Copper(I)-catalyzed cascade synthesis of 2-substituted 1,3-benzothiazoles: Direct access to benzothiazolones

Article abstract of DOI:10.1002/ejoc.200900711

An efficient cascade process for the preparation of 2-substituted 1,3-benzothiazoles directly from 2-haloaryl isothiocyanates and O or S nucleophiles by a Cu-catalyzed, intramolecular, C-S bond formation has been developed. This cascade method is viable f

Full text of DOI:10.1002/ejoc.200900711

FULL PAPER
DOI: 10.1002/ejoc.200900711
Copper(I)-Catalyzed Cascade Synthesis of 2-Substituted 1,3-Benzothiazoles:
Direct Access to Benzothiazolones
Siva Murru,[a] Pravat Mondal,[a] Ramesh Yella,[a] and Bhisma K. Patel*[a]
Keywords: Cascade reaction / Benzothiazole / Copper catalysis / Sulfur heterocycles / Synthetic methods / Solvent effects
An efficient cascade process for the preparation of 2-substi-
tuted 1,3-benzothiazoles directly from 2-haloaryl isothio-
cyanates and O or S nucleophiles by a Cu-catalyzed, intra-
O- and S-substituted 1,3-benzothiazoles. Furthermore, 1,3-
benzothiazol-2(3H)-ones having an alkyl group allow easy
access to 1,3-benzothiazolones.
molecular, C–S bond formation has been developed. This (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
cascade method is viable for the efficient syntheses of both
Germany, 2009)
Novel 6-arylbenzothiazolones were examined and found
to be effective for progesterone receptor (PR) antagonist
Introduction
The 1,3-benzothiazole scaffold is ubiquitous in the activities.[1i] Recent medicinal chemistry applications of
realms of pharmacologically active agents and natural substituted 1,3-benzothiazole include leukotriene A4
products. Particularly, 2-thio- and oxy-substituted ana- (LTA4) hydrolase inhibitors (A),[2a,2b] aldolase reductase in-
logues exhibit a wide range of biological activities such as hibitors (ARIs) (B),[2c] dual antagonists for the human
antimycobacterial,[1a] antimicrobial,[1b–d] antifouling,[1e] and CCR1 and CCR3 receptors (C),[2d] potent heat shock pro-
antiviral activity.[1f] Several 2-alkoxy- and 2-(alkylthio)-1,3- tein-90 inhibitors (D),[2e] and an inhibitor of Cathepsin-D
benzothiazole derivatives display excellent anti-HRV (hu- (E, Figure 1).[2f] The herbicide benazoline (F) and fungi-
man rhinovirus) activity.[1g] A few substituted thiobenzothi- cides chlobenthiazone (G) and 2-(thiocyanatomethylthio)-
azole derivatives have been screened for human cyclooxy- 1,3-benzothiazole (TCMTB, H) are widely used in agricul-
genase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibi- ture and are benzothiazole derivatives.[3a–c] Some 2-substi-
tion.[1h]
tuted mercaptobenzothiazoles have found applications in
Figure 1. 2-Substituted 1,3-benzothiazoles in medicinal and other applications.
organic synthesis in Julia olefinations[4a,4b] and as reagents
[a] Indian Institute of Technology, Guwahati
Guwahati 781039, Assam, India
in Pd-catalyzed, cross-coupling reactions.[4c]
Fax: +91-361-2690762
Although 2-oxy- and thio-substituted 1,3-benzothiazoles
play an important role in the field of pharmaceutical sci-
ence, the available synthetic methods for these compounds
E-mail: patel@iitg.ernet.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900711.
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Copper(I)-Catalyzed Cascade Synthesis of 1,3-Benzothiazoles
are very limited. Traditional methods for the synthesis of benzothiazoles by intra/intermolecular C–N and C–S bond
this structural moiety include nucleophilic substitution of a formations and our interest in the construction of various
2-chloro-1,3-benzothiazole or its equivalents with either O heterocycles prompted us to develop a Cu-catalyzed cas-
(alcohols and phenols) or S (thiols and thiophenols) nucleo- cade process for easy access to 2-substituted benzothi-
philes.[2a,5] Alternatively, S-alkylation of preformed 2-mer- azoles.[13] The present strategy involves an initial nucleo-
captobenzothiazole with alkylating agents is the common philic addition of S or O nucleophiles to isothiocyanate fol-
strategy to prepare (alkylthio)benzothiazoles.[4a,6] However, lowed by an intramolecular S-arylation leading to substi-
by this strategy, the synthesis of S-(arylthio)benzothiazoles tuted 2-oxy/thio-benzothiazoles in the same pot (Scheme 1).
is impossible. They are generally prepared by two types of The success of this strategy depends on the formation of
nucleophilic substitution reactions: by the nucleophilic at- thiocarbamate or dithiocarbamate esters by O or S nucleo-
tack of arylthiols upon preformed 2-halobenzothiazoles or philes, respectively. Unlike amino nucleophiles, which quan-
by a nucleophilic attack of mercapto-benzothiazole upon titatively form stable, isolable thioureas, the corresponding
haloarenes containing electron-withdrawing substituents thiocarbamate or dithiocarbamate esters derived from
such as -NO2 and -CN under strongly basic conditions.[7] phenol or thiophenol are unstable, particularly under basic
An alternative method for the synthesis of 2-(arylthio)- conditions due to their better leaving-group ability.[14] The
benzothiazoles by the S-arylation of benzothiazole-2-thiols in-situ-generated thiocarbamate or dithiocarbamate un-
with diaryliodonium salts in an ionic liquid has been re- dergoes rapid intramolecular S-arylation to give 2-oxy/thio-
ported.[8a,8b] Many of these methods rely on harsh reaction benzothiazoles.
conditions with limited functional group tolerance. Recent
approaches have focused on the use of transition-metal (Cu,
Pd, and Fe)-catalyzed, intermolecular, C–S bond forma-
tions for the synthesis of 2-(arylthio)-1,3-benzothiazoles un-
der milder conditions with better efficiency and selectivity.[9]
However, the preparation of substituted 2-oxo and mer-
Scheme 1. Reaction pathway for the formation of 2-substituted
benzothiazoles.
capto benzothiazoles using these methods depends largely
on the availability of the prerequisites, suitably substituted
2-halobenzothiazole or mercaptobenzothiazoles, which are
often difficult to prepare and involve tedious multi-step
processes.
Results and Discussion
Recent advances in the field of transition-metal-cata-
lyzed, C–heteroatom bond formation have proven to be the
For the optimization of this cascade process, we selected
most efficient method for the construction of various het- o-bromophenyl isothiocyanate (1) and phenol (a) as the re-
erocycles.[10a–e] In general, one-pot, tandem, cascade or action partners. In the absence of any ligands, we did not
domino strategies, whereby multiple bonds can be con- observe the desired product (1a). Therefore, we carried out
structed in a single reaction without the need to isolate the an initial ligand screen with different N,N-, N,O-, and O,O-
intermediates, are used to improve the efficiency of a chemi- donor ligands by taking CuI as the precatalyst and K2CO3
cal reaction.[10f–i] Numerous heterocycles have been synthe- as the base. To our delight, we found 1,10-phenanthroline
sized by one-pot, Cu-catalyzed, C-heteroatom (N, O, and (L3) to be the most effective ligand for the present transfor-
S) bond formations. As compared to C–N and C–O bond mation. This observation is consistent with our previous in-
formations, C–S bond formations are comparatively less ex- tramolecular C–N bond formation and similar intramolec-
plored because oxidative dimerization (S–S bond forma- ular C-heteroarylations observed by others.[12c,12d,13a] In
tion) and the affinity of thiols towards metals makes the contrast to our recent finding involving intra and intermo-
catalyst less efficient.[11]
lecular C–S bond formation, the 1,2-cyclohexyldiamine
An intramolecular, Cu-catalyzed, S-arylation of thioacet- (L7) ligand was totally ineffective, possibly because thiourea
anilides or thiobenzanilides to produce 2-alkyl- or 2-aryl- formation outcompeted metal complexation.[13b] Similar bi-
1,3-benzothiazoles was first reported by Bowmann et al.[12a] pyridyl (L1), substituted phenanthroline (L2), and TMEDA
Later, the same synthesis was achieved by a Pd-catalyzed (L5) ligands were not very effective, but -proline (L4) and
process in a more efficient manner.[12b] Batey et al. explored ethyleneglycol (L6) ligands provided the cyclized product
intramolecular C–S bond formation for the synthesis of 2- (1a) in moderate yields.
arylbenzothiazoles and 2-aminobenzothiazoles using either
This cascade reaction was equally effective in a range of
Cu or Pd catalytic systems from the corresponding o-halo- high-boiling, polar, aprotic solvents (DMSO, DMF, and
thiobenzanilides or thioureas, respectively.[12c,12d] Other DMA) as well as nonpolar solvents (dioxane and toluene).
groups have made further improvements in the Cu-catalytic However, the use of anhydrous dioxane provided a superior
system for similar reactions.[12e,12f] Recently, Bao et al. re- conversion to that of other solvents tested. We found the
ported a CuI-catalyzed synthesis of 2-imino-1,3-benzoxathi- optimum reaction temperature to be 90 °C. Although we
oles from aryl isothiocyanates and o-iodophenols in one achieved faster conversion at higher temperature (100 °C),
pot.[12g] Our recent success in the Cu-catalyzed synthesis of due to the formation of undesirable side products, we chose
substituted 2-mercaptobenzimidazoles and 2-(arylthio)- 90 °C for all the substrates. From further experimentation,
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S. Murru, P. Mondal, R. Yella, B. K. Patel
FULL PAPER
we achieved the optimum conversion using o-haloaryl iso- Table 1. Synthesis of substituted 2-oxa/thio benzothiazoles (reac-
tion conditions: * 12 h at 90 °C; ** 16 h at 90 °C).
thiocyanate (1, 1 equiv.), phenol (a, 1.2 equiv.), CuI (5 mol-
%), L3 (10 mol-%), and K2CO3 (2 equiv.) in dry dioxane
(Figure 2).
Figure 2. Effect of ligands on Cu-catalyzed, intramolecular S-aryl-
ation.
With the optimized conditions in hand, we then explored
the scope and generality of the method. We were delighted
to find that a series of O and S nucleophiles react with o-
haloaryl isothiocyanates smoothly, giving 2-oxo/thio-substi-
tuted benzothiazoles in moderate to high yields (Table 1).
We prepared o-haloaryl isothiocyanates 1–4 in excellent
yields following our recently reported “green” protocol.[15]
The present Cu-catalyzed system is efficient and compatible
with various o-halo (Br and I) isothiocyanates (1–4 and 1Ј).
This intramolecular heteroarylation was equally effective
either with o-bromo (1) and o-iodo (1Ј) isothiocyanates.
Due to the easy preparation and low cost of o-bromo sub-
strates, we performed the reactions mostly with o-bromo
substrates 1–3. We confirmed the structure of the product
1b by X-ray crystallography (Figure 3).[16]
A wide variety of O and S nucleophiles such as phenols
Figure 3. ORTEP molecular diagram of 1b with ellipsoids at 50%
probability.
(a–g), alcohols (k–l), thiophenols (h–i), and thiol-contain-
ing (j), electron-withdrawing (b, c, and g) and electron-do-
nating substituents (d, e, f, and i) reacted well with o-
haloaryl isothiocyanates 1Ј and 1–4 to give oxy- and thio- withdrawing groups (b, c, and g) gave higher yields. This
substituted 1,3-benzothiazoles (Table 1). We found both was due to their more facile deprotonation under basic
phenols and thiophenols to be equally effective in this cas- (K2CO3) conditions to give the corresponding phenolate
cade process. An aliphatic thiol (j) and aromatic alcohols ions, which served as better nucleophiles. This also explains
(k and l) were not that efficient as compared to phenols and why alcohols k and l and thiol j were less reactive. Further-
thiophenols. Bis-nucleophiles such as 2-mercaptoethanol more, we observed a good correlation between the substitu-
(m) gave the bis-heterocyclic 1m containing both 2-oxy and ents (p-Me, p-Cl, and p-Br) attached to the isothiocyanates
2-thio-substituted 1,3-benzothiazoles in moderate yield. A 1Ј and 1–4 and their reactivity. A weakly electron-donating
closer look at Table 1 reveals that phenols having electron- substituent (p-Me) in the isothiocyanate resulted in lower
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Copper(I)-Catalyzed Cascade Synthesis of 1,3-Benzothiazoles
yields (2a and 2h) compared to that obtained with weakly
electron-withdrawing substituents (p-Cl and p-Br, 3a, 3h,
4a, and 4h).
Conclusions
We have developed an efficient cascade process for the
synthesis of a library of 2-substituted 1,3-benzothiazoles.
The thiocarbamate or dithiocarbamate generated in situ by
the reaction of 2-haloaryl isothiocyanates with O or S nu-
cleophiles undergoes CuI–L-catalyzed intramolecular C–S
bond formation giving substituted benzothiazoles. Both
phenols and thiophenols reacted with equal ease. On the
other hand, alcohols and thiols were less reactive. The rate
of the reaction was faster and gave better yields when elec-
tron-withdrawing substituents were present in either of the
coupling partners. 1,3-Benzothiazolones were prepared in
one pot using ethanol as the solvent and nucleophile (O
source).
Derivatives of 1j have been identified as COX-1 and
COX-2 inhibitors[1h] and have antimicrobial activity.[1a] Ad-
ditionally, the benzothiazolone core structure can be found
in a large number of compounds having a range of bio-
logical activities as progesterone receptor (PR) antago-
nists,[1i] fungicides, and herbicides.[3a–c] Traditionally they
are synthesized by the condensation of 2-aminothiophenol
with ethyl chloroformate,[17a] urea,[17b] ammonium thiocar-
bamate,[17c] or disuccinimido carbonate.[17d] Methods are
also available for the preparation of benzothiazolones using
precursors such as 2-chloro-1,3-benzothiazole and 2-benzo-
thiazolylalkyl sulfide.[17e–g]
We envisaged an O-dealkylation strategy could allow ac-
cess to these valuable heterocycles. The nucleophilic ad-
dition of ethanol to o-bromophenyl isothiocyanate (1)
would give a thiocarbamate ester, which would then un-
dergo an intramolecular S-arylation by a CuI–L system to
give 2-ethoxy-1,3-benzothiazole (Z). In these reactions, eth-
anol serves the dual purpose of nucleophile and solvent.
Since ethanol is a weaker leaving group and is in excess, it
drives the reaction forward, giving quantitative yields of
(Z). The O-dealkylation of Z using trifluoroacetic acid
(TFA) provided 1,3-benzothiazol-2-one 5p in 65% overall
isolated yield. We note that using a similar strategy, 1,3-
benzothiazolones have been prepared using benzoic acid at
170 °C for 24 h.[17f] In an analogous approach, other benzo-
thiazolones 5q and 5r were prepared in moderate yields
(Scheme 2). We confirmed the structure of the product 5p
by X-ray crystallography (Figure 4).[18]
Experimental Section
General Remarks: All reagents were of commercial grade and puri-
fied according to commonly used procedures. Organic extracts were
dried with anhydrous Na2SO4. Solvents were removed in a rotary
evaporator under reduced pressure. Silica gel (60–120 mesh) was
used for column chromatography. Reactions were monitored by
TLC on silica gel 60 F254 (0.25 mm). NMR spectra were recorded
in CDCl3 with tetramethylsilane as the internal standard for 1H
NMR (400 MHz) and CDCl3 solvent as the internal standard for
13C NMR (100 MHz). HR mass spectra were recorder by using a
Waters MS system (Q-tof) according to the MS-MS method, and
date were analyzed by Mass Lynx 4.1 software (Waters Corpora-
tion, USA, 2005). IR spectra were recorded neat or in KBr with a
Nicolet Impact 410 spectrophotometer. Melting points were re-
corded with a Büchi B-545 melting point apparatus and are uncor-
rected.
Crystallographic Description: Crystal data were collected with a
Bruker Smart Apex-II CCD diffractometer by using graphite-mo-
nochromated, Mo-Kα radiation (λ = 0.71073 Å) at 298 K. Cell pa-
rameters were retrieved using SMART[19] software and refined with
SAINT[19] on all observed reflections. Data reduction was per-
formed with the SAINT software and corrected for Lorentz and
polarization effects. Absorption corrections were applied with the
program SADABS.[20] The structure was solved by direct methods
implemented in SHELX-97[21] and refined by full-matrix least-
squares methods on F2. All non-hydrogen atomic positions were
located in difference Fourier maps and refined anisotropically. The
hydrogen atoms were placed in their geometrically generated posi-
tions. All the colourless crystals were isolated in rectangular shape
from absolute ethanol at room temperature.
Scheme 2. Cascade synthesis of 2-benzothiazolones.
General Procedure for the Preparation of 2-(Bromophenyl) Isothio-
cyanate (1): To a stirred and ice-cooled suspension of the dithiocar-
bamate of 2-bromoaniline (344 mg, 2 mmol) in acetonitrile (5 mL),
was added triethylamine (416 µL, 3 mmol). To this was added io-
dine (508 mg, 2 mmol) portionwise over a period of 30 min. Aceto-
nitrile was evaporated, and ethyl acetate (15 mL) was added to the
mixture, which was washed with HCl (1 , 2ϫ5 mL) and water
(1ϫ5 mL). The organic layer was dried with anhydrous Na2SO4,
concentrated under reduced pressure, and purified over a short col-
umn of silica gel (100% hexane), and 2-bromophenyl isothiocya-
nate was isolated (393 mg, 92%).
General Procedure for the Synthesis of 2-Phenoxy-1,3-benzothiazole
(1a): A round-bottomed flask with a magnetic stir bar, fitted with
Figure 4. ORTEP molecular diagram of 5p with ellipsoids at 50%
probability.
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S. Murru, P. Mondal, R. Yella, B. K. Patel
FULL PAPER
a reflux condenser, was charged with 2-bromophenyl isothiocya-
nate (1, 1 mmol, 214 mg), phenol (a, 1.1 mmol, 103 mg), CuI
(0.05 mmol, 9.5 mg), 1,10-phenanthroline (L3, 0.1 mmol, 18 mg),
K2CO3 (2 mmol, 276 mg), and dry 1,4-dioxane (3 mL). The mix-
ture was heated at 90 °C for 12 h, protected with a guard tube. The
reaction mixture was then cooled and filtered through Celite using
ethyl acetate. The filtrate was evaporated to dryness, and the prod-
uct was purified by column chromatography giving 1a (166 mg,
cm–1. C13H9NS2 (243.35): calcd. C 64.18, H 3.73, N 5.76, S 26.35;
found C 64.23, H 3.75, N 5.80, S 26.31. HRMS (ESI): calcd. for
C13H9NS2 [M + H]+ 244.0255; found 244.0259.
2-(p-Tolylthio)benzothiazole (1i): White solid; m.p. 70–72 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H), 7.17–7.24 (m, 3 H),
7.34 (t, J = 8.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 3 H), 7.84 (d, J =
8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5, 120.8,
121.8, 124.2, 126.1, 126.2, 130.8, 135.4, 135.6, 141.1, 154.0, 170.8
1
73%) as a colourless gum. H NMR (400 MHz, CDCl3): δ = 7.20–
ppm. IR (KBr): ν = 3059, 2916, 1592, 1455, 1422, 1310, 1235, 1005,
˜
7.45 (m, 7 H), 7.63 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H)
816, 757 cm–1. C14H11NS2 (257.37): calcd. C 65.33, H 4.31, N 5.44,
S 24.92; found C 65.41, H 4.29, N 5.39, S 24.90.
ppm. 13C NMR (100 MHz, CDCl3): δ = 120.8, 121.4, 121.8, 124.2,
126.3, 126.4, 130.1, 132.4, 149.2, 154.8, 172.1 ppm. IR (KBr): ν =
˜
2-(Benzylthio)benzothiazole (1j): Colourless gum. 1H NMR
(400 MHz, CDCl3): δ = 4.60 (s, 2 H), 7.26–7.34 (m, 4 H), 7.39–
7.46 (m, 3 H), 7.74 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 37.8, 121.2, 121.7, 124.5,
126.2, 127.9, 128.9, 129.3, 135.5, 136.3, 153.3, 166.6 ppm. IR
3064, 2753, 1942, 1784, 1683, 1598, 1562, 1528, 1487, 1456, 1440,
1310, 1285, 1230, 1158, 1126, 1066, 1017, 1004 cm–1. C13H9NOS
(227.28): calcd. C 68.69, H 3.99, N 6.16, S 14.11; found C 68.78,
H 4.03, N 6.21, S 13.72.
General Procedure for the Synthesis of 1,3-Benzothiazolone (5p): A
round-bottomed flask with a magnetic stir bar, fitted with a reflux
condenser, was charged with 2-bromophenyl isothiocyanate (1,
1 mmol, 214 mg), CuI (0.05 mmol, 9.5 mg), 1,10-phenanthroline
(L3, 0.1 mmol, 18 mg), K2CO3 (2 mmol, 276 mg), and dry ethanol
(3 mL). The resulting solution was heated at reflux for 12 h, pro-
tected with a guard tube. The reaction mixture was then cooled,
TFA (2 mL) was added to it, and the mixture was refluxed for
another 5 h. The solvent was removed under vacuum, and the reac-
tion mixture was treated with aq. sodium hydrogen carbonate. The
product was extracted with ethyl acetate (2ϫ15 mL). The organic
phase was dried with Na2SO4 and then concentrated. The crude
product was purified using a short column of silica gel to give prod-
(KBr): ν = 3065, 3027, 2923, 2846, 1494, 1455, 1427, 1309, 1239,
˜
1073, 1017, 993, 754 cm–1. C14H11NS2 (257.37): calcd. C 65.33, H
4.31, N 5.44, S 24.92; found C 65.27, H 4.27, N 5.39, S 24.84.
2-[2-(1,3-Benzothiazol-2-yloxy)ethylthio]-1,3-benzothiazole
(1m):
1
Yellowish solid; m.p. 106–108 °C. H NMR (400 MHz, CDCl3): δ
= 3.84 (t, J = 6.8 Hz, 2 H), 4.93 (t, J = 6.4 Hz, 2 H), 7.20–7.42 (m,
4 H), 7.60–7.67 (m, 2 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.84 (d, J =
7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 31.7, 69.7,
121.1, 121.2, 121.5, 121.8, 123.8, 124.6, 126.2, 126.3, 132.2, 135.5,
149.3, 153.2, 165.5, 172.4 ppm. IR (KBr): ν = 3049, 2923, 2851,
˜
1525, 1454, 1440, 1426, 1259, 1218, 960, 754 cm–1. C16H12N2OS3
(344.47): calcd. C 55.79, H 3.51, N 8.13, S 27.93; found C 55.86,
H 3.55, N 8.09, S 27.88.
1
uct 5p (98.3 mg, 65%) as a white solid; m.p. 136–137 °C. H NMR
6-Methyl-2-phenoxy-1,3-benzothiazole (2a): Colourless gum. 1H
NMR (400 MHz, CDCl3): δ = 2.40 (s, 3 H), 7.16 (d, J = 8.0 Hz, 1
H), 7.26 (t, J = 7.2 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.39–7.44
(m, 3 H), 7.61 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.6, 120.7, 121.3, 121.4, 126.3, 127.7, 130.1, 132.4,
(400 MHz, CDCl3): δ = 7.16 (m, 2 H), 7.28 (t, J = 7.6 Hz, 1 H),
7.40 (d, J = 7.6 Hz, 1 H), 10.45 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 112.1, 122.7, 123.4, 124.1, 126.7, 135.7, 173.7 ppm. IR
(KBr): ν = 3154, 3110, 3054, 2922, 2853, 1666, 1591, 1463, 1214,
˜
743, 642 cm–1. C7H5NOS (151.01): calcd. C 55.61, H 3.33, N 9.26,
S 21.21; found C 55.53, H 3.29, N 9.21, S 21.22.
134.1, 147.0, 154.9, 171.3 ppm. IR (KBr): ν = 3057, 2921, 1593,
˜
1533, 1488, 1464, 1406, 1306, 1234, 1203, 1157, 1004 cm–1.
C14H11NOS (241.31): calcd. C 69.68, H 4.59, N 5.80, S 13.29;
found C 69.73, H 4.61, N 5.85, S 13.23.
1-(4-(1,3-Benzothiazol-2-yloxy)phenyl)ethanone (1b): White solid;
1
m.p. 106–108 °C. H NMR (400 MHz, CDCl3): δ = 2.59 (s, 3 H),
7.27 (t, J = 7.4 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.45 (d, J =
8.5 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.0 Hz, 1 H),
8.02 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
26.6, 120.2, 121.4, 121.9, 124.5, 126.4, 130.4, 132.3, 134.6, 148.7,
6-Methyl-2-(4-nitrophenoxy)-1,3-benzothiazole (2c): White solid;
1
m.p. 140–142 °C. H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H),
7.22 (d, J = 8.4 Hz, 1 H), 7.50 (s, 1 H), 7.54 (d, J = 9.2 Hz, 2 H),
7.62 (d, J = 8.4 Hz, 1 H), 8.27 (d, J = 9.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.6, 120.5, 121.4, 121.7 125.7, 128.0,
157.9, 170.4, 196.6 ppm. IR (KBr): ν = 3057, 3007, 2913, 1674,
˜
1598, 1520, 1500, 1460, 1442, 1440, 1361, 1300, 1265, 1249, 1226,
1203, 1160, 1105, 1066, 1013, 959, 910, 855, 844 cm–1. C15H11NO2S
(269.32): calcd. C 66.89, H 4.11, N 5.20, S 11.90; found C 66.86,
H 4.09, N 5.18, S 11.85.
132.5, 135.0, 144.8, 146.3, 159.0, 168.8 ppm. IR (KBr): ν = 3118,
˜
2924, 2850, 1614, 1591, 1532, 1515, 1488, 1458, 1380, 1349, 1326,
1307, 1294, 1253, 1210, 1182, 1161, 1109, 1057, 862 cm–1.
C14H10N2O3S (286.31): calcd. C 58.73, H 3.52, N 9.78, S 11.19;
found C 58.79, H 3.54, N 9.84, S 11.05. HRMS (ESI): calcd. for
C14H10N2O3S [M + H]+ 287.0490; found 287.0463.
2-(4-Nitrophenoxy)-1,3-thiazole (1c): White solid; m.p. 111–112 °C.
1H NMR (400 MHz, CDCl3): δ = 7.33 (t, J = 8 Hz, 1 H), 7.42 (t,
J = 8 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 2 H), 7.74 (t, J = 8 Hz, 2 H),
8.30 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
120.7, 121.6, 122.2, 125.0, 125.8, 126.7, 132.5, 145.0, 148.6, 159.0,
1
6-Methyl-2-(p-tolyloxy)-1,3-benzothiazole (2d): Colourless gum. H
NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H), 2.38 (s, 3 H), 7.15 (m,
1 H), 7.19 (s, 4 H), 7.38 (s, 1 H), 7.60 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.0, 21.5, 120.5, 121.2, 121.3, 127.6, 130.5,
169.7 ppm. IR (KBr): ν = 3077, 2920, 2851, 1591, 1516, 1488, 1440,
˜
1351, 1250, 1235, 1160, 853, 751 cm–1. C13H8N2O3S (272.28): calcd.
C 57.35, H 2.96, N 10.29, S 11.78; found C 57.29, H 2.93, N 10.28,
S 11.71.
132.3, 133.9, 136.0, 147.0, 152.7, 171.7 ppm. IR (KBr): ν = 3032,
˜
2922, 1605, 1535, 1466, 1234, 1200, 1017, 813 cm–1. C15H13NOS
(255.33): calcd. C 70.55, H 5.13, N 5.48, S 12.55; found C 70.46,
H 5.11, N 5.42, S 12.43. HRMS (ESI): calcd. for C15H13NOS [M
+ H]+ 256.0796; found 256.0734.
2-(Phenylthio)-1,3-benzothiazole (1h): Colourless gum. 1H NMR
(400 MHz, CDCl3): δ = 7.20 (t, J = 8.0 Hz, 1 H), 7.33–7.46 (m, 4
H), 7.58 (d, J = 7.6 Hz, 1 H), 7.69 (m, 2 H), 7.87 (d, J = 8.4 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.7, 121.8, 124.2,
126.0, 129.7, 129.8, 130.4, 135.2, 135.4, 153.8, 169.5 ppm. IR
2-(4-Methoxyphenoxy)-6-methyl-1,3-benzothiazole (2e): Colourless
gum. 1H NMR (400 MHz, CDCl3): δ = 2.40 (s, 3 H), 3.80 (s, 3 H),
6.92 (d, J = 9.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 1 H), 7.25 (d, J =
(KBr): ν = 3060, 1582, 1455, 1426, 1310, 1237, 1020, 1007, 752
˜
5410
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5406–5413

Copper(I)-Catalyzed Cascade Synthesis of 1,3-Benzothiazoles
9.0 Hz, 2 H), 7.41 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.7, 55.9, 115.1, 121.4, 122.1, 127.8,
6-Chloro-2-phenoxy-1,3-benzothiazole (4a): White solid; m.p. 88–
1
90 °C. H NMR (400 MHz, CDCl3): δ = 7.26–7.34 (m, 4 H), 7.40–
132.5, 134.1, 147.3, 148.7, 157.9, 172.4 ppm. IR (KBr): ν = 3049,
7.46 (m, 2 H), 7.58–7.61 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 120.7, 121.0, 122.6, 126.6, 127.0, 129.6, 130.1, 133.4,
˜
3000, 2928, 2835, 1663, 1609, 1535, 1498, 1459, 1409, 1306, 1229,
1101, 1057, 1033, 920, 850, 816 cm–1. C15H13NO2S (271.33): calcd.
147.7, 154.6, 172.2 ppm. IR (KBr): ν = 3057, 2962, 1672, 1598,
˜
C 66.39, H 4.83, N 5.16, S 11.81; found C 66.45, H 4.79, N 5.12, 1529, 1490, 1445, 1399, 1304, 1255, 1155, 1097, 915 cm–1.
S 11.68. HRMS (ESI): calcd. for C15H13NO2S [M + H]+ 272.0745;
found 272.0705.
C13H8ClNOS (261.73): calcd. C 59.66, H 3.08, N 5.35, S 12.25;
found C 59.71, H 3.13, N 5.40, S 12.17.
6-Chloro-2-(phenylthio)-1,3-benzothiazole (4h): White solid; m.p.
72–74 °C. H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.6 Hz, 2
2-(3,4-Dimethylphenoxy)-6-methyl-1,3-benzothiazole (2f): Colour-
less gum. H NMR (400 MHz, CDCl3): δ = 2.25 (s, 3 H), 2.26 (s,
1
1
H), 7.40–7.52 (m, 2 H), 7.56 (d, J = 2.0 Hz, 1 H), 7.70–7.75 (m, 3
3 H), 2.40 (s, 3 H), 7.03–7.09 (m, 2 H), 7.16 (d, J = 8.0 Hz, 2 H),
7.40 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 19.4, 20.1, 21.5, 117.9, 121.2, 121.3, 127.6, 130.9,
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 120.5, 122.6, 126.9,
129.5, 130.2, 130.9, 135.6, 136.6, 152.6, 170.7 ppm. IR (KBr): ν =
˜
3064, 2967, 2922, 2851, 1585, 1542, 1456, 1431, 1397, 1300, 1260,
1172, 1061, 1103, 1061, 1013, 851, 829 cm–1. C13H8ClNS2 (277.79):
calcd. C 56.21, H 2.90, N 5.04, S 23.08; found C 56.27, H 2.89, N
5.11, S 22.93.
132.4, 133.9, 134.9, 138.6, 147.1, 152.9, 171.9 ppm. IR (KBr): ν =
˜
2924, 2857, 1604, 1537, 1496, 1466, 1244, 1225, 1195, 1146, 1056,
1021, 872, 813 cm–1. C16H15NOS (269.36): calcd. C 71.34, H 5.61,
N 5.19, S 11.90; found C 71.43, H 5.59, N 5.17, S 11.88.
6-Chloro-2-(phenethyloxy)-1,3-benzothiazole (4k): White solid; m.p.
96–98 °C. H NMR (400 MHz, CDCl3): δ = 3.16 (t, J = 6.8 Hz, 2
H), 4.75 (t, J = 6.8 Hz, 2 H), 7.24–7.33 (m, 5 H), 7.50–7.60 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 35.3, 72.6, 121.1, 121.7,
126.7, 126.9, 128.8, 129.0, 129.1, 133.2, 137.4, 148.0, 172.9 ppm.
4-(6-Methyl-1,3-benzothiazol-2-yloxy)benzaldehyde (2g): White so-
lid; m.p. 99–100 °C. 1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3
H), 7.21 (d, J = 8.0 Hz, 1 H), 7.48 (s, 1 H), 7.53 (d, J = 8.6 Hz, 2
H), 7.63 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.6 Hz, 2 H), 9.97 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.6, 120.6, 121.4,
121.6, 127.9, 131.8, 132.5, 133.7, 134.8, 146.5, 159.1, 169.3, 190.8
1
IR (KBr): ν = 3061, 2921, 1595, 1536, 1498, 1452, 1436, 1402, 1371,
˜
1303, 1254, 1242, 1217, 1198, 1096, 1052, 977, 816 cm–1.
C15H12ClNOS (289.78): calcd. C 62.17, H 4.17, N 4.83, S 11.06;
found C 62.10, H 4.13, N 4.78, S 10.91.
ppm. IR (KBr): ν = 2920, 2833, 1693, 1585, 1534, 1499, 1466, 1455,
˜
1385, 1301, 1231, 1205, 1180, 1157, 1101, 1056, 1010, 963, 917,
851, 823 cm–1. C15H11NO2S (269.32): calcd. C 66.89, H 4.12, N
5.20, S 11.89; found C 66.93, H 4.15, N 5.16, S 11.83.
6-Chloro-2-(3,4-dichlorobenzyloxy)-1,3-benzothiazole (4l): White so-
1
lid; m.p. 220–222 °C. H NMR (400 MHz, CDCl3): δ = 5.62 (s, 2
6-Methyl-2-(phenylthio)-1,3-benzothiazole (2h): Colourless gum. 1H
NMR (400 MHz, CDCl3): δ = 2.40 (s, 3 H), 7.19 (d, J = 8.4 Hz, 1
H), 7.41–7.47 (m, 4 H), 7.70–7.76 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.7, 120.9, 121.7, 127.9, 130.1, 130.4,
H), 7.29 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 1.6 Hz, 1 H), 7.48 (d, J
= 8.4 Hz, 1 H), 7.59 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 70.1, 121.2, 121.9, 126.9, 127.5, 129.3, 131.0, 131.6, 133.4,
134.6, 135.4, 147.8, 172.4 ppm. IR (KBr): ν = 3088, 2922, 2852,
˜
130.6, 134.7, 135.4, 136.0, 152.2, 168.3 ppm. IR (KBr): ν = 3056,
˜
1682, 1599, 1565, 1540, 1509, 1458, 1447, 1336, 1253, 1232, 1211,
1187, 1148, 1096, 1052, 1006, 812 cm–1. C14H8Cl3NOS (344.64):
calcd. C 48.78, H 2.34, N 4.06, S 9.30; found C 48.82, H 2.35, N
4.01, S 9.27.
2919, 1582, 1468, 1439, 1242, 1012, 813, 749, 689 cm–1. C14H11NS2
(257.37): calcd. C 65.33, H 4.31, N 5.44, S 24.92; found C 65.25,
H 4.29, N 5.38, S 24.83.
6-Methyl-2-(p-tolylthio)-1,3-benzothiazole (2i): White solid; m.p.
6-Methyl-1,3-benzothiazol-2(3H)-one (5q): White solid; m.p. 169–
1
80–81 °C. H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.43 (s,
1
170 °C. H NMR (400 MHz, CDCl3): δ = 2.23 (s, 3 H), 6.93 (m, 2
3 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.41 (s,
1 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.6, 120.8, 121.5, 126.7, 127.7,
H), 7.04 (s, 1 H), 10.93 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 20.4, 110.9, 121.7, 123.2, 126.4, 131.6, 133.4, 170.9 ppm. IR
(KBr): ν = 3148, 3070, 3017, 2915, 2850, 1660, 1485, 1229, 802,
˜
130.8, 134.5, 135.6, 135.8, 141.1, 152.3, 169.3 ppm. IR (KBr): ν =
˜
665 cm–1. C8H7NOS (165.21): calcd. C 58.16, H 4.27, N 8.48, S
19.41; found C 58.23, H 4.25, N 8.51, S 19.32.
2918, 2852, 1594, 1438, 1003, 810, 504 cm–1. C15H13NS2 (271.40):
calcd. C 66.38, H 4.83, N 5.16, S 23.63; found C 66.46, H 4.84, N
5.20, S 23.56.
6-Bromo-1,3-benzothiazol-2(3H)-one (5r): White solid; m.p. 230–
231 °C. 1H NMR (400 MHz, CDCl3): δ = 7.02 (d, J = 8.8 Hz, 1
H), 7.32 (d, J = 8.8 Hz, 1 H), 7.49 (s, 1 H), 11.62 (s, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 112.5, 114.0, 124.0, 125.4, 128.4,
6-Bromo-2-phenoxy-1,3-benzothiazole (3a): White solid; m.p. 109–
1
111 °C. H NMR (400 MHz, CDCl3): δ = 7.26 (s, 1 H), 7.31–7.37
(m, 2 H), 7.45–7.50 (m, 3 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.79 (s, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 117.1, 120.8, 123.1,
124.0, 126.7, 129.9, 130.2, 134.0, 148.2, 154.7, 172.4 ppm. IR
134.9, 170.2 ppm. IR (KBr): ν = 3139, 3074, 3013, 2890, 1673,
˜
1597, 1463, 1210, 801, 648 cm–1. C7H4BrNOS (230.08): calcd. C
36.54, H 1.75, N 6.09, S 13.94; found C 36.48, H 1.73, N 5.98, S
13.86.
(KBr): ν = 3056, 2924, 1589, 1522, 1489, 1440, 1393, 1303, 1250,
˜
1234, 1202, 1153, 1050, 915, 807 cm–1. C13H8BrNOS (306.18):
calcd. C 50.99, H 2.63, N 4.57, S 10.47; found C 50.86, H 2.57, N
4.54, S 10.35.
Supporting Information (see also the footnote on the first page of
1
this article): Copies of the H and 13C NMR spectra.
1
6-Bromo-2-(phenylthio)-1,3-benzothiazole (3h): Colourless gum. H
NMR (400 MHz, CDCl3): δ = 7.49 (m, 3 H), 7.69 (s, 1 H), 7.20
(m, 2 H), 7.75 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
118.0, 122.8, 123.1, 123.5, 129.5, 130.3, 131.0, 135.7, 137.2, 153.0,
Acknowledgments
B. K. P. acknowledges support of this research by the Department
171.0 ppm. IR (KBr): ν = 3059, 2924, 2851, 1581, 1528, 1494, 1456, of Science and Technology (DST) (SR/S1/OC-15/2006), New Delhi
˜
1429, 1390, 1093, 1013, 813, 748 cm–1. C13H8BrNS2 (322.24): calcd.
C 48.45, H 2.50, N 4.35, S 19.90; found C 48.41, H 2.47, N 4.31, [01(2270)/08/EMR-II]. S. M. and R. Y. thank the CSIR for fellow-
and the Council of Scientific and Industrial Research (CSIR)
S 19.78.
ships. Thanks are also due to the Central Instruments Facility
Eur. J. Org. Chem. 2009, 5406–5413
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5411

S. Murru, P. Mondal, R. Yella, B. K. Patel
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[16]
Crystallographic data for 1b: C15H11NO2S, crystal dimensions
[mm]: 0.31ϫ0.26ϫ0.21, Mr = 269.31, monoclinic, space group
P2(1); a = 5.42480(10) Å, b = 12.5880(3) Å, c = 9.4882(2) Å; α
= 90.00°, β = 97.728(10)°, γ = 90.00°, V = 642.04(2) Å3; Z = 2;
ρcal = 1.393 mg/m3; µ(mm–1) = 0.248; F(000) = 280, reflections
collected/unique: 4204/3581; refinement method: full-matrix le-
ast-squares on F2; final R indices [I Ͼ 2σl] R1 = 0.0411, wR2
= 0.0719, R indices (all data): R1 = 0.0338, wR2 = 0.0693;
goodness of fit: 1.137. CCDC-737681 (for 1b) contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallo-
5412
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5406–5413

Copper(I)-Catalyzed Cascade Synthesis of 1,3-Benzothiazoles
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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ρcal = 1.503 mg/m3; µ(mm–1) = 0.400; F(000) = 312, reflections
collected/unique: 1705/1476, refinement method: full-matrix
least-squares on F2, final R indices [I Ͼ 2σl] R1 = 0.0390, wR2
= 0.0996, R indices (all data): R1 = 0.0340, wR2 = 0.0951;
goodness of fit: 1.043. CCDC-737682 (for 5p) contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
SMART, SAINT and XPREP, Siemens Analytical X-ray In-
struments Inc., Madison, Wisconsin, 1995.
G. M. Sheldrick, SADABS: Empirical Absorption and Correc-
tion Software, University of Göttingen, 1999–2003.
[19]
[20]
[18] Crystallographic data for 5p: C7H5NOS, crystal dimensions
[mm]: 0.33ϫ0.25ϫ0.24, Mr = 151.18, monoclinic, space group
P21/c; a = 5.9695(2) Å, b = 14.6738(4) Å, c = 7.6570(2) Å; α =
90.00°, β = 95.202(2)°, γ = 90.00°, V = 667.95(3) Å3; Z = 4;
[21] G. M. Sheldrick, SHELXS-97, University of Göttingen, 1997.
Received: June 26, 2009
Published Online: September 18, 2009
Eur. J. Org. Chem. 2009, 5406–5413
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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