Copper-Catalyzed Three-Component Coupling Reaction of Azoles, Se Powder, and Aryl Iodides

Article abstract of DOI:10.1021/acs.joc.6b02388

A copper-catalyzed three-component coupling reaction of azoles, Se powder, and aryl iodide is described for the first time. This transformation provides a straightforward and facile pathway to synthesis 2-arylselanyl-azoles via a copper-catalyzed double C-Se bonds formation process. This reaction is attractive and practical since the cheap copper catalyst is employed and it does not require ligands, proceeds in generally good yields, and has a broad range of functional groups tolerance.

Full text of DOI:10.1021/acs.joc.6b02388

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Article
Copper-Catalyzed Three Component Coupling
Reaction of Azoles, Se Powder, and Aryl Iodides
Chao Gao, Ge Wu, Lin Min, Miaochang Liu, Wenxia Gao,
Jinchang Ding, Jiuxi Chen, Xiaobo Huang, and Huayue Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02388 • Publication Date (Web): 30 Nov 2016
Downloaded from http://pubs.acs.org on December 1, 2016
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Copper-Catalyzed Three Component Coupling Reaction of Azoles, Se Powder,
and Aryl Iodides
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Chao Gao,† Ge Wu,*,‡ Lin Min,† Miaochang Liu,† Wenxia Gao,† Jinchang Ding,† Jiuxi Chen,†
Xiaobo Huang, † and Huayue Wu*, †
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†College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035,
People’s Republic of China
‡School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, People’s Republic of China
Abstract: A copperꢀcatalyzed threeꢀcomponent coupling reaction of azoles, Se powder and aryl
iodide is described for the first time. This transformation provides a straightforward and facile
pathway to synthesis 2ꢀarylselenation of azoles via copperꢀcatalyzed double CꢀSe bonds formation
process. This reaction is attractive and practical since the cheap copper catalyst is employed and
don’t require ligands proceed in generally good yields and a broad range of functional groups
tolerance.
Introduction
Seleniumꢀcontaining compounds have aroused the interest of organic chemists over the last few
years, due to organoselenium compounds are widely founded in pharmaceutical, agrochemical
molecules, fluorescent molecular probes as well as in promising biomaterials.1 Particularly
relevance is the emergence of diary selenides, versatile skeleton are found in drug candidates, for
example, human cancer cell growth inhibitor,2a antitumor agent,2a antioxidant,2b RAR agonist,2c
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even important application to synthesis useful intermediates and catalysts.3 a large number of
approaches to access diaryl selenides including transitionꢀmetal catalyzed selenation of aryl
halides / boronic acids with diselenides or selenols.4 However, these methoeds commonly suffer
from immense limination and shortcoming. For example, the starting aryl selenium reagents have
to be to synthesis and restricted the substrate scope. Therefore, it will be significant synthetic
value to provide an efficient and concise pathway to access diverse unsymmetrical diaryl
selenides.
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The introduction of selenium elemental into organic molecules via transitionꢀmetalꢀcatalyzed
insertion of selenium powder is attractive and promising in organic synthesis, due to their stable,
easily operated, and commercial available. Therefore, in the last decade, it witnessed wonderful
achievements have been made in this area. In these cases, selenium elemental is utilized as bridge
atom to link two crossꢀcoupling partners. In 2005, Taniguchi5a reported a pioneer work of
copperꢀcatalyzed selenation of aryl iodides to gain symmetrical diaryl diselenides, using
aluminium as reductant and MgCl2 as additive. The same group5b also described a
copperꢀcatalyzed oxidative coupling diarylation of chalcogen elements, employing aryboronic
acids as substrates to generate symmetrical diaryl selenides. During the reaction process, PhSeCu
was reasoned as the key intermediate, which was generated via copperꢀcatalyzed insertion of
selenium elemental with aryl iodides, consequently, this intermediate proceed through
homoꢀcoupling to provide symmetrical diaryl selenides. Copperꢀcatalyzed cascade reactions of Se
powder have attracted immensely attetion, rapid progress has been made in the synthesis
seleniumꢀcontaining heterocycles6, trifluoromethylthiolation7 and bioactive ebselen8. Lately, our
group has established the copperꢀcatalyzed double CꢀSe bonds formation strategy to synthesis
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C3ꢀphenylselenation of indoles,9 this protocol also further exteneded to intramolecular CꢀH
phenylselenation of (hetero)aryl to build benzoselenopheno[3,2ꢀb]indole. We also described that
copperꢀcatalyzed ringꢀopening reaction of epoxides with Se and aryl iodides,10 this approach
provides a concise method to the synthesis of β ꢀhydroxy phenylselenides with highly
regioselectivity. In despite of the great advancements, it is still necessary to broaden the substrates
to construct diverse seleniumꢀcontaining compounds in a versatile way remains a significant
challenge.
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Scheme 1. Strategies for the formation of Double CꢀSe Bonds
In recent years, Daugulis and Miura reported the copperꢀcatalyzed CꢀH arylation of azoles
derivatives with iodobenzene,13 this reaction represents one of the most powerful strategies
because of their economic advantage. Nonetheless, the electrophile aryl halides and azoles were
utilized in this type reactions are limited. One significant reaction remains largely unexplored,
namely the insertion of selenium elemental (Scheme 1). Simple copper catalyzed selenation of
iodobenze followed by direct CꢀH arylselenation of azoles in the presence of selenium elemental
is under developed albeit of its practical importance and high demand in present context. Herein,
we wish to report a copperꢀcatalyzed cascade reaction of aryl iodides, Se and azoles for the first
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time. This transformation supplies a concise and convenient route to dissymmetric diaryl selenides
under ligandꢀfree condition. Notably, single atom Se links different crossꢀcoupling partner strategy
will be widespread in the synthesis of complex pharmaceutical compounds by synthetic chemists.
Results and Discussion
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Table 1. Reaction Optimizationa
S
[Cu] (10 mol %)
S
N
Se
base
Se
I
N
solvent, N2, 24 h
1a
entry
1
2a
3a
[Cat]
base
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
dioxane
CH3CN
DCE
yield %b
0
Pd(OAc)2
Pd(PPh3)4
Ni(acac)2
Ni(PPh3)2Cl2
CuCl2
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2
0
3
0
4
0
5
88
6
CuCl2
trace
63
7
CuCl2
8
CuCl2
91
9
CuCl2
85
10c
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12
13
14
15
16
17
18
19
20
21
22
23d
24e
CuCl2
75
CuO
68
CuI
30
CuBr
35
CuCl
27
CuBr2
51
Cu(OAc)2
CuCl2
47
50
CuCl2
trace
trace
trace
trace
trace
0
CuCl2
CuCl2
CuCl2
toluene
CH3CN
DMF
DMF
CuCl2
CuCl2
0
aReaction conditions unless specified otherwise: 0.4 mmol of Benzothiazole, 1.0 mmol of
Iodobenzene, 1.0 mmol of Se, 0.04 mmol of [Cu], 2.0 mmol of base, 1 mL of solvent, under N2,
150 ℃, 24 h. bIsolated yield. cAt 140 oC. dUnder O2. eIn the absence of copper catalyst.
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We began our investigation with the reaction of benzothiazole 1a and iodobenzene 2a in the
presence of elemental selenium to study reaction conditions including the optimization of catalyst,
base and solvents. As shown in Table 1, at the outset, palladium and nickel were used as catalyst,
no desired product was gained when the reaction conducted in the presence of K3PO4 as the base
in DMF at 150 oC under N2 atmosphere for 24 h (entry 1ꢀ4). Gratifyingly, the yield of product 3a
was obtained in 88% when the catalyst changed to CuCl2 (entries 5). By screening different bases
for this double CꢀSe bonds formation reaction, K2CO3 was demonstrated to be more suitable base
than others such as Li2CO3, Na2CO3 and Cs2CO3, it is worthy that the effect of bases to the
reaction was depended on the amounts of bases and their anions (entries 6ꢀ9). It is perhaps that
base was required to activate the selenium powder to destroy the structure of high polymer
catenation, and assist copperꢀcatalyzed CꢀH activation of azoles to trigger the reaction. The
examination of all commercial available copper catalysts including CuO, CuI, CuBr, CuCl, CuBr2
and Cu(OAc)2(entry 8, 11ꢀ16), CuCl2 was proved to be the best efficient catalyst species for this
transformation. The choice of proper solvent is critical for this reaction, when the reactions were
conducted in apolar solvent such as toluene and DCE, or weak coordination solvent dioxane and
CH3CN, trace product was detected(entry 18ꢀ22). In addition, replacing DMF with DMSO, gave
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no better yield. Reducing yield was obtained in the reaction operated in 140 C. Remarkably, no
desired product was obtained under O2 atmosphere (entry 23), indicating that N2 was essential for
present reaction. Additionally, no coupling product was detected by GC in the absence of copper
catalyst, this control experiment suggested that the copper is critical for successful for this
transformation.
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Scheme 2. Aryl Iodides Scopea
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6
7
8
S
N
S
N
Se
CuCl2 (10 mol %)
K2CO3, DMF
Se
I
R
R
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S
S
S
N
S
N
Se
Se
Se
Se
Se
Se
Se
Se
N
N
3b, 86%
3c, 88%
3d, 90%
3a, 91%
S
N
S
S
N
S
Se
Se
N
N
OMe
NH2
NO2
3f
3h, 53%
, 72%
3e, 80%
3g, 82%
S
S
N
S
N
S
N
Se
Se
Se
N
3i
(X=F), 84%
3j (X=Cl),62%
3k (X=Br), 77%
3l (X=I), 36%
3o
,30%
3m
3n
, 46%
, 83%
CF3
X
OMe
CO2Me
S
S
N
S
N
S
N
Se
Se
Se
N
CHO
O
O
3q, 48%
3r, 72%
3p, 32%
CN
NH2
3s, 60%
aReaction conditions unless specified otherwise: benzothiazole (0.4 mmol), Se8 (1.0 mmol), aryl
iodides (1.0 mmol), CuCl2 (0.04 mmol), K2CO3 (2.0 mmol), DMF (1 mL), 150 °C, 24 h, N2.
Isolated yields are given.
Next, the respect of aryl iodides scope was examined under the optimal conditions, the results
were shown in Scheme 2. Generally, aryl iodides bearing both electronꢀdonating and
elecetronꢀwithdrawing groups in ortho, meta or para position of the iodide group, smoothly
proceeded and afforded the corresponding productins in moderat to good yields, indicated a broad
range of functional groups tolerance. Noteworthy, sterically hindered groups on the aromatic ring
could afford the desired product (3e) showed less effect toward the reaction of transformation.
Halogen atoms fluoro (3i), chloro (3j), bromo (3k) are well tolerated, remarkably, when
employing the 1, 4ꢀdiiodobenzene as substance, just one iodide was substituted to generate the 3l
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product. Moreover, sensitive cyan (3p), aldehyde (3q), ester (3o) and nitro (3h) were also
compatible under current optimal reaction condition. These transformation groups provide a
platform for the further decoration of the complex products. Surprisingly, the free proton
containing substrates, aniline underwent the reaction smoothly and provided corresponding
products 3g and 3r in good yields, which is a big challenge in several coupling reactions.
After the group tolerance of aryl iodides derivatives were demonstrated, the diversity of
1,3ꢀazoles partners were further investigated under the optimized reaction conditions. The results
were shown in Scheme 3, overall, moderate to good yields of 4 were obtained, and various
substituents on the benzene ring of azoles showed little effect on the efficiency of the reaction
except the product 4d. It perhaps that free proton amine group could strongly coordinate with
copper catalyst, which attenuates the reactivity of transitionꢀmetal. A variety of functional groups
including methyl (4a, 4f, 4i and 4j), methoxy (4c), chloride (4b, 4k), bromide (4e, 4l) were
compatible. Next, we attempted the direct arylselenation of benzoxazole under the current reaction
condition, however, only decomposition of the starting material without the expected product.
Scheme 3. 1,3-Azoles Scope
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aReaction conditions unless specified otherwise: Iodobenzene (1.0 mmol), Se8 (1.0 mmol), azoles
(0.4 mmol), CuCl2 (0.04 mmol), K2CO3 (2.0 mmol), DMF (1 mL), 150 °C, 24 h, N2. Isolated
yields are given.
Base on previous literature 12, it’s perhaps that the relative more CꢀH acidic (pKa < 16) of C2
benzoxzaole, liable to occur the ringꢀopening reaction under the strong base condition.
Scheme 4. A gram-scale cross-coupling reaction
The utility of this new method was further demonstrated by an efficient gramꢀscale synthesis
(Scheme 4), the copperꢀcatalyzed double CꢀSe bond formation produced the product 3a in 47%
yield as 1.21 gram under standard reaction conditions.
To gain more insights into the reaction mechanism, some selective and control experiments
were performed (Scheme 5). we have examined the chemical conpetence of PhSeCu5a under our
optimal condtion in the presence of benzothizaole under N2 and O2 atmosphere (Scheme 5, eq 1).,
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however, no desired product was detected by GC. An amusing phenomenon was also observed,
when 2.5 equiv of selenium powder was added into the standard reaction condition, the desired
product 3a was obtained in 47 % isolated yield, (Scheme 5, eq 2); These data for stoichiometric
reactions of PhSeCu suggested that selenium elemental perhaps play a key role in the process of
double CꢀSe formation and also reason this transformation waste excess amount of Se powder.
Scheme 5. Preliminary Mechanism Investigation
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As shown in eq 3, which is consistent with our envision that PhSeCu may be a chemically
competent intermediate, which first through Ullmanꢀtype selenation between aryl iodides and
selenium in situ during the catalytic cycle. Finally, by the addition of radical inhibitor TEMPO
under the optimized reaction conditions(Scheme 5, eq 4), the desired transformation was shut
down, this result indicated that the arylselenation of azoles might go through the radical pathway.
In conclusion, a novel and concise route to gain the unsymmetrical diaryl selenides via
copperꢀcatalyzed threeꢀcomponent coupling reaction of azoles, Se powder, and aryl iodides has
been developed. This reaction proceeds through activation of commercially available elemental
selenium and the formation of double CꢀSe bonds. Importantly, copperꢀcatalyzed azole CꢀH
arylselenation enrich the functionalized reaction of oxazoles, which will drive the development of
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rapid, and cost effective methods for their elaboration. This reaction is attractive and practical
since the cheap copper catalyst is employed and don’t require ligands proceed in generally good
yields and a broad range of functional groups tolerance. Further studies on the reaction mechanism,
the development of new strategies of selective selenation transformation, broaden the reaction new
types of insertion of selenium elemental are underway in our laboratory.
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Experimental Section
General Remarks. 1H NMR (500 MHz), 13C NMR (125 MHz) and 19F NMR (470 MHz) spectra
were recorded in DMSOꢀd6 solutions using a 500 MHz spectrometer. Highꢀresolution mass spectra
were recorded on an ESIꢀQꢀTOF mass spectrometer. All reactions were conducted using standard
Schlenk techniques. Column chromatography was performed using EM silica gel 60 (300−400
mesh). 1H NMR and 13C NMR spectra are provided as Supporting Information.
6ꢀmethylbenzothiazole,13
5ꢀchlorobenzothiazole,13
6ꢀmethoxybenzothiazole,13
13
5ꢀaminobenzothiazole,13 6ꢀbromobenzothiazole,13 4ꢀmethylbenzothiazole,13 4ꢀphenylthiazole
1
were prepared according to the reported procedures. H and 13C spectra of known compounds
were in accordance with those described in the literature.
Procedure for C-H Phenylselenation of Azoles Reactions. In a 25 mL Schlenk tube equipped
with a stir bar were placed benzothiazole 1 (0.4 mmol), iodobenzene 2 (1.0 mmol), Se (1.0 mmol),
CuCl2 (10 mol %), and K2CO3 (2.0 mmol) in DMF (1 mL). The tube was evacuated and refilled
o
with N2 three times. The reaction mixture was stirred at 150 C for 24 h. After it was cooled, the
reaction mixture was diluted with 10 mL of ethyl ether, and filtered through a pad of silica gel,
followed by washing the pad of silica gel with the same solvent (20 mL). The filtrate was washed
with water (3×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under
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reduced pressure. The residue was then purified by flash chromatography on silica gel to provide
the corresponding product.
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Preliminary Mechanism Investigation. In Two 10 mL of Schlenk tubes equipped with a stir bar
were placed with PhSeCu (1.0 mmol), benzothiazole (0.4 mmol), and K2CO3 (2.0 mmol) in DMf
(1 mL). The first tube, was evacuated and refilled N2 three times. The other tube, was fitted with a
rubber septum, and then it was evacuated and refilled with O2 three times. These reaction mixtures
were stirred at 150 oC for 24 h (see Scheme 5, eq 1). To a 10 mL Schlenk tube equipped with a stir
bar were placed PhSeCu (1.0 mmol), Se (1.0 mmol), benzothiazole (0.4 mmol), and K2CO3 (2.0
mmol) in DMF (1 mL). The tube was evacuated and refilled with N2 three times. The reaction
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mixture was stirred at 150 C for 24 h (see Scheme 5, eq 2). In a 10 mL Schlenk tube equipped
with a stir bar were placed benzothiazole (0.4 mmol), iodobenzene (1.0 mmol), Se (1.0 mmol),
PhSeCu (10 mol %), and K2CO3 (2.0 mmol) in DMF (1 mL). The tube was evacuated and refilled
with N2 three times. The reaction mixture was stirred at 150 oC for 24 h (see Scheme 5, eq 3). In a
10 mL Schlenk tube equipped with a stir bar were placed benzothiazole 1 (0.4 mmol),
iodobenzene 2 (1.0 mmol), Se (1.0 mmol), TEMPO (0.4 mmol), CuCl2 (10 mol %), and K2CO3
(2.0 mmol) in DMF (1 mL). The tube was evacuated and refilled with N2 three times (see Scheme
5, eq 4). After it was cooled, the reaction mixture was diluted with 10 mL of ethyl ether, and
filtered through a pad of silica gel, followed by washing the pad of silica gel with the same solvent
(20 mL). The filtrate was washed with water (3×15 mL). The organic phase was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash
chromatography on silica gel to provide the corresponding product.
Characterization Data of Compounds 3 and 4:
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2ꢀphenylselenobenzothiazole (3a). Following the general procedure, using 20 / 1 petroleum ether /
EtOAc as the eluant afforded a yellow solid (105.6 mg, 91 % yield), mp 41ꢀ42 °C. The 1 H and 13
C NMR spectra were in accordance with those described in the literature.14
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2ꢀ(2ꢀmethylphenylseleno)benzothiazole (3b). Following the general procedure, using 20 / 1
petroleum ether / EtOAc as the eluant afforded a yellow viscous oil liqid (105 mg, 86 % yield). 1H
NMR (500 MHz, DMSOꢀd6): δ 7.91 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.0
Hz, 1H), 7.44 – 7.38 (m, 3H), 7.27 – 7.22 (m, 2H), 2.55 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6) :
δ 162.9, 154.8, 143.0, 138.3, 136.6, 130.9, 130.9, 127.7, 127.3, 125.9, 124.2, 121.9, 120.7, 23.2.
HRMS (TIC): calcd for C14H12NSSe [M + H]+ 305.9850, found 305.9823. The 1 H and 13 C NMR
spectra were in accordance with those described in the literature.14
2ꢀ(3ꢀmethylphenylseleno)benzothiazole (3c). Following the general procedure, using 20 / 1
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petroleum ether / EtOAc as the eluant afforded a yellow liqid (107.6mg, 88 % yield). H NMR
(500 MHz, DMSOꢀd6): δ 7.95 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J
= 7.5 Hz, 1H), 7.47 – 7.33 (m, 4H), 2.36 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6): δ 162.5,
154.1, 139.8, 136.6, 135.9, 133.3, 131.0, 130.0, 126.2, 125.7, 124.4, 121.6, 121.4, 20.7. HRMS
(TIC): calcd for C14H12NSSe [M + H]+ 305.9850, found 305.9823.
2ꢀ(4ꢀmethylphenylseleno)benzothiazole (3d). Following the general procedure, using 20 / 1
petroleum ether / EtOAc as the eluant afforded a yellow solid (109.4 mg, 90 % yield)，mp
72ꢀ74 °C.. 1H NMR (500 MHz, DMSOꢀd6): δ 7.90 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H),
7.65 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5Hz, 1H), 7.26 – 7.13 (m, 3H), 2.42 (s, 3H). 13C NMR (125
MHz, DMSOꢀd6): δ 163.7, 154.7, 140.6, 136.8, 136.6, 130.8, 126.0, 124.2, 122.9, 121.9, 120.7,
21.4. HRMS (TIC): calcd for C14H12NSSe [M + H]+ 305.9850, found 305.9823. The 1 H and 13
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2ꢀ(2,4,6ꢀtrimethylphenylseleno)benzothiazole (3e). Following the general procedure, using 20 / 1
petroleum ether / EtOAc as the eluant afforded a pale yellow solid (106.2 mg, 80 % yield), mp
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70ꢀ71 °C. H NMR (500 MHz, DMSOꢀd6): δ 7.89 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H),
7.42 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.15 (s, 2H), 2.46 (s, 6H), 2.32 (s, 3H). 13C NMR
(125 MHz, DMSOꢀd6): δ 163.4, 154.5, 143.3, 140.7, 135.6, 129.3, 126.1, 125.4, 124.0, 121.6,
121.0, 23.8, 20.7. HRMS (TIC): calcd for C16H16NSSe [M + H]+ 334.0163, found 334.0132. The 1
H and 13 C NMR spectra were in accordance with those described in the literature.14
2ꢀ(3ꢀmethoxyphenylseleno)benzothiazole (3f). Following the general procedure, using 15 / 1
petroleum ether / EtOAc as the eluant afforded a yellow viscous oil liquid (92.4 mg, 72 % yield).
1H NMR (500 MHz, DMSOꢀd6): δ 7.97 – 7.89 (m, 2H), 7.46 – 7.34 (m, 5H), 7.14 (s, 1H), 3.81 (s,
3H). 13C NMR (125 MHz, DMSOꢀd6): δ 162.2, 159.9, 154.0, 135.9, 131.1, 128.2, 126.7,
126.3,124.5, 121.7, 121.4, 121.2, 116.1, 55.4. HRMS (TIC): calcd for C14H12NOSSe [M + H]+
321.9800, found 321.9801.
3ꢀ(benzothiazolꢀ2ꢀylseleno)aniline (3g). Following the general procedure, using 15 / 1 petroleum
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ether / EtOAc as the eluant afforded a yellow viscous oil liquid (105 mg, 86 % yield). H NMR
(500 MHz, DMSOꢀd6): δ 7.95 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.5 Hz,
1H), 7.33 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 8.5 Hz, 1H), 7.07 (s, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.75
(d, J = 9.0Hz, 1H), 5.46 (s, 2H). 13C NMR (125 MHz, DMSOꢀd6): δ 163.1, 154.1, 150.3, 135.9,
130.5, 126.2, 125.9, 124.4, 122.8, 121.6, 121.3, 120.8, 115.6. HRMS (TIC): calcd for
C13H11N2SSe [M + H]+ 306.9803, found 306.9815.
2ꢀ(3ꢀnitrophenylseleno)benzothiazole (3h). Following the general procedure, using 5 / 1 petroleum
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ether / EtOAc as the eluant afforded a yellow viscous oil liquid (71.2 mg, 53 % yield). 1H NMR
(500 MHz, DMSOꢀd6): δ 8.27 – 8.19 (m, 2H), 8.08 – 7.98 (m, 4H), 7.52 (t, J = 7.0 Hz, 1H), 7.44
(d, J = 7.0 Hz, 1H). 13C NMR (125 MHz, DMSOꢀd6): δ 157.9, 153.6, 147.7, 136.6, 136.5, 135.0,
133.4, 126. 6,125.3, 124.5, 122.0, 121. 9, 121.9. HRMS (TIC): calcd for C13H9N2O2SSe [M + H]+
336.9545, found 336.9564.
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2ꢀ(4ꢀfluorophenylseleno)benzothiazole (3i). Following the general procedure, using 20 / 1
petroleum ether / EtOAc as the eluant afforded a yellow viscous oil liquid (105.4 mg, 84 % yield).
1H NMR (500 MHz, DMSOꢀd6): δ 7.98 – 7.89 (m, 4H), 7.46 (t, J = 7.5 Hz, 1H), 7.40 – 7.34 (m,
3H). 13C NMR (125 MHz, DMSOꢀd6): δ 163.5 (d, JF = 224.4 Hz), 162.4, 154.1, 139.1 (d, JF = 8.6
Hz), 135.8, 126.3, 124.5, 121.7, 121.4, 121.3 (d, JF = 3.2 Hz), 117.4 (d, JF = 21.8 Hz). 19F NMR
(470 MHz, DMSOꢀd6): δ ꢀ110.15(s, 1F). HRMS (TIC): calcd for C13H9FNSSe [M + H]+ 309.9600,
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found 309.9603. The H and 13 C NMR spectra were in accordance with those described in the
literature.14
2ꢀ(4ꢀchlorophenylseleno)benzothiazole (3j). Following the general procedure, using 20 / 1
petroleum ether / EtOAc as the eluant afforded a yellow viscous oil liquid (82.9 mg, 62 % yield).
1H NMR (500 MHz, DMSOꢀd6): δ 7.98 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.87 (d, J =
8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5Hz, 1H). 13C NMR
(125 MHz, DMSOꢀd6): δ 161.6, 153.9, 137.9, 135.9, 135.4, 130.2, 126.3, 124.9, 124.6, 121.7,
121.5. HRMS (TIC): calcd for C13H9ClNSSe [M + H]+ 325.9304, found 325.9329. The 1 H and 13
C NMR spectra were in accordance with those described in the literature.14
2ꢀ(4ꢀbromophenylseleno)benzothiazole (3k). Following the general procedure, 0.04 mmol CuCl2,
using 15 / 1 petroleum ether / EtOAc as the eluant afforded a yellow liquid (116.4mg, 77 % yield).
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1H NMR (500 MHz, DMSOꢀd6): δ 7.96 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.77 – 7.68
(m, 4H), 7.45(t, J = 7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H). 13C NMR (125 MHz, DMSOꢀd6): δ
161.4, 153.9, 138.0, 135.9, 133.0, 126.1, 125.4, 124.6, 124.1, 121.6, 121.4. HRMS (TIC): calcd
for C13H9BrNSSe [M + H]+ 369.8799, found 369.8795.
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2ꢀ(4ꢀiodophenylseleno)benzothiazole (3l). Following the general procedure, using 15 / 1
petroleum ether / EtOAc as the eluant afforded a white solid (59.8mg, 36 % yield), mp 46ꢀ47 °C.
1H NMR (500 MHz, DMSOꢀd6): δ 7.96 (d, J = 7.5 Hz, 1H), 7.90 – 7.85 (m, 2H), 7.75 (t, J = 6.5
Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.47 – 7.44 (m, 2H), 7.37 – 7.32 (m, 1H). 13C NMR (125 MHz,
DMSOꢀd6): δ 161.3, 153.9, 138.9, 138.6, 137.9, 137.0, 135.8, 132.8, 126.3, 124.6, 121.5. HRMS
(TIC): calcd for C13H9INSSe [M + H]+ 417.8660, found 417.8662.
2ꢀ(4ꢀmethoxyphenylseleno)benzothiazole (3m). Following the general procedure, using 15 / 1
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petroleum ether / EtOAc as the eluant afforded a yellow liqid (106.6 mg, 83 % yield). H NMR
(500 MHz, DMSOꢀd6): δ 7.94 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 8.5 Hz,
2H), 7.44 (t, J = 7.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.09 (d, J =9.0 Hz, 2H), 3.84 (s, 3H). 13
C
NMR (125 MHz, DMSOꢀd6): δ 164.5, 161.1, 154.3, 138.6, 135.7, 126.2, 124.3, 121.3, 121.2,
115.9, 115. 9, 55.4. HRMS (TIC): calcd for C14H12NOSSe [M + H]+ 321.9800, found 321.9803.
The 1 H and 13 C NMR spectra were in accordance with those described in the literature.14
2ꢀ(4ꢀtrifluoromethylphenylseleno)benzothiazole (3n). Following the general procedure, using 15 /
1 petroleum ether / EtOAc as the eluant afforded a yellow solid (66.0mg, 46 % yield), mp
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75ꢀ76 °C. H NMR (500 MHz, DMSOꢀd6): δ 8.03 (t, J = 8.5 Hz, 3H), 7.95 (d, J = 8.5 Hz, 1H),
7.85(d, J = 8.0 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H). 13C NMR (125 MHz,
DMSOꢀd6): δ 159.6, 153.7, 136.1, 135.9, 132.2, 129.9 (q, JF = 32.5 Hz), 126.6 (q, JF = 3.8Hz),
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126.4, 124.9 122.8, 121.8, 121.7. 19F NMR (470 MHz, DMSOꢀd6): δ ꢀ61.40(s, 3F). HRMS (TIC):
calcd for C14H9F3NSSe [M + H]+ 359.9568, found 359.9566.
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3ꢀ(benzothiazolꢀ2ꢀylseleno)benzoate (3o). Following the general procedure, using 15 / 1
petroleum ether / EtOAc as the eluant afforded a pale yellow solid (41.6mg, 30 % yield), mp
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83ꢀ85 °C. H NMR (500 MHz, DMSOꢀd6): δ 8.06 (t, J = 8.0 Hz, 3H), 8.00 (d, J = 8.0 Hz, 2H),
7.64 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 3.94 (s, 3H). 13C NMR
(125 MHz, DMSOꢀd6): δ 165.6, 159.8, 153.7, 135.3, 132.5, 130.4, 130.2, 126.4, 124.9, 121.8,
121.7, 52.4. HRMS (TIC): calcd for C15H12NO2SSe [M + H]+ 349.9749, found 349.9752.
2ꢀ(4ꢀcyanophenylseleno)benzothiazole (3p). Following the general procedure, using 10 / 1
petroleum ether / EtOAc as the eluant afforded a yellow solid (40.0mg, 32 % yield), mp 75ꢀ76 °C.
1H NMR (500 MHz, DMSOꢀd6): δ 7.97 – 7.90 (m, 4H), 7.80 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5
Hz, 1H), 7.50(t, J = 7.5 Hz, 1H), 7.41(t, J = 8.0 Hz, 1H). 13C NMR (125 MHz, DMSOꢀd6): δ 158.6,
153.6, 136.3, 135.1, 134.0, 133.3, 133.1, 126.5, 125.1, 121.9, 111.9, 110.5. HRMS (TIC): calcd
for C14H9N2SSe [M + H]+ 316.9646, found 316.9664..
3ꢀ(benzothiazolꢀ2ꢀylseleno)benzaldehyde (3q). Following the general procedure, using 10 / 1
petroleum ether / EtOAc as the eluant afforded a yellow viscous oil liqid (61.3 mg, 48 % yield).
1H NMR (500 MHz, DMSOꢀd6): δ 10.08 (s, 1H), 8.36 (s, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.08 (d, J
= 8.0 Hz, 1H), 7.98(d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.48 (t, J
= 7.0Hz, 1H), 7.38 (t, J = 8.0Hz, 1H). 13C NMR (125 MHz, DMSOꢀd6): δ 192.4, 160.9, 153.9,
141.6, 137.5, 136.7, 136.0, 130.6, 127.6, 126.4, 124.7, 121.7. HRMS (TIC): calcd for
C14H10NOSSe [M + H]+ 319.9643, found 319.9648.
4ꢀ(benzothiazolꢀ2ꢀylseleno)aniline (3r). Following the general procedure, using 15 / 1 petroleum
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ether / EtOAc as the eluant afforded a yellow viscous oil liquid (101.6 mg, 83 % yield). 1H NMR
(500 MHz, DMSOꢀd6): δ 7.91 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.0 Hz,
2H), 7.42 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0Hz, 2H), 5.73 (s, 2H). 13C
NMR (125 MHz, DMSOꢀd6): δ 166.9, 154.6, 151.2, 138.3, 135.7, 126.0, 124.0, 121.5, 121.0,
115.1, 108.8. HRMS (TIC): calcd for C13H11N2SSe [M + H]+ 306.9803, found 306.9815.
2ꢀ(benzo[1,3]dioxolꢀ5ꢀylseleno)benzothiazole (3s). Following the general procedure, using 30 / 1
petroleum ether / EtOAc as the eluant afforded a yellow liqid (80.3mg, 60% yield). 1H NMR (500
MHz, DMSOꢀd6): δ 7.96 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.46 – 7.43 (m, 2H), , 7.38
(d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.16 (s, 2H). 13C NMR (125
MHz, DMSOꢀd6): δ 163.9, 154.2, 149.5, 148.4, 135.8, 131.5, 126.2, 124.3, 121.6, 121.2, 116.8,
116.4, 109.9, 101.9. HRMS (TIC): calcd for C14H10NO2SSe [M + H]+ 335.9592, found 335.9598.
6ꢀmethylꢀ2ꢀphenylselenobenzothiazole (4a). Following the general procedure, using 15 / 1
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petroleum ether / EtOAc as the eluant afforded a yellow liqid (109.1mg, 89% yield). H NMR
(500 MHz, DMSOꢀd6): δ 7.84 (d, J = 7.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.58 –
7.50 (m, 3H), 7.26 (d, J = 8.5 Hz, 1H), 2.38 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6): δ 165.6,
157.4, 141.4, 141.3, 139.5, 135.4, 132.9, 132.8, 131.5, 126.4, 126.2, 26.1. HRMS (TIC): calcd for
C14H12NSSe [M + H]+ 305.9850, found 305.9823.
5ꢀchloroꢀ2ꢀphenylselenobenzothiazole (4b). Following the general procedure, using 10 / 1
petroleum ether / EtOAc as the eluant afforded a white solid (115.4 mg, 91 % yield), mp 40ꢀ41 °C.
1H NMR (500 MHz, DMSOꢀd6): δ 7.97 – 7.94 (m, 2H), 7.86 (d, J = 7.5 Hz, 2H), 7.61 – 7.52 (m,
3H), 7.37 (d, J = 9.5 Hz, 1H). 13C NMR (125 MHz, DMSOꢀd6): δ 165.9 154.8, 136.5, 134.5, 131.0,
130.5, 130.3, 125.7, 124.4, 123.0, 120.7. HRMS (TIC): calcd for C13H9ClNSSe [M + H]+
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325.9304, found 325.9329. The H and
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6ꢀmethoxyꢀ2ꢀphenylselenobenzothiazole (4c). Following the general procedure, using 10 / 1
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petroleum ether / EtOAc as the eluant afforded a yellow liqid (87.7 mg, 68 % yield). H NMR
(500 MHz, DMSOꢀd6): δ 7.83 – 7.80 (m, 3H), 7.55 – 7.48 (m, 4H), 7.06 (d, J = 8.5 Hz, 1H), 3.79
(s, 3H). 13C NMR (125 MHz, DMSOꢀd6)：δ 157.5 156.8, 148.5, 137.6, 135.7, 130.1, 129.9, 126.6,
122.0, 115.2, 104.7, 55.6. HRMS (TIC): calcd for C14H12NOSSe [M + H]+ 321.9800, found
321.9802.
5ꢀaminoꢀ2ꢀphenylselenobenzothiazole (4d). Following the general procedure, using 10 / 1
petroleum ether / EtOAc as the eluant afforded a yellow liqid (18.3 mg, 15% yield). 1H NMR (500
MHz, DMSOꢀd6): δ 7.81 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.57 – 7.54 (m, 1H), 7.51 –
7.48 (m, 2H), 7.06 (d, J = 9.0 Hz, 1H), 6.91 (d, J =8.0 Hz, 1H), 5.61 (s, 2H). 13C NMR (125 MHz,
DMSOꢀd6): δ 157.9 155.6, 135.9, 130.1, 129.2, 128.8, 125.8, 124.0, 123.3, 114.9, 113.4. HRMS
(TIC): calcd for C13H11N2SSe [M + H]+ 306.9803, found 306.9815.
6ꢀbromoꢀ2ꢀphenylselenobenzothiazole (4e). Following the general procedure, using 15 / 1
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petroleum ether / EtOAc as the eluant afforded a yellow liqid (137.2 mg, 93% yield). H NMR
(500 MHz, DMSOꢀd6): δ 8.22 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.81 (d, J = 7.5 Hz,
1H), 7.62 – 7.53 (m, 4H). 13C NMR (125 MHz, DMSOꢀd6): δ 164.2, 153.1, 137.7, 136.5, 130.5,
130.3, 129.3, 125.7, 124.2, 122.7, 117.2. HRMS (TIC): calcd for C13H9BrNSSe [M + H]+
369.8799, found 369.8795.
4ꢀmethylꢀ2ꢀphenylselenobenzothiazole (4f). Following the general procedure, using 15 / 1
petroleum ether / EtOAc as the eluant afforded a yellow liqid (88.0mg, 72% yield). 1H NMR (500
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MHz, DMSOꢀd6): δ 7.86 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 7.5 Hz, 1H), 7.59 – 7.51 (m, 3H), 7.27 –
7.22 (m, 2H), 2.62 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6): δ 160.7, 153.3, 136.1, 135.7, 130.9,
130.1, 126.6, 126.3, 124.5, 118.9, 17.9. HRMS (TIC): calcd for C14H12NSSe [M + H]+ 305.9850,
found 305.9823.
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4ꢀphenylꢀ2ꢀphenylselenothiazole (4g). Following the general procedure, using 10 / 1 petroleum
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ether / EtOAc as the eluant afforded a yellow liqid (148.7mg, 40% yield). H NMR (500 MHz,
DMSOꢀd6): δ 8.11 (s, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.82 – 7.77 (m, 2H), 7.53 – 7.43(m, 5H), 7.35
(t, J = 7.5 Hz, 1H), 7.28 (s, 1H). 13C NMR (125 MHz, DMSOꢀd6): δ 155.8, 134.6, 130.2, 130.0,
129.7, 129.5, 128.8, 128.6, 125.9, 117.4. HRMS (TIC): calcd for C15H12NSSe [M + H]+ 317.9850,
found 317.9830.
2ꢀphenylselenobenzimidazole (4h). Following the general procedure, using 5 / 1 petroleum ether /
EtOAc as the eluant afforded a light yellow solid (78.9 mg, 23% yield), mp 180ꢀ181 °C. 1H NMR
(500 MHz, DMSOꢀd6): δ 7.63 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 – 7.51 (m, 2H),
7.35 – 7.34 (m, 3H), 7.28 (t, J = 7.0 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 3.78 (s, 3H). 13C NMR (125
MHz, DMSOꢀd6): δ 143.9, 143.4, 136.4, 132.2, 129.7, 128.2, 127.9, 122.7, 121.8, 118.7, 110.4,
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31.5. HRMS (TIC): calcd for C13H11N2Se [M + H]+ 275.0082, found 275.0085. The H and 13 C
NMR spectra were in accordance with those described in the literature.15
5ꢀmethylꢀ2ꢀphenylselenobenzimidazole (4i). Following the general procedure, using 15 / 1
petroleum ether / EtOAc as the eluant afforded a yellow liqid (89.4 mg, 81% yield). 1H NMR (500
MHz, DMSOꢀd6): δ 12.70 (s, 1H), 7.57 – 7.56 (m, 2H), 7.35 – 7.34 (m, 5H), 7.00 (d, J = 8.0 Hz,
1H), 2.40 (s, 3H). 13C NMR (125 MHz, DMSOꢀd6): δ 173.1, 169.9, 139.9, 134.7, 132.4, 129.6,
128.3, 127.8, 123.1, 117.7, 110.6, 21.2. HRMS (TIC): calcd for C14H13N2Se [M + H]+ 289.0239,
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found 289.0243.
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5,6ꢀdimethylꢀ2ꢀphenylselenobenzimidazole (4j). Following the general procedure, using 5 / 1
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petroleum ether / EtOAc as the eluant afforded a light yellow solid (80.8mg, 70% yield), mp
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166ꢀ167 °C. H NMR (500 MHz, DMSOꢀd6): δ 12.59 (s, 1H), 7.52 (d, J = 7.0 Hz, 2H), 7.38 –
7.33 (m, 4H), 7.22 (s, 1H), 2.30 (s, 6H). 13C NMR (125 MHz, DMSOꢀd6): δ 142.9, 139.1, 132.0,
129.8, 129.5, 128.7, 127.7, 118.4, 111.0, 99.5, 19.8. HRMS (TIC): calcd for C15H15N2Se [M + H]+
303.0395, found 303.0366.
5ꢀchloroꢀ2ꢀphenylselenobenzimidazole (4k). Following the general procedure, using 10 / 1
petroleum ether / EtOAc as the eluant afforded a yellow solid (58.2mg, 50% yield), mp 39ꢀ40 °C.
1H NMR (500 MHz, DMSOꢀd6): δ 12.91 (s, 1H), 7.62 (s, 3H), 7.39 – 7.38 (m, 4H), 7.19 (d, J =
7.5 Hz, 1H). 13C NMR (125 MHz, DMSOꢀd6) δ 133.2, 130.1, 130.0 129.6, 128.3, 127.3, 123.8,
123.7, 117.6, 112.2, 110.6. HRMS (TIC): calcd for C13H10ClN2Se [M + H]+ 308.9692, found
308.9693.
5ꢀbromoꢀ2ꢀphenylselenobenzimidazole (4l) Following the general procedure, using 10 / 1
petroleum ether / EtOAc as the eluant afforded a yellow liqid (51.0mg, 36% yield). 1H NMR (500
MHz, DMSOꢀd6): δ 12.91 (s, 1H), 7.62 (s, 3H), 7.39 – 7.38 (m, 4H), 7.30 (d, J = 8.0 Hz, 1H). 13
C
NMR (125 MHz, DMSOꢀd6): δ 133.2, 130.1, 130.1 130.0, 129.6, 129.4, 129.3, 128.3, 127.3,
123.9, 123.7. HRMS (TIC): calcd for C13H10BrN2Se [M + H]+ 352.9187, found 352.9209.
ASSOCIATED CONTENT
Supporting Information
1H, 13C and 19F NMR spectral data of all compounds reported. Supporting Information is available
free of charge the ACS Publications website at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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*Eꢀmail for G.W.: wuge@wmu.edu.cn.
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*Eꢀmail for H.W.: huayuewu@wzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation of China (21602158, 21272176,
21372177, and 21472140), the Zhejiang Provincial Natural Science Foundation (LY14B020009,
LY16B020011), the Wenzhou Medical University startꢀup funding (QTJ15026) and the Innovation
Fund Project for Graduate Student of Wenzhou University (2016R426063) is greatly appreciated.
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