Regioselective Synthesis of Angular Isocoumarinselenazoles: A Benzoselenazole-directed, Site-specific, Ruthenium-catalyzed C(sp2)-H Activation

Article abstract of DOI:10.1002/adsc.201701256

The synthesis of new, angular isocoumarinselenazoles is described, which involves the construction of 2-amino benzoselenazoles and their regioselective C2N-alkylation and alkyne insertion. An expeditious and metal-free synthesis of 2-aminobenzoselenazoles

Full text of DOI:10.1002/adsc.201701256

Title: Regioselective Synthesis of Angular Isocoumarinoselenazoles:
A Benzoselenazole Directed Site Specific Ruthenium-catalyzed
C(sp2)-H Functionalization
Authors: SANDIP DHOLE , Jen-Yu Liao, Sunil Kumar Dhull , Deepak
Salunke , and Chung-Ming Sun
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701256
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regioselective Synthesis of Angular Isocoumarinselenazoles: A
Benzoselenazole-directed, Site-specific, Ruthenium-catalyzed
C(sp2)-H Activation
Sandip Dhole,a Jen-Yu Liao,a Sunil Kumar,a Deepak B. Salunke,c and Chung-Ming
Sun*a,b
a
Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao Tung University, Hsinchu 300-10, TAIWAN
b
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, 100, Shih-Chuan 1st Road,
Kaohsiung 807-08, TAIWAN
Department of Chemistry & Centre for Advanced Studies in Chemistry, Panjab University, Chandigarh, INDIA
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
The
synthesis
of
new,
angular of the α-pyrone ring on the benzo[1,3-d]selenazole skeleton
isocoumarinselenazoles is described, which involves the was achieved via a ruthenium (II)-catalyzed oxidative
construction of 2-amino benzoselenazoles and their annulation. It is clear that the selenazole nitrogen plays an
regioselective C2 N-alkylation and alkyne insertion. An important role in the observed selectivity.
expeditious
and
metal-free
synthesis
of
2-
aminobenzoselenazoles by the reaction of methyl 3-amino-4-
fluorobenzoate and isoselenocyanates was achieved. Further
N-alkylation of the 2-aminobenzoselenazoles resulted the
formation of two regioisomers with different reactivities
towards the alkyne insertion. The regioselective construction
Keywords: selenourea, benzoselenazoles, C-H activation,
isocoumarin, chelate-assisted, acid-alkyne insertion,
catalyzed ruthenium
For instance, isocoumarin/furan-fused coriandrin
possesses a unique, UVA-dependent antiviral activity
against enveloped viruses, including HIV,[6-8] whereas
a coumarin/oxazine-fused heterocycle has excellent
anti-inflammatory properties[9] (Figure 1). Selenazole
and coumarin are biologically significant, and our
research interest is in the development of efficient
methodologies for complex heterocycles, and the
synthesis of hitherto unknown trisubstituted angular
isocoumarinselenazole, 9, is proposed from
commercially available 4-fluoro-3-nitrobenzoic acid,
1.[10]
Introduction
Functionalized 1,3-selenazole, benzoselenazole and
selenourea moieties are present in numerous
pharmacologically active substances.[1] Potent antiviral
selenazofurin,[2] anti-inflammatory and antioxidant
ebselen,[3] the histamine H2-agonist amselamine[4] and
the SOC channel regulator 2-acylamido selenazole[5]
are prominent examples of such substances, wherein
selenium-containing heterocycles are fused or linked
with other scaffolds (Figure 1). Several fused
heterocycles with diverse substitution patterns are
known to provide important leads for drug discovery.
Figure 2. A retrosynthetic approach for trisubstituted
isocoumarinselenazole 9.
The proposed synthetic route involved three
important steps, including (i) the construction of 2-
amino benzoselenazoles, (ii) regioselective C-2 N-
alkylation and (iii) site-selective acid-alkyne insertion.
A systematic literature survey revealed only a few
Figure 1. Biologically active selenazole, coumarin, and
isocoumarin derivatives.
1
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
articles to describe the synthesis of selenazoles.[11a-h]
The first attempt towards the addition/cyclization
Most reports exhibit the synthesis of 2-amino reaction of 2a with isoselenocyanate in refluxing
benzoselenazoles from ortho-halo substituted isopropanol delivered selenourea 3a as the only
benzenes mainly through copper catalysis (Scheme 1), product.[14] A trace amount (10-15 %) of the desired
and isoselenocyanate is used as a dominant synthetic product 5a was obtained with the bases pyridine and
precursor.
triethylamine. When the reaction was heated to 140 °C
in DMSO with triethylamine, the yield was improved
to 60 %. Next, various solvents were tested (see SI, S3,
Table 1, entries 6-10), and DMF proved to be a better
solvent with a 73 % yield. The optimized reaction
conditions (DMF, 140 °C, pyridine, 12 h) were used to
synthesize a diverse collection of 2-aminobenzo[1,3-
d]selenazole-5-carboxylates, 5, in moderate to good
yields (Table 1).
Scheme 1. Literature for the synthesis of 2-
aminobenzoselenazole.
Table 1. Metal-free synthesis of 2-aminobenzoselenazole
5.[a]
Kambe reported the synthesis of 1,3-
benzoselenazoles by
a
copper iodide-catalyzed
reaction of ortho-halo isocyanobenzene (Route 1),[11a]
whereas Zhou described a one-pot synthesis of 1,3-
benzoselenazoles from aryl isoselenocyanates by a
carbon-supported copper catalyst (Route 2).[11b]
Isoselenocyanates were used to construct 2-amino-1,3-
benzoselenazoles by Sashida via a Cu-catalyzed
reaction with 2-iodoaniline (Route 3).[11c] While these
literature protocols are generally efficient and reliable,
most require metal catalysts and a long reaction time.
Consequently, the development of a metal-free
synthetic method for the synthesis of 2-
aminobenzoselenazoles is a significant challenge.
[a]
General reaction conditions: 2 (1.5 g, 8.8 mmol), R1-
N=C=Se (10.6 mmol), pyridine (1.4 g, 18 mmol), DMF (40
mL) at 140 °C for 4-10 h. [b] Isolated yields.
Results and Discussion
A plausible mechanism for the formation of
benzoselenazole 5 is depicted in Scheme 3. The first
step involved the formation of selenourea 3 through the
addition of 2 with isoselenocyanate. Then, selenourea
3 underwent intramolecular C-Se bond formation
through an addition/elimination reaction. In this step,
the ipso displacement of fluorine by a selenium atom
is facilitated by the appropriately situated ester
functionality (Scheme 3).
The proposed strategy began with the synthesis of a
key substrate, methyl 3-amino-4-fluorobenzoate, 2a,
from the esterification of 4-fluoro-3-nitrobenzoic acid,
1, with sulfuric acid in methanol followed by reduction
with zinc and ammonium formate.[12] Isoselenocyanate
was prepared by the dehydration of alkyl and aryl
formamides with triphosgene and selenium.[13] The
reaction of 2 with (3-isoselenocyanatopropyl)benzene
is expected to furnish three possible products (Scheme
2).
Scheme 2. An addition/cyclization reaction for the synthesis
of 2-aminobenzoselenazole.
Scheme 3. A proposed mechanism for the formation of 2-
aminobenzoselenazole 5.
2
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
To delineate the role of the carbomethoxy group in shifted downfield at 5.4 ppm. In the 1D NOE
the selenazole formation, we performed a reaction with experiment, the irradiation of the benzyl –CH2 proton
2-fluoroaniline 2b, 2-fluoro-5-methylaniline 2c and 5- of 6c (see SI, S98) did not show any enhancement in
chloro-2-fluoroaniline
2d
with
(3- the aromatic C4-H proton, whereas 7c (see SI, S104-
isoselenocyanatopropyl)benzene under optimized S108) showed an enhancement of 5.4 % in the aromatic
conditions (Scheme 4). We found the reactions stopped C4-H proton signal intensity (Figure 4).
at selenourea 3b-3d formation even after prolonged
heating.
Figure 3. NOE correlations in 6c and 7c.
Table 2. Substrate scope for the N-alkylation of 2-
aminobenzoselenazole 5.[a]
Scheme 4. Control experiment to investigate the role of the
ester group.
The control of the regioselectivity during the direct
N-alkylation of tautomerizable heteroarenes is a
challenge because of the competitive reaction
pathways.[15-17] The selective N-alkylation of 2-
aminobenzoselenazole is not reported in the literature,
and it has two available sites for alkylation, either the
C2 amino position (exo substitution) or the N3 position
(endo substitution).
A classical reaction of 5a with benzyl bromide
(Scheme 5) was studied in the presence of various
t
bases (Cs2CO3, BuOK, Et3N, pyridine, KOH, and
K2CO3) and several solvents (DCM, acetonitrile, DMF,
p-xylene and 1,4-dioxane).
[a]
General reaction conditions: 5 (1.33 mmol), R2-Br (1.46
t
mmol), BuOK (1.60 mmol), CH3CN (20 mL) at 25 °C for
5-60 min. [b] Proportion of 7 was obtained on the basis of the
1H NMR of crude mixture.
The C2 N-alkylated products, 6, were the major
products in all the reactions, except for the cyclohexyl
analogs (Table 2, entries 5-7) where alkylation
occurred at the endocyclic nitrogen to yield 7 as the
major product.[18] This is possibly due to the non-planar
conformation of the cyclohexyl ring, which created
steric hindrance for the C2 N-alkylation of
benzoselenazole. The structures of both the
regioisomeric products were confirmed by single-
crystal X-ray analysis (Figure 4).
Scheme
aminobenzoselenazole.
5.
Study
of
N-alkylation
of
2-
Two alkylated regioisomers, 6c and 7c, were
obtained in various ratios depending on the nature of
the solvents and bases (Scheme 5).[14] The exo-
regioisomer 6c was obtained as a major product with
t
excellent yield at room temperature using BuOK in
acetonitrile within 5 minutes. Consequently, a variety
of 2-amino-1,3-benzoselenazoles with alkyl, aryl, and
cycloalkyl substituents at the C2 position were reacted
with various alkyl, alkenyl and aralkyl bromides
(Table 2). The benzylic –CH2 protons in 6c appeared
as a singlet at 4.9 ppm, and in 7c, the proton signal was
3
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
Table 4. Substrate scope and regioisomeric ratios for the
Figure 4. X-ray crystal structures of 6k and 7e.
Ru(II)-catalyzed alkyne annulation.[a]
In light of a successful N-alkylation of 2-amino
benzoselenazoles, we next proposed the construction
of a α-pyrone ring on the benzo[1,3-d]selenazole
skeleton via alkyne insertion into aryl C−H (C4 and/or
C6) and carboxylic O−H bonds.[19] The esters 6 and 7
were first hydrolyzed to their corresponding acids to
perform the heteroatom-directed transition metal
catalyzed C-H bond activation.[21] The reaction of 2-
aminobenzoselenazole-5-carboxylic acid 8a with 1,2-
diphenylethyne in the presence of [Cp*RhCl2]2 and
Cu(OAc)2.H2O in acetonitrile at 80 °C for 48 hours
resulted in the formation of 6H-isochromeno[5,6-
d][1,3]selenazol-6-one 9a and 5H-isochromeno[7,6-
d][1,3]selenazol-5-one 10a in a 3:2 ratio (Table 3). The
selectivity and reaction rate were drastically improved
with the use of an equal proportion of tert-butanol as a
co-solvent in this reaction (Table 3, entry 2). A
ruthenium complex was also applied for this
annulation reaction (Table 3, entry 3). We found that
both the Rh(III) and Ru(II) catalysts were effective for
this annulation. Without deeply exploring the
optimization, we used (Table 3, entry 3) the less
expensive ruthenium (II) complex for further substrate
scope investigations.
[a]
General reaction conditions: 8 (0.24 mmol), [Ru(p-
Table 3. Optimization study for the synthesis of 6H-
isochromeno[5,6-d][1,3]selenazol-6-one 9a.[a]
cymene)Cl2]2 (0.024 mmol), alkyne (0.28 mmol), NaOAc
(0.33 mmol), MeOH (15 mL), 65 °C for 4-10 h. [b] Isolated
yields. [c] NR: No Reaction, [d] A minor amount of 8-alkyl-9-
phenyl isomers was formed (see the text).
which coordinated with the Ru catalyst, resulting in
C4-H bond activation and the formation of angular
isocoumarinselenazoles. Diaryl alkynes bearing
electron-withdrawing groups as well as donating
groups reacted smoothly and afforded major angular
regioisomers (Table 4, entries 13, 14) in good yields.
No reaction was observed with electron-deficient
dimethyl acetylenedicarboxylate and phenyl acetylene,
even with longer reaction times at high temperatures
(entries 4 and 15).
We also examined the regioselectivity with
unsymmetrical internal alkynes (Table 4, entries 2, 7,
8), where the major angular isomers 9b, 9g and 9h
constitute one in which the aliphatic substituent was
installed away from the oxygen heteroatom along with
a minor amount of the other angular regioisomers, 9g'
and 9h' (8 and 5 % for entries 7 and 8, respectively),
where the aliphatic group is attached at the C8 position
adjacent to the lactone oxygen. It is possible to reveal
the steric repulsion between the phenyl group and the
benzoselenazole ring after cyclometalation, and the
selective migratory insertion occurs at the less
hindered position of the unsymmetrical alkyne to
generate a more stable seven-membered ruthenacycle
complex that yields angular isomer regioselectively
after a reductive elimination. We also observed the
minor linear isomers 10b, 10g and 10h (14, 12 and
10 % for entries 2, 7 and 8, respectively), but we did
Product
Entry
1[c]
Catalyst(mol%)
[RhCl2Cp*]2(1)
Solvent
T°C
80
Time
Ratio[b]
9a:10a
CH3CN
48
8
60:40
80:20
85:15
2[c]
[RhCl2Cp*]2(1)
CH3CN:tBuOH
MeOH
80
3[d],[e]
[RuCl2(p-cymene)]2(10)
65
4
[a]
Reaction conditions: 8a (100 mg, 0.24 mmol),
diphenylacetylene (51 mg, 0.28 mmol), and solvent (20 mL).
[b]
[c]
Based on the NMR spectra of the crude mixture.
Cu(OAc)2.H2O (15 mol%) was used as an oxidant. [d] O2 was
used as an oxidant. [e] NaOAc was used as an additive.
A further substrate scope investigation for two
regioisomers (9:10) in this reaction is included in Table
4. As shown, several substituted alkynes, including
aryl as well as alkyl groups, yielded good products.
The selenazole ring nitrogen controlled the
regioselectivity of the products (9:10) formed using
symmetrical alkynes. The annulation with substituted
acetylenes resulted in the formation of the major
angular isomer 9 (Table 4, entries 1, 2, 5, 7-12) or an
exclusive product (entries 3 and 6). This is possibly due
to the directing effect of the selenazole ring nitrogen,
4
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
not observe other linear isomers 10b', 10g', and 10h'. 12f' and 12g'. The regiochemistry of the products was
The observed regioselectivity in the angular isomer determined by a 1D NOE experiment (see SI, S387-
was ascertained by the single-crystal X-ray analysis of S388, S394-S396, and S403-S404).
compound 9g (see SI, S470), whereas the linear isomer
The single-crystal X-ray diffraction analysis was
10g was confirmed by the 1D NOE experiment (see SI, used to confirm the molecular structures of both the
S283-S285).
angular as well as linear isocoumarins (Figure 5). The
tricyclic planar ring skeleton in both 9a and 12c was
clearly observed in the ORTEP diagrams. The overall
non-planar structure in 9a occurs because the two
phenyl rings are situated ortho to each other at the C8
and C9 positions of the fused heterocyclic skeleton,
forcing both phenyl rings out of the plane and resulting
in the steric inhibition of the resonances. However, in
12c, one of the phenyl rings at C7 could remain
coplanar to the core scaffold, maintaining the possible
resonance. The other phenyl ring at C8 was removed
from the plane, minimizing the Van der Walls
interactions.
Table 5. Substrate scope for the regiospecific alkyne
insertion
on
2-imino-2,3-dihydrobenzoselenazole-5-
carboxylic acid 11.[a]
Figure 5. X-ray crystal structures of angular 9a and linear
12c isomers.
To understand the mechanism and role of the –N3
nitrogen in the selectivity, control experiments were
performed as shown in Scheme 6. An intermolecular
competition experiment was conducted between the
equimolar regioisomers 8e and 11e with
diphenylacetylene. This reaction yielded 9e, 10e, and
12e in a 10:1:3 ratio, respectively, as established by the
proton NMR analysis, indicating that the formation of
the major angular isomer 9e predominates over the
linear isomers 10e and 12e due to the possible
coordination of the selenazole ring nitrogen with metal.
[a] General reaction condition: 11 (0.24 mmol), alkyne (0.28
mmol), [Ru(p-cymene)Cl2]2 (0.024 mmol), NaOAc (0.33
mmol), MeOH (15 mL), 65 °C for 4-10 h.; [b] Isolated yields.
We next studied the reactivity of 2-imino-2,3-
dihydrobenzo[1,3-d]selenazole-5-carboxylates
11
with alkynes (Table 5). Interestingly, substrate 11
resulted in the exclusive formation of linear
isocoumarins 12 with carboxylate assistance
[19, 20]
because of the presence of R2 substituent at N3, which
blocked the possible coordination of the ring nitrogen
with the Ru metal. This observation clearly evidenced
the probable role of the selenazole ring nitrogen in the
catalytic cycle. To build a diverse compound collection,
a few methyl esters 7 were hydrolyzed to their
corresponding acids and were treated with aliphatic,
and aromatic compounds with electron-rich and
deficient alkynes to furnish 2,3-dihydro-5H-
isochromeno[7,6-d][1,3]selenazol-5-ones 12 as the
only products (Table 5). In the proton NMR spectra of
the linear isomer 12, two characteristic singlets
appeared at 7.4 and 7.7 ppm, corresponding to the two
protons at C4 and C9, respectively. The unsymmetrical
alkynes gave the desired products 12f and 12g in
moderate yield along with their minor regioisomers
5
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
Conclusion
Scheme 6.
competition between 8e and 11e.
A cross experiment for intermolecular
In conclusion, novel angular and linear
isocoumarinselenazoles were synthesized from
commercially available 4-fluoro-3-nitrobenzoic acid.
The current design involved an efficient, metal-free
synthesis of the 2-aminobenzoselenazoles followed by
N-alkylation of the 2-aminobenzoselenazoles to
deliver two regioisomers. Ruthenium-catalyzed α-
pyrone ring construction was achieved on both
benzo[1,3-d]selenazole skeletons via alkyne insertion
into aryl C−H (C4 and/or C6) and carboxylic O−H
bonds. Benzoselenazole-directed significant site-
selectivity in Ru-catalyzed C(sp2)-H bond activation
for the synthesis of the major angular
isocoumarinselenazoles was observed. The role of the
selenazole N3 nitrogen in the synthesis of the
isochromenoselenazol-5-ones was evidenced by an
intermolecular competition experiment to support the
predominant formation of the angular isomer over the
linear isomer. To the best of our knowledge, this is the
first report on the alkyne annulation of benzo[1,3-
d]selenazole-5-carboxylates.
On the basis of the experimental results and previous
reports on chelate-assisted metal-catalyzed C-H bond
activation [21], we proposed a plausible mechanism for
the formation of angular isocoumarinselenazole 9
(Scheme 7). The catalytic cycle is likely initiated by
the dissociation of the [Ru(p-cymene)2Cl2]2 dimer into
the coordinately unsaturated monomer followed by the
exchange of chloro ligands with acetate to form species
I. Complex RuCl(OAc)(p-cymene) undergoes
coordination with the sp2-hybridized selenazole-N and
is followed by activation of the C4-H bond by C-H
deprotonation with acetate to yield the highly strained
four-membered ruthenacycle II, which further
rearranges to the five-membered ruthenacycle III.[19]
Alkyne coordination (step C) followed by migratory
insertion (step D) may generate the seven-membered
ruthenacycle V. The intermediate V further performs a
reductive elimination to yield the Ru(0) complex
VI[19b] (step E), and oxidation with molecular oxygen
in the presence of the initially formed acetic acid
regenerates complex I and releases isocoumarin 9 (step
F) (Scheme 7). The mechanism for the exclusive Experimental Section
formation of the linear isocoumarinselenazole 12 is
General Procedure for the Synthesis of 2-
expected to proceed by coordination of the carboxylate
to the ruthenium (II) site, which is based on the
previous carboxylic-assisted C-H activation in the
literature reports [19,20], as presented in the supporting
information (see SI, S7).
Amino[1,3]benzoselenazoles (5)
To the stirred solution of methyl 3-amino-4-fluorobenzoate
2a (1.5 g, 8.8 mmol) in dry DMF (40 mL), freshly prepared
(3-isoselenocyanatopropyl)benzene (2.4 g, 10.6 mmol) and
pyridine (1.4 g, 18 mmol) were added under N2 atmosphere
and the reaction mixture was refluxed for 4h. Upon
completion, reaction mixture was diluted with H2O (50 mL)
and extracted with ethyl acetate (3 x 40 mL). Organic layer
was dried over MgSO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography to
methyl 2-((3-phenylpropyl)amino)benzo[1,3-d]selenazole-
5-carboxylate
5a: (2.6 g, 80%) as a white solid; m.p. 135-137 °C; 1H NMR
(400 MHz, C3D6O) δ 8.01 (d, J = 1.7 Hz, 1H), 7.82 (d, J =
8.1 Hz, 1H), 7.60 (dd, J = 8.2, 1.7 Hz, 1H), 7.34 – 7.12 (m,
5H), 3.88 (s, 3H), 3.54 (t, J = 7.0 Hz, 3H), 2.76 (t, J = 8.7
Hz, 2H), 2.12 – 1.98 (m, 2H) ppm; 13C NMR (101 MHz,
CDCl3) δ 168.8, 167.4, 154.1, 140.8, 138.8, 128.5, 128.4,
128.3, 126.1, 123.9, 122.3, 120.6, 52.1, 46.3, 33.0, 30.9
ppm; FT-IR (neat): 3361 (NH), 2947, 1717 (C=O)1554cm-1;
MS (ESI) m/z: 375 (MH+); HRMS (ESI, m/z) Calcd.
C18H18N2O2Se [M+H]+: 375.0607; Found 375.0610 (M+H)+.
Similarly, other 2-aminobenzoselenazoles (5b-f) were
synthesized by the same procedure.
General Procedure for the Synthesis of Regioisomers
Methyl 2-((alkyl/aryl)amino)benzo[1,3-d]selenazole-5-
carboxylate (6) and Methyl 3-alkyl/aryl-2-imino-2,3-
dihydrobenzo[1,3-d]selenazole-5-carboxylate (7)
To a stirred solution of 5a (0.50 g, 1.33 mmol) in dry CH3CN
(20 mL), benzyl bromide(0.25 g, 1.46 mmol) and t-BuOK
(0.18 g, 1.60 mmol) were added under N2 atmosphere and
the reaction mixture was stirred at room temperature for 10
min. Upon completion, reaction mixture was concentrated in
vacuo. The crude product was purified by flash column
chromatography
to
afford
methyl
2-(benzyl(3-
Scheme 7. A proposed mechanism for the formation of
angular isocoumarinselenazole 9.
phenylpropyl)amino)benzo[1,3-d]selenazole-5-carboxylate
6c (0.55 g, 88%) along with other isomer methyl 3-benzyl-
6
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
2-((3-phenylpropyl)imino)-2,3-dihydrobenzo[1,3-
d]selenazole-5-carboxylate 7c (49 mg, 8%).
reaction of 11 with alkynes which afforded 12 in 91-95%
yields.
6c: White solid; mp 95-96 °C; 1H NMR (400 MHz, C3D6O)
δ 8.20 (d, J = 1.7 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.67 (dd,
J = 8.2, 1.7 Hz, 1H), 7.46 – 7.07 (m, 10H), 4.79 (s, 2H), 3.87
(s, 3H), 3.50 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.7 Hz, 2H),
2.00 (quint, J = 7.5 Hz, 2H); 13C NMR (101 MHz, C3D6O) δ
169.3, 166.8, 155.3, 141.3, 139.9, 137.0, 128.7, 128.4, 128.4,
128.4, 127.7, 127.6, 125.9, 124.1, 121.6, 120.4, 54.9, 52.1,
51.5, 32.7, 28.7; FT-IR (neat): 3062, 1718 (C=O), 1645 cm-
1; MS (ESI) m/z: 465 (MH+); HRMS (ESI, m/z) calc.
C25H24N2O2Se [M+H]+: 465.1077; Found 465.1079 (M+H)+.
Acknowledgements
The authors thank the Ministry of Science and Technology of
Taiwan for the financial assistance and Mr. Danny tayung Ni to
prepare some compounds.
References
7c: White solid; mp 101-103 °C;1H NMR (400 MHz,
C3D6O) δ 7.71 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.0, 1.6 Hz,
1H), 7.51 (d, J = 1.6 Hz, 1H), 7.42 – 7.12 (m, 10H), 5.38 (s,
2H), 3.82 (s, 3H), 3.20 (t, J = 6.6 Hz, 2H), 2.72 (dd, J = 8.5,
6.6 Hz, 2H), 2.02 – 1.91 (m, 2H); 13C NMR (101 MHz,
C3D6O) δ 166.0, 152.5, 142.2, 142.1, 136.7, 128.8, 128.5,
128.4, 128.2, 127.23, 127.0, 126.9, 125.8, 125.6, 121.9,
110.4, 56.9, 51.5, 47.4, 33.2, 32.6; FT-IR (neat): 3062, 1718
(C=O), 1590 cm-1; MS (ESI) m/z: 465 (MH+); HRMS (ESI,
m/z) Calcd. C25H24N2O2Se [M+H]+: 465.1077; Found
465.1079 (M+H)+.
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d][1,3]selenazol-5-one (9) and 8,9-Disubstituted-2-
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acid 8a (100 mg, 0.24 mmol), diphenylacetylene (51 mg,
0.28 mmol), [RuCl2(p-cymene)]2(15 mg, 0.024mmol) and
NaOAc (27 mg, 0.33 mmol) were dissolved in dry MeOH
(15 ml) under N2 atmosphere and the reaction mixture was
heated to reflux for 4h under O2 atmosphere. Upon
completion, reaction mixture was concentrated in vacuo.
The residual mixture was purified and separated by column
chromatography on silica gel to yield the two regioisomers
9a (111 mg, 78%) and 10a (23 mg, 16%).
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9a: White solid; mp 76-78 °C; 1H NMR (400 MHz, CD3OD)
δ 7.95 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.27 –
7.10 (m, 15H), 4.79 (s, 1H), 4.67 (s, 1H), 3.54 (s, 2H), 3.08
– 2.93 (m, 2H), 2.49 (t, J = 7.4 Hz, 2H), 1.75-1.70 (m, 2H),
1.50 (s, 3H); 13C NMR (101 MHz, CD3OD) δ 167.8, 163.4,
151.0, 149.5, 143.8, 141.1, 137.8, 133.8, 131.5, 129.2, 128.7,
128.4, 128.1, 128.0, 127.9, 127.3, 127.1, 126.3, 125.5, 124.1,
120.5, 118.1, 117.6, 112.2, 32.2, 28.0, 18.4; FT-IR (neat)
3025, 2927, 1721 (C=O) cm-1;MS (ESI) m/z: 591 (MH+);
HRMS (ESI, m/z) Calcd. C35H30N2O2Se [M+H]+: 591.1548;
Found 591.1558 (M+H)+.
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10a: White solid; mp 81-83 °C; (Hexane/EtOAc = 97:03);
1H NMR (400 MHz, C3D6O) δ 8.26 (s, 1H), 7.57 (s, 1H),
7.49 – 7.42 (m, 3H), 7.38 – 7.32 (m, 4H), 7.32 – 7.16 (m,
8H), 4.92 (d, J = 10.4 Hz, 2H), 4.21 (s, 2H), 3.61 (s, 2H),
2.73 (t, J = 7.7 Hz, 2H), 2.11 (t, J = 7.7 Hz, 2H), 1.75 (s,
3H); 13C NMR (101 MHz, C3D6O) δ 167.7, 161.7, 151.3,
149.6, 143.3, 138.1, 134.3, 131.7, 129.5, 128.5, 128.3, 128.2,
128.2, 127.5, 127.4, 126.4, 125.8, 124.3, 120.8, 118.9, 117.1,
112.4, 55.9, 50.5, 32.4, 28.3, 19.0; FT-IR (neat) 3025, 2927,
1721 (C=O) cm-1; MS (ESI) m/z: 591 (MH+); HRMS (ESI,
m/z) Calcd. C35H30N2O2Se [M+H]+: 591.1548; Found
591.1561 (M+H)+.
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7
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10.1002/adsc.201701256
Advanced Synthesis & Catalysis
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8
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Advanced Synthesis & Catalysis
FULL PAPER
Regioselective
Synthesis
of
Angular
Isocoumarinoselenazoles:
A
Benzoselenazole
Directed Site Specific Ruthenium-catalyzed C(sp2)-
H Activation
Adv. Synth. Catal. Year, Volume, Page – Page
Sandip Dhole, Jen- Yu Liao, Sunil Kumar, Deepak
B. Salunke and Chung-Ming Sun *
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