Syntheses of 3-[(Alkylamino)methylene]-6-methylpyridine-2,4(1 H,3 H)-diones, 3-substituted 7-methyl-2 H -pyrano[3,2- c ]pyridine-2,5(6 H)-dione fluorescence probes, and tetrahydro-1 H,9 H -2,10-dioxa-9-azaanthracen-1-ones

Article abstract of DOI:10.1055/s-0033-1339027

Various condensation and ring-closing reactions were used for the syntheses of 3-[(alkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones, bicyclic pyridinones, and tricyclic morpholinopyrones. For instance, 3-[(dialkylamino) methylene]-6-methylpyridine-2,4(1H,3H)-diones were synthesized from the condensation of dialkylamines and 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one. 3-Formyl-4-hydroxy-6-methylpyridin-2(1H)-one, derived from 3-formyl-4-hydroxy-6- methylpyridin-2(1H)-one, was used to construct a number of bicyclic pyridinones via a one-pot Knoevenagal and intramolecular lactonization reaction. Tricyclic morpholinopyrones were assembled from a dialkylation reaction involving a dinucleophile, 3-amino-4-hydroxy-6-methyl-2H-pyran-2-one, and a dielectrophile, trans-3,6-dibromocyclohexene. Depending on the reaction conditions, isomers of the tricyclic molecules can be selectively produced, and their chemical structures were unequivocally determined using single-crystal X-ray analyses and 2D COSY spectroscopy. The fluorescently active bicyclic pyridinone compounds show longer absorption (368-430 nm; maximum) and emission wavelengths (450-467 nm) than those of 7-amino-4-methylcoumarin (AMC; λ_abs,max = 350 nm; λ_em = 430 nm) suggesting these molecules, such as 3-(2-aminoacetyl)-7-methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione, can be employed as fluorescence activity based probes for tracing biological pathways. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339027

PAPER
▌2179
paper
Synthesesof3-[(Alkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones,
3-Substituted7-Methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dioneFluorescence
Probes, and Tetrahydro-1H,9H-2,10-dioxa-9-azaanthracen-1-ones
Monocyclic and Bicyclic Pyridinones and Tricyclic Morpholinopyrones
Allan M. Prior,a Medha J. Gunaratna,a Daisuke Kikuchi,a John Desper,a Yunjeong Kim,b Kyeong-Ok Chang,b
Izumi Maezawa,c Lee-Way Jin,c Duy H. Hua*a
a
Department of Chemistry, College of Arts and Sciences, Kansas State University, Manhattan, KS 66506-0401, USA
b
Department of Diagnostic Medicine and Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506-0401,
USA
c
M.I.N.D. Institute and Department of Pathology, 2825 50th Street, UC Davis Health System, Sacramento, CA 95817, USA
Fax +1(785)5326666; E-mail: duy@ksu.edu
Received: 04.03.2014; Accepted after revision: 09.04.2014
ring-closing reactions of 3-amino-4-hydroxy-2H-pyran-
Abstract: Various condensation and ring-closing reactions were
2-ones with trans-3,6-dibromocyclohexene to give tricy-
used for the syntheses of 3-[(alkylamino)methylene]-6-methylpyri-
clic morpholinopyrones. Bicyclic pyridinones possess
dine-2,4(1H,3H)-diones, bicyclic pyridinones, and tricyclic mor-
pholinopyrones. For instance, 3-[(dialkylamino)methylene]-6-
strong fluorescence activity at wavelengths of 450–467
methylpyridine-2,4(1H,3H)-diones were synthesized from the con- nm, which are suitable for activity-based probes8 and
activity-based proteomics studies.9
densation of dialkylamines and 3-formyl-4-hydroxy-6-methylpyri-
din-2(1H)-one. 3-Formyl-4-hydroxy-6-methylpyridin-2(1H)-one,
derived from 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one, was
In the search for new heterocyclic molecules possessing
biological activity, monocyclic pyridinones 1–7, bicyclic
pyridinones 8–12, and tricyclic morpholinopyrones 13–
16 were synthesized (Figure 1). Since the synthesis of a
used to construct a number of bicyclic pyridinones via a one-pot
Knoevenagal and intramolecular lactonization reaction. Tricyclic
morpholinopyrones were assembled from a dialkylation reaction in-
volving a dinucleophile, 3-amino-4-hydroxy-6-methyl-2H-pyran-
2-one, and a dielectrophile, trans-3,6-dibromocyclohexene. De-
pending on the reaction conditions, isomers of the tricyclic mole-
cules can be selectively produced, and their chemical structures
were unequivocally determined using single-crystal X-ray analyses
and 2D COSY spectroscopy. The fluorescently active bicyclic pyr-
monocyclic
pyridinone,
6-methyl-3-[(phenylami-
no)methylene]pyridine-2,4(1H,3H)-dione (18), has been
reported through the coupling reaction of 4-hydroxy-6-
methylpyridin-2(1H)-one (17), triethyl orthoformate, and
aniline,4 we treated compound 17 with primary amines
idinone compounds show longer absorption (368–430 nm; maxi- such as benzylamine and adenine separately under similar
mum) and emission wavelengths (450–467 nm) than those of 7-
amino-4-methylcoumarin (AMC; λabs,max = 350 nm; λem = 430 nm)
suggesting these molecules, such as 3-(2-aminoacetyl)-7-methyl-
yields (Scheme 1). In the case of adenine, the C6-primary
2H-pyrano[3,2-c]pyridine-2,5(6H)-dione, can be employed as fluo-
rescence activity based probes for tracing biological pathways.
reaction conditions, and found that monocyclic pyridi-
nones 1 and 3, respectively, formed in 68% and 50%
amino function appears to react faster than the C9-second-
ary amino group. In both cases a mixture of stereoisomers
Key words: dialkylation, fluorescence probes, heterocycles, 3-sub-
(Z and E at the enamine function) formed in an insepara-
stituted 7-methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-diones, tetra-
hydro-1H,9H-2,10-dioxa-9-azaanthracen-1-ones
ble 1:4.5 ratio for compound 1 and a 1:2 ratio for com-
pound 3, based on NMR spectral data. The regiochemistry
of compound 3 was determined from its 2D COSY NMR
spectrum in which the enamine C7H of the major isomer
In an effort to find new structures differing from the tricy-
at δ = 9.55 (d, J = 12 Hz) correlates with C6′-NH at δ =
clic pyrone pharmacophore,1,2 we investigated various
13.95 (d, J = 12 Hz) and that of the minor isomer at δ =
mono- and bicyclic pyridinone and tricyclic morpholino-
9.51 (d, J = 12.9 Hz) correlates with C6′-NH at δ = 12.82
pyridinone molecules that may possess bioactivity.1,2 Al-
(d, J = 12.9 Hz); N1- and N9′-hydrogens of 3 appear as
though several methods have been reported for the
broad singlets. However this three-component coupling
preparation of bicyclic pyridinones,3–7 a method for the
reaction appears to be applicable only with primary
synthesis of tricyclic morpholinopyrones (such as 13–16;
amines, when a secondary amine such as piperidine was
Figure 1) is not available. Herein, we described a number
used under similar reaction conditions no condensation
of reactions including the coupling of 3-formyl-4-hy-
product, i.e. monocyclic pyridinone 4, was found.
droxypyridin-2(1H)-one (19) with secondary amines to
produce exocyclic enamines and with α-sulfinyl, α-sulfo-
nyl, and α-keto esters to afford bicyclic pyridinones, and
To overcome this problem, we utilized 3-formyl-4-hy-
droxy-6-methylpyridin-2(1H)-one (19), which pre-in-
stalled with a carbaldehyde function at C3 of the
pyridinone, as our starting material in a two-component
condensation reaction with various secondary amines
(Scheme 1). Aldehyde 19 was prepared according to a
SYNTHESIS 2014, 46, 2179–2190
Advanced online publication: 14.05.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339027; Art ID: ss-2014-m0160-op
© Georg Thieme Verlag Stuttgart · New York

2180
A. M. Prior et al.
PAPER
H
N
H
N
H
N
1
O
O
O
H
8
5
O
6
N
3
7
3
1
O
N
Y
O
N
NH
O
R
2'
1'
6'
Ar
NH
O
N3'
O
7' N
8: R = SOPh
9: R = SO2Ph
10: R = COPh
11: R = COCH2NH2
12: R = COCH2NH(CH2C6H4-4-OH)
HN
8'
1: Ar = Ph
2: Ar = 4-HOC6H4
4: Y = CH2
5: Y = NMe
6: Y = NPh
7: Y = O
3
O
O
O
O
O
O
O
O
O
O
O
O
1
4
HN
8a
HN
H
t-BuO
N
H
HN
H
H
H
H
HO
O
10a
H
O
8 H
5
16
15
14
13
Figure 1 Synthesized monocyclic pyridinones 1–7, bicyclic pyridinones 8–12, and tricyclic morpholinopyrones 13–16
previously established synthetic route starting from pyrid- none enamines, 1–7, were synthesized in good to excel-
inone 174 as described in Scheme 1.
lent yields by treating aldehyde 19 with primary and
secondary amines in ethanol (Scheme 1). Compounds 1,
2, and 4–7 could be obtained at room temperature by treat-
ing aldehyde 19 with benzylamine, 4-hydroxybenzyl-
amine, piperidine, N-methylpiperazine, N-phenylpiper-
azine, and morpholine, respectively, however, condensa-
The enamine intermediate 18, formed as a 4:1 mixture of
E- and Z-isomers, was hydrolyzed using aqueous potassi-
um carbonate at 100 °C to provide aldehyde 19 (90%
yield). The spectral data for aldehyde 19 are similar to
those previously reported.4 Various monocyclic pyridi-
H
H
N
N
O
H
N
aniline, CH(OEt)3
DMF–AcOH (3:1)
103 °C, 1 h
O
O
O
K2CO3
H2O, 100 °C
H
H
90%
61%
NH
O
OH
OH
17
19
18
Me
N
NH
HO
CH2NH2
Ph CH2NH2
19
5
17
1
19
2
CH(OEt)3
DMF–AcOH (3:1)
68%
EtOH, 25 °C
93%
EtOH, 25 °C
48%
H
N
N
N
N
Ph
N
NH
adenine, CH(OEt)3
DMF–AcOH (3:1)
NH2
17
19
3
1
19
19
3
6
7
19
19
EtOH, 90 °C
75%
EtOH, 25 °C
75%
50%
NH
O
NH
Ph CH2NH2
4
EtOH, 25 °C
82%
EtOH, 25 °C
65%
EtOH, 25 °C
65%
Scheme 1 Synthesis of monocyclic pyridinones 1–7
Synthesis 2014, 46, 2179–2190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Monocyclic and Bicyclic Pyridinones and Tricyclic Morpholinopyrones
2181
tion with adenine to form compound 3 required an elevat-
ed temperature to achieve product formation. During the
course of the reaction, compounds 1–6 precipitated out
from the ethanolic reaction solvent, which facilitated
product formation and isolation, however, compound 7
remained soluble and hence 2–3 equivalents of morpho-
line were necessary to drive product formation and a lon-
ger reaction time was required. The 1H NMR spectral data
of compounds 4–7 show the presence of single stereoiso-
mers and that of compounds 1–3 indicate two stereoiso- Figure 2 An ORTEP drawing of a single-crystal X-ray structure of
(E)-3-[(benzylamino)methylene]-6-methylpyridine-2,4(1H,3H)-di-
one (1) (CCDC 989745); C14H14N2O2, triclinic, space group P-1, Z =
2, R1 factor 0.0702.
mers. The stereochemistry of 4–7 was not determined.
Single crystals of the major stereoisomer of 1 could be
grown by slow cooling and evaporation in ethanol. An
ORTEP diagram of compound 1 from a single-crystal X-
ray analysis is shown in Figure 2, which unequivocally
determined the E enamine double bond geometry of 1
clic pyridinones 8, 9, and 10 could be obtained in 69%,
81%, and 100% isolated yields, respectively, after filtra-
(NMR spectrum of the single crystals confirms it to be the
tion of the products from the crude reaction mixtures or
major stereoisomer). Selected bond lengths and bond an-
column chromatography on silica gel. The bicyclic pyrid-
gles of compounds 1, 13, and 16 derived from single-crys-
inone 11 containing an amino function in the side chain
was obtained in 45% overall yield from the coupling of 19
tal X-ray structure analyses are listed in Table 1.
Aldehyde 19 proved to be a versatile scaffold4 through and 2010 followed by removal of the Boc protecting group
which to construct various bicyclic pyridinone structures of 21 with trifluoroacetic acid.
by treating it with various doubly activated esters such as
methyl α-(phenylsulfinyl)acetate, methyl α-(phenylsulfo-
Similarly, coupling of 19 and β-keto ester 22 followed by
Boc deprotection gave compound 12. Compound 22 was
prepared by modifying the reported synthesis of com-
nyl)acetate, ethyl 3-oxo-3-phenylpropanoate, γ-(Boc-
amino)-β-keto ester 20,10 and β-keto ester 22 in refluxing
pound 20.10 The amino function of 11 or 12 can condense
ethanol, employing piperidine as the catalyst (Scheme 2).
with the carboxylic acid group of various amino acids or
peptides to generate fluorescence-active molecules.
The mechanism by which compounds 8–12 are formed is
expected to proceed via Knoevenagel condensation4 of
Molecules containing tricyclic pyrone scaffolds have
been synthesized in our laboratory and have been shown
the ester with aldehyde 19 followed by intramolecular lac-
tone formation. Notably, the ester function is required to
orient at the cis configuration with the phenolic OH group
for the lactonization. When one equivalent of piperidine
to possess strong cell protective action against oligomeric
amyloid β peptide toxicity1,11 and antiviral activity.2 To
explore new structures, a tricyclic pyrone scaffold
was used, byproduct 4 formed predominantly. The bicy-
Table 1 Selected Bond Lengths and Bond Angles of Compounds 1, 13, and 16 from Single-Crystal X-ray Structure Analyses
Compound 1
Compound 13
Compound 16
Bond lengths (Å) Bond angles (°)
Bond lengths (Å) Bond angles (°)
Bond lengths (Å)
Bond angles (°)
N(1)–C(2)
1.362(3)
C(2)–N(1)–C(6)
124.60(19)
C(1)–O(12)
1.2236(15)
O(2)–C(1)–C(9A)
117.48(10)
C(1)–O(12)
1.2239(17)
O(12)–C(1)–O(2)
117.12(12)
N(1)–C(6)
1.386(3)
O(17)–C(2)–N(1)
119.57(19)
C(1)–O(2)
1.3749(15)
C(3)–O(2)–C(1)
122.73(10)
C(1)–O(2)
1.3757(17)
C(1)–O(2)–C(3)
122.99(11)
C(2)–O(17)
1.258(2)
O(17)–C(2)–C(3)
124.0(2)
C(1)–C(9A)
1.4283(16)
C(3)–C(4)–C(4A)
119.39(11)
C(1)–C(9A)
1.4395(18)
C(3)–C(4)–C(4A)
119.23(13)
C(2)–C(3)
1.446(3)
N(1)–C(2)–C(3)
116.38(19)
O(2)–C(3)
1.3686(15)
C(7)–C(8)–C(8A)
123.73(12)
O(2)–C(3)
1.3764(17)
C(6)–C(5)–C(10A)
123.20(14)
C(3)–C(7)
1.387(3)
C(7)–C(3)–C(2)
116.65(19)
C(3)–C(4)
1.3446(17)
N(9)–C(8A)–C(8)
113.59(11)
C(3)–C(4)
1.3476(19)
C(5)–C(6)–C(7)
123.53(13)
C(3)–C(4)
1.448(3)
C(5)–C(4)–C(3)
116.64(19)
C(4)–C(4A)
1.4235(17)
N(9)–C(8A)–C(10A)
108.92(10)
C(4)–C(4A)
1.4269(19)
N(9)–C(8A)–C(8)
113.03(13)
C(4)–O(18)
1.257(3)
N(8)–C(7)–C(3)
127.3(2)
C(7)–C(8)
1.3314(19)
O(10)–C(10A)–C(8A)
111.68(10)
C(5)–C(6)
1.332(2)
N(9)–C(8A)–C(10A)
110.16(11)
C(7)–N(8)
1.303(3)
C(7)–N(8)–C(9)
123.29(19)
N(9)–C(9A)
1.3955(16)
C(5)–C(10A)–C(8A)
111.43(11)
C(8A)–C(10A)
1.533(2)
C(9A)–N(9)–C(8A)
119.03(12)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2179–2190

2182
A. M. Prior et al.
PAPER
O
O
O
S
O
O
S
Ph
OMe
Ph
OMe
19
19
9
8
piperidine (cat.)
EtOH, reflux
69%
piperidine (cat.)
EtOH, reflux
81%
O
O
Ph
OEt
10
19
piperidine (cat.)
EtOH, reflux
100%
O
O
H
N
H
O
t-BuO
N
OEt
O
TFA
45% overall
20
O
19
11
piperidine (cat.)
EtOH, reflux
O
t-BuO
N
H
O
O
21
BocO
H
N
Boc
N
O
O
O
OEt
22
TFA
19
O
piperidine (cat.)
EtOH, reflux
41% overall
N
H
O
O
HO
12
Scheme 2 Synthesis of bicyclic pyridinones 8–12
containing a nitrogen atom in the central ring (such as 13) sulting nitro function to amine over hydrogen/palladium,
would provide additional hydrogen bond donor (N–H) ca- in 62% overall yield. To examine the two-component
pacity. We therefore examined a two-component coupling ring-closing reaction, we first study N-protected pyrone
reaction for the synthesis of tricyclic morpholinopyrones 24. Aminopyrone 23 was capped with a tert-butoxycar-
from dinucleophile 3-aminopyrone 23 and dielectrophile bonyl protecting group to afford Boc-aminopyrone 24 in
trans-3,6-dibromocyclohexene (25).12 The expeditious 57% yield (Scheme 3). Upon treatment of pyrone 24 with
synthesis started from commercially available 4-hydroxy- one equivalent of sodium hydride followed by dibromide
6-methyl-2H-pyran-2-one, which was converted into 3- 25, Boc-tricyclic morpholinopyrone 27 resulted in 25%
aminopyrone 23 via a two-step process,13 involving the yield, and no other isomers were found (Table 2, entry 1).
nitration of 4-hydroxy-6-methyl-2H-pyran-2-one at C3 by We envision that the initial step requires deprotonation of
nitric acid/sulfuric acid followed by reduction of the re- 24 with sodium hydride to form a pyrone oxy anion,
which upon treatment with dibromide 25 supposedly
forms O-alkylated intermediate 26. This O-alkylated in-
termediate undergoes a ring-closing reaction to give 27.
The Boc protecting group of 27 was readily removed us-
ing 10% trifluoroacetic acid in dichloromethane at 40 °C
to furnish tricyclic morpholinopyrone 13 in quantitative
yield. Only the cis-diastereomer 13 was detected from the
cyclization reaction and the stereochemistry was unequiv-
ocally determined through a single-crystal X-ray structure
analysis (Figure 3). Single crystals of tricyclic morpholin-
opyrone 13 were achieved by slow evaporation of a solu-
tion of 13 in ethanol. The crystal structure shows that the
tricyclic scaffold forms a cis-fused ring junction upon cy-
clization and the double bond is situated between C7 and
C8 implying a SN2′ reaction takes place from intermediate
Figure 3 An ORTEP drawing of a single-crystal X-ray structure
analysis of 3-methyl-5,8a,9,10a-tetrahydro-1H,6H-2,10-dioxa-9-
26 with retention of configuration. The two synclinal
azaanthracen-1-one (13) (CCDC 989746); C12H13NO3, monoclinic,
bridgehead protons have a torsion angle of 48.1°.
space group P21/c, Z = 4, and R1 factor 0.0538.
Synthesis 2014, 46, 2179–2190
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Monocyclic and Bicyclic Pyridinones and Tricyclic Morpholinopyrones
2183
Dibromide 25 was prepared from a one-step double bro- oxidation of 28 to ketone 15 using 2-iodoxybenzoic acid
mination of cyclohexene with N-bromosuccinimide (2 in dimethyl sulfoxide. Only two alkanyl downfield hydro-
equiv)14 and the trans-stereochemistry was verified by gens at δ = 5.20 (d, J = 4 Hz, C8aH) and 4.75 (q, J = 4 Hz,
1
comparing its H NMR spectral data with the literature C10aH) were found in the 1H NMR spectrum of 15. The
values.12 We have also obtained a single-crystal X-ray Boc protecting group of 28 can be removed by 10% triflu-
structure of this compound which agrees with that report- oroacetic acid in dichloromethane at 40 °C to give 8-hy-
ed.12 The presence of a double bond in the six-membered droxy tricyclic morpholinopyrone 14. These results are
carbocyclic ring of the tricyclic skeleton is significant be- encouraging because the alkene, hydroxy, and ketone
cause it allows for further modification of the tricyclic functionalities provide a means for further structural mod-
scaffold as demonstrated in Scheme 3. The double bond of ification of the tricyclic ring system making further syn-
27 was regioselectively hydroxylated by employing stan- thesis of analogues possible.
dard hydroboration/oxidation conditions to give 8-hy-
droxy tricyclic morpholinopyrone 28 as a single
stereoisomer. The stereochemistry at C8 was assumed in
that borane approaches the C7–C8 double bond from the
Intriguing differences were observed in the aforemen-
tioned double alkylation reaction for the formation of a
tricyclic morpholinopyrone scaffold. A regioisomer of 27,
30, was found when a different protecting group, p-meth-
least hindered face (same side of C8aH and C10aH).
oxybenzyl (PMB), was used (Scheme 4). The PMB group
The regiochemistry of the C8 hydroxy function was as- was installed via a two-step reductive amination proce-
signed from the appearances of C8H at δ = 3.33 showing dure1 by treating 3-aminopyrone 23 with p-anisaldehyde
a triplet of doublets with J = 10.5 and 3.5 Hz, C8aH at δ = in methanol followed by sodium cyanoborohydride and
4.22 showing a doublet of doublets with J = 10.1 and 3.5 acetic acid in ethanol to give 29 in 89% yield. Various re-
Hz, and C10aH at δ = 4.40 showing a quartet with J = 3.5 action conditions were examined for the dialkylation reac-
Hz, suggesting C8H orients at the axial, C8aH at axial, tions and results are summarized in Scheme 5 and Table
and C10aH at equatorial position based on the J values. 2. A single diastereomer of the olefin regioisomer 30 re-
The chemical shift assignments and couplings were sup- sulted when treating 29 with dibromide 25 and triethyl-
ported from the 2D COSY, HMBC, and HSQC spectra of amine in 50% isolated yield (Table 2, entry 5) after
28. The regiochemistry at C8 was further verified from the column chromatographic purification. No other isomers
O
O
O
O
O
O
O
O
O
Boc2O
1
NaH, DMF
then
MeCN, 85 °C
4
BocN9
BocHN
57%
BocHN
H2N
Br
H
H
O
8
OH
OH
23
10
H
5
24
Br
Boc = t-BuOCO
Br
25
27
26
O
O
O
10% TFA
CH2Cl2, 40 °C
HN
H
quantitative
yield
H
13
O
O
O
BH3⋅THF
OH
O
Boc
25 °C
IBX, DMSO
87%
8a
8
N
O
27
5
t-BuO
N
H
then
H2O2, NaOH
87%
10a
H
1
O
O
O
4
28
15
O
O
O
1
TFA, CH2Cl2
40 °C, 1 h
4
28
HN
8a
65%
H
HO
10a
8
H
5
14
Scheme 3 Synthesis of tricyclic morpholinopyrones 13–15
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2179–2190

2184
A. M. Prior et al.
PAPER
O
O
O
O
O
i) p-anisaldehyde
MeOH
Et3N, DMF
80 °C, 25
TFA, CH2Cl2
59%
PMBN
23
16
H
PMBHN
ii) NaCNBH3
89%
50%
OH
H
5
29
6
30
Et3N, DMF
120 °C, 25
16
23
13%
Scheme 4 Synthesis of tricyclic morpholinopyrone 16
were found. When sodium hydride was used in place of (with retention of configuration) followed by ring closing
triethylamine in the above double alkylation reaction, due to SN2 nucleophilic substitution (inversion) by the
only 7% yield of 30 was obtained (entry 4). The PMB amine function. We further discovered that pyrone 16 can
group was removed by 5% trifluoroacetic acid in di- be synthesized in a single step (in a lower yield; Table 2,
chloromethane at 40 °C to give tricyclic morpholinopy- entry 7) by the direct treatment of amine 23 with dibro-
rone 16, which structure was unequivocally determined mide 25 and triethylamine in N,N-dimethylformamide at
from a single-crystal X-ray structure analysis (Figure 4).
120 °C for two hours without PMB protection. Table 2
summarizes the reaction conditions that formed tricyclic
morpholinopyrone scaffolds. The alkylation of Boc-pro-
tected pyrone 24 with 25 and potassium carbonate or tri-
ethylamine gave only 3% and 7% yield, respectively
(entries 2 and 3). The protecting groups appear to affect
the regiochemistry of the olefinic moiety of the tricyclic
products. The use of Boc as an amine protecting group re-
sulted in C7–C8 double bond isomer, while an amine sub-
stituent (with or without PMB protecting group) gave the
C5–C6 double bond isomer. The strengths of the N–H
acidities appear to affect the initial alkylation step, which
resulted in different regioisomers. Notably, no tricyclic
product was found when amine 23 was treated with sodi-
um hydride or DBU and dibromide 25 (entries 6 and 9),
and the use of other bases such as pyridine only produced
trace amounts of 16 (entry 8).
Br
O
O
O
O
O
O
O
O
Br
25
RHN
H
RHN
H
RHN
+
H
H
conditions
(Table 2)
OH
23: R = H
24: R = Boc
29: R = PMB
30: R = PMB
16: R = H
27: R = Boc
Scheme 5 Synthesis of tricyclic morpholinopyrones 27, 30, and 16
Table 2 Reaction Conditions and Yields of the Formation of Tricy-
clic Morpholinopyrones 27, 30, and 16
Entry R
Conditions
Product Yield
(%)
1
Boc
(i) NaH, DMF; (ii) Et3N, MeCN,
95 °C, 8 h
27
25
Figure 4 An ORTEP drawing of a single-crystal X-ray analysis of
3-methyl-7,8,8a,10a-tetrahydro-1H,9H-2,10-dioxa-9-azaanthracen-
1-one (16) (CCDC 989747); C12H13N1O3, monoclinic, space group
P21/c, Z = 4, and R1 factor 0.0595.
2
3
4
5
6
Boc
Boc
K2CO3, DMF, 90 °C, 8 h
Et3N, DMF, 80 °C, 3 h
27
27
3
7
PMB NaH, DMF–MeCN (1:1), 80 °C, 8 h 30
7
The tricyclic scaffold of 16 also formed a cis-fused ring
junction upon cyclization and the two synclinal bridge
head protons have a torsion angle of 44.2°. Of interest is
the position of the double bond which is now found be-
tween C5 and C6. This suggests that the cyclization steps
took place either via initial SN2 N-alkylation of 29 with di-
bromide 25 followed by SN2′ nucleophilic substitution
(with retention of configuration) by the hydroxy function,
or by initial SN2′ O-alkylation of 29 with dibromide 25
PMB Et3N, DMF, 80 °C, 2.5 h
30
16
50
0
H
(i) NaH, DMF; (ii) Et3N, MeCN,
80 °C, 8 h
7
8
9
H
H
H
Et3N, DMF, 120 °C, 2 h
16
16
13
2
pyridine, DMF, 120 °C, 0.5 h
DBU, DMF, 120 °C, 0.5 h
–
Synthesis 2014, 46, 2179–2190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Monocyclic and Bicyclic Pyridinones and Tricyclic Morpholinopyrones
2185
All melting points are uncorrected. 1H NMR spectra (400 MHz) and
13C NMR spectra (100 MHz) were measured from a solution in CD-
Cl3 or DMSO-d6 relative to TMS (δ = 0 ppm) or CHCl3 (δ = 7.26
ppm) (1H NMR) or CDCl3 (δ = 77.0 ppm) or DMSO (δ = 39.5 ppm)
(13C NMR). The E and Z assignment in 13C NMR spectral data are
assumed and based on the signal intensities. LR-MS were taken
from an API 2000-triple quadrupole ESI-MS/MS mass spectrome-
ter. HRMS were obtained using a LCT Premier ToF mass spectrom-
eter. IR spectra were measured directly in either solid or liquid
form. UV-Vis absorption measurements were recorded on a Hewl-
ett Packard 8453 UV-VIS spectrophotometer and fluorescence
emission spectra were recorded on a Jobin Yvon-spec fluoromax-2
fluorescence spectrophotometer (slits: 2.5 nm; integration time: 0.5
s); fluorescence emission spectra excitation wavelength: 380 nm,
and emissions: 400–600 nm. The fluorescence quantum yields were
determined by following a procedure reported by Brouwer16 using
perylene (ΦF = 0.94, cyclohexane) as the standard reference com-
pound. Perylene was chosen as the reference because it has an emis-
sion wavelength similar to compounds 8–12 thus allowing the same
excitation wavelength (380 nm) to be used for all molecules. Fluo-
rescence emission spectra and UV-VIS absorption spectra for com-
pounds 8–12, and 21 were recorded at 2 μM and 20 μM,
respectively, in (MeOH), and perylene recorded at 1 μM and 10 μM,
respectively, in cyclohexane. Refractive indices for MeOH and cy-
clohexane were incorporated when calculating relative fluorescence
quantum yields.16 X-ray crystal structure data sets were collected on
a Bruker Kappa APEX II systems using MoKα radiation. Data were
collected using APEX2 software (APEXII v2009, Bruker Analyti-
cal X-ray Systems, Madison, WI). Data collection strategies were
determined using COSMO (v1.60, 1999–2009, Bruker Analytical
X-ray System, Madison, WI). Scan speed and scan width were cho-
sen based on scattering power and peak rocking curves. All datasets
were collected at –153 °C using an Oxford Cryostream low-tem-
perature device. Unit cell constants and orientation matrix were im-
proved by least-squares refinement of reflections threshold from the
entire dataset. Integration was performed with SAINT (v7.60a,
1997–2008, Bruker Analytical X-ray System, Madison, WI), using
this improved unit cell as a starting point. Precise unit cell constants
were calculated in SAINT from the final merged dataset. Lorenz
and polarization corrections were applied. Multiscan absorption
corrections was performed with SADABS (v2008/1, Bruker Ana-
lytical X-ray System, Madison, WI). Data were reduced with
SHELXTL (v2008/4, Bruker Analytical X-ray System, Madison,
WI). The structures were solved in all cases by direct methods with-
out incident. The molecules were fully ordered, no solvent was
present, and no constraints or restraints were applied. Coordinates
for N–hydrogen atoms were allowed to refine. All other hydrogen
atoms were located in idealized positions and were treated with a
riding model. Refinement was continued to convergence using the
recommended weighting scheme. 4-Hydroxy-6-methylpyridin-
2(1H)-one (17) and 4-hydroxy-6-methyl-2H-pyran-2-one were pur-
chased from Fisher Scientific and Sigma-Aldrich, respectively. All
solvents were dried over appropriated drying chemical such as
CaH2 (for DMF), Mg (for EtOH), or Na/benzophenone (for THF)
followed by distillation. All low-molecular-weight amines were pu-
rified by distillation.
One of our goals in the synthesis of bicyclic pyridinones
is the construction of new fluorescence activity based
probes.8,9 Based on the reported bicyclic heterocycles,15
bicyclic pyridinones 8–12 should be fluorescently active.
Indeed, Table 3 summarizes photophysical data from the
UV absorption and fluorescence emission spectra of 8–12
and 21 showing longer absorption and fluorescence emis-
sion wavelengths compare with those of commercially
available 7-amino-4-methylcoumarin (AMC; λex = 351
nm; λem = 430 nm; λabs,max = 350 nm in ethanol), a widely
used fluorescence probe.15 All five compounds possess
similar fluorescence emission wavelengths, λem, of 450–
467 nm and quantum yields, ΦF, ranging from 0.03 to
0.54. Perylene was used as a standard for the calculation
of quantum yields.16 The C3 electron-withdrawing group
such as sulfoxide, sulfone, and ketone of the bicyclic pyr-
idinone system contributes bathochromic and bathofluor-
ic shifts in the absorption and fluorescence spectra,
respectively. The extended conjugation contributed from
the phenyl ring of ketone 10 leads to a longer emission
wavelength of 467 nm than other measured compounds,
and sulfone 9 possesses the highest quantum yield.
Table 3 Photophysical Data for Absorption (abs) and Emission (em)
of Compounds 8–12 and 21 in Methanol
Compounds
λabs (nm)b
8
9
10
11
12
21
Perylenea
368
385 381 427 430 393 436
log ε (M–1cm–1)c 4.16 4.26 4.18 3.85 3.67 4.18 4.40
λex (nm)d
λem (nm)e
380
450
380 380 380 380 380 380
450 467 450 458 460 439
f
ΦF
0.03 0.54 0.03 0.14 0.06 0.22 0.94g
a Data were obtained in cyclohexane due to solubility.
b Wavelengths of maximum absorption.
c Extinction coefficient.
d Wavelengths of fluorescence excitation.
e Wavelengths of maximum fluorescence emission.
f Fluorescence quantum yields were calculated by following the re-
ported method16 from two independent experiments.
g Literature quantum yield of perylene is 0.94 (in cyclohexane).16
One-pot condensations of 3-formyl-4-hydroxy-6-meth-
ylpyridin-2(1H)-one (19) with secondary amines afforded
various 3-[(dialkylamino)methylene]-6-methylpyridine-
2,4(1H,3H)-diones and with α-sulfinyl, α-sulfonyl, and β-
keto esters gave bicyclic pyridinones, which can be used
as fluorescence probes for biochemical research. More-
3-Formyl-4-hydroxy-6-methylpyridin-2(1H)-one (19)4
over, one-pot dialkylation reactions of 3-amino-4-hy- A solution of 4-hydroxy-6-methylpyridin-2(1H)-one (17, 8.0 g, 64
mmol), triethyl orthoformate (53 mL, 0.32 mol), and aniline (5.8
droxy-6-methyl-2H-pyran-2-ones
with
trans-3,6-
mL, 64 mmol) in DMF and AcOH (3:1, 60 mL) under argon was
heated at 130 °C for 1 h. The solution was cooled to 25 °C, diluted
with H2O (300 mL), and extracted with CH2Cl2 (4 × 100 mL). The
combined organic layers were washed with brine and concentrated
to dryness. Et2O (200 mL) was added to the residue, the solution
cooled to 0 °C, and the precipitated solid was collected by filtration,
washed with Et2O, and dried under vacuum to give 6-methyl-3-
dibromocyclohexene under various reaction conditions
were investigated and different regioisomers can be selec-
tively produced albeit in low yields. Bioactivity of the
newly synthesized monocyclic, bicyclic, and tricyclic
molecules will be evaluated and reported in due course.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2179–2190

2186
A. M. Prior et al.
PAPER
[(phenylamino)methylene]pyridine-2,4(1H,3H)-dione (18)4 (8.9 g,
61%, E/Z 4:1).
1H NMR: δ = 9.76 (br s, 1 H, NH), 8.87 (d, J = 12.5 Hz, 1 H, =CHN,
minor), 8.83 (d, J = 12.5 Hz, 1 H, =CHN, major), 7.45–7.25 (m, 5
H), 5.67 (s, 1 H, =CH, minor), 5.64 (s, 1 H, =CH, major), 2.20 (s, 3
H, major), 2.18 (s, 3 H, minor).
13C NMR (100 MHz, DMSO-d6): δ = 193.3 (E/Z), 185.1 (E/Z),
180.8 (E/Z), 174.7 (Z), 167.6 (E), 153.5 (E), 152.4 (Z), 151.9 (E/Z),
150.4 (E), 149.7 (Z), 146.8 (Z), 144.4 (E), 122.3 (Z), 106.5 (Z),
106.4 (E), 105.1 (E/Z), 19.5 (E), 19.4 (Z).
MS (ESI, MeOH): m/z = 292.9 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C12H10N6O2Na: 293.0763;
A solution of 18 (2.0 g, 8.7 mmol) and K2CO3 (40 g, 0.29 mol) in
H2O (800 mL) was heated at 100 °C for 4 h, cooled to 25 °C, acid-
ified with concd HCl to pH 2, and extracted with CH2Cl2 (2 ×). The
combined organic layers were washed with brine, dried (MgSO4),
and concentrated to give 19 as a yellow solid; yield: 1.2 g (90%);
mp 256 °C (dec.).4
1H NMR (400 MHz, CDCl3): δ = 13.71 (s, 1 H, NH), 11.50 (br s, 1
H, OH), 10.08 (s, 1 H, CHO), 5.86 (s, 1 H, =CH), 2.36 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 193.3, 174.7, 163.3, 157.1,
found: 293.0749.
6-Methyl-3-(piperidin-1-ylmethylene)pyridine-2,4(1H,3H)-di-
one (4)
Following the typical procedure using 19 (1.31 mmol) and piperi-
dine (1.44 mmol) in EtOH (4 mL) with stirring at 25 °C for 12 h
gave 4 as a yellow solid as a single stereoisomer; yield: 0.19 g
(65%); mp 250–252 °C.
1H NMR (400 MHz, CDCl3): δ = 9.64 (br s, 1 H), 8.21 (s, 1 H), 5.52
(s, 1 H), 3.93 (br s, 2 H), 3.70 (br s, 2 H), 2.10 (s, 3 H), 1.84 (br s, 6
H).
13C NMR (100 MHz, CDCl3): δ = 182.0, 166.5, 161.3, 148.1, 107.8,
101.7, 59.2, 54.7, 27.0, 26.6, 23.4, 19.6.
MS (ESI, MeOH): m/z = 243.5 ([M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C12H17N2O2: 221.1290; found:
221.1262.
105.3, 97.7, 19.5.
MS (ESI, MeOH): m/z = 176.1 ([M + Na+]).
3-[(Benzylamino)methylene]-6-methylpyridine-2,4(1H,3H)-di-
one (1); Typical Procedure for the Synthesis of Compounds 1–7
To a solution of 19 (1.31 mmol) in distilled EtOH (4 mL) under ar-
gon was added BnNH2 (1.44 mmol), the mixture was stirred at
25 °C for 24 h, and the solution was diluted with hexane–Et2O (1:1).
The precipitated solid was collected by filtration, washed with hex-
ane–Et2O (1:1), and dried under vacuum to yield pure 1 as a yellow
solid; yield: 0.26 g (82%); ratio E/Z 4.5:1; mp 219–221 °C.
1H NMR (400 MHz, CDCl3): δ (major E-isomer) = 9.69 (br s, 1 H),
8.45 (d, J = 12 Hz, 1 H), 8.38 (s, 1 H), 7.23–7.45 (m, 5 H), 5.56 (s,
1 H), 4.65 (d, J = 4 Hz, 2 H), 2.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ (major E-isomer) = 185.0, 166.9,
160.7, 149.3, 135.5, 129,3, 128.7, 127.8, 107.0, 102.5, 54.5, 20.0.
MS (ESI, MeOH): m/z = 265.4 ([M + Na+]).
HRMS (ESI): m/z [M + Na]+ calcd for C14H14N2O2Na: 265.0953;
6-Methyl-3-(4-methylpiperazin-1-ylmethylene)pyridine-
2,4(1H,3H)-dione (5)
Following the typical procedure using 19 (1.31 mmol) and 1-meth-
ylpiperazine (1.44 mmol) in EtOH (4 mL) with stirring at 25 °C for
12 h gave 5 as a yellow solid; yield: 0.29 g (93%); mp 216 °C (dec.).
1H NMR (400 MHz, CDCl3): δ = 9.41 (br s, 1 H), 8.22 (s, 1 H), 5.53
(s, 1 H), 4.03–4.15 (m, 2 H), 3.71–3.82 (m, 2 H), 2.54–2.72 (m, 4
H), 2.35 (s, 3 H), 2.11 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 194.2, 161.2, 148.5, 107.9, 102.1,
100.0, 57.6, 55.4, 55.3, 53.6, 45.8, 19.7.
MS (ESI, MeOH): m/z = 258.4 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C12H17N3O2Na: 258.1218;
found: 265.0946.
3-[(4-Hydroxybenzylamino)methylene]-6-methylpyridine-
2,4(1H,3H)-dione (2)
found: 258.1242.
Following the typical procedure using 19 (1.7 mmol) and 4-hy-
droxybenzylamine (1.7 mmol) in EtOH (2 mL) with stirring at
25 °C for 4 h gave 2 as a yellow solid; yield: 0.21 g (48%); ratio E/Z
7:3; mp 222–225 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.07–12.19 (m, 0.7 H, E),
10.91–11.01 (m, 0.3 H, Z), 10.27 (s, 1 H), 9.50 (s, 1 H), 8.29–8.36
(m, 1 H), 7.17 (d, J = 7.4 Hz, 2 H), 6.76 (d, J = 7.4 Hz, 2 H), 5.30
(s, 1 H), 4.54–4.61 (m, 2 H), 1.98 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 183.5 (E), 180.3 (Z), 166.9
(Z), 165.0 (E), 159.4 (E), 159.0 (Z), 157.1 (E/Z), 149.5 (E), 149.0
(Z), 129.5 (E/Z), 127.3 (Z), 127.1 (E), 115.5 (E/Z), 106.2 (Z), 105.1
(E), 101.5 (E), 101.4 (Z), 52.1 (E/Z), 19.1 (E/Z).
6-Methyl-3-(4-phenylpiperazin-1-ylmethylene)pyridine-
2,4(1H,3H)-dione (6)
Following the typical procedure using 19 (1.31 mmol) and 1-phen-
ylpiperazine (1.60 mmol) in EtOH (4 mL) with stirring at 25 °C for
12 h gave 6 as a yellow solid; yield: 0.29 g (75%); mp 201 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 10.01 (s, 1 H, NH), 8.22 (s, 1
H, =CH), 7.25 (t, J = 8 Hz, 2 H), 7.00 (d, J = 8 Hz, 2 H), 6.84 (t, J
= 8 Hz, 1 H), 5.20 (s, 1 H, =CH), 4.12–4.09 (m, 2 H), 3.85–3.92 (m,
2 H), 3.42–3.35 (m, 4 H), 1.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.8, 150.1, 148.4, 148.3, 129.0,
119.5, 115.9, 112.1, 106.1, 101.5, 56.0, 52.3, 49.1, 48.8, 18.8.
MS (ESI, MeOH): m/z = 320.2 ([M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C17H20N3O2: 298.1556; found:
MS (ESI, MeOH): m/z = 281.3 ([M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C14H15N2O3: 259.1083; found:
298.1570.
259.1107.
6-Methyl-3-(morpholin-4-ylmethylene)pyridine-2,4(1H,3H)-di-
one (7)
Following the typical procedure using 19 (1.31 mmol) and morpho-
line (2.60 mmol) in EtOH (4 mL) with stirring at 25 °C for 24 h, and
crystallization of the crude product (EtOAc–Et2O, 1:1) gave 7 as a
yellow solid; yield: 0.19 g (65%); mp 180–182 °C (dec.).
1H NMR (400 MHz, CDCl3): δ =8.71, (br s, 1 H), 8.23 (s, 1 H), 5.53
(s, 1 H), 4.26–3.56 (m, 8 H), 2.11 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.0, 148.7, 130.2, 118.7, 107.8,
102.3, 67.4, 67.2, 57.6, 54.3, 19.7.
6-Methyl-3-[(9H-purin-6-ylamino)methylene]pyridine-
2,4(1H,3H)-dione (3)
Following the typical procedure using 19 (1.31 mmol) and adenine
(1.31 mmol) in EtOH (4 mL) with stirring at 90 °C for 14 h gave 3
as a yellow solid; yield: 0.27 g (75%); ratio E/Z 2:1); mp >300 °C
(had not melted).
1H NMR (400 MHz, CDCl3): δ = 13.95 (d, J = 12.0 Hz, 0.7 H, E),
13.75 (br s, 1 H, NH of E and Z), 12.82 (d, J = 12.9 Hz, 0.3 H, Z),
10.80 (br s, 0.3 H, NH of Z), 10.73 (br s, 0.7 H, NH of E), 9.55 (d,
J = 12.0 Hz, 0.7 H, E), 9.51 (d, J = 12.9 Hz, 0.3 H, Z), 8.69 (s, 1 H,
E and Z), 8.59 (s, 1 H, E and Z), 5.51 (s, 0.7 H, E), 5.48 (s, 0.3 H,
Z), 2.08 (s, 2.1 H, E), 2.07 (br s, 0.9 H, Z).
MS (ESI, MeOH): m/z = 223.2 ([M + H]+).
Synthesis 2014, 46, 2179–2190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Monocyclic and Bicyclic Pyridinones and Tricyclic Morpholinopyrones
2187
HRMS (ESI): m/z [M + Na]+ calcd for C11H14N2O3Na: 245.0902;
MS (ESI, MeOH): m/z = 357.3 ([M + Na]+).
found: 245.0892.
HRMS (ESI): m/z [M + Na]+ calcd for C16H18N2O6Na: 357.1057;
found: 357.1066.
7-Methyl-3-(phenylsulfinyl)-2H-pyrano[3,2-c]pyridine-
2,5(6H)-dione (8); Typical Procedure for the Synthesis of Com-
pounds 8–12
A solution of 21 (0.024 mmol) in 10% TFA–CH2Cl2 (1 mL) was
stirred at 25 °C for 8 h. The solvent was removed in vacuo and the
remaining solid kept under high vacuum to yield 11 as a yellow sol-
id; yield: 8 mg (100%); mp 310 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 12.39 (br s, 1 H), 8.58 (s, 1 H),
8.10–8.20 (br s, 2 H), 6.35 (s, 1 H), 4.32 (s, 2 H), 2.30 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 187.9, 165.7, 159.2, 157.1,
155.1, 144.2, 114.5, 104.5, 95.7, 46.4, 18.5.
MS (ESI, MeOH): m/z = 235.2 ([M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O4: 235.0719; found:
To a solution of 19 (0.16 mmol) and methyl α-(phenylsulfinyl)ace-
tate (0.20 mmol) in anhyd EtOH (1 mL) under argon was added
piperidine (0.01 mmol) and the mixture stirred at 80 °C for 48 h.
The mixture was cooled to 25 °C and concentrated on a rotary evap-
orator to give a solid that was washed with Et2O, suspended in CH2-
Cl2 (1 mL), and filtered. The resulting solid was washed with
CH2Cl2 (2 ×) and dried under vacuum to give 8 as a yellow solid;
yield: 34 mg (69%); mp 281–283 °C.
1H NMR (400 MHz, DMSO-d6): δ = 12.43 (s, 1 H), 8.36 (s, 1 H),
7.75–7.70 (m, 2 H), 7.52–7.50 (m, 3 H), 6.30 (s, 1 H), 2.28 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 164.7, 160.1, 156.0, 153.0,
142.8, 137.4, 132.0, 129.5, 127.2, 125.6, 105.7, 96.7, 19.3.
235.0728.
Ethyl 4-{(tert-Butoxycarbonyl)[4-(tert-butoxycarbonyloxy)ben-
zyl]amino}-3-oxobutanoate (22)
MS (ESI, MeOH): m/z = 324.2 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C15H11NO4SNa: 324.0307;
To a cold (0 °C) solution of 4-(aminomethyl)phenol (40.6 mmol)
and Et3N (40.6 mmol) in THF (50 mL) under argon was added
methyl 2-bromoacetate (28.4 mmol) dropwise, and the solution was
stirred at 25 °C for 12 h, concentrated, and column chromato-
graphed (silica gel, CH2Cl2–MeOH, 9:1) to give methyl (4-hy-
droxybenzylamino)acetate17 as an off-white solid; yield: 3.6 g
(45%); mp 105–107 °C.
found: 324.0305.
7-Methyl-3-(phenylsulfonyl)-2H-pyrano[3,2-c]pyridine-
2,5(6H)-dione (9)
Following the typical procedure using 19 (0.20 mmol), methyl α-
(phenylsulfonyl)acetate (0.235 mmol), and piperidine (0.01 mmol)
in EtOH (1 mL) with stirring at 80 °C for 48 h gave 9 as a yellow
solid; yield: 50 mg (81%); mp >300 °C (had not melted).
1H NMR (400 MHz, DMSO-d6): δ = 12.41 (s, 1 H), 8.66 (s, 1 H),
8.00 (d, J = 7.5 Hz, 2 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.60 (t, J = 7.5
Hz, 2 H), 6.33 (s, 1 H), 2.31 (s, 3 H).
1H NMR (400 MHz, DMSO-d6): δ = 9.25 (br s, 1 H, OH), 8.30 (s, 1
H, NH), 7.10 (d, J = 7.5 Hz, 2 H), 6.70 (d, J = 7.5 Hz, 2 H), 3.60 (s,
3 H), 3.55 (s, 2 H), 3.24 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 172.7, 155.4, 130.2, 129.8, 115.5,
52.7, 51.9, 49.5.
MS (ESI, MeOH): m/z = 218.1 ([M + Na]+).
13C NMR (100 MHz, DMSO-d6): δ = 167.6, 160.8, 156.5, 155.1,
145.7, 139.5, 134.8, 129.9, 129.1, 121.6, 105.6, 97.5, 20.3.
MS (ESI, MeOH): m/z = 340.4 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C15H11NO5SNa: 340.0256;
found: 340.0246.
To a solution of methyl (4-hydroxybenzylamino)acetate (5.31
mmol) in 1,4-dioxane–H2O (9:1, 5 mL), NaHCO3 (11.6 mmol) was
added and the mixture was stirred at 25 °C for 5 min. Boc2O (11.6
mmol) was added to the mixture, and it was stirred for 12 h, diluted
with brine (40 mL), and extracted with CH2Cl2 (4 × 100 mL). The
combined organic layers were washed with H2O and brine, dried
(anhyd Na2SO4), concentrated, and column chromatographed (sili-
ca gel, CH2Cl2–MeOH, 20:1) to give methyl [(tert-butoxycarbon-
yl)(4-hydroxybenzyl)amino]acetate as a colorless oil; yield: 1.19 g
(76%).
3-Benzoyl-7-methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione
(10)
Following the typical procedure using 19 (0.65 mmol), ethyl 3-oxo-
3-phenylpropanoate (0.98 mmol), and piperidine (0.03 mmol) in
EtOH (3 mL) with stirring at 80 °C for 48 h gave 10 as a yellow sol-
id; yield: 0.18 g (100%); mp 312–314 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 12.23 (br s, 1 H), 8.15 (s, 1 H),
7.84 (d, J = 7.5 Hz, 2 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.53 (t, J = 7.5
Hz, 2 H), 6.33 (s, 1 H), 2.32 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ (2 rotamers) = 7.07–7.05 (m, 2 H),
6.82–6.77 (m, 2 H), 6.47–6.45 (br s, 1 H), 4.45 / 4.42 (2 s, 2 H), 3.90
and 3.78 (2 s, 2 H), 3.71 and 3.68 (2 s, 3 H), 1.49 and 1.47 (2 s, 9 H).
MS (ESI, MeOH): m/z = 318.3 ([M + Na]+).
13C NMR (100 MHz, DMSO-d6): δ = 191.3, 165.6, 160.3, 157.5,
153.4, 143.6, 136.7, 133.3, 129.3, 128.5, 120.5, 105.2, 96.8, 19.4.
MS (ESI, MeOH): m/z = 304.1 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C16H11NO4Na: 304.0586;
To a solution of methyl [(tert-butoxycarbonyl)(4-hydroxyben-
zyl)amino]acetate (4.03 mmol) in 1,4-dioxane–H2O (1:1, 2 mL),
NaOH (12.1 mmol) was added. The solution was stirred at 25 °C for
2 h, neutralized with 1 M HCl to pH 6, and concentrated to dryness
leaving a white solid. The solid was dissolved in anhyd DMF (5
mL) under argon, and NaH (8.11 mmol) and Boc2O (4.87 mmol)
were added. The solution was stirred at 25 °C for 12 h, diluted with
H2O, and extracted with EtOAc (2 × 100 mL). The combined
organic layers were washed with brine, dried (anhyd Na2SO4), con-
centrated to give {(tert-butoxycarbonyl)[4-(tert-butoxycarbonyl-
oxy)benzyl]amino}acetic acid as a colorless oil; yield: 1.56 g
(84%).
1H NMR (400 MHz, CDCl3): δ (2 rotamers) = 7.28–7.22 (m, 2 H),
7.14–7.11 (m, 2 H), 4.53–4.49 (m, 2 H), 3.94–3.80 (m, 2 H), 1.55–
1.52 (m, 9 H), 1.48–1.47 (m, 9 H).
13C NMR (100 MHz, CDCl3): δ (2 rotamers) = 174.58, 174.57,
155.5, 155.4, 151.6, 150.3, 134.5, 134.4, 128.9, 128.2, 121.2, 83.3,
81.0, 80.8, 50.8, 50.2, 47.5, 28.1, 28.0, 27.4.
found: 304.0586.
3-(2-Aminoacetyl)-7-methyl-2H-pyrano[3,2-c]pyridine-
2,5(6H)-dione (11)
Following the typical procedure using 19 (0.99 mmol), ethyl 4-
[(tert-butoxycarbonyl)amino]-3-oxobutanoate (20, 1.5 mmol),10
and piperidine (0.05 mmol) in EtOH (3 mL) with stirring at 70 °C
for 48 h, and column chromatographic purification (silica gel, CH2-
Cl2–MeOH, 15:1) gave 21 as a colorless oil; yield: 0.15 g (45%).
1H NMR (400 MHz, DMSO-d6): δ = 12.29 (s, 1 H), 8.50 (s, 1 H),
7.69–7.70 (br s, 1 H), 6.34 (s, 1 H), 4.32 (d, J = 5.9 Hz, 2 H), 2.32
(s, 3 H), 1.39 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 192.3, 166.4, 160.4, 158.3,
155.8, 155.0, 144.6, 117.1, 105.5, 96.7, 78.0, 49.8, 28.2, 19.5.
MS (ESI, MeOH; negative ion mode): m/z = 380.5 ([M – H]–).
© Georg Thieme Verlag Stuttgart · New York
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To a solution of {(tert-butoxycarbonyl)[4-(tert-butoxycarbonyl-
oxy)benzyl]amino}acetic acid (4.09 mmol) in anhyd THF (4 mL)
under argon was added CDI (4.44 mmol). The solution was stirred
at 25 °C for 4 h to give the corresponding acylimidazole. To a mix-
ture of MgCl2 (0.54 g, 5.65 mmol) and monoethyl malonate potas-
sium salt (0.71 g, 5.36 mmol) under argon, Et3N (0.85 mL, 6.14
mmol) and THF (2 mL) were added. The solution was stirred at
25 °C for 4 h, and the above acylimidazole solution was added via
cannula. The resulting mixture was stirred at 25 °C for 18 h, diluted
with H2O and 0.1 M HCl to pH 5, and extracted with EtOAc (3 ×).
The combined organic layers were washed with aq NaHCO3, and
brine, dried (anhyd Na2SO4), concentrated, and column chromato-
graphed (silica gel, hexane–EtOAc, 15:1) to give 22 as a colorless
oil; yield: 0.66 g (36%).
1H NMR (400 MHz, CDCl3): δ (2 rotamers) = 7.28–7.20 (m, 2 H),
7.14–7.12 (m, 2 H), 4.49–4.45 (m, 2 H), 4.17 (q, J = 7.2 Hz, 2 H),
4.07 and 3.93 (2 s, 2 H, 2 rotamers), 3.42 and 3.35 (2 s, 2 H, 2 rota-
mers), 1.56 (s, 9 H), 1.47 (s, 9 H), 1.26 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ (2 rotamers) = 198.8, 198.6, 166.8,
166.6, 155.6, 155.3, 151.8, 150.5, 150.4, 134.9, 134.8, 129.2, 128.5,
121.4, 83.6, 80.9, 61.5, 55.8, 55.4, 51.0, 50.5, 46.4, 46.2, 28.3, 28.1,
27.64, 27.59, 14.0.
3-Amino-4-hydroxy-6-methyl-2H-pyran-2-one (23)13
To a cold (0 °C) solution of 4-hydroxy-6-methyl-2H-pyran-2-one
(79.3 mmol) in H2SO4 (25 mL) was added dropwise a mixture of
H2SO4 (4.23 mL) and HNO3 (119 mmol) over 10 min. After stirring
for 30 min, the mixture was poured into ice-water, and the precipi-
tate was collected by filtration, washed with cold H2O (3 ×) and
dried under vacuum to give 4-hydroxy-6-methyl-3-nitro-2H-pyran-
2-one as a white solid; yield: 10.7 g (79%); mp 163–166 °C (Lit.18
165 °C).
IR (solid form): 1748, 1639, 1530, 1215, 1194, 1086, 996, 827, 783
cm–1.
1H NMR (400 MHz, CDCl3): δ = 11.21 (br s, 1 H, OH), 6.14 (s, 1
H, =CH), 2.37 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 166.4, 165.4, 156.6, 119.5,
100.7, 19.8.
MS (ESI, MeOH, negative ion mode): m/z = 170.4 ([M – H]–).
A solution of 4-hydroxy-6-methyl-3-nitro-2H-pyran-2-one (2.0 g,
11.7 mmol) and 10% Pd/C (0.2 g) in MeOH (30 mL) was stirred un-
der 1 atm of H2 at 25 °C for 18 h. The mixture was filtered and con-
centrated to give 2313 as a brown solid; yield: 1.33 g (80%); mp
198–200 °C.
MS (ESI, MeOH): m/z = 474.5 ([M + Na]+).
1H NMR (400 MHz, DMSO-d6): δ = 6.31 (s, 1 H, =CH), 3.80 (br s,
HRMS (ESI): m/z [M + Na]+ calcd for C23H33NO8Na: 474.2098;
found: 474.2087.
3 H, NH2, OH), 2.22 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 153.5, 119.6, 104.4,
103.3, 18.9.
MS (ESI, MeOH): m/z = 164.1 ([M + Na]+).
3-[2-(4-Hydroxybenzylamino)acetyl]-7-methyl-2H-pyrano[3,2-
c]pyridine-2,5(6H)-dione (12)
To a solution of 19 (1.22 mmol) and 22 (1.22 mmol) in EtOH (8
mL) under argon was added piperidine (0.05 mmol), and the mix-
ture was stirred at 70 °C for 48 h. It was cooled to 25 °C, diluted
with Et2O (10 mL), and the solid was collected by filtration and pu-
rified by column chromatography (silica gel, CH2Cl2–MeOH, 15:1)
to give the N-Boc derivative of 12 as a yellow solid; yield: 0.26 g
(41%); mp 188–190 °C.
1H NMR (400 MHz, CDCl3): δ (2 rotamers) = 12.87 and 12.80 (2 br
s, 1 H, NH for 2 rotamers), 8.85 and 8.83 (2 s, 1 H, =CH), 7.27–7.25
(m, 2 H, Ar), 7.13–7.09 (m, 2 H, Ar), 6.16 and 6.14 (2 s, 1 H, =CH),
4.62 (s, 1 H, CH2N of 1 rotamer), 4.53 (br s, 2 H, CH2N), 4.50 (s, 1
H, CH2N of 1 rotamer), 2.47 and 2.45 (2 s, 3 H, 2 rotamers), 1.54
and 1.53 (2 s, 9 H, t-Bu, 2 rotamers), 1.45 and 1.41 (2 s, 9 H, 2 ro-
tamers).
tert-Butyl (4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)carba-
mate (24)
To a hot (85 °C) solution of 3-amino-4-hydroxy-6-methyl-2H-
pyran-2-one (23, 1.28 mmol) in MeCN (5 mL) under argon was
added Boc2O (2.46 mmol) in portionwise over a period of 6 h. The
solution was cooled and concentrated on a rotary evaporator to give
an oil, which was purified by flash chromatography (silica gel, hex-
ane–EtOAc, gradient elution) to yield 24 as a white solid; yield:
0.18 g (57%); mp 87–89 °C.
1H NMR (400 MHz, CDCl3): δ = 12.08 (s, 1 H, OH), 7.05 (s, 1 H,
NH), 5.88 (s, 1 H, =CH), 2.21 (s, 3 H, CH3), 1.50 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): δ = 162.3, 156.7, 156.6, 155.1, 103.6,
102.8, 83.7, 28.2, 19.4.
MS (ESI, MeOH): m/z = 264.0 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C11H15NO5Na: 264.0848;
13C NMR (100 MHz, CDCl3): δ (2 rotamers) = 191.7, 191.6, 166.7,
162.6, 158.2, 155.8, 153.6, 153.5, 151.8, 150.2, 145.6, 135.4, 135.2,
128.9, 128.3, 121.2, 118.5, 118.3, 105.8, 98.3, 83.5, 80.5, 80.2,
56.3, 56.2, 51.5, 50.6, 28.3, 28.2, 27.6, 20.0.
found: 264.0831.
MS (ESI, MeOH): m/z = 563.7 ([M + Na]+).
tert-Butyl (8aS*,10aR*)-3-Methyl-1-oxo-5,8a,9,10a-tetrahydro-
1H,6H-2,10-dioxa-9-azaanthracene-9-carboxylate (27)
The above solid (0.10 mmol) was dissolved in 20% TFA–CH2Cl2 (1
mL) and stirred at 25 °C for 30 min. The solvent was removed under
a rotary evaporator and the remaining solid was kept under high
vacuum to yield compound 12·TFA as a yellow solid; yield: 34 mg
(100% yield); mp 180–181 °C (dec.).
1H NMR (400 MHz, DMSO-d6): δ = 12.42 (br s, 1 H), 9.69 (br s, 1
H), 9.15 (br s, 1 H), 8.61 (s, 1 H), 7.31 (d, J = 8.6 Hz, 2 H), 6.80 (d,
J = 8.6 Hz, 2 H), 6.40 (s, 1 H), 4.46 (s, 2 H), 4.10 (s, 2 H), 2.34 (s,
3 H).
13C NMR (100 MHz, DMSO-d6): δ = 188.3, 169.5, 165.0, 158.2,
157.0, 154.1, 137.3, 129.6, 121.5, 115.5, 114.5, 105.5, 96.9, 53.7,
45.6, 18.9.
MS (ESI, MeOH): m/z = 341.4 ([M + H]+).
HRMS (ESI): m/z [M + Na]+ calcd for C18H16N2O5Na: 363.0957;
To a cold (0 °C) mixture of NaH (0.25 mmol) in anhyd DMF (1 mL)
under argon was added 24 (0.25 mmol), and the mixture was stirred
at 25 °C for 30 min. The solution was again cooled to 0 °C and a
solution of trans-3,6-dibromocyclohexene (25, 0.3 mmol) in anhyd
DMF (1 mL) was added via cannula, and the mixture was stirred at
25 °C for 18 h. To the mixture were added anhyd MeCN (10 mL)
and Et3N (0.25 mmol), and the solution was heated at 95 °C for 8 h.
The mixture was diluted with H2O (20 mL) and extracted with
EtOAc (50 mL), and the organic layer was washed with brine (20
mL), dried (MgSO4), concentrated, and column chromatographed
(silica gel, hexane–EtOAc, 1:1) to give 27 as a white solid; yield: 20
mg (25%); mp 129–130 °C.
1H NMR (400 MHz, CDCl3): δ = 5.78–5.71 (m, 1 H, C8H), 5.72 (s,
1 H, C4H), 5.35–5.25 (m, 1 H, C7H), 5.05–4.9 (m, 1 H, C8aH),
4.55–4.50 (m, 1 H C10aH), 2.25–1.85 (m, 4 H), 2.19 (s, 3 H, CH3),
1.50 (s, 9 H, t-Bu).
found: 363.0981.
13C NMR (100 MHz, CDCl3): δ = 160.5, 159.1, 157.3, 153.4, 131.6,
123.9, 102.5, 99.4, 82.2, 74.5, 48.6, 28.4, 25.9, 19.9, 19.5.
Synthesis 2014, 46, 2179–2190
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Monocyclic and Bicyclic Pyridinones and Tricyclic Morpholinopyrones
2189
2D-COSY NMR (acetone-d6, the use of acetone-d6 as a solvent has
changed the chemical shifts slightly from that of CDCl3): signal
C10aH (δ = 4.57) correlates with signal C8aH (δ = 5.04), signal
C8aH (δ = 5.04) correlates with signal C8H (δ = 5.78–5.71), and
signal C8H correlates with signal C7H (δ = 5.29).
and concentrated on a rotary evaporator to give a solid that was pu-
rified by column chromatography (silica gel, EtOAc–hexane, 8:1)
to afford 14 as a white solid; yield: 10 mg (65%); mp 92–94 °C.
1H NMR (400 MHz, CDCl3): δ = 5.81 (s, 1 H), 4.33 (s, 1 H), 4.15
(br s, 1 H), 3.60–3.54 (m, 1 H), 3.21–3.19 (m, 1 H), 2.19 (s, 3 H),
2.18–2.02 (m, 4 H), 1.43–1.32 (m, 2 H).
MS (ESI, MeOH): m/z = 342.3 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H21NO5Na: 342.1317;
found: 342.1299.
13C NMR (100 MHz, CDCl3): δ = 162.1, 152.1, 148.7, 110.7, 100.7,
74.5, 67.6, 57.4, 32.6, 29.9, 19.4, 18.8.
MS (ESI, MeOH): m/z = 260.3 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C12H15NO4Na: 260.0899;
(8aS*,10aR*)-3-Methyl-5,8a,9,10a-tetrahydro-1H,6H-2,10-di-
oxa-9-azaanthracen-1-one (13)
A solution of 27 (0.04 mmol) in CH2Cl2 containing 10% TFA was
stirred at 40 °C for 1 h. The solution was diluted with H2O (20 mL),
basified with 10% aq NH4OH, and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were washed with brine, dried
(MgSO4), concentrated, and column chromatographed (silica gel,
EtOAc–hexane, 1:1) to give 13 as a white solid; yield: 9 mg (100%);
mp 131–133 °C.
1H NMR (400 MHz, CDCl3): δ = 5.86–5.80 (m, 1 H, =CH), 5.82 (s,
1 H, =CH), 5.53–5.50 (m, 1 H, CH=), 4.48–4.40 (m, 1 H, CHO),
3.87 (s, 1 H, CHN), 3.78 (br s, 1 H, NH), 2.06–2.34 (m, 3 H,
CH2CH2), 2.17 (s, 3 H, CH3), 1.91–1.81 (m, 1 H, CH2).
13C NMR (100 MHz, CDCl3): δ = 161.9, 152.0, 148.3, 130.7, 126.7,
110.3, 100.6, 73.3, 47.4, 25.7, 22.1, 19.5.
MS (ESI, MeOH): m/z = 242.5 ([M + H]+).
HRMS (ESI): m/z [M + Na]+ calcd for C12H13NO3Na: 242.0793;
found: 242.0775.
found: 260.0884.
tert-Butyl (8aR*,10aR*)-3-Methyl-1,8-dioxo-5,7,8,8a,9,10a-
hexahydro-1H,6H-2,10-dioxa-9-azaanthracene-9-carboxylate
(15)
To a solution of 28 (0.024 mmol) in DMSO (0.5 mL) under argon
was added 2-iodoxybenzoic acid (IBX, 0.034 mmol), and the solu-
tion was stirred at 25 °C for 2 h. Additional IBX (0.034 mmol) was
added and the mixture was stirred for 12 h after which the mixture
was diluted with H2O (5 mL) and extracted with Et2O (3 × 10 mL).
The combined organic layers were washed with brine, dried (Mg-
SO4), and concentrated to give 15 as a white solid; yield: 7 mg
(87%); mp 90–92 °C.
1H NMR (400 MHz, CDCl3): δ = 5.69 (s, 1 H, C4H), 5.20 (d, J = 4
Hz, 1 H, C8aH), 4.75 (q, J = 4 Hz, 1 H, C10aH), 2.54–1.85 (m, 6
H), 2.17 (s, 3 H), 1.50 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 201.1, 159.4, 158.8, 155.0, 152.4,
104.5, 98.9, 83.2, 79.7, 60.4, 41.3, 29.5, 28.2, 21.6, 19.8.
tert-Butyl (8R*,8aS*,10aR*)-8-Hydroxy-3-methyl-1-oxo-
5,7,8,8a,9,10a-hexahydro-1H,6H-2,10-dioxa-9-azaanthracene-
9-carboxylate (28)
MS (ESI, MeOH): m/z = 358.3 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C17H21NO6Na: 358.1267;
To a solution of 27 (0.11 mmol) in anhyd THF (0.5 mL) at 0 °C un-
der argon was added 1 M BH3·THF in THF (0.109 mmol) and the
resulting solution was stirred at 25 °C for 18 h, cooled to 0 °C, and
30% H2O2 (1 mL) and 0.1% aq NaOH (1 mL) were added. The mix-
ture was stirred for 10 min at 0 °C followed by 3 h at 25 °C, diluted
with H2O, and extracted with CH2Cl2 (4 × 10 mL). The combined
organic layers were washed with brine, dried (MgSO4), concentrat-
ed, and column chromatographed (silica gel, hexane–EtOAc, gradi-
ent) to give 28 as a white solid; yield: 32 mg (87%); mp 162–
163 °C; TLC and NMR spectral data indicate it to be a single ste-
reoisomer and 2D COSY and NOESY spectra show the hydroxy
function is cis to the angular hydrogens (C8aH and C10aH).
1H NMR (400 MHz, CDCl3): δ = 5.82 (s, 1 H, C4H), 4.40 (q, J = 3.5
Hz, 1 H, C10aH), 4.22 (dd, J = 10.1, 3.5 Hz, 1 H, C8aH), 3.33 (td,
J = 10.5, 3.5 Hz, 1 H, C8H), 2.90 (br s, 1 H, OH), 2.23 (s, 3 H),
2.18–2.06 (m, 2 H), 1.72–1.63 (m, 2 H), 1.50 (s, 9 H), 1.50–1.38 (m,
2 H).
found: 358.1257.
4-Hydroxy-3-(4-methoxybenzylamino)-6-methyl-2H-pyran-2-
one (29)
A solution of 23 (1.42 mmol) and p-anisaldehyde (1.42 mmol) in
MeOH (10 mL) was stirred at 25 °C for 12 h. The solution was con-
centrated to give intermediate compound 4-hydroxy-3-(4-methoxy-
benzylideneamino)-6-methyl-2H-pyran-2-one (0.37 g, 100%) as a
yellow solid, which was used for the next step without further puri-
fication. To a solution the aforementioned imine (1.04 mmol) in
EtOH (15 mL) was added NaCNBH3 (1.25 mmol) and AcOH (1.25
mmol) at 25 °C. The solution was stirred for 30 min and then it was
diluted with aq NaHCO3 (1.5 mmol) and concentrated to give a
crude oil that was purified by column chromatography (silica gel,
5% MeOH–CH2Cl2) to give 29 as a yellow solid; yield: 0.24 g
(89%); mp 179–181 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.80 (br s, 2 H, NH, OH), 7.25
(d, J = 8.8 Hz, 2 H, Ar-H), 6.84 (d, J = 8.8 Hz, 2 H, Ar-H), 5.61 (s,
1 H, =CH), 4.17 (s, 2 H, CH2N), 3.71 (s, 3 H, OCH3), 2.00 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 160.7, 159.1, 156.0, 153.9, 102.9,
99.4, 82.8, 76.6, 65.5, 57.4, 32.2, 29.9, 28.2, 19.9, 18.4.
2D-NOESY NMR (400 MHz, CDCl3): signal C4H (δ = 5.82) cor-
relates with signal C3-Me (δ = 2.23), signal C10aH (δ = 4.40) cor-
relates with signal C8aH (δ = 4.22), and signal C8aH (δ = 4.22)
correlates with signal C8H (δ = 3.33). No correlation is found be-
tween signals C8H and C10aH.
13C NMR (100 MHz, DMSO-d6): δ = 165.8, 161.6, 158.9, 156.8,
130.6, 127.1, 113.5, 104.9, 101.5, 55.0, 48.7, 19.1.
MS (ESI, MeOH): m/z = 284.2 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C14H15NO4Na: 284.0899;
MS (ESI, MeOH): m/z = 360.5 ([M + Na]+).
found: 284.0895.
HRMS (ESI): m/z [M + Na]+ calcd for C17H23NO6Na: 360.1423;
found: 360.1411.
(8aS*,10aR*)-9-(4-Methoxybenzyl)-3-methyl-7,8,8a,10a-tetra-
hydro-1H,9H-2,10-dioxa-9-azaanthracen-1-one (30)
A solution of 29 (20 mg, 76 μmol), trans-3,6-dibromocyclohexene
(25, 31 mg, 0.13 mmol), and Et3N (39 μL, 0.28 mmol) in DMF (1
mL) was stirred at 80 °C under argon for 2.5 h. The mixture was di-
luted with EtOAc (50 mL) and washed with H2O (3 × 10 mL), and
brine, dried (MgSO4), concentrated, and column chromatographed
(silica gel, 30% EtOAc–hexane) to give 30 as a pale yellow solid;
yield: 13 mg (50%); mp 300 °C (had not melted).
(8R*,8aS*,10aR*)-8-Hydroxy-3-methyl-5,7,8,8a,9,10a-hexahy-
dro-1H,6H-2,10-dioxa-9-azaanthracen-1-one (14)
A solution of 28 (0.065 mmol) in 10% TFA (2 mL) in CH2Cl2 was
stirred at 40 °C for 1 h, partitioned between CH2Cl2 (10 mL) and
H2O (20 mL), and basified using 10% aq NH4OH. The organic layer
was removed and the aqueous layer was extracted with CH2Cl2 (3 ×
10 mL). The combined organic layers were dried (MgSO4), filtered,
© Georg Thieme Verlag Stuttgart · New York
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PAPER
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.0 Hz, 2 H, Ar-H),
6.86 (d, J = 8.0 Hz, 2 H, Ar-H), 6.04–5.97 (m, 1 H, CH=), 5.96–5.90
(m, 1 H, CH=), 5.78 (s, 1 H, CH=), 4.49 (d, J = 12 Hz, 1 H, Ar-
CH2N), 4.01 (d, J = 12 Hz, 1 H, Ar-CH2N), 3.87 (t, J = 4 Hz, 1 H,
CHO), 3.81 (s, 3 H, Ar-OCH3), 3.02 (dt, J = 12, 4 Hz, 1 H, CHN),
2.21 (s, 3 H, CH3), 2.18–2.03 (m, 2 H, CH2), 1.52–1.32 (m, 2 H,
CH2).
13C NMR (100 MHz, CDCl3): δ = 162.6, 159.1, 155.0, 152.4, 135.5,
130.5, 130.4, 123.8, 113.9, 111.1, 100.4, 66.3, 56.5, 55.4, 53.4,
26.4, 22.6, 19.6.
Acknowledgment
This project was supported by grants from the National Institute of
Allergy and Infectious Diseases (U01AI081891), National Center
for Research Resources (P20RR016475), and the National Institute
of General Medical Sciences (P20GM103418) from the National
Institutes of Health. D.H.H. thanks the Johnson Cancer Research
Center for a Faculty Travel Fellowship. The contents are solely the
responsibility of the authors and do not necessarily represent the of-
ficial views of NIH. We also thank Dr. Daniel Higgins for his
helpful advice in measurement of fluorescence emission spectra.
2D COSY NMR (400 MHz, CDCl3): signal (δ = 6.04–5.97; =CH)
correlates with signal (δ = 5.96–5.90; =CH), signal (δ = 6.04–5.97;
=CH) correlates with signal (δ = 2.18–2.03), signal (δ = 2.18–2.03)
correlates with signal (δ = 1.52–1.32), signal (δ = 1.52–1.32) cor-
relates with signal (δ = 3.02, C8aH), and signal (δ = 3.02=) cor-
relates with signal (δ = 3.87, C10aH).
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
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MS (ESI, MeOH): m/z = 362.2 ([M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C20H21NO4Na: 362.1368;
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(8aS*,10aR*)-3-Methyl-7,8,8a,10a-tetrahydro-1H,9H-2,10-di-
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A solution of 30 (17.7 μmol) and TFA (1 drop) in CH2Cl2 (1 mL)
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CH=), 5.82 (s, 1 H, =CH), 5.81–5.70 (m, 1 H, CH=), 4.61 (s, 1 H,
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Synthesis 2014, 46, 2179–2190
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