Revisit of a series of ICT fluorophores: Skeletal characterization, structural modification, and spectroscopic behavior

Article abstract of DOI:10.1016/j.tet.2014.06.032

We have revisited the synthesis of a series of ICT fluorophores, which were reported to have a core structure of 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile. However, based on the 2D NMR and X-ray diffraction analysis, their core structure was correct

Full text of DOI:10.1016/j.tet.2014.06.032

Tetrahedron 70 (2014) 5872e5877
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Revisit of a series of ICT fluorophores: skeletal characterization,
structural modification, and spectroscopic behavior
Honglin Li , Fengyu Liu , Yi Xiao , Perry J. Pellechia , Mark D. Smith , Xuhong Qian ,*,
a
b
c
a
a
d
e,
a,
*
*
Guiren Wang , Qian Wang
Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208, USA
School of Chemistry, Dalian University of Technology, Dalian 116024, China
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, School of Pharmacy, East China University of Science and
a
b
c
d
Technology, Shanghai 200237, China
e
Department of Mechanical Engineering & Biomedical Engineering Program, University of South Carolina, 300 Main Street, Columbia, SC 29208, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have revisited the synthesis of a series of ICT fluorophores, which were reported to have a core
structure of 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile. However, based on the 2D NMR and X-ray
Received 20 April 2014
Received in revised form 6 June 2014
Accepted 9 June 2014
diffraction analysis, their core structure was corrected as 1-oxo-1H-phenalene-2,3-dicarbonitrile (1).
H
Compound 1 shows a highly electron-deficient nature and can easily undergo oxidative S
N
Ar reaction
Available online 14 June 2014
on the naphthyl ring to produce a series of novel ICT fluorophores. The regioselectivity of this sub-
stitution reaction was studied by introduction of representative nucleophiles. Moreover, due to the
strong rigidity and efficient ICT nature, the obtained fluorescent dyes display very good spectroscopic
properties even in an aqueous environment.
Keywords:
ICT fluorophore
Skeletal characterization
H
Ó 2014 Elsevier Ltd. All rights reserved.
Oxidative S
D NMR
X-ray diffraction
N
Ar
2
1. Introduction
A series of novel fluorophores were synthesized in 2005 and
were reported to have a core structure of 8-oxo-8H-acenaphtho
1
[
1,2-b]pyrrol-9-carbonitrile (Scheme 1, left). It was reported that
H
N
this core structure could undergo oxidative S Ar (nucleophilic
substitutions of aromatic hydrogen) reactions with different nu-
cleophiles (on C or C ) to produce a variety of acenaphtho-
2
3
6
3
heterocyclic derivatives. These compounds have good rigidity
and strong ICT (intramolecular charge transfer) nature that afford
1,3
them with good spectroscopic properties.
Furthermore, they
Scheme 1. Comparison of the corrected structure 1 with the mistakenly assigned
structure in literature.
have been widely employed in the development of fluorescent
sensors, antitumor agents, DNA intercalators, and protein
inhibitors.7
4
5
6
assigned; and (b) the coupling between H
9
and carbonyl carbon
However, we recently discovered that the original core structure
was mistakenly assigned based on some conflicts between the
(C ) is conflicted with the original structure. The precise backbone
was then corrected as 1-oxo-1H-phenalene-2,3-dicarbonitrile (1,
1
13
assigned structure and its NMR data: (a) two carbon signals on
C
Scheme 1, right) based on detailed structural analysis with two-
8
NMR spectra (at 113.29 and 113.48 ppm) cannot be correctly
dimensional (2D) NMR (Fig. S1). As a result, we conclude that
the reported structures of all its derivatives are incorrect. In addi-
tion, it is necessary to perform a detailed structural analysis of the
H
S
N
Ar products in order to determine the regioselectivity of the
*
Corresponding authors. E-mail addresses: xhqian@ecust.edu.cn (X. Qian),
wanggu@cec.sc.edu (G. Wang), wang263@mailbox.sc.edu, wang@mail.chem.sc.edu
Q. Wang).
substitution reactions. Therefore, several typical nucleophiles were
selected in the S Ar reaction of 1 and the structures of the final
N
H
(
http://dx.doi.org/10.1016/j.tet.2014.06.032
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.
0

H. Li et al. / Tetrahedron 70 (2014) 5872e5877
5873
products were carefully elucidated. Several of these products have
shown very good spectroscopic properties even in water solution.
structure (Fig. 1, left) shows the backbone of 1-oxo-1H-phenalene-
2,3-dicarbonitrile that is consistent with 2D NMR analysis result of
8
1
. Additionally, the thiophenol moiety is linked to C
6
. This result is
consistent with our previous report that the C
6
(numbered as C in
3
2
2
. Results and discussion
3
the original report ) is the most favorable position for a nucleo-
philic attack.
.1. Preparation of 1
However, the oxidative S
pionic acid was very slow and less efficient. After refluxing in CH
N
ArH reaction of 1 with mercaptopro-
CN
Compound 1 was synthesized very efficiently via a convenient
3
for 2 days, only a small fraction of 1 was converted to the product as
a single regioisomer, 3, in a yield of w9% (Scheme 3). We hypothe-
size the sluggish reactivity is resulted from the acidic nature of
mercaptopropionic acid, which are unfavorable for the oxidative
two-step procedure. The starting material acenaphthoquinone
undergoes Knoevenagel condensation with malononitrile to yield
2
-a, which was then isomerized under basic condition to produce 1
in good yield. Different bases were screened for the isomerization
reaction. We found that although a stronger base could accelerate
the isomerization process, it would lead to more impurities (Table
H
12
S
N
Ar reaction. To confirm this, MeOH was used as the solvent to
H
N
promote the S Ar reaction. Upon being refluxed for 2 days, most
starting materials 1 was consumed, and esterified product 4 was
produced with a yield of 48% together with product 3 (w9%). The
structure of 3 was characterized by HRMS and 2D NMR, including
1
). Considering these, K
because it provided the relative fast and clean reaction. Compound
-a is common precursor for the synthesis of spiro-
acenaphthylene compounds.
2 3
CO was used as the base in our work
2
a
1
13
1
1
1
13
11
9
,10
He C HMBC, He H COSY, and He C HSQC, which support the
backbone skeleton as a 1-oxo-1H-phenalene-2,3-dicarbonitrile.
However, when treated with
base, it undergoes isomerization to produce 1. A base-catalyzed
ring-expansion mechanism is proposed as shown in Scheme 2.
Firstly, the base adds to the electron-deficient double bond of 2-a,
following a nucleophilic ring-closure of I to give II and a ring-ex-
pansion reaction to form III. Finally the nucleophilic substitution
with cyanide ion produces 1, 1-oxo-1H-phenalene-2,3-
dicarbonitrile.
1
13
Moreover, the coupling signal at (3.68 ppm,152.1 ppm) in its He
HMBC spectra (Fig. S2) was assigned as the correlation between H14
and C , indicating the thiol group is attached to C . For compound 4,
C
6
6
in addition to the MS and NMR analyses, we obtained its crystal
structure (Fig. 1 right), from which we can clearly observe the thiol
group is also on C . Both of their (3 and 4) regioselectivity results are
6
consistent with that of compound 2.
Table 1
ArH
N
Hydroxide was also employed as a nucleophile for the S
Isomerization from 2-a to 1 catalyzed by different bases
reaction of 1. It was very fast and a bright fluorescent compound 6
was produced, which was characterized by 2D NMR analyses
Inorganic base
Time
Yieldd (%)
Organic base
DIEAa
Time (h)
Yieldd (%)
a
Cs
2
CO
CO
3
a
15 min
2.0 h
2.5 h
80
88
90
93
1.0
1.0
5e6
48
81%
92%
58%
47%
(Fig. S5). The regioselectivity result shows the substitution takes
a
K
K
2
3
3
DMAP
DABCO
13
place at the C
6
exclusively. In its C NMR spectra, C
1
and C
6
show the
a
b
PO
4
b
chemical shifts of 178.31 and 186.12 ppm, respectively, indicating
that 6 offers two major resonance structures (Fig. S5, inset).
NaAc
5e6 h
Pyridinec
a
Compound 2-a (2.17 mmol), base (10 mol %).
Compound 2-a (1.09 mmol), base (10 mol %).
Compound 2-a (2.17 mmol), base (30 mol %).
Isolated yield.
When amino compounds were employed as nucleophiles, the
b
c
H
oxidative S
N
Ar reactions of 1 were much faster and more efficient
d
in comparison with thiol-based nucleophiles. Usually they could
finish within a few hours, albeit more isomers were generated. For
example, secondary amine can produce three possible products
during this substitution reactions, 6-substituted (10-ae13-a), 9-
substituted (11-be13-b) or 6,9-disubstituted (10-ce12-c) of 1
3
(
Scheme 3). However, when w1.0 equiv of amines were used, the
6
-substituted product is obviously the major product. For example,
the reaction between 1 and piperidine (1.0:1.1) was finished within
h in CH CN at room temperature, affording 10-a with a reasonable
2
3
yield and trace amount of 10-b, 10-c as side-products. When excess
3
amount of piperidine used, more 10-b and 10-c were produced.
The 2D NMR analysis was carried out again to confirm the
structure of 10-a. Here, we take 10-a as an example to show the
1
13
structural elucidation by 2D NMR. In the He C HMBC spectra
1
13
(
(
Fig. S6), the long-range H, C coupling correlation of H
8.74 ppm) to C (177.8 ppm) is clearly observed, confirming the 1-
and then H can be assigned based
on He H COSY spectra (Fig. S7), which is also supported by the
similar dd splitting pattern of H with H (0.9 Hz). Additional
(7.84 ppm) and H (7.13 ppm)
to C10 (129.7 ppm) and H to C11
115.3 ppm), respectively, are consistent with the naphthalene ring
9
1
oxo-1H-phenalene backbone. H
8
7
1
1
Scheme 2. Proposed base-catalyzed ring-expansion reaction from 2-a to 1.
7
9
1
13
He C HMBC correlations of both H
to C13 (125.5 ppm), as well as H
8
5
2
.2. Oxidative S
N
ArH reaction of 1
8
5
(
1
Due to the strong electron-withdrawing groups on 1, its naph-
thalene ring shows a highly electron-deficient nature and oxidative
skeleton. The last proton resonance (at 8.13 ppm) in H NMR
1
13
spectra can be assigned as H
(Fig. S8), C , C , C , C , and C can be assigned, and C
on its correlations to H and H at (8.13 ppm, 160.9 ppm) and
(8.48 ppm, 160.9 ppm) in He C HMBC spectra. The corrected
assignments of H , H , and H are confirmed by their simulta-
neously correlations with 12 at (8.13, 129.3 ppm), (8.48,
4
. Based on He C HSQC spectra
H
S
N
Ar reactions can precede smoothly under very mild conditions.
4
5
7
8
9
6
assigned based
Several nucleophiles, such as thiols, hydroxide, and amines, were
4
7
1
13
used for the structural modification of 1 (Scheme 3). The regiose-
H
lectivity of oxidative S
N
Ar reactions on 1 were also studied by
4
7
9
C
using 2D NMR and X-ray diffraction.
When 1 was reacted with p-methoxybenzenethiol, only a single
regioisomer 2 was produced in an isolated yield of 60%. Its crystal
1
13
129.3 ppm), and (8.74, 129.3 ppm). The long-range H, C coupling
correlation of aliphatic proton H14 (3.67 ppm) to quaternary carbon

5874
H. Li et al. / Tetrahedron 70 (2014) 5872e5877
(a)
(b)
(c)
Scheme 3. (a) S
N
ArH reactions of 1 with different nucleophiles. (b) and (c) Substitution reaction with primary amine.
All these results confirm that the amino group was modified on C
6
of
compound 7-a. The He H NOESY spectra can also support this
results, in which, the correlations between H14 and H5, and H with
, are confirmed by the coupling signals at (3.63, 6.97 ppm) and
9.52, 8.87 ppm). For compound 7-b, the coupling from aliphatic H14
1
1
N
H
7
(
(
1
13
3.79 ppm) to quaternary carbon C
9
(158.3 ppm) in He C HMBC
(Fig. 2b). Moreover,
spectra reveals the amino substitution on C
there is no proton at C as shown in the H NMR and He C HMBC
9
9
1
1
13
1
1
spectra of 7-b. In the He H NOESY spectra of 7-b (Fig. S15), H14
shows a correlation with H at (3.79 ppm, 7.35 ppm) that also
demonstrate the amino substitution on C in 7-b.
Based on the substitution study of compounds 2e13, we can
conclude that C is the most electrophilic carbon thus more favor-
Ar reaction, and C is probably the second favorable one.
8
9
6
H
able for S
N
9
Fig. 1. Crystal structures of 2 (left) and 4 (right). Displacement ellipsoids are shown at
the 60% probability level.
In addition, the substituents such as thiol groups (2, 4) and sec-
ondary amino group (10-a,c) on 1 can be easily replaced by primary
amine, for example, n-butyl amine, to give 14 or 6,9-disubstituted
11
3
C
6
(160.9 ppm) confirms the piperidinyl substitution on C
6
. In ad-
product with different amino groups (15), as reported previously.
1
1
dition, the He H NOESY spectra (Fig. S9) have further confirmed
the regiochemistry of this substitution. Two coupling signals at
(
3.67 ppm, 7.13 ppm) and (3.67 ppm, 8.48 ppm) are observed that
ascribe to the correlations of H14 with H and H , respectively. These
two coupling signals indicate that H14 is closed to H and H , sup-
porting the regiochemistry of the piperidinyl substitution.
2.3. Spectroscopic properties study
5
7
The S
N
ArH reaction resulted in a series of new ICT fluorophores
5
7
that show blue, purple or orange colors in acetonitrile with maxi-
mum absorption peaks longer than 500 nm, approaching to 600 nm
(Table 2). Among these, 4, 6, and 7-a display maximum emission
peaks of 584, 563, and 595 nm, with yellow, green, and orange
fluorescence, respectively (Fig. 3 and inset pictures). The spectro-
scopic data of selected dyes are listed in Table 2. Compounds 4, 6,
and 7-a all show high fluorescence quantum yields in acetonitrile,
demonstrating the strong ICT nature. Compound 6 has an excellent
fluorescent quantum yield even in an aqueous environment, which
can potentially be used in bioimaging applications.
H
When primary amines were used, oxidative S
N
Ar reactions with
1
mainly gave 6-substituted products (7-ae9-a). Meanwhile 9-
substituted product can be also produced in low yield, but no 6,9-
disubstituted products. For example, 3-azidopropan-1-amine can
produce two isomers by oxidative S
6 9
in Scheme 3, the amino group was modified either on C or C to
H
N
Ar reaction with 1. As shown
1
13
1
1
generate the products 7-a or 7-b. The He C HMBC and He H
NOESY spectra can help to confirm the modification position of
these two products.11 The He C HMBC of 7-a shows a coupling
1
13
signal at (3.63, 156.7 ppm), which is assigned as the correlation
In comparison, 7-b is almost non-fluorescent, likely because its
electron-donating group is located on the ortho-position of its
electron-withdrawing groups that offer 7-b a much less efficient
ICT nature than its isomer 7-a. The fluorescence of 10-a strongly
between aliphatic proton H14 and quaternary carbon C
There are also two coupling signals at (9.52, 108.9 ppm) and (9.52,
22.9 ppm) that ascribe to the correlations of (H , C ) and (H , C13).
6
(Fig. 2a).
1
N
5
N

H. Li et al. / Tetrahedron 70 (2014) 5872e5877
5875
Fig. 2. Partial 400 MHz 1He13C HMBC spectra of 7-a (a) and 7-b (b). Red arrows in inset structures highlight the correlations between H14 and C
correlations between protons observed by He H NOESY spectra.
6
9
or C . Green arrows show the
1
1
Table 2
phenalene-2,3-dicarbonitrile (1), whose skeleton was mistakenly
Spectroscopic data of selected dyes in acetonitrile
1,3
assigned in the previous report. With an electron-deficient aro-
Dyes
lab (nm)
lem (nm)
Dl (nm)
log
3
Fa
matic ring, 1 can smoothly undergo oxidative S
N
Ar reactions to
H
produce a series of novel ICT fluorophores. The regioselectivity
study shows that C is the most electrophilic carbon thus more
Ar reaction, and C is probably the second favor-
able one. In addition, the produced ICT fluorophores, for example, 4,
, and 7-a, display very good spectroscopic properties. Therefore,
4
6
7
7
1
511
533
574
533
549
584
563
595
565
607
73
30
21
32
58
4.31
3.67
4.74
4.17
3.53
0.35
0.82
0.70
0.02
0.38
6
-a
-b
0-a
H
favorable for S
N
9
b
6
a
14
Determined by comparison with rhodamine B in ethanol (
Determined in toluene.
F
¼0.49).
the core structure of 1 can be adopted as a precursor for the de-
velopment of novel ICT fluorescent dyes.
b
depends on the nature of solvent. In acetonitrile, it is almost non-
fluorescent, presumably due to the efficient radiationless de-
4
4
. Experimental
13
activation in the excited states. However, in toluene 10-a shows
a pink color and a quantum yield of 0.38, with emission of orange
fluorescence (Fig. S16).
.1. General information
Chemicals used in the synthesis were purchased from Aldrich
3
. Conclusion
and Acros without further purification. NMR spectra were run in
acetone-d , CDCl , CD Cl or DMSO-d on a Bruker AVANCE-IIIHD
6
3
2
2
6
Based on 2D NMR and X-ray diffraction study, we have pre-
sented detailed characterization on a core structure, 1-oxo-1H-
spectrometer. All chemical shifts are reported as parts per million
(ppm) w.r.t. TMS and referenced by residual solvent resonances. All

5876
H. Li et al. / Tetrahedron 70 (2014) 5872e5877
5
min. The nucleophiles (1.1 equiv for amines, 5.0 equiv for thiols)
were then added in portions and the resultant solution was con-
tinued to stir at room (for amines) or refluxed (for thiols) temper-
ature for several hours (for amines) or days (for thiols). After
removal of solvents by evaporation under reduced pressure, the
crude products were purified by silica gel chromatography with
DCM/MeOH as eluent. Compound 6 was synthesized by the pre-
3
viously reported method.
NMR data for typical compounds:
4
2
0
1
.2.1. Compound 1. HRMS [1] calculated 230.0480, observed
1
30.0484. H NMR (400 MHz, CD
2
Cl
2
):
d
H
(ppm) 8.76 (dd, 1H, J¼7.2,
.8 Hz), 8.46 (dd, 1H, J¼8.0, 0.8 Hz), 8.42 (d, 1H, J¼7.2 Hz), 8.39 (d,
1
3
H, J¼8.4 Hz), 7.97 (dd, 1H, J¼8.0, 7.6 Hz) 7.86 (t, 1H, J¼7.8 Hz);
): (ppm) 178.03 (C ), 138.33 (C ), 138.03
), 133.79 (C ), 132.65 (C13), 132.22 (C ), 129.24 (C
28.29 (C10), 127.94 (C ), 127.31 (C12), 123.01 (C11), 120.50 (C
C
NMR (100 MHz, CDCl
), 134.81 (C
3
d
C
1
7
(C
6
4
9
3
8
2
),
),
1
5
113.48 (CCN), 113.29 (CCN).
3
4.2.2. Compound 2. Compound 2 was prepared in refluxed CH CN
for 24 h and purified by silica gel chromatography with DCM as
eluent. Yield: 60%. HRMS [2] calculated 368.0613, observed
1
3
68.0619. H NMR (300 MHz, CDCl
3
):
d
H
(ppm) 8.87 (d, 1H,
J¼8.3 Hz), 8.82 (d, 1H, J¼7.4 Hz), 8.02 (d, 1H, J¼8.2 Hz), 7.96 (t, 1H,
J¼7.9 Hz), 7.58 (d, 2H, J¼8.6 Hz) 7.11 (d, 2H, J¼8.6 Hz), 7.01 (d, 1H,
1
3
J¼8.1 Hz), 3.92 (s, 3H); C NMR (100 MHz, CDCl
3 C
): d (ppm) 176.5,
1
60.9, 154.3, 136.6, 132.9, 132.6, 131.5, 130.0, 128.2, 127.7, 127.5,
126.1, 122.2, 118.5, 116.5, 115.3, 112.2, 111.8, 54.6.
4.2.3. Compounds 3 and 4. Compounds 3 and 4 were prepared in
refluxed CH
3
OH for 2 days and purified with DCM/MeOH (50:2, v/v,
for 3) and DCM (for 4) as eluent. Yields: 9% for 3 and 48% for 4.
1
HRMS [3] calculated 334.0412, observed 334.0421. H NMR
(
400 MHz, acetone-d
6
):
d
H
(ppm) 8.84 (d, 1H, J¼7.6 Hz), 8.72 (d, 1H,
J¼7.6 Hz), 8.29 (d, 1H, J¼8.2 Hz), 8.09 (t, 1H, J¼7.6 Hz), 7.94 (d, 1H,
Fig. 3. Normalized absorption (a) and emission (b) spectra of selected dyes (25 mM) in
acetonitrile. Inset pictures show dyes 7-a, 4, and 6 in acetonitrile under sunlight (inset
a) or UV light (inset b).
13
J¼8.2 Hz) 3.68 (t, 2H, J¼6.9 Hz), 2.96 (t, 1H, J¼7.1 Hz); C NMR
(100 MHz, acetone-d ): (ppm) 178.3 (C ), 172.4 (C16), 152.1 (C ),
34.7 (C ), 133.9 (C10) 133.8 (C ), 133.3 (C ), 132.2 (C ), 130.9 (C13),
29.6 (C ), 127.9 (C12), 123.7 (C ), 120.5 (C11), 118.1 (CCN), 114.5 (CCN),
114.1 (C ), 33.1 (C ), 27.5 (C15). HRMS [4] calculated 348.0569,
6
d
C
1
6
1
1
4
9
7
3
8
5
HMBC experiments were run with a delay that was optimized to
2
14
1
13
1
long-range He C coupling of 10 Hz. Mass spectra were recorded
using Micromass Q-TOF I mass spectrometer. Fluorescence quan-
tum yields were determined in acetonitrile, toluene or water using
2 2 H
observed 348.0571. H NMR (400 MHz, CD Cl ): d (ppm) 8.79 (d,
1H, J¼8.3 Hz), 8.77 (d, 1H, J¼7.5 Hz), 8.23 (d, 1H, J¼8.1 Hz), 7.93 (t,
1H, J¼7.8 Hz), 7.60 (d, 1H, J¼8.1 Hz), 3.73 (s, 3H), 3.54 (t, 2H,
14
13
rhodamine B in ethanol (
was 1 cm with a cell volume of 3.0 mL. X-ray intensity data were
collected using a Bruker SMART APEX diffractometer (Mo K radi-
F
¼0.49) as the standard. The path length
J¼7.2 Hz), 2.87 (t, 2H, J¼7.2 Hz); C NMR (100 MHz, CD Cl ):
d
C
2
2
(ppm) 177.9,171.6,151.9,134.1,134.0,133.2,130.6,129.1,128.9,127.6,
122.7, 120.0, 117.6, 113.8, 113.4, 52.4, 33.1, 27.4.
a
ꢀ
15
ation, l¼0.71073 A). The raw area detector data frames were re-
duced and corrected for absorption effects with the SAINTþ and
SADABS programs.15 Final unit cell parameters were determined by
least-squares refinement of 7220 reflections from the data set. Di-
rect methods structure solution, difference Fourier calculations and
4.2.4. Compounds 7-a and 7-b. Compounds 7-a and 7-b were
prepared in CH CN at room temperature for 12 h and purified by
3
silica gel chromatography with DCM/MeOH (50:1, v/v, for 7-a) and
DCM (for 7-b) as eluent. Yields: 36% for 7-a and 7% for 7-b. HRMS
2
þ
þ
full-matrix least-squares refinement against F were performed
[7-aþH] and [7-bþH] : calculated 329.1151, observed 329.1151.
with SHELXS/L16 as implemented in OLEX2.
17
1
Compound 7-a: H NMR (400 MHz, DMSO-d ):
6
H
d (ppm) 9.52 (s,
1
H), 8.87 (dd, 1H, J¼7.6, 0.6 Hz), 8.49 (dd, 1H, J¼7.6, 0.6 Hz), 7.87 (d,
4
.2. Synthesis
1H, J¼9.2 Hz), 7.84 (t, 1H, J¼7.8 Hz), 6.97 (d, 1H, J¼9.2 Hz), 3.63 (m,
13
2
H), 3.53 (t, 2H, J¼6.7 Hz), 1.99 (q, 2H, J¼6.8 Hz); C NMR
Synthesis of 1: 2-a was synthesized by the previously reported
(100 MHz, DMSO-d
133.3 (C ), 132.0 (C
123.0 (C13), 116.9 (CCN), 115.2 (CCN), 112.3 (C11), 108.9 (C
6
):
d
C
(ppm) 177.3 (C
1
), 156.7 (C
6
), 139.6 (C
), 126.6 (C
), 105.2 (C
4
3
2
),
),
),
1
method. Compound 2-a (2.17 mmol, 500 mg) was suspended in
9
7
), 130.4 (C10), 128.8 (C12), 127.9 (C
8
anhydrous CH
3
CN (40 mL). Under stirring, the mixture was heated
5
1
to refluxed temperature and then added the base. After complete
consumption of 2-a monitored by TLC, the solvent was removed to
afford crude product 1, which was purified by column chroma-
tography on silica gel eluted with DCM/hexane (1:1 to 5:1, v/v) to
give 1 as a yellow solid (see Table 1 for yields).
49.2 (C16), 42.0 (C14), 28.2 (C15). Compound 7-b: H NMR (400 MHz,
CD
2
Cl
2
):
d
H
(ppm) 12.70 (s, 1H), 8.33 (dd, 1H, J¼7.8, 1.0 Hz), 8.16 (dd,
1H, J¼7.6, 1.0 Hz), 8.15 (d, 1H, J¼9.4 Hz), 7.66 (t, 1H, J¼7.7 Hz), 7.35
(d, 1H, J¼9.4 Hz), 3.79 (quartet, 2H, J¼6.8 Hz), 3.58 (t, 2H, J¼6.4 Hz),
1
3
2.13 (quintet, 2H, J¼6.7, 6.5 Hz); C NMR (100 MHz, CD
2
Cl
), 129.0
), 115.7
2
),
d
C
General protocol for the synthesis of 2e13: 1 was suspended in
(ppm): 176.3 (C
1
), 158.3 (C
9
), 141.2 (C
7
), 136.7 (C
6 4
), 132.3 (C
anhydrous CH
3
CN or MeOH and stirred at room temperature for
(C12), 126.2 (C ), 125.2 (C13), 124.1 (C
3
5
), 120.9 (C11), 118.1 (C
2

H. Li et al. / Tetrahedron 70 (2014) 5872e5877
5877
(
(
C
C
8
), 114.8 (CCN), 114.2 (CCN), 109.8 (C10), 49.1 (C16), 41.0 (C14), 28.9
15).
References and notes
1. Xiao, Y.; Liu, F.; Qian, X.; Cui, J. Chem. Commun. 2005, 239e241.
2
3
. Makosza, M. Chem. Soc. Rev. 2010, 39, 2855e2868.
. Liu, F.; Xiao, Y.; Qian, X.; Zhang, Z.; Cui, J.; Cui, D.; Zhang, R. Tetrahedron 2005,
3
4.2.5. Compound 10-a. Compound 10-a was prepared in CH CN at
room temperature for 2 h and purified by silica gel chromatography
61, 11264e11269.
4
5
6
. Zhang, M.; Yu, M.; Li, F.; Zhu, M.; Li, M.; Gao, Y.; Li, L.; Liu, Z.; Zhang, J.; Zhang,
D.; Yi, T.; Huang, C. J. Am. Chem. Soc. 2007, 129, 10322e10323.
. Liu, Y.; Xu, Y.; Qian, X.; Xiao, Y.; Liu, J.; Shen, L.; Li, J.; Zhang, Y. Bioorg. Med.
Chem. Lett. 2006, 16, 1562e1566.
. Zhang, Z.; Yang, Y.; Zhang, D.; Wang, Y.; Qian, X.; Liu, F. Bioorg. Med. Chem. 2006,
14, 6962e6970.
. Zhang, Z.; Jin, L.; Qian, X.; Wei, M.; Wang, Y.; Wang, J.; Yang, Y.; Xu, Q.; Xu, Y.;
Liu, F. ChemBioChem 2007, 8, 113e121.
8. Li, H.; Pellechia, P. J.; Xiao, Y.; Smith, M. D.; Wang, G.; Qian, X.; Wang, Q. Chem.
Commun. http://www.rsc.org/suppdata/cc/b4/b413537g/addition.htm
with DCM/MeOH (100:1, v/v) as eluent. Yield: 42%. HRMS [10-a]
1
calculated 314.1293, observed 314.1296. H NMR(400 MHz, CDCl
3
):
d
H
(
1
ppm) 8.74 (dd, 1H, J¼7.6, 0.9 Hz), 8.48 (dd, 1H, J¼7.6, 0.9 Hz), 8.13 (d,
H, J¼8.6 Hz), 7.84 (t, 1H, J¼8.4 Hz), 7.13 (d, 1H, J¼8.4 Hz), 3.67 (t, 4H,
13
J¼5.5 Hz), 1.96 (m, 4H), 1.87 (m, 2H); C NMR (100 MHz, CDCl
3
):
d
C
7
(
(
(
ppm) 177.8 (C
C
C
1
), 160.9 (C
10), 129.3 (C12), 126.8 (C
CN),113.5 (C ),112.0 (CCN),108.6 (C
6
), 136.4 (C
), 125.5 (C13), 115.3 (C11), 114.6 (C
4
), 134.0 (C
7
), 133.4 (C
9
), 129.7
8
5
), 114.3
3
2
), 54.9 (C14), 26.1 (C15), 24.1 (C16).
9
. Elinson, M. N.; Ilovaisky, A. I.; Merkulova, V. M.; Belyakov, P. A.; Barba, F.; Ba-
tanero, B. Tetrahedron 2012, 68, 5833e5837.
Acknowledgements
10. Elinson, M. N.; Ilovaisky, A. I.; Merkulova, V. M.; Barba, F.; Batanero, B. Tetra-
hedron 2013, 69, 7125e7130.
1
1. See Supplementary data for details. Deposition number at Cambridge Crystal-
lographic Data Centre: CCDC 958501 (for 2) and CCDC 965504 for 4.
We gratefully acknowledge the financial support of this work by
US National Science Foundation MRI-1040227 to G.W. and Q.W.,
and the support for Q.W. from the Camille Dreyfus Teacher Scholar
Award and University of South Carolina.
12. Ma u€ kosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104, 2631e2666.
1
3. Dmitruk, S. L.; Druzhinin, S. I.; Minakova, R. A.; Bedrik, A. I.; Uzhinov, B. M. Russ.
Chem. Bull. 1997, 46, 2027e2031.
4. Casey, K. G.; Quitevis, E. L. J. Phys. Chem. 1988, 92, 6590e6594.
1
1
5. SMART Version 5.630, SAINTþ Version 6.45 and SADABS Version 2.10; Bruker
Analytical X-ray Systems: Madison, WI, USA, 2003.
Supplementary data
16. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112e122.
1
7. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. J.
Appl. Crystallogr. 2009, 42, 339e341.
1He13C HMBC, 1He H COSY, 1He13C HSQC, 1He H NOESY
spectra and single crystal data of compounds. Supplementary data
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2014.06.032.
1
1