Chemoselective copper-catalyzed acylation of benzothiazoles with aryl methyl ketones

Article abstract of DOI:10.1002/adsc.201400240

A copper(I) iodide-catalyzed, highly efficient acylation of benzothiazoles with aryl methyl ketones as carbonyl sources under a nitrogen atmosphere was developed. This is an unprecedented protocol and an extremely efficient method for the selective synthesis of 2-acylbenzothiazoles from commercially available, cheap starting materials with excellent chemoselectivity, good functional group tolerability and high turnover numbers (up to 14,200); also scaling up to 160mmol without loss of the efficiency is possible. A variety of 2-acylbenzothiazoles was smoothly prepared in good to excellent yields from aryl methyl ketones and benzothiazoles by a one-pot domino protocol of combined sp³ C-H oxidation, ring opening, and condensation.

Full text of DOI:10.1002/adsc.201400240

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DOI: 10.1002/adsc.201400240
Chemoselective Copper-Catalyzed Acylation of Benzothiazoles
with Aryl Methyl Ketones
Qiang Fenga and Qiuling Songa,*
a
Institute of Next Generation Matter Transformation, College of Chemical Engineering at Huaqiao University, 668 Jimei
Blvd, Xiamen, Fujian 361021, Peopleꢀs Republic of China
Fax : (+86)-592-616-2990; e-mail: qsong@hqu.edu.cn
Received: March 7, 2014; Revised: April 13, 2014; Published online: July 17, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400240.
Abstract: A copper(I) iodide-catalyzed, highly effi-
cient acylation of benzothiazoles with aryl methyl
ketones as carbonyl sources under a nitrogen at-
mosphere was developed. This is an unprecedented
protocol and an extremely efficient method for the
selective synthesis of 2-acylbenzothiazoles from
commercially available, cheap starting materials
with excellent chemoselectivity, good functional
group tolerability and high turnover numbers (up to
14,200); also scaling up to 160 mmol without loss of
the efficiency is possible. A variety of 2-acylbenzo-
thiazoles was smoothly prepared in good to excel-
lent yields from aryl methyl ketones and benzothia-
materials have been widely used in organic and phar-
maceutical synthesis. Recently, oxidative functionali-
3
À
zation of the sp C H bond in aryl methyl ketones
has become a hot topic and many efficient methods
have been developed[5] based on catalytic oxidative
3
À
functionalization of the sp C H bond adjacent to the
carbonyl group in aryl methyl ketones. For example,
a-keto amides were directly synthesized from aryl
methyl ketones and amines or DMF under oxidative
reaction conditions,[5b,c,6] and MacMillan et al. ob-
tained a-aminoaryl alkyl ketones directly from
copper-catalyzed aerobic oxidation of aryl alkyl ke-
tones with secondary amines.[5a] Wu and his co-work-
zoles by a one-pot domino protocol of combined
sp C H oxidation, ring opening, and condensation.
ers have developed various I2-mediated methods
3
3
À
À
which functionalize the sp C H bond in aryl methyl
ketones.[7]
Keywords: acylation; 2-acylbenzothiazoles; aryl
methyl ketones; benzothiazoles; oxidation
Very interestingly, when acetophenone (1) and ben-
zothiazole (2) were treated with CuI under an O2 at-
mosphere, not only 2-arylbenzothiazole (3) but also 2-
acylbenzothiazole (4) were formed and when the cat-
alyst loading was reduced, the ratio of compound 4 to
compound 3 increased. Compared to the prevailing
2-Substituted benzothiazoles are ubiquitous scaffolds synthesis of 2-arylbenzothiazoles, the formation of 2-
in pharmaceuticals and have shown many biological acylbenzothiazoles is rare due to the difficulties to in-
activities.[1] Great progress has been achieved for the stall an acyl group to the 2-position of benzothiazoles.
synthesis of 2-substituted benzothiazoles, especially 2- So we decided to focus on the formation of 2-acylben-
arylbenzothiazoles.[2] Very recently we developed an zothiazoles. Recently there are two methods for the
efficient method to prepare 2-arylbenzothiazoles from synthesis of 2-acylbenzothiazoles from aryl methyl ke-
phenylacetic acids and a-hydroxyphenylacetic acids tones and benzothiazoles (Scheme 1, methods 1 and
with benzothiazoles under aerobic copper-catalyzed 2).[7a,8,9] Although some significant progress has been
oxidation conditions.[3] Bi et al. reported a novel for- achieved, a stoichiometric amount of oxidants (I2)
mation of aldehydes by chemoselective oxidative and strong base (KOH) (method 1)[7a] or expensive
À
C(CO) CACHTUNGTRENNUNG(methyl) bond cleavage in aryl methyl ke- ligand, external oxidant and long reaction time (>
tones catalyzed by CuI and O2.[4] As part of our con- 20 h) (method 2)[8] were required. These disadvantag-
tinuing interest in prepare 2-arylbenzothiazoles, we es seriously limited the utility of such methods in or-
speculated that 2-arylbenzothiazoles could be formed ganic synthesis. Thus the development of a highly effi-
from aryl methyl ketones and benzothiazoles in the cient catalytic system for the synthesis of 2-acylbenzo-
presence of CuI and O2 based on our previous re- thiazoles is still desirable. Based on the principles of
search and the above literature report.[4] Aryl methyl green chemistry, if catalysis loading could be dramati-
ketones as cheap and commercially available starting cally reduced, no ligands were necessary, no strong
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Scheme 1. Methods for the synthesis of 2-acylbenzothiazoles from aryl methyl ketones and benzothiazoles.
oxidant was required and the reaction time was short, tion, when HBF4 was reduced to 10 mol%, the yield
it would be an ideal protocol in modern oxidation re- of the desired product dropped to 40% with 5% of
actions. To the best of our knowledge, there are no re- by-product 3; when acetophenone was dropped from
ported examples of the efficient synthesis of 2-acyl- 2 equiv. to 1.2 equiv. and 1.5 equiv, the desired prod-
benzothiazoles under extremely low catalysis loading uct was obtained in 51% and 58% yields, respectively
in a short reaction time under air, O2 or N2 atmos- (Table 1, entries 21, 23 and 24). In the absence of CuI,
pheres as yet. Herein, we report an unprecedented, no product was formed at all, which showed that CuI
highly efficient and selective acylation of benzothia- plays a crucial role in the reaction (Table 1, entry 22);
zoles from aryl methyl ketones.
Most remarkably, when the reaction was carried out
In our initial study, acetophenone (1) and benzo- in air or an N2 atmosphere, the desired product was
thiazole (2) were chosen as model substrates in the obtained in 81% and 83% yields, respectively
presence of CuACHTUNGTRENNUNG(OAc)2 in DMSO at 1308C under an (Table 1, entries 25 and 26), which are much higher
oxygen atmosphere. Both 2-phenylbenzothiazole (3) than from the reaction under O2 (70% in entry 20). In
and 2-acylbenzothiazole (4) were formed (Table 1, order to shorten the reaction time, higher tempera-
entry 1). Catalyst screening showed that CuI gave the tures were applied on the reaction under the optimal
highest ratio of desired product 4 to by-product 3 conditions at 3 h and 6 h (Table 1, entries 27–30), the
(Table 1, entries 1–8). Interestingly, when catalyst best result was obtained with 1408C after 6 h heating
loading (CuI) was dropped, the ratios of desired prod- (Table 1, entry 28), but the yield was only 71%, com-
uct to by-product were increased (Table 1, entries 8– pared to that at 1308C/9 h, we thus decided to take
11). However, due to accurate weighing problems, we the latter (Table 1, entry 25) as our optimized condi-
could just reduce the catalyst loading to 2 mol% tions.
(1.8 mg) based on our standard 0.5 mmol scale. Fur-
With the optimal reaction conditions available, the
ther investigation indicated that the temperature is scope of substituted acetophenones was firstly exten-
very important for this transformation, when the tem- sively explored (Scheme 2). Both electron-rich and
perature was dropped to 1108C and 1208C, no prod- electron-poor aryl methyl ketones readily converted
ucts were obtained (Table 1, entries 12 and 13). Sol- into the desired products (Scheme 2, 5–37). Further-
vent screening exhibited that DMSO is the best sol- more, substituents at different positions on the aryl
vent and other solvents caused lower ratios of the de- group (para-, meta-, and ortho-positions) did not obvi-
sired product (Table 1, entries 11, 14–16). Acids as ad- ously affect the efficiency (Scheme 2, 5–7, 10–21),
ditive were also screened and, notably, HBF4 could only in some cases did substitution at the ortho-posi-
totally suppress the by-product 3 and give a 70% of tion give slightly lower yields (Scheme 2, 10, 13, 16
the desired product 4 (Table 1, entry 20), but other and 19). Halo-substituted aryl methyl ketones sur-
acids gave inferior results (Table 1, entries 17–19). vived well leading to halo-substituted products
Further fine tuning showed that amounts of HBF4 (Scheme 2, 10–18), which could be further trans-
and acetophenone were very important for the reac- formed into other functionalities. It is noteworthy that
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Chemoselective Copper-Catalyzed Acylation of Benzothiazoles
Table 1. Optimization of the reaction conditions.[a]
[a]
Reaction conditions: phenylacetic acid (1a) (0.5 mmol), benzothiazole (2a), catalyst, solvent
(0.75 mL) in a sealed tube under the corresponding atmosphere.
GC yield using dodecane as internal standard.
Isolated yields.
With 1.2 equiv. of acetophenone.
With 1.5 equiv. of acetophenone.
[b]
[c]
[d]
[e]
reactions under N2 and O2 were conducted for all the mental effect on this reaction. Notably, there were no
halo-substituted cases under the standard conditions, desired products generated from three ortho-halo-
in all cases, the reaction under N2 gave much higher substituted aryl methyl ketones under O2 at all, yet
yields of desired product compared with the counter- good yields of the corresponding products were ob-
parts under O2 (average >20% in yields) (Scheme 2, tained under an N2 atmosphere (Scheme 2, 10, 13 and
10–18), which further proved that the N2 atmosphere 16), which either could not be achieved by the report-
is critical for the reaction and that O2 has some detri-
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Scheme 2. Reactions of benzothiazole with various aryl methyl ketones.
ed two methods or just obtained in mixture sults than the latter one (average >15% in yield in N2
(Scheme 1, methods 1 and 2). than in O2) (Scheme 2, 23, 28 and 31). These results
Besides the halo-substituted aryl methyl ketones, 4- further proved the superiority of N2 than O2 in our re-
CF3, 4-OCF3 and 3,4-dioxobenzo-fused aryl methyl actions. Both 1- and 2-naphthyl methyl ketones were
ketones were also examined under both N2 and O2 at- tolerated under the standard conditions and gave the
mospheres, in all cases, the former one gave better re- corresponding products in excellent yields (Scheme 2,
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Chemoselective Copper-Catalyzed Acylation of Benzothiazoles
24 and 25), methylthiol, phenyl, phenylacetylenyl and
nitro groups were also well tolerated under the stan-
dard conditions (Scheme 2, 34–37). Besides all these
monosubstituted groups, disubstituted or trisubstitut-
ed acetophenones were also transformed well to give
good to excellent yields of the desired products
(Scheme 2, 26, 27, 29–33).
Both 2-benzoylbenzothiazole and 4-methoxyben-
zoylbenzothiazole (Scheme 2, 4 and 21) were ob-
tained under all three atmospheres: N2, air, and O2,
but N2 always gave the best yields among the three.
Significantly, several gram-scale reactions were car- corresponding desired products were obtained in
ried out under the standard conditions, the yields good to excellent yields (Scheme 3, 38–46).
were not dramatically diminished even when the
These results astonished us, as far as we know, in
3
À
starting material was scaled up to 160 mmol (>20 g all of the reported sp C H functionalizations of aryl
of benzothiazole) and the catalyst loading was re- methyl ketone, strong oxidants were always a necessity
duced to 0.005 mol% due to the accurate weighing for the success of these reactions, no one ever report-
possible (1.5 mg of CuI, even lower catalyst loadings ed that the reaction could go smoothly in the absence
might be achieved with a larger reaction scale) of an external strong oxidant. Therefore, we carefully
(Scheme 2, 4 and 22). This result corresponds to explored the reaction: in order to exclude an impurity
a turnover number of 14,200, which is the highest effect in CuI, we purchased super pure CuI (99.995%
3
À
TON observed among all of sp C H functionaliza- purity) and did the reaction under O2, a 71% yield of
tion of aryl methyl ketone [Eq. (1)]. This is a remark- the desired product was obtained which was the same
able progress and it shows the preparative utility of result as from 98% purity CuI in O2, thus it ruled out
our new CuI-catalyzed acylation of benzothiazoles.
an impurity effect. In order to rule out effect of
Next, the scope of heteroaromatic methyl ketones a trace amount of O2 in regular N2, we also did the
and various benzothiazoles was investigated. As same reaction under super pure N2 (99.995% purity),
shown in Scheme 3, various heteroaromatic methyl and it turned out to be just as efficient as under the
ketones and different functionalities on benzothiazole regular N2. These results showed that this is an unpre-
were tolerated under the standard conditions and the cedented protocol. Since O2 is not necessary for this
Scheme 3. Reactions of various benzothiazoles and heteroaromatic methyl ketones.
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reaction, it makes us realize that the IÀ anion, not
Cu+ cation plays the crucial role in this reaction, so
we carried out the following experiments: (i) we re-
placed CuI (2 mol%) with I2 (2 mol%) under the
standard conditions; (ii) we replaced CuI (2 mol%)
with TBAI (tert-butylammonium iodide, 2 mol%)
under the standard conditions, both of the reactions
gave similar results and afforded 2-benzoylbenzothia-
zole in 70% and 71% isolated yields, respectively,
after heating at 1308C for 5 h [Eq. (2) and (3)]! These
results clearly indicated that iodide anion is very im-
portant and iodine might be the active intermediate
in this reaction.
In order to further elucidate the exact pathway of
the reaction, several control experiments were carried
out. Firstly, the 13C labelled acetophenone was treated
with benzothiazole under the standard conditions. product [Scheme 4, Eq. (4)], which clearly demon-
NMR showed that the isotopically labelled carbon strated that ring opening occurred in the benzothia-
(13C) was inserted into the benzothiazole ring of the zole during the course of the reaction. Furthermore,
Scheme 4. Control experiments.
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phenylglyoxal monohydrate was treated with 2-ami- one is solvent-free, yet in both conditions, no desired
nothiophenol and benzothiazole, respectively, under products were detected [Scheme 4, Eq. (10) and Eq.
the standard conditions, in both cases, a mixture of (11)].
compounds 3 and 4 was obtained [Scheme 4, Eq. (5)
On the basis of all the above experiments, we give
and (6)]. When benzothiazole was treated with a-ke- plausible mechanisms both under O2 and N2 atmos-
tophenylacetic acid, only compound 3 was obtained in pheres (Scheme 5): under an O2 atmosphere, aceto-
41% yield [Scheme 4, Eq. (7)], which might explain phenone was firstly oxidized into 2-hydroxyacetophe-
the above two results: phenylglyoxal monohydrate none, via the activation of oxygen by Cu(I) salt, 2-hy-
was quickly oxidized into a-ketophenylacetic acid droxyacetophenone further underwent oxidation to
under the standard conditions, thus a competitive re- give phenylglyoxal (A); under an N2 atmosphere, cop-
action occurred to give a mixture of compounds 3 and per(I) iodide was treated with HBF4 to afford HI and
4. When 2-hydroxyacetophenone and 2-iodoacetophe- CuBF4, and HI reacted with DMSO to give I2 which
none were treated with benzothiazole, respectively, could active the CH3 group in acetophenone in the
under the standard conditions, the former one gave presence of DMSO, to generate 2-iodoacetophenone
a lower yield of the mixture of compounds 3 and 4, and further phenylglyoxal (A) (Kornblum oxidation).
yet the latter one mainly generated compound 4 in Compound A further reacted with the ring-opened
34% with a trace amount of compound 3 [Scheme 4, benzothiazole (B, 2-aminobenzothiol), after hetero-
Eq. (8) and Eq. (9)]. Thus 2-hydroxyacetophenone cyclization, finally, desired product 4 was obtained.
could not be the major intermediate for this reaction, Compound A could be easily oxidized into a-keto-
yet 2-iodoacetophenone could not be ruled out as the phenylacetic acid which will react with ring-opened 2-
major intermediate. Meanwhile, acetophenone and aminothiophenol to give 2-phenylbenzothiazole (3) as
benzothiazole were treated with 2 mol% of iodine in the by-product.
additive-free conditions: one is in DMSO, the other
Scheme 5. Plausible mechanism.
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References
In summary, a highly efficient CuI-catalyzed acyla-
tion of benzothiazoles with aryl methyl ketones as
carbonyl sources has been developed. This reaction
could be carried out smoothly with extremely lower
catalyst loadings and could tolerate variety of func-
tionality on both benzothiazoles and aryl methyl ke-
tones, to selectively afford 2-acylbenzothiazoles. The
superior substrate tolerability and preparative utility
(scale-up to 160 mmol in the lab without diminishing
the isolated yield) suggested that the reaction is very
practical and could be a complementary method for
the current reported ones. Later on, I2 and TBAI also
showed great catalytic activity in this reaction. Studies
on the mechanism and application of this protocol are
ongoing in our laboratory.
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Experimental Section
Typical Procedure
A sealed tube was charged with benzothiazole (68 mg,
0.5 mmol), CuI (1.9 mg, 2 mol%), acetophenone (120 mg,
1.0 mmol), HBF4 (0.25 mmol, 40% aqueous solution) and
DMSO (0.75 mL). The resulting solution was purged by N2
and the tube sealed, then the reaction mixture was stirred at
1308C under N2 for 9 h (monitored by TLC and GC). Upon
completion of the reaction, ethyl acetate (20 mL) was
added, the organic layer was washed with saturated
NaHCO3 solution (20 mLꢂ2), brine (20 mLꢂ1), the com-
bined aqueous layers were extracted with ethyl acetate
(20 mLꢂ2). The combined organic layers were dried over
anhydrous Na2SO4. The solvents were removed via rotary
evaporator and the residue was purified by flash chromatog-
raphy (silica gel, ethyl acetate: petroleum ether=30:1) to
give desired product 4 as a light yellow solid; yield: 98.0 mg
(82%).
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Acknowledgements
We are grateful for financial support from the National Sci-
ence Foundation of China (21202049), the Recruitment Pro-
gram of Global Experts (1000 Talents Plan), Fujian Hundred
Talents Program and Research Funds of Huaqiao University.
We also thank Prof. Dr. Robert Pascal from Tulane Universi-
ty for helpful mechanism discussion and Prof. Zhenhua Gu
from USTC for generous instrumental support.
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[9] During the preparation of this manuscript, another
paper which reported the formation of 2-acylbenzothia-
zoles from aryl methyl ketones and benzothiazoles ap-
peared in Tetrahedron (J. Wang, X.-Z. Zhang, S.-Y.
Chen, X.-Q. Yu, Tetrahedron 2014, 70, 245–250). Howev-
er, the reported methods always gave a mixture of both
2-aryl- and 2-acylbenzothiazole and did not show good
chemoselectivity, thus we did not list this reference in
Scheme 1.
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