Cu(I)-Catalyzed Site Selective Acyloxylation of Indoline Using O2 as the Sole Oxidant

Article abstract of DOI:10.1002/adsc.201800040

A Cu(I)-catalyzed regioselective cross-dehydrogenative coupling of indoline with a variety aryl and alkyl carboxylic acids is described. The divergent process for the oxygenation was achieved in satisfactory yields under additive free conditions, which provides an efficient strategy for the regioselective C7 functionalization of indolines using inexpensive copper catalyst. Oxygen as the sole oxidant is required in this protocol. The method is tolerated by a wide range of functional groups. Preliminary mechanistic study provided support for a reversible C?H bond metallation step. (Figure presented.).

Full text of DOI:10.1002/adsc.201800040

Title: Cu(I)-Catalyzed Site Selective Acyloxylation of Indoline Using O2
as the Sole Oxidant
Authors: Ashfaq Ahmad, Himangsu Sekhar Dutta, Bhutttu Khan, Ruchir
Kant, and Dipankar Koley
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800040
Link to VoR: http://dx.doi.org/10.1002/adsc.201800040

10.1002/adsc.201800040
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Cu(I)-Catalyzed Site Selective Acyloxylation of Indoline Using
O2 as the Sole Oxidant
Ashfaq Ahmad,a Himangsu Sekhar Dutta,a, Bhuttu Khan,a Ruchir Kant,b Dipankar Koley,a, *
a
Medicinal and process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226031, (India)
E-mail: dkoley@cdri.res.in
b
Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, (India)
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201
Abstract.
A
Cu(I)-catalyzed regioselective cross-
environmentally toxic metal complexes. On the
contrary, methods for the corresponding C–O bond
formation is less reported.[6b] During the ongoing
process of our protocol, a rhodium catalyzed method
for C7 acetoxylation of few indoline derivatives was
reported by Deb et al.[6b] However, no other coupling
partner was used except acetic anhydride. Satoh and
Miura also reported a rhodium-catalyzed protocol for
the acetoxylation on the benzenoid moiety of
carbazole and 2-substituted indole derivatives.[5e] The
first use of copper catalyst for the C7
functionalization of indoline has been reported very
recently by Ackermann et al.[9]
dehydrogenative coupling of indoline with a variety aryl
and alkyl carboxylic acids is described. The divergent
process for the oxygenation was achieved in satisfactory
yields under additive free conditions, which provides an
efficient strategy for the regioselective C7 functionalization
of indolines using inexpensive copper catalyst. Oxygen as
the sole oxidant is required in this protocol. The method is
tolerated by a wide range of functional groups. Preliminary
mechanistic study provided support for a reversible C–H
bond metallation step.
Keywords: indole, C‒H functionalization, copper catalysis,
acyloxylation, cross-dehydrogenative coupling
Indole and indoline motifs are considered as
privileged scaffolds by reason of their omnipresence
in numerous biologically active natural products and
pharmaceuticals.[1] Thus, functionalization of indole
and indoline derivatives is in great demand.
Numerous methods for the C–H functionalization of
indole have been reported largely at the C2 and C3
positions because of the inherent reactivity of the
pyrrole ring.[2] However, regioselective C–H
functionalization on the benzenoid ring is relatively
less explored.[3] In particular, despite the
pharmacological significance of C7 functionalized
indoline derivatives,[4] only few protocols for the
regioselective C7 functionalization of indoline have
been reported.[5-9] For examples, second (Ru,[5] Rh,[6]
and Pd[7]) and third row transition (Ir[8]) metal-
catalyzed reactions were reported for arylation,[7b,g,h,l-
Scheme 1. C7 functionalization of indoline/indole.
As a part of our research interest,[10] we argued,
chelation-assisted direct acyloxylation[11] of indoline
with various carboxylic acids would offer two fold
benefits. Firstly, it would illustrate a method for the
direct acyloxylation at the C7 position. Secondly, an
indirect method for the synthesis of C7–OH would be
established. In addition, if the cross-dehydrogenative
coupling could be executed through copper
catalysis,[12] a practical and environmentally benign
method for C7 functionalization would be obtained.
To the best of our knowledge, no copper-catalyzed
n]
acylation,[5a,d,7a,d,f]
alkylation,[5c,6e,k,p,7c,k,8d-e]
alkenylation,[6a,h,i,m-o,t,u,7e,i,j,8b,c]
thioarylation,[6l]
allylation,[6r-s]
amination,[5b,f,g,6d,f,g,j,8a,f]
selenoarylation,[6l]
cyanation,[6q]
trifluoromethylation[6c], and acetoxylation[5e,6b] at the
C7 position of indolines (Scheme 1). However, these
methods mostly deal with the formation of C–C and
C–N bonds besides the use of expensive and
1
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10.1002/adsc.201800040
Advanced Synthesis & Catalysis
16). External oxidant also led to lower reaction yield
(entry 17). When 2a was replaced by sodium
benzoate, no product was isolated (entry 18). The
yield could not be further improved by either
increasing or decreasing the amount of benzoic acid
(entries 19‒21).
hydroxylation/acyloxylation method for the C7
functionalization of indoline has been reported.
Herein, we describe a first ever method for the C7
acyloxylation to indoline via copper catalysis.
Table 1. Screening of acyloxylation conditionsa.
Table 2. Scope of the acyloxylation reactiona
entry catalyst solvent
Additives
(equiv)
2a
(equiv) (%)
Yield[b]
1[c] Cu(OAc)2 CH3CN ---
2.0
2.0
---
traces
2
3
4
5
6
7
8
9
Cu(OAc)2 CH3CN ---
Cu(OAc)2 CH3CN ---
58
12[d]
---
CuCl2
CuBr2
CH3CN ---
CH3CN ---
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
---
39
trace
84
51
---
trace
16
25
65
---
72
26
---
62
70
71
Cu(acac)2 CH3CN ---
CuO
Cu2O
CuCl
CH3CN ---
CH3CN ---
CH3CN ---
CH3CN ---
10 CuBr
11 CuOAc CH3CN ---
aReactions conditions: 0.25 mmol of 1a, 2.0 equiv. of 2b-z,
2aa-bb, 2 mL of solvent, O2, 130 ºC, isolated yields.
12 Cu2O
13 Cu2O
14 Cu2O
15 Cu2O
16 Cu2O
17 Cu2O
18 Cu2O
19 Cu2O
20 Cu2O
21 Cu2O
PhCN
DMF
DCE
---
---
---
CH3CN Na2CO3 (2.0) 2.0
CH3CN PivOH (0.2) 2.0
CH3CN Ag2O (2.0) 2.0
CH3CN NaOBz (2.0) ---
CH3CN ---
CH3CN ---
CH3CN ---
The structure of 3aa was unambiguously
confirmed by X-ray analysis.
3.0
2.5
1.7
aReactions conditions: 0.25 mmol of 1a, 2.0 equiv. of 2a, 2
c
mL of solvent, O2, 130 ºC. bIsolated yield. in the presence
of air. dacetoxylated product.
Figure 1: ORTEP diagram with 30% ellipsoid probability
for non-H atoms of the crystal structure of 3aa
In the model reaction, a mixture of indoline
pyrimidine (1a), benzoic acid (2a) and Cu(OAc)2 in
CH3CN was heated at 130 °C (Table 1). Only traces
amount of product was detected in the presence of air
(entry 1), while in the presence of oxygen the desired
product 3aa was isolated in 58% yield (entry 2).
Notably, no acetoxylated product was observed.
However, 12% of acetoxylated product was isolated
in the absence of benzoic acid (entry 3). We then
screened various Cu(II) catalysts. However, none of
the catalysts provided better yield. (entries 4‒7).
Therefore, various Cu(I) catalysts were screened
(entries 8‒11). Cu2O was found to be the best and
yielded 3aa in 84% yield (entry 8). Other solvents
like benzonitrile (entry 12), DMF (entry 13), 1,2-
dichloroethane (entry 14) were less productive.
Addition of Na2CO3 as basic additive completely
stopped the reaction (entry 15). Although acidic
additive (pivalic acid, 20 mol%) yielded 3aa, a
detrimental effect on the yield was observed (entry
With the optimized reaction conditions in hand, the
scope and limitation of the protocol were tested with
respect to benzoic acid derivatives (Scheme 2). To
our delight, a wide range of benzoic acids containing
different functional groups (alkyl, fluoro, chloro,
bromo, iodo, ethoxy, nitro) were well tolerated in this
transformastion. Yields of the para-substituted
derivatives (3ai, 3am, 3an) were better than the
corresponding ortho-substituted derivatives (3ab, 3ad,
3ae). Benzoic acids bearing electron-donating groups
(methyl, isopropyl, ethoxyl) yielded the products in
good yields (3ab, 3aj, 3ak). Good yields were
obtained for the benzoic acids (3ac–3af, 3ah, 3al–
3an) having halogen substituents (fluoro, chloro,
bromo, iodo, trofluoromethyl). However, 4-
nitrobenzoic acid furnished the product (3ao) in
moderate yield. We next examined various
heteroaromatic carboxylic acids as coupling partner
(Scheme 2). Delightfully, pyrrole- (3ap), furan- (3aq),
2
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10.1002/adsc.201800040
Advanced Synthesis & Catalysis
benzofuran- (3as) and thiophene- (3ar) derived
carboxylic acids were very well tolerated.
Unfortunately, pyridine derived carboxylic acid
derivatives (2-picolinic acid, nicotinic acid and
isonicotinic acid) did not furnish any desired product
(data not shown). Possibly, due to the preferable
coordination of copper with the pyridyl group and
formation of a stable copper-pyridine complex does
not further allow copper to coordinate with the
nitrogen of pyrimidine ring. We also tested various
cinnamic acid derivatives (3at‒3ax), which furnished
the products with moderate yields. Various aliphatic
carboxylic acids also reacted, but the desired products
(3ay, 3az, 3aaa, 3abb) were obtained in moderate
yields (35–55%) in general. Neither prolonged
heating, nor the increase in equivalence of carboxylic
acid derivatives improved the yields. Most of the
cases, the unreacted starting material (1a) was
recovered.
Table 3. Scope of the acyloxylation reactiona
Various control experiments were conducted to
understand the mechanistic pathway (Scheme 4).
Under the typical radical scavenger experiment
(Scheme 4a), 3aa was isolated in 65% (with 1 equiv
of TEMPO), 65% (with 2 equiv of TEMPO), 64%
(with 3 equiv of TEMPO), and 60 % (with 1 equiv of
BHT) yields, suggesting a non-radical mediated
reaction
pathway.
Significant
deuterium
incorporation (90%) was observed at the C7 position
when CD3OD was used as a co-solvent (Scheme 4b),
indicating an involvement of reversible C–H bond
cleavage.[9] In sharp contrast, no deuterium
incorporation was observed in the absence of benzoic
acid (Scheme 4c), suggesting the requirement of
carboxylate as a suitable ligand for the facile C–H
activation. Thus, without benzoic acid, 20 mol% of
Cu(OBz)2 could catalyze the H-D isotope scrambling
process (Scheme 4d). Competitive Control
experiments (Scheme 4e and 4f) revealed that
formation of the products from electronically rich
indolines and benzoic acids are kinetically favoured
than the electronically poor substrates.
Based on the preliminary experimental data and
literature,[9,11c,12] we propose a plausible reaction
pathway for the developed protocol (Scheme 2). First,
the active catalyst generated by the oxidation of Cu2O
coordinates with 1a to form intermediate A which
subsequently facilitates reversible C–H bond
cleavage for the generation of cyclometalated Cu(II)
intermediate B. A typical disproportionation reaction
of Cu(II) ion generates highly active Cu(III)
intermediate C which follows a reductive elimination
process to liberate the product 3aa and Cu(I)OBz.
Subsequently, regeneration of active catalyst occurs
via oxidation of Cu(I)OBz by oxygen.
aReactions conditions: 0.25 mmol of 1b-p, 2.0 equiv. of 2a,
2 mL of solvent, O2, 130 ºC, isolated yields.
Next various indolines were tested (Scheme 3).
While the benzenoid ring bearing electron donating
substituents furnished the desired products (3ga and
3ha) in very good yields, no products were obtained
in case of strong electron withdrawing substituents
(3ma and 3oa). Gratifyingly, alkyl (3ba, 3da, 3ea)
and aryl (3ca) substituted indolines afforded the
products in very good yields. Fluoro (3ia), chloro
(3ja), bromo (3fa, 3ka) and iodo (3la) substituted
indolines also furnished the desired products in very
good yields. This opens for the possibility of further
functionalization of the indoline derivatives.
Unfortunately, C6 substituted derivatives (3na, 3oa)
did not furnish any product.
Table 4. Control experiments for mechanistic aspect
3
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10.1002/adsc.201800040
Advanced Synthesis & Catalysis
And the reaction mixture was kept at a pre-heated oil-bath
(130 ˚C) for 18 hours. After completion of the reaction, the
reaction mixture was quenched with saturated solution of
sodium bicarbonate. The reaction mixture was extracted
with ethyl acetate (2 x 15 mL) and the organic layer was
washed with brine solution followed by drying over
anhydrous Na2SO4. The organic layer was evaporated via
rotavapor and crude mixture was purified by silica gel
column chromatography to yield the corresponding
acyloxylated product.
CCDC-1587464
contains
the
supplementary
crystallographic data for compound 3aa reported in this
paper. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Scheme 2. Proposed reaction pathway
Acknowledgements
Financial support from DST-SERB (EMR/2016/000613), CSIR-
New Delhi (A. A., H. S. D.), and UGC-New Delhi (B. K.) is
gratefully acknowledged. We thank Dr. Tejender S. Thakur, MSB
division, CSIR-CDRI, for supervising the X-ray data collection
and structure determination. We thank the CDRI SAIF division
for analytical support. CDRI Communication No. xxxx.
We next demonstrated the usefulness of the
developed C–H acyloxylation process (Scheme 3).
Indoline (3aa) was very easily oxidized to indole in
92% yield. Further, the 7-hydroxy indole (5 and 6)
was obtained in excellent yield. Finally, an
intramolecular Heck reaction[13] was conducted to
convert 3af into indoloisochromenone scaffold.
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examples
of
C2-selective
C−H
In conclusion, an operationally simple protocol for
the C7 acyloxylation of indolines was achieved via
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carboxylic acid using inexpensive copper catalyst. A
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Experimental Section
To a solution of indoline pyrimidine (0.25 mmol) in
acetonitrile (2 mL), Cu2O (7.25 mg, 20 mol%) and
carboxylic acid (0.50 mmol, 2 equiv.) was added in sealed
tube vial and O2 was purged in the solution for 30 min.
4
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10.1002/adsc.201800040
Advanced Synthesis & Catalysis
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10.1002/adsc.201800040
Advanced Synthesis & Catalysis
COMMUNICATION
Cu(I)-Catalyzed Site
Selective Acyloxylation
of Indoline Using O2 as
the Sole Oxidant
Adv. Synth. Catal.
Year, Volume,
Page – Page
Ashfaq Ahmad,
Himangsu Sekhar Dutta,
Bhuttu Khan, Ruchir
Kant, Dipankar Koley*
7
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