Tandem Copper-Catalyzed Regioselective N-Arylation-Aza-Michael Addition: Synthesis of Tetracyclic 5 H-Benzothiazolo[3,2- a]quinazoline Derivatives

Article abstract of DOI:10.1021/acs.joc.0c00275

A copper-catalyzed tandem process integrating regioselective N-arylation, followed by aza-Michael addition, is disclosed using 2-aminobenzothiazoles and ortho-halo cinnamic acid congeners. This process generated diverse tetracyclic 5H-benzothiazolo[3,2-a]quinazoline derivatives in moderate to good yields. The present tandem reaction appears to proceed through concomitant ring opening of 2-aminobenzothiazole and S-arylation to give the ortho-cyanamide-substituted diaryl thioether intermediate. The thus generated intermediate likely undergoes an unprecedented Truce-Smiles-type rearrangement involving S- to N-aryl migration, followed by reformation of the thiazole ring and intramolecular aza-Michael addition to furnish the title products.

Full text of DOI:10.1021/acs.joc.0c00275

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Article
Tandem Copper Catalyzed Regioselective N-Arylation#aza-Michael Addition:
Synthesis of Tetracyclic 5H-Benzothiazolo[3,2-a]quinazoline Derivatives
Jyoti Honnanayakanavar, Battu Harish, Jagadeesh Babu Nanubolu, and Surisetti Suresh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00275 • Publication Date (Web): 30 Jun 2020
Downloaded from pubs.acs.org on July 1, 2020
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Tandem Copper Catalyzed Regioselective N-Arylation―aza-
Michael Addition: Synthesis of Tetracyclic 5H-Benzothiazolo[3,2-
a]quinazoline Derivatives
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Jyoti M. Honnanayakanavar,†,‡ Battu Harish,†,‡ Jagadeesh Babu Nanubolu,‖ and
Surisetti Suresh*,†,‡
†Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology (CSIR-IICT),
Hyderabad 500 007, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201 002, India
‖Laboratory of X-Ray Crystallography, Department of Analytical Chemistry, CSIR-Indian Institute of Chemical
Technology (CSIR-IICT), Hyderabad 500 007, India
* E-Mail: surisetti@iict.res.in; suresh.surisetti@yahoo.in
Supporting Information
GWE
EWG
R1
S
N
R2
R1
copper
catalysis
N
R1
EWG
S
N
+
NH2
S
N
base
Z
X
R2
Z
Z
R2
EWG = COOR, CN, COR
Z = CH, N
N
via
Smiles-type rearrangement
Tandem copper catalyzed N-arylation and aza-Michael addition
Synthesis of benzothiazolo-quinazoline derivatives (a-z examples)
Unprecedented Truce-Smiles rearrangement (S
N aryl migration)
Gram scale synthesis
via S-arylation intermediate
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ABSTRACT: A copper catalyzed tandem process integrating regioselective N-arylation
followed by aza-Michael addition is disclosed using 2-aminobenzothiazoles and ortho-halo
cinnamic acid congeners. This process generated diverse tetracyclic 5H-benzothiazolo[3,2-
a]quinazoline derivatives in moderate to good yields. The present tandem reaction appears to
proceed through concomitant ring opening of 2-aminobenzothiazole and S-arylation to give
ortho-cyanamide substituted diaryl thioether intermediate. The thus generated intermediate likely
undergoes an unprecedented Truce‒Smiles-type rearrangement involving S- to N-aryl migration
followed by re-formation of the thiazole ring and intramolecular aza-Michael addition to furnish
the title products.
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INTRODUCTION
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The pioneering discoveries by Ullmann and Goldberg on the copper-mediated and copper-
catalyzed C–C, C‒heteroatom bond forming reactions at the beginning of the twentieth century
have gained renaissance in the past three decades. This is due to their increased importance in
organic synthesis in the context of the attributed advantages of ready availability, less
expensiveness and less toxic nature of the copper catalysts when compared to their palladium
counterparts.1 Tandem reactions2 triggered by copper catalyzed N-arylation followed by
cyclization enable the synthesis of potential fused-heterocycles for applications in biology,
medicine and material science.3 For example, tandem copper catalyzed N-arylation followed by
ring-closing condensation processes have been well-reported in the literature,3,4 to access various
fused heterocycles. However, to the best of our knowledge, there have been no reports on the
tandem processes incorporating copper catalyzed N-arylation―conjugate (Michael) addition
leading to ring closure. Continuing our interest on the development of tandem copper catalyzed
arylation‒cyclization approaches and on the synthesis of fused heterocycles,5 we envisioned to
develop tandem strategies by integrating N-arylation and aza-Michael addition. This process
would advantageously allow the synthesis of a variety of fused N-heterocyclic molecules bearing
new C(sp3) centers and diverse functional groups provided by the coupling partners. We selected
2-aminobenzothiazole and ortho-halo cinnamates as model substrates to test our hypothesis.
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On the other hand quinazoline and benzothiazole nuclei are considered as 'privileged'
scaffolds in the drug discovery processes.6 Quinazoline nucleus is found in natural products7 and
several life saving therapeutics (Figure 1).8 For example, gefitinib is a drug used for the
treatment of certain breast, lung and other cancers.8a-c Letermovir is an FDA-approved antiviral
drug for the treatment of cytomegalovirus infections.8d-e Quinazoline derivatives were also
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shown to inhibit the activities of cholinesterase enzymes; targeting these enzymes is known to be
a promising approach in treating Alzheimer's disease.8f Benzothiazole moiety is an important
constituent of many natural products and drug molecules.9 In particular, 2-aminobenzothiazole
derivatives possess important therapeutic profiles.9d,10 For example, frentizole is an
immunosuppressive drug10a-c while riluzole is used for the treatment of amyotrophic lateral
sclerosis10d-e (Figure 1). Considering their intriguing structural features of the benzothiazole and
the quinazoline cores, fusion of these cores into one may provide structurally diverse derivatives
with interesting bioactivities. Additionally, N-fused benzothiazolo-quinazoline derivatives,
containing both the benzothiazole and quinazoline skeletons, exhibited antitumor activities and
also acted as functional molecules.11 We became interested to develop methods to synthesize
scaffolds containing these two nuclei by the construction of N-fused rings leading to a tetracyclic
heterocyclic system (Figure 1, inset).
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This Work
MeO
CF3O
S
S
N
NH
O
NH2
benzothiazole core
-amino ester
N
NHPh
moiety
S
N
N
Riluzole
Frentizole
COOR
OMe
quinazoline core
Cl
F
5H-benzo[4,5]thiazolo[3,2-a]quinazoline derivative
CF3
N
N
Ph
N
N
NH
N
N
O
OMe
N
5
N
N
N
COOH
N
MeO
O
3
F
CONHCH2Ph
Gefitinib
Letermovir
butyrylcholinesterase inhibitor
Figure 1. Representative Medicinal Compounds Containing Benzothiazole and Quinazoline
Cores.
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RESULTS AND DISCUSSION
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We initiated the present study by choosing the coupling partners 2-aminobenzothiazole 1a
and ethyl ortho-bromocinnamate 2a. The reaction of 1a and 2a was carried out in the presence of
9
o
CuI catalyst, (L)-proline ligand5c and DBU base at 130 C for 12 h. Gratifyingly, under the
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reaction conditions, we isolated 5H-benzo[4,5]thiazolo[3,2-a]quinazoline derivative 3a, albeit in
low yield, that resulted from the regioselective N-arylation of the ring (endo) nitrogen of the
benzothiazole (Table 1, entry1). Notably, the N-arylation of the exo-nitrogen of the
benzothiazole was not observed to lead to the 12H-benzo[4,5]thiazolo[2,3-b]quinazoline
derivative 3a'. It must be mentioned that we also isolated ortho-cyanamide substituted diaryl
thioether derivative 4a12 in 46% yield that could result from the concomitant ring opening of 2-
aminobenzothiazole 1a and S-arylation with 2a (vide infra) (Table 1, entry1). We reasoned that
4a could be the intermediate to produce the product 3a in a regioselective fashion (vide infra). In
order to improve the yield of 3a, we conducted an optimization assay by varying the reaction
conditions and catalytic settings. Accordingly, an increase in the time of the reaction drastically
improved the yields of the product 3a while suppressing the production of 4a (Table 1, entries 2
and 3). We screened different copper catalysts and found that CuI is superior for this
transformation (Table 1, entries 3-5). Screening of different ligands proved (L)-proline is more
suitable (Table 1, entries 3, 6 and 7). Inorganic bases were found to be inferior and returned
lower yields of the product 3a (Table 1, entries 3, 8 and 9). In the absence of copper catalyst or
base, this transformation was found to be unsuccessful (Table 1, entries 10 and 11). These results
indicate the crucial role of copper catalyst and base in the Ullmann-Goldberg-type cross coupling
followed by aza-Michael addition. When molecular sieves 4 Å were added to the reaction, better
yield of the product was observed (Table 1, entry 12) (for en extensive optimization survey, see
Supporting Information).
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Table 1. Optimization study.a
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S
N
S
N
N
N
COOEt
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S
N
NH2
EtOOC
Copper Catalyst
Ligand
3a'
(Not Observed)
1a
2a
3a
Base
DMSO, 130 oC, Time
COOEt
COOEt
S
Br
NH
N
4a
entry Cu catalyst
ligand
base
Time (h) %yield of 3ab %yield of 4ab
1
2
CuI
CuI
(L)-Proline
(L)-Proline
(L)-Proline
(L)-Proline
(L)-Proline
DMEDA
DBU
DBU
DBU
DBU
DBU
DBU
DBU
NaHCO3
K3PO4
DBU
―
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24
36
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14
58
65
31
57
62
55
40
37
―
―
72
46
12
―
―
―
―
―
―
―
―
―
―
3
CuI
4
Cu2O
Cu(OAc)2
CuI
5
6
7
CuI
1,10-Phen
(L)-Proline
(L)-Proline
―
8
CuI
9
CuI
10
11
12c
―
CuI
(L)-Proline
(L)-Proline
CuI
DBU
[a] Reaction conditions: 1a (1.2 mmol), 2a (1 mmol), Cu catalyst (0.1 mmol), ligand (0.2 mmol),
base (3.0 mmol), DMSO (4 mL); [b] yields are of isolated products; [c] Reaction was performed
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in the presence of molecular sieves 4 Å (0.7 g); DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;
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DMEDA: N,N'-dimethylethylenediamine.
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By selecting the best optimized conditions from Table 1 (entry 12), we turned to examine the
effect of halogen on the coupling partner 2 (Scheme 1). When the reactions were conducted
using ortho-chlorocinnamate or ortho-iodocinnamate, 3a was isolated in lower yields. Note that
the tandem copper catalyzed regioselective N-arylation―aza-Michael addition of 1a and 2a
worked well on a 10 mmol scale (Scheme 1). The reaction of 1a and methyl ortho-
bromocinnamate furnished the corresponding tetracyclic benzothiazolo-quinazoline derivative
3b in 51% yield. We then checked the scope of this reaction by using differently substituted 2-
aminobenzothiazole derivatives 1 and ethyl ortho-bromocinnamate 2a (Scheme 1). The reactions
of 2a and 2-aminobenzothiazoles 1 containing mono- and di-substituted electron-donating
groups gave the corresponding benzothiazolo-quinazoline derivatives 3c-f in moderate to good
yields.12 The reaction of 2-amino-6-fluorobenzothiazole and 2a afforded the corresponding
benzothiazolo-quinazoline 3g in good yield. Reaction of -OCF3 substituted 2-
aminobenzothiazole and 2a returned moderate yield of the respective product 3h. The reactions
of 2a with 5-fluoro-2-aminobenzothiazole and 4,6-difluoro-2-aminobenzothiazole provided the
corresponding products 3i and 3j in 32% and 37% yields, respectively. In these cases the starting
materials were found to be not fully consumed. We then turned to screen the scope of the ring-
substituents on ortho-bromocinnamate (Scheme 1). Placing electron-donating groups like
trifluoromethyl (CF3) group on benzene ring of 2 was found to deliver the respective product 3k
in high yield, while 2 bearing fluorine or bromine substituents provided low yields of the
corresponding benzothiazolo-quinazoline derivatives 3l-m, while it was observed that the
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complete conversion of the starting materials did not take place. The reaction of 2-
aminobenzothiazole 1a and heteroaryl based partner like ethyl (E)-3-(2-bromopyridin-3-
yl)acrylate 2f afforded the corresponding benzothiazolo-aza-quinazoline derivative 3n in 56%
yield.12 We also examined the tandem copper catalyzed N-arylation-aza-Michael addition by
varying substituents on both the partners (Scheme 1). The reaction of 2-aminobenzothiazole
bearing a methoxy substituent and ortho-bromocinnamate having a bromine substituent returned
in low yield of the corresponding product 3o. A combination of electron-donating group (Me or
OMe) on 2-aminobenzothiazole and electron-withdrawing group (F or CF3) on ortho-
bromocinnamate was found to provide the corresponding benzothiazolo-quinazolines 3p-s in
moderate to good yields. Having electron-withdrawing groups on both the partners provided the
respective products 3t-u in moderate yields.
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Scheme 1. Tandem Copper Catalyzed N-Arylation―aza-Michael Additiona,b
S
N
CuI (10 mol%)
(L)-Proline (20 mol%)
DBU (3 equiv)
COOR
R1
N
COOR
R2
S
N
R1
+
NH2
R2
Z
DMSO, MS 4 Å, 130 oC, 36 h
Z
2
X
3
1
3b-u
X = Br, for
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S
N
S
N
Me
S
N
S
N
N
N
N
N
COOEt
COOMe
COOEt
COOEt
5
6
3d
, 57%
3a
7
8
9
2
2
32% yield; when X = Cl in
72% yield; when X = Br in
3b
, 51%
3c
, 71%
(60% yield - 1.95 g, on a 10 mmol scale)
2
57% yield; when X = I in
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CF3O
F
Me
Me
S
N
S
MeO
S
S
N
N
N
N
N
COOEt
COOEt
COOEt
COOEt
N
N
3h
, 51%
3g
, 68%
3f
3e
, 55%
, 79%
S
N
S
N
F
S
N
S
N
N
N
F
COOEt
N
COOEt
N
COOEt
COOEt
F
F
3k
, 77%
3i
, 32%
3l
, 39%
3j
, 37%
CF3
MeO
S
N
S
N
S
N
N
N
N
COOEt
COOEt
COOEt
N
3o
, 25%
3m
, 30%
3n
, 56%
Br
Br
Me
Me
S
S
N
MeO
S
N
N
COOEt
N
COOEt
COOEt
N
N
3r
, 57%
3q
, 55%
3p
, 62%
CF3
F
F
F
MeO
S
N
S
N
F
S
N
N
COOEt
N
COOEt
COOEt
N
3u
, 49%
3s
, 54%
3t
, 43%
CF3
CF3
F
[a] Reaction conditions: 1 (1.2 mmol), 2 (1 mmol), CuI (0.1 mmol), (L)-proline (0.2 mmol),
DBU (3.0 mmol), DMSO (4 mL); [b] Yields are of isolated products.
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We were interested to assay the scope of the electron-withdrawing group of the alkene part
4
5
on the coupling partner 2 (Scheme 2). Accordingly, the tandem copper catalyzed N-
6
7
arylation‒aza-Michael addition reactions of ortho-bromocinnamonitriles
2
and 2-
8
9
aminobenzothiazoles 1 were performed to produce the corresponding benzothiazolo-quinazolines
3v-y in moderate to high yields.12 However, the reaction of 2-amino-6-methoxybenzothiazole
and ortho-bromochalcone (bearing a keto EWG) gave the corresponding benzothiazolo-
quinazoline derivative 3z in low yield. Having NO2 as an EWG on 2 was proved to be
unsuccessful substrate while it got decomposed under the reaction conditions. However, the
reactions of cinnamate 2a with 2-aminobenzimidazole or 2-aminobenoxazole failed, under the
optimized reaction conditions, while most of the starting materials were found to be unreacted.
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Scheme 2. Tandem Copper Catalyzed N-Arylation―aza-Michael Additiona,b
EWG
CuI (10 mol%)
(L)-Proline (20 mol%)
DBU (3 equiv)
S
N
R1
N
EWG
S
N
R1
+
NH2
DMSO, MS 4 Å, 130 oC, 36 h
Br
2
1
3
Me
MeO
S
S
N
S
N
N
N
CN
CN
CN
N
N
3w
3x
, 55%
, 70%
3v
, 70%
F
S
MeO
S
N
O
N
N
CN
N
3y
, 69%
3z
, 21%
[a] Reaction conditions: 1 (1.2 mmol), 2 (1 mmol), CuI (0.1 mmol), (L)-proline (0.2 mmol),
DBU (3.0 mmol), DMSO (4 mL); [b] Yields are of isolated products.
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To get insights into the reaction mechanism, we conducted some control experiments
(Scheme 3). The tandem copper catalyzed N-arylation‒aza-Michael addition transformation in
the presence radical scavengers TEMPO or BHT afforded the product 3a in 40-58% yields
(Scheme 3a). These results indicated that radical pathway is not involved in the present
transformation. It was thought that the present transformation is possibly proceeding through S-
arylated intermediate 4a that resulted from the concomitant ring opening of 2-
aminobenzothiazole 1a and copper catalyzed S-arylation with 2a.13 To prove the intermediacy of
4a, we subjected the compound 4a to a base mediated reaction. Note that the product 3a was
isolated in 57% yield from this reaction, which entails the present transformation is proceeding
through the intermediate 4a (Scheme 3b). We did not observe any aza-Michael adduct from the
reaction of 2-aminobenzothiazole 1a and ethyl cinnamate 2aa while the starting materials were
recovered (Scheme 3c, LHS). Interestingly, the reaction of 2-aminobenzothiazole 1a and
bromobenzene 2ab under the optimized reaction conditions furnished the S-arylated product
4b13a in 34% yield (Scheme 3c, RHS).
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Scheme 3. Control Experiments
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TEMPO (or) BHT (1 equiv)
S
N
COOEt
CuI (10 mol%)
(L)-Proline (20 mol%)
DBU (3 equiv)
N
COOEt
S
N
+
NH2
(a)
DMSO, MS 4 Å, 130 oC, 36 h
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Br
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2a
1a
3a
3a
, 40% with TEMPO
, 58% with BHT
S
N
COOEt
N
COOEt
S
DBU (3 equiv)
(b)
DMSO, MS 4 Å, 130 oC, 36 h
NH
N
4a
3a
, 57%
COOEt
Br
S
(c)
S
N
2aa
2ab
No
Reaction
NH
N
NH2
CuI/(L)-Proline/DBU
DMSO, MS 4 Å
130 oC, 36 h
CuI/(L)-Proline/DBU
DMSO, MS 4 Å
130 oC, 36 h
1a
4b
, 34%
Based on the above observations from control experiments and literature reports,13,14
probable sequential mechanisms may be proposed for the present tandem process (Scheme 4).
Initially, the action of Cu(I) on the coupling partner ortho-bromocinnamate 2a would result in
the formation of intermediate I via oxidative insertion. In the presence of base, 1a would
undergo ring opening followed by the reaction with intermediate I could provide intermediate II.
A proton shift might take place on the intermediate II to form intermediate III. The S-arylated
product 4a would result from the intermediate III upon reductive elimination to regenerate active
Cu(I) to continue the catalytic cycle. In the presence of base, the S-arylated product 4a would
undergo Truce‒Smiles-type rearrangement14 proceeding through S- to N-aryl migration via
Meisenheimer-type intermediate14 IV to provide intermediate V. To the best of our knowledge,
this is the first Truce‒Smiles rearrangement involving S- to N-aryl migration preserving all
atoms.14 The intermediate V would undergo concomitant ring closures triggered by the
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intramolecular addition of the thio-anion onto nitrile to give intermediate VI that could further
undergo ring-closing aza-Michael addition to eventually furnish the desired benzothiazolo-
quinazoline 3a.
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Scheme 4. Plausible Sequential Reaction Mechanisms
Base.HBr
Base
H
N
H
N
S
COOEt
1a
(III)
Cu
X
N
Ln
C
N
H
COOEt
Br
S
(III)
Cu
Ln
EtOOC
II
X
I
Oxidative
addition
Br
2a
COOEt
LnCu(I)X
Cu(I)X
Ln
(III)
Cu
X
Reductive
elimination
N
Ln
HN
S
III
Truce-Smiles rearrangement via Meisenheimer-type intermediate
EtOOC
EtOOC
S
S
N aryl
N
S
N
migration
S
N
N
N
COOEt
Base
H
V
IV
Base.H+
N
4a
S
N
S
N
Base.H+
N
N
COOEt
COOEt
VI
3a
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To demonstrate the synthetic utility of the benzothiazole fused quinazoline derivative 3a, we
performed some transformations (Scheme 5). Base-mediated hydrolysis of the ester group of 3a
provided the corresponding acid 5 (Scheme 5a, LHS). Interestingly, transesterification of 3a
occurred, instead of the reduction of the ester group,15 when it was reacted with sodium
borohydride in methanol to give the methyl ester 3b (Scheme 5a, RHS). Reduction of the ester
group of 3a was performed using lithium aluminium hydride to furnish the corresponding
alcohol 6 (Scheme 5b).
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Scheme 5. Synthetic Transformations of 3a
S
N
S
N
N
N
NaOH
NaBH4
COOMe
COOH
3a
(a)
MeOH
0 oC-rt, 16 h
THF/H2O (3:1)
rt, 12 h
5
, 90%
3b
, 47%
S
N
S
N
N
LiAlH4
N
COOEt
CH2OH
(b)
THF, 0 oC-rt, 15 min
6
, 66%
3a
CONCLUSIONS
In summary, we have described a tandem process comprising of copper catalyzed
regioselective N-arylation and aza-Michael addition. The tandem reaction process of 2-
aminobenzothiazoles and ortho-halo cinnamates/cinnamonitriles/chalcones furnished a wide
range of N-fused benzothiazolo-quinazoline derivatives in moderate to good yields. Notably, the
present reaction likely goes through S-arylation of 2-aminobenzothiazole via ring opening to give
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ortho-cyanamide substituted diaryl thioether intermediate. The diaryl thioether intermediate
appears to undergo an unprecedented Truce‒Smiles-type rearrangement causing S- to N-aryl
migration followed by the cascade ring closing events of re-formation of the thiazole ring and
aza-Michael addition to produce the 5H-benzothiazolo[3,2-a]quinazoline derivatives.
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EXPERIMENTAL SECTION
General Information. Oven dried glass wares and screw-capped vials were used for
carrying out the reactions. Reported temperatures are the metal block surrounding temperatures
of the screw-cap reaction vial. Reactions were magnetically stirred and monitored by TLC using
UV lamp; iodine was used as a developing agent. Column chromatography was used for
purifying the products by using 60-120, 100-200 silica mesh. Hexane and ethyl acetate were used
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as eluents; solvents were concentrated under reduced pressure at 40-45 C by using rotary
evaporator. All the commercially available reagents and solvents were used without further
1
purification apart from 2-aminobenzothiazole. H-NMR spectra were recorded on 300, 400 and
13
500 MHz instruments; C-NMR spectra were recorded on 101 and 126 MHz spectrometers.
Chemical shifts are reported in ppm with the reference solvent TMS = 0 internal standard CDCl3
= 7.26, DMSO-d6 = 2.50 (1H-NMR), CDCl3 = 77.16 (13C-NMR). Peaks which appear at 1.26,
0.86 in 1H-NMR and 29.7 in 13C-NMR correspond to the residual grease present in the solvent.16
Multiplicity of spectra explained by using the following abbreviations (s = singlet, d = doublet,
dd = doublet of doublet, t = triplet, q = quartet, m = multiplet). Mass spectra were analysed by
Electro Spray Ionization (ESI) method and was obtained on a Shimadzu LCMS-2020 mass
spectrometer. High resolution mass spectra were recorded on a Thermo Scientific ExactiveTM
Orbitrap mass spectrometer or Q STAR XL Hybrid MS/M. Melting points (MP) were
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determined using a Super Fit capillary point apparatus. MPs reported in this work are
uncorrected. Infrared spectroscopy (IR-neat) was performed on a BRUKER FT-IR
spectrophotometer in chloroform, and IR [KBr] spectra were recorded on a THERMO
NICOLET NEXUS 670 FT-IR instrument.
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Literature reported method was adopted for the synthesis of substituted ortho-halocinnamates
2c and 2e.17
(E)-Ethyl 3-(2,5-dibromophenyl)acrylate (2c):- White solid, 0.480 g (1.440 mmol)), 48%,
o
Rf = 0.78 (EtOAc/Hexane 5:95); MP 66-68 C; IR 734, 804, 1639, 1725, 2988 cm-1 1H-NMR
;
(400 MHz, CDCl3) δ = 1.35 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7.1 Hz, 2H), 6.38 (d, J = 15.9 Hz,
1H), 7.33 (dd, J = 8.5, 2.3 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.93 (d, J
13
= 15.9 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.3, 60.9, 121.6, 122.4, 123.7, 130.6,
133.9, 134.7, 136.5, 141.5, 166.0; HRMS (ESI, m/z): calcd for C11H11O2Br2 [M+H]+ 332.91203
found 332.9127.
(E)-Ethyl 3-(2-bromo-5-(trifluoromethyl)phenyl)acrylate (2e):- White solid, 0.620 g
o
(1.920 mmol), 64%, Rf = 0.69 (EtOAc/Hexane 2:98), MP 60-62 C; IR 755, 1331, 1605, 1707,
1
2923 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.36 (t, J = 7.1 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H),
6.46 (d, J = 15.9 Hz, 1H), 7.46 (dd, J = 8.4, 1.9 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H),
8.02 (d, J = 16.0 Hz, 1H); 13C{1H}-NMR (101 MHz, CDCl3) δ =14.3, 60.9, 122.9, 124.6, 127.3,
128.7, 130.4 (q, JC-F = 99.1 Hz), 134.1, 134.7, 135.5, 141.5, 165.9; HRMS (ESI, m/z): calcd for
C12H11O2BrF3 [M+H]+ 322.9889 found. 322.9894.
General procedure for the synthesis of benzothiazolo-quinazoline derivatives 3a-3z.
ortho-Bromocinnamates or ortho-bromocinnamonitrile or ortho-bromochalcone derivative 2 (1
equiv, 1 mmol), copper iodide (0.1 equiv, 0.1 mmol, 19 mg), (L)-proline (0.2 equiv, 0.2 mmol,
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23 mg), DBU (3 equiv, 3 mmol, 0.44 mL), DMSO (4 mL), and MS 4 Å (700 mg) were taken in a
15 mL screw-capped vial. The reaction mixture was stirred for 1 min at room temperature
followed by the addition of 2-aminobenzothiazole derivative 1 (1.2 equiv, 1.2 mmol). The
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reaction vial was placed in a preheated metal block and stirred at 130 C (temperature of metal
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block), for 36 h. The reaction mixture was cooled to room temperature, diluted with water (10
mL). The organic content was extracted with dichloromethane (2 x 15 mL), washed with brine
(10 mL), dried over anhydrous Na2SO4, filtered and solvent was evaporated under reduced
pressure to afford a crude residue, which was purified by column chromatography
(EtOAc/Hexane) on silica gel to obtain benzothiazolo-quinazoline derivatives 3a-3z.
Gram scale procedure for the synthesis of 3a. To a two necked round bottom flask were
added ortho-bromoethylcinnamate 2a (1 equiv, 10 mmol, 2.55 g), CuI (0.1 equiv, 1 mmol, 191
mg), (L)-proline (0.2 equiv, 2 mmol, 230 mg), DBU (3 equiv, 30 mmol, 4.4 mL), MS 4 Å (7 g),
and dimethylsulphoxide (40 mL). Then the reaction mixture was stirred for 1 min at room
temperature followed by the addition of 2-aminobenzothiazole 1a (1.2 equiv, 12 mmol, 2.16 g)
o
and the reaction mixture was stirred at 130 C (temperature of metal block), for 36 h. The
reaction mixture was cooled to room temperature diluted with ice cold water (50 mL) and
organic content was extracted with dichloromethane (2 x 50 mL), washed with brine (30 mL),
dried over anhydrous Na2SO4, filtered and solvent was evaporated under reduced pressure to
obtain a crude residue which was purified by column chromatography (EtOAc/Hexane, 10:90)
on silica gel to afford the ethyl 2-(5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate 3a in
60% yield (1.950 g).
Ethyl 2-(5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3a). Yellow solid, 233 mg
o
(0.720 mmol), 72%, Rf = 0.66 (EtOAc/Hexane, 10:90); MP 102-104 C; IR 771, 1466, 1622,
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1727, 2925, cm-1; H-NMR (500 MHz, CDCl3) δ = 1.24 (t, J = 7.2 Hz, 3H), 2.71 (dd, J = 14.8,
7.4 Hz, 1H), 2.82 (dd, J = 14.8, 7.1 Hz, 1H), 4.10-4.21 (m, 2H), 5.18 (t, J = 7.2 Hz, 1H), 7.13-
7.16 (m, 1H), 7.23-7.33 (m, 4H), 7.41 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.70 (d, J =
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8.1 Hz, 1H); C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 41.1, 57.2, 60.7, 112.7, 114.3, 122.7,
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123.7, 124.4, 125.1, 125.7, 125.9, 127.2, 127.8, 135.1, 136.8, 158.7, 170.9; MS (ESI, m/z):
[M+H]+ 325; HRMS (ESI, m/z): calcd for C18H17O2N2S [M+H]+ 325.1005, found 325.1009.
Methyl 2-(5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3b). Yellow solid, 157 mg
o
(0.507 mmol), 51%, Rf = 0.6 (EtOAc/Hexane 10:90); MP 102-104 C; IR 743, 1465, 1620,
1731, 2924 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 2.73 (dd, J = 15.0, 7.3 Hz, 1H), 2.84 (dd, J =
14.9, 7.2 Hz, 1H), 3.70 (s, 3H), 5.18 (t, J = 7.3 Hz, 1H), 7.13-7.17 (m, 1H), 7.25-7.34 (m, 4H),
7.42 (dd, J = 7.8, 1.1 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H); 13C{1H}-NMR
(101 MHz, CDCl3) δ = 40.9, 51.8, 57.1, 112.8, 114.3, 122.7, 123.7, 124.4, 125.1, 125.7, 125.9,
127.1, 127.8, 135.1, 136.7, 158.8, 171.3; MS (ESI, m/z): [M+H]+ 311; HRMS (ESI, m/z): calcd
for C17H15O2N2S [M+H]+ 311.0848, found 311.0853.
Ethyl 2-(9-methyl-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3c). Yellow solid,
o
239 mg (0.708 mmol), 71%, Rf = 0.66 (EtOAc/Hexane, 10:90); MP 88-90 C; IR 752, 1483,
1
1622, 1730, 2923 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.23 (t, J = 7.1 Hz, 3H), 2.37 (s, 3H),
2.70 (dd, J = 14.8, 7.4 Hz, 1H), 2.81 (dd, J = 14.8, 7.1 Hz, 1H), 4.10-4.20 (m, 2H), 5.16 (t, J =
7.2 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.21-7.32 (m, 4H), 7.47 (d, J = 8.3 Hz, 1H), 7.67 (d, J =
13
8.1 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.2, 21.0, 41.1, 57.1, 60.7, 112.6, 114.1,
123.0, 124.3, 125.0, 125.7, 126.3, 127.1, 127.7, 133.6, 134.5, 135.3, 159.0, 170.9; MS (ESI,
m/z): [M+H]+ 339; HRMS (ESI, m/z): calcd for C19H19O2N2S [M+H]+ 339.1161, found
339.1168.
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Ethyl 2-(9-isopropyl-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3d). Yellow
semi-solid, 209 mg (0.572 mmol), 57%, Rf = 0.64 (EtOAc/Hexane, 10:90); IR 745, 1480, 1621,
1729, 2960 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 1.23 (t, J = 7.1 Hz, 3H), 1.28 (d, J = 6.9 Hz,
6H), 2.70 (dd, J = 14.8, 7.4 Hz, 1H), 2.80 (dd, J = 14.8, 7.1 Hz, 1H), 2.91-2.97 (m, 1H), 4.11-
4.19 (m, 2H), 5.17 (t, J = 7.2 Hz, 1H), 7.16 (dd, J = 8.4, 1.7 Hz, 1H), 7.21-7.33 (m, 4H), 7.52 (d,
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J = 8.4 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.2, 24.1,
33.9, 41.1, 57.1, 60.7, 112.7, 114.2, 120.5, 123.9, 124.3, 125.0, 125.7, 127.1, 127.7, 134.7, 135.2,
144.8, 159.1, 170.9; MS (ESI, m/z): [M+H]+ 367; HRMS (ESI, m/z); calcd for C21H23N2O2S
[M+H]+ 367.1480, found 367.1490.
Ethyl 2-(9-methoxy-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3e). Yellow
semi-solid, 280 mg (0.791 mmol), 79%, Rf = 0.32 (EtOAc/Hexane, 10:90); IR 752, 1483, 1623,
1729, 2930 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.24 (t, J = 7.1 Hz 3H), 2.71 (dd, J = 14.8, 7.4
Hz, 1H), 2.82 (dd, J = 14.8, 7.1 Hz, 1H), 3.84 (s, 3H), 4.11-4.20 (m, 2H), 5.16 (t, J = 7.2 Hz,
1H), 6.85 (dd, J = 8.9, 2.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 7.21-7.25 (m, 2H), 7.27-7.34 (m,
1H), 7.50 (d, 8.8 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H); 13C{1H}-NMR (126 MHz, CDCl3) δ = 14.2,
40.9, 55.9, 57.1, 60.7, 108.2, 111.5, 112.3, 115.0, 124.0, 125.6, 126.4, 127.1, 127.8, 130.6, 135.4,
156.2, 159.1, 170.9; MS (ESI, m/z): [M+H]+ 355; HRMS (ESI, m/z): calcd for C19H19O3N2S
[M+H]+ 355.1110, found 355. 1120.
Ethyl 2-(9,10-dimethyl-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3f). Yellow
semi-solid, 195 mg (0.555 mmol), 55%, Rf = 0.83 (EtOAc/Hexane 10:90); IR 771, 1483, 1624,
1731, 2923 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.23 (t, J = 7.1 Hz, 3H). 2.29 (s, 3H), 2.34 (s,
3H), 2.69 (dd, J = 14.8, 7.5 Hz, 1H), 2.80 (dd, J = 14.8, 7.0 Hz, 1H), 4.10-4.18 (m, 2H), 5.15 (t, J
= 7.2 Hz, 1H), 7.17 (s, 1H), 7.20-7.25 (m, 2H), 7.30-7.34 (m, 1H), 7.40 (s, 1H), 7.71 (d, 8.1 Hz,
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1H); C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 19.5, 20.3, 41.0, 57.2, 60.6, 112.7, 115.6,
121.8, 123.3, 124.3, 125.6, 127.1, 127.7, 132.3, 134.2, 134.8, 135.4, 159.4, 170.9; MS (ESI,
m/z): [M+H]+ 353; HRMS (ESI, m/z): calcd for C20H21N2O2S [M+H]+ 353.1324, found
353.1339.
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Ethyl 2-(9-fluoro-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3g). Yellow solid,
o
233 mg (0.682 mmol), 68%, Rf = 0.70 (EtOAc/Hexane, 10:90); MP 116-118 C; IR 752, 1478,
1
1627, 1729, 2924 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.24 (t, J = 7.1 Hz, 3H), 2.72 (dd, J =
14.9, 7.3 Hz, 1H), 2.82 (dd, J = 14.9, 7.2 Hz, 1H), 4.11-4.20 (m, 2H), 5.17 (t, J = 7.2 Hz, 1H),
6.98-7.03 (m, 1H), 7.15 (dd, J = 7.8, 2.6 Hz, 1H), 7.23-7.34 (m, 3H), 7.50-7.53 (m, 1H), 7.63 (d,
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J = 8.1 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.2, 41.0, 57.2, 60.7, 110.1 (d, JC-F
=
=
30.3 Hz), 112.4, 112.5 (d, JC-F = 20.2 Hz), 114.7 (d, JC-F = 20.2 Hz), 124.2, 125.9, 126.7 (d, JC-F
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10.1 Hz), 127.2, 127.9, 133.1, 135.1, 158.5, 159.0 (d, JC-F = 242.4 Hz), 170.8; F-NMR (377
MHz, CDCl3) δ = -118.1 (s); MS (ESI, m/z): [M+H]+ 343; HRMS (ESI, m/z): calcd for
C18H16FN2O2S [M+H]+ 343.0917, found 343.0928.
Ethyl 2-(9-(trifluoromethoxy)-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3h).
Yellow semi-solid, 210 mg (0.515 mmol), 51%, Rf = 0.87 (EtOAc/Hexane, 10:90); IR 751,
1477, 1629, 1729, 2926 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 1.24 (t, J = 9.3 Hz, 3H), 2.72 (dd,
J = 14.9, 7.3 Hz, 1H), 2.82 (dd, J = 14.9, 7.2 Hz, 1H), 4.12-4.20 (m, 2H), 5.19 (t, J = 7.2 Hz,
1H), 7.17 (dd, J = 8.8, 1.5 Hz, 1H), 7.27-7.28 (m, 2H), 7.31-7.36 (m, 2H), 7.58 (d, J = 8.8 Hz,
13
1H) 7.65 (d, J = 8.2 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.2, 41.2, 57.2, 60.7,
112.6, 114.4, 116.0, 118.8, 124.4, 126.3, 126.7, 127.3, 127.9, 134.7, 135.4, 144.9, 158.1, 170.8;
19F-NMR (377 MHz, CDCl3) δ = -58.2 (s); MS (ESI, m/z): [M+H]+ 409; HRMS (ESI, m/z):
calcd for C19H16F3N2O3S [M+H]+ 409.0834, found 409.0842.
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Ethyl 2-(10-fluoro-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3i). Yellow solid,
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5
o
110 mg (0.321 mmol), 32%, Rf = 0.70 (EtOAc/Hexane, 10:90); MP 116-118 C; IR 772, 1475,
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7
1
1629, 1730, 2927 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.24 (t, J = 7.1 Hz, 3H), 2.71 (dd, J =
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14.9, 7.3 Hz, 1H), 2.81 (dd, J = 14.9, 7.1 Hz, 1H), 4.11-4.22 (m, 2H), 5.18 (t, J = 7.2 Hz, 1H),
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6.87-6.92 (m, 1H), 7.26-7.29 (m, 2H), 7.31-7.37 (m, 3H), 7.66 (d, J = 8.1 Hz, 1H); C{1H}-
NMR (101 MHz, CDCl3) δ = 14.2, 41.3, 57.1, 60.6, 102.6 (d, JC-F = 30.3 Hz), 110.6 (d, JC-F
=
23.3 Hz), 112.5, 119.9, 123.1 (d, JC-F = 9.4 Hz), 124.6, 126.2, 127.3, 127.9, 134.7, 137.5 (d, J =
19
11.2 Hz), 158.7, 161.3 (d, JC-F = 244 Hz), 170.7; F-NMR (377 MHz, CDCl3) δ = -114.7 (s);
MS (ESI, m/z): [M+H]+ 343; HRMS (ESI, m/z): calcd for C18H16FN2O2S [M+H]+ 343.0917,
found 343.0925.
Ethyl 2-(9,11-difluoro-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3j). Yellow
semi-solid, 134 mg (0.373 mmol), 37%, Rf = 0.83 (EtOAc/Hexane 10:90); IR 748, 1478, 1626,
1728, 2925 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.26 (t, J = 7.1 Hz, 3H), 2.79-2.91 (m, 2H),
1
4.14-4.21 (m, 2H), 5.11 (t, J = 7.3 Hz, 1H), 6.84-6.90 (m, 1H), 7.00-7.06 (m, 2H), 7.27 (d, J =
3.7 Hz, 2H), 7.30-7.36 (m, 1H); C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 39.3, 57.5, 60.8,
13
102.3, 102.5, 102.7, 105.9, 106.1 115.2, 115.3, 123.9, 125.9, 126.0, 127.6, 135.5, 158.9, 170.9;
19F-NMR (377 MHz, CDCl3) δ = -109.7 (s), -114.4 (s); MS (ESI, m/z): [M+H]+ 361; HRMS
(ESI, m/z): calcd for C18H15F2N2OS [M+H]+ 361.0822, found 361.0839.
Ethyl 2-(3-(trifluoromethyl)-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3k).
Yellow solid, 301 mg (0.770 mmol), 77%, Rf = 0.75 (EtOAc/Hexane, 10:90); MP 82-84 oC; IR
748, 1319, 1631, 1730, 2927 cm-1; H-NMR (500 MHz, CDCl3) δ = 1.24 (t, J = 7.1 Hz, 3H),
1
2.74 (dd, J = 15.0, 7.8 Hz, 1H), 2.85 (dd, J = 15.0, 6.8 Hz, 1H), 4.13-4.20 (m, 2H), 5.22 (t, J =
7.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.32-7.36 (m, 1H), 7.44 (d, J = 6.9 Hz, 1H), 7.54 (s, 1H),
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7.59 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 8.6 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.1,
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40.8, 56.9, 60.9, 112.9, 114.5, 122.5, 122.9, 124.4, 124.5, 124.8, 125.1 (d, JC-F = 2.9 Hz), 125.2,
125.9, 127.8 (q, JC-F = 33.1 Hz), 136.2, 137.8, 158.6, 170.4; 19F-NMR (377 MHz, CDCl3) δ = -
62.2 (s); MS (ESI, m/z): [M+H]+ 393; HRMS (ESI, m/z): calcd for C19H16F3N2O2S [M+H]+
393.0885, found 393.0917.
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Ethyl 2-(3-fluoro-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3l). Yellow solid,
o
134 mg (0.392 mmol), 39%, Rf = 0.70 (EtOAc/Hexane 10:90); MP 98-100 C; IR 771, 1625,
1
1728, 2925 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H), 2.72 (dd, J = 15.0,
7.6 Hz, 1H), 2.82 (dd, J = 15.0, 6.8 Hz, 1H), 4.12-4.21 (m, 2H), 5.14 (t, J = 7.2 Hz, 1H), 7.00-
7.03 (m, 2H), 7.14-7.18 (m, 1H), 7.29-7.33 (m, 1H), 7.43 (dd, J = 7.8, 1.0 Hz, 1H), 7.53 (d, J =
13
6.6 Hz, 1H), 7.66-7.69 (m, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.2, 40.8, 57.0, 60.8,
114.0 (d, JC-F = 22.7 Hz), 114.0, 114.1, 114.4 (d, JC-F = 23.4 Hz), 122.8, 123.8, 124.9, 125.8,
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126.6 (d, JC-F = 6.6 Hz), 131.1, 136.6, 158.9, 160.4 (d, JC-F = 245.7 Hz), 170.7; F-NMR (377
MHz, CDCl3) δ = -116.2 (s); MS (ESI, m/z): [M+H]+ 343; HRMS (ESI, m/z): calcd for
C18H16FN2O2S [M+H]+ 343.0917, found 343.0917.
Ethyl 2-(3-bromo-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3m). Yellow solid,
o
121 mg (0.300 mmol), 30%, Rf = 0.76 (EtOAc/Hexane, 10:90); MP 106-108 C; IR 748, 1460,
1
1626, 1729, 2925 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H), 2.70 (dd, J =
15.0, 7.6 Hz, 1H), 2.81 (dd, J = 15.0, 6.9 Hz, 1H), 4.13-4.21 (m, 2H), 5.14 (t, J = 7.2 Hz, 1H),
7.15-7.19 (m, 1H), 7.29-7.33 (m, 1H), 7.41-7.44 (m, 3H), 7.50 (d, J = 8.1 Hz, 1H), 7.60 (d, J =
13
8.5 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.2, 40.9, 56.8, 60.9, 114.2, 114.3, 118.3,
122.8, 124.0, 125.1, 125.8, 126.4, 130.1, 130.7, 134.1, 136.4, 158.7, 170.5; MS (ESI, m/z):
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[M+H]+ 403 [M+H+2] 405; HRMS (ESI, m/z): calcd for C18H16BrN2O2S [M+H]+ 403.0116,
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found 403.0130.
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Ethyl 2-(5H-benzo[4,5]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-yl)acetate (3n). Yellow
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o
solid, 182 mg (0.560 mmol), 56%, Rf = 0.5 (EtOAc/Hexane, 10:90); MP 104-106 C; IR 747,
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1434, 1638, 1730, 2922 cm-1; 1H-NMR (300 MHz, CDCl3) δ = 1.21 (t, J = 7.1 Hz, 3H), 2.72 (dd,
J = 15.2, 7.1 Hz, 1H), 2.84 (dd, J = 15.2, 6.5 Hz, 1H), 4.08-4.19 (m, 2H), 5.30 (t, J = 6.8 Hz,
1H), 7.11-7.17 (m, 2H), 7.28-7.35 (m, 2H), 7.52 (dd, J = 7.5, 1.0 Hz, 1H), 8.32 (dd, J = 4.8, 1.5
Hz, 1H), 8.65 (d, J = 8.3 Hz, 1H); 13C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 43.0, 56.3, 60.8,
117.7, 118.1, 121.2, 121.5, 123.3, 123.8, 125.9, 135.2, 136.9, 146.4, 148.3, 157.9, 170.5; MS
(ESI, m/z): [M+H]+ 326; HRMS (ESI, m/z): calcd for C17H16N3O2S [M+H]+ 326.0963, found
326.0967.
Ethyl 2-(3-bromo-9-methoxy-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3o).
Yellow semi-solid, 110 mg (0.255 mmol), 25%, Rf = 0.52 ((EtOAc/Hexane, 20:80); IR 772,
1467, 1625, 1728, 2925 cm-1 1H-NMR (400 MHz, CDCl3) δ = 1.26 (t, J = 7.1 Hz, 3H), 2.70 (dd,
;
J = 14.9, 7.5 Hz, 1H), 2.80 (dd, J = 14.9, 7.0 Hz, 1H), 3.84 (s, 3H), 4.14-4.20 (m, 2H), 5.11 (t, J
= 7.2 Hz, 1H), 6.85 (dd, J = 8.9, 2.6 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 7.39-7.44 (m, 3H), 7.53
13
(d, J = 8.6 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 14.3, 40.7, 55.9, 56.8, 60.8, 108.4,
111.6, 113.8, 114.9, 117.9, 126.0, 126.4, 129.9, 130.2, 130.6, 134.5, 156.4, 158.9, 170.6; MS
(ESI, m/z): [M+H]+ 433; HRMS (ESI, m/z): calcd for C19H18BrN2O3S [M+H]+ 433.0222, found
433.0224.
Ethyl 2-(3-fluoro-9-methoxy-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3p).
Yellow semi-solid, 231 mg (0.621 mmol), 62%, Rf = 0.7 (EtOAc/Hexane 10;90); IR 751, 1483,
1626, 1728, 2926 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.22-1.28 (m, 3H), 2.71 (dd, J = 15.0,
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7.7 Hz, 1H), 2.82 (dd, J = 15.0, 6.8 Hz, 1H), 3.83 (s, 3H), 4.13-4.20 (m, 2H), 5.13 (t, J = 7.2 Hz,
1H), 6.84-6.87 (m, 1H), 6.99-7.02 (m, 3H), 7.42 (d, J = 8.9 Hz, 1H), 7.59-7.62 (m, 1H); 13C{1H}-
NMR (101 MHz, CDCl3) δ = 14.2, 40.6, 55.9, 56.9, 60.8, 108.3, 111.7, 113.5 (d, JC-F = 12.6 Hz),
113.9 (d, JC-F = 12.6), 114.4 (d, JC-F = 25.2 Hz) 114.8, 126.2 (d, JC-F = 12.6 Hz), 126.3, 130.4,
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131.6, 156.3, 159.4, 160.3 (d, JC-F = 302.2 Hz), 170.7; F-NMR (377 MHz, CDCl3) δ = -116.6
(s); MS (ESI, m/z): [M+H]+ 373; HRMS (ESI, m/z): calcd for C19H18FN2O3S [M+H]+ 373.1022,
found 373.1047.
Ethyl
2-(3-fluoro-9-methyl-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate
(3q).
o
Yellow solid, 195 mg (0.548 mmol), 55%, Rf = 0.64 (EtOAc/Hexane 10:90); MP 94-96 C; IR
772, 1485, 1628, 1731, 2925 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.23-1.26 (m, 3H), 2.38 (s,
3H), 2.70 (dd, J = 15.0, 7.7 Hz, 2H), 2.81 (dd, J = 15.0, 6.8 Hz, 2H), 4.12-4.21 (m, 2H), 5.13 (t, J
= 7.2 Hz, 1H), 7.01 (t, J = 8.0 Hz, 2H), 7.10 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 11.5 Hz, 1H), 7.42
(d, J = 8.3 Hz, 1H), 7.62-7.65 (m, 1H); C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 21.0, 40.8,
13
56.9, 60.8, 113.8, 113.91, 114.0, 114.3, 114.5, 123.1, 124.9, 126.4, 131.5, 133.7, 134.4, 159.2,
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160.3 (d, JC-F = 252 Hz), 170.7; F-NMR (377 MHz, CDCl3) δ = -116.6 (s); MS (ESI, m/z):
[M+H]+ 357; HRMS (ESI, m/z): calcd for C19H18FN2O2S [M+H]+ 357.1073, found 357.1088.
Ehyl 2-(9-methyl-3-(trifluoromethyl)-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate
(3r). Yellow solid, 233 mg (0.573 mmol), 57%, Rf = 0.87 (EtOAc/Hexane 10:90); MP 96-98 oC;
IR 772, 1478, 1634, 1729, 2925 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.22-1.26 (m, 3H), 2.40
(s, 3H), 2.73 (dd, J = 14.9, 7.8 Hz, 1H), 2.84 (dd, J = 14.9, 6.7 Hz, 1H), 4.12-4.20 (m, 2H), 5.20
(t, J = 7.2 Hz, 1H), 7.12-7.14 (m, 1H), 7.25-7.26 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.53-7.58 (m,
2H), 7.77 (d, J = 8.6 Hz, 1H); 13C{1H}-NMR (126 MHz, CDCl3) δ = 14.1, 21.1, 40.7, 56.9, 60.9,
112.8, 114.3, 122.8, 123.3, 124.4 (d, JC-F = 3.2 Hz), 124.6, 124.9, 125.1 (d, JC-F = 8.9 Hz), 126.5,
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127.6 (q, JC-F = 33 Hz), 133.9, 134.4, 138.0, 158.8, 170.4; F-NMR (377 MHz, CDCl3) δ = -
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118.1 (s); MS (ESI, m/z): [M+H]+ 407; HRMS (ESI, m/z): calcd for C20H18F3N2O2S.[M+H]+
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407.1041, found 407.1051.
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2-(9-Methoxy-3-(trifluoromethyl)-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-yl)acetonitrile
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(3s). Yellow solid, 228 mg (0.542 mmol), 54%, Rf = 0.56 (EtOAc/Hexane, 10:90); MP 92-94
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oC; IR 772, 1483, 1631, 1729, 2924 cm-1; H-NMR (400 MHz, CDCl3) δ = 1.23-1.26 (m, 3H),
2.73 (dd, J = 14.9, 7.8 Hz, 1H), 2.85 (dd, J = 14.9, 6.8 Hz, 1H), 3.85 (s, 3H), 4.12-4.20 (m, 2H),
5.19 (t, J = 7.2 Hz, 1H), 6.87 (dd, J = 8.9, 2.6 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 7.47-7.58 (m,
3H), 7.73 (d, J = 8.6 Hz, 1H); 13C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 40.6, 55.9, 56.9, 60.9,
108.5, 111.8, 112.5, 115.3, 124.4 (d, JC-F = 5 Hz), 124.9, 125.1 (d, JC-F = 3.78 Hz), 126.6, 127.4,
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127.7, 129.9, 138.1, 156.7, 158.9, 170.5; F-NMR (377 MHz, CDCl3) δ = -62.1 (s); MS (ESI,
m/z): [M+H]+ 423; HRMS (ESI, m/z): calcd for C20H18F3N2O3S.[M+H]+ 423.0990, found
423.0997.
Ethyl 2-(3,9-difluoro-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate (3t). Yellow
o
solid, 154 mg (0.428 mmol), 43%, Rf = 0.64 (EtOAc/Hexane 10:90); MP 106-108 C; IR 772,
1477, 1629,1728, 2925 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H), 2.72 (dd,
J = 15.1, 7.6 Hz, 1H), 2.82 (dd, J = 15.1, 6.8 Hz, 1H), 4.13-4.21 (m, 2H), 5.14 (t, J = 7.2 Hz,
1H), 6.99-7.05 (m, 3H), 7 17 (dd, J = 7.7, 2.6 Hz, 1H), 7.45-7.48 (m, 1H), 7.58-7.61 (m, 1H);
13C{1H}-NMR (126 MHz, CDCl3) δ = 14.2, 40.7, 57.1, 60.8, 110.3 (d, JC-F = 25.2 Hz), 112.6 (d,
JC-F = 25.2 Hz), 113.6 (d, J = 3.78 Hz), 114.1 (d, JC-F = 26.4 Hz), 114.4 (d, J = 12.6 Hz), 114.6
(d, JC-F = 12.6 Hz), 126.4 (d, JC-F =12.6 Hz), 126.6 (d, JC-F = 12.6 Hz), 131.3, 133.0, 158.6, 158.7
(d, JC-F = 189 Hz), 160.0 (d, JC-F = 126 Hz), 170.6; 19F-NMR (377 MHz, CDCl3) δ = -115.9 (s), -
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361.0822, found 361.0831.
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Ethyl 2-(9-fluoro-3-(trifluoromethyl)-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetate
(3u). Orange solid, 200 mg (0.490 mmol), 49%, Rf = 0.75 (EtOAc/Hexane 10:90); MP 96-98 oC;
IR 772, 1475 1629, 1730, 2927 cm-1; 1H-NMR (300 MHz, CDCl3) δ = 1.25 (t, J = 7.1 Hz, 3H),
2.71 (dd, J = 14.9, 7.3 Hz, 1H), 2.81 (dd, J = 14.9, 7.1 Hz, 1H), 4.11-4.20 (m, 2H), 5.22 (t, J =
7.2 Hz, 1H), 6.87-6.92 (m, 1H), 7.27-7.28 (m, 1H), 7.31-7.37 (m, 3H), 7.73 (d, J = 8.5 Hz, 1H);
13C{1H}-NMR (101 MHz, CDCl3). δ = 14.2, 40.7, 57.0, 60.9, 110.4 (d, JC-F = 30.3 Hz), 112.5,
112.8 (d, JC-F = 20.2 Hz), 115.0 (d, JC-F = 10.1 Hz), 112.5 (d, JC-F = 20.2 Hz), 124.7, 125.16,
125.2 (d, JC-F = 4 Hz), 127.0 (d, JC-F = 10 Hz) 127.9 (q, JC-F = 10 Hz), 132.5, 137.8, 158.2, 159.3
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(d, JC-F = 2.4 Hz) 170.4; F-NMR (377 MHz, CDCl3) δ = -62.2 (s), -116.8 (s); MS (ESI, m/z):
[M+H]+ 411; HRMS (ESI, m/z): calcd for C19H15F4N2O2S [M+H]+ 411.0790, found 411.0801.
2-(5H-Benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetonitrile (3v). Yellow solid, 195 mg
o
(0.705 mmol), 70%, Rf = 0.52 (EtOAc/Hexane, 10:90); MP 106-108 C; IR 1467, 1547, 1621,
2195, 2248, 2924 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 2.75-2.88 (m, 2H ), 4.99-5.02 (m, 1H),
7.19 (t, J = 7.6, Hz, 1H), 7.31-7.34 (m, 3H), 7.38-7.45 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.76 (d,
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J = 8.2 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ = 24.9, 56.6, 113.2, 114.3, 117.5, 122.1,
122.8, 124.0, 124.7, 125.9, 126.3, 127.3, 128.7, 134.9, 136.4, 159.9; MS (ESI, m/z): [M+H]+
278; HRMS (ESI, m/z): calcd for C16H12N3S [M+H]+ 278.0746, found 278.0750.
2-(9-Methyl-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetonitrile (3w). Yellow solid,
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203 mg (0.700 mmol), 70%, Rf = 0.4 (EtOAc/Hexane 10:90); MP 114-118 C; IR 753, 1482,
1619, 1726, 2248, 2923 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 2.39 (s, 3H), 2.74-2.87 (m, 2H),
4.98-5.02 (m, 1H), 7.11-7.14 (m, 1H), 7.25-7.26 (m, 1H), 7.31-7.421 (m, 3H), 7.52 (d, J = 5.9
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Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H); 13C{1H}-NMR (101 MHz, CDCl3) δ = 21.1, 24.8, 56.6, 113.1,
114.1, 117.5, 121.9, 123.1, 124.7, 126.1, 126.6, 127.3, 128.6, 134.0, 134.2, 135.0, 160.1; MS
(ESI, m/z): [M+H]+ 292; HRMS (ESI, m/z): calcd for C17H14N3S [M+H]+ 292.0908, found
292.0924.
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2-(9-Methoxy-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetonitrile (3x). Yellow solid,
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168 mg (0.550 mmol), 55%, Rf = 0.32 (EtOAc/Hexane 20:80); MP 82-84 C; IR 771, 1482,
1620, 1726, 2248, 2925 cm-1; 1H-NMR (500 MHz, CDCl3) δ = 2.73-2.86 (m, 2H), 3.84 (s, 3H),
4.99 (t, J = 6.4 Hz, 1H), 6.87 (dd, J = 8.9, 2.6 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 7.31-7.42 (m,
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3H), 7.53 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H); C{1H}-NMR (101 MHz, CDCl3) δ =
24.7, 55.9, 56.6, 108.3, 111.8, 112.7, 115.1, 117.5, 121.7, 126.1, 127.2, 128.7, 130.2, 130.9,
135.1, 156.5, 160.2; MS (ESI, m/z): [M+H]+ 308; HRMS (ESI, m/z): calcd for C17H14N3OS
[M+H]+ 308.0858, found 308.0876.
2-(9-Fluoro-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)acetonitrile (3y). Yellow solid,
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204 mg (0.692 mmol), 69%, Rf = 0.4 (EtOAc/Hexane, 10:90); MP 112-114 C; IR 750, 1575,
1622, 2196, 2248, 2923 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 2.77-2.88 (m, 2H), 4.99-5.02 (m,
1H), 7.02-7.07 (m, 1H), 7.20 (dd, J = 7.7, 2.6 Hz, 1H), 7.30 (d, J = 4.3 Hz, 2H), 7.38-7.44 (m,
1H), 7.55-7.58 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H); 13C{1H}-NMR (101 MHz, CDCl3) δ = 24.9,
56.7, 110.3 (d, JC-F = 25.2 Hz), 112.7, 112.8, 113.0, 114.8 (d, JC-F = 12.6 Hz), 117.4, 121.9,
126.4, 127.4, 128.8, 132.8, 134.8, 159.1 (d, JC-F = 315 Hz), 159.6; 19F-NMR (377 MHz, CDCl3)
δ = 117.5 (s); MS (ESI, m/z): [M+H]+ 296; HRMS (ESI, m/z): calcd for C16H11FN3S [M+H]+
296.0658, found 296.0660.
2-(9-Methoxy-5H-benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl)-1-phenylethanone
(3z).
Orange semi-solid, 81 mg (0.210 mmol), 21%, Rf = 0.54 (EtOAc/Hexane 20:80); IR 748, 1622,
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1727, 2922 cm-1; 1H-NMR (400 MHz, CDCl3) δ = 3.42 (dd, J = 16.2, 7.7 Hz, 1H), 3.52 (dd, J =
16.2, 5.6 Hz, 1H), 3.84 (s, 3H), 5.39-5.41 (m, 1H), 6.85 (dd, J = 8.9, 2.6 Hz 2H), 6.99 (d, J = 2.6
Hz, 1H), 7.19-7.22 (m, 1H), 7.26-7.32 (m, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.48-7.55 (m, 2H), 7.63
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(d, J = 8.1 Hz, 1H), 7.92-7.94 (m, 2H), C{1H}-NMR (126 MHz, CDCl3) δ = 44.7, 55.9, 56.7,
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108.3, 111.5, 112.3, 115.1, 124.6, 125.6, 126.5, 127.6, 128.3, 128.6, 130.6, 133.1, 135.5, 137.0,
156.2, 159.2, 197.8; MS (ESI, m/z): [M+H]+ 387; HRMS (ESI, m/z): calcd for C23H19N2O2S
[M+H]+ 387.1182, found 387.1192.
Experimental procedure for the copper catalyzed reaction of 1a and 2a in the presence
of TEMPO (or) BHT. In a 15 mL screw-capped vial were added ortho-bromoethylcinnamate 2a
(1 equiv, 1 mmol, 255 mg), CuI (0.1 equiv, 0.1 mmol, 19 mg), (L)-Proline (0.2 equiv, 0.2 mmol,
23 mg), DBU (3 equiv, 3 mmol, 0.44 mL), TEMPO (or) BHT (1 equiv, 1 mmol), MS 4 Å (700
mg), and dimethylsulphoxide (4 mL). Then the reaction mixture was stirred for 1 min at room
temperature followed by the addition of 2-aminobenzothiazole 1a (1.2 equiv, 1.2 mmol, 180
o
mg). The reaction mixture was stirred at 130 C (temperature of metal block), for 36 h. The
reaction mixture was cooled to room temperature diluted with water (10 mL) and extracted with
dichloromethane (2 x 15 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and
filtered. Solvent was evaporated under reduced pressure afford a crude residue which was
purified by column chromatography (EtOAc/Hexane 10:90) on silica gel to obtain ethyl 2-(5H-
benzo[4,5]thiazolo[3,2-a]quinazolin-5-yl) acetate 3a in 40% yield with TEMPO and 58% yield
with BHT.
Experimental procedure for synthesis of S-arylated intermediate 4a. In a 15 mL screw-
capped vial were added ortho-bromoethylcinnamate 2a (1 equiv, 1 mmol, 0.255 g), copper
iodide (0.1 equiv, 0.1 mmol, 19 mg), (L)-proline (0.2 equiv, 0.2 mmol, 23 mg), DBU (3 equiv, 3
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mmol, 0.44 mL) dimethylsulphoxide (4 mL), and MS 4 Å (700 mg). Then the reaction mixture
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(1.2 equiv, 1.2 mmol, 0.180 g). The reaction contents were stirred at 130 C (temperature of
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metal block), for 12 h. The reaction mixture was cooled to room temperature and diluted with
water (10 mL). The organic content was extracted with dichloromethane (2 x 15 mL), washed
with brine (10 mL), organic layer was dried over anhydrous Na2SO4 and filtered. Solvent was
concentrated under reduced pressure to afford a crude residue which was purified by column
chromatography (Ethyl acetate/Hexane 10:90) on silica gel to obtain (E)-ethyl 3-(2-(2-
cyanamidophenylthio)phenyl)acrylate 4a in 46% yield.
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(E)-Ethyl 3-(2-(2-cyanamidophenylthio)phenyl)acrylate (4a). White solid, 149 mg (0.460
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mmol), 46%, Rf = 0.70 (EtOAC/Hexane 10:90); MP 102-104 C; IR 1585, 1633, 1708, 2240,
2922, 3219 cm-1; 1H NMR (400 MHz, CDCl3) δ = 1.34 (t, J = 7.1 Hz, 3H), 4.26 (q, J = 7.1 Hz,
2H), 6.40 (d, J = 15.7 Hz, 1H), 6.70-6.75 (m, 1H), 7.04 (brs, 1H), 7.11-7.15 (m, J = 7.6, 1.2 Hz,
1H), 7.18-7.23 (m, 2H), 7.37 (dd, J = 8.1, 1.1 Hz, 1H), 7.48-7.58 (m, 3H), 8.16 (d, J = 15.8 Hz,
1H); 13C{1H}-NMR (101 MHz, CDCl3) δ = 14.35, 60.8, 109.9, 115.5, 116.8, 121.3, 124.4,
126.9, 127.6, 130.8, 131.9, 133.4, 135.8, 137.55, 139.9, 140.35, 166.5. MS (ESI, m/z): [M+H]+
325; HRMS (ESI, m/z): calcd for C18H17N2O2S [M+H]+ 325.1005 found 325.1011.
Experimental procedure for synthesis of product 3a from S-arylated intermediate 4a.
To a 15 mL screw-capped vial were added S-arylated intermediate 4a (0.5 equiv, 0.5 mmol,
0.167 g), dimethylsulphoxide (2 mL) and DBU (1.5 equiv, 1.5 mmol, 0.22 mL). The reaction
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mixture was allowed to stir at 130 C for 36 h. Then the reaction mixture was cooled to room
temperature and diluted with water (5 mL). The contents were extracted with dichloromethane (2
x 10 mL), washed with brine (5 mL), organic layer was dried over anhydrous Na2SO4 and
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