Synthesis of Sterically Protected Xanthene Dyes with Bulky Groups at C-3′ and C-7′

Article abstract of DOI:10.1021/acs.joc.5b01746

Substitution of the xanthene scaffold with bulky groups at C-3′ and C-7′ is expected to protect the electrophilic central methine carbon against nucleophilic attack and inhibit stacking. However, such structures are not readily prepared via traditional xa

Full text of DOI:10.1021/acs.joc.5b01746

Note
pubs.acs.org/joc
Synthesis of Sterically Protected Xanthene Dyes with Bulky Groups
at C‑3′ and C‑7′
Zuhai Lei,† Xinran Li,† Yi Li,† Xiao Luo,† Miaomiao Zhou,† and Youjun Yang*,†,‡
†
‡State Key Laboratory of Bioreactor Engineering, and Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East
China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
S
* Supporting Information
ABSTRACT: Substitution of the xanthene scaffold with bulky
groups at C-3′ and C-7′ is expected to protect the electrophilic
central methine carbon against nucleophilic attack and inhibit
stacking. However, such structures are not readily prepared via
traditional xanthene syntheses. We have devised an alternative
and convenient synthesis to enable facile preparation of this
subset of xanthene dyes under mild conditions and in good yields.
n electronic push−pull system displays a narrow
HOMO−LUMO band gap and enables absorption in
C-1′ (Figure 2).6 Installation of bulky groups on the C-3′ and
C-7′ is expected to block the trajectories of an incoming
A
the visible and even longer-wavelength spectral region.1 Many
different classes of small-molecule organic dyes have been
constructed following this principle and found broad
applications. However, this conjugated backbone is polarized
and becomes intrinsically reactive toward both nucleophiles and
electrophiles (Figure 1). While this reactivity has been
Figure 2. Structures of the C-3′- and C-7′-disubstituted xanthene dyes.
nucleophile to attack the central methine carbon. However,
such scaffolds are not readily synthesized via existing xanthene
syntheses, and we herein report a novel and convenient method
to address this need.
Figure 1. Generic push−pull scaffold that is routinely found in a small-
molecule organic fluorophore.
Xanthenes are traditionally synthesized via acid-catalyzed
condensation between a benzophenone, typically generated in
situ, with electron-rich aromatics (Figure 3A).7 An alternative
synthesis (Figure 3B), a two-step cascade starting from a phenyl
magnesium bromide and an aromatic ester, was achieved by
Strongin et al. by employing Grignard chemistry.8 However,
both methods are not suitable for preparation of 3′- and 7′-
disubstituted xanthenes because the presence of two bulky
groups in close proximity (at starred positions in Figure 3)
renders the electrophilic carbonyl group inaccessible for a
nucleophile from either face. Another synthesis of xanthene
dyes involves the nucleophilic addition of an aromatic Grignard
(or lithium) reagent to a xanthenone (Figure 3C).9 The
carbonyl group of this xanthenone is more accessible compared
to the benzophenones in the first two methods. However, the
planarity of this molecule facilitates electron delocalization to
this carbonyl, and therefore, it is comparatively less electrophilic
and less reactive toward nucleophilic attack. Xanthenes with
two methyl9f or methoxyl groups9d at C-3′ and C-7′ were
harnessed as a modulation mechanism2 of the absorption and
fluorescence properties of a fluorophore in designing a
molecular probe or sensor, it is generally considered a
limitation.
Steric protection has been routinely employed in physical
organic chemistry to render a thermodynamically reactive
species kinetically persistent.3 Based on this idea, polymethine
dyes were threaded into various macrocycles for improved
chemostability.4 However, such supramolecular inclusion
complexes are typically large in size, and their syntheses are
not as convenient as small-molecule dyes. Bulky groups
rationally installed onto the fluorophore scaffold could serve
as a molecular alternative to the aforementioned supra-
molecular approach, providing sufficient protection to the
push−pull backbone with minimal structural cost. Protection of
an organic dye with sterics is a routine practice in material
sciences in any solid-state application to minimize dye
aggregations.5 Xanthenes are well-accepted bright fluorescent
dyes and are also known to have poor chemostability toward
nucleophilic attack at the central methine carbon atom, that is,
Received: July 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01746
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 3. Existing syntheses (A−C) and our proposed synthesis (D) of xanthene dyes. The electrophilic carbonyl group is more sterically accessible
as the coded color changes from red to orange to green.
Figure 4. Synthesis of rhodamine-type xanthene dyes (7a−i) with or without bulky groups at C-3′ and C-7′.
synthesized by this method in generally good yields but not
with bulkier functional groups. Therefore, a novel method that
allows convenient preparation of otherwise difficult-to-attain, if
at all, 3′- and 7′-disubstituted xanthene dyes is a viable addition
to the field. The retrosynthetic analysis of our proposed
method is shown in Figure 3D, with rhodamine-type dyes as an
example. The key step of this cascade is the nucleophilic
addition of a 2,6-disubstituted phenyl lithium (or magnesium
bromide) to an appropriately functionalized benzaldehyde,
whose carbonyl group is not only more reactive compared to
B
DOI: 10.1021/acs.joc.5b01746
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
the carbonyl group of the various benzophenones used in the
previous three existing xanthene syntheses but also more
sterically accessible. This rationalizes why it readily reacts with
very hindered nucleophiles (vide infra). The resulting
secondary alcohol is treated with acid to induce the cyclization
via an intramolecular electrophilic aromatic substitution to
generate a triarylmethane, which is oxidized spontaneously or
chemically to furnish the desired 3′,7′-disubstituted xanthenes.
Syntheses of such xanthene dyes with substitutions at both
C-3′ and C-7′ are detailed in Figure 4. 3-Bromoaniline (1) is
alkylated with EtI or 3-chlorobromopropane to afford
compounds 2a,b. Compounds 2a,b are readily formylated to
give 3a,b nearly quantitatively via Vilsmeier−Haack reagent at
room temperature in CH2Cl2. Nucleophilic aromatic sub-
stitution of the bromine atom of compound 3a by 3-
diethylaminophenol (4a) under Ullmann conditions yielded
the prefunctionalized benzaldehyde 5a10 in a 75% yield.
Compound 5b was prepared analogously from condensation
between 3b and 4b in a 22% yield. Then, the benzaldehydes
5a,b were reacted with a number of alkyl Grignard reagents,
aryl Grignard reagents, or aryl lithium reagents, some of which
(6e−h) are very sterically hindered, in a liquid N2/EtOAc bath.
The reaction occurred smoothly at −78 °C and was completed
in less than 10 min based on TLC monitoring. The resulting
secondary alcohols were not isolated or purified by any means.
Instead, into the reaction flask was added dilute HCl solution.
Upon heating the resulting mixture to 50 °C for 15 min, the
secondary alcohol intermediate was converted to the
corresponding triarylmethane analogues quantitatively. The
crude triarylmethanes in CH2Cl2, from a liquid−liquid
extraction, were not stable and spontaneously oxidized if not
protected from air. They were also readily oxidized with
addition of DDQ. Pure xanthene dyes (7a−i) were obtained
with a flash column typically in an overall yield of over 50%
starting from aldehydes 5a,b.
The UV−vis absorption and fluorescence properties of these
new dyes (7e−i and 11) were studied (Table 1 and Figure S2).
Table 1. Spectroscopic Properties of Dye 7e−i and 11
dyes
abs (nm)
em (nm)
ε (M−1 cm−1
)
φ
a
a
a
a
a
b
7e
7f
558
558
558
562
583
510
581
578
582
583
601
528
120000
61000
45000
75000
107000
63000
0.48
0.51
0.29
0.48
0.57
7g
7h
7i
11
0.91
a
b
In EtOH, with rhodamine B (0.49 in EtOH12) as a reference. In 0.1
M NaOH solution with 5% EtOH, with fluorescein (0.95 in 0.1 M
NaOH13) as a reference.
Rhodamine-type dyes (7e−h) display an absorption band with
a maximum at ca. 560 nm and emit at 580 nm in EtOH,
regardless of the nature of steric group substituted at C-3′ and
C-7′. The molar absorptivity of rhodamines decreases as the
sizes of the groups at C-3′ and C-7′ increase. The fluorescence
quantum yield of 7g is low at 0.29, while others are higher at ca.
0.5. In comparison, 7i is a longer-wavelength and brighter dye
than 7e−h. The molar absorptivity of 7i is notably higher.
Compound 11 in 0.1 M NaOH solution containing 5% EtOH
absorbs maximally at 510 nm (ε = 63 000 M−1 cm−1) and emits
at 528 nm with a fluorescence quantum yield of 0.91. As
expected, these dyes were found to not aggregate even at 0.1
mM in H2O/EtOH (95:5, v/v) as showcased with 7h and 7i.
High chemostability of these dyes was showcased with 7h and
7i, with 7c as a negative control (Figure S2). The absorption
spectrum of a solution of 7h and 7i in EtOH was not affected
upon addition of 10 μL of NaOH solution (20 wt %). In
comparison, the stereotypical purple color of a solution of 7c
completely disappeared with addition of the same amount of
NaOH.
This method is also suitable for preparation of 3′,7′-
disubstituted fluorescein-type xanthene dyes (Figure 5). Since
In summary, we have described a mild synthesis of sterically
protected xanthene dyes, which are not readily attainable via
other methodologies. This synthesis is complementary to all
existing methods in that it allows preparation of xanthene dyes
with bulky groups at both C-3′ and C-7′. This method is also
very versatile. Ethyl groups on the nitrogen atoms of aldehyde 3
may be replaced by any alkyl groups, as long they are
compatible to lithium/Grignard chemistry. Also, other lithium
or Grignard reagents can replace the sterically hindered lithium
reagents used in this paper, depending on the structure of
targeted xanthene dyes. Another merit of this synthesis is that
the involved reaction conditions are very mild and purification
is convenient.
EXPERIMENTAL SECTION
■
Figure 5. Synthesis of fluorescein-type xanthene dyes with bulky
groups at C-3′ and C-7.
3-Bromo-N,N-diethylaniline (2a). 3-Bromoaniline (50 g, 1 equiv,
0.29 mol), EtI (99.7 g, 2.2 equiv, 0.64 mol), K2CO3 (40 g, 1 equiv,
0.29 mol), and anhydrous MeCN (300 mL) were added into a 1 L
flask. The resulting mixture was heated to 80 °C with rigorous stirring
for 24 h before being cooled to room temperature. Solid materials
were filtered off using a Celite cake under vacuum and washed with
CH2Cl2. The filtrate was evaporated under reduced pressure to give
the crude product as a brownish-orange liquid, which was purified via
vacuum distillation (bp 90 °C at 90 Pa) to give 2a (57 g, a colorless
the syntheses of the dimethyl-9d or dimethoxyl11-substituted
analogues have been reported elsewhere, only the most bulky
lithium reagent 6h was reacted with 10 to showcase the
capability of this method. This synthesis is analogous to the
aforementioned synthesis of the rhodamine series (7a−i),
except that an extra demethylation step is needed before
oxidation. Compound 11 was obtained in an overall yield of
74% from compound 8.
1
liquid) in an 86% yield: H NMR (400 MHz, CDCl3) δ 7.07 (dd, J =
8.2, 7.9 Hz, 1H), 6.82 (t, J = 2.0 Hz, 1H), 6.77 (dd, J = 7.9 Hz, 2.0 Hz,
1H), 6.60 (dd, J = 8.2 Hz, 2.0 Hz, 1H), 3.35 (q, J = 7.1 Hz, 4H), 1.18
(t, J = 7.1 Hz, 6H).
C
DOI: 10.1021/acs.joc.5b01746
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
8-Bromo-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolone
(2b). 3-Bromoaniline (50 g, 1 equiv, 0.29 mol), excess 3-
chlorobromopropane (200 g, 1.27 mol), and K2CO3 (80 g, 2 equiv,
0.58 mol) were added into a 1 L flask. The resulting mixture was
heated to 140 °C for 48 h with rigorous stirring before being cooled to
room temperature. CH2Cl2 (200 mL) was added to dilute the viscous
mixture before all solid materials were filtered off. CH2Cl2 was
removed under reduced pressure. The resulting liquid, which is a
solution of 2b in 3-chlorobromopropane, was distillated under
vacuum. Compound 2b (bp 110 °C at 90 Pa) was obtained after 3-
chlorobromopropane. Compound 2b (63 g, a colorless liquid) was
obtained in an 83% yield: 1H NMR (400 MHz, CDCl3) δ 0.75 (d, J =
8.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 3.55 (t, J = 6.0 Hz, 4H), 3.14−
3.08 (m, 4H), 2.76 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.38−
2.32 (m, 2H), 1.98−1.93 (m, 4H).
2-Methylphenylmagnesium Bromide (6c). This Grignard
reagent as its THF solution was prepared by treatment of 2-
methylbromobenzene with I2-activated Mg powder in anhydrous THF.
Naphthalen-1-ylmagnesium Bromide (6d). This Grignard
reagent as its THF solution was prepared by treatment of 1-
bromonaphthalene with I2-activated Mg powder in anhydrous THF.
(2,6-Dimethylphenyl)lithium (6e). A solution of n-BuLi (1.6 M
in hexane) was syringed into a solution of 2-bromo-m-xylene in THF
at −78 °C dropwise, and the resulting mixture was stirred for another
30 min prior to use.
(2,6-Dimethoxyphenyl)lithium (6f). A solution of n-BuLi (1.6 M
in hexane) was syringed into a solution of 1,3-dimethoxybenzene in
THF at 0 °C dropwise, and the resulting mixture was stirred for
another 1 h prior to use.
(2,6-Diisopropylphenyl)lithium (6g). A solution of n-BuLi (1.6
M in Hexane) was syringed into a solution of 2-bromo-1,3-
diisopropylbenzene in THF at −78 °C dropwise, and the resulting
mixture was stirred for another 30 min prior to use.
(2,6-Bis(2,6-dimethylphenoxy)phenyl)lithium (6h). A solution
of n-BuLi (1.6 M in hexane) was syringed into a solution of compound
12 in THF at 0 °C dropwise, and the resulting mixture was stirred for
another 2 h prior to use.
General Procedures for Rhodamine-Type Dyes (7a−h). A
solution of various lithium reagents (0.88 mmol, 1.5 equiv) in THF
was added to a solution of compound 5a (200 mg, 1 equiv, 0.59
mmol) in THF (40 mL) at −78 °C via syringe. The reaction mixture
was allowed to warm to room temperature within 30 min. Dilute HCl
solution (2 M, 50 mL) was poured into the reaction flask, and the
resulting mixture was heated to 50 °C for 15 min with stirring. Upon
being cooled to room temperature, the reaction mixture was extracted
with CH2Cl2 repeatedly. The combined organic layer was dried with
anhydrous MgSO4 powder, and all solid was removed with a suction
filtration. DDQ (134 mg, 1 equiv, 0.59 mmol) was added into the
filtrate in one portion, and the mixture was stirred for 30 min at room
temperature for the reaction to complete. Then, all CH2Cl2 was
removed under reduced pressure to give a viscous residue, from which
compounds 7a−h were obtained from a flash column over silica with a
mixture of CH2Cl2 and MeOH [95:5].
2-Bromo-4-(diethylamino)benzaldehyde (3a). POCl3 (4.5
mL) and DMF (60 mL) were stirred together in a flask for 30 min
at 0 °C before a solution of 2a (20 g, 43.8 mmol) in anhydrous DMF
(40 mL) was added slowly. The resulting mixture was stirred at room
temperature for 6 h before being poured into ice water. Brownish-
yellow precipitates were collected via a suction filtration and washed
with water. The solid was dissolved back into CH2Cl2. Residual H2O
was removed with anhydrous MgSO4. Upon suction filtration to
remove solids, the filtrate was passed through a short silica column to
remove the colored impurities. Evaporation under vacuum afforded 3a
(20.7 g, 89%) as a yellow crystalline solid: 1H NMR (400 MHz,
CCl3D) δ 10.05 (s, 1H), 7.77 (d, J = 8.9 Hz, 1H), 6.77 (s, 2H), 6.60
(d, J = 8.9 Hz, 1H), 3.42 (q, J = 6.9 Hz, 4H), 1.22 (t, J = 6.9 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 189.9, 152.6, 131.3, 130.1, 121.5,
114.3, 110.2, 44.8, 12.4; EI-MS (m/z) [M]+ calcd for C11H14BrNO
255.01, found 255.0.
8-Bromo-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-
carbaldehyde (3b). POCl3 (11 mL) and DMF (120 mL) were
stirred together in a flask for 30 min at 0 °C before a solution of 2b
(20 g, 79 mmol) in anhydrous DMF (20 mL) was added slowly. The
reaction was carried out and worked up analogously to 3a. Compound
3b (21.6 g, 97%) was obtained as a yellow crystalline solid: mp 107.6−
108.2 °C; 1H NMR (CDCl3, 400 MHz) δ 10.08 (s, 1H), 7.40 (s, 1H),
3.24−3.30 (m, 4H), 2.82 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.4 Hz, 2H),
1.98−1.90 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 190.9, 148.9,
129.6, 128.3, 121.4, 119.7, 119.2, 77.4, 77.1, 76.8, 50.2, 49.8, 28.1, 27.4,
21.1, 21.0; HRMS (EI+) [M]+ calcd for C13H14BrNO 279.0259, found
279.0261.
N-(6-(Diethylamino)-9-methyl-3H-xanthen-3-ylidene)-N-eth-
ylethanaminium Chloride (7a14). Compound 7a (105 mg) was
1
obtained as a red-violet solid in a 45% yield: H NMR (400 MHz,
CDCl3) δ 8.10 (d, J = 9.4 Hz, 2H), 7.12 (dd, J = 9.4, 1.6 Hz, 2H), 6.69
(d, J = 1.6 Hz, 2H), 3.63 (q, J = 6.9 Hz, 8H), 2.96 (s, 3H), 1.33 (t, J =
6.9 Hz, 12H).
N-(6-(Diethylamino)-9-phenyl-3H-xanthen-3-ylidene)-N-eth-
ylethanaminium Chloride (7b15). Compound 7b (164 mg) was
obtained as a violet solid in a 70% yield: 1H NMR (400 MHz, CDCl3)
δ 7.63−7.62 (m, 3H), 7.38−7.34 (m, 4H), 6.95 (dd, J = 9.6, 2.4 Hz,
2H), 6.87 (d, J = 2.4 Hz, 1H), 3.67 (q, J = 7.0 Hz, 8H), 1.34 (t, J = 7.0
Hz, 12H).
N-(6-(Diethylamino)-9-(o-tolyl)-3H-xanthen-3-ylidene)-N-
ethylethanaminium Chloride (7c16). Compound 7c (152 mg) was
obtained as a violet solid in a 63% yield: 1H NMR (400 MHz, CDCl3)
δ 7.45 (t, J = 7.7 Hz, 1H), 7.38−7.32 (m, 2H), 7.12−7.07 (m, 3H),
6.90 (dd, J = 9.5, 2.2 Hz, 2H), 6.80 (d, J = 2.2 Hz, 2H), 3.62 (q, J = 7.1
Hz, 8H), 2.0 (s, 3H), 1.29 (t, J = 7.1 Hz, 12H).
4-(Diethylamino)-2-(3-(diethylamino)phenoxy)benz-
aldehyde (5a). Synthesis and characterizations were reported
elsewhere.10
8-((1,2,3,5,6,7-Hexahydropyrido[3,2,1-ij]quinolin-8-yl)oxy)-
1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinoline-9-carbaldehyde
(5b). Compounds 3b (500 mg, 1 equiv, 1.78 mmol), 4b (506 mg, 1.5
equiv, 2.68 mmol), K2CO3 (369.8 mg, 1.5 equiv, 2.68 mmol), CuBr
(26 mg, 0.1 equiv, 0.18 mmol), and DMF (40 mL) were added into a
flask. The reaction mixture was thoroughly deoxygenated by bubbling
Ar for 15 min, heated to 140 °C with rigorous stirring for 6 h, and
cooled to room temperature. A saturated solution of NH4Cl (50 mL)
was added, and the resulting mixture was extracted repeatedly with
CH2Cl2. The organic layer was combined, dried with MgSO4, and
filtered. Both CH2Cl2 and DMF were removed under reduced pressure
to yield a viscous residue, which was purified by a flash column using a
mixture of petroleum ether and EtOAc [20:1, v/v] as an eluent to
afford 5b (153 mg) as a yellow solid in a 22% yield: mp 209.7−210.2
°C; 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.42 (s, 1H), 6.57 (d,
J = 8.3 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 3.28 (t, J = 5.6 Hz, 2H), 3.23
(t, J = 5.6 Hz, 2H), 3.13 (q, J = 5.6 Hz, 4H), 2.88 (t, J = 6.4 Hz, 2H),
2.75 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.05−2.00 (m, 2H),
1.99−1.93 (m, 4H), 1.87−1.81 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 187.8, 155.3, 155.2, 149.1, 144.0, 126.5, 126.1, 117.8, 117.3,
115.3, 112.7, 109.1, 101.1, 50.1, 50.1, 49.7, 49.6, 27.4, 27.2, 22.3, 21.7,
21.4, 21.4, 20.8, 20.6; ESI-MS (m/z) [M + Na]+ calcd for
C25H28N2O2Na 411.2047, found 411.2047.
N-(6-(Diethylamino)-9-(naphthalen-1-yl)-3H-xanthen-3-yli-
dene)-N-ethylethanaminium Chloride (7d15). Compound 7d
1
(160 mg) was obtained as a violet solid in a 61% yield: H NMR
(400 MHz, CDCl3) δ 8.08 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.2 Hz,
1H), 7.56 (t, J = 7.1 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.38 (t, J = 8.0
Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.05 (d, J = 9.5 Hz, 2H), 6.85 (d, J
= 2.0 Hz, 2H), 6.74 (dd, J = 8.4, 2.0 Hz, 2H), 3.61−3.60 (m, 8H),
1.29−1.27 (m, 12H).
N-(6-(Diethylamino)-9-(2,6-dimethylphenyl)-3H-xanthen-3-
ylidene)-N-ethylethanaminium Chloride (7e). Compound 7e
(165 mg) was obtained as a violet solid in a 66% yield. Compound
1
7e decomposed before melting: H NMR (400 MHz, CDCl3) δ 7.36
(t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H),7.07 (d, J = 9.4 Hz, 2H),
6.90 (dd, J = 9.4, 2.0 Hz, 2H), 6.85 (d, J = 2.0 Hz, 2H), 3.64 (q, J = 7.0
D
DOI: 10.1021/acs.joc.5b01746
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 8H), 1.93 (s, 6H), 1.31 (t, J = 7.0 Hz, 12H); 13C NMR (100 MHz,
CDCl3) δ 158.0, 157.9, 155.8, 135.6, 131.1, 131.0, 129.7, 128.0, 114.6,
113.1, 96.6, 46.2, 19.9, 12.7; EI-HRMS (m/z) [M]+ calcd for
C29H35N2O 427.2749, found 427.2751.
reaction mixture was allowed to warm to room temperature within 30
min. Dilute HCl solution (2 M, 50 mL) was poured into the reaction
flask, and the resulting mixture was heated to 50 °C for 15 min with
stirring. Upon being cooled to room temperature, the reaction mixture
was extracted with CH2Cl2 repeatedly. The combined organic layer
was dried with anhydrous MgSO4 powder, and all solid was removed
with a suction filtration. Upon the filtrate being cooled to −78 °C with
a liquid N2/EtOAc bath, BBr3 in CH2Cl2 (2.3 mL, 1 M, 3.0 equiv) was
added with stirring. The mixture was allowed to warm to room
temperature within 2 h before being quenched by slow addition of
MeOH and then H2O. HBr fume was absorbed by a saturated
NaHCO3 solution by use of an inverted funnel. The reaction mixture
was then extracted with CH2Cl2, and the organic layer was combined,
dried with anhydrous MgSO4, and filtered. DDQ (176 mg, 1.0 equiv,
0.77 mmol) was added into the filtrate in one portion, and the mixture
was stirred for 30 min at room temperature for the reaction to
complete. Then, all CH2Cl2 was removed under reduced pressure to
give a viscous residue, from which pure compound 11 (304 mg) as a
red solid was obtained from a flash column over silica with a mixture of
petroleum ether/EtOAc [1:2, v/v] in a 74% yield. Compound 11
decomposed before melting: 1H NMR (400 MHz, CD3OD) δ 7.80 (d,
J = 7.6 Hz, 2H), 7.29−7.03 (m, 11H), 6.20 (d, J = 7.6 Hz, 2H), 1.96
(s, 12H); 13C NMR (100 MHz, CD3OD) δ 160.6, 157.2, 151.3, 134.1,
133.9, 132.0, 130.3, 127.1, 122.0, 118.3, 106.9, 104.1, 16.6; 13C NMR
(101 MHz, DMSO-d6) δ 155.3, 149.4, 143.9, 132.0, 130.4, 130.0,
129.2, 125.7, 108.5, 105.1, 103.4, 15.7; EI-HRMS (m/z) [M]+ calcd for
C35H28O5 528.1937, found 528.1936.
N-(6-(Diethylamino)-9-(2,6-dimethoxyphenyl)-3H-xanthen-
3-ylidene)-N-ethylethanaminium Chloride (7f). Compound 7f
(143 mg) was obtained as a violet solid in a 57% yield. Compound 7b
decomposed before melting: 1H NMR (400 MHz, CDCl3) δ 7.52 (t, J
= 8.2 Hz, 1H), 7.23 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.75
(d, J = 2.4 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 3.61 (s, 6H), 3.58 (q, J =
6.8 Hz, 8H), 1.27 (t, J = 6.8 Hz, 12H); 13C NMR (101 MHz, CDCl3)
δ 158.2, 155.9, 155.8, 153.3, 149.9, 132.3, 131.6, 130.7, 129.2, 125.8,
114.5, 113.7, 108.0, 105.7, 96.5, 77.4, 77.1, 76.8, 46.3, 16.4, 12.7; ESI-
HRMS (m/z) [M + H]+ calcd for C29H35N2O3 459.2648, found
459.2646.
N-(6-(Diethylamino)-9-(2,6-diisopropylphenyl)-3H-xanthen-
3-ylidene)-N-ethylethanaminium Chloride (7g). Compound 7g
(172 mg) was obtained as a violet solid in a 60% yield. Compound 7c
decomposed before melting: 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J
= 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 9.4 Hz, 2H), 6.98
(d, J = 2.2 Hz, 2H), 6.84 (dd, J = 9.3, 2.2 Hz, 2H), 3.66 (q, J = 7.2 Hz,
8H), 1.33 (t, J = 7.2 Hz, 12H), 1.26 (q, J = 6.8 Hz, 2H), 1.01 (d, J =
6.8 Hz, 12H); 13C NMR (100 MHz, CDCl3) δ 156.7, 154.8, 146.6,
130.3, 129.5, 122.7, 113.3, 112.8, 96.9, 46.2, 30.4, 28.7, 23.4, 11.6; EI-
HRMS (m/z) [M]+ calcd for C33H43N2O 483.3375, found 483.3377.
N-(9-(2,6-Bis(2,6-dimethylphenoxy)phenyl)-6-(diethylami-
no)-3H-xanthen-3-ylidene)-N-ethylethanaminium Chloride
(7h). Compound 7h (212 mg) was obtained as a violet solid in a
56% yield. Compound 7d decomposed before melting: 1H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 9.2 Hz, 2H), 7.17 (t, J = 8.4 Hz, 1H),
7.01−6.98 (m, 8H), 6.85 (s, 2H), 6.19 (d, J = 8.4 Hz, 2H), 3.68−3.66
(m, 8H), 1.97 (s, 12H), 1.34−1.32 (m,12H), 13C NMR (101 MHz,
CDCl3) δ 158.2, 155.9, 155.8, 153.3, 149.9, 132.3, 131.6, 130.7, 129.2,
125.8, 114.5, 113.7, 108.0, 105.7, 96.5, 77.4, 77.1, 76.8, 46.3, 16.5, 12.7.
ESI-HRMS (m/z) [M + H]+ calcd for C43H47N2O3 639.3587, found
639.3593.
1,3-Bis(2,6-dimethylphenoxy)benzene (12). 1,3-Dibromoben-
zene (500 mg,1 equiv, 2.12 mmol), 2,6-dimethylphenol (777 mg, 3
equiv, 6.36 mmol), K2CO3 (878 mg, 3 equiv, 6.36 mmol), CuBr (60
mg, 0.2 equiv, 0.42 mmol), and DMF (40 mL) were mixed in a flask.
Upon deoxygenation by bubbling Ar for 20 min, the mixture was
heated to 140 °C under Ar overnight. Then the reaction was cooled to
room temperature, and saturated NH4Cl solution (50 mL) was added.
The resulting mixture was extracted repeatedly with CH2Cl2, and the
organic layer was combined, dried with MgSO4, and filtered. Both
CH2Cl2 and DMF were removed under reduced pressure to yield a
viscous residue, which was purified by a flash column using petroleum
ether as eluent to afford 12 (403 mg) as a white crystalline solid in a
Compound 7i. Compound 7i (96 mg) was obtained as a violet
solid in a 52% yield starting from 5b (100 mg) and 6h: 1H NMR (400
MHz, CDCl3) δ 7.12 (t, J = 8.4 Hz, 1H), 7.06 (s, 2H), 6.99−6.93 (m,
6H), 6.13 (d, J = 8.4 Hz, 2H), 3.53 (t, J = 4.2 Hz, 8H), 2.99 (t, J = 4.2
Hz, 4H), 2.72 (t, J = 4.2 Hz, 4H), 2.08−2.06 (m, 4H), 2.00−1.99 (m,
4H), 1.92 (s, 12H); 13C NMR (101 MHz, CDCl3) δ 155.8, 152.5,
151.3, 150.0, 149.9, 131.8, 130.6, 129.1, 126.3, 125.6, 123.4, 113.6,
108.8, 105.5, 105.3, 77.5, 77.2, 76.8, 50.9, 50.5, 27.7, 20.8, 19.9, 19.7,
16.1; ESI-HRMS (m/z) [M]+ calcd for C47H47N2O3 687.3587, found
687.3586.
1
60% yield: mp 42.3−42.5 °C; H NMR (400 MHz, CDCl3) δ 7.12−
7.04 (m, 7H), 6.39−6.33 (m, 3H), 2.12 (s, 12H); 13C NMR (100
MHz, CDCl3) δ 159.4, 151.1, 131.4, 130.2, 129.0, 126.1, 107.5, 102.3,
16.4; EI-MS (m/z) [M]+ calcd for C22H22O2 318.2, found 318.2.
ASSOCIATED CONTENT
■
S
* Supporting Information
4-Methoxy-2-(3-methoxyphenoxy)benzaldehyde (10). A 250
mL round-bottom flask was charged with 2-bromo-4-methoxy
benzaldehyde (500 mg, 1 equiv, 2.33 mmol), 3-methoxyphenol (433
mg, 1.5 equiv, 3.49 mmol), K2CO3 (482 mg, 1.5 equiv, 3.49 mmol),
CuBr (33 mg, 0.1 equiv, 0.23 mmol), and DMF (40 mL). The reaction
mixture was deoxygenated by bubbling Ar for 15 min before being
heated to 140 °C with rigorous stirring for 6 h. Then the reaction was
cooled to room temperature, and saturated NH4Cl solution (50 mL)
was added. The resulting mixture was extracted repeatedly with
CH2Cl2, and the organic layer was combined, dried with MgSO4, and
filtered. Both CH2Cl2 and DMF were removed under reduced pressure
to yield a viscous residue, which was purified by a flash column using a
mixture of petroleum ether and EtOAc [20:1, v/v] as eluent to afford
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01746.
General procedures, aggregation measurements, absorp-
tion, fluorescence, NMR, and MS spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: youjunyang@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
1
10 (368 mg) as a colorless viscous residue in a 61% yield: H NMR
(400 MHz, CDCl3) δ 10.33 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.27 (t, J
= 8.4 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.64
(d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.38 (s, 1H), 3.80 (s, 3H), 3.78 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 187.9, 166.8, 161.7, 161.1,
157.4, 130.5, 130.2, 120.7, 111.5, 110.0, 109.7, 105.5, 103.7, 55.7, 55.5;
EI-MS (m/z) [M]+ calcd for C15H14O4 258.1; found 258.1.
ACKNOWLEDGMENTS
■
The work is supported by the Shanghai Rising-Star Program
(No. 13QA1401200) and the National Natural Science
Foundation of China (Nos. 21372080 and 21572061).
9-(2,6-Bis(2,6-dimethylphenoxy)phenyl)-6-hydroxy-3H-
xanthen-3-one (11). A solution of lithium reagent 6h (1.2 mmol, 1.5
equiv) in THF was added to a solution of compound 10 (200 mg, 1
equiv, 0.77 mmol) in THF (40 mL) at −78 °C via syringe. The
REFERENCES
■
(1) Griffiths, J. Colour and Constitution of Organic Molecules;
Academic Press: New York, 1976.
E
DOI: 10.1021/acs.joc.5b01746
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(2) (a) Dempsey, T.; Bates, M.; Kowtoniuk, W. E.; Liu, D. R.; Tsien,
R. Y.; Zhuang, X. J. Am. Chem. Soc. 2009, 131, 18192−18193.
(b) Hewage, H. S.; Anslyn, E. V. J. Am. Chem. Soc. 2009, 131, 13099−
13106. (c) Shuhendler, A. J.; Pu, K.; Cui, L.; Uetrecht, J. P.; Rao, J.
Nat. Biotechnol. 2014, 32, 373−380.
(3) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science: San Diego, CA, 2006.
(4) (a) Stanier, C. A.; O’Connell, M. J.; Clegg, W.; Anderson, H. L.
Chem. Commun. 2001, 493−494. (b) Arunkumar, E.; Forbes, C. C.;
Noll, B. C.; Smith, B. D. J. Am. Chem. Soc. 2005, 127, 3288−2389.
(c) Hsueh, S.-Y.; Lai, C.-C.; Liu, Y.-H.; Wang, Y.; Peng, S.-M.; Chiu,
S.-H. Org. Lett. 2007, 9, 4523−4526.
(5) (a) Hung, L. S.; Chen, C. H. Mater. Sci. Eng., R 2002, 39, 143−
222. (b) Figueira-Duarte, T. M.; Del Rosso, P. G.; Trattnig, R.; Sax, S.;
List, E. J. W.; Mullen, K. Adv. Mater. 2010, 22, 990−993. (c) Yang, X.;
̈
Xu, X.; Zhou, G. J. Mater. Chem. C 2015, 3, 913−944.
(6) Gomberg, M.; West, C. J. J. Am. Chem. Soc. 1912, 34, 1529−1569.
(7) (a) Sun, W. C.; Gee, K. R.; Klaubert, D. H.; Haugland, R. P. J.
Org. Chem. 1997, 62, 6469−6475. (b) Burgess, K.; Ueno, Y.; Jiao, G.-S.
Synthesis 2004, 15, 2591−2593.
(8) Yang, Y.; Escobedo, J. O.; Wong, A.; Schowalter, C. M.; Touchy,
M. C.; Jiao, L.; Crowe, W. E.; Fronczek, F. R.; Strongin, R. M. J. Org.
Chem. 2005, 70, 6907−6912.
(9) (a) Chen, C.-A.; Yeh, R.-H.; Lawrence, D. S. J. Am. Chem. Soc.
2002, 124, 3840−3841. (b) Urano, Y.; Kamiya, M.; Kanda, K.; Ueno,
T.; Hirose, K.; Nagano, T. J. Am. Chem. Soc. 2005, 127, 4888−4894.
(c) Mottram, L. F.; Boonyarattanakalin, S.; Kovel, R. E.; Peterson, B.
R. Org. Lett. 2006, 8, 581−584. (d) Wu, L.; Burgess, K. J. Org. Chem.
2008, 73, 8711−8718. (e) Shieh, P.; Hangauer, M. J.; Bertozzi, C. R. J.
Am. Chem. Soc. 2012, 134, 17428−17431. (f) Katori, A.; Azuma, E.;
Ishimura, H.; Kuramochi, K.; Tsubaki, K. J. Org. Chem. 2015, 80,
4603−4610.
(10) Lei, Z.; Yang, Y. J. Am. Chem. Soc. 2014, 136, 6594−6597.
(11) Smrcka, A. V.; Blaxall, B. C.; Bidlack, J. M. Compositions and
methods for inhibiting G protein signaling. Patent Appl.
WO2009020677 A2, Feb 12, 2009.
(12) Casey, K. G.; Quitevis, E. L. J. Phys. Chem. 1988, 92, 6590−
6594.
(13) Brouwer, A. M. Pure Appl. Chem. 2011, 83, 2213−2228.
(14) Shandura, M. P.; Poronik, Y. M.; Kovtun, Y. P. Dyes Pigm. 2005,
66, 171−177.
(15) Cardoso, I. C. S.; Amorim, A. L.; Queiros, C.; Lopes, S. C.;
Gameiro, P.; de Castro, B.; Rangel, M.; Silva, A. M. G. Eur. J. Org.
Chem. 2012, 2012, 5810−5817.
(16) Mottram, L. F.; Forbes, S.; Ackley, B. D.; Peterson, B. R.
Beilstein J. Org. Chem. 2012, 8, 2156−2165.
F
DOI: 10.1021/acs.joc.5b01746
J. Org. Chem. XXXX, XXX, XXX−XXX