Access to Thiazole via Copper-Catalyzed [3+1+1]-Type Condensation Reaction under Redox-Neutral Conditions

Article abstract of DOI:10.1021/acs.joc.6b02124

A new strategy for thiazoles via copper-catalyzed [3+1+1]-type condensation reaction from oximes, anhydrides and potassiumthiocyanate (KSCN) is developed herein. The transformation has good functional group tolerance and various thiazoles were formed smoothly in good to excellent yields under mild reaction conditions. This process involves copper-catalyzed N-O/C-S bond cleavages, activation of vinyl sp² C-H bond, and C-S/C-N bond formations which are under redox-neutral conditions as well as operational simplicity.

Full text of DOI:10.1021/acs.joc.6b02124

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Note
Access to Thiazole via Copper-Catalyzed [3+1+1]-Type
Condensation Reaction under Redox-Neutral Conditions
Xiaodong Tang, Jidan Yang, Zhongzhi Zhu, Meifang Zheng, Wanqing Wu, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02124 • Publication Date (Web): 21 Oct 2016
Downloaded from http://pubs.acs.org on October 21, 2016
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Access to Thiazole via CopperꢀCatalyzed [3+1+1]ꢀType
Condensation Reaction under RedoxꢀNeutral Conditions
Xiaodong Tang, Jidan Yang, Zhongzhi Zhu, Meifang Zheng, Wanqing Wu
and Huanfeng Jiang*
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School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: jianghf@scut.edu.cn
R2
OH
CuI (10 mol %)
KSCN (2 equiv)
N
N
S
+
(R2CO)2O
R
R
toulene, N2
120 oC
R1
R1
30 examples
up to 85 % yield
Abstract: A new strategy for thiazoles via copperꢀcatalyzed [3+1+1]ꢀtype
condensation reaction from oximes, anhydrides and potassiumthiocyanate (KSCN) is
developed herein. The transformation has good functional group tolerance and various
thiazoles were formed smoothly in good to excellent yields under mild reaction
conditions. This process involves copperꢀcatalyzed NꢀO/CꢀS bond cleavages,
activation of vinyl sp2 CꢀH bond and CꢀS/CꢀN bond formations which is under
redoxꢀneutral conditions well as operational simplicity.
The thiazole ring systems are widely located in natural products and pharmaceuticals.1
Until now, there are some methods for the synthesis of thiazoles. The classical
method is wellꢀknown Hantzsch reaction, which is the condensation of thioamide with
αꢀhaloketones.2 However, the synthesis of αꢀhaloketone involves halogenation of
ketone that causes environmental pollution. Analogously, the epoxides and
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propargylic alcohols are also used for the synthesis of thiazoles with thioamide.3
Other ways to build thiazole ring has also been reported. Banert et al. reported a
method for thiazoles via coupling of allenyl isothiocyanates with nucleophiles.4a
Sheldrake and McDonald et al. illustrated the reaction of N,Nꢀdiformylaminomethyl
aryl ketones and phosphorus pentasulfide to produce 5ꢀarylthiazole.4b In addition,
thiazoles could be synthesized by iron or palladiumꢀcatzlyzed reactions of vinyl
azides with potassium thiocyanate.4c,d However, all these methods have some
limitations, such as nonꢀavailability of raw materials, poor functional group tolerance,
and the use of equivalent amount of oxidants.
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Oximes are widely used for the construction of amides and nitriles.5 In addition, they
were widely employed for preparing the nitrogenꢀbearing heterocyclic compounds via
SN2 reaction,6 radical cyclization.7 In the late 20th century, Narasaka et al. seminally
studied
palladiumꢀcatalyzed
intramolecular
Heckꢀtype
amination
and
copperꢀcatalyzed cyclization of oxime derivatives.8 Recently, more and more
chemists gave their attentions to the transitionꢀmetal catalyzed CꢀH functionalization
with oxime derivatives served as both reactants and internal oxidants.9 These
reactions using internal oxidants have many advantages such as mild reaction
conditions, high selectivity and good functional group tolerance. More and more
transformations about oxime and its derivatives have been realized by rhodium,10
ruthenium,11 palladium12 and copper.13
Scheme 1. Our previous work and this work
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Our previous work
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OAc
R1
O
NH2
N
Cu cat.
SO2R2
SO2R2
hydrolysis
R2SO2Na
(a)
+
R
R
R
R1
R1
This work
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OH
R1
N
R2
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NH2
R
(b)
R
(R2CO)2O
N
SCN
Cu cat.
S
R1
R
cyclization
R1
(R2CO)2O
KSCN
In recent years, we focused on the transformations of oxime and its derivatives.14 In
our previous work, we developed a copperꢀcatalyzed synthesis of sulfone derivatives
via the sulfonylation of oxime acetates with sodium sulfinates. The
βꢀsulfonylvinylamines could be obtained in good yields and βꢀketosulfones also be
efficiently generated upon hydrolysis by silica gel (Scheme 1a).14a Herein, we disclose
a novel method for thiazoles via copperꢀcatalyzed [3+1+1]ꢀcyclization reaction from
oximes, anhydrides and potassium thiocyanate (Scheme 1b).
At the start of our studies, we used acetophenone oxime (1a) and acetic anhydride (2a)
as model substrates to screen catalysts, solvents, and sulfur sources and the results
were summarized in Table 1. Initial attempts were performed with a catalytic amount
of CuI, potassium thiocyanate (KSCN) as sulfur sources and DCE as solvent under N2
atmosphere. We were excited that the product 2ꢀmethylꢀ4ꢀphenylthiazole (3a) was
obtained in 33% GC yield (Table 1, entry 1). Various solvents, such as 1,4ꢀdioxane,
CH3CN and toluene were examined (entries 2ꢀ4). To our delight, toluene gave a
satisfactory yield (81% GC yield). Different copper salts such as CuCl, CuBr, CuBr2,
Cu(OAc)2, and Cu(OTf)2 could also catalyze this reaction, but none of them were
found to be more efficient than CuI (entries 5ꢀ9). Iron salts also showed the catalytic
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activity in this transformation (entries 10ꢀ13). However, when other metals such as
PdCl2 and AgCl were used as catalysts, no products were obtained (entries 14ꢀ15).
Other sulfur sources such as NaSCN, NH4SCN, S and Na2S were screened, and
except NaSCN could afford the product in 46% GC yield, while others did not form
the product (entries 16ꢀ19). Thus, the optimal catalytic system for this
copperꢀcatalyzed [3+1+1]ꢀtype cyclization reaction was: 1a (0.5 mmol), 2a (1.5
mmol), KSCN (1.0 mmol), CuI (10 mol %), in toluene (3 mL) at 120 °C under N2 for
24 h.
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Table 1. Optimization of the Reaction Conditions a
Yield b
(%)
entry
[M]
Solvent
[S]
CuI
CuI
DCE
1,4ꢀdioxane
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
4
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
KSCN
NaSCN
NH4SCN
S
33
1
2
15
CuI
42
3
4
CuI
81 (73)
68
CuCl
5
CuBr
CuBr2
Cu(OAc)2
Cu(OTf)2
Fe(OAc)2
FeBr2
FeBr3
FeCl3
PdCl2
AgCl
CuI
72
6
73
7
75
8
60
9
70
10
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12
13
14
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16
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50
47
55
n.d.
n.d.
46
CuI
n.d.
n.d.
CuI
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CuI
toluene
Na2S
n.d.
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a Reaction conditions: unless otherwise noted, all reactions were performed with 1a (0.5 mmol), 2a (1.5 mmol), [S]
(1.0 mmol), [M] (10 mol %), in solvent (3 mL) at 120 oC under N2 for 24 h. b Determined by GC and dodecane as
internal standard. Number in parentheses is yield of isolated product. n.d. = not detected.
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With the optimized reaction conditions in hand, the generality of this
copperꢀcatalyzed [3+1+1]ꢀtype condensation reaction of oximes, anhydrides and
potassium thiocyanate (KSCN) was examined. The scope of the oximes was first
explored by the adoption of acetic anhydride as the coupling partner, and the results
were summarized in Table 2. Both electronꢀrich and electronꢀpoor paraꢀsubstituted
acetophenone oximes participated in good yields (3aꢀ3k). In addition, the substrates
with methoxy at the metaꢀ, or orthoꢀposition could also react smoothly to afford the
corresponding products in good yields (3lꢀ3m). On the whole, acetophenone oximes
with an electronꢀdonating group showed higher reactivity than those with an
electronꢀwithdrawing group. It is worth noting that the disubstituted acetophenone
oximes were also suitable substrates, and the corresponding products were formed in
66% and 78% yields, respectively (3nꢀ3o). Notably, the reactions of other aromatic
ring oximes were also performed smoothly and afforded the corresponding products
in 85% and 54% yields (3pꢀ3q). Propiophenone oxime was available for the
construction of 2,4,5ꢀsubstituted thiazoles in 51% yield (3r). It was worth mentioning
that alkyl oximes were also suitable for this transformation and moderate yields could
be obtained (3sꢀ3u).
Table 2. Cu(I)ꢀcatalyzed synthesis of thiazoles from various oxime and acetic
anhydride a,b
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a Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), KSCN (1.0 mmol), CuI (10 mol %), toluene (3.0 mL), under
N2 at 120 oC for 24 h. b Isolated yield based on 1.
Next, the scope of anhydrides was examined in this reaction (Table 3). For various
alkyl anhydrides, including propionic, butyric, isobutyl, trimethylacetic and
cyclohexanecarboxylic anhydrides, the reactions proceeded smoothly to afford the
desired products 3vꢀ3z in good yields. However, benzoic anhydride could not undergo
the transformation and acetophenone oxime was converted to acetophenone.
Table 3. Cu(I)ꢀcatalyzed synthesis of thiazoles from acetophenone oxime and
various anhydride a, b
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a Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), KSCN (1.0 mmol), CuI (10 mol %), toluene (3.0 mL), under
N2 at 120 oC for 24 h. b Isolated yield based on 1a.
Scheme 2. Synthesis of naphtho[1,2ꢀd]thiazoles from 1ꢀtetralone oximes
(1) KSCN (1.0 mmol)
Ac2O (1.5 mmol)
OH
CuI (10 mol %)
toulene, N2
120 oC
N
N
S
R
R
(2) DDQ (0.6 mmol)
toulene, 120 oC
0.5 mmol
4a
, R= H, 58%
4b, R= 7-OCH3, 54%
4c, R= 8-OCH3, 52%
4d
, R= 8-Br, 48%
In order to further expand our methods, we used 1ꢀtetralone oximes to synthesize the
corresponding thiazoles, which could be obtained in moderate yields (4aꢀ4d) (Scheme
2) by further oxidation with DDQ (2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone).
In order to understand more clearly about the reaction mechanism, some control
experiments were performed (Scheme 3). When we directly used oxime acetate as the
substrate, the yield of 3a was 69%. In this case, two equivalents of acetic anhydride
was used [Eq. (1)]. When the radical trapping reagents (BHT) was added to the
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reaction system, no products were detected, which suggested a radical process might
be involved in this transformation [Eq. (2)]. In addition, When 1,1ꢀdiphenylethylene
was added in our standard conditions, the product 3a was obtained in 65% yield and
1,1ꢀdiphenylethylene did not participate in the reaction. This control experiment
showed that no stable free radical was formed in the reaction [Eq. (3)]. The reaction
was also good with (Z)ꢀacetophenone oxime, which can proved this reaction not to be
a SN2ꢀtype process [Eq. (4)]. Further, we utilized sodium thiophenoxide to capture the
free radical produced by reduction of oxime acetate, however, no crossꢀcoupling
product was generated, while acetophenone and 1,2ꢀdiphenyldisulfane were obtained
instead [Eq. (5)]. When the reaction was performed with compound 5 under the
standard conditions, the product 3a was not detected [Eq. (6)]. Therefore, compound 5
could be ruled out as the major intermediate in the transformation. Furthermore, when
the reaction of oxime acetate A with KSCN was performed in the presence of CuI but
in the absence of acetic anhydride, 4ꢀphenylthiazolꢀ2ꢀamine (6) was formed. And the
amine (6) was further converted to compound 6′ and 6′′ via the reaction with acetic
acid or acetophenone generated in situ [Eq. (7)]. When we subjected intermediate A
to the standard conditions, the product 3a was formed in 71% yield [Eq. (8)].
Scheme 3. Mechanistic studies
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Based on the control experiments and previous reports,13,14 a possible mechanism was
proposed in Scheme 4. Oxime acetate A is first generated from the acylation of
acetophenone ketoxime. Therewith, the imineꢀfree radical B is formed from A by
13dꢀe,14
singleꢀelectron transfer (SET) reduction with CuI.
The intermediate B is
quickly isomerized to intermediate C,13e and trapping of intermediate C with CuII and
thiocyanate anion provides alkylꢀCuIII intermediate D.13f Intermediate E is formed via
reductive elimination of Cu(I) from intermediate D.13f After isomerization and
acylation process, intermediate G would be obtained. Subsequently, intermediate I is
generated by twoꢀstep hydrolytic process under acidic conditions. Intermediate J is
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formed by losing carbon dioxide and ammonia of intermediate I under heating
conditions. Finally, the intramolecular nucleophilic attack of intermediate J, followed
by intramolecular dehydration to give product 3a.
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Scheme 4. Proposed Mechanism
In conclusion, an efficient and novel synthesis of thiazoles via copperꢀcatalyzed
[3+1+1]ꢀtype reaction from oximes, anhydride and KSCN has been developed.
Furthermore, the reaction was accomplished through NꢀO/CꢀS bond cleavages, and
new CꢀS/CꢀN bond formations, along with the activation of vinyl sp2 CꢀH bond. Most
of all, this transformation was realized under redoxꢀneutral conditions which provides
a new way for the construction of thiazoles from oximes.
Experimental Section
General Information.
Melting points were measured with a melting point instrument and were
1
uncorrected. H and 13C NMR spectra were recorded using a 400 MHz NMR
spectrometer. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm,
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respectively, and chloroform was used as the solvent with TMS as the internal
standard. GCꢀMS was obtained using electron ionization. HRMS was obtained with a
LCMSꢀITꢀTOF mass spectrometer. TLC was performed by using commercially
prepared 100ꢀ400 mesh silicagel plates, and visualization was effected at 254 nm. IR
spectra were obtained either as potassium bromide pellets or as liquid films between
two potassium bromide pellets with an infrared Fourier spectrometer. Highꢀresolution
mass spectra (ESI) were obtained with a LCMSꢀITTOF mass spectrometer. Starting
materials of oximes were prepared according to previously reported methods.15
General Procedure for Thiazole Products 3.
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Oxime 1 (0.5 mmol), anhydride 2 (1.5 mmol), CuI (10 mol %), KSCN (1.0 mmol), in
toluene (3 mL) were added to a 25 mL Schlenk tube with magnetic stirrer bar. The
mixture was stirred at 120 °C (oil bath temperature) for 24 h under N2. After the
reaction was finished (monitored by TLC), the mixture was cooled to room
temperature. The reaction was quenched with H2O (10 mL) and extracted with EtOAc
(3×10 mL). The combined organic layers were dried over anhydrous Na2SO4 and the
solvent was removed under vacuum. The crude product was purified by column
chromatography EtOAc/hexanes (1:20) on silica gel.
General Procedure for Naphtho[1,2ꢀd]thiazole Products 4.
Oxime 1 (0.5 mmol), anhydride (1.5 mmol), CuI (10 mol %), KSCN (1.0 mmol), in
toluene (3 mL) were added to a 25 mL Schlenk tube with magnetic stirrer bar. The
mixture was stirred at 120 °C (oil bath temperature) for 24 h under N2. After the
reaction was finished (monitored by TLC), the mixture was cooled to room
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temperature. The reaction was quenched with H2O (10 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and the
solvent was removed under vacuum. The crude products were dissolved in toluene (2
mL) with DDQ (0.6 mmol) and added to a 25 mL Schlenk tube with magnetic stirrer
bar. The mixture was stirred at 120 °C (oil bath temperature) for 10 h under N2. After
the reaction was finished (monitored by GCꢀMS), the mixture was cooled to room
temperature. The reaction was quenched with H2O (10 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and the
solvent was removed under vacuum. Finally, it was purified by column
chromatography EtOAc/hexanes (1:20) on silica gel.
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2ꢀMethylꢀ4ꢀphenylthiazole (3a)16 : Red solid (64 mg, 73 %), m.p. = 64ꢀ65 °C. 1H NMR (400
MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 6.9 Hz, 2H), 7.36 – 7.29 (m, 2H), 2.78 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 165.8, 155.1, 134.5, 128.7, 127.9, 126.3, 112.2, 19.3. MS (EI,
70 eV) m/z : 175 (M+), 134, 108, 89, 77. IR (KBr) ν (cmꢀ1): 2924, 1500, 1375, 1171, 1027, 731.
2ꢀMethylꢀ4ꢀ(pꢀtolyl)thiazole (3b)16 : Brown oil (59 mg, 62 %). 1H NMR (400 MHz, CDCl3) δ
7.77 (d, J = 8.1 Hz, 2H), 7.24 (s, 1H), 7.22 (d, J = 7.9 Hz, 2H), 2.77 (s, 3H), 2.38 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 165.8, 155.2, 137.8, 131.8, 129.4, 126.2, 111.4, 21.2, 19.3. MS (EI, 70
eV) m/z: 189 (M+), 148, 115, 91, 77. IR (KBr) ν (cmꢀ1): 2924, 1503, 1265, 1172, 832, 744.
4ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀyl)ꢀ2ꢀmethylthiazole (3c) : Red solid (68 mg, 54 %), m.p. = 108ꢀ109 °C.
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz, 2H), 7.67 – 7.62 (m, 4H), 7.47 – 7.43 (m, 2H),
7.39 – 7.32 (m, 2H), 2.79 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.0, 154.8, 140.7, 133.6,
128.8, 127.4, 127.4, 127.0, 126.7, 112.3, 19.4. MS (EI, 70 eV) m/z : 251 (M+), 210, 165, 152, 104,
91. IR (KBr) ν (cmꢀ1): 2925, 1602, 1406, 1169, 848, 743, 692. HRMSꢀESI (m/z): calcd for
C16H14NS, [M+H]+ : 252.0841; found, 252.0845.
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4ꢀ(4ꢀFluorophenyl)ꢀ2ꢀmethylthiazole (3d) : Brown oil (63 mg, 65 %).1H NMR (400 MHz,
CDCl3) δ 7.87 – 7.81 (m, 2H), 7.23 (s, 1H), 7.13 – 7.06 (m, 2H), 2.76 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 166.1, 162.6 (d, J = 246 Hz), 154.1, 130.8 (d, J = 3 Hz), 128.0 (d, J = 8 Hz), 115.6
(d, J = 22 Hz), 111.8, 19.3. MS (EI, 70 eV) m/z : 193 (M+), 152, 132, 107, 76. IR (KBr) ν (cmꢀ1):
2926, 1600, 1505, 1167, 847, 745. HRMSꢀESI (m/z): calcd for C10H9FNS, [M+H]+ :194.0434;
found, 194.0432.
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4ꢀ(4ꢀChlorophenyl)ꢀ2ꢀmethylthiazole (3e)16 : Red solid (67 mg, 64 %), m.p. = 121ꢀ122 °C. 1H
NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.29 (s, 1H), 2.77 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 166.3, 154.0, 133.7, 133.0, 128.9, 127.6, 112.6, 19.3. MS (EI,
70 eV) m/z: 209 (M+), 168, 133, 104, 89. IR (KBr) ν (cmꢀ1): 2924, 1506, 1402, 850, 826, 744.
4ꢀ(4ꢀBromophenyl)ꢀ2ꢀmethylthiazole (3f)17: Yellow solid (79 mg, 62 %), m.p. = 132ꢀ133 °C.
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.30 (s, 1H),
2.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.2, 153.9, 133.4, 131.8, 127.9, 122.0, 112.7, 19.3.
MS (EI, 70 eV) m/z : 255 (M+), 211, 133, 89, 75. IR (KBr) ν (cmꢀ1): 1638, 1505, 1170, 825, 743.
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4ꢀ(4ꢀIodophenyl)ꢀ2ꢀmethylthiazole (3g): White solid (80 mg, 53 %), m.p. = 141ꢀ143 °C. H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.31 (s, 1H), 2.76 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 166.2, 154.0, 137.8, 134.0, 128.1, 112.3, 93.6, 19.3. MS (EI,
70 eV) m/z : 301 (M+), 260, 133, 89, 74. IR (KBr) ν (cmꢀ1): 2923, 1504, 1170, 848, 743.
HRMSꢀESI (m/z): calcd for C10H9INS, [M+H]+: 301.9495; found, 301.9490.
4ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀmethylthiazole (3h)16 : Yellow solid (84 mg, 82 %), m.p. = 71ꢀ73 °C.
1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 2H), , 7.16 (s, 1H), 6.94 (d, J = 8.6 Hz, 2H),
3.83 (s, 3H), 2.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.7, 159.5, 154.9, 127.6, 127.5, 114.1,
110.5, 55.3, 19.3. MS (EI, 70 eV) m/z : 205 (M+), 190, 164, 149, 121, 77. IR (KBr) ν (cmꢀ1): 2934,
1505, 1279, 1174, 1032, 835, 749.
4ꢀ(4ꢀ(Benzyloxy)phenyl)ꢀ2ꢀmethylthiazole (3i): White solid (118 mg, 84 %), m.p. =
105ꢀ106 °C.1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.40
(t, J = 7.3 Hz, 2H), 7.37 – 7.30 (m, 1H), 7.17 (s, 1H), 7.02 (d, J = 8.6 Hz, 2H), 5.11 (s, 2H), 2.77
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.8, 158.7, 154.9, 136.9, 128.6, 128.0, 127.8, 127.6,
127.5, 115.1, 110.6, 70.1, 19.3. MS (EI, 70 eV) m/z : 281 (M+), 190, 162, 121, 91, 65. IR (KBr) ν
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(cmꢀ1): 2920, 1607, 1248, 1172, 1013, 833, 745. HRMSꢀESI (m/z): calcd for C17H16NOS, [M+H]+ :
282.0947; found, 282.0945.
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Methyl 4ꢀ(2ꢀmethylthiazolꢀ4ꢀyl)benzoate (3j): White solid (62 mg, 53 %), m.p. = 112ꢀ113 °C.
1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.3 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.43 (s, 1H),
3.92 (s, 3H), 2.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.9, 166.3, 154.0, 138.6, 130.1, 129.3,
126.1, 114.3, 52.1, 19.3. MS (EI, 70 eV) m/z : 233 (M+), 202, 161, 133, 89, 66. IR (KBr) ν (cmꢀ1):
1715, 1608, 1278, 856, 747. HRMSꢀESI (m/z): calcd for C12H12NO2S, [M+H]+ : 234.0583; found,
234.0583.
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2ꢀMethylꢀ4ꢀ(4ꢀnitrophenyl)thiazole (3k)18 : Red solid (57 mg, 52 %), m.p. = 133ꢀ134 °C. H
NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.6 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 2.78 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 166.9, 152.7, 147.2, 140.3, 126.8, 124.2, 115.9, 19.3. MS (EI,
70 eV) m/z : 220 (M+), 190, 174, 149, 89, 77. IR (KBr) ν (cmꢀ1): 2925, 1597, 1502, 1339, 1170,
849, 746.
4ꢀ(2ꢀMethoxyphenyl)ꢀ2ꢀmethylthiazole (3l) : Yellow oil (67 mg, 65 %). 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.28 –7.23 (m, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.95
(d, J = 8.2 Hz, 1H), 3.90 (s, 3H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 163.6, 156.7, 150.7,
130.1, 128.7, 123.4, 120.9, 116.6, 111.1, 55.4, 19.2. MS (EI, 70 eV) m/z : 205 (M+), 190, 164, 131,
91, 77. IR (KBr) ν (cmꢀ1): 2931, 1511, 1478, 1243, 1171, 1024, 756, 639. HRMSꢀESI (m/z): calcd
for C11H12NOS, [M+H]+ : 206.0634; found, 206.0635.
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4ꢀ(3ꢀMethoxyphenyl)ꢀ2ꢀmethylthiazole (3m): Red oil (74 mg, 72 %). H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 8.1 Hz, 2H), 7.35 – 7.28 (m, 2H), 6.88 (d, J = 7.7 Hz, 1H), 3.87 (s, 3H), 2.77
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.8, 160.0, 155.0, 135.9, 129.7, 118.8, 114.0, 112.6,
111.7, 55.4, 19.3. MS (EI, 70 eV) m/z : 205 (M+), 175, 134, 121, 91, 77. IR (KBr) ν (cmꢀ1): 2929,
1605, 1521, 1244, 1043, 792, 744. HRMSꢀESI (m/z): calcd for C11H12NOS, [M+H]+: 206.0634;
found, 206.0633.
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4ꢀ(3,4ꢀDimethylphenyl)ꢀ2ꢀmethylthiazole (3n): Red oil (67 mg, 66 %). H NMR (400 MHz,
CDCl3) δ 7.68 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.25 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 2.78 (s, 3H),
2.32 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.7, 155.3, 136.9, 136.5, 132.2, 139.0,
127.6, 123.7, 111.4, 19.8, 19.6, 19.3. MS (EI, 70 eV) m/z : 203 (M+), 162, 147, 128, 115, 77. IR
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(KBr) ν (cmꢀ1): 2920, 1501, 1378, 1178, 815, 743. HRMSꢀESI (m/z): calcd for C12H14NS,
[M+H]+ : 204.0841; found, 204.0841.
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4ꢀ(Benzo[d][1,3]dioxolꢀ5ꢀyl)ꢀ2ꢀmethylthiazole (3o): White solid (85 mg, 78 %), m.p. =
90ꢀ91 °C. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.13 (s, 1H), 6.84
(d, J = 8.1 Hz, 1H), 5.97 (s, 2H), 2.74 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.7, 154.8, 148.0,
147.5, 129.0, 120.2, 111.0, 108.5, 106.9, 101.2, 19.3. MS (EI, 70 eV) m/z : 219 (M+), 178, 148,
120, 94. IR (KBr) ν (cmꢀ1): 2896, 1520, 1286, 1240, 1040, 931, 741. HRMSꢀESI (m/z): calcd for
C11H10NO2S, [M+H]+ : 220.0427; found, 220.0426.
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2ꢀMethylꢀ4ꢀ(naphthalenꢀ1ꢀyl)thiazole (3p): Brown oil (96 mg, 85 %). H NMR (400 MHz,
CDCl3) δ 8.30 – 8.23 (m, 1H), 7.91ꢀ7.88 (m, 2H), 7.68 (d, J = 7.0 Hz, 1H), 7.54ꢀ7.50 (m, 3H),
7.28 (s, 1H), 2.85 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.4, 154.6, 133.8, 132.8, 131.5, 128.7,
128.2, 127.4, 126.3, 125.8, 125.8, 125.2, 116.3, 19.3. MS (EI, 70 eV) m/z : 225 (M+), 184, 152,
139, 92, 79. IR (KBr) ν (cmꢀ1): 2923, 1508, 1183, 1161, 805, 778. HRMSꢀESI (m/z): calcd for
C14H12NS, [M+H]+ : 226.0685; found, 226.0688.
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2ꢀMethylꢀ4ꢀ(thiophenꢀ2ꢀyl)thiazole (3q) : Brown oil (49 mg, 54 %). H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (t, J =
4.3 Hz, 1H), 2.76 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.1, 149.5, 138.4, 127.7, 125.0, 123.9,
111.0, 19.2. MS (EI, 70 eV) m/z: 181 (M+), 140, 96, 82, 68. IR (KBr) ν (cmꢀ1): 3106, 2923, 1549,
1164, 804, 735, 699. HRMSꢀESI (m/z): calcd for C8H8NS2, [M+H]+: 182.0093; found, 182.0089.
2,5ꢀDimethylꢀ4ꢀphenylthiazole (3r)19 : Yellow oil (48 mg, 51 %). 1H NMR (400 MHz, CDCl3)
δ 7.62 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.4 Hz, 1H), 2.69 (s, 3H), 2.51
(s,3H). 13C NMR (100 MHz, CDCl3) δ 162.0, 150.4, 134.9, 128.6, 128.4, 127.5, 19.0, 12.5. MS
(EI, 70 eV) m/z: 189 (M+), 175, 147, 132, 104, 77. IR (KBr) ν (cmꢀ1): 2924, 1504, 1442, 1189, 771,
700.
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4ꢀButylꢀ2ꢀmethylꢀ5ꢀpropylthiazole (3s): Yellow oil (47 mg, 48 %). H NMR (400 MHz,
CDCl3) δ 2.70 – 2.56 (m, 7H), 1.65 – 1.58 (m, 4H), 1.40 – 1.33 (m, 2H), 0.97 – 0.90 (m, 6H). 13
C
NMR (100 MHz, CDCl3) δ 161.7, 151.6, 131.4, 32.1, 28.9, 28.2, 25.3, 22.6, 19.0, 13.9, 13.7. MS
(EI, 70 eV) m/z: 197 (M+), 182, 155, 127, 85, 79. IR (KBr) ν (cmꢀ1): 2927, 2858, 1459, 1184, 801.
HRMSꢀESI (m/z): calcd for C11H20NS, [M+H]+: 198.1311; found, 198.1314.
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NMR (400 MHz, CDCl3) δ 2.96 – 2.86 (m, 2H), 2.81 – 2.71 (m, 2H), 2.57 (s, 3H), 1.83 – 1.82 (m,
2H), 1.75 – 1.66 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 159.9, 154.5, 131.8, 31.7, 31.5, 28.0,
26.6, 26.3, 18.7. MS (EI, 70 eV) m/z: 167 (M+), 126, 111, 93, 91, 77. IR (KBr) ν (cmꢀ1): 2923,
2853, 1653, 1089,802, 684. HRMSꢀESI (m/z): calcd for C9H14NS, [M+H]+: 168.0841; found,
168.0835.
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2ꢀMethylꢀ4,5,6,7,8,9ꢀhexahydrocycloocta[d]thiazole (3u): Yellow oil (48 mg, 53 %). 1H
NMR (400 MHz, CDCl3) δ 2.81 – 2.80 (m, 4H), 2.61 (s, 3H), 1.71 – 1.66 (m, 4H), 1.41 (s, 4H).
13C NMR (100 MHz, CDCl3) δ 161.4, 152.4, 130.4, 31.4, 29.7, 28.1, 26.0, 25.5, 24.5, 19.0. MS
(EI, 70 eV) m/z: 181 (M+), 153, 140, 125, 107, 79. IR (KBr) ν (cmꢀ1): 2922, 2852, 1459, 958, 801.
HRMSꢀESI (m/z): calcd for C10H16NS, [M+H]+: 182.0998; found, 182.1000.
2ꢀEthylꢀ4ꢀphenylthiazole (3v): Red oil (68 mg, 72 %). 1H NMR (400 MHz, CDCl3) δ 7.90 (d,
J = 7.2 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.35 – 7.30 (m, 2H), 3.11 (q, J = 7.6 Hz, 2H), 1.45 (t, J =
7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.8, 155.0, 134.7, 128.7, 127.9, 126.4, 111.8, 27.1,
14.3. MS (EI, 70 eV) m/z : 189 (M+), 174, 134, 108, 89, 77. IR (KBr) ν (cmꢀ1): 2928, 1499, 1378,
1031, 731, 692. HRMSꢀESI (m/z): calcd for C11H12NS, [M+H]+: 190.0685; found, 190.0683.
4ꢀPhenylꢀ2ꢀpropylthiazole (3w): Red oil (64 mg, 63 %). 1H NMR (400 MHz, CDCl3) δ 7.90 (d,
J = 7.9 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.36 – 7.30 (m, 2H), 3.05 (t, J = 7.6 Hz, 2H), 1.96 – 1.83
(m, 2H), 1.07 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 171.3, 155.0, 134.7, 128.7, 127.9,
126.4, 111.9, 35.6, 23.5, 13.7. MS (EI, 70 eV) m/z : 203 (M+), 188, 175, 134, 89, 77. IR (KBr) ν
(cmꢀ1): 2928, 1498, 1444, 1168, 1022, 730, 692. HRMSꢀESI (m/z): calcd for C12H14NS, [M+H]+:
204.0841; found, 204.0839.
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2ꢀIsopropylꢀ4ꢀphenylthiazole (3x): Yellow oil (74 mg, 73 %). H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 7.4 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.35 – 7.29 (m, 2H), 3.55 – 3.23 (m, 1H), 1.47 (s,
3H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 178.1, 154.7, 134.7, 128.7, 128.0, 126.4, 111.4,
33.4, 23.3. MS (EI, 70 eV) m/z : 203 (M+), 188, 134, 108, 89, 77. IR (KBr) ν (cmꢀ1): 2927, 1602,
1445, 1070, 843, 774. HRMSꢀESI (m/z): calcd for C12H14NS, [M+H]+: 204.0841; found,
204.0839.
2ꢀ(Tertꢀbutyl)ꢀ4ꢀphenylthiazole (3y) : Yellow oil (80 mg, 74 %). 1H NMR (400 MHz, CDCl3)
δ 7.93 (d, J = 7.6 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.35 – 7.28 (m, 2H), 1.50 (s, 9H). 13C NMR
(100 MHz, CDCl3) δ 181.0, 154.7, 135.0, 128.6, 127.8, 126.4, 111.4, 37.8, 31.0. MS (EI, 70 eV)
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m/z: 217 (M+), 202, 175, 134, 102, 89. IR (KBr) ν (cmꢀ1): 2963, 1494, 1364, 1069, 731, 692.
HRMSꢀESI (m/z): calcd for C13H16NS, [M+H]+: 218.0998; found, 218.1000.
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7.91 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.36 – 7.30 (m, 2H), 3.15 – 3.00 (m, 1H), 2.23 –
2.20 (m, 2H), 1.90 – 1.87(m, 2H), 1.78 – 1.75 (m, 1H), 1.63 – 1.55 (m, 2H), 1.47 – 1.41 (m, 2H),
1.36 – 1.28 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 177.0, 154.7, 134.9, 128.7, 127.9, 126.4,
111.3, 42.8, 33.9, 26.1, 25.9. MS (EI, 70 eV) m/z: 243 (M+), 188, 175, 134, 89, 77. IR (KBr) ν
(cmꢀ1): 2957, 2853, 1494, 1447, 1184, 730, 691. HRMSꢀESI (m/z): calcd for C15H18NS, [M+H]+:
244.1154; found, 244.1156.
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2ꢀMethylnaphtho[1,2ꢀd]thiazole (4a) : Yellow solid (58 mg, 58 %), m.p. = 94ꢀ95 °C. 1H NMR
(400 MHz, CDCl3) δ 8.78 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H),
7.77 (d, J = 8.7 Hz, 1H), 7.70 – 7.64 (m, 1H), 7.61 – 7.54 (m, 1H), 2.95 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 165.9, 149.4, 131.9, 131.8, 128.3, 128.0, 126.8, 125.9, 125.3, 123.7, 118.8, 20.1.
MS (EI, 70 eV) m/z: 199 (M+), 158, 114, 79, 63. IR (KBr) ν (cmꢀ1): 2923, 2852, 1514, 1166, 804,
744. HRMSꢀESI (m/z): calcd for C12H10NS, [M+H]+: 200.0528; found, 200.0528.
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7ꢀMethoxyꢀ2ꢀmethylnaphtho[1,2ꢀd]thiazole (4b) : Red oil (62 mg, 54 %). H NMR (400
MHz, CDCl3) δ 8.65 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.31 –
7.28 (m, 1H), 7.25 (s, 1H), 3.94 (s, 3H), 2.92 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.1, 157.8,
149.7, 133.3, 129. 8, 125.4, 124.4, 123.6, 119.4, 118.6, 107.0, 55.4, 20.1. IR (KBr) ν (cmꢀ1): 2922,
2850, 1625, 1248, 1169, 1029, 752. MS (EI, 70 eV) m/z: 229 (M+), 214, 186, 145, 101, 69.
HRMSꢀESI (m/z): calcd for C13H12NOS, [M+H]+: 230.0634; found, 230.0629.
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8ꢀMethoxyꢀ2ꢀmethylnaphtho[1,2ꢀd]thiazole (4c) : Yellow oil (60 mg, 52 %). H NMR (400
MHz, CDCl3) δ 8.09 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.70 (s, 2H), 7.22 – 7.19 (m,
1H), 4.04 (s, 3H), 2.94 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.40, 158.7, 149.2, 132.5, 129.6,
129.6, 127.1, 125.1, 118.4, 116.3, 102.4, 55.6, 20.1. IR (KBr) ν (cmꢀ1): 2925, 2853, 1624, 1230,
1044, 831, 740.MS (EI, 70 eV) m/z: 229 (M+), 214, 186, 145, 114, 101, 69. HRMSꢀESI (m/z):
calcd for C13H12NOS, [M+H]+: 230.0634; found, 230.0633.
8ꢀBromoꢀ2ꢀmethylnaphtho[1,2ꢀd]thiazole (4d): Yellow solid (66 mg, 48 %), m.p. =
162ꢀ163 °C. 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.78
(d, J = 8.7 Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 8.7, 2.0 Hz, 1H), 2.93 (s, 3H). 13C
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NMR (100 MHz, CDCl3) δ 166.4, 148.5, 132.9, 130.3, 129.6, 129.3, 129.3, 126.3, 124.9, 121.1,
119.3, 20.1. MS (EI, 70 eV) m/z: 277 (M+), 198, 154, 113, 98, 78. IR (KBr) ν (cmꢀ1): 2922, 2853,
1644, 1263, 825, 756.HRMSꢀESI (m/z): calcd for C12H9BrNS, [M+H]+: 277.9634; found,
277.9631.
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Acknowledgements
We are grateful to the National Key Research and Development Program of China
(2016YFA0602900), the National Natural Science Foundation of China (21420102003), and the
Fundamental Research Funds for the Central Universities (2015ZY001) for financial support.
Supporting Information
1H and 13C NMR spectra for all compounds prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
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