Cp*Co(III)-Catalyzed Ketone-Directed ortho-C-H Activation for the Synthesis of Indene Derivatives

Article abstract of DOI:10.1021/acs.joc.0c00727

A weakly coordinating, carbonyl-assisted C-H activation of aromatic systems with α,β-unsaturated ketone and subsequent aldol condensation has been developed using a Cp*Co(CO)I2 catalyst. The developed method is the first example of indene synthesis by cobalt-catalyzed C-H activation. In addition, the reaction requires mild reaction conditions and easily accessible starting materials, and it shows excellent functional group compatibility.

Full text of DOI:10.1021/acs.joc.0c00727

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Note
Cp*Co(III) Catalyzed Ketone Directed Ortho C-
H Activation for Synthesis of Indene Derivatives
Dattatraya Hanumant Dethe, Nagabhushana C B, and Arsheed Ahmad Bhat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00727 • Publication Date (Web): 04 May 2020
Downloaded from pubs.acs.org on May 4, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Cp*Co(III) Catalyzed Ketone Directed Ortho C-H Activation
for Synthesis of Indene Derivatives
Dattatraya H. Dethe*, Nagabhushana C B$, Arsheed Ahmad Bhat$
9
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Abstract: A weakly coordinating, carbonyl assisted C-H activation of aromatic systems with α, β-unsaturated
ketone and subsequent aldol condensation has been developed using Cp*Co(CO)I2 catalyst. The developed
method is first example of indene synthesis by cobalt catalysed C-H activation. In addition, the reaction requires
mild reaction conditions, easily accessible starting materials, and it shows excellent functional group
compatibility.
Indenes are important class of carbocyclic derivatives and are often found as basic units in a variety of naturally
occurring molecules.1 Several methods have been developed for synthesis of indenes due to their synthetic and
biological importance in organic chemistry and pharmaceutical science (e.g. antimicrobial, antiviral, antifungal
and anticancer activities).1,2 In addition, indenes possess diverse applications in the field of material science3 and
have also been used as ligands for transition metal complexes in polymerization techniques.4 Due to synthetic
and biological importance of such carbocylic system, indenes have drawn much attention of various research
groups for developing novel synthetic methods and their applications to the natural product synthesis.5-8 Our
group has also described a convenient approach for synthesis of highly substituted indenes by Lewis acid
catalysed cyclization.5,9 From past two decades, directing group assisted transition metal catalysed C-H
functionalization of aromatic compounds has been very well established and its synthetic utility in the organic
chemistry is also well documented.10 Initially, contribution of second and third-row transition metals such as Rh,
Ru, Ir, and Pd to these transition metal-catalysed C-H bond functionalizations is enormous but also constitute
severe drawbacks for streamlined applications due to their toxicity, low natural abundance and sky-rocketting
prices.11 In recent years, there is a momentum for developing similar reactions using first row transition metals
due to their low toxicity, high natural abundance, easy availability and low cost.12 Especially, cobalt catalysed
C-H bond functionalization has been explored with a variety of N-heteroaryl directing groups as well as other
directing groups such as ketones, esters, amides, etc.13 Also, weakly coordinating carbonyl directed C-H
activation reactions have enormously enhanced the application of ketones in synthetic chemistry.14 As ofinterest,
C-H alkylation of ketones has been well established since Murai's report15 but metal catalysed ketone directed
ortho C-H olefination of aromatic systems are very few.16 Similarly, various methods have been developed for
synthesis of indenes via transition metal catalysed ortho-C-H activation and subsequent tandem cyclization.17In
1999, Nicholson and Woodgate reported the synthesis of indene derivatives via stoichiometric
cyclomanganation of aromatic ketones followed by olefination in the presence of Pd as a co-catalyst.18
Similarly, Takai group demonstrated that indenes can be efficiently derived from annulation of aromatic ketones
and α, β-unsaturated esters via rhenium catalysed C-H activation (scheme 1a).19 A rhodium catalysed
carbocyclization of aryl ketones and alkynes for the synthesis of indenols was described by Cheng et al (scheme
1b).20 In 2013, Li and coworkers developed a rhodium-catalyzed cascade cyclization of aromatic ketones with α,
β-unsaturated carbonyl compounds (scheme 1c).21 Although, rhodium catalysed reactions are admirable due to
their high catalytic activity, air and thermal stability and decent functional group compatibility but above
reactions are associated with harsh reaction conditions (temperature 130-180 oC), use of precious metal with less
natural abundance, high cost and are toxicity. Therefore, the development of sustainable, efficient and
straightforward method for the synthesis of indene derivatives using earth abundant metal catalysts thus remains
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 16
1
2
3
4
5
6
highly desirable. Hence aiming the synthesis of indene derivatives in efficient way, Cp*Co(III)-catalysed
weakly coordinating ketone directed ortho C-H bond functionalization of aromatic systems with α, β-
unsaturated ketone and subsequent aldol condensation has been developed (scheme 2).
7
8
Scheme 1: Previous reports
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2: This work
To evaluate feasibility of our reaction, 4-methoxy acetophenone 1a was selected as a model substrate (Table 1).
When acetophenone 1a (1 equiv.) was treated with methyl vinyl ketone 2a (1.1 equiv.) in presence of
Cp*Co(CO)I2 (C1) (5 mol%) catalyst, AgSbF6 (15 mol%) as an additive and Cu(OAc)2.H2O (1 equiv.,) in 1,2-
dichloroethane at 60 oC for 8 h, incomplete reaction provided cyclised indene product 3a along with ortho C-H
alkenylated product 3a' in 35% and 20% yield respectively. To elevate the reaction efficacy, catalytic reaction
was tested in various solvents such as 1,2-dichloroethane, dichloromethane, t-AmOH, acetonitrile, NMP,
trifluoroethanol, DMF and DMSO (entry 3-8). Dichloromethane delivered desired product with 25% yield and
other polar solvents satisfied by producing yield in the range of 15 to 33% (entry 3-5). Highly polar solvents
such as DMF and DMSO failed in generating the required product under same conditions (entry 7-8). To our
o
delight, the reaction yield was drastically increased to 84%, when reaction was carried out at 80 C for 16 h,
(entry 9). It was found that no reaction occurred in the absence of AgSbF6 and Cu(OAc)2.H2O (entry 10 & 11)
and also replacement of Cu(OAc)2.H2O with KOAc and AgOAc generated small amount of product 3a in 12%
and 10% yield respectively (entry 12 & 13). The catalytic reaction was screened with various additives such as
NH4PF6, AgOAc and Ag2CO3 (entry 14-16). Among a set of catalytic additives, NH4PF6 acts as a competent
additive for this reaction (entry 14) and other additives failed to enable desired transformations.The optimization
of this catalytic conditions was also carried out using different catalysts such as [RuCl2(p-cymene)]2 (C2) and
[(C5H5)Ru(CH3CN)3]PF6 (C3) under same reaction conditions of entry 9. It was observed that, reaction proceeds
successfully in terms of yield (79%) and reaction rate in presence of catalyst C2. After performing the reaction
under several parameters, we decided to explore the scope of substrates under most efficient condition i.e., entry
9.
ACS Paragon Plus Environment

Page 3 of 16
The Journal of Organic Chemistry
1
2
3
4
Table 1. Optimization of Reaction Conditionsa
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
Solvent
Additive
Oxidant
hYield(%)
(3a/3a')
1
2
DCE
DCM
t-AmOH
NMP
TFE
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
-
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
AgOAc
35/20
25/0
20/0
15/0
33/0
Trace
-
3
4
5
6
CH3CN
DMF
DMSO
DCE
7
8
-
9b
10c
11d
12
13
14
15
16
17e
18f
19g
84/0
16/Trace
-
DCE
DCE
AgSbF6
AgSbF6
AgSbF6
NH4PF6
AgOAc
Ag2CO3
AgSbF6
AgSbF6
AgSbF6
-
DCE
KOAc
12/Trace
10/Trace
60/Trace
Trace/0
-
DCE
AgOAc
DCE
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2.H2O
DCE
DCE
DCE
79/0
-
DCE
DCE
55/0
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), Cp*Co(CO)I2
o
(5 mol %), additive (15 mol %) and oxidant (1 equiv.) at 60 C in a
specific solvent (2.5 mL), under argon, 8 h. bThe reaction was
performed at 80 oC for 16h. cThe reaction was performed without
AgSbF6. The reaction was performed withoutCu(OAc)2.H2O. e-fThe
d
reaction was performed using [RuCl2(p-cymene)]2 (C2) and
[(C5H5)Ru(CH3CN)3]PF6 (C3) in place of Cp*Co(CO)I2(C1)
respectively.gThe reaction was performed using0.5 equiv., of
Cu(OAc)2.H2O.hIsolated yields are of product 3a and 3a'.
With the optimized conditions in hand, we sought to investigate the generality of the cyclization reaction with
respect to various acetophenone derivatives using methyl vinyl ketone as a enone source (Scheme 3). It was
found that, reactivity of different ketones was varied significantly with respect to substituents. The results
showed that 84% yield was obtained fromelectron rich 4'-methoxy acetophenone and methyl vinyl ketone (3a).
A sudden decrease of yield (65%) was observed in case of electron poor 4'-chloroacetophenone 3b. Similarly
various alkyl and alkoxy substituted acetophenones reacted well to afford desired productsin moderate to good
yields. A simple 2'-methyl acetophenone and fluoro substituted acetophenone generated cyclised product 3c and
3din 68% and 60% yield respectively. Based on their electron density, electron rich methoxy substituted
acetophenones responded well for the cyclization reaction to generatecorresponding indene derivatives in good
to very good yields (3e-3h). Interestingly, sterically crowded benzophenone and 2-phenylacetophenone showed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 16
1
2
3
4
5
6
7
8
9
their viability towards cascade reaction without much change in yield (3i, 70% and 3j, 68%). Notably, 1-
acetonaphthone was also effective in providing expected product 3k in 65% yield. 1-tetralone afforded
corresponding indene derivative 3l in 58% yield. On the other hand, meta substituted acetophenones reacted
smoothly and delivered desired product with higher yields. But non-symmetrical meta substituted
acetophenones are expected to afford two regioisomers due to the presence of two possible C-H bond activation
sites: at C2 and C6. The results clearly accounts the role of electronic effect, m-chloroacetophenone provided
both the possible product (3m1 & 3m2) but activation at the electron rich C6 position was more prominent than
sterically hindered electron deficient site C2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Reaction of vinyl ketones with various acetophenones
a
Reaction conditions: 1 (0.30 mmol, 1 equiv.), 2 (0.33 mmol, 1.1 equiv.), Cp*Co(CO)I2 (5 mol%), AgSbF6 (15 mol %) and Cu(OAc)2.H2O
(1 equiv.) at 80 °C in 1,2-DCE (3.0 ml), under argon for 16 h.b1.1 equivalent of 2 was used. cIsolated yields are of product 3.
Similarly, substrate scope of various acetophenones were explored with respected to ethyl vinyl ketone. Without
aid of any electronic effect, simple acetophenone and propiophenone generated corresponding indene
derivatives 3n and 3o in good yields 65% and 62% respectively. It is noteworthy to mention that when scale up
reaction was performed using acetophenone (1.2 g, 10 mmol), similar results were obtained in terms of
ACS Paragon Plus Environment

Page 5 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reactivity and yield (1.3 g, 69 %). 4'-methyl and ethyl acetophenone delivered cyclised products in good yield
(3p & 3q). Also methoxy substituted highly electron rich acetophenones gave relevant product with excellent
yields in the range of 75 - 84% (3r-3v). It is very important to mention that, in case of 3r other isomer was also
formed in trace amount due to efficient activation occured at the sterically more hindered C2 position rather than
C6, which again clarifies that the reaction occurs mainly under electronic control instead of steric control. Weak
electron withdrawing substituents on the acetophenone ring led to a relatively lower efficiency, tolerance of
halides offers the opportunity for further functionalization (3w and 3x). Similarly, electron-rich 3',4'-dimethoxy
acetophenone gave electronically favoured products 3y1 and 3y2 in 75% and 70% yield respectively along with
trace amount of other regioisomer.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Deuterium Labelling Study and Kinetic Isotopic Effect (KIE) Study, Competition Experiment
In order to understand the catalyst’s mode of action, we performed multiple deuterium labelled study (scheme
4). First, C-H activation reaction was carried out to determine the reversibility of the C−H activation/metalation
step. In presence of CD3CO2D, the reaction yielded 70% of ortho-deuteration and also D5-acetophenone
afforded 50% of the ortho-deuteration when reaction was conducted under standard conditions (scheme 4a-4b).
This significant amount of deuteration scrambling at the ortho-position of the recovered starting material clearly
indicated that the C-H activation step was reversible. Also 20% of deuterium trapping at the α-position of the
carbonyl group could be attributed to the deuteration via keto-enol tautomerization. When D5-acetophenone was
subjected for cascade reaction with methyl vinyl ketone 1a, corresponding indene derivative (4a-D4) was
formed without containing any deuterium in the newly formed five membered ring (scheme 4c). A Kinetic
isotopic value of kH/kD 2.5 was obtained from intermolecular competition experiment indicated thatC-H
metalation was the rate determining step (scheme 4d). To determine the effect of substituents on the rate of
transformation, competitive reactions were conducted for electron-rich (1a) and electron-deficient (1b)
acetophenones. Electron-rich acetophenone reacted more efficiently with a reactivity difference of almost
1.0/0.71 ratio providing strong support to BIES (Base assisted Internal Electrophilic Substitution) regime
(scheme 4e).22
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 16
1
2
3
4
5
6
7
8
9
Based on kinetic studies and previous reports, the possible mechanism for cobalt catalysed cascade cyclization
is as depicted in scheme 5. The catalytic cycle is initiated by weakly coordinating ketone directed C-H
activation of acetophenone (B) under the influence of in situ generated active cobalt(III) species (A) which leads
to the formation of five membered cyclometalated species (C). Coordination followed by 1,4-addition of
arylcobalt species to the activated olefin of enone (D) would generate cobalt oxa-π species (F) which would
further undergo intramolecular aldol condensation to generate indene product (G) along with active cobalt
species in presence of Cu(OAc)2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Plausible Mechanism
In summary, a mild and modular route for synthesis of indenes was developed using weakly coordinating
carbonyl directed ortho-C-H bond functionalization of aromatic systems with activated olefins followed by
concomitant aldol condensation, using naturally abundant and less expensive cobalt catalyst.
EXPERIMENTAL SECTION
General Aspects: Experiments involving moisture and air sensitive components were performed in oven-dried
glassware. Commercial solvents and reagents were used without further purification unless otherwise noted. All
the chemicals were purchased commerciallyand are used without further purification. Yields refer to
chromatographically pure compounds, unless otherwise stated. Reactions were monitored by thin-layer
chromatography (TLC) carried out on 0.25 mm Merck silica gel plates (60F-254) using UV light as a
visualizing agent and an p-anisaldehyde or ninhydrine stain, and heat as developing agents. Merck silica gel
(particle size 100-200 and 230-400 mesh) was used for flash column chromatography. Neat compounds were
used for record IR spectra. NMR spectra were recorded on either a Bruker Avance 400 (1H, 400 MHz; 13C, 100
MHz), Bruker Avance 500 ( 1H, 500 MHz; 13C, 125 MHz), or JEOL DELTA (ECX) 500 (1H, 500 MHz; 13C,
125 MHz). Mass spectrometric data were obtained using WATERS-Q-Tof-Premier-HAB213 and WATERS-
QTof-Premier-ESI-MS instruments. Melting points measurements were made using a hot stage apparatus.
Optical rotations were measured using a polarimeter (AUTOPOL II) at 28 °C. The following abbreviations were
used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, spt= septet, dd = doublet of
doublet, ddd = doublet of a doublet of a doublet, dt = doublet of a triplet, td = triplet of a doublet, m = multiplet,
br = broad.
General Procedure for Ortho Alkenylation and Subsequent Aldol Condensation reaction between
aromatic ketones and α,β-unsaturated ketones.
ACS Paragon Plus Environment

Page 7 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A 8 mL screw-cap vial was charged with Cp*Co(CO)I2 (8 mg, 0.015 mmol, 5.0 mol%), Cu(OAc)2·H2O (60 mg,
0.3 mmol, 1.0 equiv), AgSbF6 (16 mg, 0.045 mmol, 15 mol%) in1,2-dichloroethane (3 mL) stirred for 5 minutes
at room temperature under nitrogen atmosphere. Then aromatic ketone (0.3 mmol, 1.0 equiv) and α,β-
unsaturated ketone (0.33 mmol, 1.1 equiv) were added into the solution in sequence and the vial was sealed
under N2 and heated to 80oC with stirring for 16h (using oil bath). After cooling down, the mixture was diluted
with ethyl acetate, filtrated and concentrated to give the crude compound which was directly purified by column
chromatography. [Note: All aromatic ketones were purchased from sigma aldrich, alfa easer, combi-blocks and
both methyl and ethyl vinyl ketones from sigma Aldrich].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Gram scale synthesis:
A 100 mL screw-cap vial was charged with Cp*Co(CO)I2 (238 mg, 0.5 mmol, 5.0 mol%), Cu(OAc)2·H2O (2.0
g, 10 mmol, 1.0 equiv), AgSbF6 (411 mg, 1.2 mmol, 12 mol%) in1,2-dichloroethane (30mL) stirred for 5
minutes at room temperature under nitrogen atmosphere. Then actophenone (1.2 g, 10 mmol, 1.0 equiv) and
ethyl vinyl ketone (1.1 ml, 11 mmol, 1.1equiv, density = 0.841 g/mL) were added into the solution in sequence
and the vial was sealed under N2 and heated to 80oC with stirring for 16h (using oil bath). After cooling down,
the mixture was diluted with ethyl acetate, filtrated and concentrated to give the crude compound which was
directly purified by column chromatography to obtain pure product 3n (1.3 g, 6.9 mmol, 69 %).
Deuterium Labelling Studies:
For scheme 4a:A 8 mL screw-cap vial was charged with Cp*Co(CO)I2(10 mg, 0.020 mmol, 5.0 mol%),
anhydrous Cu(OAc)2 (75mg, 0.416 mmol, 1.0 equiv), AgSbF6(22 mg, 0.062 mmol, 15 mol%) in CD3CO2D :
1,2-dichloroethane (0.3 : 2.7 = 3 mL) stirred for 5 minutes at room temperature under nitrogen atmosphere .
Then acetophenone 1n( 50mg, 0.416 mmol, 1.0 equiv) was added into the solution and the vial was sealed under
N2 and heated to 80oC with stirring for 16h. After cooling down, the mixture was diluted with ethyl acetate,
filtrated and concentrated to give the crude compound which was directly purified by column chromatography
1
to afford corresponding ortho and α-deuterated acetophenone. H NMR analysis revealed more than 70% of
ortho-deuteration and 20% deuteration at the α-position occurred in compound 1n.
For scheme 4b:A 8 mL screw-cap vial was charged with Cp*Co(CO)I2(10 mg, 0.020 mmol, 5.0 mol%),
Cu(OAc)2 (80 mg, 0.416 mmol, 1.0 equiv), AgSbF6(20 mg, 0.062 mmol, 15 mol%) in 1,2-dichloroethane ( 3
mL) stirred for 5 minutes at room temperature under nitrogen atmosphere. Then D5-acetophenone (1n-D5) ( 50
mg, 0.416 mmol, 1.0 equiv) was added into the solution and the vial was sealed under N2 and heated to 80oC
with stirring for 16h. After cooling down, the mixture was diluted with ethyl acetate, filtrated and concentrated
to give the crude compound which was directly purified by column chromatography to afford corresponding
ortho protonated acetophenone of 1n-D5. 1H NMR analysis revealed more than 50% of ortho-D/H
exchangeoccurred in compound 1n-D5.
For scheme 4c:A 8 mL screw-cap vial was charged with Cp*Co(CO)I2(10 mg, 0.020 mmol, 5.0 mol%),
Cu(OAc)2 (80 mg, 0.416 mmol, 1.0 equiv), AgSbF6(20 mg, 0.062 mmol, 15 mol%) in 1,2-dichloroethane (3
mL) stirred for 5 minutes at room temperature under nitrogen atmosphere . Then D5-acetophenone (1n-D5) (50
mg, 0.416 mmol, 1.0 equiv) and methylvinylketone2a (30 mg, 0.42 mmol, 1.1equiv) were added into the
solution and the vial was sealed under N2 and heated to 80oC with stirring for 16h. After cooling down, the
mixture was diluted with ethyl acetate, filtrated and concentrated to give the crude compound which was
directly purified by column chromatography to afford corresponding indene derivative 3n-D4 and also more
than 19% of ortho-D/H exchange was confirmed by1H NMR analysis.
For scheme 4d (KIE experiment):A 8 mL screw-cap vial was charged with Cp*Co(CO)I2(10 mg, 0.020 mmol,
5.0 mol%), Cu(OAc)2 (80 mg, 0.416 mmol, 1.0 equiv), AgSbF6(20 mg, 0.062 mmol, 15 mol%) in 1,2-
dichloroethane (3 mL) stirred for 5 minutes at room temperature under nitrogen atmosphere. Then acetophenone
1n (20 mg, 0.20 mmol, 0.5 equiv.,), D5-acetophenone (1n-D5) (25 mg, 0.20 mmol, 0.5 equiv.,) and
methylvinylketone2a (32 mg, 0.42 mmol, 1.1equiv) were added into the solution and the vial was sealed under
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 16
1
2
3
4
5
6
7
N2 and heated to 80oC with stirring for 3h (almost 1/4 th conversion). After cooling down, the mixture was
diluted with ethyl acetate, filtrated and concentrated to give the crude compound which was directly purified by
column chromatography to afford corresponding mixture of indene derivatives3n and 3n-D4 were isolated
together. The ratio of 3n and 3n-D4 was determined by 1H NMR analysis to obtain a KIE value greater than 2.5.
8
9
For scheme 4e (Competition Experiment):A 8 mL screw-cap vial was charged with Cp*Co(CO)I2 (8 mg,
0.016 mmol, 5.0 mol%), Cu(OAc)2·H2O (66 mg, 0.33 mmol, 1.0 equiv), AgSbF6 (17 mg, 0.049 mmol, 15
mol%) in1,2-dichloroethane (3 mL) stirred for 5 minutes at room temperature under nitrogen atmosphere. Then
4-methoxyacetophenone 1a(25mg, 0.16 mmol, 0.5 equiv), 4-chloro acetophenone 1b (26 mg, 0.16 mmol, 0.5
equiv) andmethylvinyl ketone2a (26mg, 0.36 mmol, 1.1equiv) were added into the solution in sequence and the
vial was sealed under N2 and heated to 80oC with stirring for 16h. After cooling down, the mixture was diluted
with ethyl acetate, filtrated and concentrated to give the crude compound which was directly purified by column
chromatography to afford corresponding mixture of indene derivatives3a and 3b were isolated together. The
ratio of 3a:3b= 1:0.71 is being calculated by 1H NMR analysis.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(6-methoxy-3-methyl-1H-inden-2-yl) ethanone (3a)
Following general procedure, 3a was obtained as a white solid (51 mg, 0.252 mmol, 84%) (EtOAc : Pet ether =
1
2:8). H NMR (500 MHz, CDCl3): δ7.42 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6.92 (dd, J = 2.6, 8.3
Hz, 1H), 3.85 (s, 3H), 3.65 (d, J = 2.3 Hz, 2H), 2.52 (t, J = 2.6 Hz, 3H), 2.42 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ196.4, 160.7, 150.5, 145.6, 138.7, 136.1, 122.6, 113.3, 109.7, 55.6, 39.2, 30.3, 13.3. HRMS (ESI)
m/z: [M+H]+calcd. for C13H14O2 203.1072; found 203.1078. IR (neat): vmax/cm-1 2922, 2850, 1657, 1557, 1430,
1376, 1228, 1030.
1-(6-chloro-3-methyl-1H-inden-2-yl) ethanone (3b)
Following general procedure, 3b was obtained as a yellow oil (40 mg, 0.195 mmol, 65%) (EtOAc : Pet ether =
1:9).1H NMR (500 MHz, CDCl3): δ7.46 - 7.39 (m, 2H), 7.36 - 7.31 (m, 1H), 3.68 - 3.63 (m, 2H), 2.53 - 2.49
(m, 3H), 2.43 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ196.6, 149.1, 144.7, 144.1, 138.0, 134.3, 127.3,
124.5, 122.6, 39.1, 30.3, 13.1. HRMS (ESI) m/z: [M+H]+calcd. for C12H11ClO207.0577; found 207.0579. IR
(neat): vmax/cm-1 2921, 2851, 1666,1650, 1558, 1358,1184, 887, 817.
1-(3, 4-dimethyl-1H-inden-2-yl) ethanone (3c)
Following general procedure, 3c was obtained as a white solid (35 mg, 0.18 mmol, 63%) (EtOAc : Pet ether =
1:9).1H NMR (400 MHz, CDCl3): δ7.32 - 7.30 (d, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.3 Hz, 1H), 3.65
(d, J = 3.1 Hz, 2H), 2.75 (t, J = 2.4 Hz, 3H), 2.65 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3):
δ197.5, 152.5, 144.0, 143.1, 137.4, 134.5, 130.0, 127.9, 122.0, 39.6, 30.6, 21.0, 16.6. HRMS (ESI) m/z:
[M+H]+calcd. for C13H14O187.1123; found 187.1123. IR (neat): vmax/cm-1 2923, 2852, 1662, 1557, 1373, 1234,
1191, 958, 765.
1-(4-fluoro-3, 7-dimethyl-1H-inden-2-yl) ethanone (3d)
Following general procedure, 3d was obtained as a colourless liquid (37 mg, 0.180 mmol, 60%) (EtOAc : Pet
ether = 1:9).1H NMR (500 MHz, CDCl3): δ 7.31 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 9.2 Hz, 1H), 3.63 (br. s., 2H),
2.51 (s, 3 H), 2.42 (s, 3H), 2.33 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ196.5, 163.0, 161.1, 149.7, 142.7,
142.7, 141.3, 137.5, 124.2, 124.2, 111.2, 39.0, 30.3, 15.0, 15.0, 13.3. HRMS (ESI) m/z: [M+H]+calcd. for
C13H13FO205.1029; found 205.1033. IR (neat): vmax/cm-1 2919, 2852, 1656, 1565, 1343, 1218, 1106, 877.
1-(4-dimethoxy-3-methyl-1H-inden-2-yl) ethanone (3e)
Following general procedure, 3e was obtained as a white solid (42 mg, 0.225 mmol,70%) (EtOAc : Pet ether =
2:8). 1H NMR (500 MHz , CDCl3): δ7.30 - 7.22 (m, 1H), 7.02 (dd, J = 2.9, 7.4 Hz, 1H), 6.77 (dd, J = 2.6, 8.3
Hz, 1H), 3.84 (d, J = 2.3 Hz, 3H), 3.62 - 3.53 (m, 2H), 2.73 (d, J = 2.9 Hz, 3H), 2.37 (d, J = 2.9 Hz, 3H).
ACS Paragon Plus Environment

Page 9 of 16
The Journal of Organic Chemistry
1
2
3
4
5
13C{1H} NMR (125 MHz, CDCl3): δ196.7, 157.2, 152.0, 145.7, 136.0, 133.2, 129.5, 116.7, 109.0, 55.3, 39.7,
30.5, 16.2. HRMS (ESI) m/z: [M+H]+calcd. for C13H14O2 [203.1072; found 203.1078. IR (neat): vmax/cm-1
2957, 2840, 1666, 1584, 1555, 1480, 1356, 1238, 960, 768.
6
7
8
1-(4-chloro-5, 7-diimethoxy-3-methyl-1H-inden-2-yl) ethanone (3f)
9
Following general procedure, 3f was obtained as colourless oil (60 mg, 0.225 mmol, 75%) (EtOAc : Pet ether =
3:7). 1H NMR (400 MHz, CDCl3): δ6.52 (s, 1H), 3.89 (s, 3H), 3.92 (s, 3H), 3.53 (d, J = 3.1 Hz, 2H), 2.80 (t, J
= 2.4 Hz, 3H), 2.40 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ197.4, 155.9, 153.8, 150.9, 142.8, 139.4,
124.4, 110.5, 96.6, 57.1, 55.7, 36.5, 30.6, 16.3. HRMS (ESI) m/z: [M+H]+calcd. for C14H15ClO3267.788; found
267.788. IR (neat): vmax/cm-1 2917, 2848, 1654, 1563, 1452, 1308, 1054, 871, 822.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(4, 5, 6-trimethoxy-3-methyl-1H-inden-2-yl) ethanone (3g)
Following general procedure, 3g was obtained as a white powder (65 mg, 0.246 mmol, 82%) (EtOAc : Pet ether
1
= 4:6). H NMR (500 MHz, CDCl3): δ6.81 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 3.60 (br. s., 2H),
2.71 (s, 3H), 2.39 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ196.3, 154.9, 151.7, 150.8, 141.7, 140.5, 135.9,
130.7, 103.6, 61.5, 61.1, 56.3, 39.9, 30.4, 15.3. HRMS (ESI) m/z: [M+H]+calcd. for C15H18O4 263.1283; found
263.1282. IR (neat): vmax/cm-1 2925, 2851, 1658, 1552, 1469, 1226, 1101, 952, 824.
1-(3-butyl-5, 7-dimethoxy-3-methyl-1H-inden-2-yl) ethanone (3h)
Following general procedure, 3h was obtained as a white crystalline solid (68 mg, 0.249 mmol, 83%) (EtOAc :
Pet ether = 3:7). 1H NMR (500 MHz , CDCl3): δ6.68 - 6.65 (m, 1H), 6.51 - 6.46 (m, 1H), 3.86 (d, J = 0.9 Hz,
3H), 3.87 (d, J = 0.9 Hz, 3H), 3.60 - 3.55 (m, 2H), 3.01 - 2.95 (m, 2H), 2.42 - 2.38 (m, 3H), 1.60 - 1.54 (m, 2H),
1.47 - 1.42 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ196.6, 161.0, 156.0, 155.2,
147.0, 137.6, 123.4, 98.8, 98.3, 55.8, 55.5, 36.6, 31.4, 30.1, 26.9, 23.2, 14.1. HRMS (ESI) m/z: [M+H]+calcd.
for C17H22O3275.1647; found 275.1643. IR (neat): vmax/cm-1 2953, 2927, 2857, 1651, 1593, 1464, 1323, 1228,
1172, 845, 833.
1-(1-phenyl-2, 3-dihydro-1H-inden-2-yl) propan-1-one (3i)
Following general procedure, 3i was obtained as a white solid (49 mg, 0.210 mmol, 70%) (EtOAc : Pet ether =
1:9). 1H NMR (400 MHz, CDCl3): δ 7.56 - 7.45 (m, 4H), 7.39 - 7.34 (m, 3H), 7.28 (t, J = 7.3 Hz, 1H), 7.16 (d,
J = 7.3 Hz, 1H), 3.86 (s, 2H), 1.99 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ152.4, 145.8, 143.4, 141.3,
135.3, 129.0, 128.8, 128.7(2C), 128.6(2C), 128.3, 126.9, 124.3, 123.3, 39.1, 30.0. HRMS (ESI) m/z:
[M+H]+calcd. for C17H16O235.1123; found 235.1121. IR (neat): vmax/cm-1 2922, 2851, 1650, 1566, 1370, 1257,
1190, 776, 725.
1-(3-benzyl-1H-inden-2-yl) ethanone (3j)
Following general procedure, 3j was obtained as a white powder (51 mg, 0.204 mmol, 68%) (EtOAc : Pet ether
= 1:9). 1H NMR (500 MHz, CDCl3): δ7.52 - 7.48 (m, 2H), 7.37 - 7.31 (m, 2H), 7.31 - 7.27 (m, 2H), 7.26 - 7.22
(m, 2H), 7.18 - 7.14 (m, 1H), 4.47 (s, 2H), 3.82 - 3.76 (m, 2H), 2.47 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3):
δ196.5, 163.0, 161.1, 149.7, 142.7, 142.7, 141.4, 137.6, 137.5, 124.2, 124.2, 123.9, 123.7, 111.2, 111.1, 39.0,
30.3, 13.3. HRMS (ESI) m/z: [M+H]+calcd. for C18H16O249.1279; found 249.1277. IR (neat): vmax/cm-1 2920,
2851, 1663, 1559, 1357,1245, 756, 712
1-(1-methyl-3H-cyclopenta (a) napthylen-1-yl) ethanone (3k)
Following general procedure, 3k was obtained as colourless oil (39.7 mg, 0.18 mmol, 60%) (EtOAc : Pet ether
= 1:9).1H NMR (400 MHz , CDCl3): δ8.64 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.9 Hz,
1H), 7.62 (d, J = 7.9 Hz, 1H), 7.58 (dd, J = 1.2, 8.5 Hz, 1H), 7.54 - 7.49 (m, 1H), 3.81 (d, J = 1.8 Hz, 2H), 3.13 -
3.07 (m, 3H), 2.50 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 197.1, 153.0, 143.2, 139.8, 138.0, 133.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
1
2
3
4
5
130.3, 129.4(2C), 126.6, 125.3, 123.6, 122.3, 40.5, 30.6, 17.5. HRMS (ESI) m/z: [M+H]+calcd. for
C16H14O223.1123; found 223.1120. IR (neat): vmax/cm-1 2921, 2851, 1713, 1655, 1543, 1357, 1253, 1183, 807.
6
7
1-(2,6,7,8-tetrahydroacenapthylen-1-yl) ethanone (3l)
8
9
Following general procedure, 3l was obtained as a yellow powder (39.3 mg, 0.16 mmol, 53%) (EtOAc : Pet
ether = 1:9). 1H NMR (400 MHz , CDCl3): δ7.33 - 7.29 (m, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.3 Hz,
1H), 3.68 (t, J = 2.7 Hz, 2H), 3.11 - 3.05 (m, 2H), 2.83 (t, J = 6.1 Hz, 2H), 2.44 (s, 3H), 2.01 (quin, J = 6.1 Hz,
2H). 13C{1H} NMR (100 MHz, CDCl3): δ196.2, 151.4, 142.5, 142.2, 136.1, 135.6, 128.6, 125.1, 121.8, 39.0,
29.8, 27.1, 26.9, 23.8. HRMS (ESI) m/z: [M+H]+calcd. for C14H14O199.1123; found 199.1127. IR (neat):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
v
max/cm-1 2923, 2852, 1647, 1567, 1370, 1247, 1180, 766.
1-(5-chloro-3-methyl-1H-inden-2-yl) ethanone (3m1)
Following general procedure, 3m1 was obtained as yellow oil (29 mg, 0.14 mmol, 47%) (EtOAc : Pet ether =
1:9). 1H NMR (500 MHz, CDCl3): δ7.48 (d, J = 1.7 Hz, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.35 - 7.30 (m, 1H), 3.66
(d, J = 2.3 Hz, 2H), 2.51 (t, J = 2.6 Hz, 3H), 2.45 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ196.7, 148.9,
147.3,141.3, 139.2, 133.1, 128.1, 125.2, 121.9, 39.0, 30.4, 30.0. HRMS (ESI) m/z: [M+H]+calcd. for
C12H11ClO207.0577; found 207.0582. IR (neat): vmax/cm-1 2922, 2851, 1659, 1561, 3116, 1242, 1190, 801.
1-(7-chloro-3-methyl-1H-inden-2-yl) ethanone (3m2)
Following general procedure, 3m2 was obtained as yellow oil (15.5 mg, 0.07 mmol, 23%) (EtOAc : Pet ether =
1:9). 1H NMR (500 MHz, CDCl3): δ7.46 - 7.40 (m, 1H), 7.37 - 7.32 (m, 2H), 3.70 (s, 2H), 2.53 (s, 3H), 2.47 (s,
3H). 13C{1H} NMR (125 MHz, CDCl3): δ196.8, 149.6, 147.2, 140.9, 138.0, 130.3, 128.7, 128.1, 120.3, 39.0,
30.4, 13.3. HRMS (ESI) m/z: [M+H]+calcd. for C12H11ClO207.0577; found 207.0582. IR (neat): vmax/cm-1
2923, 2852, 1663, 1578, 1454, 1361, 1224, 963, 782.
1-(3-methyl-1H-inden-2-yl) propan-1-one (3n)
Following general procedure, 4n was obtained as a white solid (36 mg, 0.195mmol, 65%) (EtOAc : Pet ether =
1:9). 1H NMR (500 MHz, CDCl3): δ7.55 - 7.52 (m, 1H), 7.50 - 7.47 (m, 1H), 7.39 - 7.35 (m, 2H), 3.69 (d, J =
2.4 Hz, 2H), 2.77 (q, J = 7.3 Hz, 2H), 2.56 (t, J = 2.4 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (125
MHz, CDCl3): δ199.9, 149.8, 145.6, 143.1, 137.3, 128.0, 126.9, 124.1, 121.7, 38.9, 35.4, 13.1, 8.1. HRMS
(ESI) m/z: [M+H]+calcd. for C13H14O187.1123; found 187.1122. IR (neat): vmax/cm-1 2974, 2933, 1662, 1566,
1459, 1374, 1178, 756, 719.
1-(3-ethyl-1H-inden-2-yl) propan-1-one (3o)
Following general procedure, 3o was obtained white solid (46 mg, 0.186 mmol, 62%) (EtOAc : Pet ether =
1:9). 1H NMR (400 MHz, CDCl3): δ7.57 - 7.52 (m, 1H), 7.48 (s, 1H), 7.39 - 7.33 (m, 2H), 3.69 (s, 2H), 3.04
(q, J = 7.5 Hz, 2H), 2.77 (q, J = 7.3 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.19 - 1.14 (m, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ199.6, 156.0, 144.6, 143.4, 136.2, 127.9, 126.9, 124.3, 121.7, 39.0, 35.2, 20.3, 13.5, 8.0.
HRMS (ESI) m/z: [M+H]+calcd. for C14H16O201.1279; found 201.1273. IR (neat): vmax/cm-1 2976, 2936,
1658, 1563, 1373, 1185,824.
1-(3, 6-dimethyl-1H-inden-2-yl) propan-1-one (3p)
Following general procedure, 3p was obtained white powder (41 mg, 0.204 mmol, 68%) (EtOAc : Pet ether =
1:9). 1H NMR (400 MHz , CDCl3): δ 7.41 (d, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.18 (d, J = 7.9 Hz, 1H), 3.65 (d, J
= 3.1 Hz, 2H), 2.75 (q, J = 7.3 Hz, 2H), 2.53 (t, J = 2.4 Hz, 3H), 2.42 (s, 3H), 1.17 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ 199.8, 150.0, 143.5, 143.1, 138.3, 136.5, 127.8, 124.9, 121.4, 38.7, 35.3, 21.8,
13.2, 8.1. HRMS (ESI) m/z: [M+H]+calcd. for C14H16O201.1279; found 201.1270. IR (neat): vmax/cm-1 2976,
1936, 1658, 1564, 1373, 1185, 825, 808.
1-(6-ethyl-3-methyl-1H-inden-2-yl) propan-1-one (3q)
ACS Paragon Plus Environment

Page 11 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Following general procedure, 3q was obtained as a colourless liquid (44 mg, 0.21 mmol, 70%) (EtOAc : Pet
ether = 1:9). 1H NMR (400 MHz , CDCl3): δ7.44 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.23 - 7.18 (m, 1H), 3.66 (d,
J = 2.4 Hz, 2H), 2.79 - 2.74 (m, 2H), 2.74 - 2.68 (m, 2H), 2.56 - 2.52 (m, 3H), 1.27 - 1.24 (m, 3H), 1.16 (t, J =
7.3 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ199.8, 150.0, 144.9, 143.6, 143.4, 136.6, 126.7, 123.7, 121.5,
38.8, 35.3, 29.2, 16.0, 13.2, 8.1. HRMS (ESI) m/z: [M+H]+calcd. for C15H18O215.1436; found 215.1437. IR
(neat): vmax/cm-1 2963, 2851, 1666, 1588, 1562, 1376, 1183, 823.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(7-methoxy-3-methyl-1H-inden-2-yl) propan-1-one (3r)
Following general procedure, 3r was obtained as a white solid (60 mg, 0.225 mmol, 75%) (EtOAc : Pet ether =
2:8). 1H NMR (500 MHz, CDCl3): δ7.36 (t, J = 7.7 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H),
3.91 (s, 3H), 3.65 (d, J = 2.9 Hz, 2H), 2.77 (q, J = 7.1 Hz, 2H), 2.57 - 2.51 (m, 3H), 1.17 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (125 MHz, CDCl3): δ199.9, 155.4, 150.0, 147.3, 137.2, 130.2, 128.6, 114.5, 109.9, 55.4, 36.4,
35.3, 13.3, 8.1. HRMS (ESI) m/z: [M+H]+calcd. for C14H16O2 217.1229; found 217.1222. IR (neat): vmax/cm-1
2973, 2900, 1664, 1571, 1478, 1370, 1264, 1165, 903, 780.
1-(5, 7-dimethoxy-3-methyl-1H-inden-2-yl) propan-1-one (3s)
Following general procedure, 3s was obtained as white powder (60 mg, 0.246 mmol, 82%) (EtOAc : Pet ether =
1
3:7). H NMR (400 MHz , CDCl3): δ6.65 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 1.8 Hz, 1H), 3.86 (d, J = 5.5 Hz,
6H), 3.57 (q, J = 2.0 Hz, 2H), 2.74 (q, J = 7.3 Hz, 2H), 2.51 (t, J = 2.4 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H). 13C{1H}
NMR(100 MHz, CDCl3): δ199.9, 161.1, 155.9, 149.9, 147.6, 137.9, 123.0, 99.0, 97.8, 55.8, 55.5, 35.9, 35.2,
13.2, 8.1. HRMS (ESI) m/z: [M+H]+calcd. for C15H18O3247.1334; found 247.1337. IR (neat): vmax/cm-1 2944,
2873, 1659, 1569, 1455, 1202, 1138, 1051, 811.
1-(4, 7-dimethoxy-3-methyl-1H-inden-2-yl) propan-1-one (3t)
Following general procedure, 3t was obtained as a white powder (61 mg, 0.249 mmol, 83%) (EtOAc : Pet ether
= 3:7). 1H NMR (500 MHz, CDCl3): δ6.81 - 6.74 (m, 2H), 3.86 (s, 3H), 3.83 (s, 3H), 3.60 (d, J = 2.9 Hz, 2H),
2.76 - 2.71 (m, 5H), 1.15 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ199.9, 151.7, 151.7, 149.6,
135.8, 134.6, 132.5, 110.5, 110.1, 55.9, 55.8, 36.7, 35.4, 15.9, 8.2. HRMS (ESI) m/z: [M+H]+calcd. for
C15H18O3 247.1334; found 247.1339. IR (neat): vmax/cm-1 2940, 2834, 1660, 1562, 1495, 1252, 1180, 1069, 896
1-(5-methoxy-1-(4-methoxyphenyl)-2, 3-dihydro-1H-inden-2-yl) propan-1-one (3u)
Following general procedure, 3u was obtained as a yellow crystalline solid (58.08 mg, 0.240 mmol, 80%)
(EtOAc : Pet ether = 4:6). 1H NMR (400 MHz , CDCl3): δ7.31 - 7.26 (m, J = 8.5 Hz, 2H), 7.10 - 7.05 (m, 2H),
7.04 - 6.98 (m, J = 8.5 Hz, 2H), 6.83 (dd, J = 3.1, 8.5 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.80 (s, 2H), 2.31 (q, J
= 6.9 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ200.0, 160.5, 159.8, 145.6, 139.1,
138.7, 130.0(2C), 127.6, 124.0, 114.1(2C), 113.4, 109.7, 55.7, 55.4, 39.2, 34.7, 8.6. HRMS (ESI) m/z:
[M+H]+calcd. for C20H22O3 309.1491; found 309.1490. IR (neat): vmax/cm-1 2935, 2837, 1713, 1644, 1611,
1504, 1287, 1248, 1201, 1031, 825.
1-(3-ethyl-4, 6, 7-trimethoxy-1H-inden-2-yl) propan-1-one (3v)
Following general procedure, 3v was obtained white crystalline solid (73 mg, 0.252 mmol, 84%) (EtOAc : Pet
ether = 4:6). 1H NMR (500 MHz, CDCl3): δ6.45 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H), 3.66 - 3.64 (m,
2H), 3.21 - 3.16 (m, 2H), 2.71 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ198.9, 158.2, 153.4, 153.3, 138.9, 138.0, 133.3, 125.9, 96.4, 60.4, 56.4, 55.9, 36.6,
35.2, 22.2, 13.8, 8.21. HRMS (ESI) m/z: [M+H]+calcd. for C17H22O4 291.1596; found 291.1594. IR (neat):
v
max/cm-1 2967, 2935, 1659, 1555, 1501, 1440, 1319, 1091, 808.
1-(4-chloro-7-methoxy-1-methyl-2, 3-dihydro-1H-inden-2-yl) ethanone (3w)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 16
1
2
3
4
5
6
7
8
9
Following general procedure, 3w was obtained as colourless oil (54 mg, 0.216 mmol, 72%) (EtOAc : Pet ether
= 2:8). 1H NMR (500 MHz , CDCl3): δ7.25 (d, J = 3.9 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 3.86 (s, 3H), 3.66 -
3.63 (m, 2H), 2.78 - 2.71 (m, 5H), 1.16 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ199.7, 155.9,
151.3, 142.7, 135.7, 134.3, 128.7, 121.8, 110.9, 55.7, 39.1, 35.6, 16.0, 8.1. HRMS (ESI) m/z: [M+H]+calcd. for
C13H15ClO2 251.0839; found 251.0830. IR (neat): vmax/cm-1 2919, 2850, 1666, 1655, 1559, 1455, 1275, 1085,
795.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(7-bromo-4-imethoxy-3-methyl-1H-inden-2-yl) propan-1-one (3x)
Following general procedure, 3x was obtained as colourless oil (62.6 mg, 0.20 mmol, 71%) (EtOAc : Pet ether
= 2:8). 1H NMR (400 MHz, CDCl3): δ7.38 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 9.2 Hz, 1H), 3.86 (s, 3H), 3.61 (d, J
= 3.1 Hz, 2H), 2.79 - 2.70 (m, 5H), 1.16 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ199.7, 156.6,
151.3, 144.9, 135.7, 134.4, 131.8, 111.4, 110.0, 55.7, 41.1, 35.6, 16.1, 8.1. HRMS (ESI) m/z: [M+H]+calcd. For
C14H15BrO2 295.0334; found 295.0334. IR (neat): vmax/cm-1 2921, 2850, 1662, 1579, 1473, 1278, 1081, 797.
1-(3-methyl-1H-inden-2-yl) propan-1-one (3y1)
Following general procedure, 3y1 was obtained white powder (55 mg, 0.225 mmol, 75%) (EtOAc : Pet ether =
3:7). 1H NMR (500 MHz , CDCl3): δ7.21 (dd, J = 0.7, 8.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.91
(s, 3H), 3.72 (d, J = 2.4 Hz, 2H), 2.76 (q, J = 7.3 Hz, 2H), 2.52 - 2.50 (m, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3): δ199.5, 152.8, 149.9, 145.1, 140.2, 135.8, 135.0, 117.3, 111.8, 60.3, 56.3, 36.3, 35.3,
13.2, 8.1. HRMS (ESI) m/z: [M+H]+calcd. For C15H18O3 247.1334; found 247.1339. IR (neat): vmax/cm-1 2965,
2903,1659,1564,1489,1265,1183,1071,817.
1-(6, 7-dimethoxy-3-methyl-1H-inden-2-yl) ethanone (3y2)
Following general procedure, 3y2 was obtained white powder (45.5 mg, 0.21 mmol, 65%) (EtOAc : Pet ether =
1
3:7). H NMR (500 MHz, CDCl3): δ7.22 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 3.95 (s, 3H), 3.91 (s,
3H), 3.72 (d, J = 2.3 Hz, 2H), 2.50 (t, J = 2.3 Hz, 3H), 2.43 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ196.5,
152.9, 150.3, 145.0, 140.1, 136.4, 135.1, 117.4, 111.8, 60.3, 56.3, 36.8, 30.3, 13.3. HRMS (ESI) m/z:
[M+H]+calcd. for C14H16O3 233.1178; found 233.1167. IR (neat): vmax/cm-1 2924, 2853, 1659, 1566, 1489,
1428, 1266, 1075, 802.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of 1H and 13C spectra for all products and table of results from kinetics NMR experiments
AUTHOR INFORMATION
Corresponding Author
* Email: ddethe@iitk.ac.in
ORCID
Dattatraya H. Dethe: 0000-0003-2734-210X
Author Contributions
$ N. C. B. and A. A. B. contributed equally.
Present Addresses
Department of Chemistry, Indian Institute of Technology, Kanpur, 208016, India.
ACS Paragon Plus Environment

Page 13 of 16
The Journal of Organic Chemistry
1
2
3
4
5
Conflicts of interest
There are no conflicts to declare.
6
ACKNOWLEDGMENT
7
8
9
NCB thanks UGC, New Delhi, for the award of a research fellowship and AAB thanks IIT kanpur for reaseach
fellowship. Financial support from SERB Project No. EMR/2017/001455 is gratefully acknowledged.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES:
(1) (a) Karila, D.; Freret, T.; Bouet, V.; Boulouard, M.; Dallemagne, P.; Rochais, C. Therapeutic Potential of 5-
HT6 Receptor Agonists. J. Med. Chem., 2015, 58, 7901. (b) Chandab, D.; saikiab, D.; Kumarc, J. K.; Thakurb,
J. P.; Agarwalb, J.; Chanotiyya, C. S.; Shankera, K.; Negi, A. S. 1- Chloro-2-formyl indenes and tetralenes as
antitubercular agents. Bioorg. Med. Chem. Lett., 2011, 21, 3966. (c) Alcalde, E.; Mesquida, N.; López-Pérez, S.;
Frigola, J.; Mercé, R. An Indole-Indene Switch: Discovery of Novel Indenylsulfonamides as 5-HT6 Serotonin
Receptor Agonists. J. Med. Chem., 2009, 52, 675. (d) Voets, M.; Antes, I.; Scherer, C.; Vieira, U. M.; Biemel,
K.; Oberwinkler, S. M.; Hartmann, R. W. Synthesis and Evaluation of Heteroaryl-Substituted
Dihydronaphthalenes and Indenes: Potent and Selective Inhibitors of Page 42 of 51 Aldosterone Synthase
(CYP11B2) for the Treatment of Congestive Heart Failure and Myocardial Fibrosis. J. Med. Chem., 2006, 49,
2222. (e) Kolanos, R.; Siripurapu, U.; Pullagurla, M.; Riaz, M.; Setola, V.; Roth, B. L.; Dukat, M.; Glennon, R.
A. Binding of isotryptamines and indenes at h5-HT6 serotonin receptors. Bioorg. Med. Chem. Lett., 2005, 15,
1987. (f) Alessandro, C. Enrasentan, an Antagonist of Endothelin Receptors. Cardiovasc. Drug Rev., 2003, 21,
1. (g) Watanabe, N.; Nakagava, H.; Ikeno, A.; Minato, H.; Kohayakawa, C.; Tsuji, J. 4-(4-Alkylpiperazin-1-
yl)phenyl group: A novel class of basic side chains for selective estrogen receptor modulators. Bioorg. Med.
Chem. Lett., 2003, 13, 4317. (h) Guillon, J.; Dallemagne, P.; Léger, J. -M.; Sopkova, J.; Bovy, P. R.; Jarry, C.;
Rault, S. Synthesis of a Novel Class of Non- Peptide NK-2 Receptor Ligand, Derived from 1-Phenyl-3-pyrrol-1-
ylindan-2-carboxamides. Bioorg. Med. Chem,. 2002, 10, 1043. (i) Karaguni, I. -M.; Glusenkamp, K. -H.;
Langerak, A.; Geisen, C.; Ullrich, V.; Winde, G.; Moroy, T.; Muller, O. New indene-derivatives with antiproli-
ferative properties. Bioorg. Med. Chem. Lett., 2002, 12, 709.
(2) (a) Deng, J.; Zhou, S.; Zhang, W.; Li, J.; Li, R.; Li, A. Total Synthesis of Taiwani adducts B, C, and D. J.
Am. Chem. Soc., 2014, 136, 8185. (b) Lane, A. L.; Nam, S. -J.; Fukuda, T.; Yamanaka, K.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W.; Moore, B. S. Structures and Comparative Characterization of Biosynthetic Gene
Clusters for Cyanosporasides, Enediyne-Derived Natural Products from Marine Actinomycetes. J. Am. Chem.
Soc., 2013, 135, 4171. (c) Liao, X.; Stanley, L. M.; Hartwig, J. F. Enantioselective Total Syntheses of (−)-
Taiwani-aquinone H and (−)-Taiwaniaquinol B by Iridium-Catalyzed Borylation and Palladium-Catalyzed
Asymmetric α-Arylation. J. Am. Chem. Soc., 2011, 133, 2088.
(3) (a) Kim, D. H.; Lee, J. A.; Lee, B. Y.; Chung, Y. K.; Synthesis of zirconocenes bearing benz[f]indenyl
ligand and their use as a catalyst in ethylene polymerization. J. Organomet. Chem., 2005, 690, 1822. (b) Yang,
J.; Lakshmikantham, M. V.; Cava, M. P.; Lorcy, D.; Bethelot, J. R.; Synthesis and Characterization of 5,10-
Bis(2-thienyl)indeno[2,1-a]indene Derivatives: The First Examples of Conducting Polymers Containing a Rigid
Bis(thienyl)butadiene Core. J. Org. Chem., 2000, 65, 6739. (c) Barberá, J.; Rakitin, O. A.; Ros, M. B.; Torroba,
T. Breaking the MoldofDiscotic Liquid Crystals. Angew. Chem. Int. Ed., 1998, 37, 296.
(4) Alt, H. G.; Köppl, A. Effect of the Nature of Metallocene Complexes of Group IV Metals on Their
Performance in Catalytic Ethylene and Propylene Polymerization. Chem. Rev., 2000, 100, 1205.
(5) (a) Dethe, D. H.; Murhade, G. M. FeCl3 mediated intramolecular olefin-cation cyclization of cinnamates for
the synthesis of highly substituted indenes. Chem. Commun., 2013, 49, 8051. (b) Dethe, D. H.; Murhade, G.
FeCl3 Catalyzed Prins-Type Cyclization for the Synthesis of Highly Substituted Indenes: Application to the
Total Synthesis of (±)-Jungianol and epi-Jungianol. Org. Lett., 2013, 15, 429.
(6) (a) Ye, Y.; Wang, L.; Aue, D. H.; Zhang, L. Experimental and Computational Evidence for Gold
Vinylidenes: Generation from Terminal Alkynes via a Bifurcation Pathway and Facile C–H Insertions. J. Am.
Chem. Soc., 2012, 134, 31. (b) Sanz, R.; Miguel, D.; Rodríguez, F. Gold(I)-catalyzed tandem reactions initiated
by 1,2-indole migrations. Angew. Chem. Int. Ed., 2008, 47, 7354. (c) Bi, H. -P.; Liu, X. -Y.; Gou, F. -R.; Guo,
L. -N.; Duan, X. -H.; Liang, Y. -M. Highly Regioselective Synthesis of Indene Derivatives Including an Allene
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 16
1
2
3
4
5
6
Functional Group via Pd/C-Catalyzed Cyclization Reaction in Air. Org. Lett., 2007, 9, 3527. (d) Zhang, D.;
Yum, E. K.; Liu Z.; Larock, R. C. Synthesis of Indenes by the Palladium-CatalyzedCarboannulation of Internal
Alkynes. Org. Lett. ,2005, 7, 4963. (e) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. Intramolecular Nucleophilic
Addition of Vinylpalladiums to Aryl Ketones. J. Am. Chem. Soc., 1999, 121, 3545.
7
(7) For selected examples: (a) Zhao J.; Clark, D. A. Regiodivergent Synthesis of Functionalized Indene
Derivatives via Pt-CatalyzedRautenstrauch Reaction of Propargyl Carbonates. Org. Lett., 2012, 14, 1668. (b)
Zhu, X.; Tsuji, H.; Nakabayashi, K.; Ohkoshi, S. -I.; Nakamura, E. Air- and Heat-Stable Planar Tri-p-
quinodimethane with Distinct Biradical Characteristics. J. Am. Chem. Soc., 2011, 133, 16342. (c) Liu, C. -R.;
Yang, F. -L.; Jin, Y. -Z.; Ma, X. -T.; Cheng, D. -J.; Li, N.; Tian, S. -K. Catalytic Regioselective Synthesis of
Structurally Diverse Indene Derivatives from N-Benzylic Sulfonamides and Disubstituted Alkynes. Org. Lett.,
2010, 12, 3832. (d) Yang, S.; Li, Z.; Jian, X.; He, C. Platinum(II)-catalyzed intramolecular cyclization of o-
substituted aryl alkynes through sp3 C-H activation. Angew. Chem. Int. Ed., 2009, 48, 3999.
(8) (a) Khan, Z. A.; Wirth, T. Synthesis of Indene Derivatives via Electrophilic Cyclization. Org. Lett., 2009,
11, 229.(b) Ye, S.; Gao, K.; Zhou, H.; Yang, X.; Wu, J. Synthesis of 1-methyleneindenes via palladium
catalysed tandem reactions. Chem. Commun., 2009, 5406.(c) Das, B. G.; Chirila, A.; Tromp, M.; Reek, J. N. H.;
de Bruin, B. Co (III)–Carbene RadicalApproach to Substituted 1H-Indenes. J. Am. Chem. Soc., 2016, 138,
8968.(d) Odedra, A.; Datta, S.; Liu, R. -S. Ruthenium-Catalyzed Cyclization of 2-Alkyl-1-ethynylbenzenes via a
1,5-Hydrogen Shift of Ruthenium-Vinylidene Intermediates. J. Org. Chem., 2007, 72, 3289. (e) Zhang, J.;
Zhang, J.; Fang, K.; Shu, G.; Xie, M.; Synthesis of MultisubstitutedIndenes by Fe(III)-Catalyzed Friedel-Crafts
Cyclization of Allylic Alcohols. Chin. J. Org. Chem., 2012, 32, 1533. (f) Panteleev, J.; Huang, R. Y.; Lui, E. K.
J.; Lautens, M. Addition of Arylboronic Acids to Arylpropargyl Alcohols en Route to Indenes and Quinolines.
Org. Lett., 2011, 13, 5314. Homoallylic alcohols: (g) Zhang, X.; Teo, W. T.; Rao, W.; Ma, D. -L.; Leung, C. -
H.; Chan, P. W. H. Synthesis of highly substituted indene derivatives by Bronsted acid catalyzed Friedel Crafts
reaction of homoallylic alcohols. Tetrahedron Lett., 2014, 55, 3881.
(9). (a) Dethe, D. H.; Boda, R.; Murhade, G. M. Lewis acid catalyzed Nazarov type cyclization for the synthesis
of a substituted indane framework: total synthesis of (±)-mutisianthol. Org. Chem. Front., 2015, 2, 645. (b)
Dethe. D. H.; Murhade, G. M. FeCl3 Mediated Synthesis of Substituted Indenones by Formal [2+2]
Cycloaddition/Ring Opening Cascade of O-Keto-Cinnamates. Chem. Commun., 2015, 51, 10891. (c) Dethe, D.
H.; Murhade, G. M.; Ghosh, S. FeCl3 Catalysed Intramolecular Michael Reaction of Styrenes for The Synthesis
of Highly Substituted Indene. J. Org. Chem., 2015, 80, 8367. (d) Dethe D. H.; Murhade G. M. FeCl3 mediated
intramolecular olefin-cation cyclisation of cinnamates for the synthesis of highly substituted indenes. Chem.
Comm., 2013, 49, 8051. (e) Dethe D. H.; Murhade G. M. FeCl3 Catalyzed Prins-Type Cyclization for the
Synthesis of Highly Substituted Indenes: Application to the Total Synthesis of (±)-Jungianol and epi-Jungianol.
Org. Lett., 2013, 15, 429.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) (a) Davies, H. M. L.; Bois, J. D.; Yu, J. Q. C-H functionalization in organic synthesis. Chem. Soc. Rev.,
2011, 40, 1855. (b) Keisham S. Singh. Recent Advances in C-H Bond Functionalization with Ruthenium-Based
Catalysts. Catalysts, 2019, 9, 173. (c)Liao, G.; Zhou, T.; Yao, Q. J.; Shi,B. F. Recent advances in the synthesis
of axially chiral biaryls via transition metal-catalysed asymmetric C–H functionalization. Chem. Commun.,
2019, 55, 8514. (d) Zhang,Q.; Shi.B. F. From Reactivity and Regioselectivity to Stereoselectivity: An Odyssey
of Designing PIP Amine and Related Directing Groups for C-H Activation. Chin. J. Chem., 2019, 37, 647.
(11) (a) Lia, B. J.; Shi, Z. J. From C(sp2)-H to C(sp3)-H: systematic studies on transition metal-catalyzed
oxidative C-C formation. Chem. Soc. Rev., 2012, 41, 5588. (b) Lyons, T.W.; Sanford, M.S. Palladium-catalyzed
ligand-directed C-H functionalization reactions. Chem. Rev., 2010, 110, 1147. (c) Lewis, J.C.; Bergman, R.G.;
Ellman, J.A. Direct functionalization of nitrogen heterocycles via Rh catalyzed C-H bond activation. Acc. Chem.
Res., 2008, 41, 1013. (d) Lewis, J.C.; Wiedemann, S.H.; Berg-man, R.G.; Ellman, J.A. Arylation of heterocycles
via rhodiumcatalyzed C-H bond functionalization. Org. Lett., 2004, 6, 35.
(12) For a review, see: (a) Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d
Transition Metals for C-H Activation. Chem. Rev., 2019, 119, 2192. (b) Kulkarni, A. A.; Daugulis, O. Direct
Conversion of Carbon-Hydrogen into Carbon-Carbon Bonds by First-Row Transition-Metal Catalysis.
Synthesis, 2009, 24, 4087. (c) Su, B.; Cao, Z.-C.; Shi, Z.-J. Exploration of Earth-Abundant Transition Metals
(Fe, Co, and Ni) as Catalysts in Unreactive Chemical Bond Activations. Acc. Chem. Res., 2015, 48, 886. (d)
Pototschnig, G.; Maulide, N.; Schnürch, M. Direct Functionalization of C-H Bonds by Iron, Nickel, and Cobalt
Catalysis. Chem. Eur. J., 2017,23, 9206. (e) Liu, J.; Chen, G.; Tan, Z. Copper-Catalyzed or Mediated C-H Bond
Functionalizations Assisted by Bidentate Directing Groups. Adv. Synth. Catal., 2016,358, 1174. (f) Liu, W.;
ACS Paragon Plus Environment

Page 15 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ackermann, L. Manganese-Catalyzed C-H Activation. ACS Catal.,2016, 6, 3743. (g) Yoshino; Matsunaga, S.
High Valent Cobalt-Catalyzed C-H Bond Functionalization. Adv. Organomet. Chem., 2017, 68, 197. (h)
Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. A Cationic High-Valent Cp*Co(III) Complex for the
Catalytic Generation of Nucleophilic Organometallic Species: Directed C-H Bond Activation. Angew. Chem.,
Int. Ed., 2013, 52, 2207. (i) Wang, S.; Chen, S.-Y.; Yu, X.-Q. C-H Functionalization by High-Valent Cp*Co(III)
Catalysis. Chem. Commun., 2017, 53, 3165. (j) Liu, Y. H.;Xia,Y. N.; Shi,B. F.Ni-Catalyzed Chelation-Assisted
Direct Functionalization of Inert C-H Bonds. Chin. J. Chem., 2020, 38. DOI: 10.1002/cjoc.201900468. (k)
Rao, W. H.; Shi, B. F. Recent advances in copper-mediated chelation-assisted functionalization of unactivated
C–H bonds. Org. Chem. Front., 2016, 3, 1028.
(13) (a) Yoshino, T.; Matsunaga, S. Cobalt Catalyzed C (sp3)-H Functionalization Reactions, Asian J. Org.
Chem., 2018, 7, 1193. (b) Yoshino, T.; Matsunaga, S. High Valent Cobalt-Catalyzed C-H Bond
Functionalization, Adv. Organomet. Chem., 2017, 68, 197. (c) Yoshino, T.; Matsunaga, S.
(Pentamethylcyclopentadienyl)cobalt(III)-Catalyzed C–H Bond Functionalization: From Discovery to Unique
Reactivity and Selectivity. Adv. Synth. Catal., 2017, 359, 1245.(d) Moselage, M.; Li, J.; Ackermann, L. Cobalt
Catalyzed C-H Activation, ACS Catal., 2016, 6, 498. (e) Yoshikai, N. Development of Cobalt-Catalyzed C-H
Bond Functionalization Reactions, Bull. Chem. Soc. Jpn., 2014, 87, 843. (f) Sun, B.; Yoshino, T.; Matsunaga,
S.; Kanai, M. Air-Stable Carbonyl(pentamethylcyclopentadienyl)cobalt Diiodide Complex as a Precursor for
Cationic (Pentamethylcyclopentadienyl)cobalt(III) Catalysis: Application for Directed C-2 Selective C-H
Amidation of Indoles. Adv. Synth. Catal., 2014, 356, 1491. (g) Huang, D. Y.; Yao, Q. J.; Zhang, S.; Xu, X. T.;
Zhang, K.; Shi, B. F. Amide-Directed Cobalt(III)-Catalyzed C–H Amidation of Ferrocenes. Org. Lett., 2019, 21,
951. (h) Liu, Y. H.; Li, P. X.; Yao, Q. J.; Zhang, Z. Z.; Huang, D. Y.; Le, M. D.; Song, H.; Liu, L.; Shi, B. F.
Cp*Co(III)/MPAA-Catalyzed Enantioselective Amidation of Ferrocenes Directed by Thioamides under Mild
Conditions. Org. Lett., 2019, 21, 1895.
(14) (a) Q.-Z. Zheng, N. Jiao, Transition metal catalyzed ketone directed ortho C-H functionalization
reactions.Tetrahedron Lett., 2014, 55, 1121. (b) Z. Huang, H. N. Lim, F. Mo, M. C. Young, G. Dong, Transition
metal-catalyzed ketone directed or mediated C-H functionalization. Chem. Soc. Rev., 2015, 44, 7764.
(15) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Efficient
catalytic addition of aromatic carbon-hydrogen bonds to olefins. Nature, 1993, 366, 529. (b) Guari, Y.; Sabo-
Etienne, S.; Chaudret, B. Exchange Couplings between a Hydride and a Stretched Dihydrogen Ligand in
Ruthenium Complexes. J. Am. Chem. Soc., 1998, 120, 4228. (c) Martinez, R.; Simon, M. O.; Chevalier, R.;
Pautigny, C.; Genet, J. P.; Darses, S. C-C Bond Formation via C-H Bond Activation Using an in Situ-Generated
Ruthenium Catalyst. J. Am. Chem. Soc., 2009, 131, 7887. (d) Crisenza, G. E. M.; McCreanor, N. G.; Bower, J.
F. Ir(I)-Catalyzed C–H Bond Alkylation of C2-Position of Indole with Alkenes: Selective Synthesis of Linear or
Branched 2-Alkylindoles. J. Am. Chem. Soc., 2014, 136, 10258. (e) Kimura, N.; Kochi, T.; Kakiuchi, F. Iron-
Catalyzed Regioselective Anti-Markovnikov Addition of C–H Bonds in Aromatic Ketones to Alkenes. J. Am.
Chem.Soc., 2017, 139, 14849.
(16) (a) Patureau, F. W.; Besset, T.; Glorius, F. Rhodium-Catalyzed Oxidative Olefination of C-H Bonds in
Acetophenones and Benzamides. Angew. Chem. Int. Ed., 2011, 50, 1064. (b) Padala, K.; Jeganmohan, M.
Ruthenium-Catalyzed Ortho-Alkenylation of Aromatic Ketones with Alkenes by C-H Bond Activation. Org.
Lett., 2011, 13, 6144. (c) Moon, Y.; Kwon, D.; Hong, S. Palladium Catalyzed Dehydrogenation/Oxidative
Cross-Coupling Sequence of β-Heteroatom-Substituted Ketones. Angew. Chem. Int. Ed., 2012, 51, 11333.
Angew. Chem., 2012, 124, 11495. (d) Bakthadoss, M.; Vijay Kumar, P.; Reddy, T. S. Ruthenium Catalyzed,
Keto-Directed, Site-Selective C-H Activation of Diverse Chromanones with Alkenes. Eur. J. Org. Chem., 2017,
4439. (e) Raja, M. S; Cobalt(III)-catalyzed ketone-directed C–H vinylation using vinyl acetate. Org. Chem.
Front., 2020, 7, 19. (f) Raja, M. S; Bera, S. S.; Maji, M. S. Weakly Coordinating, Ketone-Directed Cp*Co(III)-
Catalyzed C–H Allylation on Arenes and Indoles. Org. Lett., 2018, 20, 134. (g) Raja, M. S; Bera, S. S.; Maji, M.
S. Cp*Co(III)-Catalyzed C−H Alkenylation of Aromatic Ketones with Alkenes. Adv. Synth. Catal., 2019, 361,
585. (h) Bera, S. S.; Raja, M. S; Maji, M. S. Weakly Coordinating, Ketone-Directed
(η5-Pentamethylcyclopentadienyl)cobalt(III) and (η5-Pentamethylcyclopentadienyl)rhodium(III) Catalyzed C−H
Amidation of Arenes: A Route to Acridone Alkaloids. Chem. Eur. J., 2019,25, 1806. (i) Mandal, R.;
Emayavaramban, B.; Sundararaju, B. Cp*Co(III)-Catalyzed C–H Alkylation with Maleimides Using Weakly
Coordinating Carbonyl Directing Groups. Org. Lett., 2018, 20, 2835. (j) Barsu, N.; Emayavaramban, B.; and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 16
1
2
3
4
5
6
Sundararaju, B. Linear Selective C–H Bond Alkylation with Activated Olefins Catalyzed by Cp*Co(III). Eur. J.
Org. Chem. 2017, 4370. (k) Mandal, R.; Sundararaju, B.Cp*Co(III)-Catalyzed Annulation of Carboxylic Acids
with Alkynes. Org. Lett., 2017, 19, 2544.
(17) (a) Kuninobu, Y.; Tokunaga, Y.; Kawata, A.; Takai, K. Insertion of Polar and Nonpolar Unsaturated
Molecules into Carbon-Rhenium Bonds Generated by C-H Bond Activation:ꢀ Synthesis of Phthalimidine and
Indene Derivatives. J. Am. Chem. Soc., 2006, 128, 202. (b) Sun, Z.-M.; Chen, S.-P.; Zhao, P. Tertiary
Carbinamine Synthesis by Rhodium-Catalyzed [3+2] Annulation of N-Unsubstituted Aromatic Ketimines and
Alkynes. Chem. Eur. J., 2010, 16, 2619. (c) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. Diverse Strategies
toward Indenol and Fulvene Derivatives: Rh-Catalyzed C−H Activation of Aryl Ketones Followed by Coupling
with Internal Alkynes. J. Am. Chem. Soc., 2011, 133, 2154. (d) Tran, D. N.; Cramer, N. Enantioselective
rhodium(I)-catalyzed [3+2] annulations of aromatic ketimines induced by directed C-H activations. Angew.
Chem., Int. Ed., 2011, 50, 11098. (e) Zhao, P.; Wang, F.; Han, K.; Li, X. Ruthenium- and Sulfonamide-
Catalyzed Cyclization between N-Sulfonyl Imines and Alkynes. Org. Lett., 2012, 14, 5506. (f) Li, B.-J.; Wang,
H.-Y.; Zhu, Q.-L.; Shi, Z.-J. Rhodium/copper-catalyzed annulation of benzimides with internal alkynes:
indenone synthesis through sequential C-H and C-N cleavage. Angew. Chem. Int. Ed., 2012, 51, 3948.
(18) (a) L. H. P. Gommans, L. Main, B. K. Nicholson. ortho-Functionalization of aryl ketones with alkenes;
synthesis of 3-methylindene-2-carboxylates and 3-substituted-2-acetylthiophenes from η2-(o-acetylaryl)
tetracarbonyl-manganese compounds with alkenes in the presence of palladium(II). J. Chem. Soc., Chem.
Commun., 1987, 761. (b) R. C. Cambie, M. R. Metzler, P. S. Rutledge, P. D. Woodgate. Cyclomanganation of
diterpenoids; functionalization of Cl4. J. Organomet. Chem., 1990, 381, C26-C30. (c) R. C. Cambie, M. R.
Metzler, P. S. Rutledge, P. D. Woodgate. Synthesis and reactions of ν2-(2-formylphenyl)-tetra-
carbonylmanganese(I) complexes; cyclopentaanulation of a diterpenoid. J. Organomet. Chem.,1990, 398, C22-
C24.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) Kuninobu, Y.; Nishina, Y.; Shouho, M.; Takai, K. Rhenium- and aniline-catalyzed one-pot annulation of
aromatic ketones and α, β-unsaturated esters initiated by C-H bond activation. Angew. Chem., Int. Ed., 2006, 45,
2766.
(20) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Regioselective Synthesis of Indenols by Rhodium-
Catalyzed C-H Activation and Carbocyclization of Aryl Ketones and Alkynes. Angew. Chem., Int. Ed., 2011,
50, 4169.
(21) Shi, X-Y.; Li, C-J. Synthesis of Indene Frameworks via Rhodium-Catalyzed Cascade Cyclization of
Aromatic Ketone and Unsaturated Carbonyl Compounds. Org. Lett., 2013, 15, 1476.
(22) (a) Ackermann, L. Carboxylate-Assisted Transition-Metal-Catalyzed C-H Bond Functionalizations:
Mechanism and Scope. Chem. Rev., 2011, 111, 1315. (b) Zell, D.; Bursch, M.; Müller, V.; Grimme, S.;
Ackermann, L. Full Selectivity Control in Cobalt(III) Catalyzed C-H Alkylations by Switching of the C-H
Activation Mechanism. Angew. Chem., Int. Ed., 2017, 56, 10378. (c) Simmons, E. M.; Hartwig, J. F. On the
interpretation of deuterium kinetic isotope effects in C-H bond functionalizations by transition-metal complexes.
Angew. Chem., Int. Ed., 2012, 51, 3066.
ACS Paragon Plus Environment