Synthesis of Aminobenzopyranoxanthenes with Nitrogen-Containing Fused Rings

Article abstract of DOI:10.1021/acs.joc.7b02290

An efficient and practical method for the synthesis of a variety of aminobenzopyranoxanthenes (ABPXs) with different nitrogen-containing fused rings was developed. On the basis of the mechanistic studies of the formation of the xanthene framework, the presented methodology was developed to facilitate access to previously inaccessible asymmetric ABPXs.

Full text of DOI:10.1021/acs.joc.7b02290

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Note
Synthesis of Aminobenzopyranoxanthenes
with Nitrogen-Containing Fused Rings
Natsumi Fukino, Shinichiro Kamino, Minami Takahashi, and Daisuke Sawada
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02290 • Publication Date (Web): 15 Nov 2017
Downloaded from http://pubs.acs.org on November 15, 2017
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Synthesis of Aminobenzopyranoxanthenes with Nitrogen-Containing
Fused Rings
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Natsumi Fukino†, Shinichiro Kamino†,‡,*, Minami Takahashi†, Daisuke Sawada†,‡,*
†Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayamaꢀshi, Okayama 700ꢀ
8530, Japan
‡Nextꢀgeneration Imaging Team, RIKENꢀCLST, Kobeꢀshi, Hyogo 650ꢀ0047, Japan
Supporting Information Placeholder
ABSTRACT: An efficient and practical method for the synthesis of a variety of aminobenzopyranoxanthenes (ABPXs) with difꢀ
ferent nitrogenꢀcontaining fused rings was developed. Based on mechanistic studies of the formation of the xanthene framework,
the presented methodology was developed and facilitates access to previously inaccessible asymmetric ABPXs.
Over the past century, xantheneꢀbased organic dyes, includꢀ
ing rhodamines and fluoresceins, have been studied extensiveꢀ
ly owing to their diverse applications in the medical and life
sciences as biological probes,1 molecular sensors,2 photosensiꢀ
tizers,3 photocatalysts,4 and components of optoelectronic
devices.5 A number of synthetic approaches towards xanthene
scaffolds, based on organometallic coupling reactions, have
been developed.6 Although these attractive reactions allow for
the flexible derivatization of such scaffolds, they are not ameꢀ
nable to industrial applications due to the use of flammable
reagents, multistep reactions, and complex synthetic and puriꢀ
fication steps.
classical synthetic method of rhodamines and fluoresceins
utilized for industrial applications. In addition, very little is
known about the mechanistic details of the formation of xanꢀ
thene frameworks, since it involves the use of strong acids at
high temperatures.9 As part of our ongoing research regarding
the practical uses of ABPXs, we report the development of a
synthetic method for ABPXs based on mechanistic studies,
efficient synthesis of new derivatives with different nitrogenꢀ
containing rings, and their spectral characteristics.
A new class of rhodamines, aminobenzopyranoxanthenes
(ABPXs), have recently garnered considerable attention as
color materials and in chemical sensing because of their outꢀ
standing photophysical properties (Figure 1).7,8 Specifically,
ABPXs exhibit a twoꢀstep color change depending on the
presence and amount of external stimuli such as acids, pheꢀ
nols, or metal ions; this is extraordinary because traditional
xanthenes typically only display one color. In this respect, the
development of high yielding synthetic methods with few
steps is highly desirable in order to explore the functionality
and potential applications of ABPXs.
Figure 1. Chemical structures of rhodamines and aminobenꢀ
zopyranoxanthenes (ABPXs).
To develop a synthetic method for ABPXs with nitrogenꢀ
containing rings, an ABPX derivative with amino groups on
the pyrrolidine rings was used as the model substrate. Accordꢀ
ing to the classical method, the initial reaction between benzoꢀ
phenone derivative 1a and resorcinol 2 was performed in
CH3SO3H for 4, 6, and 10 h at 110 °C (Scheme 1, Scheme S1
and Table S1). Although these reaction conditions afforded the
desired ABPXꢀPYR (4) in low yields, 20% of RhodolꢀPYR (5)
was obtained and multiple colored compounds were obtained,
as confirmed by silicaꢀgel thinꢀlayer chromatography.
Conventionally, ABPXs are synthesized from the acidꢀ
catalyzed thermal reaction of resorcinol with benzophenone
derivatives. However, this synthetic methodology has some
drawbacks such as low production yield and purification isꢀ
sues owing to the formation of byꢀproducts, as seen in the
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Scheme 1. Classical synthetic approach towards ABPX-
of 8, 10, and 11 on the ipsoꢀcarbon atoms (C6 and C10). In
PYR (4) and Rhodol-PYR (5) via monocationic intermedi-
ate (3) from acid-catalyzed thermal reaction of resorcinol
with a benzophenone derivative.
contrast, nucleophilic attacks of hydroxyl oxygen in aminoꢀ
phenol moiety of 6 to C7 and C9 positions afford the ABPXꢀ
PYR in pathway 2. The stability of resonance forms of 6 diꢀ
rects which pathway is taken.
Mechanistic studies using 18Oꢀlabeled 2 revealed that pathꢀ
way 1 is preferred over pathway 2 under the classical condiꢀ
tions. Next, we confirmed the geometry of the resonance form
of 6 using density functional theory (DFT) calculations (Figꢀ
ure S3). The CꢀN bond lengths in the planar pyrrolidinyl pheꢀ
nol moieties were calculated to be 1.34 Å. The CꢀO bond disꢀ
tances in the catechol moiety were calculated to be 1.33 and
1.35 Å. These symmetric bond lengths can be attributed to the
crossꢀconjugated resonance structure 7 shown in pathway 1.
N
O
O
N
Friedel-Crafts reaction
O
O
O
O
HO
OH
OH OH
HO
N
HO
N
ABPX-PYR
4
2
O
10
11
12
13
14
15
16
17
18
19
20
21
22
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60
COOH
COOH
CH3SO3H
110°C
HO
O
N
1a
Monocationic
intermediate
COO
3
Cyclization
Rhodol-PYR
5
Overall, the mechanistic studies suggested that regulation of
the cyclization reaction pathway could be exploited to improve
the yield of ABPXs. A possible rationale for the low yield of 4
under the classical conditions is that the cyclization reaction
occurs via multiple intermediates shown in pathway 1, which
is consistent with the observation of the production of multiple
colored compounds. In contrast, pathway 2 involves an accesꢀ
sible cyclization route to 4. Therefore, we hypothesize that the
alkylation of resorcinolmay alter the cyclization pathway from
1 to 2 to give higher yields of ABPXs.
In order to gain insight into the reaction mechanism under the
classical conditions, 5 and 1a were reacted in CH3SO3H at 110
°C. A substantial amount of unreacted 1a was recovered, indiꢀ
cating that 4 was not formed through the formation of 5. Subꢀ
sequently, isotopic studies of oxygenꢀ18 (18O) labeled 2 with
1a were performed to investigate the cyclization of the xanꢀ
thene ring.10 Following the thermal reaction of 18Oꢀenriched 2
with 1a in CH3SO3H, several ABPXꢀPYR products were obꢀ
tained in yields of 56% (m/z 666), 33% (m/z 664), and 11%
(m/z 662). Enriched 18O RhodolꢀPYR was also obtained
(Scheme S1 and Figures S1–2 show the results of these studꢀ
ies). The large amount of 18O contained in 4 and 5 indicated
that the oxygen atom of the xanthene ring was mainly derived
from resorcinol.
To validate this hypothesis, we assessed the reaction beꢀ
tween 1,3ꢀdimethoybenzene (15) and 1 in neat CH3SO3H at
110 °C. Notably, the yield of 4 increased dramatically to 73%
(Table 1, entry 2) relative to that under the classical conditions
(Table 1, entry 1). The cyclization reaction proceeded via
pathway 2 under these conditions, since nonꢀlabeled ABPXꢀ
PYR was obtained in the highest percentage (92%, m/z 662),
as evidenced by tracer studies of 18O labeled 15. Next, we
screened various 1,3ꢀdialkoxybenzenes (Table 1). These studꢀ
ies demonstrated that 1,3ꢀdiisopropoxybenzene (16) was the
best substrate (Table 1, entry 5). In contrast, the cyclization
reaction did not go to completion and some intermediates such
as acetals were obtained (Figure S4), as a result of the longer
alkyl group.
Based on the mechanistic studies, a proposed mechanism for
the formation of 4 and 5 is shown in Schemes 1 and 2. Comꢀ
pounds 4 and 5 are competitively formed from monocationic
intermediate (3) via a FriedelꢀCraftsꢀtype reaction of 2 with 1a
in CH3SO3H. Intermediate 3 then reacts with 1a to give dicaꢀ
tionic intermediate (6) (Scheme 2); two possible cyclization
pathways could give 4. In pathway 1, 6 is stabilized by pyrrolꢀ
idinyl phenol moiety, and the stepwise ring closures involve
nucleophilic attacks of hydroxyl groups on the catechol moiety
HO
O
N
COOH
Pathway 1
Pathway 2
HO
OH
11 OH OH OH OH5
N
O
O
N
N
N
N
HO
10
9
8
7
6
12
13
4
3
1a
HOO1C4 15 17 19
COOH
1
20
18
2
16
HOOC
COOH
COOH
Dicationic
intermediate
3
4++
6
Pathway 1
OH OH
N
O
N
-H2O
HOOC
COOH
OH
OH OH OH
OH OH
OH OH OH OH
N
O
N
N
N
N
N
-H2O
10
OH OH
4++
6
HOOC
COOH
HOOC
COOH
HOOC
COOH
N
O
N
-H2O
7
8
9
HOOC
COOH
Pathway 2
11
OH OH
OH OH
OH OH OH OH
N
O
N
N
O
N
N
N
-H2O
-H2O
4++
6
HOOC
COOH
HOOC
COOH
HOOC
COOH
12
13
14
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Scheme 2. Proposed reaction mechanism for formation of ABPX-PYR (4++).

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Table 1. Effect of alkylation of resorcinol on the yields of
ABPX-PYR (4) and Rhodol-PYR (5’).
in 11% yield. Therefore, we further optimized the reaction
condition of ABPXꢀJUR by using the benzophenone derivaꢀ
tive 1b. We attempted the reaction at low temperatures, beꢀ
cause the second FriedelꢀCraftsꢀtype reaction seemed to proꢀ
ceed easily, and 1b decomposed in CH3SO3H at high temperaꢀ
tures (Table 2, entries 1–4). When the reaction was carried out
at rt, the formation of 18 was suppressed (Table 2, entry 1),
and then increasing the reaction temperature to 110 °C affordꢀ
ed 17 in 64% yield (Table 2, entry 4). Next, the solvents and
concentrations of CH3SO3H were screened (Table 2, entries 6–
13). To our delight, 17 was obtained in 74% yield (transꢀ
isomer 40%, cisꢀisomer 34%) when the reaction was perꢀ
formed in 20% CH3SO3H/toluene for 6 h at 110°C, after the
reaction was allowed to proceed for 48 h at rt (Table 2, entry
12).
RO
O
N
HO
O
N
N
O
O
N
RO
OR
+
O
O
COO
COOH
CH3SO3H
110°C, 24 h
O
O
5' R = H, alkyl
Rhodol-PYR
1a
4
ABPX-PYR
10
11
12
13
14
15
16
17
18
19
20
21
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yield (%)
entry
R
4
5’
1a
2
3
4
5
6
7
8
H
Me
Et
nPr
iPr
nBu
iBu
nOctyl
36
73
56
34
74
43
37
32
20
19
15
20
11
20
11
7
With the optimized reaction conditions in hand, the scope of
the reaction was examined using 16 and a variety of benzoꢀ
phenones with different nitrogenꢀcontaining rings, ranging
from pyrrolidine to tetramethyljulolidine as shown in Scheme
3 (Schemes S2ꢀS3 show the synthesis of benzophenone deꢀ
rivatives 1c-d). In all cases, a dramatic improvement in the
yield was observed as compared to the classical condition.
Notably, ABPXꢀTMJUR (20), which is difficult to prepare
under the classical conditions, was obtained in 68% yield by
using four molar equivalents of 1d to 16.
*a
reaction time of 6 h. Compound 5’ contains compound 5 and
alkylated RhodolꢀPYR.
Scheme 3. Substrate scope for ABPXs with nitrogen-
containing fused rings.
Table 2. Optimization of the reaction conditions for for-
mation of ABPX-JUR (17).
iPr
O
OiPr
OH
O
N
N
O
O
N
RO
O
N
16
+
O
O
COOH
COO
R = H, iPr
O
O
1b
17
18
ABPX-JUR
Rhodol-JUR
yield (%)
temp
(℃)
time
(h)
CH3SO3H
(vol%)
entry
solvent
17
26
56
60
64
37
0
18
< 1
9
1
2
rt
48
ꢀ
neat
neat
neat
neat
neat
50→80
20
rt→110 12→12
rt→110 20→24
ꢀ
3
ꢀ
< 1
< 1
11
ꢀ
4
rt→110
110
48→6
24
ꢀ
5
ꢀ
6
rt→110
rt→110
rt→110
rt→110
rt→110
rt→110
rt→110
rt→110
48→6
48→6
48→6
48→6
48→6
48→6
48→6
48→6
H2O
DMSO
ODCB
DCE
toluene
toluene
toluene
toluene
7
0
0
8
20
55
62
53
69
74
70
17
< 1
9
9
20
10
11
12
13
5
10
< 1
< 1
< 1
The percentage in parenthesis shows the yield under the classical
condition.
20
50
Encouraged by these results, we designed a new method to
synthesize an asymmetric ABPX based on the formation of a
diphenyl isobenzofuranone derivative, followed by condensaꢀ
tion with a different benzophenone (Scheme 4). Upon addiꢀ
tion of 15 to 1b in CH3SO3H, compound 21 was formed in
66% yield after 2 h at rt. With the compound 21 and 1a, the
condensation reaction successfully afforded asymmetric
ABPX 22 in 29% yield, by controlling the amount of
DMSO: dimethyl sulfoxide; ODCB: 1,2ꢀdichlorobenzene; DCE:
1,2ꢀdichloroethane.
With respect to the condensedꢀring xanthene structure, the
scope of this method was evaluated by reacting 16 with 9ꢀ(2ꢀ
carboxybenzoyl)ꢀ8ꢀhydroxyjulolidine (1b)7e in CH3SO3H at
110 °C. In this case, the yield of ABPXꢀJUR (17) improved
slightly (37%, Table 2, entry 5) compared to that under the
classical conditions (29%), and RhodolꢀJUR (18) was obtained
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700 (JEOL Co., Ltd.) and G6520 (Agilent Technologies, Ltd.). IR
spectra were recorded on a SHIMADZU IRAffinityꢀ1.
CH3SO3H (8% CH3SO3H/CH2Cl2) in order to minimize the
fragmentation.11
Absorption and fluorescent emission measurement. UVꢀvis specꢀ
tra were collected on a JASCO Vꢀ570 spectrophotometer at room
temperature using a 1 cm quartz cuvette. Fluorescence emission specꢀ
tra were collected on a HITACHI Fꢀ7100 fluorescence spectrophoꢀ
tometer. To obtain an accurate spectrum, spectrum correction was
carried out with rhodamine B concentrated solution and a secondaryꢀ
standard light source. A cut filter was utilized to eliminate multiple
lights, such as secondary light, due to the effects of light scattering.
Fluorescence spectra of all samples were measured with excitation
with 365 nm. All solvents for spectrophotometry were purchased
from Nacalai Tesque (Kyoto, Japan).
General procedure for the synthesis of ABPXs with different
nitrogen-containing rings (4), (17), (19). To 20% CH3SO3H/toluene
(5 mL) in a sealed tube were added benzophenone derivatives 1aꢀc
(0.16 mmol) and 1,3ꢀdiisopropoxybenzene 16 (0.08 mmol). The reacꢀ
tion mixture was allowed to stir at room temperature for 48 h, and
then heated at 110 °C for 6 h. Upon the completion of the reaction, a
small amount of ice water was poured into the reaction mixture and
the pH was adjusted to 6~8 with saturated NaHCO3. Then, the reacꢀ
tion mixture was extracted with CHCl3 three times. The organic layers
were dried over MgSO4 and evaporated to give the crude product. The
crude product was purified by silica gel column chromatography to
obtain the pure product trans-isomer, which eluted first, followed by
the cisꢀisomer as a colorless powder. The yields of the ABPXs were
given as the total weight of the transꢀ and cisꢀisomers.
Scheme 4. Synthetic route towards asymmetric ABPXs.
OH
OMe
HO
O
N
MeO
OMe MeO
15
N
O
10
11
12
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
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
COOH
CH3SO3H
O
rt, 2 h
66%
1b
21
HO
N
O
N
O
O
N
COOH
1a
O
O
8% CH3SO3H/CH2Cl2
O
O
rt, 2 h
29%
22
Finally, we investigated the spectral characteristics of
ABPXs following their conversion to dicationic species upon
dissolution in a 10% trifluoroacetic acid (TFA)/CHCl3 soluꢀ
tion. The absorption and fluorescence emission spectra of
transꢀABPXs exhibited vibronic progression bands (Figure S5
and Table S2). The fluorescence spectra of the ABPXs includꢀ
ed the farꢀred and near infrared wavelength ranges. cisꢀABPXs
showed similar spectral characteristics (Figure S6 and Table
S3).
trans-ABPX-PYR (4a). Yield 48% (27 mg). 1HꢀNMR (CDCl3, 600
MHz): δ 7.80 (dd, 2 H, J = 7.5, 0.9 Hz), 7.62 (ddd, 2 H, J = 7.9, 7.5,
1.2 Hz), 7.53 (ddd, 2 H, J = 7.9, 7.5, 1.2 Hz), 7.15 (s, 1 H), 7.13 (dd, 2
H, J = 7.9, 1.2 Hz), 6.52 (d, 2 H, J = 8.8 Hz), 6.39 (d, 2 H, J = 2.5
Hz), 6.25 (dd, 2 H, J = 8.8, 2.5 Hz), 6.06 (s, 1 H), 3.32ꢀ3.30 (m, 8 H),
2.04ꢀ2.02 (m, 8 H). 13CꢀNMR (CDCl3, 125 MHz): δ 169.2, 153.1,
153.1, 152.6, 152.2, 149.6, 135.0, 129.7, 128.6, 127.8, 126.6, 124.6,
123.9, 116.3, 108.9, 105.2, 104.2, 97.9, 83.6, 47.6, 25.5. HRMS (ESI,
+
positive mode): m/z calcd for C42H33N2O6 [M]＋ 661.2333; Found
661.2308. IR (KBr) cmꢀ1: 3365, 2926, 2851, 1728, 1643.
In conclusion, we developed an efficient and practical methꢀ
od to prepare ABPXs with various nitrogenꢀcontaining fused
rings. Using a simple acidꢀcatalyzed reaction consisting of 1,3ꢀ
diisopropoxybenzene and CH3SO3H, a variety of benzopheꢀ
nones gave ABPXs directly in excellent yields. Notably, this
methodology provides access to previously inaccessible
asymmetric ABPXs. In addition to exploring ABPXs with a
wide variety of functionalities, our findings give new insight
into the synthesis of xanthene scaffolds. Studies on substrate
scope and the photophysical properties of ABPXs are currentꢀ
ly underway and will be reported in due course.
cis-ABPX-PYR (4b). Yield 42% (24 mg). 1HꢀNMR (CDCl3, 600
MHz): δ 7.83 (dd, 2 H, J = 7.9, 1.5 Hz), 7.46ꢀ7.42 (m, 4 H), 7.16 (s, 1
H), 6.92 (dd, 2 H, J = 7.5, 1.5 Hz), 6.51 (d, 2 H, J = 8.6 Hz), 6.39 (d,
2 H, J = 2.6 Hz), 6.24 (dd, 2 H, J = 8.6, 2.6 Hz), 6.0 (s, 1 H), 3.31ꢀ
3.29 (m, 8 H), 2.05ꢀ2.01 (m, 8 H). 13CꢀNMR (CDCl3, 125 MHz): δ
168.9, 153.2, 152.8, 152.3, 149.6, 134.1, 129.2, 128.6, 128.5, 127.2,
124.9, 123.4, 116.3, 108.8, 105.3, 104.3, 98.0, 83.3, 47.7, 29.7, 25.5.
+
HRMS (ESI, positive mode): m/z calcd for C42H33N2O6 [M] ＋
661.2333; Found 661.2309. IR (KBr) cmꢀ1: 3332, 2920, 2850, 1766,
1616.
1
trans-ABPX-PIP (19a). Yield 52% (30 mg). HꢀNMR (CDCl3, 600
MHz): δ 7.81 (dd, 2 H, J = 7.6, 0.9 Hz), 7.63 (ddd, 2 H, J = 7.6, 7.5,
0.9 Hz), 7.54 (ddd, 2 H, J = 7.6, 7.5, 0.9 Hz), 7.15 (s, 1 H), 7.12 (dd, 2
H, J = 7.6, 0.9 Hz), 6.73 (d, 2 H, J = 2.4 Hz), 6.59 (dd, 2 H, J = 9.0,
2.4 Hz), 6.54 (d, 2 H, J = 9.0 Hz), 6.08 (s, 1 H), 3.27ꢀ3.25 (m, 8 H),
1.71ꢀ1.67 (m, 8 H), 1.64ꢀ1.60 (m, 4 H). 13CꢀNMR (CDCl3, 125 MHz):
δ 169.2, 153.5, 153.1, 153.1, 152.4, 152.2, 135.2, 129.8, 128.4, 127.8,
126.4, 124.7, 123.9, 116.3, 112.2, 107.8, 104.3, 101.8, 83.0, 49.3,
EXPERIMETAL SECTION
General Remarks. Materials, Reagents and solvents were purꢀ
chased from Tokyo Chemical Industries (Tokyo, Japan), Nacalai
Tesque (Kyoto, Japan) and Wako Pure Chemical Industries (Osaka,
Japan). All solvents were used without further purification. Flash
column chromatography was conducted over silica gel (Merck Silica
Gel 60 mesh 70ꢀ230). Developed TLC plates were visualized under a
shortꢀwave UV lamp, by staining with an I2ꢀSiO2 mixture, and by
heating plates that were dipped in ammonium phosphomolybdate
sulfate solution. Experiments were conducted under an atmosphere of
dry argon or using a guard tube.
+
25.4, 24.3. HRMS (ESI, positive mode): m/z calcd for C44H37N2O6
[M]＋ 689.2646; Found 689.2620. IR (KBr) cmꢀ1: 3485, 2926, 2852,
1759, 1616.
cis-ABPX-PIP (19b). Yield 44% (25 mg). 1HꢀNMR (CDCl3, 600
MHz): δ 7.84 (dd, 2 H, J = 5.9, 1.5 Hz), 7.46 (ddd, 2 H, J = 7.3, 5.9,
1.5 Hz), 7.44 (ddd, 2 H, J = 7.3, 5.9, 1.5 Hz) 7.16 (s, 1 H), 6.92 (dd, 2
H, J = 7.3, 1.5 Hz), 6.74 (d, 2 H, J = 2.3 Hz), 6.58 (dd, 2 H, J = 9.0,
2.3 Hz), 6.53 (d, 2 H, J = 9.0 Hz), 6.02 (s, 1 H), 3.26ꢀ3.25 (m, 8 H),
1.71ꢀ1.67 (m, 8 H), 1.64ꢀ1.60 (m, 4 H). 13CꢀNMR (CDCl3, 125 MHz):
δ 168.7, 153.5, 153.2, 152.7, 152.2, 134.2, 129.4, 128.5, 128.3, 127.0,
125.0, 123.3, 116.3, 112.2, 108.0, 104.4, 101.8, 82.7, 49.4, 25.4, 24.3.
1
Instruments. HꢀNMR and 13CꢀNMR spectra were recorded using
400 and 600 MHz (Varian UNITY INOVA) spectrometers. Solvents
used for NMR measurements were CDCl3. Mass spectra were recordꢀ
ed on a JMXꢀ700 (JEOL Co., Ltd.) MS instrument and G6520 (Agꢀ
ilent Technologies, Ltd.). Mass spectra were recorded by using JMXꢀ
+
HRMS (ESI, positive mode): m/z calcd for C44H37N2O6 [M] ＋
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689.2646; Found 689.2639. IR (KBr) cmꢀ1: 3447, 2932, 2851, 1767,
isomer was firstly eluted, followed by cisꢀisomer. The yield of these
ABPXs was given as the total weight of transꢀ and cisꢀisomers.
trans-ABPX-PYR-JUR (22a). Yield 2% (2.5 mg). HꢀNMR (CDCl3,
1616.
3
4
5
6
7
8
9
1
Synthesis of ABPX-TMJUR (20). To 20% CH3SO3H/toluene (5
mL) in a sealed tube were added benzophenone derivative 1d (0.32
mmol) and 1,3ꢀdiisopropoxybenzene 16 (0.08 mmol). The reaction
mixture was allowed to stir at room temperature for 48 h, and then
heated at 110 °C for 6 h. Upon the completion of the reaction, a small
amount of ice water was poured into the reaction mixture and the pH
was adjusted to 6~8 with saturated NaHCO3. Then, the reaction mixꢀ
ture was extracted with CHCl3 three times. The organic layers were
dried over MgSO4 and evaporated to give the crude product. The
crude product was purified by silica gel column chromatography to
obtain the pure product trans-isomer, which eluted first, followed by
the cisꢀisomer as a colorless powder. The yields of the ABPXs were
given as the total weight of the transꢀ and cisꢀisomers.
600 MHz): δ 7.77 (dd, 2 H, J = 7.6, 1.2 Hz), 7.59 (ddd, 2 H, J = 7.6,
7.3, 1.2 Hz), 7.49 (ddd, 2 H, J = 7.6, 7.3, 1.2 Hz), 7.14 (s, 1 H), 7.10
(dd, 2 H, J = 7.6, 1.2 Hz), 6.50 (d, 1 H, J = 8.8 Hz), 6.35 (d, 1 H, J =
2.4 Hz), 6.22 (dd, 1 H, J = 8.8, 2.4 Hz), 6.06 (s, 1 H), 6.01 (s, 1 H),
3.33ꢀ3.24 (m, 4 H), 3.19ꢀ3.17 (m, 2H), 3.14ꢀ3.12 (m, 2H), 3.00ꢀ2.94
(m, 2 H), 2.54ꢀ2.45 (m, 2 H), 2.06ꢀ1.99 (m, 6 H), 1.88ꢀ1.82 (m, 2 H).
13CꢀNMR (CDCl3, 125 MHz): δ 169.2, 153.2, 153.1, 152.6, 152.2,
151.9, 149.6, 147.9, 144.7, 135.0, 134.9, 129.6, 129.6, 128.6, 127.6,
126.8, 126.6, 124.6, 124.5, 124.0, 123.9, 118.0, 116.2, 116.1, 108.8,
107.3, 105.2, 104.9, 104.2, 97.9, 83.6, 49.8 49.4, 47.6, 29.7, 27.3,
25.4, 21.7, 21.1, 21.00. HRMS (ESI, positive mode): m/z calcd for
10
11
12
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
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
C44H35N2O6 [M]＋ 687.2495; Found 687.2507. IR (KBr) cmꢀ1: 3365,
trans-ABPX-TMJUR (20a). Yield 40% (25 mg). 1HꢀNMR (CDCl3,
600 MHz): δ 7.81 (dd, 2 H, J = 7.9, 0.9 Hz), 7.62 (ddd, 2 H, J = 7.9,
7.6, 0.9 Hz), 7.52 (ddd, 2 H, J = 7.9, 7.6, 0.9 Hz), 7.18 (s, 1 H), 7.17
(dd, 2 H, J = 7.9, 0.9 Hz), 3.19–3.12 (m, 8 H), 1.88 (dd, 4 H, J = 5.9,
5.3 Hz), 1.67–1.65 (m, 4 H) 1.65 (s, 6 H), 1.65 (s, 6 H), 1.04 (s, 6 H),
0.96 (s, 6 H). 13CꢀNMR (CDCl3, 125 MHz): δ 169.2, 153.2, 149.8,
144.4, 134.8, 129.6, 127.7, 127.1, 126.8, 124.7, 124.1, 123.0, 116.5,
116.0, 106.4, 103.5, 58.5, 47.2, 46.9, 40.2, 36.4, 32.8, 32.2, 31.2,
31.1, 30.0, 29.9, 18.5. HRMS (ESI, positive mode): m/z calcd for
2926, 2851, 1728, 1643.
cis-ABPX-PYR-JUR (22b). Yield 27% (30 mg). ¹HꢀNMR (CDCl3, 600
MHz): δ 7.83ꢀ7.78 (m, 2 H), 7.44ꢀ7.40 (m, 4 H), 7.14 (s,1 H), 6.92ꢀ
6.86 (m, 2 H), 6.48 (d, 1 H, J = 8.8 Hz), 6.35 (d, 1 H, J = 2.3 Hz),
6.21 (dd, 1 H, J = 8.8, 2.3 Hz), 6.04 (s, 1 H), 5.94(s, 1 H), 3.30ꢀ3.25
(m, 4 H), 3.19ꢀ3.10 (m, 4 H), 2.97ꢀ2.91(m, 2 H), 2.54ꢀ2.37 (m, 2 H),
2.04ꢀ1.98 (m, 6 H), 1.86ꢀ1.80 (m, 2 H). 13CꢀNMR (CDCl3, 125 MHz):
δ 168.9, 153.3, 153.2, 152.9, 152.3, 152.1, 149.6, 148.1, 144.7, 134.1,
134.0, 129.2, 129.2, 128.6, 128.4, 127.4, 127.2, 124.9, 124.9, 124.6,
123.5, 123.4, 117.9, 116.2, 116.1, 108.8, 107.4, 105.4, 105.1, 104.3,
98.0, 83.9, 83.4, 49.9, 49.4, 47.7, 27.3, 25.5, 21.7, 21.2, 21.0. HRMS
C54H53N2O6 [M]+ 825.3903; Found 825.3909. IR (KBr) cmꢀ1: 3495,
2961, 2851, 1767, 1609.
cis-ABPX-TMJUR (20b). Yield 28% (17 mg). HꢀNMR (CDCl3, 600
+
1
+
(ESI, positive mode): m/z calcd for C44H35N2O6 [M]＋ 687.2495;
Found 687.2488. IR (KBr) cmꢀ1: 3332, 2920, 2850, 1766, 1616.
Synthesis of 18O labeled resorcinol and 1,3-dimethoxybenzene.
The 18O labeled resorcinol was prepared using the method reported by
Sekar et al.12 In an overꢀdried Schlenk tube equipped with a stir bar,
diiodobenzene (165 mg, 0.5 mmol), KOH (336 mg, 6.0 mmol),
Hz): δ 7.86–7.85 (m, 2 H), 7.48–7.47 (m, 4 H), 7.20 (s, 1 H), 7.00–
6.98 (m, 2 H), 6.30 (s, 2 H), 5.97 (s, 1 H), 3.19–3.10 (m, 8 H), 1.88–
1.86 (m, 4 H), 1.66–1.64 (s, 12 H), 1.04 (s, 6 H), 0.94 (s, 6 H). 13Cꢀ
NMR (CDCl3, 125 MHz): δ 168.9, 153.1, 151.7, 145.0, 144.1, 133.9,
129.3, 127.5, 127.4, 125.0, 123.5, 122.8, 116.4, 116.1, 106.4, 103.6,
84.2, 47.2, 46.8, 40.3, 36.4, 32.8, 32.2, 31.2, 31.1, 30.1, 29.9, 29.7.
Cu(OAc) (22 mg, 0.11 mmol), and
Dꢀglucose (36 mg, 0.2 mmol)
+
HRMS (ESI, positive mode): m/z calcd for C54H53N2O6 [M]+
were combined. 1 mL of H218O purchased from Taiyo Nippon Sanso.
Co., and 1 mL of dry DMSO were added to the reaction mixture. The
Schlenk tube was heated at 120 °C for 24 h and then cooled to room
temperature. The reaction mixture was passed through a bed of Celite.
The reaction mixture was neutralized with 1 M HCl, and then resorꢀ
cinol was extracted from the water layer into the organic layer using
ethyl acetate. The combined organic layers were dried over Na2SO4,
and the solvent was evaporated in vacuo. The desired products were
obtained after purification by silica gel column chromatography. The
amounts of 18O labeled 2 were found to be 57% (m/z 114), 34% (m/z
112) and 9% (m/z 110) by EIꢀMS measurement (Scheme S4). To a
suspension of 18O labeled 2 (29 mg) and sodium hydride (31 mg, 1.3
mmol) in THF (5 mL), dimethylsulfate (69 mg, 0.55 mmol) was addꢀ
ed in an iceꢀbath and the reaction mixture was refluxed for 24 h. The
reaction mixture was then evaporated and extracted with ethyl acetate
three times. The combined organic layers were washed with water and
brine, dried over Na2SO4, and evaporated to give the crude product.
The crude product was purified by silica gel column chromatography
to obtain 18O labeled 15 as viscous oil.
825.3903; Found 825.3890. IR (KBr) cmꢀ1: 3445, 3055, 2957, 2866,
1753, 1608.
Synthesis of hydroxyjulolidine dimethoxyphenyl isobenzo-
furanone (21). Benzophenone derivative 1b (0.2 g, 0.59 mmol), 1,3ꢀ
dimethoxybenzene (0.082 g, 0.59 mmol), and CH3SO3H (2 mL) were
added to a 30 mL flask. The resulting mixture was stirred at room
temperature for 2 h before being poured into saturated NaHCO3. After
the completion of the reaction, its pH was adjusted to 6~8 with satuꢀ
rated NaHCO3. The resulting mixture was extracted repeatedly with
CHCl3, and the organic layer was combined, dried with MgSO4, and
filtered. The crude product was purified by silica gel column chromaꢀ
tography to obtain the pure products of 21 as a solid. Yield 66% (182
mg). ¹HꢀNMR (CDCl3, 600 MHz): δ 7.93 (dd, 1 H, J = 7.6, 1.0 Hz),
7.64 (ddd, 1 H, J = 1.2, 1.2, 15.1 Hz), 7.52 (ddd, 1 H, J = 0.98, 0.98,
15.1 Hz), 7.38 (dd, 1 H, J = 7.6 Hz), 7.02 (d, 1 H, J = 8.6 Hz), 6.51 (s,
1 H), 6.21 (dd, 1 H, J = 2.4, 8.6 Hz), 6.34 (d, 1 H, J = 2.5 Hz), 6.32 (s,
1 H), 3.77 (s, 3 H), 3.40 (s, 3 H), 3.19–3.06 (m, 4 H), 2.05–1.89 (m, 4
H). 13CꢀNMR (CDCl3, 125 MHz): δ 169.4, 161.8, 159.1, 151.5, 151.3,
144.4, 133.1, 130.7, 128.5, 127.3, 125.3, 125.2, 124.2, 119.2, 112.3,
111.6, 110.4, 103.9, 100.1, 92.2, 55.5, 55.3, 50.0, 49.5, 27.3, 22.2,
21.6, 21.3. HRMS (ESI, positive mode): m/z calcd for C28H27NO5:
[M+H]+ 458.1967; Found 458.1960. IR (KBr) cmꢀ1: 3228, 3195,
3097, 1712, 1558.
Synthesis of ABPX-PYR-JUR (22). To 8% CH3SO3H/CH2Cl2 (5
mL) in a sealed tube were added isobenzofuranone derivative 21 (0.16
mmol) and benzophenone derivative 1a (0.16 mmol). The reaction
mixture was allowed to stir at room temperature for 2 h. Upon the
completion of the reaction, a small amount of ice water was poured
into the reaction mixture and its pH was adjusted to 6~8 with saturatꢀ
ed NaHCO3. Then, the reaction mixture was extracted with CHCl3
three times. The organic layers were dried over MgSO4 and evapoꢀ
rated to give the crude product. The crude product was purified by
silica gel column chromatography to obtain the pure product trans-
18O studies of cyclization of xanthene ring. 18O labeled 2 (1.0
equiv.) and 1a (2.0 equiv.) were combined in CH3SO3H (2.0 mL) in a
sealed tube and heated at 95 °C for 6 h. The reaction was poured into
stirred ice water, the pH was adjusted to 6~8 with saturated NaHCO3,
and the mixture was stirred for 20 min. Then, the mixture was exꢀ
tracted with CHCl3 repeatedly. The organic layers were dried over
MgSO4 and evaporated to give the crude product. The crude product
was purified by silica gel column chromatography to give 18O labeled
4 and 5’. 18O labeled 5’ contained compound 5 and alkylated Rhodolꢀ
PYR. The percentages of 18O labeled 5’ were 45% (m/z 388), 38%
(m/z 386), and 17% (m/z 384) as determined by FABꢀMS using a 3ꢀ
nitrobenzylalcohol (NBA) matrix (Figure S1). On the other hand, the
ratio of 18O labeled 4 was determined by the conversion from the
spirolactone species to the dicationic species. 18O labeled 4 was disꢀ
solved in 2 mL of CH2Cl2 and was rapidly added to 10 mL of 1 M
HCl in diethyl ether. The mixture was stirred under argon at rt for 12
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h to obtain a precipitate. The precipitate was filtered using a PTFE
5. Ahmad, M.; King, T. A.; Ko, D. K.; Cha, B. H.; Lee, J. J. Phys. D-
membrane filter, rinsed with diethyl ether, and dried under vacuum at
room temperature. The percentages of 18O labeled 4 were 56% (m/z
666), 33% (m/z 664), and 11% (m/z 662) by FABꢀMS using a NBA
matrix (Figure S1). In addition, labeled 4 and 5’ were synthesized
from the thermal reaction of 18O labeled 15 with 1a, similarly puriꢀ
fied, and the labeled percentages were determined by the aforemenꢀ
tioned procedure (Figure S2).
Computational details. Density functional calculations were carried
out by using the Gaussian 09 program package.13 The geometry optiꢀ
mization of dicationic intermediate 6 in the gas phase was performed
with the restricted B3LYP density functional and 6ꢀ31G** basis set.
Appl. Phys. 2002, 35, 1473ꢀ1476.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is availaꢀ
ble free of charge on the ACS Publications website. H and 13C
1
NMR spectra, absorption and fluorescence spectra, and Cartesian
coordinates.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmails: skamino@okayamaꢀu.ac.jp
*Eꢀmails: dsawada@okayamaꢀu.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was partially supported by GrantꢀinꢀAid for KAKENHI
C (17K08211), and KAKENHI S (17H06173) from the Ministry
of Education, Culture, Sports, Science and Technology (MEXT)
of the Japan Society for the Promotion of Science (JSPS). We also
acknowledge funding from the Konica Minolta Imaging Science
Foundation and the Takeda Science Foundation. We thank Ms
Tsugumi Shiokawa of the Department of Instrumental Analysis,
Advanced Science Research Center of Okayama University, for
HRꢀMS measurements.
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