Synthesis of 2-C-substituted benzothiazoles via a copper-promoted domino condensation/S-arylation/heterocyclization process

Article abstract of DOI:10.1039/c4ob00564c

Two series of extremely useful 2-C-substituted benzothiazoles containing gem-bisphosphonates and aryl-substituted nitriles were synthesized here via a copper-promoted domino condensation/S-arylation/heterocyclization process. This journal is

Full text of DOI:10.1039/c4ob00564c

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Synthesis of 2-C-substituted benzothiazoles
via a copper-promoted domino condensation/
S-arylation/heterocyclization process†
Cite this: Org. Biomol. Chem., 2014,
12, 4633
Haoyue Xiang,‡a,b Jin Qi,‡a Qian He,b Min Jiang,*a Chunhao Yang*b and
Lianfu Denga
Received 14th March 2014,
Accepted 1st May 2014
Two series of extremely useful 2-C-substituted benzothiazoles containing gem-bisphosphonates and
aryl-substituted nitriles were synthesized here via a copper-promoted domino condensation/S-arylation/
heterocyclization process.
DOI: 10.1039/c4ob00564c
www.rsc.org/obc
Benzothiazole and its derivatives, a considerably important lementary methods for constructing the benzothiazole scaffold
class of heterocycles, have drawn high attention because of is highly desirable.
their extensive application in the biological and pharma-
Recently, some alternative thiol reagents have been
ceutical areas.1 Particularly, 2-substituted benzothiazoles have employed for the synthesis of benzothiazoles from con-
been intensively studied on account of their various bioactiv- veniently available starting materials in one pot.9 In 2009, Ma
ities, such as selective inhibitors of 17β-HSD1,2 anti-fungal et al. reported an efficient method to access substituted ben-
reagents,3 antitumour agents4 and the significant application zothiazoles via a Cu-catalyzed coupling reaction of aryl halides
of the core structure of benzothiazoles in clinical drugs.5
with metal sulfides.10 Successively, they developed novel syn-
In light of the importance of the benzothiazole scaffold, thetic methods to 2-S/N-substituted benzothiazoles using
considerable effort has been devoted to developing efficient carbon disulfide as a thiol surrogate (Scheme 1, path 1).9b,d It
synthetic approaches for this privileged structure. As is well- was believed that dithiocarbamate salts were formed by treat-
known, the normal methods reported before for the assembly ing amines/thiols with carbon disulfide, which might serve as
of benzothiazole moieties typically rely on the condensation of novel coupling partners to react with 2-halo-anilines. Inspired
2-aminothiophenols with carboxylic acids or aldehydes, but by these developments, we speculated that a similar transform-
such methods suffer from harsh reaction conditions and ation would occur to provide 2-carbon-substituted benzothia-
difficulties in the preparation of readily oxidized 2-aminothio- zoles if nucleophiles were replaced with carbanions generated
phenols.6 Additionally, many alternative methods to access in situ in the presence of bases. Fortunately, after great efforts
benzothiazoles involving C–H functionalized cyclization of toward developing new methods for heterocycle synthesis, we
thiobenzanilide and transition metal-catalyzed intramolecular found that nitrogen-containing bisphosphonates (N-BPs),
cyclization of 2-halophenyl benzothioamide have been 2-methylbisphosphonate-substituted
reported.7 However, these methods usually face considerable
benzothiazoles,
and
limitations, including low functional group tolerance since in
most cases P4S10 or Lawesson’s reagent was used to prepare
thioamide.8 Thus the development of alternative and comp-
aShanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of
Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong
University School of Medicine, Shanghai, 20025, China.
E-mail: jiangm263@163.com
bState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, P.R. China.
E-mail: chyang@simm.ac.cn; Fax: +86-21-50806770; Tel: +86-21-50806770
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00564c
Scheme 1 Synthetic approaches to two series of 2-C-substituted
‡These authors contributed equally to this work.
benzothiazoles.
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α-aryl-substituted nitriles, α-benzothiazol-substituted nitriles, nions from methylenebis(phosphonate) 2a, and thus a range
could readily be obtained in our laboratory by employing of stronger bases were employed. To our delight, these stron-
bis(diethoxyphosphoryl)methanides and cyano(phenyl)metha- ger bases we screened excepting Cs2CO3 could provide the
nides generated in situ respectively as nucleophiles instead of desirable products in moderate to good yields (entries 3–6).
N and/or S nucleophiles in this cascade three-component reac- Among these bases, tBuOK turned out to be the best base with
tion (Scheme 1, paths 2a and 2b). More importantly, this trans- a 75% yield. Interestingly, the corresponding product 3a was
formation is a significant complement to Ma’s reaction.9b,d
isolated as a tautomeric mixture with about 1 : 3 ratio of imine
1
As is well-known, nitrogen-containing bisphosphonates form 3a′ and enamine form 3a″ estimated by H-NMR. As the
(N-BPs) are ubiquitous in numerous pharmaceuticals and next optimization step we performed a solvent screening
agrochemicals owing to their broad range of biological activi- (entries 7–10). None of the other solvents was superior to
ties, such as γ δ T cell stimulators,11 anti-infective agents,12 DMF. Obviously, nonpolar solvents led to considerably lower
anti-cancer agents,13 etc., especially as powerful inhibitors of yields than polar solvents (entries 7, 8 vs. 6, 9, 10). After that,
bone resorption.14 Moreover, in the clinic many N-BPs are cur- we finally surveyed the effect of temperature on the reaction,
rently applied widely to treat osteoporosis, Paget’s disease and revealing that neither increasing nor lowering the reaction
malignant hypercalcemia,15 and these are the only clinically temperature gave higher yields compared to reacting at 30 °C.
t
validated drugs targeting hFPPS.16 In addition, α-aryl-substi-
With the optimized conditions (1.2 eq. CS2, 3 eq. BuOK,
tuted nitriles are also very valuable building blocks to gain 1 eq. CuCl2 in DMF at 30 °C for 12 h) in hand, a range of
amides, carboxylic acids, primary amines, ketones, hetero- 2-halo-anilines were applied to explore the scope and limitations
cycles and biologically active compounds with or without the of this reaction (Table 2). We found that substrates 1 bearing
nitrile group.17 Therefore, two series of quite useful 2-C-substi- electron-withdrawing and also electron-donating substituents
tuted benzothiazoles were synthesized here via a copper-cata-
lyzed
domino
condensation/S-arylation/heterocyclization
process.
Table 2 Scope of 2-halo-anilinesa,c
Our present study commenced with the reaction of 2-iodo-
aniline 1a with carbon disulfide and tetraethyl methylenebis-
(phosphonate) 2a as a model to examine suitable reaction con-
ditions (Table 1). Initially, previous optimized conditions
(1.2 eq. CS2, 3 eq. K2CO3, 1 eq. CuCl2 in DMF at 110 °C for 6 h)
reported by Ma’s group9d were applied, but no desired product
was detected (entry 1). Considering that carbanions might be
unstable at high temperature, we lowered the temperature to
30 °C, but no reaction took place yet. We supposed that the
base K2CO3 might not be strong enough to generate carba-
Entry
1
2-Halo-aniline
Product
Yieldb (3′ : 3″)
3a
75% (1 : 3.3)
2
3
4
5
6
7
8
3b
3c
3d
3e
3f
73% (1 : 2.4)
65% (1 : 4.0)
45% (1 : 0.94)
44% (1 : 2.3)
61% (1 : 1.3)
55% (1 : 1.8)
48% (1 : 2.3)
Table 1 Optimization of the reaction conditionsa
Entry
Base
Solvent
T [°C ]
Yieldb,c [%]
1
2
3
4
5
6
7
8
K2CO3
K2CO3
Cs2CO3
KOH
DMF
DMF
DMF
DMF
DMF
DMF
THF
Dioxane
DMSO
NMP
DMF
DMF
110
30
30
30
30
30
30
30
30
30
60
10
0
0
0
54
71
75
<5
<5
21
51
Trace
Trace
3g
3h
NaH
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
9
10
11
12
9
3b
40% (1 : 2.4)
a Reaction conditions: 1 (0.25 mmol), CS2 (0.3 mmol), 2 (0.375 mmol),
a Reaction conditions: 1a (0.25 mmol), CS2 (0.3 mmol), 2a
(0.375 mmol), CuCl2 (0.25 mmol), base (0.75 mmol), solvent (1 mL,
CuCl2 (0.25 mmol), tBuOK (0.75 mmol), solvent (1 mL, anhydrous).
anhydrous). b Isolated yield. c Ratio of imine form 3a′ and enamine b Isolated yield. c The proportions of imine form 3′ and enamine form
form 3a″ was 1 : 3.
3″ of compound 3 are given in parentheses.
4634 | Org. Biomol. Chem., 2014, 12, 4633–4636
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on the benzene ring were tolerated. However, the yields of pro- (1H,3H,5H)-trione, diphenylmethane, ethynylbenzene and
ducts were severely affected by the substituent’s properties. It ethyl 2-phenylacetate. However, only ethyl 2-phenylacetate
was also observed that weak electron-donating and electron- furnished the desired product 4m with 61% yield (Table 3).
withdrawing substituents on compounds 1 such as –Me and The others we tried gave no desired products but with benzo-
–F gave similar or slightly lower yields than 2-iodoaniline [d]thiazole-2(3H)-thione as a byproduct, which have been men-
without any substituent (entries 2, 3, 6, 7 vs. 1). When stronger tioned in Ma’s reaction.9d
electron-donating and electron-withdrawing substituents such
In summary, a straightforward route to various 2-C-substi-
as –OMe and –COOMe were introduced into the benzene ring, tuted benzothiazoles using 2-haloanilines as starting materials
the expected products 3d–e and 3h were also obtained but in and carbon disulfide as a thiol surrogate was first developed
moderate yields (entries 4, 5, 8). To our delight, the desired by our group. Two series of medicinally useful 2-gem-bisphos-
product 3b was also isolated in 40% yield when 2-iodoaniline phonate-substituted benzothiazoles and α-benzothiazol-sub-
was replaced by 2-bromoaniline (entry 9).
stituted nitriles were synthesized here via a copper-promoted
Inspired by the above results, we applied the same con- domino condensation/S-arylation/heterocyclization process.
ditions to various commercially available phenylacetonitriles These synthetic 2-C-substituted benzothiazoles bearing cyano
as another carbon nucleophile reagent. To our delight, when and bisphosphonate groups allow further formation of diverse
2-iodoaniline was treated with phenylacetonitrile under stan- medicinal derivatives.
dard conditions, α-benzothiazol-substituted nitrile 4a was iso-
This work was financially supported by NSFC (81371958),
lated in good yield. It is noteworthy that imine form 4a was the Ministry of Science and Technology of China (“Key New
isolated exclusively compared to the N-BPs series. Without Drug Creation and Manufacturing Program”, 2012ZX09301001-
further optimization, various 2-iodoanilines and phenylaceto- 001), the Chinese Academy of Sciences (“Interdisciplinary
nitriles were employed to extend the reaction scope, and thus Cooperation Team” Program for Science and Technology Inno-
another very useful series of 2-C-substituted benzothiazoles, vation), and SKLDR/SIMM (SIMM1203ZZ-0103).
α-benzothiazol-substituted nitriles, were obtained. As illus-
trated in Table 3, both electron-donating and electron-with-
drawing substituents on the benzene ring of compounds 1 and
2 were well tolerated leading to the corresponding α-aryl-sub-
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