Chemoselective reactions under solvent-free conditions: Lanthanide-catalyzed syntheses of 2-amino-3,1-benzothiazines and 3,4-dihydroquinazoline-2-thiones

Article abstract of DOI:10.1039/c3ra44829k

A catalyst-controlled chemoselective reaction of o-aminocinnamate and isothiocyanates in the presence of lanthanide complexes under mild and solvent-free conditions was developed. 2-Amino-3,1-benzothiazines were obtained in high yields when the reactions were catalyzed by Yb(OTf)₃, whereas those catalyzed by [(Me₃Si)₂N]₃La(μ-Cl) Li(THF)₃ afforded 3,4-dihydroquinazoline-2-thiones in high to excellent yields. The mechanism for the product selectivity and high efficiency of the reaction was proposed.

Full text of DOI:10.1039/c3ra44829k

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Chemoselective reactions under solvent-free
conditions: lanthanide-catalyzed syntheses of
2-amino-3,1-benzothiazines and 3,4-
dihydroquinazoline-2-thiones†
Cite this: RSC Adv., 2014, 4, 3113
*
*
Lu Hua, Zhigang Yao, Fan Xu and Qi Shen
A catalyst-controlled chemoselective reaction of o-aminocinnamate and isothiocyanates in the presence
of lanthanide complexes under mild and solvent-free conditions was developed. 2-Amino-3,1-
benzothiazines were obtained in high yields when the reactions were catalyzed by Yb(OTf)3, whereas
those catalyzed by [(Me3Si)2N]3La(m-Cl)Li(THF)3 afforded 3,4-dihydroquinazoline-2-thiones in high to
excellent yields. The mechanism for the product selectivity and high efficiency of the reaction was
proposed.
Received 2nd September 2013
Accepted 25th November 2013
DOI: 10.1039/c3ra44829k
www.rsc.org/advances
2-Amino-3,1-benzothiazine3 (Scheme 1, A) and 3,4-dihy-
droquinazoline-2-thione4 (Scheme 1, B) are both useful heterocy-
Introduction
clic compounds with a range of biological applications. The
majority of the approaches5 available for the preparation of 2-
amino-3,1-benzothiazines are based on the reactions of aromatic
amines or thioureas bearing a halomethyl or hydroxymethyl
substituent at the ortho position of the aromatic ring, with a strong
Bronsted acid or noble metal catalyst being required in most cases
to facilitate the reaction. Furthermore, these reactions invariably
required heating under reux in organic solvents, as well as
complex and sometimes inaccessible substrates, and multistep
reaction processes appeared to be essential to obtain satisfactory
results. In contrast, 3,4-dihydroquinazoline-2-thiones are generally
synthesized according to one of two routes. The rst of these
routes involves the treatment of 2-aminobenzyl alcohols or 2-
aminophenones with isothiocyanates or isothiocyanic esters,6 and
requires the addition of concentrated hydrogen chloride for high
yields, whereas the second of these routes involves the condensa-
tion of carbon disulde with aromatic amines bearing an amino-
methyl substituent at the ortho position of the aromatic ring.7
Kobayashi et al.8 recently developed an efficient method for the
selective preparation of 2-amino-3,1-benzothiazines and 3,4-
dihydroquinazoline-2-thiones by the reaction of 3-(2-iso-
thiocyanatophenyl)propanoic acid derivatives with secondary and
primary amines, respectively. In this particular case, the structural
feature of the substrate (i.e., the amine) effectively dictated the
product selectivity.
Selective reactions are powerful tools in organic synthesis because
they provide chemists with the means to produce different
products from the same starting materials, depending on what
they are trying to achieve, which not only improves the overall
level of synthetic efficiency but also reduces chemical waste and
the occurrence of undesired by-products. Catalyst-controlled
selective reactions have attracted, and continue to attract, signif-
icant levels of attention from synthetic chemists. In a recent
review of selectivity in organic synthesis, Bode1 stated that “there
is growing recognition that all classes of selectivity can be exqui-
sitely controlled by the design and choice of the appropriate
catalyst”. Compared with well-studied catalyst-controlled enan-
tioselective reactions, however, catalyst-controlled chemoselective
reactions have received a much lower level of attention.
Lanthanide ions have distinctive characteristics, such as
strong Lewis acidity, tuneable ancillary ligation properties, and
large ionic radii accompanied with lanthanide contraction.
Lanthanide complexes have therefore emerged as efficient
catalysts in many useful transformations.2 Although the subtle
combination of these characteristics may lead to divergent
reaction pathways with high levels of selectivity when multi-
center substrates are used as starting materials, reports
concerning the development and application of lanthanide-
catalyzed chemoselective reactions have been scarce.
Key Laboratory of Organic Synthesis, College of Chemistry, Chemical Engineering and
Materials Science, Soochow University, Suzhou 215123, China. E-mail: xufan@suda.
edu.cn; Fax: +86-0512-65880305
† Electronic supplementary information (ESI) available: General experimental
procedure, characterization data and copies of the 1H NMR and 13C NMR
spectra for the products. See DOI: 10.1039/c3ra44829k
Scheme 1 Projected synthetic route.
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In a recent publication, we described the synthesis of 2-amino- efforts revealed that the reaction did not proceed in the absence
3,1-benzothiazines via the ytterbium chloride-catalyzed tandem of catalyst (Table 1, entry 1). When 0.5 mol% of the well-known
addition-cyclization reactions of o-aminocinnamate with variety Lewis acid ytterbium triate [Yb(OTf)3] was added to the reac-
of different isothiocyanic esters.9 The key intermediate in this tion, ethyl 2-(2-(phenylamino)-4H-benzo[d][1,3]thiazin-4-yl)-
particular reaction process was identied as a thiourea, which acetate 3a was formed in 50% yield (Table 1, entry 2). Pleas-
behaves as a nucleophile from its S-terminal to form the target ingly, when the catalyst loading was increased to 1 mol%, the
product. Prompted by this result, we envisaged that the thiourea reaction proceeded to a greater extent, with the yield increasing
C could undergo an intramolecular cyclization reaction, in the dramatically to 98% (Table 1, entry 3). The temperature was also
presence of suitable metal catalyst, with either the S-terminal or found to have a signicant effect on the rate of the reaction. For
the N-terminal of the thiourea behaving as the nucleophile to example, when the reaction carried out at 25 ꢀC, the desired
selectively form the 2-amino-3,1-benzothiazine
A or 3,4- yield could only be obtained when the catalyst loading was
dihydroquinazoline-2-thione B, respectively (Scheme 1). In a increased to 5 mol% and the reaction time was extended to 20
continuation of our previous studies towards the development of hours (Table 1, entry 4). To assess the inuence of the central
lanthanide-catalyzed carbon–nitrogen and carbon–phosphorus metal on the catalytic activity of the Lewis acid, a variety of
bond-forming reactions,10,11 we became interested in the idea of different lanthanide triates were evaluated in the reaction
developing methods utilizing lanthanide complexes as catalysts (Table 1, entries 3 and 5–7). The results revealed that the yield of
for constructing these two heterocycles in an efficient, atom- the reaction decreased progressively as the ionic radius of the
economical, and controllable manner. Herein, we would like to Ln(III) increased from the heavy rare earth Yb to the light rare
disclose our recent results towards the realization of this idea.
earth La. The triate complex of Yb, which was the smallest and
most Lewis acidic among those tested, gave the best result in
the reaction (Table 1, entry 3). The use of Cu(OTf)2 as catalyst in
the model reaction was also evaluated (Table 1, entry 8). Inter-
Results and discussion
To begin with, we tested our idea using the reaction of ethyl estingly, another compound was isolated as the major product
o-aminocinnamate with phenyl isothiocyanate at 50 ꢀC under of this particular reaction, and the anticipated product 3a was
solvent-free conditions as a model reaction (Table 1). Our initial isolated only as a minor product in 26% yield. Structure
Table 1 Screening of catalysts for the reaction of ethyl o-aminocinnamate and phenyl isothiocyanatea
HPLC yield (%)
Entry
Catalyst
Loading (mol%)
Time (h)
3a
4a
1
2
—
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sm(OTf)3
Nd(OTf)3
5
4
4
20
4
4
Trace
50
98
92
89
Trace
Trace
Trace
Trace
Trace
6
0.5
1
5
1
1
3
4b
5
6
85
7
La(OTf)3
1
4
84
5
8
Cu(OTf)2
1
4
26
70
9
Zn(OTf)2
1
4
44
42
10
11
12
13
14b
15
16
17
18
19c
20
[(Me3Si)2N]3Yb(m-Cl)Li(THF)3
[(Me3Si)2N]3Sm(m-Cl)Li(THF)3
[(Me3Si)2N]3Nd(m-Cl)Li(THF)3
[(Me3Si)2N]3La(m-Cl)Li(THF)3
[(Me3Si)2N]3La(m-Cl)Li(THF)3
[(Me3Si)2N]3La(m-Cl)Li(THF)3
[(Me3Si)2N]3La(m-Cl)Li(THF)3
[(Me3Si)2N]3La(m-Cl)Li(THF)3
LiN(SiMe3)2
5
5
5
5
5
2.5
1
2.5
7.5
2.5
2.5
5
5
5
5
13
5
5
4
5
3
4
80
90
91
95
97
92
78
86
Trace
Trace
Trace
Trace
5
Trace
3
Trace
23
73
91
70
[(Me3Si)2N]3La(m-Cl)Li(THF)3
La[N(SiMe3)2]3 + LiCl
5
5
a
Reactions were performed with 1 mmol of ethyl o-aminocinnamate and 1.2 mmol of phenyl isothiocyanate at 50 ꢀC. b Reaction conducted at 25 ꢀC.
The catalyst in this reaction was formed in situ.
c
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elucidation by 1H NMR, 13C NMR and high resolution mass
Although the formation of 4a was observed in the Cu(OTf)2
spectroscopy (HRMS) revealed this compound to be ethyl 2-(3- and Zn(OTf)2 catalyzed reactions, the product selectivity was not
phenyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)acetate 4a. In satisfactory. Pleasingly, however, further screening of the
a separate experiment involving the use of Zn(OTf)2 as the lanthanide catalysts revealed that the addition of 5 mol% of the
catalyst, compound 4a was isolated in a 42% yield together with lanthanide amide [(Me3Si)2N]3Yb(m-Cl)Li(THF)3 to the reaction
3a, which was isolated in 44% yield (Table 1, entry 9). These effectively facilitated the selective transformation of the
results indicated that Ln(OTf)3 catalysts are highly efficient substrates into the corresponding product 4a at 50 ꢀC under
catalysts for the selective transformation of the substrates into solvent-free conditions (Table 1, entry 10), with only a minor
3a, whilst providing only minor traces of 4a.
trace of 3a being formed. Tetracoordinate lanthanide amide
12,13
We then proceeded to investigate the scope of this Yb(OTf)3 complexes of the formula [(Me3Si)2N]3Ln(m-Cl)Li(THF)3
are
catalyzed transformation by reacting a variety of different iso- chloride-bridged “ate” complex derived from homoleptic Ln
thiocyanates with o-aminocinnamate under the optimized [N(SiMe3)2]3, and have been reported as efficient catalysts for a
conditions (Table 2). It is clear from the table that all of the number of useful transformations.11,14,15 In most cases, their
reactions proceeded smoothly to afford the corresponding distinctive properties may be rationalized by the cooperation of
2-amino-3,1-benzothiazines in high yields under solvent-free their Lewis acidity and Bronsted basicity. During the optimi-
conditions. The reaction appeared to be generally applicable to zation of the reaction conditions, a relationship between the
aryl isothiocyanates bearing substitutions at the ortho-, meta- and catalytic activity and the size of the metal ion was also observed
para-positions, with electron decient and electron rich iso- (Table 1, entries 10–13). The rate of the reaction for the
thiocyanates being well tolerated under the optimized conditions. formation of 4a, however, followed an opposite trend to that
In contrast to aryl isothiocyanates, which performed well under observed for 3a, with lanthanides with a larger ionic radius
the optimized conditions, alkyl isothiocyanates exhibited lower providing greater reaction rates. Similarly, the temperature had
levels of reactivity and required extended reaction time to provide a signicant impact on the reactivity. For example, when the
yields comparable to those of aryl isothiocyanates. For example, reaction was carried out at 25 ꢀC, the desired yield of the
methyl isothiocyanate only provided a yield similar to those of aryl product could only be achieved when the reaction time was
isothiocyanates when the reaction time was prolonged to 15 extended to 13 hours (Table 1, entry 14). When the loading of
hours. The bulkier cyclohexyl isothiocyanate gave a lower yield of the catalyst was reduced to 2.5 mol%, a good yield of 92% was
79%, even when the reaction was conducted at 70 ꢀC over an still observed (Table 1, entry 15). A further reduction in the
extended reaction time of 48 hours. Overall, however, these results catalysts loading to 1 mol%, however, led to a signicant
suggested that Yb(OTf)3 was particularly active in catalyzing the reduction in the yield to 78% (Table 1, entry 16). A control
addition-cyclization reactions of o-aminocinnamate with reaction was conducted using LiN(SiMe3)2 (7.5 mol%) as the
isothiocyanates to form 2-amino-3,1-benzothiazines.
catalyst and gave 4a in a yield of 73% (Table 1, entry 18), and
effectively highlighted the importance of the lanthanide ion to
the catalytic system. It has been reported that [(Me3Si)2N]3Ln(m-
Cl)Li(THF)3 can be formed in situ by the metathesis reaction of
LnCl3 with 3 equiv. of LiN(SiMe3)2 in THF.13,14 To develop a
greater understanding of the inuence of the catalyst structure
on the catalytic activity, the model reaction was performed
using [(Me3Si)2N]3La(m-Cl)Li(THF)3 which was formed in situ
from the reaction of lanthanum chloride with lithium silyla-
mide as the catalyst (Table 1, entry 19). The result revealed that
the in situ formed catalyst showed the same level of activity as
that of the same catalyst prepared under the standard reaction
conditions. However, the use of a 1 : 1 mixture of La[N(SiMe3)2]3
and anhydrous LiCl in THF as the catalyst failed to produce the
same effect with [(Me3Si)2N]3La(m-Cl)Li(THF)3 (Table 1, entry
20). These results indicated that the nature of the combination
of La[N(SiMe3)2]3 with LiCl in crystalline [(Me3Si)2N]3La(m-Cl)-
Li(THF)3 may be a key factor in determining its catalytic ability.
On the basis of all of these results, the optimized reaction
conditions for the selective formation of 4a were selected as
Table
2 Yb(OTf)3-catalyzed reactions of o-aminocinnamate with
isothiocyanatesa
Entry
R
Temp. (ꢀC) Time (h) Product Isolated yield (%)
1
2
3
4
5
6
7
8
Ph
50
50
50
50
4
4
4
4
4
4
4
4
4
4
4
15
48
3a
3b
3c
3d
3e
3f
3g
3h
3i
97
98
93
97
95
98
99
91
90
94
96
95
79
p-FC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4 50
p-MeC6H4 50
p-MeOC6H4 50
m-MeOC6H4 50
m-ClC6H4
o-ClC6H4
o-FC6H4
CH3
ꢀ
2.5 mol% [(Me3Si)2N]3La(m-Cl)Li(THF)3 at 50 C for 5 hours.
9
50
50
50
50
70
With the optimized conditions in hand, the scope of the
[(Me3Si)2N]3La(m-Cl)Li(THF)3 catalyzed reaction of o-amino-
cinnamate was evaluated using a variety of different iso-
thiocyanates (Table 3). The results suggest that [(Me3Si)2N]3La(m-
Cl)Li(THF)3 was highly active in catalyzing the addition-cyclization
reactions of o-aminocinnamate with isothiocyanates to form
10
11
12
13
3j
3k
3l
Cyclohexyl
3m
a
Reactions were performed with 1 mmol of ethyl o-aminocinnamate
and 1.2 mmol of the isothiocyanates.
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Table 3 [(Me3Si)2N]3La(m-Cl)Li(THF)3 catalyzed reactions of o-ami-
nocinnamate with isothiocyanatesa
Entry
R
Temp. (ꢀC) Time (h) Product Isolated yield (%)
1
2
3
4
5
6
7
8
Ph
50
50
50
50
5
5
5
5
5
5
5
5
5
5
5
20
72
4a
4b
4c
4d
4e
4f
4g
4h
4i
91
95
91
89
98
89
87
96
90
96
86
97
89
p-FC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4 50
p-MeC6H4 50
p-MeOC6H4 50
m-MeOC6H4 50
m-ClC6H4
o-ClC6H4
o-FC6H4
CH3
9
50
50
50
50
70
10
11
12
13
4j
4k
4l
Cyclohexyl
4m
Scheme 2 Proposed mechanism for the [(Me3Si)2N]3Ln(m-Cl)Li(THF)3
catalyzed reaction.
a
Reactions were performed with 1 mmol of ethyl o-aminocinnamate
and 1.2 mmol of the isothiocyanates.
protonolysis of the resulting Ln–C bond to form 3,4-
dihydroquinazoline-2-thione 4 and regenerate E.
3,4-dihydroquinazoline-2-thiones in high to excellent yields. An
electronic effect was observed: the activity of isothiocyanates with
the aryl at 4-position bearing electron-withdrawing groups was
higher than that of those bearing electron-donating groups
(Table 3, entries 2–7). In a similar manner to the preceding
Yb(OTf)3 catalyzed reaction for the synthesis of 2-amino-3,1-
benzothiazines, the [(Me3Si)2N]3La(m-Cl)Li(THF)3 catalyzed reac-
tion for the synthesis of 3,4-dihydroquinazoline-2-thiones also
encountered some difficulties when alkyl isothiocyanates were
used as substrates. For example, a prolonged time of 20 hours was
necessary for the reaction with methyl isothiocyanate to reach the
desired yield (Table 3, entry 12).
From another perspective, the results obtained from
Ln(OTf)3-catalyzed reaction can be explained (Scheme 3)
according to the hard-so acid–base (HSAB) theory.17 At the
same time of activating the unsaturated ester as a Lewis acid,
lanthanide can coordinate to the thiourea and delocalize the
S]C–NH moiety. Based on the HSAB theory, nitrogen, which is
more electronegative and non-pololarizable than sulfur, is
harder than sulfur. It can therefore be considered that N is the
hard end of the thiourea D, whereas S is the so end. Following
the principles of the HSAB theory, the S-terminal of thiourea
The ability to exert such a high level of product selectivity by
changing the catalyst suggested that very different mechanisms
were in operation for the two different processes, which
compelled us to conduct a mechanistic analysis to develop some
insight into the origin of this unusual selectivity. We were already
aware that the reaction started with the rapid condensation of the
aromatic amino group of the aniline to the isothiocyanate to
form thiourea D as an intermediate, which could be detected and
isolated during the course of reaction. It was then proposed
(Scheme 2) that the use of [(Me3Si)2N]3Ln(m-Cl)Li(THF)3 as a
catalyst would lead to the rapid deprotonation of the thiourea
and result in the generation of an amine–ligated amido complex
E, which would most probably be the catalytically active species,
with concomitant liberation of (Me3Si)2NH. This proposal was
based on the unique properties of [(Me3Si)2N]3Ln(m-Cl)Li(THF)3
and the consideration that thiourea would be sufficiently acidic
to be irreversibly metallated by [(Me3Si)2N]3Ln(m-Cl)Li(THF)3. The
unsaturated C–C bond of the o-aminocinnamate would then
insert into the Ln–N bond,16 followed by the subsequent Scheme 3 Proposed mechanism for the Ln(OTf)3 catalyzed reaction.
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would be more prone to reacting as a nucleophile to attack the
carbon atom, which is so as well. Thus, cyclization takes place
via an intramolecular thia-Michael addition leading to inter-
mediate H, which would then be converted to 2-amino-3,1-
benzothiazine 3 upon work-up.
Typical procedure for the [(Me3Si)2N]3La(m-Cl)Li(THF)3-
catalyzed reactions of o-aminocinnamate and isothiocyanates
A mixture of ethyl o-aminocinnamate (191 mg, 1 mmol), iso-
thiocyanate (1.2 mmol) and [(Me3Si)2N]3La(m-Cl)Li(THF)3 (22
ꢀ
mg, 0.025 mmol) was stirred at 50 C for 5 hours. Water was
added, and the mixture was extracted with EtOAc. The
combined organic layers were dried with anhydrous Na2SO4,
concentrated in vacuo, and puried by chromatography on silica
gel [eluent–EtOAc/petroleum ether (60–90 ꢀC) 1 : 10] to afford
the desired 3,4-dihydroquinazoline-2-thione.
Ethyl 2-(3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)-
acetate (4a). Following the typical procedure above, compound
4a (297 mg, 91%) was obtained as a white solid: mp 154–155 ꢀC;
1H NMR (300 MHz, CDCl3) d 9.04 (s, 1H), 7.51–7.40 (m, 5H),
7.29–7.24 (m, 1H), 7.16 (d, J ¼ 7.5 Hz, 1H), 7.06 (t, J ¼ 7.5 Hz,
1H), 6.91 (d, J ¼ 7.8 Hz, 1H), 5.26 (dd, J ¼ 8.1, 4.8 Hz, 1H), 4.06–
3.95 (m, 2H), 2.93 (dd, J ¼ 15.0, 4.8 Hz, 1H), 2.85 (dd, J ¼ 15.0,
8.4 Hz, 1H), 1.14 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
177.1, 169.7, 143.9, 134.6, 129.6, 129.3, 128.8, 128.5, 126.0,
124.0, 120.8, 114.2, 61.20, 61.0, 40.0, 14.1; IR nmax/cmꢁ1 3332,
2980, 1730, 1594, 1514, 765; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H19N2O2S 327.1162, found 327.1164.
Conclusions
We have successfully developed a catalyst-controlled chemo-
selective reaction for the construction of 2-amino-3,1-
benzothiazines and 3,4-dihydroquinazoline-2-thiones from
o-aminocinnamate and isothiocyanates in the presence of
lanthanide complexes as catalysts under mild and solvent-free
conditions. 2-Amino-3,1-benzothiazines were obtained in high
yields when the reactions were catalyzed by Yb(OTf)3, whereas
3,4-dihydroquinazoline-2-thiones were obtained in high to
excellent yields when the reaction was catalyzed by
[(Me3Si)2N]3La(m-Cl)Li(THF)3. This product selectivity induced
by the lanthanide complexes provided efficient, atom-
economical, and practical approaches to the production of the
corresponding heterocycles. Mechanistic studies towards devel-
oping a greater understanding of the catalytic selectivity, as well
as studies aimed at identifying further applications for the
observed selectivity are currently underway in our laboratories.
Ethyl 2-(3-(4-uorophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
azolin-4-yl)acetate (4b). Following the typical procedure above,
compound 4b (327 mg, 95%) was obtained as a white solid: mp
147–149 ꢀC; 1H NMR (300 MHz, CDCl3) d 9.28 (s, 1H), 7.42–7.14
(m, 6H), 7.07 (t, J ¼ 7.5 Hz, 1H), 6.92 (d, J ¼ 7.8 Hz, 1H), 5.23 (dd,
J ¼ 7.8, 5.1 Hz, 1H), 4.07–3.96 (m, 2H), 2.90 (dd, J ¼ 15.0, 5.1 Hz,
Experimental section
General information
All manipulations were conducted under an atmosphere of dry 1H), 2.82 (dd, J ¼ 15.0, 8.1 Hz, 1H), 1.14 (t, J ¼ 7.2 Hz, 3H); 13
C
Ar with ame-dried glassware. Ln(OTf)318 and [(Me3Si)2N]3Ln(m- NMR (75 MHz, CDCl3) d 177.2, 169.5, 162.0 (1JCF ¼ 247 Hz),
13,14
Cl)Li(THF)3
were synthesized according to the literature 139.7, 134.4, 130.6 (3JCF ¼ 8 Hz), 129.3, 125.8, 124.0, 120.6, 116.5
(2JCF ¼ 22 Hz), 114.2, 61.2, 61.0, 40.0, 14.1; IR nmax/cmꢁ1 3322,
method. 1H and 13C NMR spectra were obtained on Varian
INOVA-400 and System-300 spectrometers using tetramethylsi-
lane (TMS) as an internal reference. HRMS data were obtained
on a Micromass GCT instrument. IR spectra were obtained on a
Nicolet FT-IR 1000 spectrophotometer.
2981, 1716, 1603, 1509, 1463, 1373, 1219, 837, 764; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C18H18FN2O2S 345.1068, found
345.1070.
Ethyl 2-(3-(4-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
azolin-4-yl)acetate (4c). Following the typical procedure above,
compound 4c (328 mg, 91%) was obtained as a white solid: mp
135–136 ꢀC; 1H NMR (300 MHz, CDCl3) d 8.79 (s, 1H), 7.46–7.26
(m, 6H), 7.16 (d, J ¼ 7.2 Hz, 1H), 7.08 (t, J ¼ 7.5 Hz, 1H), 6.88 (d,
J ¼ 7.8 Hz, 1H), 5.23 (dd, J ¼ 7.8, 4.8 Hz, 1H), 4.07–3.97 (m, 2H),
2.89 (dd, J ¼ 15.0, 4.8 Hz, 1H), 2.82 (dd, J ¼ 15.0, 7.8 Hz, 1H),
1.15 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 177.1, 169.5,
142.2, 134.4, 134.2, 130.2, 129.8, 129.4, 125.9, 124.1, 120.6,
114.2, 61.2, 60.9, 40.0, 14.1; IR nmax/cmꢁ1 3342, 2977, 1716,
1618, 1493, 1462, 1374, 1092, 829, 754; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C18H18ClN2O2S 361.0772, found 361.0770.
Ethyl 2-(3-(4-bromophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
azolin-4-yl)acetate (4d). Following the typical procedure above,
compound 4d (360 mg, 89%) was obtained as a white solid: mp
146–147 ꢀC; 1H NMR (300 MHz, CDCl3) d 9.90 (s, 1H), 7.59 (d, J ¼
8.7 Hz, 2H), 7.32 (d, J ¼ 8.7 Hz, 2H), 7.24 (t, J ¼ 7.5 Hz, 1H), 7.13
(d, J ¼ 7.2 Hz, 1H), 7.05 (t, J ¼ 7.5 Hz, 1H), 6.98 (d, J ¼ 7.8 Hz,
1H), 5.23 (dd, J ¼ 7.5, 5.1 Hz, 1H), 4.06–3.95 (m, 2H), 2.88 (dd,
J ¼ 14.7, 4.8 Hz, 1H), 2.81 (dd, J ¼ 14.7, 7.5 Hz, 1H), 1.13 (t, J ¼
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 176.8, 169.5, 142.7,
Typical procedure for the Yb(OTf)3-catalyzed reactions of o-
aminocinnamate and isothiocyanates
A mixture of ethyl o-aminocinnamate (191 mg, 1 mmol), iso-
thiocyanate (1.2 mmol) ꢀand ytterbium triate (6.2 mg, 0.01
mmol) was stirred at 50 C for 4 hours. Water was added, and
the mixture was extracted with EtOAc. The combined organic
layers were dried with anhydrous Na2SO4, concentrated in
vacuo, and puried by chromatography on silica gel [eluent–
EtOAc/petroleum ether (60–90 ꢀC) 1 : 10] to afford the desired 2-
amino-4H-3,1-benzothiazine.
Ethyl
2-(2-(phenylamino)-4H-benzo[d][1,3]thiazin-4-yl)-
acetate (3a).9 Following the typical procedure above,
compound 3a (316 mg, 97%) was obtained as a white solid. The
spectral data were in agreement with reported literature values:
1H NMR (400 MHz, CDCl3) d 7.57 (d, J ¼ 8.0 Hz, 2H), 7.36–7.27
(m, 3H), 7.22–7.16 (m, 2H), 7.09 (t, J ¼ 7.2 Hz, 2H), 6.71 (br s,
1H), 4.51 (dd, J ¼ 8.8, 6.4 Hz, 1H), 4.14 (q, J ¼ 7.2 Hz, 2H), 2.83
(dd, J ¼ 16.0, 8.8 Hz, 1H), 2.75 (dd, J ¼ 16.0, 6.4 Hz, 1H), 1.22
(t, J ¼ 7.2 Hz, 3H).
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134.3, 132.7, 130.5, 129.3, 125.8, 124.0, 122.3, 120.6, 114.3, 61.2,
60.8, 40.0, 14.1; IR nmax/cmꢁ1 3323, 2978, 1716, 1618, 1491,
1461, 1375, 1069, 826, 752; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H18BrN2O2S 405.0267, found 405.0269.
Ethyl 2-(3-(3-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
azolin-4-yl)acetate (4i). Following the typical procedure above,
compound 4i (324 mg, 90%) was obtained as a white solid: mp
148–150 ꢀC; 1H NMR (400 MHz, CDCl3) d 9.23 (s, 1H), 7.43–7.26
(m, 5H), 7.16 (d, J ¼ 7.6 Hz, 1H), 7.07 (t, J ¼ 7.6 Hz, 1H), 6.92
(d, J ¼ 8.0 Hz, 1H), 5.24 (dd, J ¼ 8.0, 5.2 Hz, 1H), 4.06–3.97 (m,
2H), 2.90 (dd, J ¼ 15.2, 4.8, 1H), 2.82 (dd, J ¼ 15.2, 8.0, 1H), 1.15
(t, J ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 177.0, 169.5,
144.8, 134.9, 134.4, 130.4, 129.4, 129.2, 128.7, 127.3, 125.9,
124.1, 120.7, 114.3, 61.3, 60.9, 40.0, 14.1; IR nmax/cmꢁ1 3319,
2979, 1718, 1617, 1373, 1094, 856, 788, 758, 686; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C18H18ClN2O2S 361.0772,
found 361.0773.
Ethyl 2-(3-(4-nitrophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
azolin-4-yl)acetate (4e). Following the typical procedure above,
compound 4e (364 mg, 98%) was obtained as a yellow solid: mp
155–156 ꢀC; 1H NMR (300 MHz, CDCl3) d 9.80 (s, 1H), 8.33 (d, J ¼
8.7 Hz, 2H), 7.67 (d, J ¼ 8.7 Hz, 2H), 7.28 (t, J ¼ 6.9 Hz, 1H), 7.18
(d, J ¼ 6.9 Hz, 1H), 7.10 (t, J ¼ 7.2 Hz, 1H), 6.98 (d, J ¼ 7.8 Hz,
1H), 5.33 (dd, J ¼ 7.5, 4.8 Hz, 1H), 4.08–3.97 (m, 2H), 2.90 (dd,
J ¼ 15.3, 5.1 Hz, 1H), 2.83 (dd, J ¼ 15.5, 7.8 Hz, 1H), 1.15 (t, J ¼
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 176.8, 169.3, 149.2,
146.9, 134.1, 129.9, 129.6, 125.9, 124.8, 124.5, 120.6, 114.4, 61.4,
60.7, 40.1, 14.1; IR nmax/cmꢁ1 3296, 3068, 2993, 1708, 1607,
1526, 1373, 1350, 862, 758; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H18N3O4S 372.1013, found 372.1014.
Ethyl 2-(2-thioxo-3-(p-tolyl)-1,2,3,4-tetrahydroquinazolin-4-yl)-
acetate (4f). Following the typical procedure above, compound
4f (303 mg, 89%) was obtained as a white solid: mp 157–158 ꢀC;
1H NMR (400 MHz, CDCl3) d 8.48 (s, 1H), 7.30–7.26 (m, 5H), 7.16
(d, J ¼ 7.2 Hz, 1H), 7.08–7.05 (m, 1H), 6.84 (d, J ¼ 8.0 Hz, 1H),
5.23 (dd, J ¼ 8.4, 4.8 Hz, 1H), 4.05–3.96 (m, 2H), 2.92 (dd, J ¼
15.2, 4.8 Hz, 1H), 2.84 (dd, J ¼ 15.2, 8.4 Hz, 1H), 2.40 (s, 3H),
1.14 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 177. 2,
169.7, 141.3, 138.4, 134.6, 130.2, 129.3, 128.4, 126.0, 123.8,
120.8, 114.1, 61.1, 61.0, 39.9, 21.4, 14.1; IR nmax/cmꢁ1 3335,
3120, 2927, 1716, 1615, 1506, 1463, 1373, 821, 763; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C19H21N2O2S 341.1318, found
341.1322.
Ethyl 2-(3-(2-chlorophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
azolin-4-yl)acetate (4j). Following the typical procedure above,
compound 4j (346 mg, 96%) was obtained as a white solid: mp
200–201 ꢀC; 1H NMR (400 MHz, CDCl3) d 9.01 (s, 1H), 7.64–7.62
(m, 1H), 7.55–7.53 (m, 1H), 7.40–7.25 (m, 3H), 7.17 (d, J ¼ 7.6
Hz, 1H), 7.07 (t, J ¼ 7.6 Hz, 1H), 6.90 (d, J ¼ 8.0 Hz, 1H), 5.16 (dd,
J ¼ 7.2, 5.6 Hz, 1H), 4.06–3.97 (m, 2H), 2.90 (dd, J ¼ 14.8, 5.2 Hz,
1H), 2.85 (dd, J ¼ 15.2, 7.6 Hz, 1H), 1.14 (t, J ¼ 7.2 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) d 177.1, 169.6, 140.5, 134.3, 133.2, 131.6,
130.9, 129.9, 129.2, 127.3, 126.0, 124.1, 120.7, 114.3, 61.2, 59.4,
40.2, 14.1; IR nmax/cmꢁ1 3315, 2926, 1730, 1618, 1480, 1373,
1219, 753; HRMS (ESI-TOF) m/z: [M
18H18ClN2O2S 361.0772, found 361.0777.
Ethyl 2-(3-(2-uorophenyl)-2-thioxo-1,2,3,4-tetrahydroquin-
+
H]+ calcd for
C
azolin-4-yl)acetate (4k). Following the typical procedure above,
compound 4k (296 mg, 86%) was obtained as a white solid: mp
164–165 ꢀC; 1H NMR (400 MHz, CDCl3) d 9.02 (s, 1H), 7.40–7.23
(m, 5H), 7.15 (d, J ¼ 7.6 Hz, 1H), 7.07 (t, J ¼ 7.6 Hz, 1H), 6.90 (d,
J ¼ 8.0 Hz, 1H), 5.20 (m, 1H), 4.05–3.96 (m, 2H), 3.02–2.92 (m,
Ethyl 2-(3-(4-methoxyphenyl)-2-thioxo-1,2,3,4-tetrahydroqu-
inazolin-4-yl)acetate (4g). Following the typical procedure
above, compound 4g (310 mg, 87%) was obtained as a white
1H), 2.83 (dd, J ¼ 15.6, 8.4 Hz, 1H), 1.14 (t, J ¼ 7.2 Hz, 3H); 13
C
¼
1
NMR (100 MHz, CDCl3) d 176.9, 169.6 (J ¼ 31 Hz), 156.7 (1JCF
solid: mp 145–145.5 ꢀC; H NMR (300 MHz, CDCl3) d 9.68 (s,
212 Hz), 134.2 (3JCF ¼ 13 Hz), 133.0, 130.5 (3JCF ¼ 14 Hz), 130.1,
129.1, 125.6, 123.9 (2JCF ¼ 17 Hz), 120.8, 120.3, 117.0 (2JCF ¼ 20
Hz), 114.3, 61.0, 59.7, 40.3, 13.9; IR nmax/cmꢁ1 3321, 2898, 1724,
1602, 1518, 1464, 1175, 762; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H18FN2O2S 345.1068, found 345.1060.
1H), 7.33 (d, J ¼ 8.4 Hz, 2H), 7.23 (t, J ¼ 7.8 Hz, 1H), 7.12 (d, J ¼
7.2 Hz, 1H), 7.05–6.96 (m, 4H), 5.21 (dd, J ¼ 7.5, 4.8 Hz, 1H),
4.02–3.99 (m, 2H), 3.84 (s, 3H), 2.91 (dd, J ¼ 15.0, 5.1 Hz, 1H),
2.83 (dd, J ¼ 15.0, 8.4 Hz, 1H), 1.13 (t, J ¼ 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 177.3, 169.7, 159.1, 136.6, 134.3, 129.8,
129.2, 125.9, 123.8, 120.8, 114.7, 114.1, 61.2, 61.1, 55.6, 39.9,
14.1; IR nmax/cmꢁ1 3180, 3020, 1743, 1604, 1507, 1444, 1378,
1246, 1024, 836, 751; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
Ethyl 2-(3-methyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-4-yl)-
acetate (4l). Following the typical procedure above, compound
4l (257 mg, 97%) was obtained as a white solid: mp 77–78 ꢀC; 1H
NMR (400 MHz, CDCl3) d 9.51 (s, 1H), 7.23 (t, J ¼ 7.6 Hz, 1H),
7.10 (d, J ¼ 7.2 Hz, 1H), 7.01 (t, J ¼ 7.2 Hz, 1H), 6.96 (d, J ¼ 8.0
Hz, 1H), 5.03 (dd, J ¼ 7.2, 5.6 Hz, 1H), 4.11 (q, J ¼ 7.2 Hz, 2H),
3.52 (s, 3H), 2.81 (dd, J ¼ 15.2, 4.8 Hz, 1H), 2.65 (dd, J ¼ 15.2, 8.0
Hz, 1H), 1.20 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
176.6, 170.1, 134.3, 129.1, 125.6, 123.7, 120.5, 113.7, 61.2, 59.1,
40.7, 39.3, 14.1; IR nmax/cmꢁ1 3192, 2978, 1720, 1602, 1367,
1203, 748; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H17N2O2S
265.1005, found 265.1000.
C
19H21N2O3S 357.1267, found 357.1266.
Ethyl 2-(3-(3-methoxyphenyl)-2-thioxo-1,2,3,4-tetrahydroqu-
inazolin-4-yl)acetate (4h). Following the typical procedure
above, compound 4h (342 mg, 96%) was obtained as a white
solid: mp 117–118 ꢀC; 1H NMR (400 MHz, CDCl3) d 10.07 (s, 1H),
7.37 (t, J ¼ 8.0 Hz, 1H), 7.21 (t, J ¼ 7.6 Hz, 1H), 7.12 (d, J ¼ 7.6 Hz,
1H), 7.04–7.00 (m, 3H), 6.97–6.93 (m, 2H), 5.25 (dd, J ¼ 8.0, 4.8
Hz, 1H), 4.04–3.95 (m, 2H), 3.82 (s, 3H), 2.93 (dd, J ¼ 15.2, 4.8
Hz, 1H), 2.85 (dd, J ¼ 14.8, 8.4 Hz, 1H), 1.13 (t, J ¼ 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 176.7, 169.5, 160.2, 144.7, 134.5,
130.0, 129.1, 125.7, 123.7, 120.9, 120.6, 114.5, 114.2, 113.9, 61.0,
60.8, 55.4, 40.0, 14.0; IR nmax/cmꢁ1 3122, 3202, 2939, 1730, 1608,
1497, 1441, 1047, 857, 785, 750, 692; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C19H21N2O3S 357.1267, found 357.1267.
Ethyl 2-(3-cyclohexyl-2-thioxo-1,2,3,4-tetrahydroquinazolin-
4-yl)acetate (4m). Following the typical procedure above,
compound 4m (295 mg, 89%) was obtained as a white solid: mp
1
ꢀ
76–78 C; H NMR (300 MHz, CDCl3) d 9.10 (s, 1H), 7.28–7.15
(m, 2H), 7.04–6.93 (m, 2H), 5.27–5.19 (m, 1H), 5.09 (dd, J ¼ 10.5,
3118 | RSC Adv., 2014, 4, 3113–3120
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3.0 Hz, 1H), 4.09–3.99 (m, 2H), 2.79 (dd, J ¼ 15.6, 10.8 Hz, 1H),
2.55 (dd, J ¼ 15.6, 3.0 Hz, 1H), 2.19–1.22 (m, 10H), 1.15 (t, J ¼ 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) d 177.0, 170.1, 134.6, 128.9,
125.4, 123.6, 122.0, 113.8, 60.9, 60.8, 51.3, 40.4, 31.3, 30.7, 25.8,
25.7, 25.3, 14.1; IR nmax/cmꢁ1 3370, 2929, 1740, 1608, 1498,
1371, 1032, 935, 760; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
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Czech. Chem. Commun., 1986, 51, 2802; (i) M. Schmittel,
A. Mahajan and J. P. Steffen, Synthesis, 2004, 415; (j)
K. K. Sharma, N. K. Ralhan and K. S. Narang, J. Org. Chem.,
1963, 28, 740; (k) R. Hull, P. J. van den Broek and
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18H25N2O2S 333.1631, found 333.1628.
Acknowledgements
The authors thank the nancial support received from the
National Natural Science Foundation of China (21272168,
20972107, 20872106) and the Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions.
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