Transition Metal-Free Amidoalkylation of Benzothiazoles and Amidoalkylarylation of Activated Alkenes with N,N-Dialkylamides

Article abstract of DOI:10.1021/acs.joc.6b00096

A general and practical amidoalkylation reaction, using N,N-dialkylamides in the presence of potassium persulfate as the sole reagent, has been developed. 2-Amidoalkylated benzothiazole- and 3-amidoalkyl-substituted indolinone derivatives were obtained by

Full text of DOI:10.1021/acs.joc.6b00096

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Note
Transition-Metal-Free Amidoalkylation of Benzothiazoles and
Amidoalkylarylation of Activated Alkenes with N,N-Dialkylamides
Jian Wang, Jing Li, Jinbo Huang, and Qiang Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00096 • Publication Date (Web): 14 Mar 2016
Downloaded from http://pubs.acs.org on March 15, 2016
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Transition-Metal-Free Amidoalkylation of Benzothiazoles and
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Amidoalkylarylation of Activated Alkenes with N,N-Dialkylamides
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Jian Wang, Jing Li, Jinbo Huang* and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese
Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China
huang_jinbo@gibh.ac.cn ; zhu_qiang@gibh.ac.cn
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
R2
N
H
O
N
S
N
S
K2S2O8 (4.0 equiv)
70 oC, 23 h
R1
R1
H
+
O
R2
N
R3
R4
R3
R4
41-80% yields, 16 examples
H
N
H
O
K2S2O8
O
R
N
R
O
70 oC, 23 h
N
O
N
45-81% yields, 4 examples
ABSTRACT: A general and practical amidoalkylation reaction, using N,Nꢀdialkylamides in the presence of
potassium persulfate as the sole reagent, has been developed. 2ꢀAmidoalkylated benzothiazole and 3ꢀamidoalkyl
substituted indolinone derivatives were obtained by using benzothiazoles and NꢀarylꢀNꢀmethylꢀmethacrylamides as
substrates, respectively. The transformation proceeded smoothly through amidoalkyl radical intermediates which
were trapped by benzothiazoles or activated alkenes.
C−C bond formation through direct C−H functionalization is one of the fundamental research topics, owing to
its advantages in atom economy and environmental benignity over traditional methods.1 In this context, activation
and coupling of two different C−H centres, known as oxidative crossꢀdehydrogenativeꢀcoupling (CDC), has been
recognized as an ideal approach to build C−C bonds in terms of bondꢀforming efficiency and atom economy.2
Over the past decade, substantial progress has been made in CDC reactions mainly catalysed by transition metals
including Pd, Ru, Fe, and Sc.3 However, concerns on cost as well as toxicity of transition metal contaminants from
either catalyst and/or oxidant make transitionꢀmetalꢀfree CDC processes more attractive. For example, Antonchick
and Burgmann developed a PhI(OCOCF3)/NaN3ꢀpromoted oxidative crossꢀcoupling reaction of heteroarenes with
simple alkanes.4 Recently, Liu reported an I2ꢀcatalyzed olefination of oxindoles with simple alkenes to give
3ꢀalkenylꢀ2ꢀoxindoles via CDC strategy.5 And, several protocols for C−C bond construction via freeꢀradical
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mediated CDC processes have been developed by Han and others.6 Although considerable advances in this field
have been made, more CDC reactions leading to quick assembling of drugꢀlike molecules under practical
transitionꢀmetalꢀfree conditions are still highly desirable.
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Figure 1. Representative biologically active 2-amidoalkylated benzothiazoles
Benzothiazole is an important structural motif that exists in a number of compounds of medicinal interests,
natural products, and functional materials.7 Particularly for 2ꢀamidoalkylated benzothiazole derivatives, they show
prominent activities as inhibitors of histone deacetylase (HDAC), HldE kinase, and CRTH2 receptor (Figure 1).8
To prepare C2 substituted benzothiazole derivatives, CDC reaction between benzothiazole and another C−H
species is probably the most atom economical and efficient approach.9 For example, Chang and coꢀworkers
developed a silverꢀmediated decarbonylative amination of benzothiazoles using formamides as nitrogen sources
(eq 1, Scheme 1).10 Recently, Wang and coꢀworkers reported a metalꢀ and baseꢀfree approach to prepare C2
amidated benzothiazoles with formamides via double C–H activation (eq 2, Scheme 1).11 However, the synthesis
of 2ꢀamidoalkylated benzothiazoles through the strategy of CDC has not been reported. In continuing our interest
in transitionꢀmetalꢀfree transformations,12 we herein report a practical amidoalkylation of benzothiazoles with
simple N,Nꢀdialkylamides using potassium persulfate as the sole reagent (eq 3, Scheme 1). In addition, this
amidoalkylation method is also accessible to amidoalkyl substituted oxindoles which are closely related to a
variety of biologically active molecules such as antiꢀinflammatory natural product convolutamydine A and
PDE10A inhibitor BMS 204352 (MaxiPost).13
Scheme 1. CDC reactions of benzothiazole with amides
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(1) Chang's work (in 2009)
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O
R1
R2
N
S
N
S
R1
Ag2CO3, AcOH
R
R
N
H
+
H
N
R2
R1, R2 = CH3
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(2)
R
Wang's work (in 2013)
O
O
N
N
S
N
S
R1
TBPB
R
H
+
H
N
R2
R2
R1
(3) this work
R1
O
R1
N
S
N
K2S2O8
R
CH
+
N
R2
R3
HC
O
R
H
H
N
S
R2
R3
R3 = H and alkyl
We set out on the study by treating benzothiazole 1a with excess amount of N,Nꢀdimethylacetamide 2a under
solventꢀfree conditions. After a brief survey of catalyst, additive, and oxidant, we were delighted to find out that
the reaction proceeded well in the presence of potassium persulfate (K2S2O8) at 70 oC to afford
Nꢀ(benzo[d]thiazolꢀ2ꢀylmethyl)ꢀNꢀmethylformamide 3a in 80% isolated yield (entry 1, Table 1). Other oxidants,
including Na2S2O8, PhI(OAc)2, and (NH4)2S2O8, were also surveyed. It was intriguing that these oxidants were far
less effective than K2S2O8 (entries 2ꢀ4), probably due to their poor solubility under the experimental conditions. A
combination of catalytic amount of CuBr and 1.5 equiv of TBHP can also promote the coupling reaction, albeit in
only 12% yield (entry 5). The attempt of using fewer amounts N,Nꢀdimethylacetamide 2a in nonpolar solvent such
as mesitylene or xylene and in polar solvents such as DMF, DMSO, MeOH, or isopropanol was unsuccessful
(results not shown in Table 1). Either acidic or basic additive deteriorated the reaction (entries 6 and 7). Elevating
the reaction temperature to 100 °C resulted in fewer amount of the desired product formation (entry 8). Altering
the reaction times to 16 h and 30 h was not helpful for the transformation (entry 9).
Table 1. Optimization of the reaction conditions
Entry Change from the ‘‘standard conditions’’a
Yield
(%)b
80 (84)
trace
n.d.
n.d.
(12)
(4)
1
2
3
4
5
6
7
8
none
Na2S2O8, instead of K2S2O8
PhI(OAc)2, instead of K2S2O8
(NH4)2S2O8, instead of K2S2O8
CuBr (20 mol%), TBHP (1.5 equiv)
1.0 equiv of PivOH was added as additive
1.0 equiv of Cs2CO3 was added as additive
at 100 oC
n.d.
63
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The reaction time was 16 h
The reaction time was 30 h
65
79
a The standard reactions conditions: 1a (0.2 mmol), 2a (5.3 mmol, 0.5 mL), and K2S2O8 (0.8 mmol, 4.0 equiv) at
t
b
70 °C, in air. TBHP = butyl hydroperoxide (5.5 M in decane). Isolated yield, yields in parentheses are based on
1H NMR analysis of the crude product using 4ꢀiodoanisole as an internal standard.
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With the optimized conditions established, the scope of benzothiazole was investigated first in reactions with
N,Nꢀdimethylacetamide (2a) in the presence of K2S2O8 (Table 2). Benzothiazoles bearing electronꢀdonating Me
and OMe substituents at the C6 position tolerated the oxidative conditions, furnishing 3b and 3c in 64% and 68%
yields, respectively. Substrates substituted at the same site with electronꢀwithdrawing groups such as F, Cl, and CN
provided the corresponding products 3d-3f in better yields (79ꢀ82%). However, 6ꢀnitrobenzothiazole was not
compatible with the oxidative conditions and only trace amounts of 3g was detected by GCꢀMS (most of the
starting material decomposed). In addition, aryl and heteroaryl substituted benzothiazoles were also suitable
substrates for this CDC amidoalkylation reaction in acceptable yields (3h, 73%; 3i, 51%). C4 and C5 halogenated
benzothiazoles were amidoalkylated smoothly, providing opportunities for further modification on the products
(3jꢀ3l). To be noted, when N,Nꢀdimethylformamide (DMF), a common organic solvent, was used in coupling with
benzothiazole, the corresponding aminoalkylated product 3m was obtained selectively, albeit in moderate yield.
No amidated benzothiazole 3m’ or decarbonylative amination product as described in Chang’s work10 was
detected. Cyclic formamide coupled with 1a to provide piperidinyl substituted benzothiazole 3o in 53% yield. It
was notable that Nꢀmethylpyrrolidinꢀ2ꢀone (NMP) containing two different amino carbons gave a mixture of 3p
and 3p’ in a ratio of 10:1 favouring the secondary amino carbon being arylated.
Table 2. Amidoalkylaion of benzothiazoles with amidesa
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N
N
S
N
S
O
O
O
S
N
N
N
R
O
3h, 73%
3i
, 51%
3a, R = H, 80%
3e, R = Cl, 82%%
3b, R = Me, 64% 3f, R = CN, 80%%
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3g, R = NO , trace
3c, R = OMe, 68%
3d, R = F, 79%
Cl
N
2
Br
Cl
N
S
N
S
O
O
N
O
S
N
N
3k
, 82%
3l, 68%
3j, 72%
N
S
N
S
O
N
N
S
O
N
H
O
H
N
MeO
3m'
, 0%
3m, 41%
3n, 60%
OHC
O
N
N
S
N
N
N
N
O
S
S
3o
3p 3p'
, 72% (10:1)
, 53%
+
a The reaction conditions: 1 (0.2 mmol), 2 (0.5 mL), and K2S2O8 (0.8 mmol, 4.0 equiv) at 70 °C, 23 h, in air.
Recently, transition metalꢀcatalyzed cyclizations as well as radicalꢀinitiated cascade reactions have been
developed to prepare 3,3ꢀdisubstituted oxindoles which represent a class of Nꢀheterocycles exhibiting remarkable
bioactivities.14 It was expected that 3ꢀamidoalkyloxindoles could be accessed by using
NꢀarylꢀNꢀmethylꢀmethacrylamides as substrates under the same reaction conditions. Indeed,
3ꢀmethylꢀ3ꢀamidoethyloxindole derivatives 5aꢀ5d were obtained in moderate to good yields, in which two CꢀC
bonds were formed across the activated double bond sequentially (Scheme 2). It’s worth noting that treatment of
2ꢀisocyanoꢀ5ꢀmethylꢀ1,1'ꢀbiphenyl with DMF gave the corresponding amidated product 7, while the
amidoalkylarylated compound was not observed.
Scheme 2. Cascade amidoalkylarylation of activated alkenes with 2a
N
O
R
R
O
K2S2O8
O
N
70 oC, 23 h
N
N
O
5a, R = H, 81%
5b, R = F, 45%
5c, R = Cl, 71%
5d, R = Br, 69%
5
2a (0.5 mL)
4 (0.2 mmol)
Scheme 3. Cascade amidoarylation of 2ꢀisocyanoꢀ5ꢀmethylꢀ1,1'ꢀbiphenyl with DMF
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7
O
N
NC
N
K2S2O8
+
DMF
70 oC, 6 h
8
9
6 (0.2 mmol)
0.5 mL
7, 71%
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To confirm that the current amidoalkylation reaction proceeds through radical intermediates, radicalꢀtrapping
experiments were carried out (Scheme 4). When radical scavenger 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO)
or 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) was added to the reaction, the coupling process was completely
inhibited, suggesting that a radical pathway is likely involved in this transformation.
On the basis of experimental results and literature reports,11,15 a plausible radical mechanism was proposed
(Scheme 4). Initially, sulfate anion radical is generated through homolytic cleavage of peroxydisulfate dianion.
Then, the sulfate anion radicals grab one of the hydrogen atoms in N,Nꢀdialkylamide (using DMA as an example)
and the C2 hydrogen atom in benzothiazole (1a), generating the respective radicals A and B, which react with each
other to generate the corresponding crossꢀcoupling product (3a).11 The homoꢀcoupling product (I) was also
detected by GCꢀMS, however, the other homoꢀcoupling product (II) was not observed. When
NꢀarylꢀNꢀmethylꢀmethacrylamide is applied instead of benzothiazole, a similar cascade radical process involving
addition of amidoalkyl radical A to activated alkene and intramolecular homolytic aromatic substitution (HAS) of
the resulting carbon radical takes place (not shown in the scheme).
Scheme 4. Plausible reaction mechanism
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In summary, we demonstrated an efficient and atom economical approach for the synthesis of 2ꢀamidoalkyl
benzothiazoles and 3ꢀamidoalkyl oxindoles employing a radical mediated CDC reaction. The process uses
inexpensive K2S2O8 as the only oxidant under solventꢀfree condition in open air. Unlike the reported
decarbonylative amination and amidation of benzothiazoles with formamides, the corresponding amidoalkylation
products were formed selectively using simple N,Nꢀdialkylamides including formamides. This method not only
provides a quick assembling of drugꢀlike molecules under practical transitionꢀmetalꢀfree conditions, but also
represents an alternative way of introducing nitrogen atoms to molecules by C−C bond formation.
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EXPERIMENTAL SECTION
General Information. Reactions were monitored by using thinꢀlayer chromatography (TLC) on commercial
silica gel plates (GF 254). Visualization of the developed plates was performed under UV lights (GF 254 nm).
Flash column chromatography was performed on silica gel (200ꢀ300 mesh). NMR spectra were recorded at 400,
500 MHz (H) and at 101, 126 MHz (C), respectively. Chemical shifts (δ) were reported in ppm referenced to the
1
CDCl3 residual peak (δ 7.26) or the DMSOꢀd6 residual peak (δ 2.50) for H NMR. Chemical shifts of 13C NMR
were reported relative to CDCl3 (δ 77.0) or DMSOꢀd6 (δ 39.5). The following abbreviations were used to describe
peak splitting patterns when appropriate: br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. Coupling constant, J, was reported in Hertz unit (Hz). Infrared (IR) spectra were recorded on a FTꢀIR
spectrophotometer. Melting points (mp) were taken on an apparatus which is uncorrected. HRMS were recorded
using ESIꢀTOF techniques.
NOTE: Due to the special structure of amides, most of the products exist as a mixture of two rotamers
as shown in NMR charts.
General Procedure for the Preparation of Compounds 3,5
R2
N
S
N
S
R1
R1
O
N
O
R3
R4
K2S2O8 (4.0 equiv.)
70 oC, 23 h
3
or
R2
N
R3
R4
R3
N
1
+
or
N
R4
2
R2
O
R
O
R
O
N
4
5
To a mixture of benzothiazole 1 or NꢀmethylꢀNꢀphenylmethacrylamide 4(0.2 mmol) and amides 2 (0.5 mL) in
o
a reaction tube was added K2S2O8 (4.0 equiv). The reaction mixture was stirred for 23 h at 70 C in air. The
reaction mixture was quenched with H2O (10 mL) and extracted with ethyl acetate (15 mL×3). The combined
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organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by
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column chromatography on silica gel (EtOAc/PE = 1:3ꢀ1:4) to afford the desired product 3 or 5.
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Procedure for the Preparation of Compounds 7
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O
N
NC
N
K2S2O8
+
DMF
70 oC, 6 h
6, 0.2 mmol
0.5 mL
7, 71%
To a solution of 2ꢀisocyanoꢀ5ꢀmethylꢀ1,1'ꢀbiphenyl 6 (39 mg, 0.2 mmol) in 0.5 mL of DMF, was added
o
K2S2O8 (3.0 equiv). The reaction mixture was stirred for 6 h at 70 C in air. Then 2 mL of saturated aqueous
NaHCO3 was added carefully to quench the reaction and stirred for about 5 min. The mixture was extracted with
EtOAc and the combined organic layers were evaporated under vacuum. The residue was purified by column
chromatography on silica gel to give N,N,2ꢀtrimethylphenanthridineꢀ6ꢀcarboxamide 7.
Experiments on Free-radical Inhibition
O
K2S2O8 (4.0 equiv.)
N
N
S
scavenger (2.0 equiv)
70 oC, 23 h
+
O
N
S
N
1a
2a
3a
A mixture of benzothiazole 1a (0.2 mmol), K2S2O8 (4.0 equiv), and 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy
(TEMPO) or 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol (BHT) (2.0 equiv) in 0.5 mL of DMA was heated at 70 oC for 23 h.
The reaction was monitored by TLC and no desired compound was detected by GCꢀMs.
N-(benzo[d]thiazol-2-ylmethyl)-N-methylacetamide (3a)
Yellow solid, 35 mg, 80% yield. Mp: 53ꢀ55oC. 1H NMR (400 MHz, CDCl3): δ = 8.00ꢀ8.04 (m, 1H), 7.86ꢀ7.92 (m,
1H), 7.47ꢀ7.52 (m, 1H), 7.38ꢀ7.43 (m, 1H), 4.99 (s, 2H), 3.15 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
= 170.9, 168.0, 153.2, 135.6, 126.4, 125.5, 123.1, 121.8, 49.3, 36.3, 21.4; IR (KBr pellet): ν bar = 3124, 3060,
2931, 1651, 1517, 1433, 1384, 1334, 1286, 1239, 1126, 1062, 989, 869, 762 cmꢀ1; HRMS (ESI): Exact mass calcd
for C11H12N2OS [M+H]+, 221.0743; Found: 221.0741.
N-methyl-N-((6-methylbenzo[d]thiazol-2-yl)methyl)acetamide (3b)
Yellow semiꢀsolid, 30 mg, 64% yield. 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.31
(d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 3.12 (s, 3H), 2.49 (s, 3H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.9,
166.6, 150.8,135.9, 135.4, 127.6, 122.4, 121.4, 53.0, 49.3, 36.3, 21.4; IR (KBr pellet): ν bar = 3125, 3048, 2930,
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1655, 1517, 1436, 1390, 1338, 1285, 1241, 1128, 998, 876, 768 cmꢀ1; HRMS (ESI): Exact mass calcd for
C12H15N2OS [M+H]+, 235.0900; Found: 235.0903.
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N-((6-methoxybenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3c)
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Yellow semiꢀsolid, 34 mg, 68% yield. 1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.10
(d, J = 8.0 Hz, 1H), 4.95 (s, 2H), 3.90 (s, 3H), 3.13 (s, 3H), 2.26 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.8,
165.1, 157.7, 147.7, 137.1, 123.5, 115.7, 104.3, 55.7, 52.9, 49.2, 36.2, 21.5; IR (KBr pellet): ν bar = 3020, 2926,
1653, 1579, 1546, 1460, 1361, 1342, 1236, 1098, 1070, 886, 846, 754 cmꢀ1; HRMS (ESI): Exact mass calcd for
C12H15N2O2S [M+H]+, 251.0849; Found: 251.0848.
N-((6-fluorobenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3d)
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Yellow solid, 38 mg, 79% yield. Mp = 95ꢀ97oC. H NMR (400 MHz, CDCl3): δ = 7.93ꢀ7.97 (m, 1H), 7.53ꢀ7.60
(m, 1H), 7.20ꢀ7.25 (m, 1H), 4.95 (s, 2H), 3.15 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.9,
167.4, 160.4 (d, JCꢀF = 243.6 Hz), 149.3, 136.7, 123.8, 114.6, 107.9, 49.3, 36.4, 21.5; IR (KBr pellet): ν bar = 3090,
3069, 2937, 1649, 1632, 1566, 1453, 1385, 1337, 1287, 1249, 1196, 1115, 1026, 990, 880, 763, 681, 642 cmꢀ1;
HRMS (ESI): Exact mass calcd for C11H12FN2OS [M+H]+, 239.0649; Found: 239.0647.
N-((6-chlorobenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3e)
Yellow oil, 42 mg, 82% yield. 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.43 (d, J =
8.4 Hz, 1H), 4.95 (s, 2H), 3.15 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.9, 168.5, 151.8, 136.8,
131.5, 127.2, 123.8, 121.4, 49.4, 36.4, 21.4; IR (KBr pellet): ν bar = 3076, 2937, 1631, 1543, 1482, 1407,
1337,1282, 1228, 1176, 1103, 1059, 994, 937, 865, 765 cmꢀ1; HRMS (ESI): Exact mass calcd for C11H12ClN2OS
[M+H]+, 255.0353; Found: 255.0350.
N-((6-cyanobenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3f)
1
Yellow oil, 39 mg, 80% yield. H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 5.00 (s,
2H), 3.19 (s, 3H), 2.25 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 172.5, 171.1, 155.1, 136.2, 129.2, 126.5, 123.7,
118.5, 108.8, 49.6, 36.6, 21.4; IR (KBr pellet): ν bar = 3080, 2948, 1648, 1565, 1490, 1438, 1330,1289, 1236,
1176, 1158, 1119, 998, 937, 898 cmꢀ1; HRMS (ESI): Exact mass calcd for C12H12N3OS [M+H]+, 246.0696; Found:
246.0693.
N-methyl-N-((6-(m-tolyl)benzo[d]thiazol-2-yl)methyl)acetamide (3h)
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Yellow oil, 45 mg, 73% yield. H NMR (400 MHz, CDCl3): δ = 8.08 (s, 1H), 8.03ꢀ8.06 (m, 1H), 7.69ꢀ7.75 (m,
1H), 7.46 (s, 1H), 7.35ꢀ7.43 (m, 2H), 7.20ꢀ7.23 (m, 1H), 5.00 (s, 2H), 3.15 (s, 3H), 2.45 (s, 3H), 2.21 (s, 3H); 13
C
NMR (125 MHz, CDCl3): δ = 171.0, 168.1, 152.5, 140.5, 139.2, 138.6, 136.4, 128.8, 128.4, 128.2, 126.2, 124.5,
123.1, 120.1, 49.4, 34.4, 21.5; IR (KBr pellet): ν bar = 3021, 2923, 1651, 1585, 1517, 1452, 1359, 1333, 1236,
1097, 1066, 872, 828, 752, 681 cmꢀ1; HRMS (ESI): Exact mass calcd for C18H19N2OS [M+H]+, 311.1213; Found:
311.1215.
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N-((6-(benzofuran-2-yl)benzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3i)
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Yellow solid, 34 mg, 51% yield. Mp = 175ꢀ178oC. H NMR (400 MHz, CDCl3): δ = 8.40 (s, 1H), 7.96ꢀ8.07 (m,
2H), 7.55ꢀ7.64 (m, 2H), 7.27ꢀ7.35 (m, 2H), 7.12 (s, 1H), 5.01 (s, 2H), 3.18 (s, 3H), 2.28 (s, 3H); 13C NMR (125
MHz, CDCl3): δ = 171.0, 168.7, 155.2, 155.0, 152.8, 136.6, 129.2, 127.8, 124.7, 123.7, 123.2, 123.1, 121.1, 118.0,
111.2, 102.0, 49.5, 34.4, 21.5; IR (KBr pellet): ν bar = 3425, 3110, 2967, 2927, 1647, 1573, 1454, 1396, 1335,
1296, 1228, 1167, 1109, 968, 857, 831 cmꢀ1; HRMS (ESI): Exact mass calcd for C19H17N2O2S [M+H]+, 337.1005;
Found: 337.1006.
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N-((5-chlorobenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3j)
Yellow oil, 37 mg, 72% yield. 1H NMR (400 MHz, CDCl3): δ = 7.98 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.38 (d, J =
8.4 Hz, 1H), 4.96 (s, 2H), 3.15 (s, 3H), 2.24 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 171.0, 169.8, 153.6, 133.9,
132.1, 125.7, 122.8, 122.4, 49.4, 36.5, 21.5; IR (KBr pellet): ν bar = 3139, 2926, 2854, 1645, 1513, 1482, 1399,
1384, 1276, 1261, 1170, 1103, 1069, 989, 811, 763 cmꢀ1; HRMS (ESI): Exact mass calcd for C11H12ClN2OS
[M+H]+, 255.0353; Found: 255.0352.
N-((5-chloro-4-methylbenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3k)
Yellow solid, 44 mg, 82% yield. Mp = 93ꢀ95 oC. 1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.4 Hz, 1H), 7.41
(d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 3.16 (s, 3H), 2.79 (s, 3H), 2.26 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.9,
168.3, 153.3, 133.7, 131.5, 131.2, 126.4, 119.3, 49.4, 36.4, 21.5, 15.7; IR (KBr pellet): ν bar = 3065, 2932, 1647,
1557, 1516, 1420, 1363, 1336, 1276, 1236, 1169, 1025, 990, 874, 823 cmꢀ1; HRMS (ESI): Exact mass calcd for
C12H14ClN2OS [M+H]+, 269.0510; Found: 269.0507.
N-((4-bromobenzo[d]thiazol-2-yl)methyl)-N-methylacetamide (3l)
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Yellow semiꢀsolid, 41 mg, 68% yield. H NMR (400 MHz, CDCl3): δ = 7.80ꢀ7.86 (m, 1H), 7.67ꢀ7.73 (m, 1H),
7.23ꢀ7.32 (m, 1H), 5.02 (s, 2H), 3.17 (s, 3H), 2.24 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 170.9, 169.1, 151.7,
136.5, 129.9, 126.3, 121.0, 116.5, 49.5, 36.4, 21.5; IR (KBr pellet): ν bar = 3060, 2930, 1651, 1583, 1479, 1399,
1308, 1287, 1210, 1171, 988, 860, 788, 772, 740 cmꢀ1; HRMS (ESI): Exact mass calcd for C11H12BrN2OS [M+H]+,
298.9848; Found: 298.9849.
N-(benzo[d]thiazol-2-ylmethyl)-N-methylformamide (3m)
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Yellow oil, 17 mg, 41% yield. H NMR (400 MHz, CDCl3): δ = 8.21 (s, 1H), 7.90ꢀ7.93 (m, 1H), 7.56ꢀ7.88 (m,
1H), 7.40ꢀ7.55 (m, 2H), 4.96 (s, 2H), 3.10 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 166.2, 162.6, 152.7, 135.6,
126.4, 125.6, 123.2, 121.8, 46.1, 34.6; IR (KBr pellet): ν bar = 3337, 3033, 2933, 2856, 1681, 1516, 1483, 1434,
1335, 1281, 1240, 1123, 1014, 731, 707 cmꢀ1; HRMS (ESI): Exact mass calcd for : C10H11N2OS [M+H]+,
207.0587; Found: 207.0589.
N-((6-methoxybenzo[d]thiazol-2-yl)methyl)-N-methylformamide (3n)
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Yellow oil, 28 mg, 60% yield. 1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.33 (d, J =
8.0 Hz, 1H), 7.08ꢀ7.14 (m, 1H), 4.91 (s, 2H), 3.90 (s, 3H), 3.07 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 163.3,
162.4, 157.8, 147.1, 137.0, 123.5, 115.5, 104.1, 55.7, 45.9, 30.2; IR (KBr pellet): ν bar = 2922, 2865, 1677, 1608,
1558, 1518, 1444, 1392, 1307, 1281, 1119, 960, 866 cmꢀ1; HRMS (ESI): Exact mass calcd for C11H13N2O2S
[M+H]+, 237.0692; Found: 237.0692.
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2-(benzo[d]thiazol-2-yl)piperidine-1-carbaldehyde (3o)
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Yellow oil, 26 mg, 53% yield. H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1H), 8.02ꢀ8.06 (m, 1H), 7.86ꢀ7.91 (m,
1H), 7.37ꢀ7.52 (m, 2H), 5.12ꢀ6.03 (m, 1H), 3.60ꢀ4.45 (m, 1H), 3.37ꢀ3.44 (m, 1H), 2.69ꢀ2.92 (m, 6H); 13C NMR
(125 MHz, CDCl3): δ = 170.5, 161.8, 153.6, 135.5, 126.0, 125.1, 123.1, 121.6, 50.3, 43.8, 27.9, 25.9, 20.6; IR
(KBr pellet): ν bar = 3061, 2940, 2861, 1674, 1557, 1350, 1246, 1157, 1121, 1056, 1013, 986, 825, 761 cmꢀ1;
HRMS (ESI): Exact mass calcd for C13H15N2OS [M+H]+, 247.0900; Found: 247.0900.
5-(benzo[d]thiazol-2-yl)-1-methylpyrrolidin-2-one (3p)
Yellow oil, 31 mg, 66% yield. 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H),
7.28ꢀ7.54 (m, 2H), 5.02ꢀ5.06 (m, 1H), 2.89 (s, 3H), 2.62ꢀ2.70 (m, 2H), 2.48ꢀ2.54 (m, 1H), 2.21ꢀ2.24 (m, 1H); 13C
NMR (125 MHz, CDCl3): δ = 175.1, 172.2, 153.0, 134.7, 126.4, 125.6, 123.2, 121.9, 62.7, 47.1, 30.4, 28.9, 26.6;
IR (KBr pellet): ν bar = 3543, 3061, 2952, 1696, 1557, 1436, 1421, 1391, 1312, 1277, 1239, 1111, 1036, 935, 799,
763 cmꢀ1; HRMS (ESI): Exact mass calcd for C12H13N2OS [M+H]+, 233.0743; Found: 233.0745.
N-(2-(1,3-dimethyl-2-oxoindolin-3-yl)ethyl)-N-methylacetamide (5a)
1
Yellow semiꢀsolid, 42 mg, 81% yield. H NMR (400 MHz, CDCl3): δ = 7.27ꢀ7.35 (m, 1H), 7.22ꢀ7.24 (m, 1H),
7.09ꢀ7.15 (m, 1H), 6.85ꢀ6.91 (m, 1H), 3.25 (s, 3H), 2.8ꢀ3.3 (m, 2H), 2.82 (s, 3H), 1.9ꢀ3.3 (m, 2H), 1.90 (s, 3H),
1.40 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 180.0, 170.2, 143.1, 133.1, 128.3, 122.8, 122.5, 108.4, 46.9, 43.6,
36.1, 34.5, 26.2, 24.4, 21.7; IR (KBr pellet): ν bar = 2960, 2924, 1705, 1639, 1484, 1468, 1380, 1350, 1265, 1176,
1118, 1010, 989, 886 cmꢀ1; HRMS (ESI): Exact mass calcd for C15H21N2O2 [M+H]+, 261.1598; Found: 261.1597.
N-(2-(5-fluoro-1,3-dimethyl-2-oxoindolin-3-yl)ethyl)-N-methylacetamide (5b)
Yellow solid, 25 mg, 45% yield. Mp = 103ꢀ105 oC. 1H NMR (400 MHz, CDCl3): δ = 6.96ꢀ7.04 (m, 2H), 6.75ꢀ6.84
(m, 1H), 3.21 (s, 3H), 2.8ꢀ3.3 (m, 2H), 2.84 (s, 3H), 1.9ꢀ2.3 (m, 2H), 1.91 (s, 3H), 1.38 (s, 3H); 13C NMR (125
MHz, CDCl3): δ = 179.7, 170.2, 160.4 (d, JFꢀC = 237.9 Hz), 139.1, 135.0, 114.7, 110.6, 108.9, 47.1, 43.4, 36.1,
34.6, 26.4, 24.2, 21.7; IR (KBr pellet): ν bar = 2968, 2929, 1709, 1644, 1494, 1470, 1383, 1352, 1277, 1183, 1118,
1012, 904, 872 cmꢀ1; HRMS (ESI): Exact mass calcd for C15H20FN2O2 [M+H]+, 279.1503; Found: 279.1503.
N-(2-(5-chloro-1,3-dimethyl-2-oxoindolin-3-yl)ethyl)acetamide (5c)
1
Yellow oil, 40 mg, 71% yield. H NMR (400 MHz, CDCl3): δ = 7.27ꢀ7.33 (m, 1H), 7.22 (s, 1H), 6.77ꢀ6.84 (m,
1H), 3.21 (s, 3H), 2.9ꢀ3.2 (m, 2H), 2.83 (s, 3H), 1.9ꢀ2.3 (m, 2H), 1.90 (s, 3H), 1.38 (s, 3H); 13C NMR (125 MHz,
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CDCl3): δ = 179.4, 178.9, 170.1, 141.7, 134.9, 127.9, 122.9, 109.3, 46.8, 43.3, 36.0, 34.5, 26.3, 24.4, 21.6; IR (KBr
pellet): ν bar = 2968, 2930, 1720, 1650, 1609, 1488, 1453, 1360, 1348, 1276, 1178, 1138, 1118, 890 cmꢀ1; HRMS
(ESI): Exact mass calcd for C14H18ClN2O2 [M+H]+, 281.1051; Found: 281.1053.
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(2-(5-bromo-1,3-dimethyl-2-oxoindolin-3-yl)ethyl)-N-methylacetamide (5d)
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Yellow oil, 47 mg, 69% yield. H NMR (400 MHz, CDCl3): δ = 7.45ꢀ7.48 (m, 1H), 7.40 (s, 1H), 6.72ꢀ6.79 (m,
1H), 2.8ꢀ3.3 (m, 2H), 3.20 (s, 3H), 2.82 (s, 3H), 1.9ꢀ2.3 (m, 2H), 1.88 (s, 3H), 1.37 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ = 179.3, 170.1, 142.3, 135.3, 131.2, 125.6, 115.5, 109.8, 46.7, 43.3, 36.0, 33.8, 26.3, 24.5, 21.6; IR (KBr
pellet): ν bar = 2967, 2928, 1712, 1643, 1606, 1487, 1446, 1363, 1345, 1273, 1173, 1129, 1108, 879 cmꢀ1; HRMS
(ESI): Exact mass calcd for C15H20BrN2O2 [M+H]+, 339.0703; Found: 339.0705.
N,N,2-trimethylphenanthridine-6-carboxamide (7)
Colorless oil, 37 mg, 71% yield. 1H NMR (400 MHz, CDCl3): δ = 8.67 (d, J = 8.4 Hz, 1H), 8.40 (s, 1H), 8.09 (t, J
= 7.2 Hz, 2H), 7.88 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.60ꢀ7.62 (m, 1H), 3,32 (s, 3H), 2.94 (s, 3H), 2.67
(s, 3H); 13C NMR (125 MHz, CDCl3): δ = 162.1, 158.7, 138.0, 137.5, 135.2, 134.3, 133.1, 132.1, 131.3, 129.3,
129.1, 128.0, 121.6, 118.6, 29.6, 20.8, 20.7; IR (KBr pellet): ν bar = 3026, 2920, 2866, 1693, 1592, 1517, 1442,
1290, 1153, 1024, 770, 629, 607 cmꢀ1; HRMS (ESI): Exact mass calcd for C17H17N2O [M+H]+, 265.1335; Found:
265.1336.
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: huang_jinbo@gibh.ac.cn; zhu_qiang@gibh.ac.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful for financial support of this work by National Science Foundation of China (21202167,
21272233, 21472190 and 21532009) and the Science Foundation of Guangdong Province, China
(2014A030313796) for financial support of this work.
1
Supporting Information Available: H and 13C NMR spectra of all the synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
REFERENCES
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