Synthesis of 2-aminobenzothiazoles via copper(I)-catalyzed cross-coupling with part-per-million catalyst loadings

Article abstract of DOI:10.1002/adsc.201100054

An efficient protocol has been developed for the preparation of 2-aminobenzothiazoles via a copper(I)-catalyzed tandem reaction of 2-iodoanilines with isothiocyanates at very low catalyst loadings [typically 50ppm of copper(I) iodide (CuI)]. A variety of 2-iodoanilines could be cross-coupled with isothiocyanates, affording 2-aminobenzothiazoles in moderate to good yields (49-93%) under the given conditions. The turnover number (TON) of this reaction reaches 67,000 and the reaction could be scaled up, at least, to the gram-scale. Copyright

Full text of DOI:10.1002/adsc.201100054

UPDATES
DOI: 10.1002/adsc.201100054
Synthesis of 2-Aminobenzothiazoles via Copper(I)-Catalyzed
Cross-Coupling with Part-Per-Million Catalyst Loadings
Ya-Lei Sun,a Yuan Zhang,a,* Xiao-Hui Cui,a and Wei Wanga,*
a
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou, Gansu 730000, Peopleꢀs Rupublic of China
Fax : (+86)-931-891-5557; e-mail: zhangyuan@lzu.edu.cn or wang_wei@lzu.edu.cn
Received: January 21, 2011; Revised: February 24, 2011; Published online: May 3, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100054.
Abstract: An efficient protocol has been developed
for the preparation of 2-aminobenzothiazoles via a
copper(I)-catalyzed tandem reaction of 2-iodoani-
lines with isothiocyanates at very low catalyst load-
ings [typically 50 ppm of copper(I) iodide (CuI)]. A
variety of 2-iodoanilines could be cross-coupled
with isothiocyanates, affording 2-aminobenzothia-
zoles in moderate to good yields (49–93%) under
the given conditions. The turnover number (TON)
of this reaction reaches 67,000 and the reaction
could be scaled up, at least, to the gram-scale.
Very recently, research interest in this area has fo-
cused on the possibility of copper-catalyzed cross-cou-
plings with ppm level catalyst loadings. This is be-
cause, in comparison with palladium, copper is much
cheaper, abundant, and less toxic. In 2009, Bolm and
Buchwald[6] first noticed that the catalyst activity for
iron-catalyzed cross-coupling reactions depends on
the chemical purity and commercial source of the
metal catalysts used. Further research revealed that
the residual copper in the iron salt has a dramatic in-
fluence on the efficiency of these cross-coupling reac-
tions. For example, only 5 ppm of Cu2O catalyst could
effectively catalyze the N-arylation reaction of pyrra-
zole or phenylamide, affording the corresponding
product in good yield (77% and 97%, respectively).[6]
Larsson et al.[7] also found a similar effect and report-
ed on Ullmann-type coupling reactions in the pres-
ence of “homeopathic amounts” of copper salts.
Moreover, the scope of Ullmann-type reactions could
be extended to N-, O-, and S-arylations with sub-
Keywords: 2-aminobenzothiazoles; copper; cross-
coupling; low catalyst loadings
Introduction
Utilization of transition metal-catalyzed cross-cou- mol% amounts of copper.[7] In 2010, Bolm and his co-
pling reactions has been attracting much attention in workers first investigated the catalytic effect of resid-
recent years,[1] and it has become one of the most ver- ual metals (especially the copper) in FeCl3 on the in-
satile strategies for the synthesis of natural products,[2] tramolecular cyclization of aryl 2-bromobenzyl ke-
pharmaceuticals,[3] organic functional materials,[4] and tones.[8] They found that even 0.0088 mol% of CuCl2
so on. Despite the successful applications in many re- catalyst is sufficient to provide benzo[b]furans in
search areas, the inherent limitations of these metal- moderate yields.[8] With the use of copper/DMEDA
catalyzed cross-coupling reactions cannot be neglect- (dimethylethylenediamine) at sub-mol% levels, Zui-
ed, e.g., the use of high catalyst loadings [therefore, dema and Bolm[9] further broadened the reaction
with low turnover numbers (TONs) and turnover fre- scope to Castro–Stephens coupling, the case of which
quencies (TOFs)] and difficulties in purification of is a striking example for ligand-accelerated catalysis.
products from residual metal catalyst. Accordingly, Very recently, a similar result was also found in the
more efficient catalytic systems working at lower cata- copper-catalyzed cross-coupling reaction of pyrazole
lyst loadings should be developed to overcome these and iodobenzene.[10] These research works pioneered
drawbacks. Of all the metal-catalyzed systems investi- the efficient cross-coupling reactions catalyzed by
gated, the palladium-catalyzed cross-coupling reac- sub-mol% amounts of copper catalyst loadings, al-
tions have proven successful for working with low cat- though a high reaction temperature and large amount
alyst loadings, i.e., usually at the ppm level.[5]
of ligand (usually 20 mol%) are still necessary. Issues
yet to be developed are, therefore, the generality and
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Adv. Synth. Catal. 2011, 353, 1174 – 1178

Synthesis of 2-Aminobenzothiazoles via Copper(I)-Catalyzed Cross-Coupling
facility of these cross-coupling reactions with very low oughly cleaned and all the solvents used were freshly
catalyst loadings.
distilled (see Experimental Section for more details).
We report herein a CuI/Et3N catalytic system for When 5 mol% of CuI was applied as the catalyst, the
the efficient preparation of 2-aminobenzothiazoles[11] desired product, 2-aminobenzothiazole (3a) could be
with very low catalyst loadings (at ca. 50 ppm level) obtained in 95% yield (Table 1, entry 1). Interestingly,
under mild reaction conditions (808C for 24 h under this yield remained constant even when the loading of
air). A variety of 2-iodoanilines could be cross-cou- CuI was decreased to 1 mol% (entry 2). Encouraged
pled with isothiocyanates to produce 2-aminobenzo- by this result, we tested the reaction output at the
thiazoles in moderate to good yields (49–93%) under given conditions when the amount of CuI was further
the given conditions without any additional ligands. lowered from 0.1 mol% to 0.001 mol% (entries 3–7).
The TON of this reaction could reach 67,000 and the The reaction yield was kept as 91–92% when the CuI
reaction could be scaled up, at least, to a 5 mmol loading was varied from 0.1 mol% to 0.01 mol% (en-
scale (1.10 gram).
tries 3–5). Remarkably, the reaction still gave the
product 3a in the yields of 88% (TON of 17,600) and
67% (TON of 67,000), when the CuI loading was fur-
ther decreased to 0.005 mol% (entry 6) and
0.001 mol% (entry 7), respectively. The control ex-
periment showed that, in the absence of CuI, the
product 3a could only be obtained in the yield of 27%
Results and Discussion
Reaction Test with the Loading of CuI at ppm Level
Initially, we found that the cross-coupling reaction of (entry 8), which confirms the promoting effect of CuI
2-iodoaniline (1a) and isothiocyanatobenzene (2a) catalyst.
could be efficiently catalyzed by CuI (Alfa Aesar,
purity of 99.999%) with the catalyst loading of 0.001–
5 mol% (Table 1). In the presence of Et3N (2.0 equiv.) Scope of the Reaction Catalyzed by CuI at ppm
as base and DMSO as solvent, the reaction was car- Level
ried out at 808C for 24 h under air. In order to rule
out possible effects of impurities, special measures We, therefore, start out to investigate the scope of
were taken during the experimental procedure. For this reaction, in which the CuI catalyst at ppm level
example, all the glassware and stirrer bars were thor- could also be applied. We found that the reaction of
2-iodoaniline (1a) with a variety of substituted iso-
thiocyanates (2b–2i) could also be effectively conduct-
ed in the presence of 0.005 mol% of CuI catalyst
(Table 2). The catalytic system shows good tolerance
of functional groups, such as trifluoromethyl (Table 2,
entry 1), methyl (entry 3), methoxy (entry 4), and
nitro (entry 5) groups. Both electron-rich and elec-
tron-poor aryl isothiocyanates could afford the de-
sired products 3 in moderate to good yields (62–93%,
entries 1–6). However, the alkyl isothiocyanates, such
as cyclohexyl isothiocyanate (2h) and 1-butyl isothio-
cyanate (2i) gave the corresponding products in the
low yields of 26% and 46%, respectively (entries 7
and 8), even when the larger amount of CuI catalyst
(0.01 mol%) and longer reaction time (48 h) were ap-
plied.
Furthermore, the reaction of substituted anilines
(1) and isothiocyanates (2) was examined to explore
the generality of using the CuI catalyst at a ppm level
(Table 3). To our delight, most of the tested systems
worked well with 0.005 mol% of CuI as the catalyst,
giving the desired products (3) in moderate to good
yields (49–91%, Table 3, entries 1–8). For example,
the 2-iodo-4-methylbenzenamine (1b) results in the
desired products in yields of 71–76% (Table 3, en-
tries 1–3). On the other hand, the fluoro-substituted
iodoaniline (1c) has the highest reactivity under the
given conditions, and affords the product in 91%
Table 1. Efficient synthesis of 2-aminobenzothiazole (3a)
from 2-iodoaniline (1a) and isothiocyanatobenzene (2a) in
the presence of 0.001%–5 mol% of CuI.[a]
Entry
CuI (x mol%)
Yield [%][b]
TON[c]
1
2
3
4
5
6
7
8
5
1
95
95
92
91
92
88
67
27
19
95
920
1,820
9,200
17,600
67,000
–
0.1
0.05
0.01
0.005
0.001
0
[a]
Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol), CuI
(x mol%, 5.0 mM in CH3CN), Et3N (2.0 equiv.) in
DMSO (2.0 mL) at 808C for 24 h under an air atmos-
phere.
Average isolated yields after silica gel column chromato-
graphy, from two or more experiments. The yields were
fluctuated within Æ2% for each given set of conditions.
Turnover numbers.
[b]
[c]
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Ya-Lei Sun et al.
UPDATES
Table 2. Reaction of 2-iodoaniline (1a) with isothiocyanates
(2) catalyzed by ppm levels of CuI catalyst.[a]
Table 3. Exploring the generality of using CuI catalyst at
ppm levels in the tandem reaction of 2-iodoanilines (1) and
isothiocyanates (2).[a]
[a]
[a]
Reaction conditions: 1a (0.20 mmol), 2 (0.22 mmol), CuI
Reaction conditions: 1 (0.20 mmol), 2 (0.22 mmol), CuI
(0.005 mol%, 5.0 mM in CH3CN), Et3N (2.0 equiv.) in
DMSO (2.0 mL) at 808C for 24 h under an air atmos-
phere.
Averaged isolated yields after silica gel column chroma-
tography.
(0.005 mol%, 5.0 mM in CH3CN), Et3N (2.0 equiv.) in
DMSO (2.0 mL) at 808C for 24 h under an air atmos-
phere.
Average isolated yields after silica gel column chroma-
tography.
[b]
[b]
[c]
[c]
0.01 mol% of CuI.
Reaction was run for 48 h.
0.1 mol% of CuI.
[d]
yield with a TON of 18,200 (entry 6). Interestingly,
After checking the generality of using CuI catalyst
only a trace of product was detected when 2-bromo- at the ppm level in the cross-coupling reaction of io-
aniline (1e) was applied as the substrate and a yield doanilines with isothiocyanates, we further explored
of 27% could be obtained when the CuI loading was the possibility for large-scale synthesis. As shown in
increased to 0.1 mol% (entry 9). Scheme 1, we scaled up the reaction of 2-iodoaniline
ACHTUNGTRENNUNG
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Adv. Synth. Catal. 2011, 353, 1174 – 1178

Synthesis of 2-Aminobenzothiazoles via Copper(I)-Catalyzed Cross-Coupling
Scheme 1. Scaling up the reaction of 2-iodoaniline (1a) with isothiocyanatobenzene (2a) to a 5-mmol scale. The reaction was
carried out at 808C for 48 h under an air atmosphere, in the presence of 0.005 mol% of CuI, with Et3N (2.0 equiv.) as base
and DMSO (50.0 mL) as solvent. The product 3a is an important intermediate for the preparation of antitumor agent
R116010.[12]
use. Cs2CO3 (99.9%), K2CO3 (ꢀ99%) were chosen as inor-
ganic bases. The metal content of 2-iodoaniline was deter-
mined by ICP, and was found to contain 8 ppm of Fe, and
less than 10 ppb of Cu. Isothiocyanates were purchased
from Aldrich and J&K Chemical and used without further
purification. Considering possible effects of metal impurities,
all the equipment (glassware, stirrer bar, and so on) was
washed with HNO3 (20%, v/v)À1 and KOH/isopropyl alco-
hol, followed by rinsing with distilled water and drying over-
night at 1508C. DMSO was taken via pipette (2 mL), and
solid compounds were taken via ox horn spoons in order to
(1a) to 1.10 g (5.00 mmol) in the presence of
0.005 mol% of CuI catalyst with 50.0 mL of DMSO as
solvent. The reaction took place smoothly under the
given conditions and afforded the desired product, N-
phenyl-2-benzothiazolamine (3a), in 77% yield. The
substrate/catalyst ratio was 100,000 and the TOF was
321 hÀ1. The product 3a is an important intermediate
for the preparation of the antitumor agent
R116010.[12] It is worthy of mention that the residual
copper content in the product 3a was 0.95 ppm (ICP
analysis) after silica gel column chromatography and
that this content well meets the pharmaceutical re-
quirements.[13]
1
avoid the contamination with metal items. H and 13C NMR
spectra were recorded in CDCl3 or DMSO-d6 solution on a
Bruker 400 MHz NMR spectrometer, and the coupling con-
stants J are given in Hz. In the case of CDCl3 as solvent,
TMS served as the internal standard (chemical shift d=
1
0.00 ppm) for H NMR and CDCl3 was used as the internal
Conclusions
standard (d=77.0 ppm) for 13C NMR. In the case of
DMSO-d6 as solvent, chemical shifts d are given from resid-
1
In summary, we have developed a CuI/Et3N system
for the efficient synthesis of 2-aminobenzothiazoles
with very low copper catalyst loadings (typically at
50 ppm of CuI). This system has shown broad sub-
strate scope, moderate to good yields (49–93%), and
high catalytic efficiency (TON up to 67,000). The re-
action could be scaled up, at least, to the gram-scale,
which may be applicable in the practical or industrial
synthesis of 2-aminobenzothiazoles. Further applica-
tions of similar catalytic systems to other cross-cou-
pling reactions are currently under investigation in
our laboratory.
ual non-deuterated solvent peak, i.e., 2.50 ppm for H NMR
and 39.5 ppm for 13C NMR. MS and HR-MS were per-
formed on Bruker Daltonics esquire6000 mass instrument
(ESI) and Bruker Daltonics APEX II 47e FT-ICR mass
spectrometer, respectively.
General Procedure for the Tandem Reaction of 2-
Iodoaniline (1) and Isothiocyanate (2) in the
Presence of CuI Catalyst at ppm Level
Into a 10-mL test tube, a CuI solution (0.005 mol%, 2.0 mL,
5.0 mM CuI in CH3CN) was added, then CH3CN was re-
moved under vacuum. 2-Iodoaniline (1, 0.20 mmol), isothio-
cyanate (2, 0.22 mmol), Et3N (58 mL, 2.0 equiv.), DMSO
(2.0 mL) and a teflon coated stirrer bar were added. The
tube was placed in a preheated oil bath at 808C. The mix-
ture was stirred for 24 h under an air atmosphere, and then
cooled to room temperature. The solution was diluted with
ethyl acetate, and washed with water (10 mL), brine
(10 mL). The aqueous phase was extracted with ethyl ace-
tate (3ꢂ10 mL). The organic layers were combined and
dried over anhydrous Na2SO4. After evaporating under
vacuum, the corresponding product 3 was obtained by pu-
rification on silica gel (petroleum ether/ethyl acetate=15:1
to 4:1).
Experimental Section
General Comments
Unless otherwise noted, all experiments were carried out
under an air atmosphere. CuI was purchased from Alfa
Aesar (Lot No.: C26N01) with a purity of 99.999%. CuBr
was
purchased
from
Sigma–Aldrich
(Lot
No.:
MKBC3138 V) with a purity of 99.999%. All the solvents,
such as DMSO (ꢀ99%), CH3CN (ꢀ98%), and Et3N
(ꢀ99%), were freshly distilled over calcium hydride before
Adv. Synth. Catal. 2011, 353, 1174 – 1178
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1177

Ya-Lei Sun et al.
UPDATES
Doucet, J. Org. Chem. 2009, 74, 1179–1186; e) R.
Gerber, O. Blacque, C. M. Frech, ChemCatChem 2009,
Acknowledgements
ˇ
1, 393–400; f) J. J. Dong, J. Roger, F. Pozgan, H.
This work was financially supported by the National Natural
Science Foundation of China (No. 20972064) and the 111
project.
Doucet, Green Chem. 2009, 11, 1832–1846; g) J. L. Bol-
liger, C. M. Frech, Adv. Synth. Catal. 2009, 351, 891–
902; h) F. Pozgan, J. Roger, H. Doucet, ChemSusChem
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