Acylperoxycoumarins as ortho-C?H Acylating Agent via a Palladium(II)-Catalyzed Redox-Neutral Process

Article abstract of DOI:10.1002/adsc.201600258

An unprecedented palladium(II)-catalyzed biomimetic aliphatic acyl (-COR) group transfer was observed from acyl-α-peroxycoumarins to the ortho C?H sites of directing arenes. Here, the C?H activation is associated with a concomitant acyl group transfer via a Pd(II)-catalyzed, redox-neutral process. While methods for ortho aroylation (-COAr) are well documented ortho acylation (-COR) processes are scarce, hence the present redox-neutral method is most ideal for o-acylation of directing substrates. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600258

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DOI: 10.1002/adsc.201600258
À
Acylperoxycoumarins as ortho-C H Acylating Agent via a
Palladium(II)-Catalyzed Redox-Neutral Process
a
a
a
Prakash Ranjan Mohanta, Arghya Banerjee, Sourav Kumar Santra,
a
a,
Ahalya Behera, and Bhisma K. Patel *
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati 781039, Assam, India
a
Fax : (+91)-361-2690-9762; e-mail: patel@iitg.ernet.in
Received: March 7, 2016; Revised: April 5, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600258.
Abstract: An unprecedented palladium(II)-cata-
lyzed biomimetic aliphatic acyl (-COR) group
transfer was observed from acyl-a-peroxycoumarins
to the ortho CÀH sites of directing arenes. Here,
the CÀH activation is associated with a concomitant
Supporting Information). No explosion was observed
in any of the reactions even when carried out on
a 2 mmol scale, thus the reagent is safe to handle. A
careful scrutiny of the decomposed product revealed
it to be a 4-cyclohexyl-3-hydroxy-2H-chromen-2-one
(A), which is obtained via the cleavage of both the
peroxo (OÀO) and CÀC bonds of (a) (Scheme 1).
acyl group transfer via a Pd(II)-catalyzed, redox-
neutral process. While methods for ortho aroylation
(
(
-COAr) are well documented ortho acylation
-COR) processes are scarce, hence the present
Since the acyl-a-peroxycoumarin (a) has an inbuilt
thermally labile peroxy (OÀO) linkage, homolytic
redox-neutral method is most ideal for o-acylation
of directing substrates.
cleavage of it will trigger the cleavage of an a-COR
group generating an acyl radical (COR). Thus, the in-
Keywords: acyl group transfer; CÀH activation; pal-
ladium catalysis; redox-neutral process
Transfer of various functional groups from one mole-
[
1]
cule to another is not uncommon in the literature.
Earlier our group reported on “thiocyanate transfer
agents” viz. acyl isothiocyanates which transfer iso-
thiocynate to various electrophilic sites such as a-
bromo ketones or benzyl bromides in the presence of
[
2]
a tertiary amine. However, intermolecular group
transfer in any CÀH functionalizations is unfamiliar
so far. Recently, we have achieved two cycloalkyla-
tion-peroxidation strategies for coumarins, one involv-
ing metal-free conditions and the other using a cop-
per(I) salt in which tert-butyl hydroperoxide (TBHP)
[
3]
acted as an oxidant as well as a reactant. The acyl-
a-peroxy product, i.e., 3-acetyl-3-(tert-butylperoxy)-4-
cyclohexylchroman-2-one (a) [obtained by reacting 3-
acetylcoumarin, cyclohexane and TBHP in the pres-
[
3a]
ence of catalyst Cu O ] slowly decomposed on pro-
2
longing the reaction time, but the isolated product is
[
3a]
sufficiently stable at room temperature. Thermogra-
vimetric analysis (TGA) data of 3-acetyl-3-(tert-butyl-
peroxy)-4-cyclohexylchroman-2-one (a) showed that
decomposition started only above 1708C (see the Scheme 1. Coumarin as acyl transfer reagent.
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situ released acyl radical (COR) can be trapped and model substrate to elucidate our concept of redox-
utilized for the o-acylation of directing substrates via neutral o-acylation using acyl-a-peroxycoumarin (a)
a metal-mediated CÀH functionalization process. as the acyl source as well as an internal oxidant.
Thus, the substrate (a) can be envisaged as a redox-
To verify our proposed hypothesis, 2-phenylbenzo-
neutral reagent in a Pd-catalyzed directed o-acylation thiazole (1) and 3-acetyl-3-(tert-butylperoxy)-4-cyclo-
via CÀH activation.
hexylchroman-2-one (a) were reacted in the presence
Various directing groups along with different aroyl of 10 mol% of Pd(OAc) in toluene at 1108C. A new
2
surrogates viz. aldehydes, benzyl alcohols, a-keto product was isolated; spectroscopic analysis of which
acids, benzil derivatives, benzylamines, alkenes, al- showed the presence of a singlet (Me group) at
1
kynes and even inert alkylbenzenes have been em- 2.40 ppm in its H NMR and a peak at 204.0 ppm in
[
4]
13
ployed for ortho-aroylations. The majority of these its C NMR suggesting the incorporation of an acyl
strategies are successful for the synthesis of aryl (aro- (-COMe) group in the product. Further spectroscopic
matic) ketones. However, syntheses of alkyl (aliphat- analysis revealed its structure to be 1-{2-(benzo[d]-
ic) ketones via ligand-directed CÀH activation are thiazol-2-yl)-phenyl}ethanone (1a). The product (1a)
fewer in number. Due to the lower stability of acyl was however obtained in 21% isolated yield (Table 1,
radicals compared to aroyl radicals, they are less ex- entry 1) along with the formation of a by-product (A)
[
3a]
plored towards substrate directed o-acylations. Re- (Scheme 1). The addition of AcOH is reported to
cently, a few aliphatic aldehydes and aliphatic dike- facilitate the homolytic cleavage of organic peroxi-
[
3b]
tones have been employed as the o-acyl sources with des. The yield of product (1a) improved up to 49%
limited examples using a slight excess of oxidant when 0.5 mL (35 equiv.) of AcOH was added to the
[
5]
(
TBHP) in a sealed tube. To avoid the use of excess reaction mixture under otherwise identical conditions
oxidants and specialized reaction conditions, redox- (Table 1, entry 2). To achieve the best yield for this o-
neutral CÀH functionalization strategies have been acylation process, various other reaction parameters
[
6]
developed by various groups. Our group has made such as solvent, catalyst and additives were varied.
significant contributions in the area of directing The use of polar solvents such as 1,4-dioxane (32%),
group-assisted CÀH functionalizations of various di- DMF (0%), and DMSO (0%) under identical reac-
[
7]
recting arenes, specifically 2-arylbenzothiazoles.
tion conditions were not so favourable (Table 1, en-
Therefore, 2-arylbenzothiazole was chosen as the tries 3–5) whereas among the non-polar solvents such
[a]
Table 1. Screening of the reaction conditions.
[b]
Entry
Catalyst (mol%)
Additive
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
Pd(OAc) (10.0)
–
toluene
toluene
dioxane
DMF
DMSO
CyH
21
49
32
0
2
Pd(OAc) (10.0)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
PTSA
TFA
2
Pd(OAc) (10.0)
2
Pd(OAc) (10.0)
2
Pd(OAc) (10.0)
0
2
Pd(OAc) (10.0)
43
38
53
59
63
14
10
31
44
trace
61
64
2
Pd(OAc) (10.0)
DCE
PhCl
2
Pd(OAc) (10.0)
2
Pd(OAc) (10.0)
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
2
10
11
12
13
14
15
16
17
Pd(TFA) (10.0)
2
PdCl (10.0)
2
PdBr (10.0)
2
Pd(TFA) (10.0)
2
Pd(TFA) (10.0)
2
Pd(TFA) (10.0)
PviOH
AcOH
AcOH
2
Pd(TFA) (5.0)
2
Pd(TFA) (15.0)
2
[
a]
Reaction conditions: 2-phenylbenzothiazole (1) (0.25 mmol), (a) (0.25 mmol), additive (0.5 mL, 35 equiv.) and solvent
1 mL) at 1108C for 16 h.
Yields of the isolated pure product.
(
[
b]
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as cyclohexane (43%), DCE (38%), chlorobenzene ferred the acyl group to the ortho position of 2-aryl-
53%) and p-xylene (59%) tested, the later gave the benzothiozles containing electron-donating as well as
(
best yield of o-acylated product (1a) (Table 1, en- electron-withdrawing substituents (Scheme 2). 2-Aryl-
tries 6–9). Furthermore, using p-xylene as the solvent benzothiazoles having weakly electron-donating sub-
and AcOH as an additive various Pd catalysts were stituents such as p-Me (2), p-Et (3) and 2,4-di-Me (4)
assessed. The use of 10 mol% Pd(TFA) was found to provided moderate yields of the desired products (2a,
2
be the best compared to other Pd catalysts such as 67%), (3a, 68%) and (4a, 70%). However, substrates
PdCl (14%) and PdBr (10%) (Table 1, entries 10– possessing strongly electron-donating substituents
2
2
12) tested. Other acid additives, viz. PTSA, TFA and such as p-OMe (5) and 3,4-di-OMe (6) in the 2-aryl
PivOH (Table 1, entries 13–15), screened were found ring of benzothiazole afforded o-acylated products
to be less effective compared to AcOH (Table 1, (5a) and (6a) in 73% and 74% yields, respectively. 2-
entry 10). Furthermore, on reducing the catalyst load- Arylbenzothiazoles having moderately electron-with-
ing from 10 to 5 mol% the yield of the product re- drawing substituents such as p-Cl (7), m-Br (8) and
mained virtually unaltered (61%) (Table 1, entry 16). 2,4-di-F (9) in their 2-aryl rings provided their corre-
A marginal improvement in the yield (64%) was ob- sponding o-acylated products (7a), (8a) and (9a) in
served when the catalyst loading was increased to 60%, 61% and 54% yields, respectively. 2-Arylbenzo-
15 mol% (Table 1, entry 17). Therefore, the acyl thiazoles possessing strongly electron-withdrawing
transfer from acyl-a-peroxycoumarin (a) to the direct- groups such as m-NO and p-CN in their 2-aryl ring
2
ing substrate (1) was best achieved using 5 mol% of failed to provide the desired o-acylated products. This
Pd(TFA) in the presence of additive AcOH (0.5 mL, may be due to the difficulty in electrophilic pallada-
2
35 equiv.) in p-xylene solvent at 1108C (Table 1, tion of the electron-deficient aryl rings. Electron-rich
entry 16). 2-arylbenzothiazoles (2–6) provided better yields of
Delighted by this novel acyl transfer process, we their o-acylated products compared to electron-defi-
further explored its scope with other 2-arylbenzothia- cient 2-arylbenzothiazoles, which is due to the facile
zoles. Acyl-a-peroxycoumarin (a) smoothly trans- electrophilic palladation of electron-rich substrates.
Scheme 2. Scope of the o-acylation of 2-arylbenzothiazoles via group transfer. Reaction conditions: 2-arylbenzothiazoles (1–
10) (0.25 mmol), (a–d) (0.25 mmol), AcOH (0.5 mL, 35 equiv.) in p-xylene (1 mL) at 1108C for 16–24 h. Yields of the isolat-
ed pure products.
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Single regioisomeric products (6a) and (8a) were ob- well investigated 2-arylpyridines (13), (14) and (15)
served at the less sterically hindered ortho position also underwent directed acylation leading to the for-
for meta-substituted benzothiazoles (6) and (8) be- mation of their corresponding o-acylated products
cause of the preferential palladation at these sites.
(13a), (14a) and (15a) in modest yields. Interestingly,
In a pursuit to see whether this methodology is ap- directing arene 2,3-diarylquinoxalines (16) and (17)
plicable for the transfer of other acyl groups, acyl-a- afforded exclusive mono-o-acylated products (16a)
peroxycoumarins possessing a-COEt (b), a-COBu (c) and (17a) in moderate yields (Scheme 3). This
and a-COPh (d) substituents were reacted with ben- method is equally compatible with other directing
zothiazoles (1), (2) and (10) under the optimized reac- groups such as benzo[h]quinoline (18), 3,5-diarylisox-
tion conditions (Scheme 2). Acyl-a-peroxycoumarins azole (19) and 2-arylbenzoxazole (20) demonstrating
(
b) and (c) successfully transfer their acyl groups to the versatility of this acyl transfer process (Scheme 3).
the ortho position of (2) providing acylated products When substrate (1) was treated under the opti-
2b) and (2c) in 52% and 42% yields, respectively. mized reaction conditions in the presence of a stoi-
(
Again, aroyl-a-peroxycoumarin (d) smoothly trans- chiometric amount of radical scavenger (2,2,6,6-tetra-
ferred the aroyl (-COPh) group to substrates (1), (2) methylpiperidine 1-oxyl, TEMPO), the yield of the
and (10) affording their desired o-aroylated products product (1a) remains virtually unaltered. This experi-
(
1d), (2d) and (10d), respectively, in 71%, 77%, and ment confirms the non-radical nature of the acylation
80% yields. The higher yield of product obtained process. So as per our assumption, generation of the
during aroyl group (-COPh) (d) transfer as compared acyl radical from acyl-a-peroxycoumarin (a) is not the
to acyl groups (a–c) is due to the better stability of actual path. The reaction proceeds via initial insertion
the aroyl radical (CCOPh) compared to acyl radicals of Pd(II)-arene complex (I) to the peroxy (OÀO)
(
CCOR).
linkage via an oxidative addition generating species
The scope and generality of this group transfer cum (II). Formation of species (II) was further confirmed
[
8]
o-acylation protocol was further extended to various via the HR-MS analysis of the reaction aliquot (see
nitrogen chelated directing arenes such as, phenoxy- the Supporting Information). In the next step species
pyridine, 2-arylpyridine, 2,3-diarylquinoxaline, 3,5-di- (II) is converted to an acyl-palladium species (III) via
ACHTUNGTRENNUNGa rylisooxazole, benzo[h]quinoline, and 2-phenylben- the expulsion of a hydroxycoumarin (A). The product
zoxazole (Scheme 3). The same optimized reaction (A) has been isolated and its structure was confirmed
conditions when applied to phenoxypyridines (11) by spectroscopic analysis as well as comparison with
[3a]
and (12) afforded their ortho-acylated products (11a) the reported literature data of the compound.
In
and (12a) in 66% and 69% yields, respectively. The the final step o-acylated benzothiazole (1a) was
Scheme 3. Scope of directing arenes in the o-acylation reaction via group transfer. Reaction conditions: directing arenes (11–
0) (0.25 mmol), (a) (0.25 mmol), AcOH (0.5 mL, 35 equiv.) in p-xylene (1 mL) at 1108C for 16–22 h. Yields of the isolated
2
pure products.
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Acknowledgements
B. K. P acknowledges the support of this research by the De-
partment of Science and Technology (DST), New Delhi (SB/
S1/OC-53/2013), MHRD: 5-5/2014-TS-VII and the Council
of Scientific and Industrial Research (CSIR) (02(0096)/12/
EMR-II). A.B. and S.K.S. thank CSIR-New Delhi for fellow-
ships.
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(
0
(
tert-butylperoxy)-4-cyclohexylchroman-2-one
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2
4
The crude product so obtained was purified by silica gel
column chromatography (hexane/ethylacetate, 10:0.3) to
give 1-{2-(benzo[d]thiazol-2-yl)phenyl}ethanone (1a); yield:
38 mg (61%). The identity and purity of the product was
confirmed by spectroscopic analysis.
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Acylperoxycoumarins as ortho-CÀH Acylating Agent via
7
a Palladium(II)-Catalyzed Redox-Neutral Process
Adv. Synth. Catal. 2016, 358, 1 – 7
Prakash Ranjan Mohanta, Arghya Banerjee,
Sourav Kumar Santra, Ahalya Behera, Bhisma K. Patel*
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