158.15 (2-C), 162.34 1639, 1608, 1396, 1286, 1180 cm−1; MS (CI): m/z (%) 410.1
(6a-C), 176.37 ppm (4-C); IR (KBr): νmax 3474, 2964, 2930, 2834, (100, MH+). Anal. Calcd for C20H18F3NO5: C, 58.68; H, 4.43; N,
1634, 1620, 1434, 1252 cm−1; MS (CI): m/z (%) 386.1 (100, MH+ 3.42. Found: C, 58.81; H, 4.21; N, 3.58.
− 12). Anal. Calcd for C22H23NO6: C, 66.49; H, 5.83; N, 3.52.
3-(3,4-Dimethoxyphenyl)-7-hydroxy-8-{[(2-hydroxyethyl)-
Found: C, 66.65; H, 5.91; N, 3.37.
3-(4-Fluorophenyl)-9-(2-hydroxyethyl)-2-methyl-9,10-dihydro- n = 1). White solid (595 mg, 63%); mp 230–232 °C; H NMR
amino]methyl}-2-(trifluoromethyl)-4H-chromen-4-one (6h,
1
4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4f,
n = 1). White (400 MHz, DMSO-d6): δ 2.96–3.13 (m, 2H, 1″-CH2), 3.68–3.90
solid (465 mg, 65%); mp 112–114 °C; 1H NMR (400 MHz, (m, 8H, 3′, 4′-OCH3, 2″-CH2), 4.32 (s, 2H, 8-CH2), 5.20–5.40 (br.
3
CDCl3): δ 2.30 (s, 3H, 2-CH3), 2.98 (t, 2H, J = 5.2 Hz, 1″-CH2), s, 1H, OH), 6.76–6.86 (m, 2H, 2′, 6′-H), 7.04 (d, 1H, 3J = 8.1 Hz,
3
3
3
3.77 (t, 2H, J = 5.2 Hz, 2″-CH2), 4.23 (s, 2H, 10-CH2), 4.99 (s, 5′-H), 7.31 (d, 1H, J = 9 Hz, 6-H), 8.01 (d, 1H, J = 9 Hz, 5-H),
2H, 8-CH2), 6.85 (d, 1H, 3J = 9.2 Hz, 6-H), 7.12 (t, 2H, 3J(H,H) = 8.70–9.28 (br. s, 2H, NH2 ), 11.91–12.52 ppm (br. s, 1H, 7-OH);
+
3
3
8.5 Hz, J(H,F) = 8.5 Hz, 3′, 5′-H), 7.25 (dd, 2H, J(H,H) = 8.5 13C NMR (125 MHz, DMSO-d6): δ 38.46 (1″-C), 49.33 (8-CH2),
Hz, 4J(H,F) = 5.6 Hz, 2′, 6′-H), 8.01 ppm (d, 1H, 3J = 9.2 Hz, 55.44 (3′-OCH3), 55.53 (4′-OCH3), 56.17 (2″-C), 105.56 (8-C),
5-H); 13C NMR (125 MHz, CDCl3): δ 19.38 (2-CH3), 45.05 (1″-C), 111.18 (5′-C), 113.58 (2′-C), 115.14 (6-C), 115.48 (4a-C), 119.27
53.82 (10-C), 59.43 (2″-C), 83.44 (8-C), 107.13 (10a-C), 115.03 (q, 1J(C,F) = 276.3 Hz, 2-CF3), 121.05 (6′-C), 122.33 (1′-C),
(6-C), 115.39 (d, 2J(C,F) = 21.9 Hz, 3′, 5′-C), 116.92 (4a-C), 124.71 (3-C), 127.88 (5-C), 146.55(q, 2J(C,F) = 35.9 Hz, 2-C),
124.64 (3-C), 125.36 (5-C), 128.93 (d, 4J(C,F) = 3.5 Hz, 1′-C), 147.99, 148.97 (3′, 4′-C), 154.75 (8a-C), 162.74 (7-C),
3
132.17 (d, J(C,F) = 8.0 Hz, 2′, 6′-C), 154.23 (10b-C), 158.41 (2- 175.08 ppm (4-C); 19F NMR (376 MHz, DMSO-d6):
δ
C), 162.37 (d, 1J(C,F)
= 246.8 Hz, 4′-C), 162.38 (6a-C), −60.72 ppm; IR (KBr): νmax 3400, 3126, 2962, 1655, 1612, 1454,
176.22 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ −114.83 ppm; 1272 cm−1; MS (CI): m/z (%) 440.1 (100, MH+). Anal. Calcd for
IR (KBr): νmax 3436, 2946, 2844, 1634, 1604, 1510, 1436, C21H20F3NO6-HCl: C, 53.01; H, 4.45; N, 2.94. Found: C, 52.83;
1248 cm−1; MS (CI): m/z (%) 344.1 (100, MH+ − 12). Anal. H, 4.20; N, 3.28.
Calcd for C20H18FNO4: C, 67.60; H, 5.11; N, 3.94. Found: C,
3-(4-Fluorophenyl)-7-hydroxy-8-{[(2-hydroxyethyl)amino]
67.51; H, 4.88; N, 3.79.
methyl}-2-(trifluoromethyl)-4H-chromen-4-one (6i,
n
=
1
3-(3,4-Dimethoxyphenyl)-9-(2-hydroxyethyl)-2-(trifluoro- 1). White solid (639 mg, 80%); mp 216–218 °C (decomp); H
3
methyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one NMR (400 MHz, DMSO-d6): δ 2.87 (t, 2H, J = 5.4 Hz, 1″-CH2),
(4h, n = 1). White solid (540 mg, 60%); mp 168–170 °C; 1H 3.60 (t, 2H, J = 5.4 Hz, 2″-CH2), 4.18 (s, 2H, 8-CH2), 6.60 (d,
3
NMR (400 MHz, CDCl3): δ 2.99 (t, 2H, 3J = 5.1 Hz, 1″-CH2), 3.78 1H, J = 9 Hz, 6-H), 7.23–7.33 (m, 4H, 3-C6H4F), 7.69 ppm (d,
3
3
(t, 2H, J = 5.1 Hz, 2″-CH2), 3.88 (s, 3H, 3′- OCH3), 3.93 (s, 3H, 1H, 3J = 9 Hz, 5-H); 13C NMR (100 MHz, DMSO-d6): δ 42.56 (1″-
4′-OCH3), 4.26 (s, 2H, 10-CH2), 5.03 (s, 2H, 8-CH2), 6.76–6.86 C), 49.00 (8-CH2), 57.82 (2″-C), 105.46 (8-C), 110.27 (4a-C),
(m, 2H, 2′, 6′-H), 6.92–6.96 (m, 2H, 6, 5′-H), 8.03 ppm (d, 1H, 114.69 (d, 2J(C,F) = 21.5 Hz, 3′, 5′-C), 119.39 (6-C), 119.44 (q, 1J
3J = 9 Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ 44.70 (1″-C), (C,F) = 276.1 Hz, 2-CF3), 123.34 (3-C), 125.66 (5-C), 126.17 (d,
53.80 (10-C), 55.81 (3′-OCH3), 55.84 (4′-OCH3), 59.33 (2″-C), 4J(C,F) = 3.0 Hz, 1′-C), 131.98 (d, 3J(C,F) = 8.0 Hz, 2′, 6′-C),
83.67 (8-C), 107.57 (10a-C), 110.84 (5′-C), 113.07 (2′-C), 116.36 145.14 (q, 2J(C,F) = 35.0 Hz, 2-C), 154.69 (8a-C), 161.97 (d, 1J(C,
(6-C), 116.78 (4a-C), 119.44 (q, 1J(C,F) = 277.8 Hz, 2-CF3), F) = 244.7 Hz, 4′-C), 172.27 (7-C), 173.77 ppm (4-C); 19F NMR
121.09 (6′-C), 122.50 (1′-C), 125.57 (5-C), 127.78 (3-C), 148.02 (376 MHz, DMSO-d6): δ −112.03, −61.00 ppm; IR (KBr): νmax
(q, 2J(C,F) = 35.9 Hz, 2-C), 148.59, 149.49 (3′, 4′-C), 153.37 (10b- 3425, 2913, 1639, 1601, 1450, 1286, 1143 cm−1; MS (CI): m/z
C), 159.51 (6a-C), 176.25 ppm (4-C); 19F NMR (376 MHz, (%) 398.1 (100, MH+). Anal. Calcd for C19H15F4NO4: C, 57.44;
CDCl3): δ −63.95 ppm; IR (KBr): νmax 3527, 2940, 2913, 2839, H 3.81; N, 3.53. Found: C, 57.41; H, 3.98; N, 3.76.
1651, 1608, 1435, 1216, 1144, 1134 cm−1; MS (CI): m/z (%)
440.1 (100, MH+ − 12). Anal. Calcd for C22H20F3NO6: C, 58.54; 3 mmol of bis(1,3-oxazolidin-3-yl)methane55,56 in 10 mL of 1,4-
H, 4.47; N, 3.10. Found: C, 58.30; H, 4.66; N, 2.83. dioxane was refluxed for 2–4 h. The mixture was cooled; the
7-Hydroxy-8-{[(2-hydroxyethyl)amino]methyl}-3-(4-methoxy- solvent was evaporated; and the product was treated with
Method B. A solution of 2.5 mmol of isoflavone 3a or 3d,
phenyl)-2-(trifluoromethyl)-4H-chromen-4-one (6g,
n
=
hexane to obtain a precipitate that was recrystallized from a
1). White solid (600 mg, 73%); mp 207–208 °C; 1H NMR mixture of isopropanol and hexane to afford 3a or 3d. Com-
(400 MHz, DMSO-d6): δ 2.86 (t, 2H, 3J = 5.4 Hz, 1″-CH2), 3.60 (t, pounds 3a and 3d were identical to material synthesized by
2H, 3J = 5.4 Hz, 2″-CH2), 3.80 (s, 3H, 4′-OCH3), 4.19 (s, 2H, Method A.
3
3
8-CH2), 6.63 (d, 1H, J = 9 Hz, 6-H), 6.99 (d, 2H, J = 8.5 Hz, 3′,
Method C. A solution of 2.5 mmol of isoflavone 3b–3e and
3
3
5′-H), 7.16 (d, 2H, J = 8.5 Hz, 2′, 6′-H), 7.71 ppm (d, 1H, J = 3 mmol of 3-butoxymethyl-1,3-oxazolidine57 in 10 mL of 1,4-
9 Hz, 5-H); 13C NMR (125 MHz, DMSO-d6): δ 42.74 (1″-C), dioxane was refluxed for 2–4 h. The mixture was cooled; the
49.04 (8-CH2), 55.04 (4′-OCH3), 57.92 (2″-C), 105.58 (8-C), solvent was evaporated; and the product was isolated in the
110.73 (4a-C), 113.17 (3′, 5′-C), 118.96 (6-C), 119.93 (q, 1J(C,F) = same fashion as described in Method A.
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Synthesis of 8-(2-hydroxyethylaminomethyl)-7-
hydroxyisoflavone hydrochlorides 6a–6f where n = 1
131.38 (d, 3J(C,F) = 8.5 Hz, 2′, 6′-C), 155.01 (2-C), 156.68 (8a-C),
162.25 (7-C), 163.15 (d, 1J(C,F) = 245.3 Hz, 4′-C), 178.08 ppm
(4-C); 19F NMR (376 MHz, D2O): δ −113.50 ppm; IR (KBr): νmax
A solution of 2.5 mmol of isoflavone 3a–3f, 3 mmol of 2- 3423, 2964, 1635, 1623, 1508, 1442, 1267 cm−1; MS (CI): m/z
aminoethanol, 6 mmol of aqueous 37% formaldehyde, and (%) 330.2 (100, MH+). Anal. Calcd for C18H16FNO4-HCl: C,
1–2 mg of 4-(N,N-dimethylamino)pyridine in 10 mL of ethanol 59.10; H, 4.68; N, 3.83. Found: C, 58.78; H, 4.91; N, 3.15.
was refluxed for 4–6 h. To this mixture was added 0.2 mL of
7-Hydroxy-8-{[(2-hydroxyethyl)amino]methyl}-3-(4-methoxy-
concentrated hydrochloric acid, and the mixture was refluxed phenyl)-2-methyl-4H-chromen-4-one hydrochloride (6d, n =
for 10–15 min. The product was cooled to afford precipitated 1). White solid (538 mg, 69%); mp 207–209 °C; 1H NMR
hydrochlorides that were collected and recrystallized from a (400 MHz, DMSO-d6): δ 2.33 (s, 3H, 2-CH3), 3.02–3.10 (m, 2H,
mixture of methanol and acetonitrile.
1″-CH2), 3.72–3.77 (m, 2H, 2″-CH2), 3.79 (s, 3H, 4′-OCH3),
7-Hydroxy-8-{[(2-hydroxyethyl)amino]methyl}-3-(4-methoxy- 4.30–4.37 (m, 2H, 8-CH2), 6.99 (d, 2H, 3J = 8.8 Hz, 3′, 5′-H),
phenyl)-4H-chromen-4-one hydrochloride (6a, n = 1). White 7.16–7.22 (m, 3H, 6, 2′, 6′-H), 7.94 (d, 1H, 3J = 8.8 Hz, 5-H),
solid (591 mg, 78%); mp 187–191 °C; 1H NMR (400 MHz, 8.97–9.05 (m, 2H, NH2 ), 11.78 ppm (br. s, 1H, 7-OH); 13C
+
DMSO-d6): δ 2.99–3.10 (m, 2H, 1″-CH2), 3.66–3.74 (m, 2H, 2″- NMR (125 MHz, D2O): δ 19.51 (2-CH3), 39.64 (1″-C), 49.27 (8-
CH2), 3.80 (s, 3H, 4′-OCH3), 4.28–4.37 (m, 2H, 8-CH2), 7.01 (d, CH2), 56.05 (4′-OCH3), 56.97 (2″-C), 105.02 (8-C), 114.67 (3′, 5′-
3
3
2H, J = 8.7 Hz, 3′, 5′-H), 7.20 (d, 1H, J = 8.9 Hz, 6-H), 7.51 (d, C), 114.94 (6-C), 116.02 (4a-C), 122.46 (1′-C), 125.30 (3-C),
3
3
2H, J = 8.7 Hz, 2′, 6′-H), 8.05 (d, 1H, J = 8.9 Hz, 5-H), 8.43 (s, 128.95 (5-C), 132.26 (2′, 6′-C), 156.23 (8a-C), 159.26 (4′-C),
+
1H, 2-H), 8.88–8.98 (m, 2H, NH2 ), 11.84 ppm (br. s, 1H, 161.89 (2-C), 166.19 (7-C), 178.73 ppm (4-C); IR (KBr): νmax
7-OH); 13C NMR (125 MHz, D2O): δ 39.56 (1″-C), 49.23 (8-CH2), 3392, 2962, 1641, 1631, 1513, 1450, 1267 cm−1; MS (CI): m/z
55.81 (4′-OCH3), 56.96 (2″-C), 105.02 (8-C), 114.30 (3′, 5′-C), (%) 356.3 (100, MH+). Anal. Calcd for C20H21NO5-HCl: C,
115.26 (6-C), 116.95 (4a-C), 123.79, 123.82 (3, 1′-C), 129.10 (5- 61.30; H, 5.66; N, 3.57. Found: C, 61.58; H, 5.93; N, 3.84.
C), 130.37 (2′, 6′-C), 154.43 (2-C), 156.36 (8a-C), 159.25 (4′-C),
3-(3,4-Dimethoxyphenyl)-7-hydroxy-8-{[(2-hydroxyethyl)-
162.02 (7-C), 177.76 ppm (4-C); IR (KBr): νmax 3388, 2958, 2834, amino]methyl}-2-methyl-4H-chromen-4-one hydrochloride
1626, 1512, 1448, 1294 cm−1; MS (CI): m/z (%) 342.2 (100, (6e, n = 1). White solid (540 mg, 64%); mp 234–236 °C; 1H
MH+). Anal. Calcd for C19H19NO5-HCl: C, 60.40; H, 5.34; N, NMR (400 MHz, DMSO-d6): δ 2.33 (s, 3H, 2-CH3), 3.01–3.09 (m,
3.71. Found: C, 60.16; H, 5.48; N, 4.25.
2H, 1″-CH2), 3.68–3.82 (m, 8H, 3′, 4′-OCH3, 2″-CH2), 4.29–4.37
3-(3,4-Dimethoxyphenyl)-7-hydroxy-8-{[(2-hydroxyethyl)- (m, 2H, 8-CH2), 5.29–5.38 (br. s, 1H, CH2OH), 6.78 (dd, 1H,
3
4
amino]methyl}-4H-chromen-4-one hydrochloride (6b, n = 4J = 1.7 Hz, J = 8.3 Hz, 6′-H), 6.82 (d, 1H, J = 1.7 Hz, 2′-H),
3
1). White solid (565 mg, 69%); mp 221–223 °C; 1H NMR 7.01 (d, 1H, J = 8.3 Hz, 5′-H), 7.18 (d, 1H, 3J = 8.8 Hz, 6-H),
+
(400 MHz, DMSO-d6): δ 3.01–3.09 (m, 2H, 1″-CH2), 3.69–3.75 7.94 (d, 1H, 3J = 8.8 Hz, 5-H), 8.91–9.05 (br. s, 2H, NH2 ),
(m, 2H, 2″-CH2), 3.79 (s, 6H, 3′, 4′-OCH3), 4.30–4.37 (m, 2H, 8- 11.77 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, D2O): δ 19.49 (2-
3
3
CH2), 7.02 (d, 1H, J = 8.5 Hz, 5′-H), 7.13 (dd, 1H, J = 8.5 Hz, CH3), 39.61 (1″-C), 49.31 (8-CH2), 56.32 (3′-OCH3), 56.36 (4′-
4J = 1.7 Hz, 6′-H), 7.18 (d, 1H, J = 1.7 Hz, 2′-H), 7.23 (d, 1H, OCH3), 56.97 (2″-C), 105.02 (8-C), 112.30 (5′-C), 114.70 (6-C),
4
3J = 9 Hz, 6-H), 8.05 (d, 1H, J = 9 Hz, 5-H), 8.46 (s, 1H, 2-H), 114.90 (2′-C), 116.01 (4a-C), 122.57 (1′-C), 124.04 (6′-C), 125.69
3
+
8.92–9.05 (m 2H, NH2 ), 11.85 ppm (br. s, 1H, 7-OH); 13C NMR (3-C), 128.91 (5-C), 148.59, 148.62 (3′, 4′-C), 156.17 (8a-C),
(125 MHz, D2O): δ 39.63 (1″-C), 49.35 (8-CH2), 55.84 (3′-OCH3), 161.86 (2-C), 166.22 (7-C), 178.56 ppm (4-C); IR (KBr): νmax
56.06 (4′-OCH3), 59.99 (2″-C), 104.96 (8-C), 111.60 (5′-C), 112.09 3436, 2996, 1637, 1608, 1518, 1446, 1265 cm−1; MS (CI): m/z
(2′-C), 115.15 (6-C), 116.90 (4a-C), 121.60 (6′-C), 123.36 (1′-C), (%) 386.1 (100, MH+). Anal. Calcd for C21H23NO6-HCl: C,
124.04 (3-C), 129.05 (5-C), 147.82, 148.32 (3′, 4′-C), 154.49 (2-C), 59.79; H, 5.73; N, 3.32. Found: C, 60.02; H, 6.00; N, 3.13.
156.06 (8a-C), 161.91 (7-C), 177.47 ppm (4-C); IR (KBr): νmax
3-(4-Fluorophenyl)-7-hydroxy-8-{[(2-hydroxyethyl)amino]-
3427, 3247, 3016, 1645, 1622, 1516, 1450, 1286 cm−1; MS (CI): methyl}-2-methyl-4H-chromen-4-one hydrochloride (6f, n =
m/z (%) 372.2 (100, MH+). Anal. Calcd for C20H21NO6-HCl: C, 1). White solid (465 mg, 61%); mp 140–142 °C; 1H NMR
58.90; H, 5.44; N, 3.43. Found: C, 58.61; H, 5.72; N, 3.38.
(400 MHz, DMSO-d6): δ 2.32 (s, 3H, 2-CH3), 3.03–3.11 (m, 2H,
3-(4-Fluorophenyl)-7-hydroxy-8-{[(2-hydroxyethyl)amino]- 1″-CH2), 3.70–3.77 (m, 2H, 2″-CH2), 4.34 (s, 2H, 8-CH2), 5.32
methyl}-4H-chromen-4-one hydrochloride (6c,
n
=
(br. s, 1H, OH), 7.17 (d, 1H, 3J = 8.5 Hz, 6-H), 7.24–7.34 (m, 4H,
1). White solid (551 mg, 75%); mp 238–240 °C; 1H NMR 3-C6H4F), 7.95 (d, 1H, 3J = 8.5 Hz, 5-H), 8.89–9.08 (br. s, 2H,
+
(400 MHz, DMSO-d6): δ 2.99–3.91(m, 2H, 1″-CH2), 3.68–3.75 NH2 ), 11.79 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, D2O): δ
(m, 2H, 2″-CH2), 4.33 (s, 2H, 8-CH2), 7.24 (d, 1H, 3J = 8.8 Hz, 6- 19.45 (2-CH3), 39.61 (1″-C), 49.27 (8-CH2), 56.96 (2″-C), 105.09
H), 7.29 (t, 2H, 3J(H,H) = 7.8 Hz, 3J(H,F) = 7.8 Hz, 3′, 5′-H), 7.61 (8-C), 115.03 (6-C), 115.94 (4a-C), 116.18 (d, J(C,F) = 21.9 Hz,
2
3
4
4
(dd, 2H, J(H,H) = 7.8 Hz, J(H,F) = 5.9 Hz, 2′, 6′-H), 8.05 (d, 3′, 5′-C), 122.25 (3-C), 128.82 (d, J(C,F) = 3.0 Hz, 1′-C), 128.94
1H, 3J = 8.8 Hz, 5-H), 8.49 (s, 1H, 2-H), 8.96–9.06 (br. s, 2H, (5-C), 132.85 (d, 3J(C,F) = 8.5 Hz, 2′, 6′-C), 156.36 (8a-C), 162.07
NH2 ), 11.92 ppm (s, 1H, 7-OH); 13C NMR (125 MHz, D2O): δ (2-C), 162.98 (d, 1J(C,F) = 247.8 Hz, 4′-C), 166.55 (7-C),
+
39.61, (1″-C), 49.29 (8-CH2), 56.96 (2″-C), 105.29 (8-C), 115.48 178.88 ppm (4-C); 19F NMR (376 MHz, D2O): δ −113.79 ppm;
(6-C), 116.01 (d, 2J(C,F) = 21.4 Hz, 3′, 5′-C), 117.00 (4a-C), IR (KBr): νmax 3403, 2962, 1637, 1601, 1508, 1448, 1211 cm−1
;
124.04 (3-C), 127.43 (d, 4J(C,F) = 3.5 Hz, 1′-C), 129.14 (5-C), MS (CI): m/z (%) 344.1 (100, MH+). Anal. Calcd for
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C19H18FNO4-HCl: C, 60.08; H, 5.04; N, 3.69. Found: C, 59.86; C), 127.89 (d, 4J(C,F) = 3.0 Hz, 1′-C), 130.65 (d, 3J(C,F) = 7.5 Hz,
1
H, 5.25; N, 3.98.
2′, 6′-C), 151.73 (2-C), 155.25 (8a-C), 162.69 (d, J(C,F) = 246.3
Hz, 4′-C), 163.66 (7-C), 175.52 ppm (4-C); 19F NMR (376 MHz,
CDCl3): δ −114.37 ppm; IR (KBr): νmax 3427, 2850, 1632, 1597,
1510, 1414,1232 cm−1; MS (CI): m/z (%) 344.3 (100, MH+ − 12).
General procedure for the aminomethylation of
7-hydroxyisoflavones 3 with 3-amino-1-propanol
A solution of 2.5 mmol of isoflavone 3a–3i, 3 mmol of Anal. Calcd for C20H18FNO4: C, 67.60; H, 5.11; N, 3.94. Found:
3-amino-1-propanol, 6 mmol of aqueous 37% formaldehyde, C, 67.38; H, 5.34; N, 4.17.
and 1–2 mg of 4-(N,N-dimethylamino)pyridine in 10 mL of iso-
7-Hydroxy-3-(4-methoxyphenyl)-2-methyl-8-(1,3-oxazinan-3-
propanol was refluxed for 4–6 h. The mixture was cooled and ylmethyl)-4H-chromen-4-one (5d, n = 2). White solid (444 mg,
1
the precipitate was collected. If precipitation did not occur, the 58%); mp 258–260 °C; H NMR (500 MHz, CDCl3): δ 1.79–1.91
mixture was concentrated, and the residue was treated with (m, 2H, 5″-CH2), 2.31 (s, 2H, 2-CH3), 2.96–3.06 (m, 2H, 4″-
hexane. The precipitated material was recrystallized from a CH2), 3.84 (s, 3H, 4′-OCH3), 3.88–3.96 (m, 2H, 6″-CH2), 4.28 (s,
3
mixture of isopropanol and hexane.
2H, 8-CH2), 4.40 (s, 2H, 2″-CH2), 6.86 (d, 1H, J = 8.8 Hz, 6-H),
3
3
7-Hydroxy-3-(4-methoxyphenyl)-8-(1,3-oxazinan-3-ylmethyl)- 6.96 (d, 2H, J = 8.3 Hz, 3′, 5′-H), 7.20 (d, 2H, J = 8.3 Hz, 2′, 6′-
4H-chromen-4-one (5a, n = 2). White solid (550 mg, 75%); mp H), 8.05 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (125 MHz,
1
129–131 °C; H NMR (500 MHz, CDCl3): δ 1.77–19.91 (m, 2H, CDCl3): δ 19.41 (2-CH3), 22.31 (5″-C), 47.48 (4″-C), 49.43 (8-
5″-CH2), 2.97–3.05 (m, 2H, 4″-CH2), 3.83 (s, 3H, 4′-OCH3), CH2), 55.29 (4′-OCH3), 67.84 (6″-C), 83.98 (2″-C), 106.59 (8-C),
3.86–3.93 (m, 2H, 6″-CH2), 4.28 (s, 2H, 8-CH2), 4.38 (s, 2H, 2″- 113.88 (3′, 5′-C), 115.17 (6-C), 116.33 (4a-C), 122.68 (1′-C),
3
3
CH2), 6.89 (d, 1H, J = 8.7 Hz, 6-H), 6.96 (d, 2H, J = 8.7 Hz, 3′, 125.38 (3-C), 126.84 (5-C), 131.58 (2′, 6′-C), 154.89 (8a-C),
5′-H), 7.48 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H), 7.90 (s, 1H, 2-H), 159.09 (2-C), 161.81 (4′-C), 163.23 (7-C), 176.44 ppm (4-C); IR
8.13 ppm (d, 1H, 3J = 8.7 Hz, 5-H); 13C NMR (125 MHz, CDCl3): (KBr): νmax 3432, 2958, 1651, 1606, 1400, 1261, 1213,
δ 22.11 (5″-C), 47.08 (4″-C), 49.48 (8-CH2), 55.26 (4′-OCH3), 1140 cm−1; MS (CI): m/z (%) 412.1 (100, MH+ − 12). Anal.
67.71 (6″-C), 83.59 (2″-C), 106.68 (8-C), 113.88 (3′, 5′-C), 115.59 Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found: C,
(6-C), 117.30 (4a-C), 124.15 (1′-C), 124.48 (3-C), 126.95 (5-C), 68.99; H, 6.22; N, 3.89.
130.05 (2′, 6′-C), 151.38 (2-C), 155.25 (8a-C), 159.52 (4′-C),
3-(3,4-Dimethoxyphenyl)-7-hydroxy-2-methyl-8-(1,3-oxazinan-
2). White solid
(430 mg, 52%); mp 156–158 °C; H NMR (500 MHz, CDCl3): δ
12). Anal. Calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81. 1.81–1.90 (m, 2H, 5″-CH2), 2.33 (s, 3H, 2-CH3), 2.99–3.06 (m,
Found: C, 68.39; H, 5.55; N, 4.11. 2H, 4″-CH2), 3.87–3.98 (m, 8H, 3′, 4′-OCH3, 6″-CH2), 4.29 (s,
163.39 (7-C), 175.78 ppm (4-C); IR (KBr): νmax 3425, 2964, 1633, 3-ylmethyl)-4H-chromen-4-one (5e,
n
=
1
1601, 1405, 1255 cm−1; MS (CI): m/z (%) 356.3 (100, MH+
−
3-(3,4-Dimethoxyphenyl)-7-hydroxy-8-(1,3-oxazinan-3-ylmethyl)- 2H, 8-CH2), 4.41 (s, 2H, 2″-CH2), 6.79–6.74 (m, 2H, 2′, 6′-H),
4H-chromen-4-one (5b, n = 2). White solid (623 mg, 78%); mp 6.87 (d, 1H, 3J = 8.9 Hz, 6-H), 6.93 (d, 1H, 3J = 9 Hz, 5′-H),
261–263 °C; 1H NMR (500 MHz, CDCl3): δ 1.78–1.90 (m, 2H, 8.06 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3):
5″-CH2), 3.00–3.08 (m, 2H, 4″-CH2), 3.87–3.98 (m, 8H, 3′, 4′- δ 19.39 (2-CH3), 22.15 (5″-C), 47.10 (4″-C), 49.33 (8-CH2), 55.87
OCH3, 6″-CH2), 4.30 (s, 2H, 8-CH2), 4.38 (s, 2H, 2″-CH2), (3′, 4′-OCH3), 67.70 (6″-C), 83.78 (2″-C), 106.21 (8-C), 111.23 (5′-
3
4
6.89–6.96 (m, 2H, 6-H, 5′-H), 7.05 (dd, 1H, J = 8.4 Hz, J = 2.0 C), 113.77 (2′-C), 115.19 (6-C), 116.22 (4a-C), 122.79 (6′-C),
Hz, 6′-H), 7.22 (d, 1H, 4J = 2.0 Hz, 2′-H), 7.94 (s, 1H, 2-H), 122.85 (1′-C), 125.67 (3-C), 126.95 (5-C), 148.60, 148.77 (3′, 4′-
8.14 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3): C), 154.92 (8a-C), 162.12 (2-C), 163.17 (7-C), 176.41 ppm (4-C);
δ 22.15 (5″-C), 47.28 (4″-C), 49.54 (8-CH2), 55.95 (3′-OCH3), IR (KBr): νmax 3429, 2931, 1635, 1601, 1512, 1410, 1259 cm−1
;
55.96 (4′-OCH3), 67.80 (6″-C), 83.65 (2″-C), 106.95 (8-C), 111.25 MS (CI): m/z (%) 400.2 (100, MH+ − 12). Anal. Calcd for
(5′-C), 112.64 (2′-C), 115.69 (6-C), 117.35 (4a-C), 120.99 (6′-C), C23H25NO6: C, 67.14; H, 6.12; N, 3.40. Found: C, 67.40; H, 6.03;
124.58 (3-C), 124.71 (1′-C), 126.87 (5-C), 148.81, 149.12 (3′, 4′- N, 3.58.
C), 151.53 (2-C), 155.20 (4a-C), 163.52 (7-C), 175.82 ppm (4-C);
3-(4-Fluorophenyl)-7-hydroxy-2-methyl-8-(1,3-oxazinan-
IR (KBr): νmax 3427, 1632, 1603, 1411, 1267 cm−1; MS (CI): m/z 3-ylmethyl)-4H-chromen-4-one (5f,
n
=
2). White solid
(%) 386.3 (100, MH+ − 12). Anal. Calcd for C22H23NO6: C, (496 mg, 67%); mp 141–143 °C; H NMR (400 MHz, CDCl3): δ
1
66.49; H, 5.83; N, 3.52. Found: C, 66.58; H, 5.99; N, 3.67.
1.78–1.90 (m, 2H, 5″-CH2), 2.30 (s, 2H, 2-CH3), 2.98–3.05 (m,
3-(4-Fluorophenyl)-7-hydroxy-8-(1,3-oxazinan-3-ylmethyl)-4H- 2H, 4″-CH2), 3.87–3.94 (m, 2H, 6″-CH2), 4.28 (s, 2H, 8-CH2),
3
chromen-4-one (5c, n = 2). White solid (461 mg, 65%); mp 4.40 (s, 2H, 2″-CH2), 6.86 (d, 1H, J = 8.8 Hz, 6-H), 7.06–7.15
116–118 °C; 1H NMR (400 MHz, CDCl3): δ 1.78–1.92 (m, 2H, (m, 2H, 3′, 5′-H), 7.21–7.28 (m, 2H, 2′, 6′-H), 8.04 ppm (d, 1H,
5″-CH2), 2.97–3.07 (m, 2H, 4″-CH2), 3.86–3.97 (m, 2H, 6″-CH2), 3J = 8.8 Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ 19.32 (2-CH3),
3
4.29 (s, 2H, 8-CH2), 4.38 (s, 2H, 2″-CH2), 6.91 (d, 1H, J = 9 Hz, 22.22 (5″-C), 47.40 (4″-C), 49.39 (8-CH2), 67.78 (6″-C), 83.88 (2″-
3
3
2
6-H), 7.12 (t, 2H, J(H,H) = 8.5 Hz, J(H,F) = 8.5 Hz, 3′, 5′-H), C), 106.60 (8-C), 115.30 (6-C), 116.27 (d, J(C,F) = 21.4 Hz, 3′,
3
4
4
7.53 (dd, 2H, J(H,H) = 8.5 Hz, J(H,F) = 5.6 Hz, 2′, 6′-H), 7.91 5′-C), 116.14 (4a-C), 122.16 (3-C), 126.74 (5-C), 129.04 (d, J(C,
(s, 1H, 2-H), 8.13 ppm (d, 1H, 3J = 9 Hz, 5-H); 13C NMR F) = 3.0 Hz, 1′-C), 132.16 (d, J(C,F) = 9.0 Hz, 2′, 6′-C), 154.85
3
1
(125 MHz, CDCl3): δ 22.12 (5″-C), 47.28 (4″-C), 49.53 (8-CH2), (8a-C), 161.91 (2-C), 162.28 (d, J(C,F) = 246.8 Hz, 4′-C), 163.37
67.81 (6″-C), 83.63 (2″-C), 106.99 (8-C), 115.38 (d, 2J(C,F) = 21.4 (7-C), 176.13 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ
Hz, 3′, 5′-C), 115.81 (6-C), 117.27 (4a-C), 124.09 (3-C), 126.91 (5- −115.07 ppm; IR (KBr): νmax 3427, 2964, 1634, 1605, 1510,
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1406 cm−1; MS (CI): m/z (%) 358.3 (100, MH+ − 12). Anal.
3-(4-Fluorophenyl)-7-hydroxy-8-{[(3-hydroxypropyl)amino]-
Calcd for C21H20FNO4: C, 68.28; H, 5.46; N, 3.79. Found: C, methyl}-2-(trifluoromethyl)-4H-chromen-4-one (6i,
68.57; H, 5.18; N, 3.94.
n
=
2). White solid (536 mg, 65%); mp 211–213 °C; 1H NMR
7-Hydroxy-3-(4-methoxyphenyl)-8-(1,3-oxazinan-3-ylmethyl)- (400 MHz, CDCl3): δ 1.65–1.79 (m, 2H, 2″-CH2), 2.82–2.93 (m,
2-(trifluoromethyl)-4H-chromen-4-one (5g, n = 2). White solid 2H, 1″-CH2), 3.44–3.53 (m, 2H, 3″-CH2), 4.19 (s, 2H, 8-CH2),
1
(419 mg, 48%); mp 128–130 °C; H NMR (500 MHz, CDCl3): δ 6.66 (d, 1H, 3J = 8.7 Hz, 6-H), 7.24–7.31 (m, 4H, 3-C6H4F),
1.79–1.89 (m, 2H, 5″-CH2), 2.96–3.03 (m, 2H, 4″-CH2), 3.85 (s, 7.73 ppm (d, 1H, 3J = 8.7 Hz, 5-H); 13C NMR (125 MHz, CDCl3):
3H, 4′-OCH3), 3.87–3.94 (m, 2H, 6″-CH2), 4.26 (s, 2H, 8-CH2), δ 29.83 (2″-C), 42.67 (1″-C), 44.40 (8-CH2), 58.32 (3″-C), 104.61
4.40 (s, 2H, 2″-CH2), 6.91–7.00 (m, 3H, 6, 3′, 5′-H), 7.18 (d, 2H, (8-C), 109.88 (4a-C), 114.65 (d, 2J(C,F) = 21.4 Hz, 3′, 5′-C),
3J = 8.7 Hz, 2′, 6′-H), 8.05 ppm (d, 1H, 3J = 8.7 Hz, 5-H); 13C 119.41 (q, 1J(C,F) = 276.8 Hz, 2-CF3), 119.59 (6-C), 123.32 (3-C),
4
3
NMR (125 MHz, CDCl3): δ 22.40 (5″-C), 47.34 (4″-C), 49.56 (8- 125.70 (5-C), 126.15 (d, J(C,F) = 3.5 Hz, 1′-C), 131.93 (d, J(C,
2
CH2), 55.26 (4′-OCH3), 67.75 (6″-C), 84.07 (2″-C), 107.01 (8-C), F) = 8.5 Hz, 2′, 6′-C), 145.00 (q, J(C,F) = 34.4 Hz, 2-C), 154.74
113.73 (3′, 5′-C), 116.09 (4a-C), 116.75 (6-C), 119.64 (q, 3J(C,F) = (8a-C), 161.92 (d, 1J(C,F) = 245.3 Hz, 4′-C), 172.73 (7-C),
276.3 Hz, 2-CF3), 121.05 (1′-C), 125.06 (3-C), 127.14 (5-C), 173.57 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ −112.01,
3
131.11 (2′, 6′-C), 147.35 (q, J(C,F) = 39.5 Hz, 2-C), 154.12 (8a- −60.92 ppm; IR (KBr): νmax 3433, 3084, 1641, 1601, 1396, 1282,
C), 159.97 (4′-C), 164.71 (7-C), 176.28 ppm (4-C); 19F NMR 1193, 1151 cm−1; MS (CI): m/z (%) 412.1 (100, MH+). Anal.
(376 MHz, CDCl3): δ −63.91 ppm; IR (KBr): νmax 3432, 1651, Calcd for C20H17F4NO4: C, 58.40; H, 4.17; N, 3.41. Found: C,
1610, 1516, 1295, 1192, 1140 cm−1; MS (CI): m/z (%) 424.2 58.67; H, 4.03; N, 3.12.
(100, MH+ − 12). Anal. Calcd for C22H20F3NO5: C, 60.69; H,
4.63; N, 3.22. Found: C, 60.90; H, 4.58; N, 2.99.
Aminomethylation of 7-hydroxyisoflavones with either
4-amino-1-butanol or 5-amino-1-pentanol
3-(3,4-Dimethoxyphenyl)-7-hydroxy-8-(1,3-oxazinan-3-ylmethyl)-2-
(trifluoromethyl)-4H-chromen-4-one (5h, n = 2). White solid A solution of 2 mmol of isoflavone 3a–3i, 2.4 mmol of the
1
(770 mg, 83%); mp 214–216 °C; H NMR (400 MHz, CDCl3): δ appropriate ω-aminoalkan-1-ol, 2.4 mmol of paraformalde-
1.81–1.90 (m, 2H, 5″-CH2), 2.97–3.04 (m, 2H, 4″-CH2), hyde, and 1–2 mg of 4-(N,N-dimethylamino)pyridine in 10 mL
3.83–3.95 (m, 8H, 3′, 4′-OCH3, 6″-CH2), 4.27 (s, 2H, 8-CH2), of isopropanol was refluxed for 4–6 h. The mixture was cooled
4.40 (s, 2H, 2″-CH2), 6.76–6.86 (m, 2H, 2′, 6′-H), 6.91–6.97 (m, and diluted with 40–60 mL of hexane. The precipitate was col-
2H, 6, 5′-H), 8.06 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR lected and recrystallized from a mixture of isopropanol and
(125 MHz, CDCl3): δ 22.24 (5″-C), 47.20 (4″-C), 49.38 (8-CH2), hexane.
55.70 (3′-OCH3), 55.72 (4′-OCH3), 67.60 (6″-C), 83.88 (2″-C),
9-(4-Hydroxybutyl)-3-(4-methoxyphenyl)-9,10-dihydro-4H,8H-
106.97 (8-C), 110.69 (5′-C), 112.97 (2′-C), 115.86 (4a-C), 116.62 chromeno[8,7-e][1,3]oxazin-4-one (4a,
n = 3). White solid
1
(6-C), 119.46 (q, 1J(C,F) = 276.4 Hz, 2-CF3), 121.18 (1′-C), 122.41 (625 mg, 82%); mp 145–147 °C; H NMR (400 MHz, CDCl3): δ
(6′-C), 124.94 (3-C), 126.83 (5-C), 147.33 (q, 2J(C,F) = 36.0 Hz, 2- 1.67–1.75 (m, 4H, 2″, 3″-CH2), 2.81 (t, 2H, J = 6.4 Hz, 1″-CH2),
3
3
C), 148.44, 149.28 (3′, 4′-C), 153.91 (8a-C), 164.63 (7-C), 3.77 (t, 2H, J = 5.8 Hz, 4″-CH2), 3.85 (s, 3H, 4′-OCH3), 4.20 (s,
176.13 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ −63.15 ppm; 2H, 10-CH2), 4.98 (s, 2H, 8-CH2), 6.88 (d, 1H, J = 8.8 Hz, 6-H),
3
3
3
IR (KBr): νmax 3435, 2931, 1647, 1606, 1261, 1219, 1140 cm−1
;
6.98 (d, 2H, J = 8.8 Hz, 3′, 5′-H), 7.50 (d, 2H, J = 8.8 Hz, 2′, 6′-
MS (CI): m/z (%) 424.1 (100, MH+ − 12). Anal. Calcd for H), 7.92 (s, 1H, 2-H), 8.09 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C
C23H22F3NO6: C, 59.39; H, 4.76; N, 3.01. Found: C, 59.11; H, NMR (100 MHz, CDCl3): δ 24.86 (2″-C), 30.69 (3″-C), 44.77 (1″-
4.55; N, 2.87.
C), 51.56 (10-C), 55.29 (4′-OCH3), 62.58 (4″-C), 82.84 (8-C),
7-Hydroxy-8-{[(3-hydroxypropyl)amino]methyl}-3-(4-methoxy- 107.35 (10a-C), 113.91 (3′, 5′-C), 115.14 (6-C), 118.01 (4a-C),
phenyl)-2-(trifluoromethyl)-4H-chromen-4-one
(6g,
n
=
124.05 (3-C), 124.92 (1′-C), 125.36 (5-C), 130.08 (2′, 6′-C), 151.55
2). White solid (625 mg, 74%); mp 214–216 °C; 1H NMR (2-C), 154.59 (10b-C), 158.33 (4′-C), 159.53 (6a-C), 175.86 ppm
(400 MHz, DMSO-d6): δ 1.65–1.76 (m, 2H, 2″-CH2), 2.77–2.93 (4-C); IR (KBr): νmax 3265, 2940, 1640, 1631, 1509, 1436, 1249,
(m, 2H, 1″-CH2), 3.44–3.52 (m, 2H, 3″-CH2), 3.80 (s, 3H, 4′- 1034 cm−1; MS (CI): m/z (%) 370.2 (100, MH+ − 12). Anal.
3
OCH3), 4.13 (s, 2H, 8-CH2), 6.59 (d, 1H, J = 8.8 Hz, 6-H), 6.98 Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found: C,
3
3
(d, 2H, J = 8.5 Hz, 3′, 5′-H), 7.15 (d, 2H, J = 8.5 Hz, 2′, 6′-H), 68.93; H, 6.33; N, 3.94.
7.68 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (100 MHz, DMSO-
9-(4-Hydroxypentyl)-3-(4-methoxyphenyl)-9,10-dihydro-
d6): δ 29.98 (2″-C), 42.74 (1″-C), 44.43 (8-CH2), 55.05 (4′-OCH3), 4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4a, n = 4). White
58.37 (3″-C), 104.82 (8-C), 109.94 (4a-C), 113.16 (3′, 5′-C), solid (515 mg, 65.1%); mp 110–111 °C; 1H NMR (400 MHz,
119.52 (6-C), 119.58 (q, 1J(C,F) = 275.1 Hz, 2-CF3), 121.71 (3-C), CDCl3): δ 1.40–1.50 (m, 2H, 3″-CH2), 1.58–1.68 (m, 4H, 2″, 4″-
2
3
3
123.97 (1′-C), 125.68 (5-C), 131.03 (2′, 6′-C), 144.86 (q, J(C,F) = CH2), 2.77 (t, 2H, J = 6.4 Hz, 1″-CH2), 3.77 (t, 2H, J = 6.4 Hz,
34.6 Hz, 2-C), 154.72 (4′-C), 159.05 (8a-C), 172.68 (7-C), 5″-CH2), 3.85 (s, 3H, 4′-OCH3), 4.18 (s, 2H, 10-CH2), 4.97 (s,
173.91 ppm (4-C); 19F NMR (376 MHz, DMSO-d6):
δ
2H, 8-CH2), 6.87 (d, 1H, J = 8.9 Hz, 6-H), 6.98 (d, 2H, J = 8.5
3
3
−60.82 ppm; IR (KBr): νmax 3423,3075, 2925, 1641, 1599, 1282, Hz, 3′, 5′-H), 7.50 (d, 2H, 3J = 8.5 Hz, 2′, 6′-H), 7.93 (s, 1H, 2-H),
1180, 1144 cm−1; MS (CI): m/z (%) 424.1 (100, MH+). Anal. 8.08 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3):
Calcd for C21H20F3NO5: C, 59.57; H, 4.76; N, 3.31. Found: C, δ 23.26 (3″-C), 27.79 (2″-C), 32.43 (4″-C), 44.94 (1″-C), 51.60 (10-
59.91; H, 5.07; N, 3.12.
C), 55.30 (4′-OCH3), 62.70 (5″-C), 83.14 (8-C), 107.60 (10a-C),
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113.91 (3′, 5′-C), 115.15 (6-C), 117.92 (4a-C), 124.11 (3-C), (C,F) = 3.0 Hz, 1′-C), 130.66 (d, 3J(C,F) = 8.0 Hz, 2′, 6′-C), 151.93
1
124.89 (1′-C), 125.22 (5-C), 130.09 (2′, 6′-C), 151.54 (2-C), 154.61 (2-C), 154.63 (10b-C), 158.59 (6a-C), 162.70 (d, J(C,F) = 247.2
(10b-C), 158.55 (4′-C), 159.53 (6a-C), 175.89 ppm (4-C); IR Hz, 4′-C), 175.57 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ
(KBr): νmax 3433, 2934, 1644, 1629, 1510, 1252, 1178, 1034, −114.51 ppm; IR (KBr): νmax 3348, 2939, 2863, 1647, 1511,
823 cm−1; MS (CI): m/z (%) 384.1 (100, MH+ − 12); Anal. Calcd 1433, 1246, 1224 cm−1; MS (CI): m/z (%) 358.1 (100, MH+
−
for C23H25NO5: C 69.86, H 6.37, N 3.54. Found: C 70.15, H 12). Anal. Calcd for C21H20FNO4: C, 68.28; H, 5.46; N, 3.79.
6.47, N 3.28.
Found: C, 68.47; H, 5.30; N, 4.07.
3-(3,4-Dimethoxyphenyl)-9-(4-hydroxybutyl)-9,10-dihydro-
3-(4-Fluorophenyl)-9-(4-hydroxypentyl)-9,10-dihydro-4H,8H-
4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4b, n = 3). White chromeno[8,7-e][1,3]oxazin-4-one (4c, n = 4). White solid
1
solid (684 mg, 83%); mp 132–133 °C; 1H NMR (400 MHz, (402 mg, 52.4%); mp 97–98 °C; H NMR (400 MHz, CDCl3): δ
CDCl3): δ 1.45–1.57 (m, 4H, 2″, 3″-CH2), 2.81 (t, 2H, 3J = 6.5 Hz, 1.41–1.49 (m, 2H, 3″-CH2), 1.59–1.68 (m, 4H, 2″, 4″-CH2), 2.77
1″-CH2), 3.69 (t, 2H, 3J = 5.8 Hz, 4″-CH2), 3.91 (s, 3H, 3′- OCH3), (t, 2H, 3J = 7.2 Hz, 1″-CH2), 3.70 (t, 2H, 3J = 7.2 Hz, 5″-CH2),
3
3.93 (s, 3H, 4′-OCH3), 4.20 (s, 2H, 10-CH2), 4.97 (s, 2H, 8-CH2), 4.19 (s, 2H, 10-CH2), 4.98 (s, 2H, 8-CH2), 6.88 (d, 1H, J = 8.9
3
3
3
3
6.88 (d, 1H, J = 8.9 Hz, 6-H), 6.92 (d, 1H, J = 8.3 Hz, 5′-H), Hz, 6-H), 7.13 (t, 2H, J(H,H) = 8.8 Hz, J(H,F) = 8.8 Hz, 3′, 5′-
7.04 (dd, 1H, 3J = 8.5 Hz, 4J = 2.0 Hz, 6′-H), 7.20 (d, 1H, 4J = 2.0 H), 7.53 (dd, 2H, J(H,H) = 8.8 Hz, J(H,F) = 5.5 Hz, 2′, 6′-H),
3
4
Hz, 2′-H), 7.95 (s, 1H, 2-H), 8.08 ppm (d, 1H, J = 8.9 Hz, 5-H); 7.94 (s, 1H, 2-H), 8.08 ppm (d, 1H, J = 8.9 Hz, 5-H); 13C NMR
13C NMR (100 MHz, CDCl3): δ 24.92 (2″-C), 30.75 (3″-C), 44.87 (125 MHz, CDCl3): δ 23.28 (3″-C), 27.80 (2″-C), 32.43 (4″-C),
(1″-C), 51.64 (10-C), 55.96 (3′-OCH3), 55.98 (4′-OCH3), 62.64 (4″- 44.96 (1″-C), 51.65 (10-C), 62.71 (5″-C), 83.20 (8-C), 107.68 (10a-
3
3
2
C), 82.90 (8-C), 107.37 (10a-C), 111.18 (5′-C), 112.55 (2′-C), C), 115.37 (6-C), 115.40 (d, J(C,F) = 21.2 Hz, 3′, 5′-C), 117.86
115.20 (6-C), 118.01 (4a-C), 120.98 (6′-C), 124.51 (1′-C), 124.98 (4a-C), 124.46 (3-C), 125.23 (5-C), 127.80 (d, 4J(C,F) = 3.4 Hz, 1′-
(3-C), 125.29 (5-C), 148.72, 149.09 (3′, 4′-C), 151.64 (2-C), 154.52 C), 130.66 (d, 3J(C,F) = 8.0 Hz, 2′, 6′-C), 151.92 (2-C), 154.66
(10b-C), 158.37 (6a-C), 175.77 ppm (4-C); IR (KBr): νmax 3262, (10b-C), 158.78, (6a-C) 162.70 (d, 1J(C,F) = 247.6 Hz, 4′-C),
2936, 1640, 1627, 1517, 1434, 1250, 1145, 1028 cm−1; MS (CI): 175.60 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ −114.48 ppm;
m/z (%) 400.2 (100, MH+ − 12). Anal. Calcd for C23H25NO6: C, IR (KBr): νmax 3475, 2936, 1634, 1435 1242, 1217 cm−1; MS
67.14; H, 6.12; N, 3.40. Found: C, 67.42; H, 5.81; N, 3.70.
(CI): m/z (%) 372.1 (100, MH+
− 12); Anal. Calcd for
3-(3,4-Dimethoxyphenyl)-9-(4-hydroxypentyl)-9,10-dihydro- C22H22FNO4: C 68.92, H 5.78, N 3.65. Found: C 68.77, H 5.68,
4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4b, n = 4). White N 3.91.
solid (620 mg, 73%); mp 109–110 °C; 1H NMR (400 MHz,
9-(4-Hydroxybutyl)-3-(4-methoxyphenyl)-2-methyl-9,10-dihydro-
CDCl3): δ 1.42–1.50 (m, 2H, 3″-CH2), 1.58–1.69 (m, 4H, 2″, 4″- 4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4d, n = 3). White solid
3
3
1
CH2), 2.78 (t, 2H, J = 7.2 Hz, 1″-CH2), 3.67 (t, 2H, J = 7.2 Hz, (377 mg, 48%); mp 122–123 °C; H NMR (400 MHz, CDCl3): δ
5″-CH2), 3.92 (s, 3H, 3′- OCH3), 3.93 (s, 3H, 4′-OCH3), 4.18 (s, 1.63–1.79 (m, 4H, 2″, 3″-CH2), 2.31 (s, 3H, 2-CH3), 2.82 (t, 2H,
2H, 10-CH2), 4.97 (s, 2H, 8-CH2), 6.87 (d, 1H, J = 8.9 Hz, 6-H), 3J = 6.5 Hz, 1″-CH2), 3.69 (t, 2H, J = 5.6 Hz, 4″-CH2), 3.85 (s,
3
3
6.93 (d, 1H, 3J = 8.3 Hz, 5′-H), 7.05 (dd, 1H, 4J = 2.0 Hz, 3J = 8.3 3H, 4′-OCH3), 4.20 (s, 2H, 10-CH2), 4.96 (s, 2H, 8-CH2), 6.83 (d,
Hz, 6′-H), 7.21 (d, 1H, 4J = 2.0 Hz, 2′-H), 7.96 (s, 1H, 2-H), 1H, J = 8.8 Hz, 6-H), 6.97 (d, 2H, J = 8.2 Hz, 3′, 5′-H), 7.20 (d,
3
3
8.08 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3): 2H, 3J = 8.2 Hz, 2′, 6′-H), 8.01 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13
C
δ 23.24 (3″-C), 27.76 (2″-C), 32.40 (4″-C), 44.91 (1″-C), 51.59 (10- NMR (100 MHz, CDCl3): δ 19.36 (2-CH3), 24.90 (2″-C), 30.71
C), 55.87 (3′-OCH3), 55.90 (4′-OCH3), 62.68 (5″-C), 83.14 (8-C), (3″-C), 45.03 (1″-C), 51.64 (10-C), 55.24 (4′-OCH3), 62.56 (4″-C),
107.58 (10a-C), 111.06 (5′-C), 112.42 (2′-C), 115.22 (6-C), 117.87 82.66 (8-C), 107.01 (10a-C), 113.84 (3′, 5′-C), 114.69 (6-C),
(4a-C), 120.94 (6′-C), 124.52 (1′-C), 124.90 (3-C), 125.16 (5-C), 116.98 (4a-C), 123.03 (1′-C), 125.17 (3-C), 125.26 (5-C), 131.49
148.67, 149.02 (3′, 4′-C), 151.70 (2-C), 154.56 (10b-C), 158.59 (2′, 6′-C), 154.21 (10b-C), 158.15 (2-C), 159.07 (4′-C), 162.17 (6a-
(6a-C), 175.89 ppm (4-C); IR (KBr): νmax 3300, 2935, 1634, 1517, C), 176.45 ppm (4-C); IR (KBr): νmax 3340, 2934, 2832, 1631,
1433, 1252, 1142, 1026 cm−1; MS (CI): m/z (%) 414.3 (100, MH+ 1608, 1512, 1437, 1246, 1177 cm−1; MS (CI): m/z (%) 384.1
− 12). Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. (100, MH+ − 12). Anal. Calcd for C23H25NO5: C, 69.86; H, 6.37;
Found: C, 68.01; H, 6.32; N, 3.03.
N, 3.54. Found: C, 70.14; H, 6.76; N, 3.28.
3-(4-Fluorophenyl)-9-(4-hydroxybutyl)-9,10-dihydro-4H,8H-
9-(4-Hydroxypentyl)-3-(4-methoxyphenyl)-2-methyl-9,10-dihydro-
chromeno[8,7-e][1,3]oxazin-4-one (4c, n = 3). White solid 4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4d, n = 4). White solid
1
1
(576 mg, 78%); mp 113–115 °C; H NMR (400 MHz, CDCl3): δ (541 mg, 66%); mp 120–121 °C; H NMR (400 MHz, CDCl3): δ
3
1.58–1.76 (m, 4H, 2″, 3″-CH2), 2.82 (t, 2H, J = 6.5 Hz, 1″-CH2), 1.40–1.50 (m, 2H, 3″-CH2), 1.57–1.70 (m, 4H, 2″, 4″-CH2), 2.31
3.70 (t, 2H, J = 5.6 Hz, 4″-CH2), 4.20 (s, 2H, 10-CH2), 4.98 (s, (s, 3H, 2-CH3), 2.78 (t, 2H, 3J = 7.2 Hz, 1″-CH2), 3.67 (t, 2H, 3J =
3
2H, 8-CH2), 6.88 (d, 1H, 3J = 9.0 Hz, 6-H), 6.89 (t, 2H, 3J(H,H) = 7.2 Hz, 5″-CH2), 3.85 (s, 3H, 4′-OCH3), 4.18 (s, 2H, 10-CH2),
3
3
3
8.8 Hz, J(H,F) = 8.8 Hz, 3′, 5′-H), 7.53 (dd, 2H, J(H,H) = 8.8 4.96 (s, 2H, 8-CH2), 6.82 (d, 1H, J = 8.7 Hz, 6-H), 6.97 (d, 2H,
Hz, J(H,F) = 5.4 Hz, 2′, 6′-H), 7.93 (s, 1H, 2-H), 8.08 ppm (d, 3J = 8.8 Hz, 3′, 5′-H), 7.20 (d, 2H, 3J = 8.8 Hz, 2′, 6′-H), 8.00 ppm
4
1H, J = 9.0 Hz, 5-H); 13C NMR (100 MHz, CDCl3): δ 24.82 (2″- (d, 1H, J = 8.7 Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ 19.38
3
3
C), 30.63 (3″-C), 44.81 (1″-C), 51.60 (10-C), 62.56 (4″-C), 82.92 (2-CH3), 23.27 (3″-C), 27.81 (2″-C), 32.42 (4″-C), 45.11 (1″-C),
2
(8-C), 107.47 (10a-C), 115.35 (6-C), 115.39 (d, J(C,F) = 21.7 Hz, 51.62 (10-C), 55.23(4′-OCH3), 62.70 (5″-C), 83.00 (8-C), 107.25
4
3′, 5′-C), 117.94 (4a-C), 124.47 (3-C), 125.31 (5-C), 127.74 (d, J (10a-C), 113.81 (3′, 5′-C), 114.68 (6-C), 116.85 (4a-C), 122.97 (1′-
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C), 125.14 (3-C), 125.22 (5-C), 131.50 (2′, 6′-C), 154.21 (10b-C), 1J(C,F) = 247.6 Hz, 4′-C), 162.31 (6a-C), 176.21 ppm (4-C); 19F
158.33 (2-C), 158.99 (4′-C), 162.08 (6a-C), 176.49 ppm (4-C); IR NMR (376 MHz, CDCl3): δ −115.20 ppm; IR (KBr): νmax 3459,
(KBr): νmax 3455, 2939, 1636, 1612, 1512, 1406, 1243, 2933, 2856, 1633, 1602, 1511, 1438, 1252, 1219 cm−1; MS (CI):
1029 cm−1; MS (CI): m/z (%) 398.3 (100, MH+ − 12). Anal. m/z (%) 372.1 (100, MH+ − 12). Anal. Calcd for C22H22FNO4: C,
Calcd for C24H27NO5: C, 70.40; H, 6.65; N, 3.42. Found: C, 68.92; H, 5.78; N, 3.65. Found: C, 69.21; H, 5.49; N, 3.91.
70.21; H, 6.37; N, 3.68.
3-(4-Fluorophenyl)-9-(4-hydroxypentyl)-2-methyl-9,10-
3-(3,4-Dimethoxyphenyl)-9-(4-hydroxybutyl)-2-methyl-9,10-
dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4f,
n
=
dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4e,
n
=
4). White solid (690 mg, 87%); mp 112–113 °C; 1H NMR
3). White solid (560 mg, 66%); mp 78–79 °C; 1H NMR (400 MHz, CDCl3): δ 1.40–1.50 (m, 2H, 3″-CH2), 1.58–1.70 (m,
(400 MHz, CDCl3): δ 1.63–1.78 (m, 4H, 2″, 3″-CH2), 2.32 (s, 3H, 4H, 2″, 4″-CH2), 2.30 (s, 3H, 2-CH3), 2.77 (t, 2H, 3J = 7.2 Hz, 1″-
2-CH3), 2.82 (t, 2H, 3J = 6.4 Hz, 1″-CH2), 3.69 (t, 2H, 3J = 6.7 Hz, CH2), 3.65 (t, 2H, 3J = 7.2 Hz, 5″-CH2), 4.18 (s, 2H, 10-CH2),
4″-CH2), 3.88 (s, 3H, 3′- OCH3), 3.92 (s, 3H, 4′-OCH3), 4.20 (s, 4.96 (s, 2H, 8-CH2), 6.83 (d, 1H, 3J = 8.8 Hz, 6-H), 7.12 (t, 2H, 3J
2H, 10-CH2), 4.96 (s, 2H, 8-CH2), 6.78–6.87 (m, 3H, 6, 2′, 6′-H), (H,H) = 8.3 Hz, 3J(H,F) = 8.3 Hz, 3′, 5′-H), 7.26 (dd, 2H, 3J(H,H)
3
3
4
3
6.93 (d, 1H, J = 8.9 Hz, 5′-H), 8.01 ppm (d, 1H, J = 8.5 Hz, 5- = 8.3 Hz, J(H,F) = 5.5 Hz, 2′, 6′-H), 7.99 ppm (d, 1H, J = 8.8
H); 13C NMR (125 MHz, CDCl3): δ 19.38 (2-CH3), 24.88 (2″-C), Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ 19.34 (2-CH3), 23.26
30.69 (3″-C), 44.96 (1″-C), 51.59 (10-C), 55.82 (3′-OCH3), 55.83 (3″-C), 27.78 (2″-C), 32.37 (4″-C), 45.05 (1″-C), 51.61 (10-C),
(4′-OCH3) 62.52 (4″-C), 82.67 (8-C), 106.99 (10a-C), 111.12 (5′- 62.59 (5″-C), 83.02 (8-C), 107.30 (10a-C), 114.88 (6-C), 115.30
C), 113.60 (2′-C), 114.72 (6-C), 116.91 (4a-C), 122.72 (6′-C), (d, 2J(C,F) = 21.2 Hz, 3′, 5′-C), 116.68 (4a-C), 122.46 (3-C),
4
3
123.20 (1′-C), 125.21 (5-C), 125.56 (3-C), 148.54, 148.70 (3′, 4′- 125.05 (5-C), 128.91 (d, J(C,F) = 3.2 Hz, 1′-C), 132.08 (d, J(C,
1
C), 154.19 (10b-C), 158.16 (2-C), 162.36 (6a-C), 176.46 (4-C) F) = 8.0 Hz, 2′, 6′-C), 154.22 (10b-C), 158.52 (2-C), 162.25 (d, J
ppm; IR (KBr): νmax 3433, 2934, 2836, 1634, 1607, 1516, 1252, (C,F) = 246.2 Hz, 4′-C), 162.30 (6a-C), 176.26 ppm; (4-C) 19F
1170 cm−1; MS (CI): m/z (%) 414.2 (100, MH+ − 12). Anal. NMR (376 MHz, CDCl3): δ −114.95 ppm; IR (KBr): νmax 3505,
Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C, 2936, 1632, 1510, 1434, 1252, 1222 cm−1; MS (CI): m/z (%)
68.03; H, 6.37; N, 3.68.
3-(3,4-Fimethoxyphenyl)-9-(4-hydroxypentyl)-2-methyl-9,10-
386.1 (100, MH+ − 12). Anal. Calcd for C23H24FNO4: C, 69.51;
H, 6.09; N, 3.52. Found: C, 69.57; H, 5.89; N, 3.81.
dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4e,
n
=
9-(4-Hydroxypentyl)-3-(4-methoxyphenyl)-2-(trifluoro-
4). White solid (676 mg, 77%); mp 160–161 °C; 1H NMR methyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one
(400 MHz, CDCl3): δ 1.41–1.51 (m, 2H, 3″-CH2), 1.58–1.70 (m, (4g, n = 4). White solid (380 mg, 41%); mp 114–115 °C; 1H
4H, 2″, 4″-CH2), 2.32 (s, 3H, 2-CH3), 2.78 (t, 2H, 3J = 7.2 Hz, 1″- NMR (400 MHz, CDCl3): δ 1.41–1.50 (m, 2H, 3″-CH2), 1.56–1.69
3
3
CH2), 3.67 (t, 2H, J = 7.2 Hz, 5″-CH2), 3.88 (s, 3H, 3′- OCH3), (m, 4H, 2″, 4″-CH2), 2.79 (t, 2H, J = 6.8 Hz, 1″-CH2), 3.68 (t,
3
3.92 (s, 3H, 4′-OCH3), 4.18 (s, 2H, 10-CH2), 4.96 (s, 2H, 8-CH2), 2H, J = 6.8 Hz, 5″-CH2), 3.86 (s, 3H, 4′-OCH3), 4.20 (s, 2H, 10-
6.79–6.85 (m, 3H, 6, 2′, 6′-H), 6.93 (d, 1H, 3J = 8.8 Hz, 5′-H), CH2), 5.00 (s, 2H, 8-CH2), 6.91 (d, 1H, 3J = 8.9 Hz, 6-H), 6.97 (d,
8.00 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3): 2H, 3J = 8.7 Hz, 3′, 5′-H), 7.19 (d, 2H, 3J = 8.7 Hz, 2′, 6′-H),
δ 19.42 (2-CH3), 23.27 (3″-C), 27.80 (2″-C), 32.40 (4″-C), 45.08 8.00 ppm (d, 1H, 3J = 8.9 Hz, 5-H); 13C NMR (125 MHz, CDCl3):
(1″-C), 51.62 (10-C), 55.83 (3′-OCH3), 55.85 (4′-OCH3) 65.68 (5″- δ 23.26 (3″-C), 27.76 (2″-C), 32.40 (4″-C), 44.80 (1″-C), 51.66 (10-
C), 83.02 (8-C), 107.25 (10a-C), 111.09 (5′-C), 113.56 (2′-C), C), 55.22 (4′-OCH3), 62.73 (5″-C), 83.38 (8-C), 107.89 (10a-C),
114.73 (6-C), 116.83 (4a-C), 122.73 (6′-C), 123.17 (1′-C), 125.11 113.68 (3′, 5′-C), 116.25 (6-C), 116.63 (4a-C), 119.51 (q, 1J(C,F) =
(5-C), 125.64 (3-C), 148.51, 148.8 (3′, 4′-C), 154.21 (10b-C), 277.0 Hz, 2-CF3), 120.93 (3, 1′-C), 125.34 (5-C), 131.05 (2′, 6′-C),
2
158.38 (2-C), 162.28 (6a-C), 176.47 ppm (4-C); IR (KBr): νmax 147.56 (q, J(C,F) = 35.0 Hz, 2-C), 153.47 (10b-C), 159.77 (4′-C),
3501, 2934, 1628, 1516, 1433, 1251, 1177, 1139 cm−1; MS (CI): 159.89 (6a-C), 176.40 ppm (4-C); 19F NMR (376 MHz, DMSO-
m/z (%) 428.2 (100, MH+ − 12). Anal. Calcd for C25H29NO6: C, d6): δ −63.93 ppm; IR (KBr): νmax 3517, 2943, 1646, 1606, 1580,
68.32; H, 6.65; N, 3.19. Found: C, 68.07; H, 6.57; N, 3.28.
3-(4-Fluorophenyl)-9-(4-hydroxybutyl)-2-methyl-9,10-dihydro- − 12). Anal. Calcd for C24H24F3NO5: C, 62.20; H, 5.22; N, 3.02.
4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4f, 3). White Found: C, 62.12; H, 5.39; N, 2.87.
solid (710 mg, 93%); mp 149–151 °C; 1H NMR (400 MHz,
3-(3,4-Dimethoxyphenyl)-9-(4-hydroxybutyl)-2-(trifluoro-
1430, 1249, 1154, 1026 cm−1; MS (CI): m/z (%) 452.3 (100, MH+
n
=
CDCl3): δ 1.60–1.77 (m, 4H, 2″, 3″-CH2), 2.30 (s, 3H, 2-CH3), methyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one
2.82 (t, 2H, 3J = 6.4 Hz, 1″-CH2), 3.69 (t, 2H, 3J = 5.5 Hz, 4″- (4h, n = 3). White solid (340 mg, 36%); mp 154–156 °C; 1H
CH2), 4.20 (s, 2H, 10-CH2), 4.97 (s, 2H, 8-CH2), 6.84 (d, 1H, 3J = NMR (400 MHz, CDCl3): δ 1.63–1.78 (m, 4H, 2″, 3″-CH2), 2.82
3
3
8.8 Hz, 6-H), 7.12 (t, 2H, J(H,H) = 8.8 Hz, J(H,F) = 8.8 Hz, 3′, (t, 2H, 3J = 6.2 Hz, 1″-CH2), 3.71 (t, 2H, 3J = 5.6 Hz, 4″-CH2),
5′-H), 7.25 (dd, 2H, 3J(H,H) = 8.8 Hz, 4J(H,F) = 5.4 Hz, 2′, 6′-H), 3.88 (s, 3H, 3′- OCH3), 3.93 (s, 3H, 4′-OCH3), 4.22 (s, 2H, 10-
8.00 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (100 MHz, CDCl3): CH2), 5.00 (s, 2H, 8-CH2), 6.76–6.85 (m, 2H, 2′, 6′-H), 6.90–6.98
3
δ 19.33 (2-CH3), 24.90 (2″-C), 30.69, (3″-C), 44.99 (1″-C), 51.64 (m, 2H, 6, 5′-H), 8.02 ppm (d, 1H, J = 9.0 Hz, 5-H); 13C NMR
(10-C), 62.54 (4″-C), 82.74 (8-C), 107.11 (10a-C), 114.87 (6-C), (125 MHz, CDCl3): δ 24.76 (2″-C), 30.58 (3″-C), 44.73 (1″-C),
2
115.31 (d, J(C,F) = 21.4 Hz, 3′, 5′-C), 116.84 (4a-C), 122.55 (3- 51.63 (10-C), 55.81(3′-OCH3), 55.84 (4′-OCH3), 62.58 (4″-C),
4
3
C), 125.20 (5-C), 128.91 (d, J(C,F) = 3.4 Hz, 1′-C), 132.10 (d, J 83.07 (8-C), 107.69 (10a-C), 110.81 (5′-C), 113.04 (2′-C), 116.29
(C,F) = 8.4 Hz, 2′, 6′-C), 154.23 (10b-C), 158.35 (2-C), 162.30 (d, (6-C), 116.74 (4a-C), 119.47 (q, 1J(C,F) = 277.7 Hz, 2-CF3),
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121.17 (3-C), 122.50 (1′-C), 125.51 (6′-C), 125.44 (5-C), 147.73 5.3 Hz, 2′, 6′-H), 8.00 ppm (d, 1H, J = 8.7 Hz, 5-H); 13C NMR
(q, 2J(C,F) = 35.9 Hz, 2-C), 148.57, 149.44 (3′, 4′-C), 153.44 (10b- (125 MHz, CDCl3): δ 23.26 (3″-C), 27.75 (2″-C), 32.39 (4″-C),
C), 159.59 (6a-C), 176.32 ppm (4-C); 19F NMR (376 MHz, 44.78 (1″-C), 51.66 (10-C), 62.70 (5″-C), 83.42 (8-C), 107.95 (10a-
2
CDCl3): δ −64.32 ppm; IR (KBr): νmax 3542, 2947, 1653, 1614, C), 115.34 (d, J(C,F) = 21.8 Hz, 3′, 5′-C), 116.46 (6-C), 116.55
1518, 1117, 1189, 1132 cm−1; MS (CI): m/z (%) 468.2 (100, MH+ (4a-C), 119.35 (q, 1J(C,F) = 276.8 Hz, 2-CF3), 124.65 (3-C),
4
3
− 12). Anal. Calcd for C24H24F3NO6: C, 60.12; H, 5.05; N, 2.92. 124.83 (d, J(C,F) = 3.5 Hz, 1′-C), 125.31 (5-C), 131.66 (d, J(C,
Found: C, 60.27; H, 5.32; N, 3.17.
3-(3,4-Dimethoxyphenyl)-9-(4-hydroxypentyl)-2-(trifluoromethyl)-
2
F) = 8.0 Hz, 2′, 6′-C), 147.82 (q, J(C,F) = 34.4 Hz, 2-C), 153.48
(10b-C), 159.93 (6a-C), 163.00 (d, 1J(C,F) = 248.0 Hz, 4′-C),
176.05 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ −113.47,
9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4h,
n =
4). White solid (816 mg, 83%); mp 164–166 °C; 1H NMR −64.25 ppm; IR (KBr): νmax 3365, 2936, 1656, 1611, 1512, 1437,
(400 MHz, CDCl3): δ 1.41–1.51 (m, 2H, 3″-CH2), 1.57–1.69 (m, 1219, 1138 cm−1; MS (CI): m/z (%) 440.1 (100, MH+ − 12). Anal.
3
4H, 2″, 4″-CH2), 2.78 (t, 2H, J = 7.4 Hz, 1″-CH2), 3.68 (t, 2H, Calcd for C23H21F4NO4: C, 61.20; H, 4.69; N, 3.10. Found: C,
3J = 7.4 Hz, 5″-CH2), 3.88 (s, 3H, 3′- OCH3), 3.93 (s, 3H, 4′- 61.23; H, 4.87; N, 3.15.
OCH3), 4.20 (s, 2H, 10-CH2), 5.00 (s, 2H, 8-CH2), 6.78 (d, 1H,
3
4
4J = 1.8 Hz, 2′-H), 6.83 (dd, 1H, J = 8.3 Hz, J = 1.8 Hz, 6′-H),
3
3
6.91 (d, 1H, J = 8.8 Hz, 6-H), 6.94 (d, 1H, J = 8.3 Hz, 5′-H),
8.03 ppm (d, 1H, 3J = 8.8 Hz, 5-H); 13C NMR (125 MHz, CDCl3):
Acknowledgements
δ 23.23 (3″-C), 27.73 (2″-C), 32.37 (4″-C), 44.76 (1″-C), 51.63 (10- DSW and CL were supported by R21 CA139359 and CA172379
C), 55.77 (3′-OCH3), 55.81 (4′-OCH3), 62.68 (5″-C), 83.37 (8-C), from the NIH, by the Office of the Dean of the College of Medi-
107.86 (10a-C), 110.75 (5′-C), 112.96 (2′-C), 116.28 (6-C), 116.60 cine, and by NIH Grant Number P20 RR020171 from the
(6′-C), 119.46 (q, 1J(C,F) = 276.0 Hz, 2-CF3), 121.18 (4a-C), National Institute of General Medical Sciences to L. Hersh, PI.
122.47 (1′-C), 125.30 (5-C), 125.36 (3′-C), 147.68 (q, 2J(C,F) = The contents are solely the responsibility of the authors and
35.6 Hz, 2-C), 148.52, 149.37 (3′, 4′-C), 153.43 (10b-C), 159.75 do not necessarily represent the official views of the NIH or
(6a-C), 176.34 ppm (4-C); 19F NMR (376 MHz, CDCl3): δ the NIGMS. .
−64.30 ppm; IR (KBr): νmax 3542, 2935, 1658, 1612, 1518, 1266,
1215, 1139, 1027 cm−1; MS (CI): m/z (%) 482.2 (100, MH+
−
12). Anal. Calcd for C25H26F3NO6: C, 60.85; H, 5.31; N, 2.84.
Found: C, 61.04; H, 5.57; N, 2.68.
Notes and references
3-(4-Fluorophenyl)-9-(4-hydroxybutyl)-2-(trifluoromethyl)-
9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4i, n
= 3). White solid (460 mg, 53%); mp 137–139 °C; 1H NMR
(400 MHz, CDCl3): δ 1.63–1.78 (m, 4H, 2″, 3″-CH2), 2.83 (t, 2H,
1 I. S. Ismail, Y. Nagakura, Y. Hirasawa, T. Hosoya,
M. I. M. Lazim, N. H. Lajis, M. Shiro and H. Morita, J. Nat.
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2 S. Zhai, A. M. Senderowicz, E. A. Sausville and W. D. Figg,
Ann. Pharmacother., 2002, 36, 905–911.
3 T. Liu, Z. Xu, Q. He, Y. Chen, B. Yang and Y. Hu, Bioorg.
Med. Chem. Lett., 2007, 17, 278–281.
4 T. B. Nguyen, O. Lozach, G. Surpateanu, Q. Wang,
P. Retailleau, B. I. Iorga, L. Meijer and F. Guéritte, J. Med.
Chem., 2012, 55, 2811–2819.
5 W. Zhang, V. Sviripa, X. Chen, J. Shi, T. Yu, A. Hamza,
N. D. Ward, L. M. Kril, C. W. Vander Kooi, C.-G. Zhan,
B. M. Evers, D. S. Watt and C. Liu, ACS Chem. Biol., 2013, 8,
796–803.
6 M. Tramontini and L. Angiolini, Tetrahedron, 1990, 46,
1791–1837.
3
3J = 6.2 Hz, 1″-CH2), 3.70 (t, 2H, J = 5.6 Hz, 4″-CH2), 4.22 (s,
3
2H, 10-CH2), 5.01 (s, 2H, 8-CH2), 6.93 (d, 1H, J = 8.8 Hz, 6-H),
3
7.14 (t, 2H, J(H,H) = 8.6 Hz, 3J(H,F) = 8.6 Hz, 3′, 5′-H), 7.24 (t,
3
4
2H, J(H,H) = 8.6 Hz, J(H,F) = 5.2 Hz, 2′, 6′-H), 8.00 ppm (d,
3
1H, J = 8.8 Hz, 5-H); 13C NMR (125 MHz, CDCl3): δ 24.75 (2″-
C), 30.56 (3″-C), 44.74 (1″-C), 51.65 (10-C), 62.58 (4″-C), 83.11
(8-C), 107.78 (10a-C), 115.35 (d, 2J(C,F) = 21.7 Hz, 3′, 5′-C),
116.46 (6-C), 116.67 (4a-C), 119.33 (q, 1J(C,F) = 276.6 Hz, 2-
4
CF3), 124.73 (3-C), 124.80 (d, J(C,F) = 3.5 Hz, 1′-C), 125.42 (5-
C), 131.66 (d, 3J(C,F) = 8.4 Hz, 2′, 6′-C), 147.87 (q, 2J(C,F) = 36.6
Hz, 2-C), 153.48 (10b-C), 159.75 (6a-C), 163.02 (d, 1J(C,F) =
248.3 Hz, 4′-C), 176.02 ppm (4-C); 19F NMR (376 MHz, CDCl3):
δ −113.51, −64.30 ppm; IR (KBr): νmax 3410, 2944, 2867, 1658,
1611, 1514, 1435, 1216, 1196, 1142 cm−1; MS (CI): m/z (%)
426.1 (100, MH+ − 12). Anal. Calcd for C22H19F4NO4: C, 60.41;
H, 4.38; N 3.20. Found: C, 60.65; H, 4.71; N, 2.95.
7 M. Tramontini and L. Angiolini, Mannich Bases: Chemistry
and Uses, CRC Press, Boca Raton, 1994.
8 H. A. Bruson, J. Am. Chem. Soc., 1936, 58, 1741–1744.
9 W. D. Kingsbury, J. C. Boehm, D. R. Jakas, K. G. Holden,
S. M. Hecht, G. Gallagher, M. J. Caranfa, F. L. McCabe,
L. F. Faucette, R. K. Johnson and R. P. Hertzberg, J. Med.
Chem., 1991, 34, 98–107.
3-(4-Fluorophenyl)-9-(4-hydroxypentyl)-2-(trifluoromethyl)-
9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one (4i, n =
4). White solid (510 mg, 57%); mp 89–90 °C; 1H NMR
(400 MHz, CDCl3): δ 1.41–1.51 (m, 2H, 3″-CH2), 1.58–1.69 (m, 10 A. L. Johnson, M. G. Davidson, Y. Perez, M. D. Jones,
3
4H, 2″, 4″-CH2), 2.78 (t, 2H, J = 7.2 Hz, 1″-CH2), 3.67 (t, 2H,
3J = 7.2 Hz, 5″-CH2), 4.20 (s, 2H, 10-CH2), 5.00 (s, 2H, 8-CH2),
N. Merle, P. R. Raithby and S. P. Richards, Dalton Trans.,
2009, 5551–5558.
3
3
3
6.92 (d, 1H, J = 8.7 Hz, 6-H), 7.14 (t, 2H, J(H,H) = 8.6 Hz, J 11 J.-Q. Wu, J.-S. Mu, S.-W. Zhang and Y.-S. Li, J. Polym. Sci.,
(H,F) = 8.6 Hz, 3′, 5′-H), 7.25 (t, 2H, J(H,H) = 8.6 Hz, J(H,F) =
3
4
Part A: Polym. Chem., 2010, 48, 1122–1132.
Org. Biomol. Chem.
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