Domino aryne precursor: Efficient construction of 2,4-disubstituted benzothiazoles

Article abstract of DOI:10.1021/jacs.5b02566

An aryne precursor with a potential to perform domino aryne chemistry was proposed and synthesized. The reaction of this reagent with benzothioamide derivatives could afford 2,4-disubstituted benzothiazole with sequential incorporation of C-S, C-N, and C-C bonds on the consecutive three positions of the aryne precursor.

Full text of DOI:10.1021/jacs.5b02566

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Communication
A Domino Aryne Precursor: Efficient
Construction of 2,4-Disubstituted Benzothiazoles
Jiarong Shi, Dachuan Qiu, Juan Wang, Hai Xu, and Yang Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02566 • Publication Date (Web): 16 Apr 2015
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A Domino Aryne Precursor: Efficient Construction of 2,4-
Disubstituted Benzothiazoles
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Jiarong Shi,† Dachuan Qiu,† Juan Wang, Hai Xu, Yang Li*
School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng St. Chongqing, P. R. China,
400030.
Supporting Information Placeholder
ABSTRACT: An aryne precursor with a potential to perform
domino aryne chemistry was proposed and synthesized. The
reaction of this reagent with benzothioamide derivatives
could afford 2,4-disubstituted benzothiazole with sequential
incorporation a C-S, C-N, and C-C bond on the consecutive
three positions of the aryne precursor.
Arynes are among the most reactive organic species and
have been broadly employed in numerous organic syntheses.1
In particular, the success of Kobayashi reagents,2 o-
trimethylsilylphenyl triflates, in recent aryne chemistry is
primarily attributed to their convenient and mild aryne gen-
eration conditions.1f,1g Due to the formal triple bond charac-
ter of arynes, however, normally only 1,2-disubstituted aro-
We started our reagent design with the same generation
matics are attainable via aryne intermediates. The prepara-
method as Kobayashi reagents and looked for a suitable leav-
tion of 1,2,3-trisubstituted benzenes, the structure of which
ing group on intermediate i. Although several Kobayashi
reagents are known to generate intermediate i with halo-
prevails in vast groups of organic compounds, are still be-
gens5 or sulfamoyloxy (-OSO2NMe2) group6 on its 3-position,
yond the boundary of standard aryne chemistry and have yet
to be well-documented.3 Aryne precursors that can assemble
they have been traditionally employed as directing groups to
control the regioselectivity upon nucleophilic reactions3b and
three consecutive functional groups on a benzene ring in
“one-pot” fashion, are compatible with various reagents and
none of them could conduct the transformation in Scheme 1a.
functional groups, and can perform versatile transformations
Due to the supreme leaving ability of triflyloxy (OTf) group,
would largely expand the realm of current aryne chemistry.
we
proposed
2-(trimethylsilyl)-1,3-phenylene
bis(tri-
To reach the goal for trisubstitution, a domino aryne pro-
cess can be conceived. As depicted in Scheme 1a, this process
could sequentially accept two nucleophiles, namely Nu1 and
Nu2, and an electrophile (E) through two aryne intermedi-
ates, i and ii. The generation of consecutive 1,2- and 2,3-
arynes in Scheme 1a could deliver the reaction towards tri-
functionalization. To the best of our knowledge, domino
aryne pathway was only reported by Hart in the construction
of m-terphenyls from 2,6-dibromo-iodobenzene (Scheme
1b).4 Utilizing Grignard reagents to generate aryne from pol-
yhalobenzenes, however, falls short of functional group
compatibility and restricts the synthetic application of this
approach. Herein, we report a reagent that can carry out
domino aryne chemistry under mild aryne generation condi-
tions and exhibit its efficient synthesis of 2,4-disubstituted
benzothiazoles.
fluoromethanesulfonate) (TPBT) (1) as our reagent, which
could generate 3-triflyloxybenzyne (iv) for our domino aryne
process study (Scheme 1c).7 TPBT 1 is a stable, low melting
point solid and could be prepared in grams scale in a batch
from 2-bromoresorcinol in an overall yield between 60% and
80% (see SI for the preparation procedure).
Scheme 2. Initial tests.
To demonstrate the proposed domino process with TPBT 1,
we designed protected benzothioamides 2 as the substrates
(Scheme 1c), on which the sulfur8 and nitrogen9 atoms corre-
spond to Nu1 and Nu2, respectively. We also envisioned that a
Scheme 1. Proposed construction of 1,2,3-
trisubstituted benzene.
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carbonyl group migration from carbamide would take place
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in the final stage, which has been accomplished previously in
aryne chemistry.9a,9c,10 When 2a and 2b were treated with
TPBT 1, to our surprise, two different products, 3a and 4a,
respectively, were obtained (Scheme 2). When pivaloyl (Piv)
group was employed, the reaction gave 2,4-disubstituted
benzothiazole 3a in 51% yield (see SI for its crystal structure);
whereas, with acetyl protected 2b, 2-phenylbenzothiazole
(4a) was found the product in 36% isolated yield. The for-
mation of 4a from 2b is in contrast with aryne acyl-alkylation
reactions, which give readily acetyl group migration.11
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Table 1. Optimization conditions to make 3a.
a
condition B: slow addition of TPBT 1 (0.3 mmol) in di-
oxane (10 mL) to a mixture of 2 (0.9 mmol), K2CO3 (1.8
mmol), and 18-c-6 (0.9 mmol) in dioxane (40 ml); b condition
A: slow addition of TPBT 1 (0.6 mmol) in dioxane (10 mL) to
2 (0.4 mmol) and CsF (2.0 mmol) in dioxane (30 mL) over 8
h; c isolated yield.
a conditions: slow addition of TPBT 1 (0.6 mmol) in solvent
(10 mL) to 2 (0.4 mmol) in solvent (30 mL) over 8 h; b isolat-
c
d
ed yield; Tol./MeCN = 1 : 1; 18-c-6 (2.0 equiv.)/K2CO3 (3.0
e
equiv.); TBAT = tetrabutylammonium difluorotriphenylsili-
cate.
As shown in Table 1, different solvents were screened first
(entries 1-6), and dioxane was found the best solvent (entry
6). In the absence of CsF, no 3a was observed (entry 7), and
the optimal temperature is 80oC (entries 8-10). Further study
revealed that CsF is the best fluoride source (entries 12-15).
Finally, the optimal condition is slow addition of TPBT 1 via a
syringe pump at 80oC in dioxane (condition A), and 3a was
obtained in 82% yield (entry 6).
This preliminary study indicates that by varying the pro-
tecting groups on benzothioamide 2 the reaction path can be
altered. Intriguingly, it is the first mild and direct domino
aryne chemistry to incorporate three functional groups on a
benzene ring with strict 1-2-3 sequence. In view of the broad
spectrum of biological activities of benzothiazoles, such as
antitumor, antimicrobial, anticonvulsant, antidiabetic, and
anti-inflammatory activities,12,13 in addition with the anti-
tumor property of benzothiazole-4-carboxamides as
poly(ADP-ribose) polymerase (PARP) inhibitors,12a our
method could provide a quick structural diversification on
both the 2- and 4-positions of a benzothiazole core. Alt-
hough the syntheses of benzothiazoles have been well docu-
mented,12a,14 preparing 2,4-disubstituted benzothiazoles with
the core of 3a usually requires multistep manipulation.13
With the optimal condition to make 3a in hand, we exam-
ined the reaction outcomes with other protecting groups. It
was found that whenever there is a α-hydrogen on the car-
bonyl group, such as acetyl, phenylacetyl, diphenylacetyl,
and dimethylacetyl groups, 4a was found the dominant
product (entries 1-4, Table 2). Since 4a could also react with
aryne, excess amount of thioamides was used in these reac-
tions. Dimethylacetamide 2e could also produce 1,4-
disubstituted benzothiazole 3e in 14% yield, along with 4a in
48% yield (entry 4). In the absence of α-H, thioamides with
benzoyl, dimethylphenylacetyl, and 1-adamantylcarbonyl
could all produce the corresponding carbonyl migration
products (entries 5-8, Table 2). Other functional groups ei-
ther gave unstable thioamides (with trifluoroacetyl or p-
toluene-sulfonyl) or received no desired product (with t-
butoxycarbonyl) under the reaction conditions.
Table 2. Reaction with various R groups.
Table 3. Substrate scope for the preparation of 3.
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to a series of biologically active compounds,13 indicates that
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our methodology is versatile in structural diversification.
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Scheme 4. Mechanistic study.
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a condition: slow addition of TPBT 1 (0.6 mmol) in dioxane
(10 mL) to 2 (0.4 mmol) and CsF (2.0 mmol) in dioxane (30
mL) over 8 h; isolated yield; Cs2CO3 (2.0 mmol) was used
instead of CsF.
To elucidate the hydrogen source of the 4-position in 4a,
deuterium labeling studies were carried out (Scheme 4a).
When 2b reacted with TPBT 1 in acetonitrile-d3, surprisingly,
4a-d was not observed. In contrast, when 2b-d3 was treated
with TPBT 1 in dioxane, 4a-d was obtained with 88% deuter-
ation on its 4-position. These observations indicate that the
4-hydrogen on 4a originates from the intramolecular 1,5-
hydrogen abstraction via intermediate v as a major pathway
(Scheme 4a). In addition, crossover experiment with 2h and
2o as a mixture gave only two products, 3h and 3o, respec-
tively (Scheme 4b). The absence of crossover products in this
experiment suggests that the carbonyl group migration step
is solely intramolecular.
b
c
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As shown in Table 3, further study on the reaction scope
reveals that various protected thioamides, both aromatic and
aliphatic, could react with TPBT 1. When aromatic thioam-
ides were employed, both electron donating groups (3i, 3j,
and 3p) and electron withdrawing groups (3k-3o) could give
the desired products in moderate to high yields. Heteroaro-
matic rings, such as thiophene, could give the corresponding
product 3q in 71% yield. Moreover, aliphatic analogs could
also afford the desired products, albeit with lower efficiency
(3r and 3s). At last, when 1,3-bis(benzothioamide) 2t was
employed, the corresponding bisbenzothiazole 3t was ob-
tained in 41% yield.
While demonstrated for benzothiazole synthesis, our rea-
gent has great potential for use with other nucleophiles as
well. For example, when TPBT 1 was treated with N-tosylated
aniline 9 in the presence of CsF, 1,3-diaminated product 10
could be achieved in 67% isolated yield (eq 1). This example
indicates that the reaction mode of nucleophile, nucleophile
attack on our TPBT reagent is general when it combines with
different types of nucleophiles.
Scheme 3. Synthetic applications of 3a.
In summary, a series of 2,4-disubstituted benzothiazoles
are prepared from aryne precursor TPBT 1, whose conversion
involves a domino aryne mechanism. By varying the carbonyl
groups, either 2-substituted or 2,4-disubstituted benzothia-
zoles were obtained. A sequential formation of C-S, C-N, and
C-C bond on the 1,2,3-positions of the TPBT 1 benzene ring
was achieved. This method is versatile and the 2,4-
disubstituted benzothiazole product could be further con-
verted to other derivatives. Our ongoing projects focus on
the development of the other useful synthetic applications of
TPBT 1.
To further expand the scope of our method, we turned to
convert the t-butyl ketone on 3a to either acid or amide via
Baeyer-Villiger oxidation or Beckmann rearrangement, re-
spectively. Satisfyingly, under Baeyer-Villiger oxidation con-
dition, benzothiazole 3a could be oxidized to carboxylic acid
5 in 80% yield (Scheme 3). Moreover, both benzamide 7 and
benzonitrile 8 were obtained in 97% and 75% yields, respec-
tively, from oxime 6. The successful achievement of acid 5,
amide 7, and benzonitrile 8, the structures of which belong
ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
y.li@cqu.edu.cn
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Author Contributions
†J. S. and D. Q. contributed equally to this work.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors gratefully acknowledge research support of this
work by NSFC (21372268) and 100 Young Plan by Chongqing
University.
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