NIS-catalyzed reactions: Amidation of acetophenones and oxidative amination of propiophenones

Article abstract of DOI:10.1002/chem.201202703

Single-step amination: The N-iodosuccinimide (NIS)-catalyzed amidation of acetophenone derivatives by using tert-butylhydroperoxide (TBHP) as an oxidant is presented. A variety of acetyl derivatives of heterocyclic compounds were easily converted to their corresponding ketoamides under these conditions. A new, NIS-catalyzed amination of propiophenone and its derivatives in the presence of TBHP to furnish the corresponding 2-aminoketone derivatives is the first reported single-step amination of propiophenone derivatives. Copyright

Full text of DOI:10.1002/chem.201202703

DOI: 10.1002/chem.201202703
NIS-Catalyzed Reactions: Amidation of Acetophenones and Oxidative
Amination of Propiophenones
Manjunath Lamani and Kandikere Ramaiah Prabhu*[a]
Table 1. Optimization studies for the amidation of acetophenone.
a-Ketoamides are important intermediates in organic syn-
thesis that are present in a variety of natural products and
pharmaceutically active compounds.[1] Traditionally, a-keto-
ACHTUNGTRENNUNG
amides are synthesized by the amidation of a-ketoacids[2] or
cyanoketones,[3] oxidation of amides by metal oxidants, such
as SeO2, RuO2, or CAN, and by photochemical reactions of
amides.[4] Double carbonylation of aryl halides with carbon
monoxide in the presence of Pd or Cu complexes is an alter-
nate method for the synthesis of a-ketoamides.[5] Recently,
Jiao and co-workers reported the synthesis of a- ketoamides
by reacting phenyl acetylenes or aryl acetaldehydes by using
a copper catalyst.[6,7] In addition to these reports, Ji and co-
workers reported the synthesis of ketoamides by using a
CuI/oxygen system with acetophenone derivatives.[8] Howev-
er, the use of toxic metal oxidants, harsh reaction conditions,
heavy metal impurities in drug intermediates, and the limit-
ed availability of starting materials restricts the utility of
these methods. In view of the increased attention on design-
ing environmentally benign and metal-free methods for oxi-
Entry
Iodine source
([mol%])
Oxidant
ACHTUNGTRENN(UNG [equiv])
Yield
[%][a]
G
1
2
3
4
5
6
7
8
9
10
11
12[b]
13[c]
14[d]
15[e]
16
17
18
I2 (30)
I2 (30)
oxygen
H2O2
H2O2
H2O2
nr
<10
<10
<10
15
75
85
90
92
60
75
61
70
60
62
nr
nr
TBAI (30)
NIS (30)
NIS (30)
NaI (10)
NaI (20)
NaI (30)
NIS (30)
NIS (30)
NIS (20)
NIS (30)
NIS (30)
NIS (30)
NIS (30)
–
CHP
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (1)
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (3)
aq. TBHP (3)
–
dative transformations to form C N bonds,[9] and in continu-
À
NIS (30)
NBS (30)
ation of our research in this area, we herein present a mild
and efficient conversion of acetophenones to a-ketoamides
by using N-iodosuccinamide (NIS) as a catalyst and tert-bu-
tylhydroperoxide (TBHP) as a terminal oxidant at room
temperature.
aq. TBHP (3)
nr
[a] Yield of isolated product. [b] One equivalent of amine was used.
[c] Two equivalents of amine were used. [d] Toluene was used as the sol-
vent. [e] THF was used as the solvent. CHP=cumene hydroperoxide,
nr=no reaction.
Optimization studies began with the reaction of acetophe-
none and piperidine. As can be seen from the results in
Table 1, the reaction of acetophenone (1a) with piperidine
(2a) in the presence of iodine and oxygen failed to give the
expected product 3a (Entry 1, Table 1). The use of a termi-
nal oxidant, such as hydrogen peroxide, with iodine showed
the formation of product ketoamide 3a in low yield (10%;
Entry 2, Table 1). The use of tetrabutylammonium iodide
(TBAI) or NIS with hydrogen peroxide, or NIS with
cumene hydrogen peroxide, resulted in the formation of
product 3a in 10% yield (Entries 3–5, Table 1). The reaction
of 1a with sodium iodide (10 mol%) as an iodine source
and TBHP (3 equiv) as the terminal oxidant resulted in a
significant improvement, forming 3a in 75% yield (Entry 6,
Table 1). Increasing the amount of sodium iodide (to 20 or
30 mol%) resulted in an enhancement of the yield of 3a to
85 and 90%, respectively (Entries 7 and 8, Table 1).[11] Fur-
thermore, it was noticed that changing the iodine source to
NIS increased the formation of product 3a to a 92% yield
(Entry 9, Table 1). Additional screening experiments re-
vealed that lowering the amount of NIS and TBHP was not
useful in improving the yield of the product 3a (Entries 10
and 11, Table 1). Decreasing the amount of amine or chang-
ing the solvent to toluene or THF resulted in the formation
of 3a in lower yields (Entries 12–15, Table 1). The reaction
did not proceed in the absence of NIS or TBHP (Entries 16
and 17, Table 1), indicating the necessity of an iodine source
as well as TBHP. It was found that the combination of N-
bromosuccinimide (NBS) and TBHP was not useful for this
reaction (Entry 18, Table 1). Therefore, we carried out fur-
[a] M. Lamani, Dr. K. R. Prabhu
Department of Organic chemistry
Indian Institute of Science
Bangalore 560 012, Karnataka (India)
Fax : (+91)80-23600529
E-mail: prabhu@orgchem.iisc.ernet.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202703.
14638
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14638 – 14642

COMMUNICATION
ther reactions by using acetophenone (1 mmol), amine
(3 mmol), NIS (30 mol%), and TBHP (3 equiv) in acetoni-
trile (0.5 mL) at room temperature.
in good yield (Entry 4, Table 2). 4-Chloroacetophenone (1d)
reacted well with piperidine (2a) and morpholine (2b) in
the presence of NIS and TBHP to form the corresponding
ketoamides 3 f and 3g in good yields (74 and 75%, respec-
tively; Entries 5 and 6, Table 2). On reaction with a variety
of amines, such as 4-benzylpiperidine (2d) and 2a and 2b,
acetophenone derivatives containing bromo or iodo sub-
stituents at the para position (e.g., 1e and 1 f) gave the cor-
responding products 3h, 3i, and 3j in good yields (En-
tries 7–9, Table 2). Acetophenone derivatives that contain
electron-withdrawing groups, such as a nitro group at the
para position (1g), reacted satisfactorily with piperidine
(2a), morpholine (2b), and 4-benzylpiperidine (2d) to pro-
vide the corresponding products 3k, 3l, and 3m in good
yields (70, 72, and 61% respectively; Entries 10–12,
Table 2). Heterocyclic ketones such as 2-acetylpyridine (1h)
and 2-acetylthiophene (1i) reacted well with piperidine (2a)
Under the optimized reaction conditions, a variety of
amines were reacted with acetophenone and its derivatives
to provide the corresponding ketoamides in good to excel-
lent yields (Table 2). Acetophenones with electron-donating
and electron-withdrawing groups provided the correspond-
ing ketoamides in good yields. Acetophenone (1a) reacted
well with morpholine (2b) and pyrrolidine (2c) to form the
corresponding ketoamides 3b and 3c in 90 and 70% respec-
tively (Entries 1–2, Table 2). 4-Methoxyacetophenone (1b)
underwent a smooth reaction with 2a under the standard re-
action conditions to give the corresponding ketoamide 3d in
moderate yield (50%; Entry 3, Table 2). 4-Methylacetophe-
none (1c) reacted well with piperidine (2a) in the presence
of NIS and TBHP to form the corresponding ketoamide 3e
Table 2. Amidation of aromatic ketones.[a]
Entry Ketone
Amine
Time Product
[h]
Yield Entry Ketone
[%][b]
Amine
2a
Time Product
[h]
Yield
[%][b]
1
12
12
90
70
10
11
10
10
70
72
2
1a
1g
1g
2b
3
4
5
2a
2a
2a
24
24
14
50
70
74
12
13
14
2d
2a
2b
10
10
24
61
65
60
6
7
1d
2b
14
16
75
62
15
16
1a
12
12
68
70
8
9
2a
16
16
65
68
17
12
74
1 f
2b
[a] Reaction conditions: acetophenone derivative (1 mmol), amine (3 mmol), aq. TBHP (70%, 3 mmol, 0.412 mL), NIS (0.3 mmol, 67.5 mg), CH3CN (0.5 mL),
RT. [b] Yield of isolated product.
Chem. Eur. J. 2012, 18, 14638 – 14642
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14639

K. R. Prabhu and M. Lamani
and morpholine (2b) to form the corresponding products 3n
and 3o in good yields (Entries 13–14, Table 2). Furthermore,
the compatibility of acyclic amines for use in this reaction
was established by the reaction of N,N-diisobutylamine (2j)
with acetophenone (1a). As expected, the corresponding ke-
toamide 3p was obtained in moderate yield (68%; Entry 15,
Table 2). The general scope of this reaction was further ex-
plored by reacting 2-fluroacetophenone (1j) and 3-nitroace-
tophenone (1k) with morpholine (2b) to obtain the corre-
sponding ketoamides 3q and 3r in good yields (Entries 16
and 17, Table 2).
Having found suitable conditions for the satisfactory reac-
tion of acetophenone and its derivatives with secondary
amines, we focused our attention in investigating the reac-
tion of propiophenones with secondary amines under these
conditions. We thought that it would be interesting to see
the outcome of this reaction because there is no possibility
of the formation of an a-ketoamide in the reaction of pro-
piophenones with secondary amines. Under the established
reaction conditions, propiophenone (4a) underwent a cross
dehydrogenative coupling (CDC) reaction at the a-position
of propiophenone 4a to furnish 2-amino-1-phenylpropan-1-
one derivative 5a in good yield (80%; Scheme 1). These de-
Scheme 2. Synthesis of 2-aminoacetophenones.
avoid the use of bromine and obtain the required com-
pounds in moderate to good yields by using the same cata-
lytic system as described above. To the best of our knowl-
edge, this is the first report of the amination of propiophe-
none derivatives in a single step, which may find many po-
tential applications.
The scope of the CDC reaction of various propiophenone
derivatives leading to the formation of a-aminoketones is
shown in Table 3. By following the standard protocol, pro-
piophenone (4a) was coupled with secondary amines, such
as morpholine (2b) and 4-benzyl piperidine (2d), to form
the corresponding a-aminoketones in good yields (Entries 1
and 2, Table 3). Under the standard reaction conditions, bu-
tyrophenone (4b) reacted well with morpholine (2b) to
form the corresponding amino derivative 5d in good yield
(Entry 3, Table 3). m-Fluoropropiophenone (4c) underwent
a smooth reaction with morpholine (2b) to provide the ami-
nated product 5e in good yield (Entry 4, Table 3). A deriva-
tive of ifenprodil was synthesized by treating 4-benzyloxy-
propiophenone (4e) with 4-benzylpiperidine (2d) in
(Entry 6, Table 3). Heterocyclic compounds, such as 1-(thio-
phen-2-yl)propan-1-one (4 f) and 1-(furan-2-yl)propan-1-one
(4g), underwent facile reactions with morpholine (2b), 4-
benzyl piperidine (2d), and N-methylbenzylamine (2e) to
yield compounds 5h–5l (Entries 7–11, Table 3).
To understand the reaction mechanism of the amidation
of acetophenone, acetophenone (1a) was treated with the
secondary amine 2a in the presence of NIS (30 mol%) and
TBHP (3 equiv) and a radical inhibitor, such as 2,6-bis(1,1-
dimethylethyl)-4-methylphenol (BHT) or 2,2,6,6-tetrameth-
yl-piperidin-1-yl)oxyl (TEMPO). This reaction resulted in
the formation of the a-ketoamide 3a in 30% yield. This ex-
periment suggests that the reaction probably proceeds
through a radical intermediate.[17] Furthermore, acetophe-
none (1a) was reacted with stoichiometric amount of NIS
and TBHP in the absence of an amine in the hope that the
corresponding a-iodo compound could be obtained, but this
reaction did not produce the expected iodo-intermediate.
However, the reaction of 4-chlorophenacyliodide (I) with pi-
peridene (2a, 3 equiv) in the presence of TBHP (3 equiv)
and NIS (30 mol%) in CH3CN gave the product 3 f in 70%
yield (Scheme 3a). This observation is in agreement with
those made by Wang et al.[17] Furthermore, the reaction of 1-
(4-chlorophenyl)-2-(piperidin-1-yl)ethanone (II) with TBHP
(3 equiv) and NIS (30 mol%) in CH3CN furnished the prod-
uct 3 f in 72% yield (Scheme 3b). These experiments sug-
gested that the reaction might proceed through the 1-(4-
Scheme 1. Cross dehydrogenative coupling reaction with propiophenone.
rivatives are ubiquitous scaffolds that are present in a wide
variety of therapeutic agents. Some of these compounds are
used in the treatment of depression, smoking cessation, as
monoamine-uptake inhibitors,[12] and as drugs for cancer.[13]
They are photoinitiators[14] and precursors to b-aminoalco-
hols, such as pseudoephedrine analogues.[15] 2-Aminoaceto-
phenone analogues are also important intermediates for the
formation of several heterocyclic compounds[16] and are
active moieties in several important drugs, such as ifenpro-
dil, bupropion, and amfepramone, and different derivatives
could be used as potential pharmacotherapies for cocaine
addiction.[12c] In this context, we focused our attention on
preparing different analogues of propiophenone derivatives
by using this methodology.
Existing methods for the formation of amino derivatives
of propiophenone involve the traditional nucleophilic dis-
placement of an a-haloderivative of a propiophenone with
an appropriate amine (Scheme 2).[12] In these methods, bro-
mine, which is toxic, corrosive and not easy to handle, is
used extensively. Often, the a-haloderivative of carbonyls
are lachrymatory and will decompose on exposure to excess
light. Hence, it is important to develop a user-friendly
method to accomplish the synthesis of amino derivatives of
propiophenone without the use of bromine (Scheme 1). In
this part of the paper, we present an elegant method to
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Chem. Eur. J. 2012, 18, 14638 – 14642

NIS-Catalyzed Reactions: Amidation and Oxidative Amination
Table 3. Cross dehydrogenative coupling reactions.[a]
COMMUNICATION
Entry Ketone
Amine Time Product
[h]
Yield
[%][b]
1
2
3
4a
4a
2b
2d
2b
4
7
74
67
70
24
4
5
2b
2b
5
5
63
60
Scheme 3. Tentative mechanism for the amidation of acetophenone.
reaction proceeded to give the product in good yield with-
out the formation of any TEMPO-coupled product, indicat-
ing that this reaction does not involve the radical inter-
mediate.[17] Further work is ongoing in our laboratory to
understand the reaction mechanism and expand the scope
of these reactions.
6
2d
24
50
In conclusion, we have successfully demonstrated an
NIS-catalyzed amidation of acetophenone derivatives by
using TBHP as an oxidant. This amidation reaction is ver-
satile and several acetophenone derivatives containing elec-
tron-withdrawing and electron-donating substituents can
undergo facile amidation. It was also found that acetyl de-
rivatives of heterocyclic compounds could be easily con-
verted to their corresponding ketoamides. A new amination
of propiophenone and its derivatives, catalyzed by NIS in
the presence of TBHP, to provide their corresponding 2-
aminoketone derivatives is reported. This is the first report
of the amination of propiophenone derivatives in a single
step that can be used to synthesize potentially important
and active pharmaceutical reagents.
7
8
2b
2d
4
6
75
70
4 f
9
2b
2d
6
74
10
11
4g
4g
5
5
76
50
[a] Reaction conditions: propiophenone derivative (1 mmol), amine
(3 mmol), aq. TBHP (70%, 3 mmol, 0.412 mL), NIS (0.3 mmol, 67.5 mg),
CH3CN (0.5 mL), RT. [b] Yield of isolated product.
Experimental Section
chlorophenyl)-2-(piperidin-1-yl)ethanone intermediate (II;
Scheme 3c).[19]
General procedures: 1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3a):
Piperidine (255 mg, 3 mmol) was added dropwise to a stirred suspension
of acetophenone (120 mg, 1 mmol) and NIS (67.5 mg, 0.3 mmol) in aceto-
nitrile (0.5 mL), and was followed by the slower addition of TBHP (70%
solution in water, 3 mmol, 0.412 mL). The reaction mixture was stirred at
room temperature until the starting material was consumed (12 h, as
monitored by TLC), then extracted with ethyl acetate (3ꢁ15 mL) and
the combined organic layers were washed with water (2ꢁ50 mL), dried
over anhydrous Na2SO4, and the solvent was removed under vacuum.
The residue was purified by column chromatography on silica gel
(EtOAc/Hexane 5:95–10:90) to provide 3a as a pale-yellow liquid (92%,
200 mg).
To further understand the reaction mechanism of the
CDC reaction of propiophenone, a few control experiments
were carried out. The reaction of propiophenone (4a) under
standard reaction conditions, or in the presence of excess
NIS (1 equiv) and TBHP (3 equiv), did not yield any detect-
able amounts of 2-iodopropiophenone, suggesting that the
reaction does not proceed through an a-iodointermediate.
In the presence of a radical scavenger such as TEMPO, the
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14641

K. R. Prabhu and M. Lamani
1-phenyl-2-(piperidin-1-yl)propan-1-one (5a): Piperidine (255 mg,
3 mmol) was added dropwise to a stirred suspension of propiophenone
(135 mg, 1 mmol) and NIS (67.5 mg, 0.3 mmol) in acetonitrile (0.5 mL),
and was followed by the slower addition of TBHP (70% solution in
water, 3 mmol, 0.412 mL). The reaction mixture was stirred at room tem-
perature until the starting material was consumed (4 h, as monitored by
TLC), the extracted with ethyl acetate (3ꢁ15 mL) and the combined or-
ganic layers were washed with water (2ꢁ50 mL), dried over anhydrous
Na2SO4, and the solvent was removed under vacuum. The residue was
purified by column chromatography on silica gel (EtOAc/Hexane 5:95–
10:90) to provide 5a as a colorless liquid (80%, 174 mg).
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in reactions with 1a and 2a. However, in reactions with other sub-
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Acknowledgements
The authors thank the Indian Institute of Science and Ray Chemicals for
financial support of this investigation, Dr. A. R. Ramesha for useful dis-
cussions, and Prof. Sosale Chandrasekhar and Mr. Anjan Roy for encour-
agement. One of the authors (M.L.) thanks the CSIR, New-Delhi for a
senior research fellowship.
Keywords: acetophenones · amination · dehydrogenation ·
N-iodosuccinimide · oxidation · propiophenones
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