C-Alkylation of Various Carbonucleophiles with Secondary Alcohols under CoIII-Catalysis

Article abstract of DOI:10.1021/acscatal.0c01728

Oxindoles have been successfully α-alkylated under Cp*CoIII catalysis by a vast array of secondary alcohols, including cyclic, acyclic, symmetrical, and unsymmetrical, to produce C-alkylated oxindoles. This protocol was also extended to the α-alkylation of N,N-dimethyl barbituric acid and benzyl cyanides. The kinetic profile and other preliminary mechanistic investigations suggest a first-order reaction rate in oxindoles and catalysts. A plausible catalytic cycle is proposed on the basis of the kinetic profile, of other preliminary mechanistic investigations, and of previous mechanistic studies on similar transformations, whereas density functional theory calculations provide insight into the nature of the active species.

Full text of DOI:10.1021/acscatal.0c01728

Subscriber access provided by the University of Exeter
Article
C-Alkylation of Various Carbonucleophiles
with Secondary Alcohols Under CoIII-Catalysis
Priyanka Chakraborty, Nidhi Garg, Eric Manoury, Rinaldo Poli, and Basker Sundararaju
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 26 Jun 2020
Downloaded from pubs.acs.org on June 26, 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 13
ACS Catalysis
1
2
3
4
5
6
7
8
9
C-Alkylation of Various Carbonucleophiles with Secondary Alcohols
Under CoIII-Catalysis
Priyanka Chakraborty,† Nidhi Garg,† Eric Manoury,‡ Rinaldo Poli,‡,* Basker Sundararaju†,*
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
†Department of Chemistry, Indian Institute of Technology Kanpur, Uttar Pradesh, India.
‡ CNRS, LCC (Laboratoire de Chimie de Coordination), Université de Toulouse, UPS, INPT, 205 Route de Narbonne, F-31077 Toulouse Cedex 4, France.
KEYWORDS C-Alkylation, Secondary Alcohol, Dehydrogenation, Cobalt, Borrowing Hydrogen Catalysis.
ABSTRACT: Oxindoles have been successfully α-alkylated under Cp*CoIII catalysis by a vast array of secondary alcohols,
including cyclic, acyclic, symmetrical, and unsymmetrical, to produce C-alkylated oxindoles. This protocol was also extended to
the α-alkylation of N, N-dimethyl barbituric acid and benzyl cyanides. The kinetic profile and other preliminary mechanistic
investigations suggest a first order reaction rate in oxindole and catalyst. A plausible catalytic cycle is proposed on the basis of the
kinetic profile, of other preliminary mechanistic investigations and of previous mechanistic studies on similar transformations,
while DFT calculations provide insight into the nature of the active species.
Key chemical transformations by making use of fundamental
feedstocks towards the expansion of new sustainable
approaches is being highly explored in contemporary science.1
Heterocyclic scaffolds are quite prevalent in natural products,
pharmaceuticals, and other biologically active compounds.2
Therefore, the development of protocols for their selective
alkylation is of particular interest. For example, carbo-
nucleophilic motifs such as oxindoles,3 benzyl cyanides4 and
barbituric acids5 are prominent features in the core structure of
various alkaloids or pharmaceutically relevant drugs (Figure
1a). Researchers across the World involved in drug discovery
programs have started to validate the importance of these
special scaffolds in numerous low-molecular-weight bioactive
molecules and to identify and design novel chemical libraries
against new biological targets.6 Conventional methods to
access such rare secondary alkylated structures require the use
of toxic reagents (alkyl or alkylaryl halides along with strong
bases such as NaH, LiHMDS etc.) which obviously generates
a considerable amount of waste.7 In addition, low-reactivity
and poor selectivity of traditional approach, due to the
competing N-alkylation reaction is a cause of concern.8 Of
late, traditional alkylation using alkyl halides tend to be
Alkylation of various carbo-/heteronucleophiles with
replaced by the metal-catalyzed borrowing hydrogen
secondary alcohols is limited and it is mostly restricted to
methodology,9 by directly employing biomass derived
Figure 1. Overview of C-Alkylation of carbonucleophiles
noble transition metals,11,12 only
a handful of reports
oxidized hydrocarbons such as alcohols as alkylating agent,
thereby producing only water as the sole side product. In this
process the alcohol undergoes a temporary dehydrogenation
with the help of a transition metal catalyst to form a reactive
carbonyl intermediate, which can then undergo a nucleophilic
addition to an in-situ generated carbonucleophile to form an
unsaturated intermediate. Finally, the hydrogen that was
borrowed is returned by the metal to form the hydrogenated
product. However, the currently known reactions catalyzed by
transition-metals for such C-alkylation of carbonucleophiles
are largely limited to primary alcohols as coupling partner,
leaving room for further developments.10
demonstrated the use of 3d transition metals.13 In this regard,
Morril and co-workers reported iron-catalyzed C-alkylation of
oxindoles with a broad scope of primary alcohols, except for
two examples with linear aliphatic secondary alcohol.13a In our
quest to design inexpensive protocols under base metal
catalysis, our group earlier reported C- and N-alkylation of
ketones and amines with secondary alcohols under high-valent
cobalt catalysis.13b-13c,14 Renaud and co-workers reported the
iron-catalyzed direct α-alkylation of ketones using secondary
alcohols.13d Leitner and co-workers reported the α-alkylation
of secondary alcohols with diol for the synthesis of
ACS Paragon Plus Environment

ACS Catalysis
Page 2 of 13
cycloalkanes using manganese catalyst.13e Based on the
of complex B (79%, Table 1, entry 2) whereas significant
1
2
3
4
5
6
7
8
Gunanathan’s pioneering work for the synthesis of α-
olefinated benzylnitriles with secondary alcohol,12c Balaraman
and co-workers reported Mn-catalyzed C-alkylation of benzyl
nitrile to α-olefinated benzylnitriles without forming any
alkylation products.13f Although the α-alkylation of nitriles
with primary alcohols catalyzed by 3d metals is known,15 no
example of nitrile for α-alkylation by secondary alcohol is
documented to date with any-metals as the rehydrogenation of
tetra-substituted olefins is extremely difficult.12c To the best of
our knowledge, efficient catalytic system based on 3d metals
for the C-alkylation of carbonucleophiles (e.g. oxindole,
benzyl nitriles, etc) using secondary alcohols are hitherto
unknown. Herein, we report the C-alkylation of oxindoles,
N,N-dimethyl barbituric acid and benzyl cyanides with a
broad scope of benzylic, linear and cyclic aliphatic secondary
alcohols using air- and moisture stable Cp*CoIII precatalysts
(Figure 1b).
reduction in the yields of 3aa was observed in case of
complexes C&D (31% and 12%, Table 1, entries 3 and 4).
However, increasing the reaction concentration to 1M led to
remarkably better results wherein product 3aa formation
improved to 86% (Table 1, entry 5). A brief screening of other
bases, ligands and solvents did not improve the performance
(entries 6-7, also see SI for comprehensive screening). The
yield of 3aa dropped to 52% when the catalyst loading was
lowered from 10 mol% to 5 mol% (entry 8) and to 71% when
the base loading was reduced to 1.5 equiv. (entry 9). Addition
of a phosphine ligand (PCy3) did not improve the yield further
(entry 10). Finally, control experiments revealed that the
reaction does not proceed in the absence of either the cobalt
catalyst or the base (entry 11-12), indicating that both the
catalyst and base are essential for the alkylation to occur.
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
With optimized conditions in hand, the scope of the reaction
was explored as summarized in Scheme 1. A diverse range of
aryl secondary alcohols with various substitutions were found
to be compatible and afforded the desired C-alkylated products
as diastereomer mixtures in good-to-excellent yields (Scheme
1a, 3aa-3ae). The diastereomeric ratios were determined from
1H NMR analyses. Heteroatom-containing aryl secondary
alcohols were also effective in yielding the corresponding C-
alkylated products in moderate-to-good yields (3af-3ag).
Bulky aryl secondary alcohols such as naphthyl and fluorenyl
formed the desired products in satisfactory yields (3ah-3ai).
Next, 1-phenylpropanol and 1-phenylpentan-1-ol were
employed and the expected products (3aj-3ak) were isolated
in decent yields. Moving on, we then evaluated the tolerance
of aliphatic secondary alcohols under our reaction conditions.
To our extreme delight, various cyclic secondary alcohols
were found to be reactive and afforded the corresponding C-
alkylated products in good-to-excellent yields (3al-3as).
Finally, the scope was further extended to unactivated linear
aliphatic secondary alcohols. Gratifyingly, both symmetrical
and unsymmetrical linear alcohols, including isopropyl, 3-
pentyl, sec-butyl, 2-hexyl and 2-octyl, provided the desired
product in good yields (3at-3ax). This protocol was employed
in the late-stage functionalization of cholesterol and the
corresponding alkylated derivative 3ay was obtained as
expected. To further verify the reaction scope, various
substituted oxindoles, including N-substituted derivatives,
along with cyclohexanol 2m afforded the corresponding C-
alkylated products under the optimized conditions (3bm–
3em).
Table 1. Optimization Studies and Control Experimentsa
Entry
[Co] cat ( mol %)
A (10)
Base (equiv.)
Yield (%)b
1
2
3
4
5
6
KOH (2)
KOH (2)
77
79
B (10)
KOH (2)
KOH (2)
K2CO3 (2)
KOH (2)
KOH (2)
KOH (2)
KOH (1.5)
KOH (2)
-
C (10)
31
D (10)
12
A(10)
86c
43c
A (10)
7
8
A(10)
A (5)
A (10)
A(10)
A(10)
-
73d
52c
71c
n.re
n.r.
n.r.
9
10
11
12
Barbituric acids comprise another class of heterocyclic
compounds that exhibits a wide array of biological activities
such as hypnotic, antimicrobial, antitumor and sedative
properties.5 Since, they comprise an interesting class of
carbonucleophiles, we examined the reactivity of N,N-
dimethyl barbituric acid (4) under our standard conditions.
Pleasingly, the expected products were obtained in good yields
(Scheme 1b, 5aa–5ah). This is the first report on alkylation of
barbituric acids using secondary alcohols and the reaction does
not require any base unlike in the previous reaction. This is
likely due to the greater acidity of barbituric acid (pKa = 4.8)
in comparison to other carbonucleophiles. We were also
interested in employing benzyl cyanides as the
carbonucleophile and a brief optimization (see SI) revealed
that the C-alkylated product 6am was formed
KOH (2)
a Standard reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol),
[Co] (0.002 – 0.01 mmol), KOH (0.4 mmol) in toluene (0.2 M),
b
c
at 150 °C for 16 h.
Isolated yield. Conducted at 1M
concentration. d TFT used as solvent.e PCy3 (10 mol%) was used
along with A. n.r. = no reaction.
We began our investigations with 2-oxindole (1a) and 1-
phenylethanol (2a) as model reactants and by employing 10
mol% of [Cp*Co(CO)I2] as precatalyst in the presence of
KOH as the base in toluene (0.2 M) at 150 °C for 16 hours.
Delightfully, the expected C-alkylated product was isolated in
77% yield (Table 1, entry 1). Intrigued by this, screening of
other Cp*CoIII complexes led to marginal improvement in case
ACS Paragon Plus Environment

Page 3 of 13
1
ACS Catalysis
Scheme 1. Scope of Secondary Alcohols and Carbonucleophiles.
2
3
4
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
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 13
(a) Scope of Oxindoles
1
N
O
2
3
4
5
6
7
S
Me
Me
R
Me
Me
Me
Me
R
O
O
O
O
O
N
N
N
H
N
N
N
H
H
H
H
H
(3ab)
82%, R = Me; (1.7:1 dr),
(3ac)
76%, R = Br; (1.2:1 dr),
(3ad)
60%, R = Cl; (1.1:1 dr),
(3ae)
87%, R = OMe; (1.7:1 dr),
(3aa)
(3af)
86%, (1.7:1 dr)
61%, (1.8:1 dr),
(3ag)
43%, (1.0:0.8 dr),
(3ah)
77%, (1.8:1 dr),
8
9
Me
n
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
O
O
N
H
O
O
O
O
N
H
N
H
N
H
N
H
N
H
(3ai)
(3aj)
(3ak)
56%
42%, n = 1
31%, n = 2
)
(10 mol% (Cp*CoI2)2
(3an)
80%,
Me
(3al)
(3ao)
68%,
84%
% (3am)
91
40% (7.5 mmol, 2 mol%, TON = 20)
Me
Me
Me
Me
Me
n
Me
O
Me
n
O
O
O
N
N
H
O
H
O
N
H
N
H
N
H
N
H
(3at)
(3at,
29%
55%
(3av)
73%; n = 1; (1.3:1 dr),
72%; n = 3; (1.3:1 dr), (3aw)
77%; n = 5; (1.4:1 dr),
(3ap)
(3aq)*
*(10 mol% (Cp*CoI2)2)
41%; n = 1
33%; n = 5
)
36 h
(3as)
45%, (1:1 dr)
(3ar)
(3au)
90%, (1:0.3 dr)
51%
(3ax)
Me
Me
Me
Me
3
H
Me
H
Br
Cl
O
O
N
O
O
H
N
Me
N
H
N
H
Ph
N
O
(3bm)
(3cm)
(3dm)
(3em)
82%
67%
56%
44%
(3ay)
31% (36 h) (6.7:1 dr)
H
O
(b) Scope of N,N Dimethyl Barbituric Acid
R2
O
O
Me
Cp*Co(CO)I2 - 10 mol %
Toluene (1M), 150 °C, 16 h, Ar
OH
R2
Me
N
R1
N
+
R1
O
N
O
N
O
Me
Me
Me
Me
O
N
Me
O
O
N
Me
O
N
Me
O
O
O
Me
O
Me
O
Me
O
Me
O
Me
N
N
N
N
N
O
Me
O
R
N
O
N
O
Cl
Me
Me
(5aa)
Me
Me
Me
(5ab)
(5ac)
(5az)
58%
R = Br; 73%
R = F ; 77%
83%
(5ah)
70%
(5ad)
72%
(c) Scope of Cyanides
R1
R2
Cp*Co(CO)I2 - 5 mol %
L - 10 mol %
PPh2
KOtBu - 2 equiv
OH
L =
CN
CN
R
+
R
CO2H
R1
R2
Toluene, 150 °C, 24 h, Ar
Me
CN
CN
CN
CN
CN
CN
Br
(6an)
(6am)
73%;
(6ao)
46%;
77%
(6as)
77%
(6bm)
57%
(6cm)
44%
ACS Paragon Plus Environment

Page 5 of 13
ACS Catalysis
1
2
3
4
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
Figure 2: (a) Concentration vs.time plot for the 3am formation in the C-alkylation of oxindole (1a) with cyclohexanol (2m) at various
catalyst concentrations. (b) First-order plots of the 3am formation at various concentrations (see SI for more details).
in 77% yield from benzyl cyanide and cyclohexanol in the
(a) Deuterium labelling experiment
presence of 5 mol% of [Cp*Co(CO)I2], 10 mol% of 2-
(diphenylphosphino)benzoic acid as the ligand and 2 equiv. of
tBuOK. The scope of the cyanides was extended to a few more
cyclic secondary alcohols giving the products in good yields
(Scheme 1c, 6am-6da). However, linear and aryl secondary
alcohols were found to be incompatible with our catalytic
system. Although limited, this protocol is still attractive
because it forms C-alkylated products directly from secondary
alcohols which are unexplored so far under any catalytic
system.
(63%)
Cp*Co(CO)I2 - 10 mol %
KOH - 2 equiv.
OH
H/D
D
H/D
O
O
(8%)
+
N
Toluene (1M), 150 °C,
16 h, Ar
H
N
H
1a
2m-D
> 99% D
3am-D; 68%
(b) Hg(0) drop experiment
Cp*Co(CO)I2 - 10 mol %
KOH - 2 equiv.
Hg(0) - 10 equiv.
OH
O
+
N
O
H
Toluene (1M), 150 °C,
16 h, Ar
N
H
1a
2m
3am; 82%
Scheme 2. Control Experiments
(c) Hydrogenation of intermediate with cyclohexanol
Me
Me
Cp*Co(CO)I2 - 10 mol %
Me
OH
Me
O
KOH - 2 equiv.
+
+
O
O
Toluene (1M), 150 °C,
16 h, Ar
N
N
H
H
2m
7
3au; 75%
(detected by
NMR and GCMS)
(d) Intermolecular competive experiment (one-pot)
OH
Me
Me
5
Cp*Co(CO)I2 - 10 mol %
KOH - 2 equiv.
Me
5
2y
+
O
O
N
Toluene (1M), 150 °C,
16 h, Ar
Me
N
H
H
HO
6
3ay; 71%
1a
2y'
(e) Intermolecular competive experiment (parallel)
OH
Cp*Co(CO)I2 - 10 mol %
KOH - 2 equiv.
+
3ay'
+
O
O
2o
N
Toluene (1M), 150 °C,
16 h, Ar
N
H
H
Me
traces
HO
3ao; 71%
6
1a
2y'
To gain insights into the reaction mechanism, we monitored
1
the reaction profile via H NMR. The product formation data
(Fig. 2a) gave a linear semilog plot, consistent with first-order
dependence on the oxindole concentration.(Fig. 2b, see SI for
details), v = Kobs[1a]. The pseudo-first order rate constant Kobs
is obtained from the slope of this plot (0.0112 min-1).The study
was repeated at different catalyst concentrations, showing
again linear semilog plots (Fig. 2b) and slopes that scaled
linearly with the catalyst concentration (see SI for details), kobs
= k[A], indicating that the rate law also has a first-order
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 13
dependence in catalyst. The rate constant (k) obtained from the
than the alcohol, raising questions about its possible
best fit of the k vs. [A] data is 0.111±0.001 L mol-1 min-1).
implication as a ligand (Scheme 3), forming a new precatalyst
[Cp*CoIX] or [Cp*CoX2], where X is the deprotonated
oxindole. When R = H, deprotonation may occur either at the
N atom or at the C atom, whereas only the latter is possible for
the N-substituted oxindoles, in which case the resulting anion
is an enolate capable of bonding to the metal via either the C
or the O atom. Subsequently, further exchange of the residual I
ligand from [Cp*CoIX], or of an X ligand from [Cp*CoX2],
introduces the deprotonated alcohol to afford the alkoxide
complex E, which may initiate the hydrogen borrowing
chemistry. Preliminary DFT calculations have explored the
possible nature of these species. Since electron pairing
energies may be considerable, particularly in high oxidation
state complexes of the first row metals, the 16-electron
Cp*CoXI complex may adopt either a singlet or a triplet
ground state.17 In addition, either a monodentate (κ1) or a
chelating (κ2:N,O) coordination mode is possible for both N-
and O-bonded indolate, whereas the C-bonded ligand can only
be monodentate. All these possibilities were probed for the
two oxindoles 1a (R = H) and 1d (R = Me).
1
2
3
4
5
6
7
8
Next, we carried out various control experiments to further
understand the reaction pathways as shown in Scheme 2.
Deuterium labelling experiments were performed with 1a and
alcohol 2m-D to validate the hydrogen-borrowing process.
Under standard reaction conditions, the product 3am-D
formed in 68% yield and exhibited 8 and 63% deuterium
incorporation at the - and -positions relative to the carbonyl
group (Scheme 2a). Next, a mercury poisoning test where the
reaction was carried out in the presence of 10 equiv. of Hg
under standard conditions, which provided the alkylated
product 3am in 82% yield (91% without Hg) confirming that
the system is indeed homogeneous (Scheme 2b). For further
verification, intermediate 7 was prepared and a reaction was
carried out under standard conditions using cyclohexanol as
the hydride source. This yielded the product 3au in 75% yield
indicating that the final hydrogenation of the tetra substituted
olefin is achieved with hydrogen originated from alcohol
(Scheme 2c). We then performed an one-pot intramolecular
competitive experiment by employing both 1-octanol (2y’)
and 2-octanol (2y). Under standard reaction conditions 3ay
was isolated exclusively, confirming that our catalytic system
is selective for alkylation with secondary alcohols over
primary alcohols (Scheme 2d). However, parallel experiments
provide the expected product in 71% (3ao) and traces (3ao’)
respectively under the standard conditions (Scheme 2e). The
reason for this selectivity appears to be associated to the
decreased thermodynamic cost of the hydrogen borrowing step
for secondary alcohol relative to primary ones.16
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
In order to save computational time, the calculations were
carried on a simplified model system where the Cp* ring was
replaced with the unsubstituted Cp ligand. The results (see SI
for details) are summarized in Fig. 3. For the
CpCo(oxindolate-1-H) (derived from deprotonated 1a), N-and
C-coordination are much more favoured than O-coordination.
For all three linkage isomers, the preferred binding is
monodentate and the preferred spin state is triplet. Chelation to
afford an electronically saturated configuration stabilizes the
N-bonded complex in the singlet state, as expected from the
formation of an additional bond, but is insufficient to
compensate the cost of pairing the two electrons in the more
stable 16-electron spin triplet complex. Chelation is not
favoured for the spin triplet because it would place one
electron in a high-energy antibonding orbital (attempts to
optimize 18-electron chelate structures in the triplet state led
back to the corresponding monodentate minimum). For the O-
bonded complex in the singlet state, although a minimum
could be located, chelation destabilizes the system because the
energy gain associated to the formation of the additional bond
insufficiently compensates the loss of pyrrole ring aromaticity
caused by the N lone pair involvement in the N-Co bond. It is
interesting to note that the N-bonded isomer is actually more
stable that the C-bonded one in terms of electronic energy (by
5.8 kcal/mol), but this advantage is compensated, according to
the calculations,
In previous Cp*CoIII-catalyzed hydrogen borrowing
chemistry,13b-13c it was established that thermal CO loss from
[Cp*CoI2(CO)] A, or bridge rupture from [Cp*CoI2]2 B,
generate the 16-electron [Cp*CoI2] complex (the two
precatalysts have the same activity). Then, alcohol (ROH)
deprotonation by the strong base and ligand exchange yields
[Cp*CoI(OR)], from which ketone is produced by β-H
elimination. In the present case, however, the oxindole
substrate is more acidic
Scheme 3. Possible Interactions Between [Cp*CoI2] and
Deprotonated [Oxindole]
ACS Paragon Plus Environment

Page 7 of 13
ACS Catalysis
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Figure 3: Energetic profile for the Cp*CoIX system with X = deprotonated oxindole 1a (R = H) and 1d (R = Me).
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: Proposed Catalytic Cycle
ACS Paragon Plus Environment

ACS Catalysis
Page 8 of 13
1
2
3
4
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
by the combined effect of a lower zero-point vibrational
insertion selectively at the γ-position to afford I. Proton
energy, higher entropy, and a greater solvation stabilization for
the C-bonded isomer. For the CpCo(oxindolate-1-Me)
(derived from deprotonated 1d), no N binding is possible and
the C-bonded 16-electron spin triplet complex is the most
stable species. The relative energies obtained for the other
possible binding modes and spin states are rather similar for
the 1-H and 1-Me oxindolate systems. Thus, the calculation
suggests that the key catalytically active species E most
probably contains a monodentate C-bonded oxindolate ligand
for both 1-H and 1-Me oxindoles. The calculation also confirm
the greater oxindole stability in the 2-oxo form than in the
tautomeric 2-hydroxo form (by 17.4 kcal/mol for 1a and 16.6
kcal/mol for 1d).These collective results, together with those
previously obtained for other Cp*CoIII-catalyzed alkylations
by the “hydrogen borrowing” strategy (e.g. of amines13b and
ketones13c), allow us to propose the mechanism shown in
Scheme 4. The cycle can proceed, similarly to the amine
alkylation cycle,13b by β-H elimination from intermediate E to
produce intermediate F with the coordinated ketone.
exchange with a new alcohol molecule regenerates E and
releases the product as the 2-hydroxyindole tautomer, which
finally rearranges to the alkylated oxindole. The small amount
of deuterium incorporation at the β-position, observed for the
experiment carried out with 2m-D, may be rationalized by the
competition of a reversible dehydrogenation process via
intermediate G, producing HD. The reverse of this step would
place the deuterium atom in the alcohol at the protic hydroxide
position. Then, this deuterium atom can get involved in the
final proton transfer step (I to E), ending up at the β-position
of the alkylated product by tautomerization. The same process
also rationalizes the reduced deuterium fraction at the product
γ-position from the control experiments.
A full DFT
investigation of the catalytic cycle is ongoing and will be
reported in due course.
In conclusion, we herein report the use of a bench-stable, high-
valence Cp*CoIII catalyst for the C-alkylation of various
carbonucleophiles with secondary alcohols. A diverse array of
aryl, cyclic and acyclic aliphatic secondary alcohols are
tolerant with the developed method for the selective C-
alkylation of oxindoles. Preliminary investigations reveal that
the reaction follows first order kinetics and is indeed a
homogenous hydrogen autotransfer process. Based on
After dissociation to generate the 16-electron hydride complex
G, the ketone is attacked by the deprotonated oxindole to yield
the unsaturated intermediate 7, which coordinates to yield
intermediate H. The latter then receives the hydride ligand by
ACS Paragon Plus Environment

Page 9 of 13
ACS Catalysis
Their Pharmaceutical Significance - An Overview. Asian J. Res.
inferences from DFT calculations, a mechanistic pathway has
1
2
3
4
5
6
7
8
Chem. 2011, 4, 335-338. (d) Gupta, A. K.; Kalpana, S.; Malik, J.
K. Synthesis and in Vitro Antioxidant Activity of New 3-
Substituted-2-Oxindole Derivatives. Indian J. Pharm Sci. 2012,
74, 481-486. (e) Antonchick, A. P.; Gerding-Reimers, C.;
Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.;
Waldmann, H. Highly Enantioselective Synthesis and Cellular
Evaluation of Spirooxindoles Inspired by Natural Products. Nat.
Chem., 2010, 2, 735-740. (f) Ball-Jones, N. R.; Badillo, J. J.;
Franz, A. K. Strategies for the Enantioselective Synthesis of
Spirooxindoles. Org. Biomol. Chem., 2012, 10, 5165-5181. (g)
Rodrigues, D. Reker, P.; Schneider, G.; Schneid-er, Counting on
Natural Products for Drug Design. Nat. Chem. 2016, 8, 531-541.
(h) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-Ronchi, A. A
Journey Across Recent Advances in Catalytic and Stereoselective
Alkylation of Indoles. Synlett 2005, 1199-1222.
(4) (a) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.;
Shook, B. C. Nitrile-Containing Pharmaceuticals: Efficacious
Roles of the Nitrile Pharmacophore. J. Med. Chem. 2010, 53,
7902-7917. (b) Simpol, L. R.; Otsuka, H.; Ohtani, K.; Kasai, R.;
Yamasaki, K. Nitrile Glucosides and Rosmarinic Acid, The
Histamine Inhibitor from Ehretia Philippinensis. Phytochemistry
1994, 36, 91-95. (c) Berteotti, A.; Vacondio, F.; Lodola,
A.; Bassi, M.; Silva, C.; Mor, M.; Cavalli, A. Predicting the
Reactivity of Nitrile-Carrying Compounds with Cysteine: A
Combined Computational and Experimental Study. ACS Med
Chem Lett. 2014, 5, 501-505. (d) Jones, L. H.; Summerhill, N. W.;
Swain, N. A; Mills, J. E. Aromatic chloride to nitrile
transformation: medicinal and synthetic chemistry. Med. Chem.
Commun. 2010, 1, 309-318.
been proposed. We have also demonstrated the selective C-
alkylation of N,N-dimethyl barbituric acid and benzyl
cyanides with secondary alcohols under high valent Co(III)
catalysis. This developed protocol forms an entire library of
new scaffolds, thereby opening the gateway for many other
applications.
ASSOCIATED CONTENT
Supporting Information
9
The Supporting Information is available free of charge on the
ACS Publications website at DOI: .
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
Experimental methods, optimization of reaction conditions, and
other supplementary data (PDF)
AUTHOR INFORMATION
Corresponding Author
*Email for BS: basker@iitk.ac.in and for RP:rinaldo.poli@lcc-
toulouse.fr
ORCID
BS: 0000-0003-1112-137X
RP: 0000-0002-5220-2515
EM: 0000-0001-7991-8890
(5) (a) Jansson, I.; Orrenius, S.; Ernster, L.; Schenkman, J. B.
Archives of Biochemistry and Biophysics 1972, 151, 391-400. (b)
Levi, L.; Hubley, C. E. Detection and Identification of Clinically
Important Barbiturates. Anal. Chem. 1956, 28, 1591-1605.
Notes
(6) (a) Lee, Y.-C.; Patil, S.; Golz, C.; Strohmann, C.; Zigler, S.;
Kumar, K.; Waldmann, H. A Ligand-Directed Divergent Catalytic
Approach to Establish Structural and Functional Scaffold
Diversity. Nat. Commun. 2017, 8, 14043-14054. (b) Krug, M.;
Hilgeroth, A. Recent Advances in the Development of Multi-
Kinase Inhibitors. Mini. Rev. Med. Chem. 2008, 8, 1312-1327. (c)
Antoniu, S. A.; Kolb, M. R. Intedanib, a Triple Kinase Inhibitor
of VEGFR, FGFR and PDGFR for the Treatment of Cancer and
Idiopathic Pulmonary Fibrosis. IDrugs, 2010, 13, 332-345. (d)
Chen, G.; Weng, Q.; Fu, L.; Wang, Z.; Yu, P.; Liu, Z.; Li, X.;
Zhang, H.; Liang, G. Synthesis and Biological Evaluation of
Novel Oxindole-based RTK Inhibitors as Anti-Cancer Agents.
Bioorg. and Med. Chem. 2014, 22, 6953-6960. (e) Boldi, A. M.
Libraries from Natural Product-like Scaffolds. Curr. Opin. Chem.
Biol. 2007, 8, 281-286. (f) Thomas, G. L.; Johannes, C. W.
Natural Product-like Synthetic Libraries. Curr.Opin. Chem. Biol.
2011, 15, 516-522. (g) Camp, D.; Davis, R. A.; Evans-Illidge, E.
A.; Quinn, R. J. Guiding Principles for Natural Product Drug
Discovery. Future Med. Chem. 2012, 4, 1067-1084. (h) Lachance,
H.; Wetzel, S.; Kumar, K.; Waldmann, H. Charting, Navigating,
And Populating Natural Product Chemical Space forDrug
Discovery. J. Med. Chem. 2012, 55, 5989-6001. (i) Zuegg, J.;
Cooper, M. A. Drug-Likeness and Increased Hydrophobicity of
Commercially Available Compound Libraries for Drug Screening.
Curr. Top. Med. Chem. 2012, 12, 1500-1513.
The author declares no competing financial interest.
ACKNOWLEDGMENT
Financial support provided by CEFIPRA (IF-5805-1) for an
Indo-French project for BS, RP and EM is gratefully
acknowledged. P.C and N.G thankful to IITK and CSIR for
their fellowship. The authors thank Dr. Bhuttu Khan for
carrying out few experiments and isolation of some of the
products during the revision.
REFERENCES
(1) (a) Yeung, C. S.; Dong, V. M. Catalytic Dehydrogenative
Cross-Coupling: Forming Carbon-Carbon Bonds by Oxidizing
Two Carbon-Hydrogen Bonds. Chem. Rev. 2011, 111, 1215-1292.
(b) Jenck, J. F.; Agterberg, F.; Droescher, M. J. Products and
Processes for a Sustainable Chemical Industry: A Review of
Achievements and Prospects. Green Chem., 2004, 6, 544-556.
(2) (a) Bräse, S. Privileged Scaffolds in Medicinal Chemistry.
Design, Synthesis, Evaluation, RSC, Cambridge, 2015, 476 pp.,
ISBN: 978-1-78262-030-3. (b) Dinges, J.; Lamberth, C. Bioactive
Heterocyclic Compound Classes: Pharmaceuticals, Wiley-VCH,
Weinheim, Germany, 2012, pp 1-20.
(3)(a) Kaur, M.; Singh, M.; Chadha, N.; Silakari, O. Oxindole:
A Chemical Prism Carrying Plethora of Therapeutic Benefits.
Eur. J. Med. Chem. 2016, 123, 858-894. (b) Sun, Y.; Liu, J.;
Jiang, X.; Sun, T.; Liu, L.; Zhang, X.; Ding, S.; Li, J.; Zhuang, Y.;
Wang, Y.; Wang, R. One-Step Synthesis of Chiral Oxindole-type
Analogues with Potent Anti-inflammatory and Analgesic
Activities. Scientific Reports, 2015, 5, 13699-13705. (c) Rudrangi,
S. R. S.; Bontha, V. K.; Manda, V. R., Bethi, S. Oxindoles and
(7) Conventional methods: (a) Rueping, M.; Nachtsheim, B. J.
A Review of New Developments in the Friedel-Crafts Alkylation
- from Green Chemistry to Asymmetric Catalysis. Beilstein J.
Org. Chem. 2010, 6, 6-30. (b) Ziarani, G. M.; Gholamzadeh, P.;
Lashgari, N.; Hajiabbasi, P. Oxindole as Starting Material in
Organic Synthesis. Reviews and Accounts, 2013, 470-535.
ACS Paragon Plus Environment

ACS Catalysis
Page 10 of 13
(8) (a) Gruda, I. Formation Des Dérivés N- et C-Substitués Au
Hydrogenation/Dehydrogenation Catalysts: Similarities and
1
2
3
4
5
6
7
8
Cours De L'Alkylation De L'Indol-2(3H)-one. Can. J. Chem.
1972, 50, 18-23. (b) Kende, A. S.; Hodges, J. C. Regioselective
C-3 Alkylations of Oxindole Dianion. Synth. Commun. 1982, 12,
1-10.
Divergences. Acc. Chem. Res. 2018, 51, 1558-1569. (j) Maji, B.;
Barman, M. K. Recent Developments of Manganese Complexes
for Catalytic Hydrogenation and Dehydrogenation Reactions.
Synthesis 2017, 49, 3377-3393. (k) Garbe, M.; Junge, K.; Beller,
M. Homogeneous Catalysis by Manganese-Based Pincer
Complexes. Eur. J. Org. Chem. 2017, 4344-4362. (l) Valyaev, D.
A.; Lavigne, G.; Lugan, N. Manganese Organometallic
Compounds in Homogeneous Catalysis: Past, Present, and
Prospects. Coord. Chem. Rev. 2016, 308, 191-235.
(9) Selected reviews: (a) Reed-Berendt, B.G.; Polidano, K.;
Morrill, L. C. Recent Advances in Homogeneous Borrowing
Hydrogen Catalysis using Earth-Abundant First Row Transition
Metals Org. Biomol. Chem. 2019, 17, 1595-1607. (b) Faisca
Phillips, A. M.; Pombeiro, A. J. L.; Kopylovich, M. N. Recent
Advances in Cascade Reactions Initiated by Alcohol Oxidation.
ChemCatChem 2017, 9, 217-246. (c) Obora, Y.; Ishii, Y. Iridium-
Catalyzed Reactions Involving Transfer Hydrogenation, Addition,
N-Heterocyclization, and Alkylation Using Alcohols and Diols as
Key Substrates. Synlett 2011, 30-51. (d) Dobereiner, G. E.;
Crabtree, R. H. Dehydrogenation as a Substrate-Activating
Strategy in Homogeneous Transition-Metal Catalysis. Chem. Rev.
2010, 110, 681-703. (e) Crabtree, R. H. Homogeneous Transition
Metal Catalysis of Acceptorless Dehydrogenative Alcohol
Oxidation: Applications in Hydrogen Storage and to Heterocycle
Synthesis. Chem. Rev. 2017, 117, 9228-9246 (f) Corma, A.;
Navas, J.; Sabater, J. M. Advances in One-Pot Synthesis through
Borrowing Hydrogen Catalysis. Chem. Rev. 2018, 118, 1410-
1459. (g) Huang, F.; Liu, Z.; Yu, Z. C-Alkylation of Ketones and
Related Compounds by Alcohols: Transition-Metal-Catalyzed
Dehydrogenation. Angew. Chem. Int. Ed. 2016, 55, 862-875;
Angew. Chem. 2016, 128, 872-885 (h) Obora, Y. C-Alkylation by
Hydrogen Auto-transfer Reactions. Top. Curr. Chem. 2016,
374:11, pp 1-29. (i) Khusnutdinova, J. R.; Milstein, D. Metal-
Ligand Cooperation. Angew. Chem. Int. Ed. 2015, 54, 12236-
12273; Angew. Chem. 2015, 127, 12406-12445 (j) Gunanathan,
C.; Milstein, D. Bond Activation and Catalysis by Ruthenium
Pincer Complexes. Chem. Rev. 2014, 114, 12024-12087. (k)
Gunanathan, C.; Milstein, D. Applications of Acceptorless
Dehydrogenation and Related Transformations in Chemical
Synthesis. Science 2013, 341, 1229712; l) Marr, A. C.
Organometallic hydrogen transfer and dehydrogenation catalysts
for the conversion of bio-renewable alcohols. Catal. Sci. Technol.
2012, 2, 279-287. (m) Zhang, J.; Leitus, G.; Ben-David, Y.;
Milstein, D. Facile Conversion of Alcohols into Esters and
Dihydrogen Catalyzed by New Ruthenium Complexes. J. Am.
Chem. Soc. 2005, 127, 10840-10841.
(11) (a) Kawahara, R.; Fujita, K.; Yamaguchi, R.
Multialkylation of Aqueous Ammonia with Alcohols Catalyzed
by Water-Soluble Cp*Ir-Ammine Complexes. J. Am. Chem. Soc.
2010, 132, 15108-15111. (b) Imm, S.; Bähn, S.; Neubert, L.;
Neumann, H.; Beller, M. An Efficient and General Synthesis of
Primary Amines by Ruthenium‐Catalyzed Amination of
Secondary Alcohols with Ammonia. Angew. Chem., Int. Ed. 2010,
49, 8126-8129. (c) Fujita, K. I.; Fujii, T.; Yamaguchi, R. Cp*Ir
Complex-Catalyzed N-Heterocyclization of Primary Amines with
Diols:ꢀ A New Catalytic System for Environmentally Benign
Synthesis of Cyclic Amines. Org. Lett. 2004, 6, 3525-3528. (d)
Fujita, K. I.; Yamamoto, K.; Yamaguchi, R. Oxidative
Cyclization of Amino Alcohols Catalyzed by a Cp*Ir Complex.
Synthesis of Indoles, 1,2,3,4-Tetrahydroquinolines, and 2,3,4,5-
Tetrahydro-1-benzazepine. Org. Lett. 2002, 4, 2691-2694. (e) Xu,
Q.; Xie, H.; Zhang, E.-L.; Ma, X.; Chen, J.; Yu, X.-C.; Li, H.
Selective catalytic Hofmann N-alkylation of poor nucleophilic
amines and amides with catalytic amounts of alkyl halides. Green
Chem. 2016, 18, 3940-3944. (f) Montgomery, S. L.; Mangas-
Sanchez, J.; Thompson, M. P.; Aleku, G. A.; Dominguez, B.;
Turner, N. J. A Biocatalytic Cascade for the Amination of
Unfunctionalised Cycloalkanes. Angew. Chem., Int. Ed. 2017, 56,
10491-10494. (g) Rong, Z.-Q.; Zhang, Y.; Bing Chua, R. H.; Pan
H.-J.; Zhao, Y. Dynamic Kinetic Asymmetric Amination of
Alcohols: From A Mixture of Four Isomers to Diastereo- and
Enantiopure α-Branched Amines. J. Am. Chem. Soc. 2015, 137,
4944-4947. (h) Mutti, F.G.; Knaus, T.; Scrutton, N. S.; Breuerand,
M.; Turner, N. J. Conversion of Alcohols to Enantiopure Amines
Through Dual-Enzyme Hydrogen-Borrowing Cascades. Science,
2015, 349, 1525-1529. (i) Akhtar, W. M.; Armstrong, R. J.; Frost,
J. R.; Stevenson, N. G.; Donohoe, T. J. Stereoselective Synthesis
of Cyclohexanes via an Iridium Catalyzed (5 + 1) Annulation
Strategy. J. Am. Chem. Soc. 2018, 140, 11916-11920. (j) Cheang,
D. M. J.; Armstrong, R. J.; Akhtar, W. M.; Donohoe, T. J.
Enantio-convergent Alkylation of Ketones with Racemic
Secondary Alcohols via Hydrogen Borrowing Catalysis. Chem.
Commun., 2020, 56, 3543-3546. (k) Armstrong, R. J.; Akhtar, W.
M.; Young, T. A.; Duarte, F.; Donohoe, T. J. Catalytic
Asymmetric Synthesis of Cyclohexanes by Hydrogen Borrowing
Annulations. Angew. Chem., Int. Ed., 2019, 58, 12558-12562.
(12) (a) Chelucci, G. Recent Advances in Osmium-Catalyzed
Hydrogenation and Dehydrogenation Reactions. Coord. Chem.
Rev. 2017, 331, 1-36. (b) Porcheddu, A.; Chelucci, G. Base-
Mediated Transition-Metal-Free Dehydrative C-C and C-N Bond-
Forming Reactions from Alcohols. Chem. Rec. 2019, 19, 1-39. (c)
S. Thiyagarajan, C. Gunanathan, Ruthenium-Catalyzed α-
Olefination of Nitriles Using Secondary Alcohols. ACS Catal.
2018, 8, 2473-2478. (d) Thiyagarajan, S.; Gunanathan, C. Facile
Ruthenium(II)-Catalyzed α-Alkylation of Arylmethyl Nitriles
Using Alcohols Enabled by Metal–Ligand Cooperation. ACS
Catal. 2017, 7, 5483-5490. (e) Akhtar, W. M.; Cheong, C. B.;
Frost, J. R.; Christensen, K. E.; Stevenson, N. G.; Donohoe, T. J.
Hydrogen Borrowing Catalysis with Secondary Alcohols: A New
Route for the Generation of β-Branched Carbonyl Compounds. J.
Am. Chem. Soc. 2017, 139, 2577-2580. (f) Kishore, J.;
Thiyagarajan, S.; Gunanathan, C. Ruthenium(II)-catalysed Direct
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) Reviews: (a) Guillena, G.; Ramón, D. J.; Yus, M. Alcohols
as Electrophiles in C-C Bond‐Forming Reactions: The Hydrogen
Auto-transfer Process. Angew. Chem. Int. Ed. 2007, 46, 2358-
2364. (b) Obora, Y. Recent Advances inα-Alkylation Reactions
using Alcohols with Hydrogen Borrowing Methodologies. ACS
Catal.2014, 4, 3972-3981. (c) Chelucci, G. Ruthenium and
Osmium Complexes in C-C Bond-forming Reactions by
Borrowing Hydrogen Catalysis. Coord. Chem. Rev. 2017, 331, 1-
36. (d) Cai, Y.; Li, F.; Li, Y.-Q.; Zhang, W.-B.; Liu, F.-H.; Shi,
S.-L. Base Metal-Catalyzed Alcohol C−C Couplings under
Hydrogen Transfer conditions. Tetrahedron Lett. 2018, 59, 1073-
1079. Also see with 3d metals, (e) Irrgang, T.; Kempe, R. 3d-
Metal Catalyzed N- and C-Alkylation Reactions via Borrowing
Hydrogen or Hydrogen Auto transfer. Chem. Rev. 2019, 119,
2524-2549. (f) Corma, A.; Navas, J.; Sabater, M. J. Advances in
One-Pot Synthesis through Borrowing Hydrogen Catalysis. Chem.
Rev., 2018, 118, 1410-1459. (g) Holmes, M.; Schwartz, L. A.;
Krische, M. J. Intermolecular Metal-Catalyzed Reductive
Coupling of Dienes, Allenes, and Enynes with Carbonyl
Compounds and Imines. Chem. Rev., 2018, 118, 6026-6052. (h)
Kallmeier, F.; Kempe, R. Manganese Complexes for
(De)Hydrogenation Catalysis: A Comparison to Cobalt and Iron
Catalysts. Angew. Chem., Int. Ed. 2018, 57, 46-60. (i) Gorgas, N.;
Kirchner,
K.
Isoelectronic
Manganese
and
Iron
ACS Paragon Plus Environment

Page 11 of 13
ACS Catalysis
Synthesis of Ketazines Using Secondary Alcohols. Chem.
(17) Poli, R. Open-Shell Organometallics as a Bridge between
1
2
3
4
5
6
7
8
Commun., 2019, 55, 4542-4545. (g) Thiyagarajan, S.;
Gunanathan. C. Catalytic Cross-Coupling of Secondary Alcohols.
J. Am. Chem. Soc., 2019, 141, 3822-3827. (h) Lu, Y.; Zhao, R.;
Guo, J.; Liu, Z.; Menberu, W. Wang, Z.‐X. A Unified Mechanism
to Account for Manganese‐ or Ruthenium‐Catalyzed Nitrile
α‐Olefinations by Primary or Secondary Alcohols: A DFT
Mechanistic Study. Chem. Eur. J. 2019, 25, 3939.
(13) (a) Dambatta, M. B.; Polidano, K.; Northey, A. D.;
Williams, J. M. J.; Morrill, L. C. Iron-Catalyzed Borrowing
Hydrogen C-Alkylation of Oxindoles with Alcohols.
ChemSusChem 2019, 12, 2345-2349. (b) Emayavaramban, B.;
Chakraborty, P.; Manoury, E.; Poli, R.; Sundararaju, B.
Cp*Co(III)-Catalyzed N-Alkylation of Amines with Secondary
Alcohols. Org. Chem. Front. 2019, 6, 852-857. (c) Chakraborty,
P.; Gangwar, M. K.; Manoury, E.; Poli, R.; Sundararaju, B.
α‐Alkylation of Ketones with Secondary Alcohols Catalyzed by
Well‐Defined Cp*CoIII‐Complexes. ChemSusChem 2019, 12, 1-6.
(d) Bettoni, L.; Gaillard, S.; Renaud, J.-L. Iron-Catalyzed α-
Alkylation of Ketones with Secondary Alcohols: Access to β-
Disubstituted Carbonyl Compounds. Org. Lett. 2020, 22, 2064-
2069; (e) Kaithal, A.; Gracia, L.-L.; Camp, C.; Quadrelli, E. A.;
Leitner, W. Direct Synthesis of Cycloalkanes from Diols and
Werner-Type and Low-Valent Organometallic Complexes.
The Effect of the Spin State on the Stability, Reactivity, and
Structure. Chem. Rev. 1996, 96, 2135-2204.
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
Secondary Alcohols or Ketones Using
a
Homogeneous
Manganese Catalyst. J. Am. Chem. Soc. 2019, 141, 17487−17492;
(f) Yadav, V.; Landge, V. G.; Subaramanian, M.; Balaraman, E.
Manganese-Catalyzed α Olefination of Nitriles with Secondary
Alcohols. ACS Catalysis 2020, 10, 947-954.
(14) (a) Gangwar, M. K.; Dahiya, P.; Emayavaramban, B.;
Sundararaju, B. Cp*Co(III) -Catalyzed Dehydrogenation of
Secondary Alcohols. Chem. Asian J. 2018, 13, 2445 -2448. (b)
Emayavaramban, B.; Roy, M.; Sundararaju, B. Iron Catalyzed
Allylic Amination Directly from Allylic Alcohol. Chem. Eur. J.
2016, 22, 3952. (c) Emayavaramban, B.; Sen, M.; Sundararaju, B.
Iron Catalyzed Sustainable Synthesis of Pyrrole. Org. Lett. 2017,
19, 6-9. Also see, (d) Biswas, N.; Sharma, R.; Srimani, D.
Ruthenium Pincer Complex Catalyzed Selective Synthesis of C-3
Alkylated Indoles and bisindolylmethanes directly from Indoles
and
Alcohols.
Adv.
Synth.
Catal.
2020,
DOI:
10.1002/adsc.202000326. (e) Löfberg, C.; Grigg, R.; Keep, A.;
Derrick, A.; Sridharan, V.; Kilner C. Chem. Commun., 2006,
5000-5002..
(15) Selected examples on α-Alkylation nitrile with primary
alcohols, see:(a) Chakraborty, S.; Das, U. K.; Ben-David, Y.;
Milstein, D. Manganese Catalyzed α-Olefination of Nitriles by
Primary Alcohols. J. Am. Chem. Soc. 2017, 139, 11710-11713.
(b) Jana, A.; Reddy, C. B.; Maji, B. Manganese Catalyzed α-
Alkylation of Nitriles with Primary Alcohols. ACS Catal. 2018, 8,
9226-9231. (c) Borghs, J. C.; Tran, M. A.; Sklyaruk, J.; Rueping,
M.; El-Sepelgy, O. Sustainable Alkylation of Nitriles with
Alcohols by Manganese Catalysis. J. Org. Chem. 2019, 84, 7927-
7935. (d) Luque-Urrutia, J. A.; Solà, M.; Milstein, D.; Poater, A.
Mechanism of the Manganese-Pincer-Catalyzed Acceptorless De-
hydrogenative Coupling of Nitriles and Alcohols. J. Am. Chem.
Soc. 2019, 141, 2398−2403. Also see, (e) Roy, B. C.; Ansari, I.
A.; Samim, S. A.; Kundu, S. Base-Promotedα-Alkylation of Aryl
Acetonitriles with Alcohols. Chem.-Asian J. 2019, 14,
2215−2219.
(16) (a) Wiberg, K. B.; Crocker, L. S.; Morgan, K. M.;
Thermochemical Studies of Carbonyl Compounds. 5. Enthalpies
of Reduction of Carbonyl Groups. J. Am. Chem. Soc., 1991,
113, 3447-3450. (b) Nyhlén, J.; Privalov, T. Hydrogenation of
Carbon-heteroatom Unsaturated Bonds: An Assesment of
Consistency of Density Functional Methods. J. Mol. Cata. A.
2010, 324, 97-103.
ACS Paragon Plus Environment

ACS Catalysis
Page 12 of 13
1
2
3
4
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
ACS Paragon Plus Environment

Page 13 of 13
ACS Catalysis
“For Table of Contents only”
1
2
3
4
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
ACS Paragon Plus Environment