Catalyst-Free Chemoselective Synthesis of 3,4-Dihydroquinazoline-2-thiones and 2-Imino[1,3]benzothiazines

Article abstract of DOI:10.1021/acs.joc.6b01232

A solvent-controlled catalyst-free chemoselective reaction was developed. Both 3,4-dihydroquinazoline-2-thiones and 2-imino[1,3]benzothiazines could be efficiently constructed by the reaction of 2-amino chalcones with isothiocyanates via two different chemoselective reactions depending on the solvents. The reaction was modulated by the solvents to proceed via either aza-Michael addition or thia-Michael addition as the major reaction with excellent yields.

Full text of DOI:10.1021/acs.joc.6b01232

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Note
Catalyst-free Chemoselective Synthesis of 3, 4-
dihydroquinazoline-2-thiones and 2-imino [1, 3] benzothiazines
Ting Xie, Yu Xiao, Shuai Zhao, Xiu-Qin Hu, and Peng-Fei Xu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Aug 2016
Downloaded from http://pubs.acs.org on August 13, 2016
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Catalyst-free Chemoselective Synthesis of 3, 4-dihydroquinazoline-2-thiones and
2-imino[1, 3]benzothiazines
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Ting Xie†, Yu Xiao†, Shuai Zhao‡, XiuꢀQin Hu*† and PengꢀFei Xu*†
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, P. R. China
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‡School of Pharmaceutical Engineering & Life Science, Changzhou University, Changzhou 213164, P. R. China
ABSTRACT: A solventꢀcontrolled catalystꢀfree chemoselective reaction was developed. Both of
3,4ꢀdihydroquinazolineꢀ2ꢀthiones and 2ꢀimino[1, 3]benzothiazines could be efficiently constructed
by the reaction of 2ꢀamino chalcones with isothiocyanates via two different chemoselective
reactions depending on the solvents. The reaction was modulated by the solvents to proceed via
either azaꢀMichael addition or thiaꢀMichael addition as the major reaction with excellent yields.
Chemoselective reactions are an enduring topic in organic synthesis. The strategy of using
controls such as solvents to direct reactions down different pathways to favor distinct products is a
wellꢀestablished approach and also an efficient methodology to gain access to chemoꢀdiversity1ꢀ15
.
However, the most practical solutions to switch the chemoselective reactive sites rely on the
catalysts, since finding an appropriate condition such as a solvent for efficiently and selectively
obtaining a certain product has been a longꢀstanding challenge. We were wondering whether or
not we could develop a catalystꢀfree chemoselestive reaction controlled only by a solvent instead
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of a catalyst. To realize that goal, an unavoidable obstacle was how to reach the transition state of
the reaction for the starting materials with a solvent to provide the desired product.16ꢀ20
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3, 4ꢀDihydroquinazolineꢀ2ꢀthiones21ꢀ28 and 2ꢀimino[1, 3]benzothiazines29ꢀ36 are valuable
heterocyclic moieties with broad biological and pharmaceutical activities. Numerous efficient
methods28,37ꢀ40 and novel procedures41ꢀ48 have been developed to produce these compounds.
Michael addition was the most common strategy that has been utilized to construct
both scaffolds, with this strategy, the initial product of the reaction was a thiourea intermediate
which underwent Michael addition to selectively form one of the core structures under certain
conditions.28,37,40,49ꢀ51 Kobayashi et al. reported that the 3ꢀ (2ꢀisothiocyanatophenyl) propanoic
derivatives reacted with secondary and primary amines to selectively construct
3,4ꢀdihydroquinazolineꢀ2ꢀthiones and 2ꢀaminoꢀ3,1ꢀbenzothiazines.52 Qi Shen et al. reported a
catalystꢀcontrolled chemoselective reaction with the corresponding skeletons delivered upon
reacting 2ꢀaminophenyl acrylates with isothiocyanates catalyzed by different lanthanide
complexes.53 It can be seen that the strategies for selectively producing these products required
either rigorous reaction conditions or costly catalysts. However, the use of heavy metal
compounds should better be avoided in the production of medicine due to their toxicity. Therefore,
it is still highly desirable to develop a novel practical catalystꢀfree chemoselective reaction. So far,
there have been no reports of switching between the reactive sites of the starting materials to
obtain different products by changing the experiment conditions. Here, we report the development
of the reaction which was modulated by the solvents to proceed via either azaꢀMichael addition or
thiaꢀMichael addition as the major reaction.
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Scheme 1. Chemoselective Synthesis of 3,4-dihydroquinazoline-2-thiones and [1, 3]
benzothiazines
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Our group has been committed to the synthesis of various structures with bioactivities
through organocatalytic asymmetric cascade/tandem reactions over the past years.54ꢀ58 We
investigated the reaction by selecting 2ꢀamino chalcone 1a and isothiocyanate 2a as the model
substrates under the catalysis of I or II in DCM at room temperature (Table 1, entries 1, 2). The
desired product 4a was obtained with moderate yield. Surprisingly, when the reaction was
performed in DCM for 24 h at room temperature in the absence of any catalysts, (Table 1, entry 3),
the other desired product 3a was formed with excellent yield. Various solvents such as DCE, THF,
toluene, dioxane and acetonitrile were examined (Table 1, entries 4ꢀ8), only product 3a was
formed albeit with poor yield under similar conditions. When the reaction temperature was
increased to 40oC (Table 1, entry 11), the product 3a was afforded as the only product with
excellent yields (up to 96%) in DCM. It was also found that the other structure 4a was formed as
the only product in the polar solvent such as MeOH or DMSO (Table 1, entries 9ꢀ10), and the
yield of 4a was up to 98% within 30 minutes in DMSO in the absence of any catalysts. We were
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then wondering whether or not the product 4a could be obtained as the only product in pure water
since water is a polar solvent. However, both of the compounds were formed at room temperature
(Table 1, entry 12). Interestingly, when the reaction was performed in water at 80oC for 3.5 h,
product 4a was formed with 85% yield as the only product (Table 1, entry 13).
Table 1. Optimization of experiment conditionsa
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Entrya
Solvent
DCM
Catalyst
t (h)
50
T (oC)
rt
Yield of 3a (%)b
Yield of 4a (%)b
1
2
I
II
ꢀ
0
45
45
3
DCM
50
rt
0
3
DCM
24
rt
94
88
17
57
42
36
0
4
DCE
ꢀ
120
120
120
120
120
10
rt
0
5
THF
ꢀ
rt
0
6
Toluene
Dioxane
Acetonitrile
MeOH
DMSO
DCM
ꢀ
rt
0
7
ꢀ
rt
0
8
ꢀ
rt
0
9
ꢀ
rt
50
98
0
10
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12
13
ꢀ
0.5
24
rt
0
ꢀ
40
rt
96
42
0
H2O
ꢀ
120
3.5
44
85
H2O
ꢀ
80
aUnless otherwise noted, the reaction was carried out with 1a (0.2 mmol), 2a (0.6 mmol) and the catalyst (30
mol%) in 1 mL of the solvent. b Isolated yield.
OMe
OMe
OH
OH
N
N
N
N
II
I
With the reaction conditions optimized, we explored the scope of the thiaꢀMichael addition.
The results are outlined in table 2. A range of metaꢀ, paraꢀ substitutional, electronꢀpoor, and
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electronꢀrich chalcones 1a-k were well tolerated under the optimized conditions, giving the
desired products with moderate to excellent yields. Obviously, when the R1 was an
electronꢀwithdrawing group (EWG) (Table 2, entry 2), the yield of 3 was lower than that with an
electronꢀdonating (ED) R1 (Table 2, entry 3). It can be seen that the electronic effect of R1 had a
remarkable impact on the rate and yield of the reaction. Subsequently, the effect of R2 on the
reaction was investigated. The chalcones with various substituent groups on phenyl ring were also
well tolerated in reaction (Table 2, entries 4ꢀ11). Furthermore, the results indicated that the yields
of the product were higher with substrates bearing paraꢀsubstituted phenyl rings than those with
metaꢀsubstituted phenyl rings, no matter the substituents were EDG or EWG. However, the
reactions with substrates bearing EDG proceeded faster than those with EWG. This could be
attributed to substrates containing EDG having higher nucleophilic activities. The reaction with
fluoroꢀsubstituted substrate (Table 2, entry 11) took less time than those with other halogen
substituted substrates (Table 2, entries 9ꢀ10) to complete. We hypothesized that the rate of the
reaction was also influenced by the steric effect of substituents. To prove our hypothesis, two
substrates were prepared, one was substituted by a smallꢀsized methyl group (Table 2, entry 12),
and the other was substituted by a largeꢀsized αꢀnaphthyl group (Table 2, entry 13). The reaction
results proved our hypothesis to be true. The hetero aromatic group (furyl) as R2 was also well
tolerated and gave a moderate yield (Table 2, entry 14).
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Table 2. Thia-Michael addition under the optimized conditionsa
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Entrya
1
R1
H
R2
t (h)
24
28
24
24
24
36
36
30
36
36
24
12
30
18
yield of 3 (%)b
96 (3a)
64 (3b)
91 (3c)
90 (3d)
99 (3e)
65 (3f)
C6H5
2
5ꢀCl
4ꢀOMe
H
C6H5
3
C6H5
4
3ꢀMeC6H4
4ꢀMeC6H4
3ꢀMeOC6H4
4ꢀMeOC6H4
3ꢀBrC6H4
4ꢀBrC6H4
4ꢀClC6H4
4ꢀFC6H4
Me
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5
H
6
H
7
H
86 (3g)
92 (3h)
96 (3i)
8
H
9
H
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12
13
14
H
98 (3j)
H
87 (3k)
72 (3l)
H
H
αꢀnaphthyl
furyl
88 (3m)
65 (3n)
H
aUnless otherwise noted, the reaction was carried out with 1 (0.2 mmol), 2 (0.6 mmol) in 1 mL of DCM at 40oC.b
Isolated yield.
We then examined the scope of the azaꢀMichael addition, which was shown in table 3. A
variety of chalcones with various substituents on the phenyl ring 1a-k were well tolerated, and
gave good to excellent yields under the optimized conditions. In all cases, the reactions in DMSO
proceeded remarkably faster than those in DCM. The rate and yield of the reaction were
influenced by the electronic effect of R1, as shown by the different reaction results between
chloroꢀsubstituted substrate (Table 3, entry 2) and mthoxylꢀsubstituted substrate (Table 3, entry 3).
We also examined the effect of R2 on the reaction, and found that reactions with the substrates
bearing EDG proceeded faster than those with substrates (Table 3, entries 4ꢀ7) bearing EWG
(Table 3, entries 8, 10). It was noticed that the reaction with the substrate bearing
fluoroꢀsubstitutedꢀphenyl group completed within 1 h (Table 3, entry 11), which was similar to the
reactions with substrates containing EDG but faster than that with substrate bearing other halogen
substitutedꢀphenyl group (Table 3, entries 4ꢀ7). Considering all these factors, we concluded that
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both of the electronic and the steric effect of substituents had a vital impact on the rate of the
reaction. To further confirm the steric effect of substituents, two more experiments were
performed. It was found that the reaction of the substrate with a smallꢀsized methyl group could be
finished within 30 minutes (Table 3, entry 12), while the reaction of the substrate with a
largeꢀsized αꢀnaphthyl group needed 3 h to complete (Table 3, entry 13). The substrate containing
a hetero aromatic group (furyl) as R2 (Table 3, entry 12) could also be employed, giving the
desired product with moderate yield.
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Table 3. Aza-Michael addition under the optimized conditionsa
entrya
1
R1
H
R2
t (h)
0.5
2
yield of 4 (%)b
98 (4a)
76 (4b)
96 (4c)
95 (4d)
93 (4e)
95 (4f)
C6H5
2
5ꢀCl
4ꢀOMe
H
C6H5
3
C6H5
0.5
1
4
3ꢀMeC6H4
4ꢀMeC6H4
3ꢀMeOC6H4
4ꢀMeOC6H4
3ꢀBrC6H4
4ꢀBrC6H4
4ꢀClC6H4
4ꢀFC6H4
Me
5
H
1
6
H
1
7
H
1
97 (4g)
96 (4h)
98 (4i)
8
H
2
9
H
0.5
2
10
11
12
13
14
H
95 (4j)
H
1
98 (4k)
98 (4l)
H
0.5
3
H
αꢀnaphthyl
furyl
94 (4m)
70 (4n)
H
2
aUnless otherwise noted, the reaction was carried out with 1 (0.2 mmol), 2 (0.6 mmol) in 1 mL of DMSO
at RT.b Isolated yield.
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The absolute structures of thiaꢀMichael addition product, compound 3i and azaꢀMichael
addition product, compound 4b were determined by Xꢀray crystal structure analysis. The data of
Xꢀray crystal structures can be seen in the Supporting Information.59
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To demonstrate the potential application of this methodology, a nucleophilic substitution
reaction of 4a with benzyl bromide was performed, giving the desired product 5a with moderate
yield (Scheme 2).
Scheme 2.The potential application of this methodology
Based on the highly selective experimental results, a plausible reaction mechanism was
proposed (Scheme 3). In the initial step, the 2ꢀAmino chalcone
1
reacts with
isothiocyanatobenzene 2 to form a crucial active intermediate 6. Both of the Sꢀterminal and
Nꢀterminal of thiourea 6 have the potential to undergo an intramolecular Michael addition (route a
and route b). To the thiaꢀMichael addition, the route a can be well explained on the basis of the
hardꢀsoft acidꢀbase (HSAB) theory. Sulfur is less electronegative but has a greater atomic radius
than nitrogen, and therefore can be regarded as a soft base. Since carbon cation is a typical soft
acid, Sꢀterminal rather than Nꢀterminal of thiourea will serve as a nucleophile site to react with the
carbon to afford the cyclizing product 3. To the azaꢀMichael addition, DMSO, as broadly applied,
will easily form hydrogen bonds60ꢀ70 with the hydrogens from the amino group of thiourea to
activate the NꢀH bond. An Nꢀterminal nucleophile active site is then produced from the weak NꢀH
bond of 6, which will attack the carbon and give the cyclized product 4. Obviously, the hydrogen
bond plays a significant role in the process of azaꢀMichael addition reaction due to its function of
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accelerating this reaction. The data of table 1 can now be well explained by this proposed
mechanism. The desired product 4a can’t be obtained in the solvents of low polarity due to the
absence of hydrogen bonding, but 4a can be formed in DCM under the catalyst of I or II with the
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hydrogen bonding donor.
Scheme3. Proposed mechanism of the chemoselective reaction
CONCLUSION:
In summary, we have developed a novel practical catalystꢀfree chemoselective reaction
switched by solvents. The 2ꢀimino[1, 3]benzothiazines was afforded with moderate to excellent
yield in DCM, while the 3,4ꢀdihydroquinazolineꢀ2ꢀthiones was obtained with excellent yield
within a very short reaction time in DMSO. The hardꢀsoft acidꢀbase (HSAB) theory and
hydrogenꢀbonding activated the NꢀH bond can be well used to explain the outstanding chemical
selectivity in the reaction process.
EXPERIMENTAL SECTION
General information: All glassware was thoroughly ovenꢀdried. Chemicals and solvents were
either purchased from commercial suppliers or purified by standard techniques. Thinꢀlayer
chromatography plates were visualized by exposure to ultraviolet light. Flash chromatography was
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carried out using silica gel (200ꢀ300 mesh).1H NMR and 13C NMR spectra were recorded on a 400
MHz spectrometer. Data for 1H NMR are reported as follows: chemical shift (δ ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m= multiplet, dd = doublet), integration, coupling
constant (Hz) and assignment. The spectra of 3 were recorded in CDCl3 as the solvent at room
temperature and the spectra of 4 were recorded in dꢀDMSO as the solvent at room temperature.
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1
TMS served as internal standard (δ = 0 ppm) for H NMR and CDCl3 was used as an internal
standard (δ= 77.00 ppm) for 13C NMR. IR spectra were recorded on a FTꢀIR instrument and are
reported in wavenumbers (cmꢀ1). HRMS spectra using ESI were obtained on an ESIꢀFTMS mass
spectrometer.
General procedure for the Thia-Michael addition under the optimized DCM conditions: A
solution of 2ꢀAminochalcone 1 (0.2 mmol), isothiocyanatobenzene 2 (0.6 mmol) in DCM (1 mL)
was stirred and refluxed at 40oC. The reaction was monitored by TLC spectroscopy. After the
reaction was completed, the reaction mixture was directly purified by flash column chromatograph
(eluted with EtOAc/petroleum ether = 5:1) to afford the product 3.
1ꢀphenylꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3a): White
solid; 68.8 mg, 96% yield; mp 48ꢀ49oC. 1H NMR (400 MHz, CDCl3): δ 3.30 (dd, J = 17.6 Hz, 5.1
Hz, 1H), 3.61 (dd, J = 17.6 Hz, 5.1 Hz, 1H), 4.76ꢀ4.79 ( m, 1H), 7.03ꢀ7.08 (m, 2H), 7.18ꢀ7.31 (m,
5H), 7.39 (t, J = 7.92 Hz, 2H), 7.50ꢀ7.54 (m, 3H), 7.84ꢀ7.86 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 39.4, 44.9, 55.5, 111.6, 114.1, 119.8, 123.1, 123.7, 125.9, 128.1, 128.6, 128.8, 133.4,
136.4, 137.1, 140.2, 147,4, 156.6, 196.8. IR (KBr): ν 505.5, 577.0, 917.7, 110.6, 1149.7, 1233.7,
1314.0, 1439.4, 1479.5, 1496.9, 1579.4, 1683.0, 2925.5, 3344.5 cmꢀ1. HRMS (ESI) for
C22H19N2OS [M+H]+ calcd. 359.1213, found 359.1218.
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2ꢀ(7ꢀchloroꢀ2ꢀphenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ꢀ1ꢀphenylethanone
(3b):
5
6
7
8
White solid; 49.6 mg, 64% yield; mp 59ꢀ60oC. 1H NMR (400 MHz, CDCl3): δ 3.30 (dd, J = 17.6
Hz, 5.1 Hz, 1H), 3.61 (dd, J = 17.6 Hz, 5.1 Hz, 1H), 4.73ꢀ4.77 (m, 1H), 7.01ꢀ7.13 (m, 3H),
7.24ꢀ7.42 (m, 5H), 7.51ꢀ7.58 (m, 3H), 7.84 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
38.7, 45.0, 120.4, 121.4, 123.9, 124.3, 124.7, 127.7, 128.1, 128.7, 129.0, 133.6, 133.8, 136.4,
139.9 144.9, 150.3, 196.4. IR (KBr): ν 508.4, 597.5, 689.3, 753.5, 1155.0, 1221.5, 1313.3, 1440.5,
1466.3, 1570.4, 1597.5, 1683.3, 2925.3, 2955.1, 3338.7 cmꢀ1. HRMS (ESI) for C22H18ClN2OS
[M+H]+ calcd. 393.0623, found 393.0626.
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2ꢀ(6ꢀmethoxyꢀ2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ꢀ1ꢀphenylethanone (3c):
White solid; 70.6 mg, 91% yield; mp 39ꢀ40oC. 1H NMR (400 MHz, CDCl3): δ 3.28 (dd, J = 17.6
Hz , 5.2 Hz, 1H), 3.62 (dd, J = 17.6 Hz , 8.7 Hz, 1H), 3.78 (s, 1H), 4.70ꢀ4.74 (m, 1H), 6.74 (d, J =
2.8 Hz, 1H), 6.384 (dd, J = 8.68 Hz, 2.8 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H),
7.29 (t, J = 8.28 Hz, 2H ), 7.4 (t, J = 7.6 Hz, 2H) , 7.53 (t, J = 7.44 Hz, 1H), 7.58 (d, J = 7.84 Hz,
2H), 7.86 (d, J = 7.28 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 39.4, 44.9, 55.5, 111.6, 114.1,
119.8, 123.1, 123.7, 125.9, 128.1, 128.6, 128.8, 133.4, 136.4, 137.1, 140.2, 147,4, 156.6, 196.8. IR
(KBr): ν 503.5, 690.3, 756.4, 1042.2, 1122.1, 1150.5, 1235.8, 1311.0, 1376.3, 1461.7, 1492.2,
1584.6, 1685.3, 1736.4, 2370.8, 2851.8, 2924.7, 2955.5, 3337.4 cmꢀ1. HRMS (ESI) for
C23H21N2O2S [M+H]+ calcd. 389.1318, found 389.1320.
2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ꢀ1ꢀ(mꢀtoꢀlyl)ethanone (3d): White
solid; 66.9 mg, 90% yield; mp 62ꢀ63oC. 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.28 (dd, J =
17.2 Hz, 5.2 Hz, 1H), 3.61 (dd, J = 17.6 Hz, 8.8 Hz, 1H), 4.75ꢀ4.78 (m, 1H), 7.02ꢀ7.08 (m, 2H),
7.18ꢀ7.34 (m, 7H), 7.54 (d, 6.0 Hz, 2H), 7.65 (d, J = 9.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
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21.3, 39.3, 45.1, 120.3, 123.0, 123.4, 124.4, 125.4, 126.6, 128.54, 128.58, 128.7, 128.9, 134.3,
136.6, 138.5, 140.9, 143.3, 149.4, 196.9. IR (KBr): ν 505.0, 576.7, 689.6, 737.3, 758.2, 1154.9,
1313.6, 1439.2, 1496.8, 1524.7, 1579.6, 1614.1, 1679.4, 2924.7, 2955.3, 3057.8, 3343.3 cmꢀ1.
HRMS (ESI) for C23H21N2OS [M+H]+ calcd. 373.1369, found 373.1364.
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2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ꢀ1ꢀ(pꢀtolꢀyl)ethanone (3e): White
solid; 73.7 mg, 99% yield; mp 53ꢀ55oC. 1H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 3.27 (dd, J =
17.2 Hz, 5.6 Hz, 1H), 3.60 (dd, J = 17.2Hz, 8.8 Hz, 1H), 4.75ꢀ4.78 (m, 1H), 7.06 (m, 2H),
7.18ꢀ7.32 (m, 7H), 7.53 (d, 7.88 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 21.7, 39.3, 44.9, 120.4, 123.0, 123.5, 124.3, 124.4, 126.6, 128.3, 128.5, 128.9, 129.3, 134.1,
140.8, 143.2, 144.5, 149.86, 196.9. IR (KBr): ν 505.3, 572.9, 692.0, 757.2, 814.0, 1181.0, 1233.4,
1313.7, 1439.4, 1496.7, 1578.8, 1610.9, 1677.2, 2924.8, 2954.7, 3337.1 cmꢀ1. HRMS (ESI) for
C23H21N2OS [M+H]+ calcd. 373.1369, found 373.1373.
1ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3f):
White solid; 50.4 mg, 65% yield; mp 70ꢀ71oC. 1H NMR (400 MHz, CDCl3): δ 3.32 (dd, J = 17.6
Hz, 5.4 Hz, 1H), 3.61 (dd, J = 17.6 Hz, 8.6 Hz, 1H), 3.80 (s, 3H), 4.75ꢀ4.79 (m, 1H), 7.06 (m, 2H),
7.04ꢀ7.10 (m, 3H), 7.19ꢀ7.32 (m, 6H), 7.40ꢀ7.42 (m, 2H), 7.53 (d, J = 7.92, 2H); 13C NMR (100
MHz, CDCl3): δ 39.2, 45.1, 55.3, 112.0, 120.1, 120.4, 120.7, 122.8, 123.4, 124.1, 124.3, 126.5,
128.4, 128.8, 129.5, 137.7, 140.8, 142.9, 149.8, 159.7, 196.4. IR (KBr): ν 503.3, 618.2, 695.6,
757.6, 1038.2, 1158.1, 1194.4, 1255.1, 1286.2, 1437.7, 1493.3, 1526.0, 1579.7, 1597.3 1679.3,
2369.0, 2925.3, 3335.1 cmꢀ1. HRMS (ESI) for C23H21N2O2S [M+H]+ calcd. 389.1318, found
389.1323.
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1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3g):
White solid; 67.0 mg, 86% yield; mp 71ꢀ72oC. 1H NMR (400 MHz, CDCl3): δ 3.34 (dd, J = 17.2
Hz, 5.6 Hz, 1H), 3.57 (dd, J = 17.6 Hz, 8.8 Hz, 1H), 3.82 (s, 3H), 4.74ꢀ4.79 (m, 1H), 6.86 (d, J =
7.6 Hz, 2H), 7.04ꢀ7.09 (m, 2H), 7.18 (d, J = 7.3 Hz, 1H), 7.24ꢀ7.32 (m, 4H), 7.53 (d, J = 7.48 Hz,
2H), 7.83 (d, J = 9.2 Hz, 2H) 13C NMR (100 MHz, CDCl3): δ 39.4, 44.5, 55.4, 113.7, 120.4, 123.0,
123.5, 124.2, 124.4, 126.6, 128.5, 128.9, 129.6, 130.4, 140.6, 143.0, 149.9, 163.7, 195.0. IR (KBr):
ν 501.8, 617.8, 757.6, 1028.0, 1114.7, 1200.9, 1261.3, 1313.7, 1439.6, 1479.1, 1577.8, 1599.3,
1671, 2925.2, 2955.0, 3332.1 cmꢀ1. HRMS (ESI) for C23H21N2O2S [M+H]+ calcd. 389.1318, found
389.1324.
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1ꢀ(3ꢀbromophenyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3h):
White solid; 80.2 mg, 92% yield; mp 74ꢀ75oC. 1H NMR (400 MHz, CDCl3): δ 3.28 (dd, J = 17.6
Hz, 5.4 Hz, 1H), 3.57 (dd, J = 17.6 Hz, 8.5 Hz, 1H), 4.73ꢀ4.77 (m, 1H), 7.04ꢀ7.09 (m, 2H),
7.17ꢀ7.32 (m, 6H), 7.54 (d, J = 7.88 Hz, 2H), 7.64 (d, J = 7.92 Hz, 1H), 7.74 (d, J = 7.84 Hz, 1H),
7.98 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 39.1, 45.2, 120.3, 122.6, 123.0, 123.5, 124.3, 124.4,
126.6, 128.6, 128.6, 130.2, 131.1, 163.3, 138.1, 140.6, 143.1, 149.3, 195.3. IR (KBr): ν 505.1,
577.5, 759.6, 1194.9, 1230.2, 1313.5, 14398.1, 1479.2, 1496.7, 1579.2, 1614.3, 1687.2, 2925.7,
2955.3, 3061.0, 3356.3 cmꢀ1. HRMS (ESI) for C22H18BrN2OS [M+H]+ calcd. 437.0318, found
437.0324.
1ꢀ(4ꢀbromophenyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3i):
White solid; 83.7 mg, 96% yield; mp 75ꢀ76oC. 1H NMR (400 MHz, CDCl3): δ 3.28 (dd, J = 17.6
Hz, 5.4 Hz, 1H), 3.57 (dd, J = 17.6 Hz, 8.5 Hz, 1H), 4.73ꢀ4.76 (m, 1H), 7.04ꢀ7.09 (m, 2H),
7.17ꢀ7.32 (m, 6H), 7.54 (d, J = 7.88 Hz, 2H), 7.64 (d, J = 7.92 Hz, 1H), 7.74 (d, J = 7.84 Hz, 1H),
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7.98 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 39.2, 44.9, 120.2, 122.6, 123.5, 124.5, 126.5,
m128.6, 128.7, 1287.9, 129.5, 131.9, 135.2, 140.5, 143.2, 149.1, 195.7. IR (KBr): ν 508.6, 757.4,
1071.0, 1231.2, 1313.0, 1349.7, 1439.2, 1581.2, 1614.2, 1685.2, 2852.5, 2924.9, 2955.2, 3348.1
cmꢀ1. HRMS (ESI) for C22H18BrN2OS [M+H]+ calcd. 437.0318, found 437.0313.
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1ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3j):
White solid; 76.8 mg, 98% yield; mp 70ꢀ71oC. 1H NMR (400 MHz, CDCl3): δ 3.28 (dd, J = 17.6
Hz, 5.5 Hz, 1H), 3.57 (dd, J = 17.6 Hz, 8.4 Hz, 1H), 4.73ꢀ4.77 (m, 1H), 7.06 (t, J = 7.36 Hz, 2H),
7.17ꢀ7.33 (m, 5H), 7.35ꢀ7.37 (m, 2H), 7.52 (d, J = 7.84 Hz, 2H), 7.76ꢀ7.79 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 39.2, 45.0, 120.4, 122.6, 123.6, 124.3, 124.4, 126.5, 128.6, 128.95, 128.96,
129.5, 134.7, 140.0, 140.5, 143.0, 149.6, 149.5, 195.4. IR (KBr): ν 503.5, 617.4, 693.0, 758.2,
827.1, 981.7, 1092.9, 1149.0, 1232.4, 1313.8, 1400.6, 1439.4, 1496.3, 1532.1, 1579.6, 1684.6,
2925.8, 3058.7, 3346.8 cmꢀ1. HRMS (ESI) for C22H18ClN2OS [M+H]+ calcd. 393.0823, found
393.0826.
1ꢀ(4ꢀfluorophenyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3k):
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White solid; 65.5 mg, 87% yield; mp 154ꢀ155oC. H NMR (400 MHz, CDCl3): δ 3.28 (dd, J =
17.5 Hz, 5.5 Hz, 1H), 3.57 (dd, J = 17.6 Hz, 8.4 Hz, 1H), 4.73ꢀ4.76 (m, 1H), 7.02ꢀ7.07 (m, 4H),
7.16ꢀ7.32 (m, 5H), 7.53 (d, J = 7.88 Hz, 2H), 7.84ꢀ7.88 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
39.3, 45.0, 115.7, 115.9, 120.4, 122.8, 123.6, 124.3, 124.6, 126.6, 128.6, 129.0, 130.8, 130.9,
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132.9, 133.0, 140.8, 143.1, 149.6, 166.0 (d, JCꢀF = 254.3 Hz), 195.1. IR (KBr): ν 502.8, 571.5,
696.2, 757.8, 838.1, 983.0, 1155.9, 1233.0, 1313.5, 1439.2, 1479.5, 1523.5, 1579.3, 1614.0,
1681.8, 2925.9, 2955.6, 3061.1, 3347.2 cmꢀ1. HRMS (ESI) for C22H18FN2OS [M+H]+ calcd.
377.1118, found 377.1114.
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1ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)propanꢀ2ꢀone (3l): White solid;
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37.5 mg, 72% yield; mp 140ꢀ142oC. H NMR (400 MHz, CDCl3): δ 2.05 (s, 3H), 2.86 (dd, J =
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17.7 Hz, 6.0 Hz, 1H), 3.03 (dd, J = 17.7 Hz, 8.0 Hz, 1H), 4.52ꢀ4.56 (m, 1H), 7.05ꢀ7.10 (m, 2H),
7.13ꢀ7.19 (m, 2H), 7.24ꢀ7.28 (m, H), 7.33 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3): δ 30.7, 38.7, 49.8, 120.4, 122.7, 123.6, 124.4, 126.6, 128.5, 129.0, 140.8,
142.9, 149.3, 205.2. IR (KBr): ν 500.7, 692.7, 757.4, 1112.9, 1149.5, 1228.9, 1314.5, 1439.9,
1479.2, 1534.8, 1579.9, 1615.0, 1710.1, 2924.8, 2956.0, 3334.2 cmꢀ1. HRMS (ESI) for
C17H17N2OS [M+H]+ calcd. 297.1056, found 297.1060.
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1ꢀ(naphthalenꢀ1ꢀyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3m):
White solid; 71.8 mg, 88% yield; mp 76ꢀ77oC. 1H NMR (400 MHz, CDCl3): δ 3.41 (dd, J = 16.8
Hz, 5.6 Hz, 1H), 3.57 (dd, J = 17.2 Hz, 8.4 Hz, 1H), 4.81ꢀ4.85 (m, 1H), 7.01ꢀ7.06 (m, 2H),
7.15ꢀ7.27 (m, 5H), 7.35 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.48ꢀ7.57 (m, 2H), 7.64 (d, J
= 7.2 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 39.6, 47.9, 120.8, 122.7, 123.3, 123.5, 124.0, 124.1, 125.5, 126.4,
126.5, 128.0, 128.3, 128.4, 128.7, 129.4, 129.8, 133.0, 133.7, 134.9, 141.5, 142.3, 150.2, 200.3. IR
(KBr): ν 491.9, 695.7, 735.4, 759.4, 775.0, 908.8, 1096.4, 1147.8, 1234.0, 1313.8, 1438.8, 1479.2,
1496.7, 1578.9, 1614.7, 1676.6, 2925.8, 2955.3, 3055.8, 3347.7 cmꢀ1. HRMS (ESI) for
C26H21N2OS [M+H]+calcd. 409.1369, found 409.1372.
1ꢀ(furanꢀ2ꢀyl)ꢀ2ꢀ(2ꢀ(phenylimino)ꢀ2,4ꢀdihydroꢀ1Hꢀbenzo[d][1,3]thiazinꢀ4ꢀyl)ethanone (3n): White
solid; 45.3 mg, 65% yield; mp 59ꢀ60oC. 1H NMR (400 MHz, CDCl3): δ 3.17 (dd, J = 16.8 Hz, 5.9
Hz, 1H), 44.7 (dd, J = 16.8 Hz, 8.4 Hz, 1H), 4.70ꢀ4.74 (m, 1H), 6.46ꢀ6.47 (m, 1H), 7.05ꢀ7.11 (m,
3H), 7.15ꢀ7.17 (m, 1H), 7.20ꢀ7.25 (m, 2H), 7.27ꢀ7.33 (m, 2H), 7.52ꢀ7.55 (m, 3H); 13C NMR (100
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MHz, CDCl3): δ 39.1, 44.7, 112.3, 117.9, 120.3, 122.6, 123.4, 124.2, 124.3, 126.5, 128.5, 128.9,
140.8, 143.0, 146.8, 149.2, 152.3, 185.4. IR (KBr): ν 509.3, 509.3, 694.3, 758.7, 903.7, 1021.8,
1149.9, 1226.6, 1314.2, 1394.4, 1439.8, 1465.3, 1534.7, 1568.5, 1613.6, 1668.4, 2853.2, 2925.3,
3320.3 cmꢀ1. HRMS (ESI) for C20H17N2O2S [M+H]+ calcd. 349.1005, found 349.1009.
General procedure for the Aza-Michael addition under the optimized DMSO conditions: A
solution of 2ꢀAminochalcone 1 (0.2 mmol), isothiocyanatobenzene 2 (0.6mmol) in DMSO (1 mL)
was stirred at room temperature. The reaction was monitored by TLC spectroscopy. After the
reaction was completed, the reaction mixture was directly purified by flash column chromatograph
(eluted with EtOAc /petroleum ether = 5:1) to afford the product 4.
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1ꢀphenylꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ethaꢀnone (4a): White solid; 70.2
mg, 98% yield; mp 231ꢀ232oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.51ꢀ3.65 (m, 2H), 5.42 (s, 1H),
6.93 (s, 1H), 7.12ꢀ7.20 (m, 3H), 7.31ꢀ7.42 (m, 7H), 7.53ꢀ7.55 (m, 1H), 7.77 (d, J = 6.68 Hz, 2H),
11.0 (s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 44.0, 51.5, 60.5, 114.9, 122.6, 123.7, 126.7, 128.3,
128.8, 129.4, 129.5, 129.8, 124.3, 135.7, 137.2, 145.1, 173.3, 197.7. IR (KBr): ν 535.9, 628.2,
693.7, 743.9, 760.7, 1118.6, 1205.5, 1251.4, 1283.8, 1305.3, 1436.0, 1467.0, 1493.0, 1523.8,
1595.3, 1675.0, 2924.1, 2954.3, 3113.0, 3333.5 cmꢀ1. HRMS (ESI) for C22H19N2OS [M+H]+ calcd.
359.1213, found 359.1218.
2ꢀ(7ꢀchloroꢀ3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ꢀ1ꢀphenylethanone (4b): White
solid; 59.6 mg, 76% yield; mp 205ꢀ206oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.54 (dd, J = 17.2 Hz,
8.04 Hz, 1H), 3.65 (dd, J = 17.2 Hz, 3.64 Hz, 1H), 5.42 (dd, J = 7.88 Hz, 3.48 Hz, 1H), 7.01
(dd, J = 8.20 Hz, 2.08 Hz, 1H), 7.11 (d, J = 2.08 Hz, 1H), 7.19 (d, J = 8.24 Hz, 1H), 7.31ꢀ7.36 (m,
1H), 7.41ꢀ7.45 (m, 6H), 7.57ꢀ7.61 (m, 1H), 7.79ꢀ7.81 (m, 2H); 13C NMR (100 MHz, dꢀDMSO):
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δ 43.8, 59.9, 114.3, 121.5, 123.3, 128.5, 128.6, 128.9, 129.5, 129.7, 129.9, 133.6, 134.4, 137.0,
137.1, 144.8, 177.3, 197.7. IR (KBr): ν 530.2, 596.9, 696.0, 736.8, 1085.5, 1125.5, 1209.1, 1231.8,
1281.6, 1395.1, 1457.8, 1492.5, 1597.3, 1682.3, 2925.1, 2956.0, 3178.7 cmꢀ1. HRMS (ESI) for
C22H18ClN2OS [M+H]+ calcd. 393.0823, found 393.0829.
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2ꢀ(6ꢀmethoxyꢀ3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ꢀ1ꢀphenylethanone (4c): White
solid; 74.5 mg, 96% yield; mp 240ꢀ241oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.50 (dd, J = 16.8 Hz,
8.12 Hz, 1H), 3.62ꢀ3.67 (m, 4H), 5.37 (dd, J = 7.06 Hz, 3.56 Hz, 1H), 6.70 (d, J = 2.56 Hz, 1H),
6.80 (dd, J = 8.72 Hz, 2.68 Hz, 1H), 7.02 (d, J = 8.72 Hz, 1H), 7.29ꢀ7.32 (m, 1H), 7.38ꢀ7.44 (m,
6H), 7.58 (t, J = 7.36 Hz, 1H), 7.58 (t, J = 7.36 Hz, 1H), 7.78 (d, J = 7.32 Hz, 2H), 10.92 (s, 1H);
13C NMR (100 MHz, dꢀDMSO): δ 44.0, 56.2, 60.6, 111.8, 115.7, 116.0, 123.7, 128.2, 128.9, 129.5,
129.8, 129.9, 130.7, 134.3, 137.2, 145.1, 155.9, 176.6, 197.8. IR (KBr): ν 518.8, 762.7, 1002.7,
1026.6, 1118.4, 1169.0, 1257.4, 1284.5, 1448.9, 1463.1, 1504.4, 1676.6, 2370.8, 2852.2, 2923.4,
3420.6 cmꢀ1. HRMS (ESI) for C23H21N2O2S [M+H]+ calcd. 389.1318, found 389.1324.
2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ꢀ1ꢀ(mꢀtolyl)ethanone (4d): White solid;
70.6 mg, 95% yield; mp 224ꢀ225oC. 1H NMR (400 MHz, dꢀDMSO): δ 2.29 (s, 3H), 3.50 (dd, J =
16.8 Hz, 8.4 Hz, 1H), 3.61 (dd, J = 16.8 Hz, 3.6 Hz, 1H), 5.40 (dd, J = 8.28 Hz, 3.56 Hz, 1H),
6.92ꢀ6.96 (m, 1H), 7.10 (t, 1H), 7.19ꢀ7.23 (m, 1H), 7.28ꢀ7.42 (m, 7H), 7.56ꢀ7.58 (m, 2H), 10.99
(s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 21.6, 44.1, 60.6, 114.9, 122.7, 123.8, 126.0, 126.8,
128.4, 129.4, 129.8, 129.9, 134.9, 135.7, 137.2, 138.9, 145.1, 177.4, 197.8. IR (KBr): 622.9, 763.2,
824.9, 1005.9, 1026.0, 1051.4, 1656.2, 2126.9, 2253.7, 3424.4 cmꢀ1. HRMS (ESI) for C23H21N2OS
[M+H]+ calcd. 373.1369, found 373.1374.
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2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ꢀ1ꢀ(pꢀtolyl)ethꢀanone (4e): White solid;
70.6 mg, 93% yield; mp 168ꢀ169oC. 1H NMR (400 MHz, dꢀDMSO): δ 2.35 (s, 3H), 3.47 (dd, J =
16.8 Hz, 3.2 Hz, 1H), 3.71 (dd, J = 16.8 Hz, 9.6 Hz, 1H), 5.56 (dd, J = 9.20 Hz, 3.20 Hz, 1H),
6.94ꢀ7.01 (m, 2H), 7.01ꢀ7.18 (m, 3H), 7.23 (d, J = 8.01 Hz, 1H), 7.36ꢀ7.47 (m, 5H), 7.65 (d, J =
8.40 Hz, 2H), 9.94 (s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 22.0, 43.8, 60.6, 144.9, 122.7,
123.7, 126.7, 128.3, 129.0, 129.4, 129.6, 129.8, 130.0, 130.7, 134.8, 135.7, 144.8, 145.1, 171.2,
177.4, 197.1. IR (KBr): ν 618.8, 697.0, 734.1, 761.3, 822.8, 1005.5, 1025.8, 1050.3, 1121.5,
1284.5, 1429.8, 1492.9, 1675.1, 2923.6, 3424.8 cmꢀ1. HRMS (ESI) for C23H21N2OS [M+H]+ calcd.
373.1369, found 373.1378.
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1ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ethanone (4f): White
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solid; 73.7 mg, 95% yield; mp 179ꢀ180oC. H NMR (400 MHz, dꢀDMSO): δ 3.49ꢀ3.66 (m, 2H),
3.73 (s, 3H), 5.41ꢀ5.42 (m, 1H), 6.94 (t, J = 7.28 Hz, 1H), 7.11ꢀ7.14 (m, 3H), 7.18ꢀ7.22 (m, 1H),
7.26ꢀ7.42 (m, 8H), 11.0 (s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 44.2, 56.1, 60.5, 113.2, 114.9,
120.6, 121.4, 122.6, 123.7, 1265.7, 128.3, 129.4, 129.8, 129.9, 130.6, 135.7, 138.6, 145.0, 160.2,
177.3, 197.5. IR (KBr): ν 618.2, 735.8, 1005.7, 1026.6, 1195.1, 1259.7, 1286.1, 1430.9, 1464.9,
1492.7, 1617.8, 1676.3, 2853.2, 2924.9, 2955.6, 3191.0, 3398.3 cmꢀ1. HRMS (ESI) for
C23H21N2O2S [M+H]+ calcd. 389.1318, found 389.1319.
1ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ethanone (4g): White
solid; 75.3 mg, 97% yield; mp 186ꢀ187oC. 1H NMR(400 MHz, dꢀDMSO): δ 2.29 (s, 3H), 3.50 (dd,
J = 16.8 Hz, 8.4 Hz, 1H), 3.61 (dd, J = 16.8 Hz, 3.6 Hz, 1H), 5.40 (dd, J = 8.28 Hz, 3.56 Hz, 1H),
6.92ꢀ6.96 (m, 1H), 7.10 (t, 1H), 7.19ꢀ7.23 (m, 1H), 7.28ꢀ7.42 (m, 7H), 7.56ꢀ7.58 (m, 2H), 10.99 (s,
1H); 13C NMR (100 MHz, dꢀDMSO): δ 42.9, 43.4, 59.5, 113.9, 121.5, 122.0, 122.8, 125.8, 126.9,
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127.4, 128.1, 128.6, 128.9, 129.0, 129.1, 130.6, 134.8, 138.2, 144.1, 176.4, 196.5. IR (KBr): ν
621.5, 763.6, 825.3, 1004.7, 1026.1, 1050.4, 1655.9, 2923.2, 2956.1, 3423.3 cmꢀ1. HRMS (ESI)
for C23H21N2O2S [M+H]+ calcd. 389.1318, found 389.1323.
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1ꢀ(3ꢀbromophenyl)ꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ethanone (4h): White
solid; 83.7 mg, 96% yield; mp 227ꢀ228oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.53 (dd, J = 16.9 Hz,
8.0 Hz, 1H), 3.67 (dd, J = 17.0 Hz, 3.2 Hz, 1H), 5.39ꢀ5.41 ( m, 1H), 6.96 (t, J = 7.36 Hz, 1H), 7.08
(t, J = 7.80 Hz, 1H), 7.15ꢀ7.23 (m, 2H), 7.33ꢀ7.42 (m, 6H), 7.76 (d, J = 7.84 Hz, 2H), 7.91 (s, 1H),
11.0 (s, 1H); 13C NMR(100 MHz, dꢀDMSO): δ 43.9, 55.3, 59.6, 114.4, 122.0, 122.5, 123.3, 126.3,
127.4, 127.9, 129.0, 129.4, 131.1, 131.2, 135.3, 136.4, 138.6, 144.6, 176.8, 196.4. IR (KBr): ν
757.5, 825.9, 1001.4, 1025.3, 1050.6, 1196.5, 1303.0, 1436.2, 1464.0, 1492.2, 1677.6, 2922.0,
3406.8 cmꢀ1. HRMS (ESI) for C22H18BrN2OS [M+H]+ calcd. 437.0318, found 437.0325.
1ꢀ(4ꢀbromophenyl)ꢀ (3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinolinꢀ4ꢀyl)ethanone (4i): White solid;
83.7 mg, 96% yield; mp 236ꢀ237oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.51 (dd, J = 17.0 Hz, 8.12
Hz, 1H), 3.63 (dd, J = 17.0 Hz, 3.3 Hz, 1H), 5.39ꢀ5.42 (m, 1H), 6.94 (t, J = 7.36 Hz, 1H),
7.07ꢀ7.22 (m, 3H), 7.31ꢀ7.41 (m, 5H), 7.59ꢀ7.71 (m, 4H), 11.03 (s, 1H); 13C NMR (100 MHz,
dꢀDMSO): δ 44.1, 60.4, 114.9, 122.5, 123.7, 126.7, 128.3, 128.5, 129.4, 129.7, 129.8, 130.8, 130.9,
132.5, 135.7, 136.1, 145.0, 177.3, 197.0. IR (KBr): ν 694.9, 727.6, 758.5, 817.5, 1025.2, 1121.1,
1204.9, 1224.7, 1285.7, 1378.2, 1423.1, 1460.0, 1489.7, 1583.4, 2852.4, 2922.6, 2956.4, 3316.8,
3406.0 cmꢀ1. HRMS (ESI) for C22H18BrN2OS [M+H]+ calcd. 437.0318, found 437.0323.
1ꢀ(4ꢀchlorophenyl)ꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinolinꢀ4ꢀyl)ethanone (4j): White
solid; 74.5 mg, 95% yield; mp 210ꢀ211oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.52 (dd, J = 16.8 Hz,
8.0 Hz, 1H), 3.64 (dd, J = 17.2 Hz, 4.0 Hz, 1H), 5.43 (dd, J = 7.60 Hz, 3.61 Hz, 1H), 6.93ꢀ6.97 (m,
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1H), 7.08ꢀ7.10 (m, 1H), 7.14ꢀ7.16 (m, 1H), 7.21ꢀ7.23 (m, 1H), 7.31ꢀ7.34 (m,2H), 7.38ꢀ7.42 (m,
4H), 7.48 (d, J = 8.60 Hz, 2H), 7.79 (d, J = 8.56 Hz, 2H), 11.03 (s, 1H); 13C NMR (100 MHz,
dꢀDMSO): δ 44.1, 60.5, 114.9, 122.5, 123.7, 124.5, 125.3, 126.8, 128.3, 129.3, 129.4, 129.5, 129.8,
130.8, 130.8, 135.7, 135.8, 139.3, 140.4, 145.0, 177.7, 196.8. IR (KBr): ν 540.2, 693.1, 759.4,
1025.7, 1119.2, 1206.7, 1287.3, 1461.3, 1491.3, 1612.6, 1671.7, 1370.3, 2924.8, 3321.5 cmꢀ1.
HRMS (ESI) for C22H18ClN2OS [M+H]+ calcd. 393.0623, found 393.0629.
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1ꢀ(4ꢀfluorophenyl)ꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ethanone (4k): White
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solid; 73.7 mg, 98% yield; mp 212ꢀ213oC. H NMR (400 MHz, dꢀDMSO): δ 3.52 (dd, J = 16.9
Hz, 8.0 Hz, 1H), 3.63 (dd, J = 16.9 Hz, 3.8 Hz, 1H), 5.39ꢀ5.42 (m, 1H), 6.93ꢀ6.97 (m,1H),
6.92ꢀ6.96 (m, 1H), 7.07ꢀ7.15 (m, 1H), 7.18ꢀ7.26 (m, 3H), 7.31ꢀ7.34 (m, 1H), 7.40ꢀ7.41 (m, 4H),
7.85ꢀ7.89 (m, 2H), 10.98 (s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 44.0, 60.4, 114.9, 116.3,
116.6, 122.6, 123.7, 126.7, 128.3, 129.4, 129.8, 131.9, 132.0, 133.9, 134.0, 135.7 145.0, 166.0 (d,
1JC–F = 250.8 Hz), 177.3, 196.4. IR (KBr): ν 537.3, 580.7, 753.1, 834.3, 986.3, 1052.6, 1119.7,
1155.0, 1203.7, 1286.8, 1437.9, 1493.9, 1518.5, 1614.3, 1702.3, 2922.3 cmꢀ1. HRMS (ESI) for
C22H18FN2OS [M+H]+ calcd.377.1118, found 377.1121.
1ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)propanꢀ2ꢀone (4l): White solid; 58.0 mg,
98% yield; mp 152ꢀ153oC. 1H NMR (400 MHz, CDCl3): δ 1.97 (s, 3H), 3.03 (dd, J = 16.8 Hz, 3.5
Hz, 1H), 3.14 (dd, J = 16.8 Hz, 9.3 Hz, 1H), 5.32 (dd, J = 9.3 Hz, 3.5 Hz, 1H), 6.93 (d, J = 7.88
Hz, 1H), 7.02ꢀ7.05 (m, 1H), 7.18 (d, J = 7.36 Hz, 1H), 7.22ꢀ7.26 (m, 1H), 7.37ꢀ7.39 (m, 3H),
7.44ꢀ7.48 (m, 2H), 9.25 (s, 1H); 13C NMR (100 MHz,CDCl3): δ 31.1, 47.6, 59.7, 113.9, 121.6,
123.9, 126.3, 128.2, 128.4, 129.0, 129.4, 134.3, 143.8, 177.3, 204.9. IR (KBr): ν 695.4, 757.0,
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1158.0, 1193.7, 1463.2, 1596.1, 1710.2, 2370.2, 2852.0, 2923.6, 2955.1, 3184.1 cmꢀ1. HRMS (ESI)
for C17H17N2OS [M+H]+ calcd. 297.1056, found 297.1062.
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solid; 76.7 mg, 94% yield; mp 230ꢀ231oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.58 (dd, J = 16.5 Hz,
8.4 Hz, 1H), 3.78 (dd, J = 16.5 Hz, 3.8 Hz, 1H), 5.49 (dd, J = 8.3 Hz, 1H), 6.95 (t, J = 7.44 Hz,
1H), 7.09ꢀ7.11 (m, 1H), 7.18ꢀ7.23 (m, 2H), 7.33ꢀ7.37 (m, 1H), 7.41ꢀ7.48 (m, 5H), 7.54ꢀ7.56 (m,
2H), 7.80 (d, J = 7.04 Hz, 2H), 7.94ꢀ7.96 (m, 1H), 8.07 (d, J = 8.20 Hz, 1H), 8.28ꢀ8.31 (m, 1H),
11.04 (s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 46.4, 60.5, 114.4, 121.9, 123.4, 125.0, 125.5,
126.3, 126.9, 128.0, 128.4, 128.9, 129.0, 129.3, 129.4, 129.5, 129.6, 133.5, 133.8, 135.1, 135.3,
144.7, 176.9, 200.8. IR (KBr): ν 620.8, 762.4, 825.3, 1002.9, 1025.5, 1049.0, 1226.6, 1266.9,
1430.2, 1462.2, 1491.8, 1656.4, 2921.6, 2955.6, 3419.2 cmꢀ1. HRMS (ESI) for C26H21N2OS
[M+H]+ calcd. 409.1369, found 409.1376.
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1ꢀ(furanꢀ2ꢀyl)ꢀ2ꢀ(3ꢀphenylꢀ2ꢀthioxoꢀ1,2,3,4ꢀtetrahydroquinazolinꢀ4ꢀyl)ethanone (4n): white solid;
48.7 mg, 70% yield; mp 221ꢀ222oC. 1H NMR (400 MHz, dꢀDMSO): δ 3.36 (dd, J = 15.9 Hz, 3.8
Hz, 1H), 3.57 (dd, J = 15.9 Hz, 9.6 Hz, 1H), 5.48 (dd, J = 9.6 Hz, 3.8 Hz, 1H), 6.64ꢀ6.65 (m, 1H),
6.91 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 7.48 Hz, 1H), 7.03 (d, J = 3.6 Hz, 1H), 7.16ꢀ7.22 (m, 2H),
7.36ꢀ7.49 (m, 6H), 9.18 (s, 1H); 13C NMR (100 MHz, dꢀDMSO): δ 43.2, 60.2, 113.0, 114.4, 119.8,
121.7, 123.3, 126.2, 127.9, 129.1, 129.3, 129.4, 135.2, 144.5, 148.7, 152.1, 176.8, 185.0. IR (KBr):
ν 537.0, 757.4, 1025.5, 1120.3, 1157.8, 1229.3, 1291.1, 1464.3, 1492.5, 1668.1, 2371.2, 2923.2,
3397.1 cmꢀ1. HRMS (ESI) for C20H17N2O2S [M+H]+ calcd. 349.1005, found 349.1011.
2ꢀ(2ꢀ (benzylthio)ꢀ3ꢀphenylꢀ3,4ꢀdihydroquinazolinꢀ4ꢀyl)ꢀ1ꢀphenylethanone (5a): Yellow solid; 70.6
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mg, 70% yield; mp 64ꢀ65oC. H NMR (400 MHz, CDCl3): δ 3.32 (dd, J = 16.2 Hz, 4.5 Hz, 1H),
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3.53 (dd, J = 16.2 Hz, 8.4 Hz, 1H), 4.27 (d, J = 13.3 Hz, 1H), 4.45 (d, J = 13.3 Hz, 1H), 5.41ꢀ5.45
(m, 1H), 6.95ꢀ6.99 (m, 1H), 7.03ꢀ7.05 (m, 1H), 7.19ꢀ7.30 (m, 10H), 7.34ꢀ7.39 (m, 4H), 7.47ꢀ7.51
(m, 1H), 7.74ꢀ7.76 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 43.1, 52.8, 58.9, 115.6, 124.1, 125.4,
126.5, 127.2, 127.3, 127.6, 127.8, 127.9, 128.5, 128.6, 128.7, 129.3, 133.5, 136.1, 136.3, 136.9,
146.0, 180.8, 192.2. IR (KBr): ν 695.4，738.2，754.5，981.6，1073.4，1212.5，1358.1，1425.1，
1494.0，1532.7，1683.4，2925.6，3344.7 cmꢀ1. HRMS (ESI) for C29H25N2OS [M+H]+ calcd.
449.1682, found 449.1683.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H and 13C spectra, Xꢀray crystal data.
AUTHOR INFORMATION
Corresponding Author
*Email: huxiuqin@lzu.edu.cn
*Eꢀmail: xupf@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for the NSFC (21572087, 21372105, 21302075), the International S&T
Cooperation Program of China (2013DFR70580), the Fundamental Research Funds for the
Central Universities (lzujbkyꢀ2014ꢀ242), and the“111” program from MOE of P.R. China.
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