Oxidative aminocarbonylation of terminal alkynes for the synthesis of alk-2-ynamides by using palladium-on-carbon as efficient, heterogeneous, phosphine-free, and reusable catalyst

Article abstract of DOI:10.1002/adsc.201200041

Palladium-on-carbon (Pd/C)-catalyzed oxidative aminocarbonylations of alk-1-ynes with secondary amines provide the corresponding alk-2-ynamides in a good to excellent yields. This new methodology is applicable for the synthesis of a wide range of biologically active alk-2-ynamide derivatives. The developed protocol avoids the use of phosphine ligands, with an additional advantage of palladium catalyst recovery and reuse for up to four consecutive cycles. Copyright

Full text of DOI:10.1002/adsc.201200041

UPDATES
DOI: 10.1002/adsc.201200041
Oxidative Aminocarbonylation of Terminal Alkynes for the
Synthesis of Alk-2-ynamides by Using Palladium-on-Carbon as
Efficient, Heterogeneous, Phosphine-Free, and Reusable
Catalyst
Sandip T. Gadge,a Mayur V. Khedkar,a Satish R. Lanke,a
and Bhalchandra M. Bhanagea,*
a
Department of Chemistry, Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai – 400019, India
Fax : (+91)-22-33611020; e-mail: bm.bhanage@gmail.com or bm.bhanage@ictmumbai.edu.in
Received: January 16, 2012; Revised: March 23, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200041.
Abstract: Palladium-on-carbon (Pd/C)-catalyzed
oxidative aminocarbonylations of alk-1-ynes with
secondary amines provide the corresponding alk-2-
ynamides in a good to excellent yields. This new
methodology is applicable for the synthesis of
a wide range of biologically active alk-2-ynamide
derivatives. The developed protocol avoids the use
of phosphine ligands, with an additional advantage
of palladium catalyst recovery and reuse for up to
four consecutive cycles.
In 2001, Gabriele et al. first reported a direct oxida-
tive aminocarbonylation for the synthesis of a,b-alk-
AHCTUNGTREGyNNUN nylamides from alk-1-ynes and secondary amines by
using PdI2 and KI as a catalytic system in the pres-
ence of a CO/air mixture (20 atm) at 1008C for
24 h.[5b] This seminal work was then followed by
a report from Yamamoto et al. on using homogeneous
PdCl2/PPh3 as a catalytic system for the direct oxida-
tive aminocarbonylation using carbon monoxide/
oxygen (CO/O2) in basic conditions with NaOAc as
base.[5c] All these above reported protocols made use
of homogeneous catalysts; however the major draw-
back of homogeneous catalysis is the difficulty in sep-
arating the catalyst from the reaction mixture and its
subsequent reuse for consecutive reactions. The high
costs and toxicity of the transition metal catalysts has
led to an increased interest in immobilizing catalysts
on to a suitable solid support. In this context hetero-
Keywords: alk-2-ynamides; heterogeneous catalysis;
oxidative aminocarbonylation; palladium-on-carbon
(Pd/C); phosphine-free conditions
The alk-2-ynamides (a,b-alkynylamides) are impor- geneous catalysis was found to be best alternative. In
tant building blocks in the synthesis of various hetero-
cyclic compounds[1] and biologically active mole-
cules.[2] They exhibit excellent affinity for the
mGluR5 receptor and antifilarial activity (Figure 1).[3]
Moreover a,b-alkynylamides also play an crucial role
in drug discovery and manufacturing processes.
The common route for the synthesis of a,b-alkyn-
ACHTUNGTRENNUNGylamide involves a Pd/Cu-catalyzed reaction between
alk-1-ynes and carbamoyl chlorides.[2b,d,f,4a] Hoberg
and co-workers reported a non-catalytic synthesis of
a,b-alkynylamides by reacting alk-1-ynes, secondary
amines, carbon monoxide (CO) in the preesence of
a Ni(II) complex.[4b] The synthesis of a,b-alkynyl-
ACHTUNGTRENNUNGamides using oxidative aminocarbonylation, conceptu-
ally constitutes an alternative methodology, which has
been scarcely studied.[5] In such reactions two nucleo-
philes get coupled together by a carbonylation reac-
tion in the presence of a suitable oxidant.[6]
Figure 1. Structures of some biologically active a,b-alkynyla-
mide derivatives.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ÞÞ
These are not the final page numbers!

Sandip T. Gadge et al.
UPDATES
spite of this, all the above reported methods for direct a range of secondary amines using Pd/C as a catalyst
oxidative aminocarbonylation suffer from one or under aa low pressure of CO/O2 (5/1 atm)
more drawbacks such as use of expensive, air/mois- (Scheme 1).
ture sensitive phosphine ligands, use of bases, longer
The reaction of phenylacetylene with piperidine in
reaction time, high temperature, low yield of products, the presence of CO/O2 and tetrabutylammonium
use of high pressure of CO/O2, that limit their appli- iodide (TBAI) as an additive using 10% Pd/C as a cat-
cations. Therefore, the search for a heterogeneous alyst was chosen as a model reaction. A series of ex-
and reusable catalyst which could efficiently catalyze periments was performed to optimize various reaction
the oxidative aminocarbonylation reaction under parameters such as nature of the catalyst, effect of
milder reaction conditions without the aid of phos- catalyst loading, solvent, additive, reaction tempera-
phine ligands is subject of the present work. In search ture, time and CO pressure. The results obtained are
for new catalytic systems which can overcome the summarized in Table 1 and Table 2.
above drawbacks, Pd/C was found to be the best alter-
Initially we screened various heterogeneous palladi-
native. Pd/C is an economical and commercially avail- um catalysts such PS-Pd-NHC (polymer-supported
able catalyst, also it is easy to handle and could be re- palladium-N-heterocyclic carbene), 10% Pd/C and
covered from the reaction mixture by simple filtration 5% Pd/C (Table 1, entries 1–3) on the model reaction
and further reused. Application of Pd/C as a ligand- system, in which 10% Pd/C was found to be the best
free catalyst has been well explored for various cou-
pling reaction.[7]
Table 2. Optimization of the Pd/C-catalyzed oxidative ami-
In continuation of our interest in the aminocarbo-
nylation reaction[8] and phosphine-free carbonylation
reactions,[9] herein we report the first heterogeneous,
phosphine-free and efficiently recyclable protocol for
the synthesis of a,b-alkynylamides (3) by direct oxida-
tive aminocarbonylation of terminal alkynes with
nocarbonylation reaction of alk-1-yne.[a]
Entry Solvent
Additive Temp.
Time
[h]
Yield
[%][b]
[8C]
Effect of solvent
Scheme 1. Pd/C catalyzed oxidative aminocarbonylation of
alk-1-ynes (2).
1
2
3
4
toluene
cyclohexane TBAI
THF TBAI
1,4-dioxane TBAI
TBAI
80
80
80
80
14
14
14
14
25
32
66
95
Table 1. Effect of catalyst screening and loading on the oxi-
dative aminocarbonylation of alk-1-ynes.[a]
Effect of additive
5
6
7
8
9
1,4-dioxane KI
80
80
80
80
80
14
14
14
14
14
80
88
84
82
–
1,4-dioxane NaI
1,4-dioxane TBAB
1,4-dioxane KBr
1,4-dioxane
–
Effect of temperature
10
11
12
13
1,4-dioxane TBAI
1,4-dioxane TBAI
1,4-dioxane TBAI
1,4-dioxane TBAI
40
60
70
120
14
14
14
14
49
61
70
88
Entry Catalyst
Catalyst loading [mol%] Yield [%][b]
Catalyst screening
Effect of time
1
2
3
PS-Pd-NHC
Pd/C (10%)
Pd/C (5%)
8
8
8
75
95
82
14
1,4-dioxane TBAI
1,4-dioxane TBAI
1,4-dioxane TBAI
80
80
80
80
10
12
14
14
70
80
65
63
15
16[c]
Catalyst loading
17[d] 1,4-dioxane TBAI
4
5
Pd/C (10%)
Pd/C (10%) 10
6
52
96
[a]
Reaction conditions: phenylacetylene (1 mmol), piperi-
dine (1.5 mmol), 10% Pd/C (8 mol%), CO/O2 pressure
(5/1 atm), TBAI (0.90 mmol), 1, 4-dioxane (10 mL), tem-
perature 808C, time 14 h.
GC yield.
CO pressure: 2 atm.
[a]
Reaction conditions: phenylacetylene (1 mmol), piperi-
dine (1.5 mmol), CO/O2 pressure (5/1 atm), TBAI
(0.90 mmol), 1,4-dioxane (10 mL), temperature 808C,
time 14 h.
[b]
[c]
[d]
[b]
2
GC yield.
CO/air pressure: 5/1 atm.
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Oxidative Aminocarbonylation of Terminal Alkynes for the Synthesis of Alk-2-ynamides
catalyst providing an excellent yield of the desired confirm the role of an additive in our system, the re-
product (Table 1, entry 2). We further studied catalyst action was performed without additive, but no forma-
loadings ranging from 6 to 10 mol% wherein the in- tion of the desired product was observed which indi-
crease in catalyst concentration from 6 to 8 mol% cates the essential role of an additive in the reaction
showed an increase in the yield of desired product (Table 2, entry 9). While studying effect of tempera-
(Table 1, entries 4 and 2); while on further increases ture, the yield of the desired product increased with
in catalyst concentration no profound effect on the increasing the reaction temperature from 40 to 808C,
yield of desired product was observed (Table 1, whereby 808C proves to be the optimum temperature
entry 5). Next by using 10% Pd/C as a catalyst, we for the reaction (Table 2, entries 4, 10–12). Thereafter
studied the effect of the solvent on the oxidative ami- no profound increase in the yield of the desired prod-
nocarbonylation reaction. The solvents like toluene uct was observed upon increasing reaction tempera-
and cyclohexane provided lower yields of the expect- ture up to 1208C (Table 2, entry 13). Then the reac-
ed product (Table 2, entries 1 and 2), while THF pro- tion time was also optimized (Table 2, entries 14 and
vided a moderate yield of the desired product 15) and maximum yield of the desired product was
(Table 2, entry 3). Using 1,4-dioxane as a solvent obtained after 14 hours (Table 2, entry 4). When the
a 95% yield of the a,b-alkynylamide was observed, reaction was run at a lower CO pressure (2 atm) a re-
hence it was used for further study (Table 2, entry 4). duced yield of the expected product was observed
It is well known that an iodide-containing additive (Table 2, entry 16), hence all reactions were carried
along with molecular oxygen as an oxidant plays out at 5 atm CO pressure, as it provides the maximum
a vital role in the oxidative aminocarbonylation reac- yield of desired product. When air was used as an oxi-
tion.[5a,b,10]
dant a poor yield of the desired product was observed
Therefore we screened various iodide-containing (Table 2, entry 17). With these optimized reaction
additives such as TBAI, KI and NaI (Table 2, en- conditions in hand, we screened different aliphatic
tries 4–6), the maximum yield of the expected product linear/cyclic amines, asymmetric amines and aromatic
was observed using TBAI. We also screened bromide- substituted amines. The results obtained are summar-
containing additives like TBAB (tetrabutylammonium ized in Table 3.
bromide) and KBr which provided moderate yields of
The model reaction of phenylacetylene with piperi-
the respective product (Table 2, entries 7 and 8). To dine under the optimized reaction condition provides
Table 3. Oxidative aminocarbonylation of alk-1-ynes with various secondary amines.[a]
Entry
Secondary amine
Alk-1-yne
Product
Yield [%][b]
1
2
3
93
1a
2a
2a
3a
89[c]
92
4
5
6
7
2a
2a
2a
2a
91
85
90
86
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3
ÞÞ
These are not the final page numbers!

Sandip T. Gadge et al.
UPDATES
Table 3. (Continued)
Entry
Secondary amine
Alk-1-yne
Product
Yield [%][b]
88
8
2a
9
2a
2a
2a
89
92
10
11
12
87
55
1a
1a
13
14
94
1a
1a
88
94
15
[a]
Reaction conditions: alk-1-yne (1 mmol), secondary amine (1.5 mmol), 10% Pd/C (8 mol%), CO/O2 pressure (5/1 atm),
TBAI (0.90 mmol), 1,4-dioxane (10 mL), temperature 808C, time 14 h.
Isolated yield.
[b]
[c]
The reaction was scaled up to 4 mmol of alk-1-yne.
a
93% yield of corresponding amide (Table 3, amines, we observed the formation of side products
entry 1). Cyclic secondary amines like pyrollidine and along with trace amounts of the desired product.
morpholine provide excellent yield of desired product However, hindered amines like diisopropyl amine and
(Table 3, entries 3 and 4). Furthermore, we could syn- low nucleophilic amines like N-methylaniline were
thesize the piperazylamides of 3-phenylpropynoic found to be unreactive.
acid in excellent yields starting from N-methyl-, N-
Next we examined the reaction between various ali-
acyl- and N-benzylpiperazines (Table 3 entries 5–7). phatic, aromatic and heteroaromatic substituted al-
Secondary aliphatic amines such as diethylamine and kynes with piperidine in the presence of CO. 1-
dibutylamine also showed excellent activity in this Hexyne was found to react smoothly with piperidine
transformation (Table 3, entries 8 and 9). To our de- furnishing a moderate yield of the corresponding
light, unsymmetrical amines such as N-methyl-1-phe- product (Table 3, entry 12). Aromatic alkynes such as
nylmethanamine and 1,2,3,4-tetrahydroisoquinoline 4-ethynyl-N,N-dimethylaniline and 3-ethynylanisole
gave the corresponding products in high yield provided the carbonylated products in good to excel-
1
(Table 3, entries 10 and 11). The H and 13C NMR lent yield (Table 3, entries 13 and 14). Heteroaromatic
spectra showed that the amides 3i and 3j were ob- alkynes such as 5-ethynylimidazole also reacted effi-
tained mostly as a 1/1 mixture of E/Z rotamers ciently giving a 94% yield of desired product (Table 3,
around the amide bond. While screening primary entry 15). In this way, the present methodology was
4
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Oxidative Aminocarbonylation of Terminal Alkynes for the Synthesis of Alk-2-ynamides
Experimental Section
Materials and Methods
All the chemicals were purchased from Sigma Aldrich, S.D.,
Fine chemical, Lancaster (Alfa-Aesar) and other commer-
cial suppliers. The progress of the reaction was monitored
by gas chromatography on a Perkin–Elmer Clarus 400 GC
equipped with flame ionization detector (FID) and capillary
column (30 mꢁ0.25 mmꢁ0.25 mm) or thin layer chromatog-
raphy using Merck silica gel 60 F254 plates. The product
was visualized with a 254 nm UV lamp. Products were puri-
fied by column chromatography on silica gel (100–200)
mesh. All yields reported in Table 1, Table 2 and Figure 2
are GC yields, while yields reported in Table 3 refer to iso-
1
lated yields and pure compounds as determined by H NMR
Figure 2. Recycle study of the oxidative aminocarbonylation
of alk-1-yne.
and 13C NMR. All new compounds were confirmed by LC-
MS, GC-MS, FT-IR, H NMR, 13C NMR and HR-MS tech-
1
niques. However known compounds were confirmed by
comparison with authentic samples on GC and GC-MS.
Mass spectra were obtained on a Shimadzu LCMS-2010EV
instrument (column length 50 mm, internal diameter
4.6 mm, particle size 3 m, nebulizing gap 1.5 LminÀ1, vacuum
10À3 Pa) (column flow 1.2 mLminÀ1, serial temperature
2608C and heat block temperature- 2008C), GC-MS-QP
2010 instrument (Rtx-17, 30 mꢁ25 mm ID, film thickness
0.25 mm df) (column flow 2 mLminÀ1, 808C to 2408C at 108/
min rise.).The HR-MS were recorded on a quadrapole time-
of-flight (Q-STAR XL) mass spectrometer (Applied Biosys-
tem, USA). The IR spectra were recorded with an FT-IR
(Perkin–Elmer) spectrometer. The GC analysis was carried
out on a Perkin–Elmer (Clarus-400) gas chromatograph
equipped with flame ionization detector with a capillary
column (Elite-1, 30 mꢁ0.32 mmꢁ0.25 mm). The 1H NMR
spectra were recorded with Varian-400 MHz FT-NMR spec-
trometer in CDCl3. The 13C NMR spectra were recorded
with JEOL FT-NMR, Model-AL300 (75 MHz) spectrometer
in CDCl3. Chemical shifts are reported in parts per million
(d) relative to tetramethylsilane as internal standard. J (cou-
pling constant) values are reported in Hz, splitting patterns
of proton are described as s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet).
successfully applied to aryl- and heteroarylacetylenes
which are consistently more reactive than alkylacety-
lenes and gave excellent yields of the desired product.
To make the synthetic protocol more economical,
we have also demonstrated the recyclability of Pd/C
under the optimized reaction conditions; it was found
that the catalyst could effectively be recycled for four
consecutive cycles without loss in activity and selectiv-
ity (Figure 2). The leaching of palladium metal was in-
vestigated after the 1st and 4th recycle runs by ICP-
AES analysis revealing Pd to be below the detectable
level (0.01 ppm) in solution after completion of the
reaction. Thus we estimate no significant leaching of
this palladium metal catalyst. To check palladium
metal leaching on a larger scale of reagents, we per-
formed ICP-AES of a reaction mixture on a larger
scale (4 mmol of alk-1-yne) but the palladium content
was still below the detectable level indicating no sig-
nificant leaching of the palladium.
In summary, we have reported a first heterogene-
ous, phosphine-free and reusable catalytic system for
the direct oxidative aminocarbonylation of alk-1-ynes
for the synthesis of a,b-alkynylamides. The developed
protocol uses simple starting materials such as alk-1-
ynes, secondary amines, the stable heterogeneous re-
cyclable Pd/C as a catalyst, carbon monoxide gas and
oxygen as oxidant. The protocol furnishes good to ex-
General Procedure for Oxidative Aminocarbony-
lation of Alk-1-ynes
To
a 100-mL stainless steel autoclave, the 1-alkyne
(1 mmol), secondary amine (1.5 mmol), 10% Pd/C
(8 mol%), TBAI (0.90 mmol), 1,4-dioxane (10 mL, solvent
purged by oxygen – balloon pressure – for one hour at room
cellent yields of a,b-alkynylamides starting from a va- temperature) were added. The autoclave was closed, pres-
surized with oxygen (1 atm) and CO (5 atm) without flush-
ing. The reaction mixture stirred with a mechanical stirre
(625 rpm) and heated at 808C for 14 hour. The reactor was
then cooled to room temperature, degassed carefully and
opened. The reactor vessel was washed with ethyl acetate
(3ꢁ5 mL) to remove traces of product and catalyst if pres-
ent. The reaction mixture was filtered and filtrates washed
with saturated solution of sodium thiosulphate (3ꢁ5 mL),
dried over Na2SO4, and the solvent was evaporated under
vacuum. Purification of residue was carried out by column
chromatography (silica gel 100–200 mesh, petroleum ether/
riety of nucleophilic secondary amines and alk-1-ynes,
demonstrating a good functional group tolerance. Fur-
thermore, the recyclability of the developed catalytic
system for up to four consecutive cycles without loss
in activity makes it most attractive. We believe that
the developed methodology will find wide use by al-
lowing a practical access to a variety of a,b-alkynyla-
mide.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Sandip T. Gadge et al.
UPDATES
À1
ꢀ
ethyl acetate) to afford the corresponding products in good
to excellent yield. The purity of compounds was confirmed
by LC-MS and GC-MS analysis. However known com-
pounds were confirmed by comparison with their authentic
samples on GC and GC-MS. The structures of new com-
pounds were confirmed by LC-MS, GC-MS, FT-IR,
1H NMR, 13C NMR, and HR-MS techniques.
(C C), 1620, 1440, 1285, 1260, 1031,998, 756, 688 cm
;
1H NMR (400 MHz, CDCl3): d=7.57–7.54 (m, 2H, CH, Ar),
ꢀ
7.47–7.36 (m, 3H, CH, Ar), 3.81 (m, 2H,
C
ꢀ
CCONCH2CH2), 3.73–3.67(m, 4H, C CCONCH2CH2,
CH3CONCH2CH2), 3.58–3.48 (m, 2H, CH3CONCH2CH2),
2.15(s, 3H, CH3CO); 13C NMR (75 MHz, CDCl3): d=169.26
ꢀ
(CH3CO), 153.30 (C CCO), 132.42 (2CH, Ar), 130.33 (CH,
Ar), 128.60 (2H, Ar), 120.04 (Cq, Ar), 91.56 (Cq, C C),
ꢀ
ꢀ
ꢀ
ꢀ
80.57 (Cq, C C), 46.94 (C CCONCH2CH2), 46.44 (C
Procedure for Catalyst Recycling
CCONCH2CH2),
41.30
(CH3CONCH2CH2),
40.87
The filtered catalyst was washed with distilled water (3ꢁ
5 mL), methanol (3ꢁ5 mL) to remove trace amounts of or-
ganic material. The catalyst was then dried in an oven at
808C for 6 h and used for the next run.
(CH3CONCH2CH2), 21.39 (CH3CO); LC-MS: m/z =257
(M+ +1); HR-MS (ESI): m/z=257.1299, calcd. for
[(C15H16N2O2)H]+: 257.1290.
1-(4-Benzylpiperazin-1-yl)-3-phenylprop-2-yn-1-one
(3f): yellowish oil; yield: 86%; IR (neat): n=2921, 2810,
À1
ꢀ
Spectroscopic Data of the Products
3-Phenyl-1-(piperidin-1-yl)prop-2-yn-1-one (3a):[11a] Yel-
2212 (C C), 1618, 1491, 1459, 1296, 1043, 998, 690 cm
;
1H NMR (400 MHz, CDCl3): d=7.54–7.51 (m, 2H, 2CH,
ꢀ
Ar), 7.41–7.27 (m, 8H, 8CH, Ar), 3.84 (t, J=5 Hz, 2H, C
CCONCH2CH2), 3.70 (t, 2H, C CCONCH2CH2), 3.55 (s,
ꢀ
lowish solid; yield: 93%; IR (KBr): n=2923, 2855, 2216 (C
ꢀ
C), 1610, 1456, 1284, 1140, 854, 761, 693 cmÀ1
;
1H NMR
2H, PhCH2), 2.51 (t, J=5.08 Hz, 2H, PhCH2NCH2CH2),
2.47 (t, J=5.2 Hz, 2H, PhCH2NCH2CH2); 13C NMR
(75 MHz, CDCl3): d=152.98 (Cq, C=O), 137.43 (Cq, Ar),
132.34 (2CH, Ar), 130.03 (CH, Ar), 129.14 (2CH, Ar),
128.51 (2CH, Ar), 128.36 (2CH, Ar), 127.34 (CH, Ar),
(400 MHz, CDCl3): d=7.56–7.54 (m, 2H, CH, Ar), 7.38–
7.36 (m, 3H, CH, Ar), 3.78 (t, J=5.68 Hz, 2H, NCH2CH2),
3.63 (t, J=5.64 Hz, 2H, NCH2CH2), 1.69–1.65 (m, 4H,
NCH2CH2CH2), 1.61–1.59 (m, 2H, NCH2CH2CH2);
13C NMR (75 MHz, CDCl3): d=152.93 (Cq, C=O), 132.31
(2CH, Ar), 129.87 (CH, Ar), 128.47 (2CH, Ar), 120.72 (Cq,
ꢀ
ꢀ
120.45 (Cq, Ar), 90.66 (Cq, C C), 81.13 (Cq, C C), 62.78
(C CCONCH2CH2), 53.08 (C CCONCH2CH2), 52.37
ꢀ
ꢀ
ꢀ
ꢀ
Ar), 90.25 (Cq, C C), 81.46 (Cq, C C), 48.22 (NCH2CH2),
42.37 (NCH2CH2), 26.45 (NCH2CH2), 25.39 (NCH2CH2),
24.53 (NCH2CH2CH2); GC-MS (EI, 70 eV): m/z (% relative
intensity)=213 (35, M+), 212 (35), 184 (18), 171 (3), 157 (6),
143 (4), 136 (13), 130 (12), 129 (100), 116 (6), 102 (10), 101
(13), 75 (18).
(PhCH2),
47.05
(PhCH2NCH2CH2),
41.50
(PhCH2NCH2CH2); LC-MS: m/z=305 (M+ +1); HR-MS
(ESI): m/z=305.1663, calcd. for [(C20H20N2O)H]+: 305.1653.
N,N-Diethyl-3-phenylpropiolamide (3g):[4b] yellowish
ꢀ
liquid; yield: 88%; IR (neat): n=2982, 2221 (C C), 1622,
1431, 1280, 1139, 755, 690 cmÀ1
;
1H NMR (400 MHz,
3-Phenyl-1-(pyrrolidin-1-yl)prop-2-yn-1-one
(3b):[11b]
CDCl3): d=7.55–7.53 (m, 2H, CH, Ar), 7.41–7.34 (m, 3H,
CH, Ar), 3.66 (q, J=8 Hz 2H, NCH2CH3), 3.48 (q, J=
7.16 Hz, 2H, NCH2CH3), 1.28 (t, J=7.16 Hz, 3H, CH2CH3),
1.18 (t, J=7.16 Hz, 3H, CH2CH3); 13C NMR (75 MHz,
CDCl3): d=153.94 (Cq, C=O), 132.27 (2CH, Ar), 129.85
ꢀ
Yellowish solid; yield: 92%: IR (KBr): n=2926, 2212 (C
C), 1622, 1422, 1342, 1176, 762, 729, 692 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=7.53 (m, 2H, CH, Ar), 7.41–7.34 (m,
3H, CH, Ar), 3.74 (t, J=6.64 Hz, 2H, NCH2CH2), 3.54 (t,
J=6.28 Hz,
2H,
NCH2CH2),
2.00–1.94
(m,
4H,
ꢀ
NCH2CH2CH2); 13C NMR (75 MHz, CDCl3): d=152.70 (Cq,
C=O), 132.35 (2CH, Ar), 129.92 (CH, Ar), 128.46 (2CH,
(CH, Ar), 128.46 (2CH, Ar), 120.68 (Cq, Ar), 88.98 (Cq, C
), 81.89 (Cq, C C), 43.59 (NCH2CH3), 39.30 (NCH2CH3),
ꢀ
14.37 (CH3CH2), 12.83
(CH3CH2); GC-MS (EI, 70 eV): m/z
ꢀ
ꢀ
Ar), 120.56 (Cq, Ar), 88.72 (Cq, C C), 82.60 (Cq, C C),
48.14 (NCH2CH2), 45.35 (NCH2CH2), 25.34 (NCH2CH2),
24.69 (NCH2CH2); GC-MS (EI, 70 eV): m/z (% relative in-
tensity)=199 (36, M+), 170 (17), 143 (10), 129 (100), 116
(14), 103 (10), 102 (26), 101 (17), 89 (27), 87 (19), 75 (24), 73
(24), 45 (92).
(% relative intensity)=201 (11, M+), 200 (27), 186 (9), 129
(100), 101 (9), 75 (13).
N-benzyl-N-methyl-3-phenylpropiolamide (3i): yellowish
ꢀ
solid; yield: 92%; IR (KBr): n=2857, 2216 (C C), 1621,
1443, 1199, 922, 692 cmÀ1; H and 13C NMR spectra are de-
1
1
scribed for both rotamers about the amide bond; H NMR
1-(4-Methylpiperazin-1-yl)-3-phenylprop-2-yn-1-one
(3d):[3a] Yellowish liquid; yield: 85%; IR (neat): n=2944,
(400 MHz, CDCl3): d=7.61–7.50 (m, 2H, CH, Ar), 7.48–
7.30 (m, 8H, CH, Ar), 4.88 (s, 2H, NCH2), 4.68 (s, 2H,
NCH2), 3.20 (s, 3H, NCH3), 2.92 (s, 3H, NCH3); 13C NMR
(100 MHz, CDCl3): d=154.75, 154.67, 136.18, 136.07, 132.34,
132.28, 129.99, 128.81, 128.63, 128.45, 128.43, 128.12, 127.89,
127.57, 127.40, 120.44, 120.32, 90.68, 90.18, 81.53, 54.89,
49.78, 35.77, 31.87; GC-MS (EI, 70 eV): m/z (% relative in-
tensity)=249 (29, M+), 248 (50), 220 (27), 192 (14), 191
(20), 144 (17), 129 (100), 118 (33), 102 (21), 91 (25), 75 (20),
65 (11), 42 (20); HR-MS (ESI): m/z=250.1241, calcd. for
[(C17H15NO)H]+: 250.1231.
À1
ꢀ
2215 (C C), 1623, 1437, 1296, 1144, 1042, 756, 690 cm
;
1H NMR (400 MHz, CDCl3): d=7.56–7.54 (m, 2H, CH, Ar),
7.43–7.35 (m, 3H, CH, Ar), 3.89 (t, J=5.2 Hz 2H,
CONCH2CH2), 3.75 (t, J=5.08 Hz, 2H, CONCH2CH2), 2.52
(t, J=5.04 Hz, 2H, CH3NCH2CH2), 2.46 (t, J=5.04 Hz, 2H,
CH3NCH2CH2), 2.36 (s, 3H, NCH3); 13C NMR (75 MHz,
CDCl3): d=152.90 (Cq, C=O), 132.24 (2CH, Ar), 130.03
ꢀ
(CH, Ar), 128.44 (2CH, Ar), 120.19 (Cq, Ar), 90.76 (Cq, C
ꢀ
C), 80.84 (Cq, C C), 54.77 (CONCH2CH2), 54.03
(CONCH2CH2),
46.50
(CH3NCH2CH2),
45.61
(CH3NCH2CH2), 40.95 (NCH3); LC-MS: m/z=229 (M+ +
1); HR-MS (ESI): m/z=229.1350, calcd. for
[(C14H16N2O)H]+: 229.1340.
1-(4-Acetylpiperazin-1-yl)-3-phenylprop-2-yn-1-one
(3e): yellowish solid; yield: 90%; IR (KBr): n=2928, 2224
1-(3,4-Dihydroisoquinolin-2(1H)-yl)-3-phenylprop-2-
yn-1-one (3j): yellowish solid; yield: 87%; IR (KBr): n=
1
2921, 2219 (C C), 1622, 1444, 1272, 1195, 924, 754 cmÀ1; H
ꢀ
and 13C NMR spectra are described for both rotamers about
1
the amide bond; H NMR (400 MHz, CDCl3): d=7.61–7.55
6
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

Oxidative Aminocarbonylation of Terminal Alkynes for the Synthesis of Alk-2-ynamides
(m, 2H, CH, Ar), 7.47–7.35 (m, 3H, CH, Ar), 7.25–7.14 (m,
4H, CH, Ar), 5.00 (s, 2H, NCH2Ph), 4.82 (s, 2H, NCH2Ph),
Acknowledgements
4.08 (t, J=5.96 Hz, 2H, NCH2CH2Ph), 3.92 (t, J=6.08 Hz,
2H, NCH2CH2Ph), 2.99 (t, J=5.84 Hz, 2H, NCH2CH2Ph),
2.92 (t, J=6.04 Hz, 2H, NCH2CH2Ph); 13C NMR (100 MHz,
CDCl3): d=153.63, 153.31, 134.50, 133.79, 132.35, 132.28,
132.19, 130.03, 128.91, 128.57, 128.48, 126.96, 126.66, 126.63,
126.55, 126.46, 126.06, 120.39, 91.02, 90.28, 81.38, 81.28,
48.57, 44.61, 43.97, 39.59, 29.45, 28.25; LC-MS: m/z=262
(M+ +1); HR-MS (ESI): m/z=262.1242, calcd. for
[(C18H15NO)H]+: 262.1231.
Author STG is thankful to Mr. Yogesh S. Shinde from De-
partment of Chemistry, University of Pune and Mr. Nitin V.
Patil from Emcure pharmaceuticals Ltd, Pune for both LC-
MS and NMR analysis. We are also thankful to National
Centre for Mass Spectrometry, IICT Hyderabad for provid-
ing HR-MS analysis of products. The authors are thankful to
CSIR (Council of Scientific and Industrial Research) New
Delhi, India for providing research fellowship.
3-[4-(Dimethylamino)phenyl]-1-(piperidin-1-yl)prop-2-
yn-1-one (3l): yellowish solid; yield: 94%; IR (KBr): n=
2926, 2195 (C C), 1610, 1435, 724, 529 cm
(400 MHz, CDCl3): d=7.40 (d, J=8.84 Hz, 2H, CH, Ar),
6.60 (d, J=8.92 Hz, 2H, CH, Ar), 3.76 (t, J=5.76 Hz, 2H,
NCH2CH2), 3.60 (t, J=5.6 Hz, 2H, NCH2CH2), 2.99 [s, 6H,
À1
;
1H NMR
References
ꢀ
[1] a) Z. T. Fomum, A. E. Nkengfack, G. W. P. Mpango,
S. R. Landor, P. D. Landor, J. Chem. Res. Miniprint
1985, 3, 901–924; b) W. D. Rudorf, R. Schwarz, Hetero-
cycles 1986, 24, 3459–3465.
[2] a) J. H. Ryan, P. J. Stang, J. Org. Chem. 1996, 61, 6162–
6165; b) L. A. Hay, T. M. Koenig, F. O. Ginah, J. D.
Copp, D. Mitchell, J. Org. Chem. 1998, 63, 5050–5058;
c) X. Xie, X. Lu, Y. Liu, W. Xu, J. Org. Chem. 2001, 66,
6545–6550; d) G. Pattenden, M. Tankard, Tetrahedron
Lett. 1993, 34, 2677–2680; e) H. Peng, G. Liu, Org. Lett.
2011,13, 772–775; f) T. Suda, K. Noguchi, M. Hirano,
K. Tanaka, Chem. Eur. J. 2008, 14, 6593–6596; g) P. A.
Donets, E. V. Van der Eycken, Org. Lett. 2007, 9, 3017–
3020.
[3] a) P. Gayral, P. M. Loiseau, C. Bories, M. J. Brienne, M.
Leclercq, J. Jacques, Arzneim.-Forsch. 1995, 45, 1122–
1127; b) M. Haurand, K. Schiene, S. Kuhnert, M.
Reich, Z. Zemolka, (Grunenthal GmbH), U.S. Patent
2008/261996A1, 2008; c) M. Haurand, K. Schiene, S.
Kuhnert, M. Reich, Z. Zemolka, (Grunenthal GmbH),
U.S. Patent 2009/0075978A1, 2009; d) M. Perez, M. La-
mothe, C. Maraval, E. Mirabel, C. Loubat, B. Planty, C.
Horn, J. Michaux, S. Marrot, R. Letienne, C. Pignier,
A. Bocquet, F. Nadal-Wollbold, D. Cussac, L. Vries, B.
Grand, J. Med. Chem. 2009, 52, 5826–5836; e) J. C.
Lanter, Z. Sui, M. J. Macielag, J. J. Fiordeliso, W. Jiang,
Y. Qiu, S. Bhattacharjee, P. Kraft, T. M. John, D.
Haynes-Johnson, E. Craig, J. Clancy, J. Med. Chem.
2004, 47, 656–662.
NACHTUNGTRENNUNG(CH3)2], 1.66–1.62 (m, 6H, CH2CH2CH2CH2CH2);
13C NMR (75 MHz, CDCl3): d=153.72 (Cq, C=O), 151.04
(Cq, Ar), 133.85 (2CH, Ar), 111.48 (2CH, Ar), 106.65 (Cq,
ꢀ
ꢀ
Ar), 92.64 (Cq, C C), 80.49 (Cq, C C), 48.15 (NCH2CH2),
42.22 (NCH2CH2), 40.01 [N(CH3)2], 26.43 (NCH2CH2CH2),
AHCTUNGTRENNUNG
25.44 (NCH2CH2CH2), 24.60 (NCH2CH2CH2); LC-MS:
m/z=257 (M+ +1); HR-MS (ESI): m/z=257.1660, calcd. for
[(C16H20N2O)H]+: 257.1653.
3-(3-Methoxyphenyl)-1-(piperidin-1-yl)prop-2-yn-1-one
(3m): yellowish solid; yield: 88%; IR (KBr): n=2939, 2857,
ꢀ
2215 (C C), 1614,1476, 1294,1164,1044,853,789,636 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.26 (t, J=7.92 Hz, 1H,
CH, Ar), 7.14–7.07 (m, 1H, CH, Ar), 7.06 (s, 1H, CH, Ar),
6.97–6.94 (m, 1H, CH, Ar), 3.75 (m, 5H, OCH3, NCH2CH2),
3.61 (t, 2H, NCH2CH2), 1.65 (m, 4H, NCH2CH2CH2), 1.62–
1.56 (m, 2H, NCH2CH2CH2); 13C NMR (75 MHz, CDCl3):
d=159.30 (Cq, C=O), 152.86 (Cq, Ar), 129.56 (CH, Ar),
124.74 (CH, Ar), 121.62 (Cq, Ar), 117.00 (CH, Ar), 116.52
ꢀ
ꢀ
(CH, Ar), 90.17 (Cq, C C), 81.15 (Cq, C C), 55.33 (OCH3),
48.21
(NCH2CH2),
25.37
42.35
(NCH2CH2),
26.43
24.50
(NCH2CH2CH2),
(NCH2CH2CH2),
(NCH2CH2CH2); GC-MS (EI, 70 eV): m/z (% relative in-
tensity)=243 (61, M+), 242 (45), 214 (27), 159 (100), 116
(26), 88 (23), 84 (14), 45 (44); HR-MS (ESI): m/z=
244.1348, calcd. for [(C15H17NO2)H]+: 244.1337.
3-(1-Methyl-1H-imidazol-5-yl)-1-(piperidin-1-yl)prop-
2-yn-1-one (3n): yellowish solid; yield: 94%; IR (KBr): n=
[4] a) Y. Tohda, K. Sonogashira, N. Hagihara, Synthesis
1977, 777–778; b) H. Hoberg, H. J. Riegel, J. Organo-
met. Chem. 1983, 241, 245–250.
ꢀ
2923, 2855, 2216 (C C), 1610, 1456, 1223, 1140, 854, 761,
1
693 cmÀ1; H NMR (400 MHz, CDCl3): d=7.52 (s, 1H, CH,
Ar), 7.44 (s, 1H, CH, Ar), 3.74–3.72 (m, 5H, NCH3,
NCH2CH2), 3.62 (t, J=5.68 Hz, 2H, NCH2CH2), 1.72–1.57
(m, 6H, NCH2CH2CH2); 13C NMR (75 MHz, CDCl3): d=
152.46 (Cq, C=O), 139.62 (CH, Ar), 137.30 (CH, Ar), 114.13
[5] a) B. Gabriele, G. Salerno, M. Costa, Top. Organomet.
Chem. Vol. 18, (Ed.: M. Beller), Springer, Berlin, Hei-
delberg, 2006, pp 239–272; b) B. Gabriele, G. Salerno,
L. Veltri, M. Costa, J. Organomet. Chem. 2001, 622, 84–
88; c) Y. Izawa, I. Shimizu, A. Yamamoto, Bull. Chem.
Soc. Jpn. 2004, 77, 2033–2045; d) Q. Liu, H. Zhang, A.
Lei, Angew. Chem. 2011, 123, 10978–10989; Angew.
Chem. Int. Ed. 2011, 50, 10788–10799.
[6] a) B. Gabriele, P. Plastina, G. Salerno, R. Mancuso, M.
Costa, Org. Lett. 2007, 9, 3319–3322; b) B. Gabriele, G.
Salerno, L. Veltri, R. Mancuso, Z. Li, A. Crispini, A.
Bellusci, J. Org. Chem. 2006, 71, 7895–7898; c) B. Ga-
briele, G. Salernob, M. Costac, Synlett 2004, 2468–2483;
d) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011,
111, 1780–1824; e) W. Shi, C. Liu, A. Lei, Chem. Soc.
Rev. 2011, 40, 2761- 2776.
ꢀ
ꢀ
(Cq, Ar), 89.53 (Cq, C C), 78.80 (Cq, C C), 48.17 (NCH3),
42.35
(NCH2CH2),
25.32
32.32
(NCH2CH2),
26.40
24.45
(NCH2CH2CH2),
(NCH2CH2CH2),
(NCH2CH2CH2); GC-MS (EI, 70 eV): m/z (% relative in-
tensity)=217 (32, M+), 188 (21), 161 (12), 106 (76) 133
(100), 84 (32), 78 (22), 42 (25); HR-MS (ESI): m/z=
218.1295, calcd. for [(C12H15N3O)H]+: 218.1293.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

Sandip T. Gadge et al.
UPDATES
[7] a) Y. Kitamura, S. Sako, T. Udzu, A. Tsutsui, T. Maega-
wa, Y. Monguchi, H. Sajiki, Chem. Commun. 2007,
5069–5071; b) T. Maegawa, Y. Kitamura, S. Sako, T.
Udzu, A. Sakurai, A. Tanaka, Y. Kobayashi, K. Endo,
U. Bora, T. Kurita, A. Kozaki, Y. Monguchi, H. Sajiki,
Chem. Eur. J. 2007, 13, 5937–5943; c) S. Mori, T.
Yanase, S. Aoyagi, Y. Monguchi, T. Maegawa, H.
Sajiki, Chem. Eur. J. 2008, 14, 6994–6999; d) Y. Kita-
mura, A. Sakurai, T. Udzu, T. Maegawa, Y. Monguchi,
H. Sajiki, Tetrahedron 2007, 63, 10596–10602; e) S.
Mori, M. Takubo, T. Yanase, T. Maegawa, Y. Mongu-
chi, H. Sajiki, Adv. Synth. Catal. 2010, 352, 1630–1634.
[8] a) M. V. Khedkar, S. R. Khan, D. N. Sawant, D. B.
Bagal, B. M. Bhanage, Adv. Synth. Catal. 2011, 353,
3415–3422; b) D. N. Sawant, Y. S. Wagh, K. D. Bhatte,
B. M. Bhanage, J. Org. Chem. 2011, 76, 5489–5494;
c) D. N. Sawant, Y. S. Wagh, K. D. Bhatte, B. M. Bhan-
age, Eur. J. Org. Chem. 2011, 6719–6724; d) P. J. Tam-
bade, Y. P. Patil, M. J. Bhanushali, B. M. Bhanage, Syn-
thesis 2008, 2347–2352; e) P. J. Tambade, Y. P. Patil,
M. J. Bhanushali, B. M. Bhanage, Tetrahedron Lett.
2008, 49, 2221–2224.
[9] a) M. V. Khedkar, P. J. Tambade, Z. S. Qureshi, B. M.
Bhanage, Eur. J. Org. Chem. 2010, 6981–6986; b) P. J.
Tambade, Y. P. Patil, A. G. panda, B. M. Bhanage, Eur.
J. Org. Chem. 2009, 3022–3025; c) Z. S. Qureshi, K. M.
Deshmukh, P. J. Tambade, B. M. Bhanage, Synthesis
2011, 243–250.
[10] a) D. J. Diaz, A. K. Darko, L. McElwee-White, Eur. J.
Org. Chem. 2007, 4453–4465; b) M. R. Didgikara, S. S.
Joshi, S. P. Gupte, M. M. Diwakara, R. M. Deshpande,
R. V. Chaudhari, J. Mol. Catal. A: Chem. 2011, 334, 20–
28.
[11] a) C. Pan, F. Luo, W. Wang, Z. Ye, J. Cheng, Tetrahe-
dron Lett. 2009, 50, 5044–5046; b) U. Yoshitaka, F. Ta-
kahide, M. Keisuke, N. Osaniu, N. Hidefumi, R. Il-
hyong, Helv. Chim. Acta 2006, 89, 2483–2494.
8
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

UPDATES
Oxidative Aminocarbonylation of Terminal Alkynes for the
Synthesis of Alk-2-ynamides by Using Palladium-on-Carbon
as Efficient, Heterogeneous, Phosphine-Free, and Reusable
Catalyst
9
Adv. Synth. Catal. 2012, 354, 1 – 9
Sandip T. Gadge, Mayur V. Khedkar, Satish R. Lanke,
Bhalchandra M. Bhanage*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!