Palladium-Catalyzed Oxidative N-Dealkylation/Carbonylation of Tertiary Amines with Alkynes to α,β-Alkynylamides

Article abstract of DOI:10.1021/acs.joc.6b00386

The first highly effective Pd/C-catalyzed oxidative N-dealkylation/carbonylation of various aliphatic as well as cyclic tertiary amines with alkynes has been described. The selective sp³ C-N bond activation of tertiary amines at the less steric side using O₂ as a sole oxidant and a plausible reaction pathway for the reaction are discussed. The general and operationally simple methodology provides an alternative for the synthesis of a wide range of alk-2-ynamide derivatives under mild conditions. The present protocol is ecofriendly and practical, and it shows significant recyclability.

Full text of DOI:10.1021/acs.joc.6b00386

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Article
Palladium-Catalyzed Oxidative N-dealkylation/carbonylation
of Tertiary Amines with Alkynes to alpha,beta-Alkynylamides
Rajendra Shivaji Mane, and Bhalchandra M. Bhanage
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00386 • Publication Date (Web): 16 May 2016
Downloaded from http://pubs.acs.org on May 17, 2016
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Palladium-Catalyzed Oxidative N-dealkylation/carbonylation of Tertiary
Amines with Alkynes to α,β-Alkynylamides
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Rajendra S. Mane and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, Mumbai-400019, India.
Tel: +91 22 33612603; Fax: +91 22 33611020.
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E-mail: bm.bhanage@ictmumbai.edu.in, bm.bhanage@gmail.com.
ABSTRACT:
The first highly effective Pd/C-catalyzed oxidative N-dealkylation/carbonylation of
various aliphatic as well as cyclic tertiary amines with alkynes has been described. The selective
sp3 C-N bond activation of tertiary amines at the less steric side using O2 as a sole oxidant and a
plausible reaction pathway for the reaction are discussed. The general and operationally simple
methodology provides an alternative for the synthesis of a wide range of alk-2-ynamide
derivatives under mild conditions. The present protocol is an ecofriendly, practical and besides it
shows significant recyclability.
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INTRODUCTION:
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Alk-2-ynamide (α,β-alkynylamide) derivatives are important building blocks in organic
synthesis and often fundamental scaffold of pharmaceutically relevant compounds.1 These class
of compounds play a crucial role in natural products as well as key intermediates in the synthesis
of heterocycles.2 Historically, tertiary amides were synthesized by Pd/Cu-catalyzed cross
coupling reaction of alkynes with carbamoyl chlorides (Scheme 1, eq 1).3 Moreover, Cu/TBHP
mediated synthesis of tertiary amides can be achieved by using propiolic acids and its derivatives
treated with secondary amines4 or formamides5 (Scheme 1, eq 2). Some drawbacks exist;
nevertheless, these methodologies suffer from multistep synthesis, limited stability of carbamoyl
chlorides, i.e., moisture sensitive and lack of functional group tolerance with severe conditions.
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Over the past decade, transition-metal catalyzed carbonylation reactions have gained
great prominence in organic chemistry.6 Carbon monoxide is a C1 building block in organic
synthesis and is valued because of its simplicity and atom economy.7 Palladium-catalyzed
oxidative carbonylation reactions of alkynes with amines represents the most straightforward
Scheme 1. Synthetic Approach for the synthesis of Alkynylamides
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approach to generate alkynylamides (Scheme1, eq 3). The oxidative carbonylation between two
nucleophiles is a very challenging task.8 A literature survey reveals that there are few reports
known for the oxidative carbonylation of alkynes or propiolic acid using primary/secondary
amines.9 Hoberg et al. reported Ni(II)-catalyzed carbonylative synthesis of alkynylamides by
treating with alkynes using secondary amines as amine source.9a,b Furthermore, Gabriele et al.
reported first PdI2/KI-catalyzed oxidative carbonylation for the synthesis of alkynylamides from
alkynes and secondary amines in the presence of a CO/air mixture (20 atm) for 24 h.9c
Yamamoto group employed PdCl2/PPh3 as a catalytic system for the direct oxidative
aminocarbonylation using CO/O2with 2 equiv of AcONa as base.9d Our group also disclosed
Pd/C and TBAI as a catalytic system and the Xia group employed Pd-NHC/K3PO4 (2 equiv) for
the synthesis of alkynylamides using secondary amines as an aminal source.9e,f Lee and Wu et al.
also reported Pd(OAc)2/AgO (1 equiv) and Pd2(dba)3/Xphos/Co2(CO)8 as a carbonyl source
mediated synthesis of alkynylamides through the carbonylation of propiolic acids with
primary/secondary amines.9g,h Although their catalytic activities are excellent, the development
of a more efficient, selective and general method for the direct synthesis of alkynylamides is thus
highly desirable. The development of heterogeneous, recyclable, cost-efficient and
environmentally benign protocols to reduce the high production costs as well as the possible
heavy-metal contamination is remaining essential. Nevertheless, these reported methodologies
typically suffer from harsh conditions, requirement of stoichiometric copper as a co-catalyst or
oxidant, excess base to inhibit the undesired homocoupling of alkynes and limited substrate
scope with tedious workup. To circumvent these problems, we envisioned tertiary amines as an
aminal source, which slowly release in situ secondary amines through the oxidative N-
dealkylation/carbonylation of tertiary amines with alkynes which in turn could easily lead us to
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direct synthesis of alkynylamides (Scheme 1, eq 4). However, the oxidative N-
dealkylation/carbonylation of tertiary amines with alkynes using Pd/C with O2 remains elusive,
because of several fundamental challenges such as homocoupling of alkynes, tandem annulations
and urea formation. Hence these challenges ought to be overcome.
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In recent years, the C-N bond activation of highly stable tertiary amines has emerged as
an important approach in synthetic chemistry.10,11 In this context, among the various known
amine surrogates that could be used as nucleophile, tertiary amines stand out as particularly
attractive substrates in terms of their availability. To the best of our knowledge, the use of stable
tertiary amines as an aminal source for this transformation is unprecedented. Very recently, we
demonstrated oxidative C-N bond activation of inert tertiary amines to tertiary amides via
aminocarbonylation of aryl iodides.12 Based on our research interest in oxidative carbonylation
reactions,13 herein, we report the first phosphine free Pd/C-catalyzed oxidative N-
dealkylation/carbonylation of aliphatic as well as cyclic tertiary amines with terminal alkynes.
RESULTS AND DISCUSSIONS:
We began the alk-2-ynamides synthesis using phenylacetylene (1a) and Bu3N (2a) as
model substrates. When the reaction was performed in MeCN, using 5 mol % PdCl2(PPh3)2 as a
catalyst and 3 mmol K3PO4 as a base under the pressure of CO/O2 at 100 °C for 24 h. The
alkynylamide product 3aa was only obtained in <5% yield. The iodide additive had a significant
impact on the reaction efficiency. Surprisingly, when TBAI was used as an additive, overall
yield of the desired product increased to 68% (Table 1, entry 2). Subsequently, the evaluation of
additives revealed that KI was the best, and afforded 86% yield of 3aa (Table 1, entry 4). Next,
various palladium precursors including heterogeneous sources were screened as shown in Table
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1. Interestingly, 10% Pd/C was found to be the most effective catalyst for this transformation and
furnished an excellent yield of 3aa in absence of base (Table 1, entry 11). The use of 3 mol %
Pd/C was found to be adequate for this reaction. Next, we studied the effect of amount of KI and
it was observed that 0.1 mmol of KI provides the highest yield of 3aa (Table 1, entry 12).
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Table 1. Effect of Additive, Catalyst, and Catalyst Loadinga
yield
entry
catalyst
base additive
(%)b
<5
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59
86
79
91
63
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92
84
95
94
94
87
1c
2
PdCl2(PPh3)2 K3PO4
-
PdCl2(PPh3)2 K3PO4 TBAI
PdCl2(PPh3)2 K3PO4 TBAB
3
4
PdCl2(PPh3)2 K3PO4
PdCl2(PPh3)2 K3PO4
KI
NaI
KI
KI
KI
KI
KI
KI
KI
KI
KI
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6
PdCl2
K3PO4
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PdBr2
K3PO4
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Pd(OAc)2
10% Pd/C
5% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
K3PO4
9
K3PO4
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11
12d
13e
14f
K3PO4
-
-
-
-
aReaction conditions: 1a (1 mmol), 2a (1.5 mmol), Pd (5 mol %), K3PO4 (3 mmol), additive (0.5
mmol), CO/O2 = 9/1 in a 10 mL MeCN, 100 oC, 8 h. bYields were determined by GC. c24 h.d0.1
mmol KI was used.e3 mol % and f2 mol % Pd/C were used.
In the next set of experiments, the effect of solvents such as acetonitrile, 1,4-dioxane,
THF and toluene were examined. Among these, acetonitrile was the best solvent and provided a
94% yield of 3aa (Table 2, entry 1). Remarkably, under CO/O2 (5:1) pressure, the alkynylamide
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product 3aa was obtained with an yield of 94% (Table 2, entry 6).9 Notably, while using air as
oxidant instead of O2, the yield of 3aa decreased significantly and no formation of product was
noted when the reaction was performed under inert atmosphere (Table 2, entries 8 and 9). This
suggests that the additives are crucial in this transformation with molecular oxygen as sole
oxidant. Decrease in the reaction temperature to 70 °C led to a decrease in the yield of 3aa, while
an increase had no significant effect on the yield (Table 2, entries 10-12).
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Table 2. Optimization of Reaction Parametersa
yield
(%)b
94
CO/O2
atm
T
time
entry solvent
(°C) (h)
1
2
MeCN
9:1
9:1
100
100
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8
1,4-
dioxane
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4
THF
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
9:1
9:1
7:1
5:1
3:1
5:1
5:0
5:1
5:1
5:1
5:1
5:1
5:1
100
100
100
100
100
100
100
120
80
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8
67
74
95
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92
69
NR
89
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86
77
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8c
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70
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100
100
100
12
5
4
aReaction conditions: 1a (1 mmol), 2a (1.5 mmol), 10% Pd/C (3 mol %), KI (0.1 mmol), CO/O2
= 5/1 in a 10 mL MeCN, 100 oC, 8 h. bGC yield. cOne atm of air. NR = No Reaction.
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To demonstrate the general applicability of this new catalytic system, initially the N-
dealkylation/carbonylation of various tertiary amines with 1a was examined under the optimized
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Table3. Scope of Carbonylation of 1a with Tertiary Amine as Amine Sourcea
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yield
entry
1
amine
Bu3N
product
(%)b
94,
82c
3aa
2
3
4
Me3N
Me2Noct
Et3N
3ab
3ab
3ac
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87
88
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Pr3N
3ad
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3aea R2, R3 = i-Pr
3aebR2 = Et, R3 = i-Pr
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i-Pr2EtN
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Hex3N
3af
93
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9
Oct3N
Ph3N
3ag
3ah
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NR
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PhNEt2
PhNMe2
Bn3N
3ai
3aj
3ak
NR
NR
NR
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3al
3al
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32
34
29
45
3am
3am
3an
aReaction conditions: 1a (1 mmol), 2 (1.5 mmol), 10% Pd/C (3 mol %), KI (0.1 mmol), CO/O2 =
5/1 in 10 mL of MeCN, 100 oC, 8 h. bIsolated yield. cWith 5.0 mmol of 1a.
reaction conditions. As shown in Table3, this transformation proceeded quite smoothly and
afforded desired alkynylamides in a good to excellent yields. Both, symmetrical as well as
unsymmetrical tertiary amines could be well tolerated (3aa-3an). For symmetrical tertiary
amines, the selectivity of the N-dealkylation was found to be independent of the alkyl chain
lengths and oxidative N-dealkylation/carbonylation of different aliphatic amines with 1a afforded
the corresponding amides in high yields. When N,N-diisopropylethyl amine was employed,
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Scheme 2. Scope of Carbonylation of Various Terminal Alkynes with 2aa
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aReaction conditions: 1 (1 mmol), 2a (1.5 mmol), 10% Pd/C (3 mol %), KI (0.1 mmol), CO/O2 =
5/1 in a 10 mL MeCN, 100 oC, 8 h. bIsolated yield.
potentially two kinds of N-dealkylation were observed. This resulted into formation of two types
of products (3aea and 3aeb). Gratifyingly, N,N-dimethyloctyl amine also efficiently utilized in
this transformation and selectively cleavage of C-N bond at longest chain was observed (3ab).
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Surprisingly no products were observed with Ph3N, PhNEt2and PhNMe2as a tertiary
amine source, which could be because of the lacks of hydrogen atoms α to the nitrogen and the
lone pair of nitrogen is conjugated with phenyl ring, thus suggesting that the sp2 C−N bond does
not cleave under these conditions (Table 3, entries 9-11). When Bn3N was employed, reaction
did not also proceed, which could be because of the steric hindrance of benzyl group (Table 3,
entry 12). To our delight, cyclic tertiary amines i.e., N-ethyl or N-methyl substituted afforded
3al, 3am and 3anrespectively. These results indicate that sterically less hindered alkyl group was
much more facile for this transformation.
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We next investigated the scope of aromatic alkynes 1 with N-dealkylation of Bu3N 2a under
the optimal conditions and the results are shown in Scheme 2. Both, the electron donating and
deficient substituent on the phenyl ring of alkynes were well tolerated and afforded excellent
yields (3ba-3ha). Remarkably, the reaction with heteroaromatic alkyne 1i (3-ethynylpyridine)
furnished the corresponding product (3ia). However, alkyne 1j(2-ethynylpyridine) did not
undergo the transformation, possibly due to the formation of a chelate with the nitrogen atom of
the pyridine ring and the alkyne. It is worth noting that aliphatic alkynes were also found to be
compatible with this protocol, thus providing 3ja and 3ka in high yield. Interestingly, the
reaction with highly conjugated 2-ethynylpyrene also gave an excellent yield of 3ka. It is worth
mentioning that, pyrene and its derivatives show fluorescence, having potential applications in
OLEDs as efficient emitters.14
To gain insight into the role of additives in the reaction mechanism, several control
experiments were carried out (Scheme 3). First, when Bu3N 2a as amine source was subjected to
the optimized conditions, the alkynylamide product was obtained in an excellent yield (3aa, 96%
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yield). While, in the absence of additive, the reaction failed to generate carbonylated product
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3aa, indicating that additives are crucial in this transformation. To our delight, when we used
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Scheme 3. Some control experiments
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Bu2NH as amine source, only 57% of 3aa was obtained with tetrabutylurea as by product. These
results indicate that the tertiary amine slowly releases in situ secondary amine under the
optimized reaction conditions which in turn could led to provide highest yield of 3aa.
From the green and sustainable chemistry point of view, the recyclability of Pd/C-catalyst
was investigated. After the first reaction cycle, the catalyst was recovered from the reaction
mixture and washed with excess of solvent, then finally with methanol to remove trace amounts
of product. After washing and drying, recovered catalyst could be reused up to six times with a
slight decrease in catalytic activity (95% to 89%). In order to check the leaching of palladium
metal, 1st and 6th recycled samples were subjected to the inductively coupled plasma atomic
emission spectrometry (ICP-AES) technique. No detectable amounts of palladium (below 0.1
ppm) were found, indicating a negligible catalyst leaching.
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On the basis of the results obtained and previous reports, we propose two plausible
reaction pathways for the N-dealkylation of tertiary amine to secondary amine as shown in
Scheme 4.10,11 In path A, the nitrogen of tertiary amine coordinates with Pd0 to give Pd-iminium
type intermediate.15b,d Then, the iminium intermediate gets hydrolyzed to provide secondary
amine and aldehyde.10g,h,12 At this stage another possible pathway cannot be ruled out (path B).
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Scheme 4. Plausible Reaction Mechanism
In path B, the tertiary amine reacts with iodine to give an ammonium iodide.16a,c,d Subsequently,
iminium iodide can be generated through the elimination of HI. Further, iminium iodide
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hydrolyzes to provide secondary amine and aldehyde. The mechanism for the oxidative
carbonylation of alkynes with amines using Pd/C-KI is not clear at the moment, on the basis of
the experimental results and previous reports a plausible reaction pathway is outlined. Initially,
in situ Pd(0) to Pd-I as an active species I could be generated in the presence of iodide promoter
(KI) with O2 as an terminal oxidant.8h,i,j As shown in Scheme 4, N-palladated II can be generated
from amine and Pd-I. Then, the insertion of CO to form intermediate III, which can further
reacts with alkyne to produce desired amide 3 and IV. The intermediate IV is re-oxidized to Pd-I
as an active catalytic species I, in the presence of O2 which completes the catalytic cycle.
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In summary, we have illustrated a highly efficient strategy for the oxidative N-
dealkylation/carbonylation of inert tertiary amines with alkynes. This conversion has been
accomplished by using O2 as an ideal oxidant and is catalyzed by Pd/C. This is the first instance
where an extensive synthesis of alkynylamides via sp3 C-N bond activation of various tertiary
amines as an aminal source has been achieved. It is striking that, substrates including heteroaryl
as well as aliphatic alkynes were also compatible. Additionally, this approach has numerous
advantageous such as being recyclable, phosphine free, co-catalyst free, base free and uses
molecular oxygen as an ideal and greener oxidant.
EXPERIMENTAL SECTION
General.
The Pd/C was purchased from Sigma-Aldrich (10 wt% loading, matrix: activated carbon support,
product number: 205699, brand: Aldrich). Solvents were purchased with high purity and used
without purification. All the reactions were monitored by using TLC, GC, GC-MS techniques.
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Products were purified by column chromatography on silica (100-200 mesh). The H NMR
spectrum was recorded on 400 MHz and 500 MHz spectrometer in CDCl3 using
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tetramethylsilane (TMS) as internal standard. The 13C NMR spectrum was recorded on 100 MHz
and 125 MHz spectrometer in CDCl3. Chemical shifts are reported in parts per million (δ)
relative to tetramethylsilane as internal standard. The J (coupling constant) values are described
in Hz. Splitting patterns of proton are depicted as s (singlet), d (doublet), t (triplet) and m
(multiplet). HRMS (ESI) were taken on Orbitrap (quadrupole plus ion trap) and TOF mass
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analyzer. The products were confirmed by the comparison of their GC-MS, LC-MS, H NMR,
13C NMR and High Resolution Mass Spectra (HR-MS).
General Experimental Procedure for Oxidative N-dealkylation/carbonylation of Tertiary
Amines with Alkynes:
To a 100 mL stainless steel reactor, alkyne (1 mmol), tertiary amine (1.5 mmol), 10% Pd/C (3
mol %), KI (0.1 mmol) in 10 mL of MeCN were added. Then autoclave was closed and
pressurized with oxygen (1 atm) and CO (5 atm) without flushing. Reaction mixture stirred with
mechanical stirred (550 rpm), heated at 100 °C for 8 hour. The reactor was then cooled to room
temperature, degassed carefully and the reactor was opened. The reactor vessel was washed with
ethyl acetate (3 × 5 mL) to remove traces of product and catalyst if present. The reaction mixture
filtered and filtrates washed with saturated solution of sodium thiosulphate (3 × 5 mL), dried
over Na2SO4, and the solvent was evaporated under vacuum. Products were purified using
column chromatography (Silica gel 100-200 mesh, petroleum ether/ethyl acetate) to afford the
corresponding products in good to excellent yield. The purity of compounds was confirmed by
LCMS and GCMS analysis. The structure of products was confirmed by LCMS, GCMS, HRMS,
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1H NMR and C NMR spectroscopic techniques. (Caution! CO and O2 may form an explosive
mixture under certain conditions).
Procedure for Recycling of Catalyst:
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After completion of reaction, the recovered catalyst was washed with distilled water (3 × 5 mL)
and finally with methanol (3 × 5 mL) to remove trace amount of organic material. The catalyst
was then dried in oven at 80 °C for 5 h. After washing and drying, the recovered catalyst was
found it to be effectively recycled up to six run without any loss of its catalytic activity and
selectivity.
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N,N-Dibutyl-3-phenylpropiolamide (3aa). Yellowish oil; 244.5 mg, 94% yield.1H NMR (400
MHz, CDCl3): δ 7.50 (dd, J = 8.1, 1.4 Hz, 2H), 7.41–7.16 (m, 3H), 3.74–3.46 (m, 2H), 3.43–3.23
(m, 2H), 1.70–1.46 (m, 2H), 1.44–1.14 (m, 2H), 0.99–0.72 (m, 6H).13C NMR (100 MHz,
CDCl3): δ 154.4, 132.2, 129.8, 128.4, 120.8, 89.2, 82.1, 48.9, 44.6, 31.0, 29.5, 20.2, 19.9, 13.8,
13.8.GC-MS (EI, 70 eV) m/z (%): 257 (2) [M]+, 228 (3), 214(13), 173(4), 129 (100), 101(5),
75(6).HRMS (ESI) calcd for [(C17H23NO)H] [M+H]+: 258.1858; found: 258.1856.
N,N-Dimethyl-3-phenylpropiolamide (3ab).5b White Solid, mp 97–99 °C; 143.6 and 150.5 mg,
83 and 87% yield.1H NMR (400 MHz, CDCl3): δ7.52–7.49 (m, 2H), 7.35 (dd, J = 14.9, 7.3 Hz,
3H), 3.25 (s, 3H), 2.99 (s, 3H).13C NMR (100 MHz, CDCl3): δ154.6, 132.3, 129.9, 128.4, 120.6,
90.1, 81.5, 77.3, 77.0, 76.7, 38.3, 34.1.GC-MS (EI, 70 eV) m/z (%): 173 (55) [M]+, 172 (4), 144
(9), 130 (12), 129 (100), 101 (11), 75 (17), 51 (7).
N,N-Diethyl-3-phenylpropiolamide (3ac).5b,9fColorless oil; 176.9 mg, 88% yield.1H NMR
(400 MHz, CDCl3): δ7.52–7.49 (m, 2H), 7.38–7.24 (m, 3H), 3.64 (q, J = 7.1 Hz, 2H), 3.45 (q, J
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= 7.2 Hz, 2H), 1.27–1.23 (m, 3H), 1.17–1.13 (m, 3H). C NMR (100 MHz, CDCl3): δ 153.9,
132.3, 129.8, 129.6, 128.9, 128.4, 120.7, 89.0, 81.9, 77.3, 77.0, 76.7, 43.6, 39.3, 14.4, 14.0,
12.8.GC-MS (EI, 70 eV) m/z (%): 201 (17.5) [M]+, 200 (44), 186 (25), 130 (11.4), 129 (100),
101 (11), 75 (14.5), 51 (5).
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N,N-Dipropyl-3-phenylpropiolamide (3ad).9f,9g Colorless oil; 210.8 mg, 92% yield.1H NMR
(400 MHz, CDCl3): δ7.50 (t, J = 8.7 Hz, 2H), 7.44–7.34 (m, 3H), 3.57–3.54 (t, 2H), 3.37–3.34 (t,
2H), 1.71–1.57 (m, 4H), 0.93 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 154.5, 133.6, 132.2,
130.1, 128.4, 128.4, 120.8, 89.3, 82.1, 77.3, 76.9, 76.6, 50.8, 46.5, 22.2, 20.7, 11.3, 11.2.GC-MS
(EI, 70 eV) m/z (%): 229 (4) [M]+, 214 (6), 200 (23), 130 (11.5), 129 (100), 101 (6), 75 (6).
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N,N-Diisopropyl-3-phenylpropiolamide (3aea).5bYellowish oil; 112.2 mg, 49% yield.1H NMR
(400 MHz, CDCl3): δ 7.51 (dd, J = 8.0, 1.4 Hz, 2H), 7.38–7.28 (m, 3H), 4.64–4.52 (m, 1H),
3.75–3.62 (m, 1H), 1.34 (m, 12H).13C NMR (100 MHz, CDCl3): δ 153.6, 132.1, 129.6, 128.4,
121.0, 88.5, 83.1, 50.3, 45.7, 29.6, 22.4, 21.0, 20.1. GC-MS (EI, 70 eV) m/z (%): 229 (5) [M]+,
214 (8), 186 (11), 129 (100), 79 (15), 43 (5). HRMS (ESI) calcd for [(C15H19NO)H] [M+H]+: `
N-Ethyl-N-isopropyl-3-phenylpropiolamide (3aeb). Colorless oil; 68.5 mg, 32% yield.1H
NMR (400 MHz, CDCl3): δ7.58–7.43 (m, 2H), 7.36 (dd, J = 6.8 Hz, 3H), 4.82–4.55 (m, 1H),
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3.55 (q, J = 7.1 Hz, 1H), 3.34 (q, J = 7.1 Hz, 1H), 1.35–1.16 (m, 9H). C NMR (100 MHz,
CDCl3): δ 153.9, 132.3, 132.2, 129.8, 128.4, 128.4, 120.8, 89.5, 81.9, 50.6, 39.3, 21.8, 20.4, 14.5.
GC-MS (EI, 70 eV) m/z (%): 214 (18) [M]+, 200 (11), 172 (3), 129 (100), 101 (6.5), 75 (3), 42
(4). HRMS (ESI) calcd for [(C14H17NO)H] [M+H]+: 216.1388; found: 216.1383.
N,N-Dihexyl-3-phenylpropiolamide (3af). Yellowish oil; 291.1 mg, 93% yield.1H NMR (400
MHz, CDCl3): δ7.56–7.45 (m, 2H), 7.32 (m, 3H), 3.61–3.52 (m, 2H), 3.41–3.32 (m, 2H), 1.57
(m, 4H), 1.27 (m, 12H), 0.85–0.79 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 154.4, 132.2, 129.8,
128.4, 120.7, 89.4, 82.0, 49.2, 44.9, 34.0, 31.5, 31.4, 31.2, 28.8, 27.4, 26.6, 26.4, 24.4, 22.5, 22.3,
14.0, 13.9. GC-MS (EI, 70 eV) m/z (%): 313 (2) [M]+, 312 (4), 284 (2), 256 (4), 242 (10), 200
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(3.5), 172(6), 162 (10), 129 (100), 119 (10), 92 (7), 75 (3), 43(5). HRMS (ESI) calcd for
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[(C21H31NO)H] [M+H]+: 314.2484; found: 314.2479.
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N,N-Dioctyl-3-phenylpropiolamide (3ag). Colorless oil; 312.5 mg, 85% yield.1H NMR (400
MHz, CDCl3): δ 7.51 (dd, J = 8.1, 1.4 Hz, 2H), 7.41–7.29 (m, 3H), 3.75–3.54 (m, 4H), 3.43–3.20
(m, 4H), 1.61 (s, 4H), 1.32–1.21 (m, 20H), 0.87–0.81 (m, 6H).13C NMR (100 MHz, CDCl3): δ
154.4, 132.2, 129.8, 128.4, 120.8, 89.2, 82.1, 49.1, 44.8, 31.7, 31.7, 29.3, 29.2, 29.2, 29.1, 28.9,
27.5, 27.0, 26.7, 22.6, 22.5, 14.0. GC-MS (EI, 70 eV) m/z (%): 368 (2) [M]+, 355 (4), 326 (2.6),
298 (3.4), 270 (10), 172 (5), 129 (100), 115 (4), 77 (8), 57 (9), 44 (20), 32 (92). HRMS (ESI)
calcd for [(C25H39NO)H] [M+H]+: 370.3110; found: 370.3104.
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3-Phenyl-1-(piperidin-1-yl)prop-2-yn-1-one (3al).5b,9gWhite solid, mp 79–81 °C; 80.9 and 68.1
mg, 38 and 32% yield.1H NMR (400 MHz, CDCl3): δ7.53–7.51 (m, 2H), 7.39–7.32 (m, 3H),
3.77–3.74 (m, 2H), 3.62–3.59 (m, 2H), 1.67–1.54 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
152.9, 132.3, 129.8, 128.4, 120.7, 90.2, 81.4, 48.2, 42.3, 26.4, 25.3, 24.5. GC-MS (EI, 70 eV)
m/z (%): 213 (43.23) [M]+, 212 (45), 196 (8), 184 (20.5), 136 (14), 130 (12), 129 (100), 101 (12),
75 (14), 55 (7), 42 (6).
1-Morpholino-3-phenylprop-2-yn-1-one (3am).5b,9gWhite solid, mp 56–58 °C; 73.5 and 62.3
mg, 34 and 29% yield.1H NMR (400 MHz, CDCl3): δ7.50–7.48 (m, 2H), 7.39–7.28 (m, 3H),
3.78 (dd, J = 5.4, 3.8 Hz, 2H), 3.70–3.68 (m, 2H), 3.64 (s, 4H). 13C NMR (100 MHz, CDCl3): δ
153.1, 132.3, 130.1, 128.5, 120.2, 91.1, 80.7, 66.8, 66.4, 47.2, 41.9. GC-MS (EI, 70 eV) m/z
(%): 215 (26.5) [M]+, 186 (10.9), 130 (12.6), 129 (100), 116 (10), 101 (11.6), 75 (16.35), 56
(29.58).
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3-Phenyl-1-(pyrrolidin-1-yl)prop-2-yn-1-one (3an).9g,9fYellowish oil; 89.5 mg,45% yield.1H
NMR (400 MHz, CDCl3): δ 7.51 (dd, J = 8.1, 1.4 Hz, 2H), 7.34 (dd, J = 7.2, 2.1 Hz, 3H), 3.70
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δ152.7, 132.3, 129.9, 128.4, 120.6, 88.7, 82.6, 77.3, 77.0, 76.7, 48.1, 45.3, 25.3, 24.7. GC-MS
(EI, 70 eV) m/z (%): 199 (39.5) [M]+, 198 (15), 170 (18), 143 (10), 130 (11.1), 129 (100), 116
(12.39), 102 (19.81), 101 (12.5), 75 (16.3), 51 (6).
N,N-Dibutyl-3-(p-tolyl)propiolamide (3ba). Yellowish oil; 243.9 mg, 90% yield.1H NMR (400
MHz, CDCl3): δ 7.40 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 3.60–3.54 (m, 2H), 3.40–3.34
(m, 2H), 2.35 (s, 3H), 1.62–1.50 (m, 4H), 1.40–1.29 (m, 4H), 0.93 (m, 6H).13C NMR (100 MHz,
CDCl3): δ 154.5, 140.3, 132.2, 129.2, 117.7, 89.6, 81.7, 48.9, 44.5, 30.9, 29.5, 21.6, 20.2, 20.0,
13.9, 13.8.GC-MS (EI, 70 eV) m/z (%): 271 (2) [M]+, 242 (3), 228 (11), 187 (4), 143 (100), 115
(8), 89 (4.5), 65 (2), 43 (2). HRMS (ESI) calcd for [(C18H25NO)H] [M+H]+: 272.2014; found:
272.2009.
N,N-Dibutyl-3-(o-tolyl)propiolamide (3ca). Yellowish oil; 235.8 mg, 87% yield.1H NMR (500
MHz, CDCl3): δ 7.50 (d, J = 7.6 Hz, 1H), 7.25 (m, 3H), 3.65–3.56 (m, 2H), 3.44–3.36 (m, 2H),
2.47 (s, 3H), 1.67–1.54 (m, 4H), 1.35 (m, 4H), 0.95 (m, 6H).13C NMR (125 MHz, CDCl3): δ
154.5, 141.1, 132.9, 129.8, 129.6, 125.7, 120.6, 88.3, 85.9, 49.0, 44.6, 31.1, 29.6, 20.7, 20.2,
20.0, 13.8. GC-MS (EI, 70 eV) m/z (%): 271 (5) [M]+, 256 (12.5), 242 (10.5), 228 (14.5), 214
(10), 186 (6), 143 (100), 144 (15), 115 (43.7), 89 (8), 65 (3), 41 (6).HRMS (ESI) calcd for
[(C18H25NO)H] [M+H]+: 272.2014; found: 272.2009.
N,N-Dibutyl-3-(4-ethylphenyl)propiolamide (3da). Yellowish oil; 270.6 mg, 95% yield.1H
NMR (400 MHz, CDCl3): δ7.42 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 3.59–3.55 (m,
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2H), 3.39–3.35 (m, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.64–1.51 (m, 4H), 1.37–1.29 (m, 4H), 1.21 (t,
J = 7.6 Hz, 3H), 0.96–0.89 (m, 6H). 13C NMR (100 MHz, CDCl3): δ154.5, 146.5, 132.3, 128.0,
117.9, 89.6, 81.7, 77.3, 77.0, 76.7, 48.9, 44.5, 31.0, 29.6, 28.9, 20.2, 20.0, 15.1, 13.8, 13.8.GC-
MS (EI, 70 eV) m/z (%): 285 (6) [M]+, 242 (23.2), 201 (8), 200 (4), 157 (100), 142 (18), 114 (7),
77 (2), 44 (2).HRMS (ESI) calcd for [(C19H28NO)H] [M+H]+: 286.2171; found: 286.2165.
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N,N-Dibutyl-3-(4-propylphenyl)propiolamide (3ea). Yellowish oil; 281 mg, 94% yield.1H
NMR (400 MHz, CDCl3): δ 7.41 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 3.59–3.50 (m,
2H), 3.41–3.34 (m, 2H), 2.62–2.54 (m, 2H), 1.62–1.21 (m, 10H), 0.99–0.87 (m, 9H).13C NMR
(100 MHz, CDCl3): δ 154.5, 145.0, 132.2, 128.6, 117.9, 89.6, 81.7, 77.3, 48.9, 44.5, 38.0, 31.0,
29.6, 24.2, 20.2, 20.0, 13.8, 13.8, 13.7. GC-MS (EI, 70 eV) m/z (%): 299 (4) [M]+, 270 (5), 256
(19), 214 (8), 200 (2.5), 171 (100), 157 (4), 142 (25), 114 (9.5), 84 (2), 57 (3), 41 (5).HRMS
(ESI) calcd for [(C20H29NO)H] [M+H]+: 300.2327; found: 300.2321.
N,N-Dibutyl-3-(4-methoxyphenyl)propiolamide (3fa). Yellowish oil; 264 mg, 92% yield.1H
NMR (400 MHz, CDCl3): δ 7.43 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H),
3.57–3.54 (m, 2H), 3.38–3.34 (m, 2H), 1.52–1.45 (m, 4H), 1.30 (m, 4H), 0.94–0.88 (m, 6H).13C
NMR (100 MHz, CDCl3): δ160.8, 154.7, 134.0, 114.1, 112.7, 89.8, 81.3, 77.3, 77.0, 76.7, 55.3,
48.9, 44.5, 30.9, 29.6, 20.1, 20.0, 13.8, 13.8.GC-MS (EI, 70 eV) m/z (%): 287 (6) [M]+, 258 (8),
245 (10), 244 (15), 202 (13), 160 (13), 159 (100), 144 (10), 116 (6), 88 (2), 77 (2), 41 (4).
HRMS (ESI) calcd for [(C18H25NO)H] [M+H]+: 288.1964; found: 288.1958.
N,N-Dibutyl-3-(2-methoxyphenyl)propiolamide (3ga). Yellowish oil; 252.5 mg, 88% yield.1H
NMR (500 MHz, CDCl3): δ 7.50 (dd, J = 7.6, 1.6 Hz, 1H), 7.36 (dd, J = 8.5 Hz, 1H), 6.95–6.86
(m, 2H), 3.86 (s, 3H), 3.67–3.63 (m, 2H), 3.42–3.37 (m, 2H), 1.64–1.55 (m, 4H), 1.42–1.31 (m,
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4H), 0.97–0.92 (m, 6H). 13C NMR (125 MHz, CDCl3): δ 161.0, 154.6, 134.3, 131.4, 120.5,
110.6, 110.1, 86.2, 85.9, 55.6, 48.9, 44.5, 31.0, 29.6, 20.2, 20.0, 13.8, 13.8. GC-MS (EI, 70 eV)
m/z (%): 287 (2.5) [M]+, 256 (29.5), 244 (12.3), 214 (10), 200 (9), 159 (100), 160 (12.7), 131
(21.5), 115 (34), 103 (10), 77 (17), 41 (5). HRMS (ESI) calcd for [(C18H25NO)H] [M+H]+:
288.1964; found: 288.1958.
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N,N-Dibutyl-3-(4-fluorophenyl)propiolamide (3ha). Yellowish oil; 239.2 mg, 87% yield.1H
NMR (400 MHz, CDCl3): δ 7.63–7.41 (m, 2H), 7.10–6.92 (m, 2H), 3.65–3.47 (m, 2H), 3.41–
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3.26 (m, 2H), 1.66–1.49 (m, 4H), 1.39–1.26 (m, 4H), 1.00–0.87 (m, 6H). C NMR (100 MHz,
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88.2, 81.9, 48.9, 44.6, 30.9, 29.5, 20.8, 19.9, 13.8, 13.8. GC-MS (EI, 70 eV) m/z (%): 275 (2)
[M]+, 232 (14), 218 (2), 191 (4), 147 (100), 119 (5), 99 (6), 41 (2.5). HRMS (ESI) calcd for
[(C17H22FNO)H] [M+H]+: 276.1764; found: 276.1761.
N,N-Dibutyl-3-(pyridin-3-yl)propiolamide (3ia). Yellowish brown oil; 162.5 mg, 63%
yield.1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.28 (dd,
J = 7.1 Hz, 1H), 3.63–3.50 (t, 2H), 3.39–3.35 (t, 2H), 1.66–1.48 (m, 4H), 1.44–1.23 (m, 4H),
0.97–0.74 (m, 6H).13C NMR (100 MHz, CDCl3) δ 153.7, 152.5, 149.9, 139.2, 123.2, 85.6, 85.1,
48.9, 44.6, 30.9, 29.5, 20.1, 19.9, 13.8, 13.7. GC-MS (EI, 70 eV) m/z (%): 258 (2) [M]+, 215
(17), 201 (3), 173 (5), 160 (2.5), 130 (100), 102 (10), 75 (5), 43 (3). HRMS (ESI) calcd for
[(C16H22N2O)H] [M+H]+: 259.1810; found: 259.1805.
N,N-Dibutyl-3-(pyren-2-yl)propiolamide (3ka). Yellow oil; 339.9 mg, 89% yield.1H NMR
(400 MHz, CDCl3): δ 8.53 (d, J = 9.1 Hz, 1H), 8.26–8.01 (m, 8H), 3.78–3.73 (t, 2H), 3.50–3.46
(t, 2H), 1.81–1.73 (m, 2H), 1.66–1.62 (m, 2H), 1.51–1.35 (m, 4H), 1.02–0.95 (m, 6H). 13C NMR
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(100 MHz, CDCl3): δ 154.6, 130.3, 129.0, 128.9, 127.1, 126.4, 126.1, 126.0, 125.0, 124.45,
114.8, 88.7, 87.5, 49.2, 44.7, 31.2, 29.7, 20.2, 20.1, 13.9, 13.9. HRMS (ESI) calcd for
[(C27H27NO)H] [M+H]+: 382.2171; found: 382.2165.
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N,N-Dibutylnon-2-ynamide (3la). Colorless oil; 246.4 mg, 93% yield.1H NMR (400 MHz,
CDCl3): δ3.57–3.41 (m, 2H), 3.34–3.23 (m, 2H), 2.32 (t, J = 7.1 Hz, 2H), 1.64–1.21 (m, 18H),
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0.99–0.81 (m, 9H). C NMR (100 MHz, CDCl3): δ 154.6, 92.1, 74.5, 48.8, 44.4, 31.2, 30.9,
29.5, 28.5, 27.8, 22.4, 20.1, 19.9, 18.9, 14.0, 13.8, 13.7. GC-MS (EI, 70 eV) m/z (%): 265 (2.5)
[M]+, 266 (4), 250 (11), 236 (26.5), 222 (50), 208 (17), 166 (17), 137 (100), 86 (10), 67 (63.5),
55 (32), 43 (23), 41 (32.7). HRMS (ESI) calcd for [(C17H31NO)H] [M+H]+: 266.2484; found:
266.2479.
N,N-Dibutyl-3-cyclopropylpropiolamide (3ma). Colorless oil; 207.7 mg, 94% yield.1H NMR
(400 MHz, CDCl3): δ3.50 – 3.39 (m, 2H), 3.37–3.25 (m, 2H), 1.54–1.21 (m, 10H), 0.9 –0.83 (m,
8H), 0.81–0.79 (m, 2H).13C NMR (100 MHz, CDCl3): δ 154.5, 95.4, 69.7, 48.6, 44.3, 30.8, 29.5,
20.1, 19.9, 13.8, 13.8, 13.7, 8.8,-0.4.GC-MS (EI, 70 eV) m/z (%): 221 (1) [M]+, 206 (4.3), 192
(5.3), 136 (8), 122 (5), 93 (100), 65 (17.6), 41 (6.4).HRMS (ESI) calcd for [(C14H23NO)H]
[M+H]+: 222.1858; found: 222.1854.
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra analysis, this material is available free of charge via the Internet
athttp://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
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*E-mail: bm.bhanage@gmail.com; bm.bhanage@ictmumbai.edu.in. Phone: +91 2233612603.
Fax: +91 2233611020.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
R.S.M gratefully acknowledges to Council of Scientific & Industrial Research (CSIR), New
Delhi, India for the award Senior Research Fellowship (SRF).
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