Palladium-Catalyzed Regioselective Synthesis of 3-(Hetero)Arylpropynamides from gem-Dibromoalkenes and Isocyanides

Article abstract of DOI:10.1002/adsc.201800963

An alternative method related to the formation of 3-(hetero)arylpropynamides using palladium/Cs₂CO₃, regiochemically-controlled coupling of isocyanides with 1,1-dibromo-1-alkenes is described. It was found that the presence of palladium?is crucial in the media so activated the C?Br bond in the 1,1-dibromo-1-alkenes. Subsequent isocyanide?insertion followed by reductive elimination yielded an intermediate that could be easily converted to the desired product in satisfactory yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201800963

Title: Palladium-catalyzed highly regioselective synthesis of 3-
(hetero)arylpropynamides from gem-dibromoalkenes and
isocyanides
Authors: Parvin Salehi and Morteza Shiri
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800963
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
FULL PAPER
Palladium-catalyzed highly regioselective synthesis of 3-
(hetero)arylpropynamides from gem-dibromoalkenes and
isocyanides
Parvin Salehi,a Morteza Shiri,a*
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
a
Department of Chemistry, Alzahra University, Vanak, Tehran 1993893973, Iran, Tel and Fax: +98 21 88041344,
E-mail: mshiri@alzahra.ac.ir
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201
Abstract. An alternative method related to the formation of 3-
Keywords: 3-Propynamides; Cross-coupling reaction;
Isocyanides; 1,1-Dibromo-1-alkenes, Palladium acetate;
Tandem reaction
(hetero)arylpropynamides using palladium/Cs2CO3, the
regiochemically-controlled coupling of isocyanides with 1,1-
dibromo-1-alkenes is described.
and ynsilanes.[12] Piguel et al. proposed a method for
copper-catalyzed, C2-directed alkynylation of 3H-
imidazo[4,5-b]pyridine derivatives using 1,1-
dibromo-1-alkenes.[13] Bach et al. reported the
synthesis of propynamides by utilizing gem-
dibromoalkenes and isocyanate under harsh, multi-
step conditions,[14] whereas Xu et al. established a
process for the selective synthesis of 1,2-
heterodisubstituted alkenes via nucleophilic β-addition
to gem-dibromoalkenes followed by a cross-coupling
reaction.[15]
Further, the synthesis of 2‐ynamides by transition
metal‐catalyzed aminocarbonylation of alkynes
(bromoalkynes, alkynes, and propynoic acids) with
amines that utilize carbon monoxide sources, such as
CO gas and Co2(CO)8, has been discovered.[16]
Introduction
Substituted acetylenes are considered as organic
structures owing to their occurrence in several natural
products. Since they are well known as the main
building blocks for a number of organic syntheses,
chemical and biological processes, and in the field of
material sciences,[1] finding new routes for the
synthesis of alkynyl compounds has attracted the
significant attention of organic chemists.
It has been found that 1,2-disubstituted acetylenes are
excellent substrates for a number of reactions,
including cycloisomerization,[1] palladium-mediated
coupling
reactions,[2]
ring-closing,[3]
and
cycloadditions,[4] as well as for many other useful
transformations. 1,1-Dibromo-1-alkenes, which are
easily derived from aldehydes or ketones with
CBr4/PPh3, are extremely versatile precursors and are
often used for synthesizing diverse molecules.[5]
Applications of these building block molecules have
been extended to the generation of acetylene
derivatives, including alkynylphosphonates,[6] ynol
ethers,[7] symmetric and asymmetric 1,3-diynes,[8]
ynamides,[9] 1,2-diarylacetylenes,[10] ynoate esters,[11]
Recently, Zhang et al. reported the Co(II)/DPE-
phos/Ag(I)-catalyzed
insertion
reaction
of
isocyanide to terminal alkynes based on the formation
of alkynamide derivatives.[17] Further, in this context,
one of the common and practical method for the
synthesis of terminal alkynes (Corey-Fuchs
reaction)[18,19a] as well as bromoacetylenes[19] is the
reaction from aldehydes and CBr4/PPh3 to form 1,1-
1
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
dibromo-1-alkenes followed by treatment with base.
Therefore, if a compound which can be prepared from
either a) the reaction of 1,1-dibromo-1-alkene or b)
reaction of terminal alkyne and bromoacetylene, it is
more logical to follow pathway a, since some steps are
avoided as well as complying with the green chemistry
principles.
Recently, the synthesis of substituted 5-
iminopyrrolones by utilizing palladium(II)/CsF-
catalyzed nucleophilic β-addition in sequential cross-
coupling reactions that involve bromoalkynes and
isocyanides was reported by Jiang et al. (Scheme 1, eq.
2).[20] They also observed that propynamides were
produced in the form of byproducts during this
process.[20]
Inspired by their work and based on our continued
interest in exploring the reactivity and synthetic
applications of isocyanides,[21] we speculated that the
increased reactivity of the C–Br bond in 1,1-dibromo-
1-alkenes 1 made this class of compounds more
susceptible to cross-coupling C–C bond formation
with isocyanides 2, especially in the presence of a
palladium catalyst. The propynamides 3 that would be
generated from this reaction could be achieved through
the subsequent HBr elimination processes (Scheme 1,
eq. 3).
results were in agreement with those reported by Jiang
et al. for 1-(bromoethynyl)-4-methylbenzene 4a
formation[20] and was indicative of a two-step reaction
mechanism in which HBr elimination initially
occurred and was followed by the β-addition of
isocyanide to obtain the desired bromoalkynes.
Formation of 3a as a byproduct in a 25% yield under
this condition revealed that α-addition to the proposed
bromoalkyne followed by second HBr elimination is
also possible. When changes were made to the reaction
conditions, such as the use of DMF as the solvent and
Cs2CO3 as the base, it was noted that the yield of 4a
diminished (Table 1, entries 2 and 3). Additionally,
using CsF in the presence of a catalytic amount of
Pd(OAc)2 in DMSO generated 3a in 50% yield;
however, the results that were obtained when the
reaction was conducted in DMF at 90 ºC were
uninspiring (Table 1, entries 6 and 7). Fortunately, 3a
could be isolated in a 90% yield in the presence of
Cs2CO3 with Pd(OAc)2 in DMF (Table 1, entry 9).
Reactions that were focused on optimizing the
palladium catalyst, base, and solvent revealed that the
best conditions for the formation of 3a were Pd(OAc)2
(5 mol%) and Cs2CO3 (1 equiv.) in DMF at 90 °C
(Table 1). It should be noted that using an excess
amount of isocyanide (up to 3 equiv.) only increased
the rate of the reaction and resulted in no new products.
Table 1. Optimization of the reaction conditionsa
Entry Catalyst
Base
Solvent
Isolated
yield (%)
Scheme 1. Selective metal-catalyzed cross-coupling
reactions using 1-bromo-1-alkynes and 1,1-dibromo-1-
alkenes
3a
25
-
4a
60
40
5
1
2
-
-
-
-
-
CsF
DMSO
DMF
CsF
Results and Discussion
3
Cs2CO3
Cs2CO3
K2CO3
DMSO
DMF
-
4
-
5
First, we carried out the reaction of 1-(2,2-
dibromovinyl)-4-methylbenzene (1a) with tert-butyl
isocyanide (2a) under the same conditions as those
proposed in Scheme 1, eq. 1 (1.5 equiv. of CsF in
DMSO at 90 °C for 5 h). 3-Bromo-N-(tert-butyl)-2-(p-
tolyl)acrylamide (4a) was isolated in a 60% yield, and
5
DMF
-
-
6
Pd(OAc)2 CsF
DMSO
DMF
50
22
17
90
20
15
-
-
7
Pd(OAc)2 CsF
-
8
Pd(OAc)2 Cs2CO3
Pd(OAc)2 Cs2CO3
DMSO
DMF
10
-
9
10
11
12
PdCl2
Pd(PPh3)4 Cs2CO3
CuI Cs2CO3
Cs2CO3
DMF
-
N-(tert-butyl)-3-(p-tolyl)propynamide
(3a)
was
DMF
-
isolated in less than 25% yield (Table 1, entry 1). These
DMF
-
2
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
Table 2. Synthesis of various 3-arylpropynamides 3a
13
14
15
16
17
18
19
20
Pd(OAc)2 Na2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 MeONa
Pd(OAc)2 AcONa
DMF
DMF
DMF
DMF
-
-
-
-
-
-
-
-
-
10
20
30
73
5
Pd(OAc)2 t-BuONa DMF
Pd(OAc)2 Et3N
DMF
Pd(OAc)2 Cs2CO3
Pd(OAc)2 Cs2CO3
toluene trace
CH3CN trace
aReaction
conditions:
1-(2,2-Dibromovinyl)-4-
methylbenzene (1.0 mmol), tert-butyl isocyanide (1.3
equiv.), catalyst (5 mol%), base (1 equiv.) and 0.5 mL of
H2O in 5.0 mL of solvent at 90 ºC for 4 h.
After achieving optimal reaction conditions, we
examined the reactivity between a variety of
substituted dibromoalkenes 1 and isocyanides 2; the
results are summarized in Table 2. It was found that
1,1-dibromo-1-alkenes that contained para-, meta-,
and ortho-electron donating and/or electron-
withdrawing substituents were all easily converted to
their corresponding 3-arylpropiolamides 3a–h in good
to excellent yields. Interestingly, the presence of
electron-withdrawing groups seemed to increase the
reaction efficiency and reduce the reaction time (as
seen in the case of compound 3b and 3h, Table 2). Of
all the tested reactions, the desired product was
produced in ≥ 75% yield; this indicated that the
coupling reaction was not very sensitive to sterically-
hindered compounds.
2-Chloroquinolines-bearing dibromoalkene were also
evaluated under optimal reaction conditions. These
substrates proved to be a challenge, especially when it
came to reaction selectivity. This is attributed to the
presence of the reactive Cl at position 2. The reaction
of 2-chloro-3-(2,2-dibromo vinyl)quinoline with
cyclohexyl isocyanide directly produced 3i in an
isolated yield of 75% with quinoline’s ring remaining
inactive at position 2 (Table 2). When other quinolines
bearing Me, Cl, and OMe substituents were employed
in reactions with aliphatic and aromatic isocyanides,
the corresponding compounds 3i–3p were obtained.
When R2 replaced by aromatic moiety the reactions gave
efficiently corresponding amide 3q in 75% yield (Table 2).
The scope of the reaction was also expanded to include
aAll reactions were carried out using 1,1-dibromo-1-alkenes
(1.0 mmol), isocyanides (1.3 mmol), Pd(OAc)2 (5 mol%),
Cs2CO3 (1 mmol) and 0.5 mL of H2O in 5.0 mL of DMF at
90 ºC for 2-5 h.
Scheme 2 highlights a plausible mechanism for this
Pd-catalyzed coupling reaction of isocyanides with
1,1-dibromo-1-alkenes 1. In the absence of palladium,
the formation of bromoalkynes in base media becomes
more favorable, after which the addition of isocyanide
at the β-position yields 4.[20] However, the existence of
palladium in the basic media appears to activate the C–
Br bond in compound 1, thereby forming intermediate
A. Subsequently, isocyanide was inserted into A to
produce B. The base-mediated replacement of OH by
X resulted in the formation of C.[22] This step is crucial
because the reaction will not proceed well in the
benzoquinoline
1,1-dibromo-1-alkene
coupling
partners; these produced compounds 3p–3s in 75%–
82% yields with a variety of isocyanides (Table 2).
3
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
absence of water even under an O2 atmosphere. A
subsequent reductive elimination of palladium results
in amide D (Scheme 2). Finally, the elimination of HBr
using a base enables D to be converted to the desired
product 3 (Scheme 2).[7b,9a]
5973 Network Mass Selective Detector operating at an
ionization potential of 70 eV and a Leco CHNS, model
932 was used for elemental analysis.
Experimental Section
General procedure for the synthesis of 3-
(hetero)arylpropynamides 3a-3s
To the mixture of gem-dibromo alkenes 1 (1.0 mmol),
Pd(OAc)2 (5 mol%), Cs2CO3 (1.0 mmol) and 0.5 mL of H2O
in 5.0 mL of DMF (5.0 mL), isocyanide 2 (1.3 mmol) was
added. Then the mixture was stirred at 90 ᵒC for 2-5 hours.
Upon completion, to the reaction mixture, water (20 mL)
was added then extracted with CH2Cl2 (3×10 mL), and the
combined extract was dried with anhydrous MgSO4.
Solvent was removed, and the residue was separated by
column chromatography using n-hexane-ethyl acetate (9:1)
to obtain products 3 in pure form.
Scheme 2. Possible pathways involved in the Pd-catalyzed
cross-coupling of 1,1-dibromo-1-alkenes with isocyanides
Characterization Data for All Prepared Compounds
N-tert-Butyl-3-(p-tolyl)propynamide (3a)
Conclusion
Thus, we developed
a
highly selective and
straightforward protocol for the synthesis of 3-
(hetero)arylpropynamides from gem-dibromo alkenes
and isocyanides by utilizing Pd(OAc)2 and Cs2CO3.
Further, one of the challenging methodologies for
synthesizing propynamides is the transition metal-
Yield: 176 mg (82%). White solid. MP = 98-100 ºC. FT-
IR (KBr): 3286, 3030, 2969, 2204, 1629, 1532, 1473, 816
1
cm-1. H NMR (500 MHz, CDCl3) δ = 7.41 (d, J = 7.5 Hz,
2H), 7.15 (d, J = 8.0 Hz, 2H), 5.76 (s, 1H), 2.36 (s, 3H),
1.41(s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ = 152.7,
140.3, 132.3, 129.2, 117.3, 83.7, 82.9, 52.3, 28.6, 21.6 ppm.
MS (EI) m/z: calcd for C14H17NO, 115.13, found, 115. Anal.
calcd. For C14H17NO; C, 78.10; H, 7.96; N, 6.51%; Found;
C, 78.20; H, 8.12; N, 6.42%.
catalyzed
aminocarbonylation
of
alkynes
(bromoalkynes, alkynes, and propynoic acid) by
utilizing CO and amines.[16] However, we used
isocyanide, which was safer than CO and which acted
simultaneously as both carbonyl and amines source.
Therefore, this method is operationally simple and
works well with an extensive range of aromatic and
aliphatic isocyanides and 1,1-dibromo-1-alkene
coupling partners.
N-tert-Butyl-3-(4-nitrophenyl)propynamide (3b)
Yield: 236 mg (96%). Light yellow solid. MP = 160-163 ºC.
FT-IR (KBr): 3291, 3055, 2967, 2928, 2221, 1643, 1596,
1221, 855 cm-1. 1H NMR (500 MHz, CDCl3) δ = 8.22 (d, J
= 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 5.84 (s, 1H), 1.42
(s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ = 151.5, 148.1,
133.1, 127.2, 123.7, 87.9, 79.8, 52.8, 28.6 ppm. MS (EI)
m/z: calcd for C13H14N2O3; 246.10, found, 246. Anal. calcd.
For C13H14N2O3; C, 63.40; H, 5.73; N, 11.38%, Found; C,
63.19; H, 5.55; N, 11.22%.
General Remarks. The solvents and chemicals
purchased from Merck and Aldrich chemical
companies. Unless otherwise mentioned they were
used without further purification.
The 1,1-
dibromoalkenes were prepared according to the
reported procedures.[23] Melting points are taken on an
Electrothermal 9100 apparatus and are uncorrected.
FT-IR spectra were recorded on a Shimadzu Infra-Red
Spectroscopy IR-435. Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker AVANCE
Spectrometer (300, 400, 500 MHz for 1H, 75, 100, 125
MHz for 13C) in DMSO-d6 and CDCl3 as a solvent.
Mass spectra recorded on Agilent Technology (HP)
N-tert-Butyl-3-(4-chlorophenyl)propynamide (3c)
Yield: 212 mg (90%). White solid. MP = 120-123 ºC. FT-
IR (KBr): 3288, 3041, 2971, 2929, 2221, 1629, 1543, 1363,
4
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
1220, 828 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.44 (d, J
= 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 5.79 (s, 1H), 1.41
(s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ = 152.2, 136.1,
133.6, 128.9, 118.9, 84.9, 81.3, 52.5, 28.6 ppm. MS (EI)
m/z: calcd for C13H14ClNO; 235.08, found, 235. Anal. calcd.
For C13H14ClNO; C, 66.24; H, 5.99; N, 5.94%; Found; C,
66.13; H, 5.83; N, 5.77%.
For C15H16ClNO; C, 68.83; H, 6.16; N, 5.35%; Found; C,
68.71; H, 6.22; N, 5.39%.
N-Butyl-3-(4-chlorophenyl)propynamide (3g)
Yield: 212 mg (90%). White solid. MP = 131-134 ºC. FT-
IR (KBr): 3289, 3057, 2957, 2924, 2854, 2222, 1627, 1540,
N-tert-Butyl-3-(3-methoxyphenyl)propynamide (3d)
1
1298, 1219, 1090, 830, 722 cm-1. H NMR (500 MHz,
CDCl3) δ = 7.46 (d, J =8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H),
5.94 (s, 1H), 3.38-3.34 (m, 2H), 1.59-1.53 (m, 2H), 1.43-
1.36 (m, 2H), 0.95 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (125
MHz, CDCl3) δ = 153.1, 136.3, 133.7, 128.9, 118.8, 83.9,
83.2, 39.7, 31.4, 20.0, 13.6 ppm. MS (EI) m/z: calcd for
C13H14ClNO; 235.08, found, 235. Anal. calcd. For
C13H14ClNO; C, 66.24; H, 5.99; N, 5.94%; Found; C, 66.14;
H, 6.12; N, 5.75%.
Yield: 180 mg (78%). Light yellow solid. MP = 108-112 ºC.
FT-IR (KBr): 3293, 3055, 2969, 2932, 2215, 1636, 1601,
1536, 1364, 1223, 876, 784, 687 cm-1. 1H NMR (300 MHz,
CDCl3) δ = 7.17 (t, J = 6.2 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H),
6.97 (s, 1H), 6.88 (d, J = 7.8 Hz,, 1H), 5.70 (s, 1H), 3.72 (s,
3H), 1.34 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ =
159.4, 152.5, 129.6, 124.9, 121.4, 117.1, 116.6, 83.8, 82.5,
55.3, 52.5, 28.7 ppm. MS (EI) m/z: calcd for C14H17NO2;
231.13, found, 231. Anal. calcd. For C14H17NO2; C, 72.70;
H, 7.41; N, 6.06%; Found; C, 72.63; H, 7.30; N, 6.11%.
N-(tert-butyl)-3-(4-(trifluoromethyl)phenyl)
propiolamide (3h)
Yield: 245 mg (92%). White crystal. MP =117-122 ºC. FT-
IR (KBr): 3240, 3058, 2924, 2854, 2229, 1634, , 1558, 1328,
841 cm-1. 1H NMR (300 MHz, CDCl3) δ = 7.54 (s, 4H), 5.74
(s, 1H), 1.35 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ =
152.0, 132.7, 131.3, 125.5 (q, J = 3.75 Hz) , 124.3, 121.8,
85.8, 80.7, 52.7, 28.6 ppm. MS (EI) m/z: calcd for
C14H14F3NO, 269.10 found, 369. Anal. calcd. For
C14H14F3NO; C, 62.45; H, 5.24; N, 5.20. Found; C, 62.30;
H, 5.14; N, 5.11%.
3-(2-Bromophenyl)-N-(tert-butyl)propynamide (3e)
Yield: 245 mg (88%). Light yellow solid. MP = 61-65 ºC.
FT-IR (KBr): 3274, 3055, 2969, 2928., 2219, 1634, 1541,
1221, 1120, 755 cm-1. 1H NMR (500 MHz, CDCl3) δ = 7.59
(dd, J = 1.0 Hz, J = 8.0 Hz, 1H), 7.54 (dd, J = 1.5 Hz, J =
7.5 Hz, 1H), 7.31-7.23 (m, 2H), 5.82 (s, 1H), 1.42 (s, 9H)
ppm. 13C NMR (125 MHz, CDCl3) δ = 152.1, 134.4, 132.6,
126.0, 122.9, 87.8, 80.6, 52.5, 28.6 ppm. MS (EI) m/z: calcd
for C13H14BrNO; 279.03, found, 279. Anal. calcd. For
C13H14BrNO; C, 55.73; H, 5.04; N, 5.00%; Found; C, 55.48;
H, 5.19; N, 4.85%.
3-(2-Chloroquinolin-3-yl)-N-cyclohexylpropynamide
(3i)
Yield: 224 mg (75%). White solid. MP = 211-213 ºC. FT-
IR (KBr): 3263, 3050, 2926, 2851, 2212, 1626, 1584, 1446,
1247, 1137, 803, 746 cm-1. 1H NMR (400 MHz, DMSO-d6)
δ = 8.89 (d, J = 7.6 Hz, 1H), 8.86 (s, 1H), 8.11-8.06 (m, 1H),
8.02-7.99 (m, 1H), 7.93-7.89 (m, 1H), 7.76-7.72 (m, 1H),
3.68-3.61 (m, 1H), 1.80-1.19 (m, 10H) ppm. 13C NMR (100
MHz, DMSO-d6) δ = 151.1, 149.4, 146.8, 144.7, 133.1,
128.74. 128.72, 128.4, 126.4, 115.1, 90.0, 78.4, 48.9, 33.8,
32.5, 25.6, 25.1 ppm. MS (EI) m/z: calcd for C18H17ClN2O;
312.10, found, 312. Anal. calcd. For C18H17ClN2O; C,
69.12; H, 5.48; N, 8.96%; Found; C, 68.99; H, 5.54; N,
9.05%.
3-(4-Chlorophenyl)-N-cyclohexylpropynamide (3f)
Yield: 235 mg (90%). White solid. MP =155-159 ºC. FT-
IR (KBr): 3269, 3059, 2929, 2854, 2220, 1625, 1539, 1486,
1
1291.31, 1089, 826, 706 cm-1. H NMR (500 MHz, CDCl3)
δ = 7.46 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 5.83
(d, J =10.5 Hz, 1H), 3.91-3.85 (m, 1H), 2.01-1.18 (m, 10H)
ppm. 13C NMR (125 MHz, CDCl3) δ = 152.2, 136.3, 133.6,
128.9, 118.8, 84.1, 82.9, 49.0, 32.8, 25.4, 24.8 ppm. MS (EI)
m/z: calcd for C15H16ClNO; 261.09, found, 261. Anal. calcd.
3-(2-Chloro-6-methoxyquinolin-3-yl)-N-
cyclohexylpropynamide (3j)
5
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
Yield: 304 mg (89%). White solid. MP = 222-224 ºC. FT-
IR (KBr): 3264, 3068, 2922, 2853, 2225, 1625, 1578, 1317,
Yield: 270 mg (83%). White solid. MP = 218-221 ºC. FT-
IR (KBr): 3257, 3056, 2918, 2852, 2220, 1630, 1579, 1390,
1
1284, 1128, 834, 707cm-1. H NMR (400 MHz, DMSO-d6)
1
1282, 1152, 893, 769, 611 cm-1. H NMR (300 MHz,
δ = 8.93 (d, J = 7.6 Hz, 1H), 8.72 (s, 1H), 7.93 (d, J = 9.2
Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 3.93 (s, 3H),
3.66 (s, 1H), 1.82-1.23 (m, 10H) ppm. 13C NMR (100 MHz,
DMSO-d6) δ = 158.8, 151.2, 146.7, 143.1, 142.8, 129.8,
127.7, 125.2, 115.2, 106.4, 90.0, 78.5, 56.3, 48.9, 32.5, 25.6,
25.1 ppm. MS (EI) m/z: calcd for C19H19ClN2O2; 342.11,
found, 342. Anal. calcd. For C19H19ClN2O2; C, 66.57; H,
5.59; N, 8.17%; Found; C, 66.42; H, 5.67; N, 7.89%.
DMSO-d6) δ = 8.91 (t, J = 8.1 Hz, 1H), 8.83 (s,1H), 7.91 (d,
J = 7.8 Hz, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.67-7.60 (m, 1H),
3.69-3.62 (m, 1H), 2.52 (s, 3H), 1.83-1.57 (m, 5H), 1.37-
1.10 (m, 5H) ppm. 13C NMR (75 MHz, DMSO-d6) δ = 151.2,
148.4, 145.8, 144.9, 136.2, 133.0, 128..4, 126.5, 114.9, 90.0,
78.5, 48.8, 32.5, 25.6, 25.1, 17.7 ppm. MS (EI) m/z: calcd
for C19H19ClN2O; 326.12, found, 326. Anal. calcd. For
C19H19ClN2O; C, 69.83; H, 5.86; N, 8.57%; Found; C,
70.94; H, 5.95; N, 8.67%.
N-Cyclohexyl-3-(2,6-dichloroquinolin-3-
yl)propynamide (3k)
N-(tert-Butyl)-3-(2-chloroquinolin-3-yl)propynamide
(3n)
Yield: 315 mg (91%). White solid. MP = 242-247 ºC. FT-
IR (KBr): 3251, 3058, 2931, 2853, 2221, 1625, 1546, 1477,
Yield: 226 mg (79%). White solid. MP = 215-218 ºC. FT-
IR (KBr): 3273, 3051, 2926, 2851, 2215, 1625, 1578, 1549,
1239, 1135, 813, 747 cm-1. 1H NMR (400 MHz, DMSO-d6)
δ = 8.84 (s, 1H), 8.59 (s,1H), 8.09-8.06 (m, 1H), 8.02-7.99
(m, 1H), 7.93-7.89 (m, 1H), 7.76-7.71 (m, 1H), 1.32 (s, 9H)
ppm. 13C NMR (100 MHz, DMSO-d6) δ = 151.0, 146.2,
144.1, 143.3, 132.5, 128.2, 128.1, 127.8, 125.9, 114.8, 90.1,
76.5, 51.5, 28.2 ppm. MS (EI) m/z: calcd for C16H15ClN2O;
286.09, found, 286. Anal. calcd. For C16H15ClN2O; C,
67.02; H, 5.27; N, 9.77%; Found; C, 67.21; H, 5.38; N,
9.85%.
1
1284, 974, 885, 714, 618cm-1. H NMR (400 MHz, DMSO-
d6) δ = 8.92 (d, J = 7.6 Hz, 1H), 8.81 (s, 1H), 8.23-8.20 (m,
1H), 8.05-8.02 (m, 1H), 7.93-7.90 (m, 1H), 3.66-3.61 (m,
1H), 1.80-1.18 (m, 10H) ppm. 13C NMR (100 MHz, DMSO-
d6) δ = 150.5, 149.4, 144.7, 143.3, 132.8, 132.5, 130.0,
126.8, 118.4, 115.7, 90.0, 77.4, 48.4, 31.9, 25.0, 24.5 ppm.
MS (EI) m/z: calcd for C18H16Cl2N2O; 346.06, found, 346.
Anal. calcd. For C18H16Cl2N2O; C, 62.26; H, 4.64; N,
8.07%; Found; C, 62.12; H, 4.73; N, 8.19%.
3-(2-Chloro-6-methylquinolin-3-yl)-N-
cyclohexylpropynamide (3l)
N-(tert-Butyl)-3-(2-chloro-6-methoxyquinolin-3-
yl)propynamide (3o)
Yield: 254 mg (78%). White solid. MP = 220-222 ºC. FT-
IR (KBr): 3255, 3057, 2924, 2853, 2221, 1624, 1580, 1352,
Yield: 272 mg (86%). White solid. MP = 172-176 ºC. FT-
IR (KBr): 3281, 3039, 2969, 2935, 2217, 1620, 1533, 1360,
1
1200, 889, 762 cm-1. H NMR (400 MHz, DMSO-d6) δ =
1
1222, 1184, 832, 744, 639 cm-1. H NMR (400 MHz,
8.93 (d, J = 7.6 Hz, 1H), 8.77 (s, 1H), 7.92 (d, J = 8.0 Hz,
1H), 7.86 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 3.66 (d, J = 4.8
Hz, 1H), 1.82-1.23 (m, 10H) ppm. 13C NMR (100 MHz,
DMSO-d6) δ = 151.1, 148.5, 145.4, 143.9, 138.6, 135.2,
128,1, 127.2, 126.4, 115.0, 89.9, 78.5, 48.8, 32.5, 25.5, 25.1,
21.6 ppm. MS (EI) m/z: calcd for C19H19ClN2O; 326.12,
found, 326. Anal. calcd. For C19H19ClN2O; C, 69.83; H,
5.86; N, 8.57%; Found; C, 69.73; H, 5.77; N, 8.41%.
DMSO-d6) δ = 8.67 (s, 1H), 8.58 (s, 1H), 7.93-7.89 (m, 1H),
7.55-7.51 (m, 1H), 7.47-7.45 (m, 1H), 3.91 (s, 3H), 1.32 (s,
9H) ppm. 13C NMR (100 MHz, DMSO-d6) δ = 158.3, 151.0,
146.2, 142.4, 142.2, 129.3, 127.2, 124.6, 114.9, 105.9, 90.1,
76.6, 55.8, 51.5, 28.2 ppm. MS (EI) m/z: calcd for
C17H17ClN2O2; 316.10, found, 316. Anal. calcd. For
C17H17ClN2O2; C, 64.46; H, 5.41; N, 8.84%; Found; C,
64.33; H, 5.57; N, 9.02%.
3-(2-Chloro-8-methylquinolin-3-yl)-N-
cyclohexylpropynamide (3m)
3-(2-Chloroquinolin-3-yl)-N-(2,4,4-trimethylpentan-2-
yl)propynamide (3p)
6
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
Yield: 291 mg (85%). White crystal. MP = 186-189 ºC. FT-
IR (KBr): 3280, 3046, 2955, 2223, 1647, 1534, 1481, 1359,
1277, 1132, 958, 771 cm-1. 1H NMR (400 MHz, DMSO-d6)
δ = 8.84 (s, 1H), 8.49 (s, 1H), 8.10-8.07 (m, 1H), 8.02-7.99
(m, 1H), 7.93-7.88 (m, 1H), 7.76-7.71 (m, 1H), 1.76 (s, 2H),
1.35 (s, 6H), 0.99 (s, 9H) ppm. 13C NMR (100 MHz,
DMSO-d6) δ = 151.0, 148.9, 146.2, 144.0, 132.5, 128.3,
128.2, 127.8, 125.9, 114.8, 90.3, 76.3, 55.2, 49.5, 31.4, 31.1,
29.1 ppm. MS (EI) m/z: calcd for C20H23ClN2O; 342.15,
found, 342. Anal. calcd. For C20H23ClN2O; C, 70.06; H,
6.76; N, 8.17%; Found; C, 70.21; H, 6.82; N, 8.33%.
Yield: 302 mg (77%). Light yellow crystal. MP = 179-182
ºC. FT-IR (KBr): 3243, 3055, 2956, 2937, 2221, 1635, 1546,
1465, 1389, 1291, 1220, 1143, 887, 759 cm-1. 1H NMR (400
MHz, DMSO-d6) δ = 9.01-8.99 (m, 1H), 8.85 (s, 1H), 8.51
(s, 1H), 8.11-8.09 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.94 (d,
J = 9.2 Hz, 1H), 7.85-7.82 (m, 2H), 1.77 (s, 2H), 1.36 (s,
6H), 1.00 (s, 9H) ppm. 13C NMR (100 MHz, DMSO-d6) δ =
151.1, 148.7, 144.8, 143.3, 134.1, 129.7, 129.1, 129.0, 128.3,
127.9, 124.5, 124.4, 124.0, 115.5, 90.8, 76.3, 55.2, 49.5,
31.4, 31.1, 29.1 ppm. MS (EI) m/z: calcd for C24H25ClN2O;
392.17, found, 392. Anal. calcd. For C24H25ClN2O; C,
73.36; H, 6.41; N, 7.13%; Found; C, 73.19; H, 6.58; N,
7.19%.
3-(2-Chloro-6-methoxyquinolin-3-yl)-N-(2,6-
dimethylphenyl) propiolamide (3q)
N-(tert-Butyl)-3-(2-chlorobenzo[h]quinolin-3-
yl)propynamide (3t)
Yield: 273 mg (75%). White solid. MP = 186-188 ºC. FT-
IR (KBr): 3239, 3009, 2950, 2922, 2217, 1641, 1622, 1496,
1381, 1228, 710 cm-1. 1H NMR (500 MHz, DMSO-d6) δ =
10.38 (s, 1H), 8.80 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 7.57
(d, J = 10.0 Hz, 1H). 7.52-7.50 (m, 1H), 7.17-7.11 (m, 3H),
3.93 (s, 3H), 2.21 (s, 6H) ppm. 13C NMR (75 MHz, DMSO-
d6) ȱ = 158.9, 150.5, 146.8, 143.4, 142.9, 135.6, 134.1,
129.9, 128.6, 128.4, 127.8, 127.7, 125.3, 115.0, 106.6, 89.7,
79.5, 56.3, 18.5 ppm. MS (EI) m/z: calcd for C21H17ClN2O2,
364.10, found, 364. Anal. calcd. For C21H17ClN2O2; C,
69.14; H, 4.70; N, 7.68%; Found; C, 69.10; H,4.60; N,
7.65%.
Yield: 269 mg (80%). White solid. MP = 212-216 ºC. FT-
IR (KBr): 3233, 3051, 2966, 2926, 2220, 1632., 1547, 1399,
1291, 1219, 1143, 877, 751 cm-1. H NMR (400 MHz,
1
DMSO-d6) δ = 9.01-8.98 (m, 1H), 8.85 (s, 1H), 8.62 (s, 1H),
8.11-8.10 (m, 1H). 8.07 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.8
Hz, 1H), 7.85-7.82 (m, 2H), 1.33 (s, 9H) ppm. 13C NMR
(100 MHz, DMSO-d6) δ = 151.0, 148.6, 144.9, 143.4, 134.1,
129.8, 129.1, 129.0, 128.3, 127.9, 124.4, 124.0, 115.4, 90.7,
76.5, 51.5, 28.2 ppm. MS (EI) m/z: calcd for C20H17ClN2O;
336.10, found, 336. Anal. calcd. For C20H17ClN2O; C,
71.32; H, 5.09; N, 8.32%; Found; C, 71.22; H, 5.17; N,
8.43%.
3-(2-Chlorobenzo[h]quinolin-3-yl)-N-
cyclohexylpropynamide (3r)
N-(tert-butyl)-3-(1-tosyl-1H-indol-3-yl)propiolamide
(3u)
Yield: 297 mg (82%). White solid. MP = 216-218 ºC. FT-
IR (KBr): 3268, 3050, 2935, 2853, 2219, 1621, 1534, 1438,
1
1342, 1283, 1150, 817, 753 cm-1. H NMR (400 MHz,
DMSO-d6) δ = 9.02-9.00 (m, 1H), 8.97-8.95 (m, 1H), 8.89
(s, 1H), 8.13-8.12 (m, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.95 (d,
J = 8.8 Hz, 1H), 7.87-7.84 (m, 2H), 3.68-3.64 (m, 1H), 1.83-
1.22 (m, 10H) ppm. 13C NMR (100 MHz, DMSO-d6) δ =
151.2, 149.2, 145.4, 144.6, 144.0, 134.6, 130.3, 129.6, 129.5,
128.8, 128.4, 125.0, 124.6, 115.8, 90.5, 78.4, 48.9, 32.5,
25.6, 25.1 ppm. MS (EI) m/z: calcd for C22H19ClN2O;
362.12, found, 362. Anal. calcd. For C22H19ClN2O; C,
72.82; H, 5.28; N, 7.72%; Found; C, 73.01; H, 5.17; N,
7.59%.
Yield: 370 mg (94%). White solid. MP = 114-119 ºC. FT-
IR (KBr): 3230, 3050, 2969, 2926, 2212, 1623, 1540, 1451,
1381, 1117, 810, 740 cm-1. 1H NMR (300 MHz, DMSO-d6)
δ = 8.45 (s, 1H), 8.36 (s, 1H), 7.99 (t, J = 8.4 Hz, 3H), 7.77
(d, J = 7. 5 Hz, 1H), 7.50-7.38 (m, 4H), 2.34 (s, 3H), 1.33 (s,
9H) ppm. 13C NMR (75 MHz, DMSO-d6) ȱ = 152.0, 146.7,
134.0, 133.8, 132.5, 130.9, 130.2, 127.5, 126.6, 124.8, 120.9,
113.9, 102.5, 89.6, 73.8, 51.8, 28.8, 21.5 ppm. MS (EI) m/z:
calcd for C22H22N2O3S , 394.14, found, 394. Anal. calcd.
For C22H22N2O3S; C, 66.98; H, 5.62; N, 7.10%; Found; C,
66.9; H, 5.5; N, 7.05%.
3-(2-Chlorobenzo[h]quinolin-3-yl)-N-(2,4,4-
trimethylpentan-2-yl)propynamide (3s)
7
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10.1002/adsc.201800963
Advanced Synthesis & Catalysis
Acknowledgements
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Science Foundation (INSF) for the financial support
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8
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Advanced Synthesis & Catalysis
FULL PAPER
Palladium-catalyzed highly regioselective synthesis of
3-(hetero)arylpropynamides from gem-dibromoalkenes
and isocyanides
Adv. Synth. Catal. Year, Volume, Page – Page
Parvin Salehi, Morteza Shiri,*
9
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