Silver catalyzed decarboxylative direct C2-alkylation of benzothiazoles with carboxylic acids

Article abstract of DOI:10.1039/c3cc48069k

A novel and efficient silver catalyzed decarboxylative direct C2-alkylation of benzothiazoles with carboxylic acids for the synthesis of 2-alkyl benzothiazoles was developed.

Full text of DOI:10.1039/c3cc48069k

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Silver catalyzed decarboxylative direct
C2-alkylation of benzothiazoles with
carboxylic acids†
Cite this: Chem. Commun., 2014,
50, 2018
Received 21st October 2013,
Accepted 10th December 2013
Wei-Ming Zhao,a Xiao-Lan Chen,*a Jin-Wei Yuan,b Ling-Bo Qu,b Li-Kun Duana and
Yu-Fen Zhao*ac
DOI: 10.1039/c3cc48069k
www.rsc.org/chemcomm
A novel and efficient silver catalyzed decarboxylative direct C2-alkylation reagents is rarely reported despite the fact that benzothiazoles,
of benzothiazoles with carboxylic acids for the synthesis of 2-alkyl benzoxazoles and their derivatives exhibit a lot of biological activities
benzothiazoles was developed.
such as being anti-inflammatory, etc.17 According to the literature
most of the successful direct C–H alkylation of benzothiazoles and
In recent years, transition-metal-catalyzed1 and photo-catalyzed2 benzoxazoles were performed using transition metals as catalysts
decarboxylative cross-coupling reactions using simple carboxylic acids and alkyl halides,18 Grignard reagents,19 N-tosylhydrazones20 and
as coupling partners have been widely studied in organic synthesis as potassium alkyltrifluoroborates21 as alkylating reagents under
novel methods for formation of various carbon–carbon3 and carbon– very harsh reaction conditions. A metal free DTBP catalyzed direct
heteroatom4 bonds. Since carboxylic acids and their derivatives as sp2C–H bond alkylation of heteroaromatics with cycloalkanes, which
cross-coupling components are non-toxic, low cost, stable and struc- has very recently been reported by Guo and co-workers, appears to
turally diverse, extensive studies have been accomplished in this area, be an environmentally friendly method, however, these processes
particularly since Ag-catalyzed decarboxylative alkylation of pyridines are limited to cyclic alkanes as alkylating reagents.22 Therefore,
and quinolines was reported by F. Minisci in the 1970s.5 Afterward, further developments for more general alkylation methodologies
Pd-catalyzed decarboxylative Heck-type reactions of benzoic acids with are strongly desired. Herein, we report silver catalyzed alkylation of
alkenes and Pd-catalyzed decarboxylative coupling of benzoic acids or benzothiazoles with carboxylic acids through direct decarboxylative
heteroaromatic carboxylic acids with aryl halides, etc. were developed cross-coupling reaction, in which a wide range of carboxylic acids
by Myers,6 Goossen,3b,7 Forgione8 and others,3a,c–e,9 respectively. including secondary or tertiary a-substituted, cyclic and acyclic
Recently, Greaney10 reported that in the presence of K2S2O8, aroyl- carboxylic acids were employed as the alkylation reagents.
benzoic acids can undergo intramolecular radical decarboxylation
We began our studies with the commercially available benzothi-
coupling reactions to form fluorenones. In addition, a-oxo-,3j,11 azole (1a) and pivalic acid (2a). When 1 equiv. of 2a was reacted with
alkenyl3g,12 and alkynyl3h,i,13 carboxylic acids (or their salts) can also 1a in the presence of 10 mol% of AgNO3 and 2 equiv. of K2S2O8 in
be employed as coupling partners. Despite the significant advances, CH2Cl2–H2O (v/v = 1/1) at room temperature, we were delighted to
the reactions reported in the literature were mainly focused on know that our desired product, 2-(tert-butyl)benzothiazole (3a), was
decarboxylative cross-coupling reactions involving the breaking of indeed formed in 52% yield (Table 1, entry 1). The control experi-
Csp–COOH or Csp2–COOH bonds. Only recently, Liu,14 Li,15 and ment showed that a silver catalyst was necessary for the reaction to
others16 examined transition metal catalyzed decarboxylative coupling proceed (entry 2). With this intriguing result in hand, we investigated
reactions involving the breaking of Csp3–COOH bonds. Such reactions other silver catalysts. The use of AgSbF6 was worse (entry 6), while
are synthetically useful for making aliphatic compounds but still have Ag2CO3, AgOAc and Ag2O catalyzed the reaction with moderate
been less studied. In particular, the alkylation of benzothiazoles and efficiency (entries 3–5). But Cu cannot catalyze this reaction although
benzoxazoles using saturated aliphatic carboxylic acids as alkylating Cu and Ag are in the same group in the periodic table (entry 7).
Subsequently, the effect of other different oxidants such as Na2S2O8,
a College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, 450052, China. E-mail: chenxl@zzu.edu.cn; Fax: +86 371 67767051;
Tel: +86 371 67767051
H2O2, TBHP and DTBP was also screened, and unfortunately, only
Na2S2O8 can catalyze this reaction with a moderate yield (51%)
(entries 8–11). Then, the effect of the amount of carboxylic acid,
AgNO3 and K2S2O8 was examined, and the results showed that an
increase in the amount of carboxylic acid, AgNO3 and K2S2O8 led to
higher conversion of 1a (entries 12 and 13). When we used 2 equiv.
of 2a, 20 mol% AgNO3 and 4 equiv. of K2S2O8, a full conversion was
b Chemistry and Chemical Engineering School, Henan University of Technology,
Zhengzhou, 450001, China
c Department of Chemistry, Xiamen University, Xiamen, 361005, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc48069k
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Table 1 Optimization of reaction conditionsa
Table 2 Scope of decarboxylative alkylationa
Entry Catalyst (equiv.) Oxidant (equiv.) Mixed solvent Yieldb (%)
1
AgNO3(10%)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
K2S2O8(2)
Na2S2O8(2)
H2O2(2)
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH2Cl2–H2O
CH3CN–H2O
DMF–H2O
52(45)
0
49
51
47
40
0
51
0
2c
3
4
5
Ag2CO3(10%)
AgOAc(10%)
Ag2O(10%)
AgSbF6(10%)
Cu salts
AgNO3(10%)
AgNO3(10%)
AgNO3(10%)
AgNO3(10%)
AgNO3(15%)
AgNO3(20%)
AgNO3(10%)
AgNO3(20%)
AgNO3(20%)
AgNO3(20%)
AgNO3(20%)
6
7d
8
9
10
11
12e
13f
14f
15f
16f
17f
18f
TBHP(2)
DTBP(2)
0
0
K2S2O8(3)
K2S2O8(4)
K2S2O8(4)
K2S2O8(4)
K2S2O8(4)
K2S2O8(4)
K2S2O8(4)
73
96(91)
78
Trace
Trace
Acetone–H2O Trace
CHCl3–H2O 63
a
Reaction conditions: 0.2 mmol of 1a, 1 equiv. of 2a, catalyst, oxidant
and 2 mL of mixed solvent (v/v = 1/1) in a 25 mL round-bottom flask
b
at room temperature for 8 h. Yield determined by GC analysis. Yield
c
d
of isolated products given in parentheses. No AgNO3 added. CuI,
CuBr and CuCl were tested. e 1.5 equiv. of 2a added. 2 equiv. of 2a added.
f
a
Reaction conditions: 0.5 mmol of 1, 2 equiv. of 2, 20 mol% of AgNO3,
4 equiv. of K2S2O8 and 5 mL of CH2Cl2–H2O (v/v = 1/1) in a 25 mL
round-bottom flask at room temperature for 8 h.
obtained and the isolated yield of 3a reached 91% (entry 13).
Disappointedly, when we reduced the amount of the silver catalyst
to 10 mol%, a lower conversion of 1a was obtained (entry 14).
Solvents were crucial for this reaction, as well. Using CH3CN–H2O,
DMF–H2O, or acetone–H2O as solvent led to a trace amount of 3a, result in the formation of the corresponding products, testified
while CHCl3–H2O led only to a moderate yield (entries 15–18). by our purposely designed experimental reaction of 2-bromo-
Further screening of reaction time showed that 8 h was the best isobutyric acid with benzothiazole, in which an immediate
choice. Therefore, optimal reaction conditions involved 2 equiv. of AgBr precipitate was observed. The reactivity of different sub-
carboxylic acid, AgNO3 (20 mol%) and K2S2O8 (4 equiv.) in the mixed stituted benzothiazoles toward secondary and tertiary a-substituted
solvent of CH2Cl2–H2O (v/v = 1/1) at room temperature for 8 h.
carboxylic acids was subsequently examined. The alkylated
With the optimized reaction conditions established, the benzothiazoles (3o–u) were obtained with moderate to excellent
scope of this transformation was subsequently investigated. yields. It was noteworthy that the electronic effect had an
We evaluated the reactivity of benzothiazole toward different obvious influence on the decarboxylative coupling reactions.
tertiary and secondary a-substituted carboxylic acids (Table 2). Benzothiazole with an electron-donating methyl group under-
2-tert-Butyl benzothiazole and 2-tert-pentyl benzothiazole were went the secondary and tertiary alkylation smoothly under
obtained with 91% (3a) and 93% (3b) yield, respectively. Nota- standard conditions (3o–p), while the electron-withdrawing
bly, the silver catalysis could also be applied to cyclic carboxylic nitro-, bromo- and chloro-substituents only participated in the
acids. 2-Adamantan-1-yl-benzothiazole 3c was synthesized from alkylation with tertiary a-substituted carboxylic acid, forming the
1-adamantanecarboxylic acid in an excellent yield (95%). The corresponding alkylated benzothiazole derivatives with relatively
cyclic and acyclic secondary alkylation was also achieved, low yields (3q–u). It is worth mentioning that the coupling
affording the corresponding products 3d–j in good to excellent reaction was also suitable for the direct alkylation of thiazoles
yields. Comparatively, the cyclopropyl benzothiazole cannot be (not limited to benzo-substituted). Thiazole and methylthiazole
obtained from the corresponding coupling reaction perhaps underwent the secondary and tertiary alkylation smoothly under
owing to ring-opening of the cyclopropyl radical formed after standard conditions with good yields (3v–x). We next attempted
decarboxylation of cyclopropane carboxylic acid.23 The toler- to apply the reaction to other 1,3-azoles and immediately found
ance of functional groups in aliphatic carboxylic acids and that the abovementioned silver catalysis was also suitable for the
benzothiazoles during this transformation were further inves- direct alkylation of benzoxazoles. Both secondary and tertiary
tigated. Carboxylic acids that contain hydroxyl, ether and amide a-substituted carboxylic acids gave rise to corresponding products
groups, respectively, afforded the corresponding products in 3y–ad in satisfactory yields.
moderate to good yields (3k–n). It is worth noticing that
A plausible mechanism for this novel decarboxylative coupling
halogen-containing saturated aliphatic carboxylic acids cannot reaction is proposed. If tetramethylpiperidinyloxy (TEMPO),
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Scheme 1 Plausible mechanism.
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a widely used radical scavenger, was added into the reaction
system, decarboxylative cross-coupling reactions of both pivalic
acid 2a and isobutyric acid 2d with benzothiazole 1a
were quenched. The results suggest that the reactions may
undergo a radical mechanism. The plausible mechanism of
the decarboxylative cross-coupling reaction may be as follows
(Scheme 1). Initially, an Ag(I) cation is oxidized to an Ag(II)
cation by peroxodisulfate. Then, carboxylic acid 2 reacts with
the Ag(II) cation to form cation salt 4 by losing a proton. 4 further
loses one molecule of CO2 and the Ag(I) cation to form alkyl
radical 5. The obtained free radical 5 subsequently underwent
hydrogen atom abstraction from the C2 of benzothiazole forming
the corresponding benzothiazole radical 7. Subsequently, another
alkyl radical 5 couples with benzothiazole radical 7, forming the
coupling product 3. The ease of carboxylic acid decarboxylation
seems to be closely related to the stability of the in situ formed
alkyl radical, as the reactivity appears to increase on going from
secondary to tertiary radicals. This may explain the slightly lower
yields of 3d–j obtained.
In conclusion a novel and efficient silver catalyzed decarboxyla-
tive direct C2-alkylation of benzothiazoles, thiazoles and benzox-
azoles was developed. To the best of our knowledge, this reaction is
the first example that uses carboxylic acids as coupling partners to
perform direct C2-alkylation of benzothiazoles, thiazoles as well as
benzoxazoles. In comparison with Minisci reaction, our decarboxyl-
ative alkylation of heterocycles was carried out at room temperature
and under acid-free conditions. The approach has advantages in
terms of experimental simplicity, mild reaction conditions and easy
work-up. Further expansion of this novel method to a more broader
spectrum of substrates is underway.
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