Nickel-Catalyzed Alkylation of Ketone Enolates: Synthesis of Monoselective Linear Ketones

Article abstract of DOI:10.1021/acs.joc.8b02609

Herein we have developed a Ni-catalyzed protocol for the synthesis of linear ketones. Aryl, alkyl, and heteroaryl ketones as well as alcohols yielded the monoselective ketones in up to 90% yield. The catalytic protocol was successfully applied in to a gram-scale synthesis. For a practical utility, applications of a steroid derivative, oleyl alcohol, and naproxen alcohol were employed. Preliminary catalytic investigations involving the isolation of a Ni intermediate and defined Ni-H species as well as a series of deuterium-labeling experiments were performed.

Full text of DOI:10.1021/acs.joc.8b02609

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Article
Nickel-Catalyzed Alkylation of Ketone Enolates:
Synthesis of Mono-Selective Linear Ketones
Jagadish Das, Mari Vellakkaran, and Debasis Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02609 • Publication Date (Web): 14 Dec 2018
Downloaded from http://pubs.acs.org on December 14, 2018
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Page 1 of 13
The Journal of Organic Chemistry
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Nickel-Catalyzed Alkylation of Ketone Enolates: Synthesis of Mono-
Selective Linear Ketones
Jagadish Das, Mari Vellakkaran, and Debasis Banerjee*
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Department of Chemistry, Laboratory of Catalysis and Organic Synthesis, Indian Institute of Technology Roorkee, Roorkee
247667 (India)
ABSTRACT: Herein we have developed a Ni-catalyzed protocol for the synthesis of linear ketones. Aryl, alkyl and hetero-aryl
ketones as well as alcohols yielded the mono-selective ketones in up to 90% yield. Catalytic protocol successfully applied in gram
scale synthesis. For a practical utility, applications of steroid derivative, oleyl alcohol and naproxen alcohol were employed.
Preliminary catalytic investigations involving isolation of a Ni-intermediate and defined Ni-H species as well as a series of
deuterium labeling experiments were performed.
KEYWORDS: Alcohols • Nickel • Borrowing-hydrogen catalysis • -Alkylation • Earth-abundant metal • Ketones • Mechanistic
Scheme 1: Transition-metal catalyzed ketone alkylation
Previous Work
INTRODUCTION
Utilization of high natural abundant and inexpensive alcohols
and versatility to a broad range of amine and C-nucleophiles
enables the synthesis of valuable agrochemicals,
pharmaceuticals and bioactive heterocycles involving
hydrogen auto-transfer strategy.1-2 Furthermore, -alkylation
of carbonyl compounds involving ketone enolates using un-
activated alcohols represents the most important milestones to
forge the new C-C bonds.3
O
O
M
R2
OH
R
R2
(a)
R
Base
M = Rh, Ru, Ir, Pd, Mn, Fe, Co etc.
Present Work
O
O
Ni Catalyst [5 mol%]
R2
OH
(b)
R
R2
R
Traditionally, hazardous alkyl halides and stoichiometric
amount of strong bases are used for such methodologies and
equivalent excess of waste are formed. However, the main
advantages of HB process is to avoid such stoichiometric salt
waste as water is formed as the sole by-product makes this
Gram-scale
synthesis
H2O
Post synthetic drug modulation
Broad Substrate Scope
>40 examples
up to 90% yield
Functionalization to steroid hormone and fatty acid derivatives
Mechanistic studies/ determination of rate and order of reaction
technology
more
sustainable
and
atom-economic.1
Importantly, catalytic upgradation of alcohols to energy
efficient biofuels has been developed using Guerbet process.
These self-coupling of alcohols could be performed using
bifunctional Ir- or Ru-catalysts.4a-b In this context, it is
noteworthy to mention that, (de)hydrogenative coupling of
alcohols for -alkylation of carbonyl compounds, were
generally performed with precious noble-metal catalysts, such
as, Ru,4c-f Rh,5 Ir 6 and Pd-complexes (Scheme 1a).7 In spite of
notable progress, potential application of renewable resources
along with earth-abundant, inexpensive and non-precious
transition metal catalysts for key chemical transformations is a
long standing goal and crucial challenge in catalysis.8 More
recently, significant achievements for -alkylation of carbonyl
compounds with alcohols were realized using Fe,9 Mn,10 and
Co-catalysts.11 However, use of fancy pincer ligands based on
pyridinyl, diethylamine or triazinyl framework is required to
achieve higher efficiency.9-11 Further, application of these
highly expensive ligands and their multi-step synthesis often
are major concern in comparison to base-metal catalysts.
In this direction, nickel has economic benefits and would
function as sustainable alternative to palladium.12 Thus still,
there is a need to develop more exciting and challenging
methodologies using nickel. However, due to poor leaving
ability and strong binding capacity of free hydroxyl group in
alcohol, often un-activated alcohols behaves as an inferior
substrate class for such nickel-catalyzed transformations.13a-d
Notably, Yus and co-workers studied the nickel nanoparticle
mediated coupling of ketones using primary alcohols.13e-f In
this direction, herein we demonstrated the homogeneous Ni-
catalyzed alkylation of acetophenone derivatives to a range of
-alkylated long chain ketones with a variety of primary
alcohol. The catalytic protocol is highly selective to linear -
alkylated ketones following hydrogen-borrowing strategy.3,14
RESULTS AND DISCUSSION
Optimization of the catalytic protocol for -alkylation of
carbonyl compounds. As part of our ongoing studies,
recently we developed the nickel catalyzed protocols for the
synthesis of secondary amines, amides as well as five and six
membered heteroarenes.14a-c More recently, we established a
practical route to bis-substituted branched ketones.14d
Nevertheless, used of 1 equivalent of t-BuOK was crucial to
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Page 2 of 13
achieve such goal. At this point, we wondered, whether such Previously we demonstrated the nickel-catalyzed hydrogen
1
2
3
4
5
6
7
8
Ni-catalyzed system would be beneficial for α-alkylation of
methyl ketones or acetophenone derivatives to linear products.
Notably, we observed quite poor selectivity to ketone 3a under
the optimized conditions of methylene ketones.14d Using 5
mol% NiBr2, 6 mol% 1,10-phenanthroline L1 and 100 mol%
of t-BuOK afford the mono-selective ketone 3a albeit with
lower product conversions when toluene was used as solvent
in 140 °C (Table 1, entry 17). Notably, application of excess
base transformed to reduce alcohol product of 3a along with
higher order ketones.14d Therefore, we realized the crucial role
of base to achieve higher linear product selectivity. Further,
we envisioned that, relatively milder basic conditions might be
useful for recent studies (Scheme 1b). For instance, mild basic
conditions not only allow higher selectivity to 3a, it will also
prevent in situ bis-alkylation to higher order ketones.14d
However, addition of excess alcohols often displayed reduced
alcohol product of 3a.
borrowing strategy using primary alcohols in combination
with various coupling partners.14 During this present study, our
prime focus was to control the undesired side reactions, such
as, hydrogenation of carbonyl group as well as base-mediated
coupling of ketones (Table 1 and Supporting Information (SI),
Table S1-S2).15 At this point, we realized that, a combination
of suitable nickel-catalyst with nitrogen ligand is crucial for
such mono-selective transformations.16
To achieve this goal, primarily we studied the model reaction
9
of Table
1 using five different nickel pre-catalysts.
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Gratifyingly, application of 10 mol% NiBr2, 20 mol% 1,10-
phenanthroline L1 and 10 mol% of Cs2CO3 afford the desired
product 3a in 76 % isolated yield, when 1,4-dioxane was used
as solvent in 140 °C (Table 1, entries 1-5). Under identical
catalytic conditions various ligands with electronically
different nature were tested and did not improve the product
yield further (Table 2).
Table 1. Discovery of reactions: Mono-alkylation of
acetophenone with benzylalcohol.a,b
Table 2. Influence of ligands for alkylation of 1a with 2a.a,b
O
O
O
O
L1-L8
O
NiBr2/
base
1,4-dioxane, 140 ºC, 36 h
Ni-Cat./L
OH
2a
+
base
Ph
+
Ph
Ph
Ph
HO
Ph
Ph
+
1a
3a
solvent, 140 ºC, 36 h
1a
2a
3a
3a'
entry
catalyst
base (mol %) GC-MS conv. (%)
(mol %)
NiBr2 (10)
3a
80 (76)
3a'
7
N
N
N
N
N
N
N
N
1
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
L4
L3
(traces)
P
(42%)
L1
(80%)
L2
(30%)
2
NiCl2 (10)
29
2
3
Ni(acac)2 (10)
Ni(cod)2 (10)
63
9
P
4
10
0
P
P
5
NiCl2.dme (10) Cs2CO3 (10)
22
4
N
N
6c
7d
7e
8f
9g
0h
11i
12j
13
14k
15
NiBr2 (10)
NiBr2 (5)
NiBr2 (10)
NiBr2 (10)
NiBr2 (10)
NiBr2 (7.5)
NiBr2 (5.0)
NiBr2 (2.5)
NiBr2(10)
NiBr2(10)
-
Cs2CO3 (10)
85 (80)
10
1
L8
(traces)
L5
L7
(traces)
(70%)
L6
(13%)
t-BuOK (20) 94 (82)
aSee Table 1 and Supporting Information for detailed of reaction
conditions. bConversion was determined by GC-MS.
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
-
6
0
0
0
At this point, application of various polar solvents such as, n-
propanol, N, N-dimethyl-formamide (DMF), as well as
replacement of 1,4-dioxane with toluene and xylene were
found inefficient for alkylation of acetophenone (see SI, Table
S2). Notably, in absence of solvents only trace amount of
enone intermediate was detected along with unidentified side
products. Next, influence of different organic and inorganic
bases were performed and resulted poor or no product yield
(see SI, Table S1). To our delight, we observed a slight
increment of product yield, when a lower equivalent of alcohol
was used (Table 1, entries 1, 6 and 9). Further reaction using
20 mol% of t-BuOK in place of 10 mol% of Cs2CO3 with
lower catalyst loading resulted 82% isolated yield of 3a (Table
1, entry 7). As expected, we did not observe any alkylation
product in absence of catalyst and base whereas, control
experiment in absence of ligand or variable amount of catalyst
loading resulted albeit with moderate to poor product yield
(Table 1, entries 8-17). Notably, in some cases we observed 2-
10% C=O bond reduced product during alkylation process
(Table 1).
81
63
42
25
0
5
16
8
3
0
Cs2CO3 (10)
Cs2CO3 (10)
t-BuOK (20)
27
6
12
11
16
17d
-
25
50
0
NiBr2 (5)
t-BuOK (100) 20
aReaction conditions: Acetophenone (0.25 mmol), benzyl alcohol
(0.375 mmol), Ni-catalyst. (0.025 mmol), 1,10-phenanthroline (0.05
mmol), Cs2CO3 (0.025 mmol), N2 atmosphere, pre-heated oil bath at
140 °C in 1,4-dioxane for 36 h in a Schlenk tube. Turnover number
(TON = 16.4) and turnover frequency (TOF = 0.46 h-1) calculation
based on the formation of product 3a under standard reaction
conditions. bConversions were determined using GC-MS considering
(starting material + 3a + 3a' = 100%) and isolated yield was reported
c
in parenthesis (average yield of two runs). Reaction was performed
using benzyl alcohol (0.3125 mmol). Reaction was performed using
d
NiBr2. (0.0125 mmol), 1,10-phenanthroline (0.015mmol), N2
atmosphere, pre-heated oil bath at 140 °C in toluene for 36 h. e130 oC.
fReaction was performed at 120 oC. gReaction was performed using 2a
(0.275 mmol). hL1 (15 mol%) was used. iL1 (10 mol%) was used. jL1
Mono-selective alkylation of acetophenone with alcohol. A
series of ketones with aryl, alkyl and heteroaryl alcohols were
tested for selective mono-alkylation (Scheme 2). To our
delight, ethyl, methoxy, as well as halide substituents on the
aryl ring of acetophenone are well tolerated and resulted -
k
(5 mol%) was used. No ligand was used.
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The Journal of Organic Chemistry
alkylated acetophenone in up to 90% yield (3a-3i).
acetophenones afford the linear mono-selective ketones 3h-3i
in moderate yields and unreacted acetophenones were
1
2
3
Importantly, sterically hindered ortho-methoxy acetophenone
efficiently converted into 55% yield of 3e. It is to be note that,
under standard conditions 2-naphthyl and 4-cyano substituted
recovered
(Scheme
2).
4
5
Scheme 2: Synthesis of linear α-alkylated ketones
Earth-abundant metal
Broad Substrate Scope
>40 Examples, upto 90% yield
6
7
8
9
O
O
A
condition (or)
HO
R
Ar
1a-n
Ar
R
Functionalization of Steroid and fatty acids
Post-synthetic drug modulation (Naproxen)
B
condition
2a-2u
3-7
Scope of acetophenone derivatives: synthesis of linear -alkylated ketones

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60
O
O
O
O
O
OMe
OMe
Ph
Ph
Ph
Ph
OMe
Ph
3a
80%
82%
3c
63%
90%
3b
65%
76%
3e
52%
55%
3d
64%
85%
A:
B:
O
O
O
O
O
Ph
Ph
Ph
Ph
3g
42%
50%
3h
30%
50%
3f
50%
62%
Ph
3i
4a
54%
63%
Cl
CN
A:
B:
Br
-
35%
Scope of alcohols: synthesis of linear -alkylated ketones

O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
4d
40%
42%
4e
43%
45%
4f
4b
60%
70%
4c
64%
71%
A:
B:
CN
74%
73%
F
O
O
O
O
OMe
O
OMe
OMe
OMe
OMe
O
O
Ph
OMe
Ph
Ph
Ph
Ph
4g
65%
64%
4h
35%
40%
4k
4i
39%
42%
4j
40%
58%
A:
B:
51%
60%
OMe
O
O
O
O
Ph
Ph
Ph
Ph
4l
30%
4m
46%
4n
34%
4o
36%
B:
Alkylation using heteroaryl derivatives: synthesis of linear heteroaryl ketones
O
O
O
O
O
N
N
MeO
N
5a
76%
80%
5c
78%
80%
5b
5d
50%
60%
Et
N
A:
B:
70%
73%
O
O
From oleyl alcohol
N
5e
60%
70%
5f
30%
75%
N
N
F
A:
B:
OMe
Synthetic utility: natural products and drugs
OMe
O
MeO
O
Ph
From naproxen alcohol:
From steroid hormone:
Ph
6b
A:
B:
Tandem alkylation/intermolecular cyclization: green synthesis of quinoline and pyridine
R
R
OMe
N
X
N
X
N
N
N
7a
7b
7c
, R = H; X = C, 85%
, R = Et; X = C, 82%
, R = H; X = N, 50%
7g
7h
, R = H; X = N, 70%
, R = OMe; X = C, 45%
7d
, 88%
7f
, 68%
B:
Reaction conditions: For details of conditions A, B, and C, see experimental section.
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Notably, the catalytic protocol is highly selective for methyl-ketone derivative and we did not observe any bis-alkylated ketones
(Table 1 and SI, Table S1-S2).
1
2
3
4
5
6
7
8
9
-Alkylation of acetophenone with a range of benzyl and
alkyl alcohols. Having witnessed excellent catalytic activity
of acetophenone derivatives with benzyl alcohol, next, we
studied the reactivity profile of various benzyl alcohols with a
series of electronically different acetophenones (Scheme 2, 4a-
4k). Benzyl alcohols bearing electron rich functionalities
including 2-methyl substituent at aryl ring, resulted
corresponding mono-alkylated products 4a-4d in 42-71%
yield respectively. Advantageously, 4-fluoro and 4-nitrile
substituted benzyl alcohols efficiently transformed into the
desired products 4e-4f in up to 74% yield. Notably, when
using benzyl alcohols having multiple electron rich
substituents, resulted a lower product yield due to strong
electronic effect (Scheme 2, 4g-4i). Gratifyingly, 1-naphthyl
methanol as well as benzyl alcohol having oxygen
heterocycles selectively converted into linear ketone
derivatives 4j-4k. Further, we employed long chain renewable
aliphatic primary alcohols with acetophenone (4l-4o, Scheme
2). However, using optimized conditions (Table 1, entry 6),
only poor or no product conversions were observed.
Therefore, application of t-BuOK under standard catalytic
conditions resulted in up to 46% isolated yield of 4l-4o (Table
1, entry 7 and Scheme 2). It is noteworthy to mention that,
renewable terpenoid intermediate citronellol efficiently
converted to 4l under standard catalytic conditions. Notably,
this is a rare instance of a chemo-selective transformation of
an alkyl alcohol having internal double-bond using nickel,
often quite challenging under precious-metal catalysis.4-7
corresponding -alkylated product in moderate yield (6c). All
these examples demonstrate the potential application of the
present methodology and could be useful for selective and
efficent post-synthetic drug functionalization using nickel
catalyst.
Scheme 4: Catalytic and mechanistic studies.
4a: Catalytic and stoichiometric studies using define cat. A
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17
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cat. A
[10 mol%]
HO
Ph
O
2a
85%
conditions A
Ph
Ph
N
N
O
Ni
3a
70%
Br Br
cat. A
Ph
1a
cat. A
[100 mol%]
4b: Evidence for intermediate nickel-alkoxy species
t-BuOK
( 50 mol%)
HO
Ph
(2 equiv.)
O
N
N
N
N
toluene d8,
140 C, 3h
toluene
Ph
H
Ni
O
Ni
cat. C
140 C, 24h
Cl
Cl
cat. B
Ph
proposed Ni-alkoxy intermediate
4c:Stoichiometric studies using define Ni-H catalyst
O
O
PCy3
standard conditions
Br Ni
PCy3
H
Ph
Ph
Ph
3a
Ph
3a'
, 38%
Alkylation using hetero aromatic ketones and alcohols.
Pleasingly, we analyzed the scope of hetero-aryl alcohols for
4d: Reduction of enone with alcohols
O
O
alkylation
with
methyl
ketones.
Gratifyingly,
conditions A
(a)
(b)
HO
Ph
Ph
Ph
Ph
Ph
2-pyridinemethanol efficiently alkylated with acetophenone
derivatives and resulted in up to 80% yield (Scheme 2, 5a-5c).
Notably, more challenging, 3-acetyl pyridine gave 60% yield
of 5d with benzyl alcohol. Furthermore, 4-fluorophenyl benzyl
alcohol and 2-pyridinemethanol afford pharmaceutically
active ketones 5e-5f in 70-75% yield, respectively. It is
important to note that, the catalytic protocol is tolerant to the
pyridine derivatives, otherwise known to poison the catalytic
system.
Ph
Ph
, 81%
81%
3a
3a'
2a
O
D 50%
H/
O
D
D
conditions B
25%
Ph
3a-d2
Ph
D 13%
HO
Ph
2a-d2
3a'
H/
4e: Deuterium incorporation experiments and H/D exchange
D 77%
H/
O
O
D
D
Scheme 3: Practical utility: gram scale synthesis of 3a.
conditions B
40%
(c)
(d)
Ph
3a-d2
Ph
HO
Ph
2a-d2
O
Ph
O
NiBr2 (5 mol%)
Phen (6 mol%)
1a
D 63%
H/
HO
+
t-BuOK ( 20 mol%),
HO
Ph
D 50%
H/
O
O
toluene, 140 ºC, 36 h
2a
3a
(1.050 g)
2a
1a
conditions B
66%
60 %
D
Ph
Ph
D 36%
D
Ph
Ph
Reaction Conditions (Procedure B): 1a (1.0 g, 8.33 mmol), 2a (1.125 g,
10.42 mmol), NiBr2 (91 mg, 5 mol%), phen (90 mg, 6 mol%), t-BuOK
(187 mg, 7.46 mmol) and toluene (15.0 mL) in a 100 mL pressure tube
under nitrogen atmosphere at 140 ºC in oil bath for 36 h.
H/
3a-d2
1a
HO
2a-d2
Ph
O
D 46%
H/
O
D
conditions B
15%
(e)
(f)
Ph
Ph
D 70%
HO
Ph
D
Synthetic applications. Thereafter, we extend our nickel-
catalyzed selective alkylation in the synthesis of complex
natural products and drug molecules with impressive
functional group compatibility (Scheme 2, 6a-6c). For
instance, alcohol derived from sensitive fatty acid, such as,
oleic acid, alkylated with 4-methoxy acetophenone to 6a
without significantly affecting the double bond and resulted
reasonable product yield. Methyl ketone from steriod hormone
efficiently alkylated with benzyl alcohol to 6b. Again, alkyl
alcohol derived from drug, naproxen, transformed to the
D
2a
3a-d2
H/
1a-d3
O
D 45%
H/
O
conditions B
55%
D
O
Ph
2a-d
Ph
Ph
Ph
D 51%
1a
3a-d2
H/
Control experiments: Reaction condition A: Ketone (0.1 mmol),
alcohol (0.125 mmol), NiBr2 (10 mol%), 1,10-phenanthroline (20 mol%),
Cs2CO3 (50 mol%) and 1,4-dioxane as solvent (2.0 mL) at 140 °C for 48
h. Reaction condition B: Ketone (0.1 mmol), alcohol (0.125 mmol),
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NiBr2 (10 mol%), 1,10-phenanthroline (20 mol%), and t-BuOK (20
mol%) in toluene as solvent (2.0 mL) at 140 °C for 48 h.
Additionally, in similar line of methylene ketones we
performed detailed deuterium-labeling experiments for -
alkylation of methyl ketones too (Scheme 4, 4d-4e). When
using intermediate 3a ’ with benzyl alcohol and 2a-d2, we
observed 13% and 50% incorporation of deuterium in -, and
-position of 3a-d2 respectively (Scheme 4d). Further reaction
using acetophenone with 2a-d2, resulted equal distribution of
deuterium atom in -, and -position of 3a-d2 (Scheme 4e, c
1
2
3
4
5
6
7
8
Further, we applied our optimized protocol for the synthesis of
C-2 substituted quinolines and pyridines using amino alcohols
with acetophenone derivatives and resulted in up to 88%
yields (Scheme 2, 7a-7h).
Notably, we observed impressive functional group tolerance
for the present catalytic protocol. For instance, halides (Cl, Br,
and F), alkyl, alkoxy and di-oxolone functionalities including
heteroarenes were used efficiently for alkylation reactions.
Importantly, presence of sensitive functionalities such as,
nitrile, internal double bond in fatty acid alcohol, citronellol
including steroid framework highlights the significance of the
developed methodology. Unfortunately, ketones or alcohols
bearing nitro, free amines, amides, alkynes and free alcohol
functionalities could participate for alkylation process. For a
practical utility, the alkylation process was performed using
acetophenone (1.0 g, 8.33 mmol) with benzyl alcohol and
resulted the linear ketone 3a in 60% product yield (1.050 g,
Scheme 3).
and Supporting Information Scheme S1). Thereafter
a
crossover experiments under optimized conditions also
resulted 3a-d2 and detected deuterium incorporation at , and
-position in almost equivalent ratio (Scheme 4e, d and
Supporting Information Scheme S2). Next, when 1a-d3
reacted with benzyl alcohol 1a, a variable D/H exchange-ratio
in the product 3a-d2 observed. To our delight, catalytic
experiment using 1a-d, resulted deuterium incorporation at ,
and -position in equal distribution in product 3a-d2 (Scheme
4e, e-f and SI Scheme S4-S5).
We believe that, results obtained using deuterated
investigation for alkylation of methyl ketones are in strong
agreement for involvement of hydrogen auto-transfer strategy
and D/H exchange during the course of the reaction (Scheme 4
and SI Schemes S1-S5).19a Notably, alcohol was crucial for
generic hydride source, involvement of alkoxy-nickel species
as well as in situ generated nickel-hydride species was the key
for catalytic α-alkylation of methylene ketones.19 Finally, we
also performed kinetic profile for the optimized process and
observed first order rate (see Supporting Information, Schemes
S7 and S8).
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Kinetic and mechanistic studies. Having observed excellent
catalytic activity for -alkylation of ketones with primary
alcohols, we next focused to study the mechanistic
investigation for the course of the reactions. In our earlier
studies we observed that,14 Ni-catalyzed alcohol
dehydrogenation is a
multi-step process following HB
methodology (Scheme 5). Similar to our previous studies, we
performed a series of control and mechanistic studies to
understand the catalytic behaviour of the Ni-catalyst in case of
alkylation of acetophenone derivatives.
Notably, we observed a similar deuterium studies profile for
methyl as well as methylene ketones under nickel-catalysis
with the exceptions that; methyl ketones responded under
milder conditions in compare to the methylene ketones and
displayed the linear products with high selectivity.
Therefore, active nickel pre-catalyst, cat. A was prepared,18
and tested for alkylation as presented in Scheme 4a. During
optimization studies we observed that, base plays a key role to
obtain higher product yield (Table 1, entry 13).14 We
anticipated that, base facilitate the process for activation of
nickel pre-catalysts via dehalogenation of NiX2 and
Scheme 5: Plausible mechanistic cycle for α-alkylation of
methyl ketones.
substitution with alcohol counterpart resulted alkoxy-nickel
14d,18
O
species.
Next, the pre-formed alkoxy-nickel species
1a
O
undergoes β-hydride elimination in presence of a base and
aldehyde is formed. Importantly, active nickel-hydride species
generate during this process, facilitate enone reduction.
Therefore, we synthesized the nickel-alkoxy species of cat. B,
tested under standard conditions using 50 mol% t-BuOK for
three hours and as expected, benzaldehyde formation was
detected (Scheme 4b and SI Scheme S6). These experiments
proof the involvement of the nickel-alkoxy intermediate for
alkylation process.14d
Further to strengthen our hypothesis, we made an attempt to
prepare the Ni-H species of cat. A., unfortunately, after
several attempt at variable temperature we failed to detect any
Ni-H species even using an in situ NMR studies at -75 °C.14
Therefore, as observed earlier, we choose highly electron rich
phosphine ligand, tri-cyclohexyl phosphine, L7 and prepared
the defined Ni-H complex, [(Cy)3]2PNiBrH.17 Further,
stoichiometric reaction of [(Cy)3]2PNiBrH with enone 3a’
using 20 mol% t-BuOK gave 38% yield of 3a (Scheme 4c).
These experimental outcomes strongly support our hypothesis
for the involvement of nickel-alkoxy as well as Ni-H species
for -alkylation of methyl ketones using dehydrogenative
coupling of alcohols under nickel catalysis as observed in case
of methylene ketones.14d
R
[LnNi]
Ph
R
Ph OH
2a
3a
A
[LnNi-OBn]
hydrogenation
B
dehydrogenation
via -hydride elimination
C
O
R
[LnNi-H]
Ph
2a'
O
Ph
condensation
3a'
1a
H2O
Based on the above mechanistic studies we herein proposed a
plausible mechanism for the nickel catalyzed α-alkylation of
methyl ketones (Scheme 5). Initially, nitrogen ligated nickel-
complex A transformed into the alkoxy-nickel species B via
dehalogenation followed by substitution with benzyl alcohol.
Base mediated β-hydride elimination of complex B, resulted
the formation of transition Ni-H species C and benzaldehyde
2a’ is formed. Subsequently, a base catalyzed condensation of
benzaldehyde with acetophenone 1a generates the
intermediate enone 3a’, which, thereafter undergoes
hydrogenation by Ni-H species selectively at C=C bond and
deliver the product 3a. Overall, the process is sustainable,
atom-economic and water is released as by product. Further
detailed mechanistic and kinetic studies regarding α-alkylation
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The Journal of Organic Chemistry
Page 6 of 13
of ketones are presently undergoing in our laboratory and will In a 15 mL oven dried Schlenk tube under atmosphere of N2
1
2
3
4
5
6
7
8
be disclosed in future communications.
acetophenone (0.25 mmol) was taken followed by t-BuOK
(0.050 mmol), 1,10-phenanthroline (6 mol%), NiBr2 (5 mol%)
and alcohols (0.3125 mmol) were added. Next, 2.0 mL toluene
was added to the whole mixture and was placed in a pre-
heated oil bath at 140 °C for 36 h in a closed system. After the
reported time, reaction mixture was cooled to room
temperature and 3.0 mL of ethyl acetate was added and
concentrated in vacuo. The residue was purified by column
chromatography using a gradient of hexane and ethyl acetate
(eluent system) to afford the pure product.
CONCLUSIONS
In summary, we demonstrated an inexpensive and operational
simple base-metal catalyzed protocol for selective mon-
alkylation of methyl ketones with alcohols using borrowing
hydrogen approach. This Ni-catalyzed dehydrogenative
coupling of alcohol could be performed in gram scale and
extended to a range of aryl, alkyl and hetero-aryl derivatives
(>40 examples) in up to 90% yield including green synthesis
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Procedure [C]:
of
N-heterocycles.
For
a
synthetic
application,
In a 15 mL oven dried Schlenk tube under atmosphere of N2
acetophenone (0.25 mmol) was taken followed by t-BuOK
(0.375 mmol), 1,10-phenanthroline (6 mol%), NiBr2 (5 mol%)
and alcohols (0.375 mmol) were added. Next, 2.0 mL toluene
was added to the whole mixture and was placed in a pre-
heated oil bath at 140 °C for 36 h in a closed system. After the
reported time, reaction mixture was cooled to room
temperature and 3.0 mL of ethyl acetate was added and
concentrated in vacuo. The residue was purified by column
chromatography using a gradient of hexane and ethyl acetate
(eluent system) to afford the pure product.
Synthesis of [NiCl2(bpy)] complex (cat. B): A solution of
bpy (78 mg, 0.5 mmol) in EtOH (2 mL) was added to a
solution of NiCl2•6H2O (119 mg, 0.5 mmol) in EtOH (2 mL)
at room temperature. After stirring for 6 h, a pale green
precipitate was formed and filtered off, washed with EtOH
(3×3 mL), and dried in vacuo to afford cat. B as a pale green
solid 114 mg (80%) yield. Anal. Calcd for C10H8Cl2N2Ni: C,
42.03; H, 2.82; Cl, 24.81; N, 9.80; Found: C, 41.75; H, 2.76;
N, 9.61.
Synthesis of (cat. C): cat. B (57 mg, 0.2 mmol) and benzyl
alcohol (43.2 mg, 0.4 mmol) in toluene (2 mL) was heated at
140 °C under nitrogen atmosphere in a Schlenk tube, after 24h
the precipitate was filtered off, washed with hexane (3×5 mL),
and dried in vacuo to afford cat. C as a pale green solid 50 mg
(78%) yield. Then in a Schlenk cat. C (40 mg, 0.12 mmol),
acetophenone (21.6 mg, 0.18 mmol) and t-BuOK (14 mg, 0.12
mmol) in toluene d8 (0.5mL) under nitrogen atmosphere was
heated at 140 °C, after 3h the reaction mixture was cooled to
room temperature and the crude reaction mixture was analyzed
by GC-MS which confirmed the formation of benzaldehyde
(EI, m/z = 106.0).
functionalization of steroid hormone, unsaturated fatty acids
and post synthetic modification of naproxen drug have shown.
Detailed mechanistic studies involving isolation of a Ni-
intermediate, defined Ni-H species, intermediate Ni-alkoxy
species and determination of rate and order of reaction as well
as a series of deuterium labeling experiments were crucial for
preliminary mechanistic studies for selective alkylation of
methyl ketones. Notably, at this stage, recovery and reuse of
the catalytic system for alkylation process were not successful.
EXPERIMENTAL SECTION
General Experimental Details:
All solvents and reagents were used, as received from the
suppliers. TLC was performed on Merck Kiesel gel 60, F254
plates with the layer thickness of 0.25 mm. Column
chromatography was performed on silica gel (100-200 mesh)
using a gradient of ethyl acetate and hexane as mobile phase.
1H NMR spectral data were collected at, 400 MHz (JEOL),
500 MHz (Bruker) and 13C NMR were recorded at 100, 125
1
MHz. H NMR spectral data are given as chemical shifts in
ppm followed by multiplicity (s- singlet; d- doublet; t- triplet;
q- quartet; m- multiplet), number of protons and coupling
constants. 13C NMR chemical shifts are expressed in ppm.
HRMS (ESI) spectral data were collected using Agilent Q-
TOF mass spectrometer. GC-MS were recorded using Agilent
GC Mass Spectrometer. All the reactions were performed in a
close system using Schlenk tube. All nickel salts were
purchased from Sigma Aldrich. Nickel(II) bromide (Assay-
98%; CAS Number 13462-88-9; EC Number 236-665-0; Pack
Size- No 217891-10G). Potassium tert-butoxide (Purity-98%,
CAS No: 865-47-4, Catalog No- ASP2012) and Sodium tert-
butoxide (Purity-97%, CAS No: 865-48-5, Catalog No-
ASS2615) were purchased from Avra Synthesis Pvt. Ltd.,
India.
Gram scale reaction procedure: Gram Scale reaction was
performed using acetophenone 1a (1.0 g, 8.33 mmol), benzyl
alcohol 2a (1.125 g, 10.42 mmol), NiBr2 (91 mg, 5 mol%),
phen (90 mg, 6 mol%), t-BuOK (187 mg, 1.67 mmol), toluene
(15.0 mL) in a 100 mL pressure tube under nitrogen
atmosphere at 140 ºC in oil bath for 36 h. The reaction mixture
was cooled to room temperature and 15.0 mL of ethyl acetate
was added and concentrated in vacuo. The residue was
purified by silica-gel column chromatography eluting with 1%
ethyl acetate in hexane to afford the pure product 3a as a white
solid (1.050 g, 60% Yield).
General procedure for nickel-catalyzed alkylation of
acetophenone with benzyl alcohols:
Procedure [A]:
In a 15 mL oven dried Schlenk tube under atmosphere of N2
acetophenone (0.25 mmol) was taken followed by Cs2CO3
(0.025 mmol), 1,10-phenanthroline (20 mol%), NiBr2 (10
mol%) and alcohols (0.3125 mmol) were added. Next, 1,4-
dioxane 2.0 mL was added to the whole mixture and was
placed in a pre-heated oil bath at 140 °C for 36-48 h in a
closed system. After the reported time, reaction mixture was
cooled to room temperature and 3.0 mL of ethyl acetate was
added and concentrated in vacuo. The residue was purified by
column chromatography using a gradient of hexane and ethyl
acetate (eluent system) to afford the pure product.
1,3-diphenylpropan-1-one (3a)10: Following the general
procedure A and B, the title compound was isolated as a white
solid using silica-gel column chromatography eluting with 1%
ethyl acetate in hexane. Yield (A: 80%, 42 mg; B: 82%, 43
1
mg). H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H),
7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.32-7.19 (m,
Procedure [B]:
5H), 3.33-3.29 (m, 2H), 3.09 – 3.05 (m, 2H); 13C{1H} NMR
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The Journal of Organic Chemistry
(100 MHz, CDCl3) δ 199.3, 141.4, 136.9, 133.2, 128.7, 128.6, 1-(naphthalen-2-yl)-3-phenylpropan-1-one
(3h)21c
:
1
2
3
4
5
6
7
8
128.5, 128.1, 126.2, 40.5, 30.2.
Following the general procedure A and B, the title compound
was isolated as a white solid using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane.
1-(4-ethylphenyl)-3-phenylpropan-1-one (3b)21c: Following
the general procedure A and B, the title compound was
1
isolated as
a
white solid using silica-gel column
Yield (A: 30%, 19.5 mg; B: 50%, 32.5 mg). H NMR (500
chromatography eluting with 1% ethyl acetate in hexane.
Yield (A: 65%, 39 mg; B: 76%, 45 mg). H NMR (400 MHz,
MHz, CDCl3) δ 8.49 (s, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H),
7.96 (d, J = 8.0 Hz, 1H), 7.93 – 7.90 (m, 2H), 7.64 – 7.61 (m,
1H), 7.59 – 7.56 (m, 1H), 7.37 – 7.32 (m, 4H), 7.25 (dd, J =
9.0, 4.3 Hz, 1H), 3.49 – 3.46 (m, 2H), 3.18 – 3.15 (m, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 199.1, 141.4, 135.6,
134.2, 132.5, 129.7, 129.6, 128.6, 128.5, 127.8, 126.8, 126.2,
123.9, 40.4, 30.4.
1
CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.32-7.24 (m, 6H), 7.20 (t,
J = 7.0 Hz, 1H), 3.28 (t, J = 7.9 Hz, 2H), 3.06 (t, J = 7.6 Hz,
2H), 2.70 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.3 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 199.0, 150.1, 141.5,
134.7, 128.6, 128.5, 128.4, 128.2, 126.2, 40.7, 30.3, 29.0,
15.3.
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4-(3-phenylpropanoyl)benzonitrile (3i)22b: Following the
general procedure B, the title compound was isolated as a
white solid using silica-gel column chromatography eluting
1-(4-methoxyphenyl)-3-phenylpropan-1-one
(3c)21c
:
1
Following the general procedure A and B, the title compound
was isolated as a white solid using silica-gel column
chromatography eluting with 5% ethyl acetate in hexane.
with 5% ethyl acetate in hexane. (Yield 35%, 20.5 mg). H
NMR (500 MHz, CDCl3) δ 8.01 (d, J = 8.7 Hz, 2H), 7.74 (d, J
= 8.6 Hz, 2H), 7.31-7.28 (m, 2H), 7.23-7.21 (m, 3H), 3.30 (t, J
= 7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 197.9, 140.9, 138.6, 132.6, 128.7, 128.5,
128.4, 126.4, 117.9, 116.5, 40.8, 29.9.
1
Yield (A: 63%, 38 mg; B: 90%, 54 mg). H NMR (400 MHz,
CDCl3) δ 7.94 (d, J = 8.5 Hz, 2H), 7.32-7.20 (m, 5H), 6.92 (d,
J = 9.2 Hz, 2H), 3.86 (s, 3H), 3.25 (t, J = 7.9 Hz, 2H), 3.06 (t,
J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9,
163.5, 141.6, 130.4, 130.1, 128.6, 128.5, 126.2, 113.8, 55.6,
40.2, 30.4.
1-phenyl-3-(p-tolyl)propan-1-one (4a)20a
: Following the
general procedure A and B, the title compound was isolated as
a white solid using silica-gel column chromatography eluting
with 1% ethyl acetate in hexane. Yield (A: 54%, 30 mg; B:
1-(3-methoxyphenyl)-3-phenylpropan-1-one
(3d)21d
:
1
Following the general procedure A and B, the title compound
was isolated as a colorless oil using silica-gel column
chromatography eluting with 5% ethyl acetate in hexane.
63%, 35 mg). H NMR (400 MHz, CDCl3 ) δ 7.95 (d, J = 8.0
Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 6.8 Hz, 2H), 7.20
– 7.09 (m, 4H), 3.29 – 3.25 (m, 2H), 3.04 – 3.00 (m, 2H), 2.31
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.4, 138.3,
136.9, 135.7, 133.1, 129.3, 128.7, 128.4, 128.1, 40.7, 29.8,
21.1.
1
Yield (A: 64%, 38.5 mg; B: 85%, 51 mg). H NMR (400
MHz, CDCl3) δ 7.53 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.37-
7.19 (m, 6H), 7.11-7.08 (m, 1H), 3.84 (s, 3H), 3.29 (t, J = 7.6
Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.1, 159.9, 141.4, 138.3, 129.7, 128.6, 128.5,
126.2, 120.8, 119.7, 112.3, 55.5, 40.7, 30.3.
3-(4-ethylphenyl)-1-phenylpropan-1-one (4b)20b: Following
the general procedure A and B, the title compound was
isolated as
a
yellow oil using silica-gel column
1-(2-methoxyphenyl)-3-phenylpropan-1-one
(3e)21d
:
chromatography eluting with 1% ethyl acetate in hexane.
Yield (A: 60%, 36 mg; B: 70%, 41.5 mg).1H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 7.19-7.12 (m, 4H), 3.29 (t, J = 7.8 Hz,
2H), 3.04 (t, J = 7.8 Hz, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.23 (t,
J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.5,
142.2, 138.5, 136.9, 133.1, 129.8, 128.7, 128.5, 128.1, 40.7,
29.8, 28.5, 15.7.
Following the general procedure A and B, the title compound
was isolated as a colorless oil using silica-gel column
chromatography eluting with 5% ethyl acetate in hexane.
1
Yield (A: 52%, 31 mg; B: 55%, 33 mg). H NMR (400 MHz,
CDCl3) δ 7.69 (d, J = 7.7 Hz, 1H), 7.43-7.48 (m, 1H), 7.16-
7.31 (m, 5H), 6.95–7.02 (m, 2H), 3.88 (s, 3H), 3.30 (t, J = 8.0
Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H).
1-(4-chlorophenyl)-3-phenylpropan-1-one (3f)21c: Following
the general procedure A and B, the title compound was
3-(4-isopropylphenyl)-1-phenylpropan-1-one
Following the general procedure A and B, the title compound
was isolated as yellow oil using silica-gel column
(4c)20c
:
isolated as
a
white solid using silica-gel column
a
chromatography eluting with 1% ethyl acetate in hexane.
Yield (A: 50%, 30.5 mg; B: 62%, 38 mg). H NMR (400
chromatography eluting with 1% ethyl acetate in hexane.
Yield (A: 64%, 40 mg; B: 71%, 45 mg). H NMR (400 MHz,
1
1
MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz,
2H), 7.30 (t, J = 6.5 Hz, 2H), 7.28 – 7.21 (m, 3H), 3.29 – 3.25
(m, 2H), 3.08 – 3.04 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 198.1, 141.1, 139.6, 135.3, 129.6, 129.0, 128.6,
128.5, 126.3, 40.5, 30.1.
CDCl3) δ 7.96 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 6.7 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 7.15-7.20 (m, 4H), 3.30 (t, J = 7.6 Hz,
2H), 3.04 (t, J = 7.6 Hz, 2H), 2.90-2.85 (m, 1H), 1.24 (d, J =
6.7 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ199.5, 146.8,
138.7, 136.9, 133.1, 128.7, 128.4, 128.1, 126.6, 40.6, 33.8,
29.8, 24.1.
1-(4-bromophenyl)-3-phenylpropan-1-one
(3g)21c
:
1-phenyl-3-(o-tolyl)propan-1-one (4d)11: Following the
general procedure A and B, the title compound was isolated as
a yellow oil using silica-gel column chromatography eluting
with 1% ethyl acetate in hexane. Yield (A: 40%, 22.5 mg; B:
42%, 23.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.6
Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H),
7.23-7.12 (m, 4H), 3.25 (t, J = 7.9 Hz, 2H), 3.05 (t, J = 7.9 Hz,
2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.5,
139.5, 136.9, 136.1, 133.2, 130.4, 128.7, 128.6, 128.1, 126.4,
126.3, 39.2, 27.6, 19.4.
Following the general procedure A and B, the title compound
was isolated as a white solid using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane.
Yield (A: 42%, 30 mg; B: 50%, 36 mg).1H NMR (500 MHz,
CDCl3) δ 7.84 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H),
7.33 (dd, J = 9.3, 5.5 Hz, 2H), 7.26 – 7.17 (m, 3H), 3.31 – 3.27
(m, 2H), 3.11 – 3.06 (m, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.3, 141.4, 133.1, 132.0, 129.6, 128.7, 128.6,
128.5, 126.2, 40.5, 30.2.
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4-(3-oxo-3-phenylpropyl)benzonitrile (4e)22a: Following the – 3.56 (m, 2H), 3.48 – 3.45 (m, 2H); 13C{1H} NMR (125
1
2
3
4
5
6
7
8
general procedure A and B, the title compound was isolated as
a colorless solid using silica-gel column chromatography
eluting with 5% ethyl acetate in hexane. Yield (A: 43%, 25
mg; B: 45%, 26.5 mg). 1H NMR (400 MHz, CDCl3) δ 7.95 (d,
J = 7.3 Hz, 2H), 7.57 (t, J = 6.7 Hz, 3H), 7.46 (t, J = 7.7 Hz,
2H), 7.37 (d, J = 8.1 Hz, 2H), 3.33 (t, J = 7.3 Hz, 2H), 3.14 (t,
J = 7.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.3,
147.1, 136.6, 133.4, 132.4, 129.4, 128.8, 128.1, 119.1, 110.2,
39.5, 30.1.
MHz, CDCl3) δ 199.3, 137.4, 136.9, 133.9, 133.1, 131.7,
128.9, 128.6, 128.1, 127.0, 126.2, 126.1, 125.7, 125.6, 123.5,
39.8, 27.2.
3-(benzo[d][1,3]dioxol-5-yl)-1-phenylpropan-1-one (4k)21a
:
Following the general procedure A and B, the title compound
was isolated as a colorless oil using silica-gel column
chromatography eluting with 4% ethyl acetate in hexane.
1
Yield (A: 51%, 32 mg; B: 60%, 38 mg). H NMR (400 MHz,
CDCl3) δ 7.87 (d, J = 7.3 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H),
7.37 (t, J = 7.6 Hz, 2H), 6.66-6.60 (m, 3H), 5.84 (s, 2H), 3.18
(t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.3, 147.7, 145.9, 136.9, 135.2, 133.2,
128.7, 128.1, 121.3, 109.0, 108.4, 100.9, 40.7, 29.9.
9
3-(4-fluorophenyl)-1-phenylpropan-1-one (4f)20d: Following
the general procedure A and B, the title compound was
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
isolated as
a
yellow oil using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane.
Yield (A: 74%, 42 mg; B: 73%, 41.5 mg).1H NMR (400 MHz,
CDCl3) δ 7.96-7.94 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.45 (t, J
= 7.6 Hz, 2H), 7.22-7.19 (m, 2H), 6.99-6.95 (m, 2H), 3.28 (t, J
= 7.6 Hz, 2H), 3.04 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 199.1,161.5 (d, JC-F= 243 Hz), 136.9, 136.8,
133.2, 129.9 (d, JC-F= 9 Hz), 128.7, 128.1, 115.3(d, JC-F= 19
Hz), 40.5, 29.3.
5,9-dimethyl-1-phenyldec-8-en-1-one (4l)23a: Following the
general procedure C, the title compound was isolated as a
yellow oil using silica-gel column chromatography eluting
with 2% ethyl acetate in hexane. Yield (30%, 19.5 mg). 1H
NMR (400 MHz, CDCl3) δ 7.96 (dd, J = 8.3, 1.0 Hz, 2H), 7.59
– 7.54 (m, 1H), 7.46 (t, J = 7.6 Hz, 2H), 5.09 (td, J = 5.6, 4.2
Hz, 1H), 2.95 (t, J = 7.4 Hz, 2H), 1.99 – 1.94 (m, 2H), 1.77
(dddd, J = 10.6, 8.6, 6.0, 3.3 Hz, 2H), 1.68 (s, 3H), 1.60 (s,
3H), 1.46 – 1.42 (m, 1H), 1.38 – 1.32 (m, 2H), 1.20 – 1.14 (m,
2H), 0.90 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 200.7, 137.2, 132.9, 131.2, 128.6, 128.1, 124.9, 39.0,
37.1, 36.7, 32.4, 25.8, 25.6, 21.9, 19.6, 17.7.
3-(4-methoxyphenyl)-1-phenylpropan-1-one
(4g)20c
:
Following the general procedure A and B, the title compound
was isolated as a white solid using silica-gel column
chromatography eluting with 5% ethyl acetate in hexane.
1
Yield (A: 65%, 39 mg; B: 64%, 38.5 mg). H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.6 Hz,
1H), 7.46 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.85 (d,
J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.28 (t, J = 7.6 Hz, 2H), 3.02 (t,
J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.5,
158.1, 137.0, 133.4, 133.1, 129.4, 128.7, 128.1, 114.0, 55.3,
40.8, 29.4.
1-phenylnonan-1-one (4m)22c
:
Following the general
procedure C, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 46%, 25 mg). 1H NMR (400 MHz) δ
7.96 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J =
7.2 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 1.77 – 1.70 (m, 2H),
1.35-1.25 (d, J = 8.1 Hz, 10H), 0.88 (t, J = 7.4 Hz, 3H); GC-
MS (EI) m/z = 218.1.
1-phenyl-3-(3,4,5-trimethoxyphenyl)propan-1-one (4h)21b
:
Following the general procedure A and B, the title compound
was isolated as a colorless oil using silica-gel column
chromatography eluting with 15% ethyl acetate in hexane.
1-phenyldecan-1-one (4n)20c
:
Following the general
procedure C, the title compound was isolated as a yellow oil
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 34%, 20 mg). 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 7.4 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H),
7.45 (t, J = 7.9 Hz, 2H), 2.95 (t, J = 7.4 Hz, 2H), 1.76-1.71 (m,
2H), 1.33-1.22 (m, 9H), 0.88- 0.85 (m, 6H); GC-MS (EI) m/z
= 232.2.
1
Yield (A: 35%, 34 mg; B: 40%, 30 mg). H NMR (400 MHz,
CDCl3) δ 7.96 (dd, J = 8.7, 1.3 Hz, 2H), 7.56 (t, J = 7.5 Hz,
1H), 7.46 (t, J = 8.0 Hz, 2H), 6.47 (s, 2H), 3.84 (s, 6H), 3.82
(s, 3H), 3.32 – 3.28 (m, 2H), 3.04 – 3.00 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 199.4, 153.3, 137.2, 136.9, 133.2,
128.7, 128.1, 105.4, 60.9, 56.2, 40.7, 30.7.
1-phenyl-3-(2,3,4-trimethoxyphenyl)propan-1-one
(4i):
1-phenyldodecan-1-one (4o)22d
:
Following the general
Following the general procedure A and B, the title compound
was isolated as a colorless oil using silica-gel column
chromatography eluting with 15% ethyl acetate in hexane.
procedure C, the title compound was isolated as a colorless oil
using silica-gel column chromatography eluting with 1% ethyl
acetate in hexane. (Yield: 36%, 23.5 mg). 1H NMR (500 MHz,
CDCl3) δ 7.99 (d, J = 7.1 Hz, 2H), 7.58 (t, J = 6.1 Hz, 1H),
7.49 (t, J = 7.9 Hz, 2H), 2.99 (t, J = 7.4 Hz, 2H), 1.79 – 1.73
(m, 2H), 1.42-1.21 (m, 16H), 0.88 (t, J = 7.1 Hz, 3H); GC-MS
(EI) m/z = 260.2.
1
Yield (A: 39%, 29 mg; B: 42%, 31.5). H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.61 (d, J =
8.5 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.25 (t, J
= 7.9 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 199.9, 152.5, 152.0, 142.4, 136.9, 133.1,
128.6, 128.2, 127.2, 124.1, 107.3, 60.9, 60.8, 56.1, 39.9, 25.2;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H21O4 301.1434;
Found 301.1437.
1-phenyl-3-(pyridin-2-yl)propan-1-one (5a)23b
the general procedure A and B, the title compound was
isolated as yellow oil using silica-gel column
: Following
a
chromatography eluting with 10% ethyl acetate in hexane.
1
Yield (A: 76%, 40 mg; B: 80%, 42 mg). H NMR (400 MHz,
3-(naphthalen-1-yl)-1-phenylpropan-1-one
(4j)21c
:
CDCl3) δ 8.51 (d, J = 4.6 Hz, 1H), 7.99 (d, J = 7.1 Hz, 2H),
7.62 – 7.52 (m, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 7.9
Hz, 1H), 7.12 – 7.09 (m, 1H), 3.51 (t, J = 7.2 Hz, 2H), 3.24 (t,
J = 7.3 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.4,
160.8, 149.4, 136.9, 136.4, 133.1, 128.6, 128.1, 123.5, 121.3,
37.9, 32.2.
Following the general procedure A and B, the title compound
was isolated as a colorless solid using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane.
1
Yield (A: 40%, 26 mg; B: 58%, 38 mg). H NMR (500 MHz,
CDCl3) δ 8.09 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 7.2 Hz, 2H),
7.91 (d, J = 7.3 Hz, 1H), 7.79 – 7.77 (m, 1H), 7.60 – 7.50 (m,
2H), 7.49 – 7.44 (m, 4H), 7.32 (dd, J = 11.6, 7.9 Hz, 1H), 3.59
1-(4-ethylphenyl)-3-(pyridin-2-yl)propan-1-one
(5b):
Following the general procedure A and B, the title compound
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yellow oil using silica-gel column
was isolated as
chromatography eluting with 10% ethyl acetate in hexane.
a
yellow oil using silica-gel column chromatography eluting
1
1
with 5% ethyl acetate in hexane. (Yield: 40%, 40 mg); H
1
2
3
4
5
6
7
8
9
Yield (A: 70%, 42 mg; B: 73%, 43.5 mg). H NMR (400
NMR (400 MHz, CDCl3) δ 7.96 – 7.91 (m, 2H), 6.95 – 6.90
(m, 2H), 5.33 (t, J = 4.8 Hz, 2H), 3.86 (s, 3H), 2.89 (t, J = 8.0
Hz, 2H), 2.02 – 1.97 (m, 4H), 1.72 – 1.67 (m, 2H), 1.27 – 1.25
(m, 24H), 0.87 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.3, 163.4, 130.4, 130.3, 130.00, 129.9, 113.7,
55.5, 38.4, 31.9, 29.85, 29.84, 29.60, 29.59, 29.57, 29.52,
29.40, 29.37, 27.3, 24.7, 22.8, 14.2. Anal. Calcd for C27H44O2:
C, 80.94; H, 11.07; Found: C, 80.65; H, 10.76.
MHz,CDCl3 ) δ 8.49 (dd, J = 4.8, 0.6 Hz, 1H), 7.90 (d, J = 8.2
Hz, 2H), 7.56 (ddd, J = 7.7, 1.8, 0.9 Hz, 1H), 7.25 – 7.22 (m,
3H), 7.08 (dd, J = 7.0, 5.4 Hz, 1H), 3.46 (t, J = 7.3 Hz, 2H),
3.21 (t, J = 7.3 Hz, 2H), 2.67 (q, J = 7.6 Hz, 2H), 1.23 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.0,
160.9, 150.0, 149.3, 136.4, 134.7, 128.4, 128.1, 123.4, 121.3,
37.8, 32.2, 28.9, 15.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C16H18NO 240.1383; Found 240.1387.
1-(3-methoxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,
16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-
yl)-3-phenylpropan-1-one (6b): Following the general
procedure A (50 mol% of Cs2CO3was used), the title product
was obtained as a yellow oil using silica-gel column
chromatography eluting with 5% ethyl acetate in hexane.
(Yield: 66%, 69 mg); 1H NMR (400 MHz, CDCl3 ) δ 7.26 (dd,
J = 10.2, 4.6 Hz, 2H), 7.19 – 7.14 (m, 3H), 5.35 – 5.31 (m,
1H), 3.34 (s, 3H), 3.04 (tt, J = 11.2, 4.4 Hz, 1H), 2.88 (t, J =
7.6 Hz, 2H), 2.74 – 2.63 (m, 2H), 2.47 (t, J = 8.9 Hz, 1H), 2.41
– 2.35 (m, 1H), 2.22 – 2.11 (m, 2H), 1.97 – 1.82 (m, 4H), 1.63
– 1.37 (m, 8H), 1.30 – 1.15 (m, 3H), 0.98 – 0.95 (m, 4H), 0.56
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 210.6, 141.6,
140.9, 128.5, 126.1, 121.4, 121.3, 80.4, 63.2, 60.7, 57.1, 55.7,
50.7, 50.1, 49.6, 47.3, 46.1, 44.4, 39.1, 38.7, 37.0, 31.9, 29.9,
28.1, 24.6, 23.0, 21.1, 19.4, 13.5; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C29H41O2 421.3101; Found 421.3108.
4-(6-methoxynaphthalen-2-yl)-1-(4-
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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
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43
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46
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48
49
50
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55
56
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59
60
1-(3-methoxyphenyl)-3-(pyridin-2-yl)propan-1-one
Following the general procedure A and B, the title compound
was isolated as yellow oil using silica-gel column
chromatography eluting with 15% ethyl acetate in hexane.
Yield (A: 78%, 47 mg; B: 80%, 48 mg). H NMR (400 MHz,
(5c):
a
1
CDCl3) δ 8.51 (d, J = 4.7 Hz, 1H), 7.61 – 7.57 (m, 2H), 7.52 –
7.51 (m, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.8 Hz,
1H), 7.12 – 7.08 (m, 2H), 3.84 (s, 3H), 3.50 (t, J = 7.2 Hz,
2H), 3.23 (t, J = 7.2 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 199.2, 160.8, 159.9, 149.3, 138.3, 136.4, 129.6,
123.4, 121.3, 120.9, 119.7, 112.3, 55.5, 37.9, 32.2; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C15H16NO2 242.1176;
Found 242.1186.
3-phenyl-1-(pyridin-3-yl)propan-1-one (5d)23c
the general procedure A and B, the title compound was
isolated as yellow oil using silica-gel column
: Following
a
chromatography eluting with 10% ethyl acetate in hexane.
1
Yield (A: 50%, 26.5 mg; B: 60%, 31.5 mg). H NMR (400
methoxyphenyl)pentan-1-one (6c): Following the general
procedure C, the title product was obtained as a colorless solid
using silica-gel column chromatography eluting with 5% ethyl
acetate in hexane.(Yield: 45%, 36 mg); 1H NMR (400 MHz,
CDCl3) δ 7.72 – 7.65 (m, 4H), 7.57 – 7.51 (m, 2H), 7.31 (dd, J
= 8.3, 1.2 Hz, 1H), 7.15 – 7.11(m, 3H), 3.91 (s, 6H), 2.81 –
2.75 (m, 2H), 2.11 (dd, J = 8.0, 0.9 Hz, 2H), 1.86-1.84 (m,
1H), 1.33-1.29 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
198.9, 157.2, 139.5, 135.4, 132.9, 129.6, 128.9, 127.6, 126.8,
125.5, 124.9, 123.7, 122.4, 118.7, 112.2, 105.8, 55.4, 28.9,
21.9, 15.7, 14.5. Anal. Calcd for C23H24O3: C, 79.28; H, 6.94;
Found: C, 78.92; H, 6.27.
MHz, CDCl3) δ 9.15 (s, 1H), 8.77 (s, 1H), 8.21 (d, J = 8.0 Hz,
1H), 7.42 – 7.34 (m, 2H), 7.32 – 7.27 (m, 2H), 7.21 (ddd, J =
7.1, 4.8, 2.9 Hz, 2H), 3.33 – 3.28 (m, 2H), 3.08 (t, J = 7.6 Hz,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.1, 153.5, 149.6,
140.8, 135.3, 128.6, 128.4, 126.3, 123.7, 115.0, 40.7, 29.8.
3-(4-fluorophenyl)-1-(pyridin-3-yl)propan-1-one
Following the general procedure A and B, the title compound
was isolated as yellow oil using silica-gel column
(5e):
a
chromatography eluting with 10% ethyl acetate in hexane.
1
Yield (A: 60%, 34 mg; B: 70%, 40 mg). H NMR (500 MHz,
CDCl3) δ 9.16 (d, J = 1.5 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz,
1H), 8.23 – 8.21 (m, 1H), 7.43 – 7.40 (m, 1H), 7.21 (dd, J =
8.5, 5.5 Hz, 2H), 6.98 (t, J = 8.7 Hz, 2H), 3.30 (t, J = 7.4 Hz,
2H), 3.07 (t, J = 7.5 Hz, 2H); 13C{1H} NMR (125 MHz,
CDCl3) δ 197.8, 161.5 (d, JC-F= 240 Hz), 153.6, 149.6, 136.4,
135.3, 132.0, 129.9(d, JC-F= 7.5 Hz), 123.7, 115.4(d, JC-F= 21.3
Hz), 40.7, 28.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H13FNO 230.0976; Found 230.0983.
2-phenylquinoline (7a)14c: Following the general procedure
B, t-BuOK (0.125 mmol) was used, the title compound was
isolated as
a
white solid using silica-gel column
chromatography eluting with 1% ethyl acetate in hexane.
1
(Yield: 85%, 43.5 mg). H NMR (400 MHz, CDCl3) δ 8.13 –
8.07 (m, 4H), 7.78 (d, J = 8.6 Hz, 1H), 7.74 – 7.72 (m, 1H),
7.64 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.46 – 7.41 (m, 3H), 7.40
– 7.36 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.5,
148.4, 139.8, 136.9, 129.8, 129.4, 128.9, 127.7, 127.6, 127.3,
126.4, 119.1, 119.0.
3-(pyridin-2-yl)-1-(pyridin-3-yl)propan-1-one
Following the general procedure A and B, the title compound
was isolated as yellow oil using silica-gel column
(5f):
a
chromatography eluting with 25% ethyl acetate in hexane.
Yield (A: 30%, 16 mg; B: 75%, 40 mg).1H NMR (400 MHz,
CDCl3) δ 9.20 (d, J = 2.1 Hz, 1H), 8.75 (dd, J = 4.8, 1.7 Hz,
1H), 8.49 (d, J = 4.6 Hz, 1H), 8.24 (ddd, J= 7.9, 3.8, 1.8 Hz,
1H), 7.59 (td, J = 7.7, 1.8 Hz, 1H), 7.39 (dd, J = 8.2, 4.8 Hz,
1H), 7.25 (d, J = 3.2 Hz, 1H), 7.10 (dd, J = 7.5, 4.9 Hz, 1H),
3.52 (t, J = 7.1 Hz, 2H), 3.25 (t, J = 7.1 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 198.4, 160.2, 153.5, 149.8, 149.3,
136.5, 135.4, 132.3, 123.6, 123.4, 121.4, 37.9, 31.7; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C13H13N2O 213.1022;
Found 213.1029.
2-(4-Ethylphenyl)quinoline (7b)14c: Following the general
procedure B, t-BuOK (0.125 mmol) was used, the title
product was obtained as a colorless solid using silica-gel
column chromatography eluting with 1% ethyl acetate in
1
hexane. (Yield: 82%, 48 mg); H NMR (400 MHz, CDCl3) δ
8.17 (t, J = 8.0 Hz, 2H), 8.09 (d, J = 6.8 Hz, 2H), 7.85 (d, J =
8.7 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H),
7.50 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 2.73 (q, J =
7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 157.5, 148.4, 145.8, 137.3, 136.7, 129.8,
129.7, 128.5, 127.6, 127.5, 127.2, 126.2, 119.0, 28.8, 15.7.
(Z)-1-(4-methoxyphenyl)icos-11-en-1-one (6a): Following
the general procedure C, the title product was obtained as a
2-(Pyridin-3-yl)quinoline (7c)14c
procedure B, t-BuOK (0.125 mmol) was used, the title product
: Following the general
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The Journal of Organic Chemistry
was obtained as a colorless solid using silica-gel column
Page 10 of 13
1
2
3
4
5
6
7
8
chromatography eluting with 5% ethyl acetate in hexane.
(Yield: 50%, 26 mg); 1H NMR (400 MHz, CDCl3) δ 9.34 (d, J
= 1.6 Hz, 1H), 8.69 (dd, J = 4.8, 1.5 Hz, 1H), 8.53 – 8.48 (m,
1H), 8.26 (d, J = 8.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.86
(dd, J = 12.8, 8.4 Hz, 2H), 7.75 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H),
7.55 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.45 (dd, J = 7.3, 4.8 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.7, 150.3, 148.9,
148.5, 137.3, 135.2, 135.1, 130.1, 129.8, 127.7, 127.5, 126.9,
123.8, 118.6.
AUTHOR INFORMATION
Corresponding Author
* E-mail: dbane.fcy@iitr.ac.in
ASSOCIATED CONTENT
Supporting Information
9
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.xxxxxxxx.
2-(Naphthalen-2-yl)quinoline (7d)24a: Following the general
procedure B, t-BuOK (0.125 mmol) was used, the title
product was obtained as a colorless solid using silica-gel
column chromatography eluting with 1% ethyl acetate in
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
1H NMR, 13C NMR spectra, kinetic studies (PDF)
1
Notes
hexane. (Yield: 88%, 56 mg); H NMR (500 MHz, CDCl3) δ
8.65 (s, 1H), 8.41 (dd, J = 8.6, 1.7 Hz, 1H), 8.27 (dd, J = 12.5,
8.6 Hz, 2H), 8.05 (dd, J = 15.8, 8.2 Hz, 3H), 7.93 (dd, J = 5.9,
3.4 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.79 (ddd, J = 8.3, 6.9,
1.3 Hz, 1H), 7.57 (dd, J = 6.4, 2.9 Hz, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 157.2, 148.4, 136.9, 136.9, 133.9, 133.5,
129.8, 128.9, 128.6, 128.5, 127.8, 127.5, 127.3, 127.1, 126.8,
126.4, 119.2, 115.0.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank DAE-BRNS, India (Young Scientist Research
Award to D. B., 37(2)/20/33/2016-BRNS) and (SMILE-32) IITR.
J. D. thank IIT-R for financial support. M. V. Thank SERB-NPDF
(PDF/2017/002784), India for a fellowship.
2-methoxy-5,6-dihydrobenzo[c]acridine (7e)14c: Following
the general procedure B, t-BuOK (0.125 mmol) was used, the
title product was obtained as a colorless solid using silica-gel
column chromatography eluting with 5% ethyl acetate in
hexane. (Yield: 50%, 32.5 mg); 1H NMR (400 MHz, CDCl3) δ
8.17 – 8.11 (m, 2H), 7.90 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H),
7.64 (dd, J = 8.2, 7.1 Hz, 1H), 7.47 (dd, J = 8.0, 7.0 Hz, 1H),
7.18 (d, J = 8.3 Hz, 1H), 6.94 (dd, J = 8.3, 2.8 Hz, 1H), 3.96
(s, 3H), 3.12 – 3.06 (m, 2H), 2.96 – 2.90 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 159.2, 153.4, 147.6, 135.8, 133.8,
131.9, 130.8, 129.5, 129.1, 128.7, 128.0, 127.0, 126.2, 117.0,
109.7, 55.7, 29.2, 27.6.
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Broad Substrate Scope
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OH
Functionalization of Steroid and fatty acids
Post-synthetic drug modulation (Naproxen)
Mechanistic studies and isolation of catalytic
intermediates
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up to 90% yield
Ph
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Determination of rate and order/isotope
labeling experiments
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