A concise construction of 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones via an unusual TBHP/Na2CO3 promoted cascade oxidative cyclization and interrupted Dimroth rearrangement

Article abstract of DOI:10.1039/c6cc09376k

An efficient transition-metal-free cascade reaction has been developed for the facile synthesis of 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-one derivatives from commercially available isatins and 2-haloaryl isothiocyanates. A preliminary mechanistic study suggested an interrupted Dimroth rearrangement was the key step for the successful transformation.

Full text of DOI:10.1039/c6cc09376k

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DOI: 10.1039/C6CC09376K
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Concise construction of 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-
12-ones via an unusual TBHP/Na2CO3 promoted cascade oxidative
cyclization and interrupted Dimroth rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx
Zhi-Wen Zhou, Feng-Cheng Jia, Cheng Xu, Shi-Fen Jiang, Yan-Dong Wu,* and An-Xin Wu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient transition-metal-free cascade reaction has been have been established for the preparation of benzothiazolo[2,3-
developed for the facile synthesis of 12H-benzo[4,5]thiazolo[2,3- b]quinazolinones, but some have limitations such as multiple
b]quinazolin-12-one derivatives from commercially available synthetic steps, harsh reaction conditions, or limited substrate
isatins and 2-haloaryl isothiocyanates. A preliminary mechanistic scope.4 Recently, Huang and Yin reported an elegant copper-
study suggested an interrupted Dimroth rearrangement was the catalyzed domino reaction towards the benzothiazolo[2,3-
key step for the successful transformation.
b]quinazolinone scaffold triggered by an Ullmann coupling (eqn
(1), Scheme 1).5 Xu also demonstrated that benzothiazolo[2,3-
b]quinazolinones can be obtained by an effective copper-
catalyzed oxidation/amination/decarbonylation sequence of
pre-synthesized arylactetamides (eqn (2), Scheme 1).6 Despite
these fulfilling methods discovered in recent years, the
development of concise methods towards benzothiazolo[2,3-
b]quinazolinones, especially under metal-free conditions, is still
highly desirable in terms of step economy, reaction efficiency,
and substrate availability.
Isatins, a unique structure possessing a γ-lactam and a ketone,
have been employed extensively since the early 19th century
for the construction of a wide range of biologically useful
compounds.7 On account of its potential to serve as both an
electrophile and a nucleophile, various reactions have been
established using isatins or its derivatives as a substrate.8
Recently, the development of isatin-based reactions mainly
Benzothiazolo[2,3-b]quinazolinone scaffolds are important
structural motifs in various biologically active agents and
functional molecules (Fig 1). They exhibit an extensive range of
promising biological activities, including cytotoxicity against HL-
60, inhibitory activities towards EGFR, anti-bacterial, antiviral
and antitumor activities.1 Moreover, owing to its distinct
electrochemical properties,
8,9-dihydroxy-7-methyl-12H-
benzothiazolo[2,3-b]quinazolin-12-one can be applied to
electrochemical sensors for glutathione, amoxicillin or L-
cysteine.2
Due to their great importance, a series of methods has been
developed for the construction of benzothiazolo[2,3-
b]quinazolinones. Traditionally, molecules with such a scaffold
were synthesized from 2-aminobenzoic acids and 2-halobenzoic
acids (or their derivatives) via
a nucleophilic aromatic
substitution and acylation sequence.3 Several other methods
Previous work: Transition-metal-catalyzed cascade reactions
This work: Transition-metal-free cascade reactions
Fig 1. Representative functional benzothiazolo[2,3-b]quinazolinone scaffolds.
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, Hubei, Wuhan 430079, P. R. China
Electronic Supplementary Information (ESI) available: Experimental details,
characterization of compounds, copies of 1H and 13C spectra for selected
compounds, and CIF files of 3f. See DOI: 10.1039/x0xx00000x
Scheme
b]quinazolinones
1 Recent advances for the preparation of benzothiazolo[2,3-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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focused on nucleophilic additions to the C-3 carbonyl group,9 and organic bases, with Na2CO3 giving the highest yield (Table 1,
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spiro-annulations,10 ring-expansions,5,6,10a,11 decarboxylative entries 2–8). Further screening of oxidants revealed that the
DOI: 10.1039/C6CC09376K
couplings12 and C-H activations13. However, ring-expansions, green oxidant H2O2 could also promote this reaction smoothly,
especially transition-metal-free ring-expansions11a of isatins, albeit in lower yield (Table 1, entry 9). Other oxidants such as
are still relatively rare. Recently, we disclosed an elaborate ring- DTBP or DDQ failed to deliver the target product (Table 1,
expansion reaction of isatins for the divergent synthesis of entries 10, 11). Further survey of reaction media suggested that
quinazolin-4(3H)-ones and tryptanthrins, enabled by
a
DMSO was the best choice of solvent (Table 1, entries 12–14). A
synergetic tert-butyl hydroperoxide (TBHP)/K3PO4 promoted diminished yield was obtained when the reaction was
oxidative cyclization.11a In conjunction with our ongoing performed at a lower or higher temperature (Table 1, entries 15,
research into developing isatin-based oxidative cyclization 16), while the employment of an aqueous solution of TBHP
methodologies for valuable heterocycles,11a,12 herein we demonstrated that the reaction was also compatible with a
present a transition-metal-free cascade oxidative cyclization for small amount of water (Table 1, entry 17). Finally, the optimal
the convenient access to various 12H-benzo[4,5]thiazolo[2,3- conditions were determined as 1a (0.5 mmol), 1 equiv of 2a, 1.5
b]quinazolin-12-one derivatives in one pot (eqn (3), Scheme 1). equiv of TBHP and 3 equiv of Na2CO3 in DMSO at 100 °C for 9h.
This method uses commercially available starting materials,
Having established optimal reactions conditions, we then
occurs under mild conditions, and is compatible with a wide sought to evaluate the generality of this oxidative cyclization
substrate scope. Notably, an interrupted Dimroth process. As shown in Table 2, we were pleased to find that the
rearrangement14 served as the key step for this smooth reaction demonstrated wide scope for isatins. Electron-
transformation. To the best of our knowledge, this is the first donating groups (5-Me, 5-OMe and 6-OMe) proved to be
example of using an interrupted Dimroth rearrangement to favorable for this transformation, affording the desired
synthesize N-heterocycles.
products in excellent yields (3b–3d, 78–88%). In addition, an
Initially, isatin (1a) and 1-fluoro-2-isothiocyanatobenzene (2a
) array of halogen-substituted isatins, including fluoro-, chloro-
were selected as the model substrates to examine the feasibility and bromo- at the C-4, C-5 or C-6 position, underwent the
of this oxidative cyclization in the presence of TBHP and K3PO4 desired reaction smoothly, delivering the corresponding
in DMSO at 100 °C in a sealed vessel under air. Gratifyingly, the products in moderate to good yields (3e–3k, 55–77%), which
reaction proceeded smoothly, and the desired 12H- provided opportunities for further synthetic elaboration. The 7-
benzo[4,5]thiazolo[2,3-b]quinazolin-12-one (3a) was obtained fluoro substituted isatin was also tolerated in this reaction,
in 45% yield (Table 1, entry 1). Encouraged by this preliminary albeit in a lower yield of 33% (3l). It is worth noting that 1-fluoro,
result, we continued to evaluate the effect of various inorganic 1-chloro, 1-bromo and 1-iodo-2-isothiocyanatobenzenes were
all compatible with these reaction conditions without any
Table 1 Optimization studies
transition-metal catalysts.15
Table 2 Substrate scope of isatinsa,b
Entry
1
2
3
4
5
6
7
8
Base
K3PO4
K2CO3
Na2CO3
Cs2CO3
Li2CO3
NaOH
DBU
DABCO
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Oxidantc
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
H2O2
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
t (°C)
100
100
100
100
100
100
100
100
100
100
100
100
100
reflux
90
Yieldb (%)
45(33)
68(12)
82(<5)
61(15)
73(10)
72(19)
56(7)
trace(trace)
55(9)
trace(trace)
trace(trace)
55(38)
31(43)
trace(trace)
72(<5)
9
10
11
12
13
14
15
16
17d
DTBP
DDQ
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
NMP
CH3CN
DMSO
DMSO
DMSO
110
100
74(<5)
78(<5)
aReaction conditions:
1 (0.5 mmol), 2 (0.5 mmol), Na2CO3 (1.5 mmol), TBHP
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), base (1.5 mmol), oxidant
(0.75 mmol) were heated in 4 mL solvent in a sealed vessel under air for 9 h.
bIsolated yield. Yield of side product 4a was given in parenthesis. cTBHP (5.5 M
in decane); H2O2 (30% aqueous solution); DTBP = di-tert-butyl peroxide; DDQ =
2,3-dichloro-5,6-dicyano-1,4-benzoquinone. dTBHP (70% aqueous solution).
(0.75 mmol) were heated in DMSO (4mL) at 100°C in a sealed vessel under
air for 9 h. bIsolated yield.
2 | J. Name., 2012, 00, 1-3
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Table 3 Substrate scope of 2-haloaryl isothiocyanatesa,b
amount of the target product was formed (eqn (4V)i,ewScAhrteicmle Oenl2in)e.
To further illustrate whether the reaction proceeded through
DOI: 10.1039/C6CC09376K
the
Dimroth
rearrangement,
2-(phenylamino)-4H-
benzo[d][1,3]thiazin-4-one (
7
) was prepared and subjected to
optimal conditions, and the corresponding product from the
Dimroth rearrangement, 3-phenyl-2-thioxo-2,3-dihydroquina-
zolin-4(1H)-one (
2). These results clearly demonstrated that the Dimroth
rearrangement of was interrupted by intramolecular
8), was formed in 75% yield (eqn (5), Scheme
6
nucleophilic aromatic substitution.
On the basis of the above results and literature precedents, a
possible mechanism was proposed using isatin (1a) and 1-
fluoro-2 isothiocyanatobenzene (2a) as an example (Scheme 3).
Initially, isatin (1a) transformed into intermediate
A by
TBHP/Na2CO3 mediated nucleophilic attack, followed by an
intramolecular rearrangement to generate isatoic anhydride
aReaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Na2CO3 (1.5 mmol), TBHP (0.75
mmol) were heated in DMSO (4mL) at 100°C in a sealed vessel under air for 9 h.
bIsolated yield.
The fluoro-, bromo- and iodo-substituted substrates
demonstrated greater reactivity over the chloro-substituted
substrates, furnishing the corresponding molecules in higher
yields (3a, 3c and 3h).
Inspired by this result, we continued to evaluate the diversity
of substituted 2-haloaryl isothiocyanates. As highlighted in
Table 3, the electronic properties and substitution positions on
the phenyl ring exert little influence on the outcome of the
reaction. Substrates bearing halogenic substituents such as 3-F,
4-F and 6-F were well tolerated, delivering the target structures
in good to high yields (3m–3o, 64%–81%). Substitution at C-6 on
the phenyl ring led to a small decrease in the yield, which was
probably due to steric hindrance. Electron-donating groups (4-
OMe, 4-Me, 5-Me) had a slight adverse effect on the reaction
outcome (3p–3r, 61%–75%). To our delight, the reaction also
Scheme 2 Control experiments
proceeded smoothly with other halogenated substrates to give
the corresponding products in good to high yields (3s–3u, 66–
80%).
To shed light on the mechanism of this oxidative cyclization
reaction, a series of control experiments were conducted as
shown in Scheme 2. Initially, when isatoic anhydride (5) and 1-
fluoro-2-isothiocyanatobenzene (2a) were mixed under optimal
conditions, the desired product 12H-benzo[4,5]thiazolo[2,3-
b]quinazolin-12-one (3a) was obtained in 77% yield (eqn (1),
Scheme 2). Additionally, when isatin (1a) and 1-fluoro-2-
isothiocyanatobenzene (2a) were subjected to the reaction
under the optimal conditions for
fluorophenyl)amino)-4H-benzo[d][1,3]thiazin-4-one
isolated in 78% yield (eqn (2), Scheme 2). Further treatment of
in the presence of Na2CO3 in DMSO at 100 °C gave the desired
product 3a in 92% yield (eqn (3), Scheme 2). These experiments
indicated that isatoic anhydride ( ) and benzothiazinone (
might be intermediates in this reaction. To probe the pathway
of the transformation from to 3a, 3-(2-fluorophenyl)-2-thioxo-
3
min, 2-((2-
(6)
was
6
5
6)
6
2,3-dihydroquinazolin-4(1H)-one (4a) was synthesized and
treated under optimal conditions; surprisingly, only a trace
Scheme 3 Possible mechanism
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T. Yokosaka, D. Uraguchi, J. S. Johnson, T. Ooi, Chem. Sci.,
(5
), the product of a Baeyer-Villiger-type oxidation16. The
decarboxylative cyclization between isatoic anhydride ( ) and 1-
fluoro-2-isothiocyanatobenzene 2a would give the
benzothiazinone intermediate . Subsequently, the Dimroth-
rearrangement of was interrupted by intramolecular aromatic
nucleophilic substitution, giving intermediate . Finally, the
intramolecular amidation of would deliver the target
molecule 3a
In summary,
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C
C
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a
transition-metal-free cascade oxidative
cyclization reaction for the facile synthesis of 12H-
benzo[4,5]thiazolo[2,3-b]quinazolin-12-one derivatives has
been developed. Preliminary mechanistic study suggested that
the reaction proceeds through consecutive oxidation,
decarboxylative cyclization, and interrupted Dimroth
rearrangement. Further applications of this isatin-based
oxidative cyclization strategy for the synthesis of other
interesting heterocycles are currently underway in our
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Acknowledgements
We are grateful to the National Natural Science Foundation
of China (Grant Nos. 21472056 and 21602070) for financial
support. This work is also supported by the Fundamental
Research Funds for the Central Universities (CCNU15ZX002) and
the Fundamental Research Funds for the Central Universities
(CCNU16A05002). We also acknowledge an excellent graduate
education innovation grant from Central China Normal
University (2016CXZZ67).
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