Microwave-assisted decarboxylative three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne

Article abstract of DOI:10.1021/jo2013725

A novel and efficient microwave-assisted decarboxylative three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne (OA²- coulpling) has been developed. This new multicomponent coupling constitutes an efficient approach for the syn

Full text of DOI:10.1021/jo2013725

NOTE
pubs.acs.org/joc
Microwave-Assisted Decarboxylative Three-Component Coupling
of a 2-Oxoacetic Acid, an Amine, and an Alkyne
Huangdi Feng,†,‡ Denis S. Ermolat’ev,*,† Gonghua Song,‡ and Erik V . Van der Eycken*,†
†Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, B-3001 Leuven, Belgium
‡Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
China
S Supporting Information
b
ABSTRACT: A novel and efficient microwave-assisted decarboxylative
three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne
(OA2-coulpling) has been developed. This new multicomponent cou-
pling constitutes an efficient approach for the synthesis of polysubstituted
propargylamines in the presence of a catalytic amount of copper(I)
catalyst.
ropargylamines are abundantly occurring components and
valuable intermediates for the preparation of many nitrogen-
strategy for the synthesis of ketones13 and azomethines.14
However, to the best of our knowledge, there are no literature
examples describing the application of 2-oxoacetic acids in a
decarboxylative process to access propargylamines. Herein, we
report an unprecedented Cu(I)-catalyzed new three-component
coupling of a 2-oxoacetic acid, an amine, and an alkyne under
microwave irradiation.
P
containing biologically active compounds and natural products.1
The traditional syntheses of propargylamines use strong bases
such as butyllithium, organomagnesium reagents, or lithium
diisopropylamide, exploiting the relatively high acidity of the
terminal acetylene to form alkynyl metal compounds. The
stoichiometric quantities of the reagents required, as well as
their high sensitivity to moisture, render these processes fairly
unattractive.2
Our initial investigations employing phenylglyoxylic acid 1a,
N-methylbenzylamine 2a, and phenylacetylene 3a as model
substrates in combination with 20% CuI as a catalyst focused
on the evaluation of the efficiency of various solvents under
microwave irradiation (Table 1, entries 1À5). Among the
solvents tested, toluene seemed to be the most effective for this
decarboxylative coupling reaction (Table 1, entry 5). A slightly
lower yield was obtained when using acetonitrile as a solvent.
Encouraged by this result, we subsequently examined various
catalysts and reaction times. This led to the discovery that CuBr
and CuCl were superior catalysts compared to CuI (Table 1,
entries 5À7). Regarding the concentrations of the catalysts, we
found that 15% CuBr resulted in a high yield, contrary to the use
of 10% CuBr or 15% CuCl (Table 1, entries 12À14). A lower
reaction temperature of 80 °C reduced the yield of the propar-
gylamine 4a to 70% (Table 1, entry 15), while reducing the
irradiation time to 15 min also resulted in a decreased yield of
87% (Table 1, entry 16). In comparison, when the reaction was
conducted under conventional heating using the same condi-
tions, the desired propargylamine 4a was obtained in a yield of
86% after an extended reaction time of 20 h (Table 1, entry 17).
Having optimized the conditions in hand (Table 1, entry 13),
we next evaluated the scope of the procedure by varying the
2-oxoacetic acid, the amine, and the alkyne (Table 2). Both
secondary and primary amines were explored as reaction partners
(Table 2, entries 1À10), and good yields were obtained using
During recent years, significant efforts have been made in
order to develop useful approaches for the synthesis of propar-
gylamines, especially employing multicomponent reactions
(MCRs).3 The three-component coupling of an aldehyde, an
alkyne, and an amine, commonly referred to as A3-coupling, has
received much attention.4 This excellent type of multicompo-
nent reaction provides with its synthetic efficiency, intrinsic
atom economy, and procedural simplicity an elegant entry to
propargylamines.5 Recently, substantial progress has been
achieved for their synthesis. Urriolabeitia6 and Zhang7 discov-
ered a new approach to propargylamines involving CÀC and
CÀN bond formation through CÀCl bond activation of di-
chloromethane. Li reported a copper-catalyzed alkynylation of
sp3-CÀH adjacent to nitrogen,8 and Seidel and Li described a
decarboxylative coupling of R-amino acids9 with terminal al-
kynes. In our previous studies, we demonstrated that the
aldehyde could be efficiently replaced by a ketone (KA2-
coupling),10 and we also successfully applied primary amines,
which are known to be difficult reaction partners, for the
generation of secondary alkylpropargylamines in high yields.11
The decarboxylative coupling reactions have recently gained
particular interest due to the inherent advantage that simple
carboxylic acids represent a powerful alternative for CÀC bond
formation under relatively neutral conditions compared to pre-
formed organometallic reagents.12 The decarboxylative coupling
of 2-oxoacetic acids has been widely used as a valuable synthetic
Received: July 4, 2011
Published: August 08, 2011
r
2011 American Chemical Society
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|

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NOTE
Table 1. Optimization of the Conditionsa
Scheme 1. Proposed Mechanism for the OA2-Coupling
entry
Cu catalyst (mol %)
solvent
time (min)
yieldb (%)
1
2
CuI (20)
EtOH
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
15
20 h
61
39
83
75
85
96
94
76
63
40
15
78
95
73
70c
87
86d
CuI (20)
THF
3
CuI (20)
MeCN
DCE
4
CuI (20)
5
CuI (20)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
CuBr (20)
CuCl (20)
CuOTf (20)
Cu(OTf)2 (20)
Cu(OAc)2 (20)
Cu2O (20)
CuCl (15)
CuBr (15)
CuBr (10)
CuBr (15)
CuBr (15)
CuBr (15)
7
8
OA2-coupling can be regarded as a welcomed additional method
for the generally applied A3-coupling reaction.
9
10
11
12
13
14
15
16
17
’ EXPERIMENTAL SECTION
General Information. All solvents and reagents were purchased
from commercial sources and were used without prior purification. All
microwave irradiation experiments were carried out in a dedicated CEM-
Discover monomode microwave apparatus, operating at a frequency of
2.45 GHz with continuous irradiation power from 0 to 300 W. The
reactions were carried out in 10 mL glass tubes, sealed with Teflon
septum, and placed in the microwave cavity. The reaction mixture was
irradiated at a required ceiling temperature using maximum power for
the stipulated time, and the reaction mixture temperatures were
measured by the external IR sensor. The reaction tube was cooled to
ambient temperature with air jet cooling. TLC analysis was performed
on aluminum-backed plates SIL G/UV254. The products were purified
a Reactions were performed using phenylglyoxylic acid (1.1 mmol),
N-methylbenzylamine (1.0 mmol), phenylacetylene (1.5 mmol), and
solvent (1 mL) under microwave irradiation at 100 °C and 80 W
maximum power. b Isolated yields based on N-methylbenzylamine.
c Reaction carried out at 80 °C. d Conventional heating.
secondary amines, except in the case of dibutylamine (Table 2,
entry 5). However, similar to A3-coupling,15 primary amines
provided the desired compounds only in low to moderate yields
(Table 2, entries 9 and 10). All reactions seemed to be working
excellently when various alkynes were used. Both electron-rich
(Table 2, entries 11À15) and electron-poor aryl-substituted
alkynes (Table 2, entry 16) were effective, although a slightly
lower yield was obtained with a para-butoxy substituent (Table 2,
entry 15). The reaction also worked well with thiophen-2-alkyne
(Table 2, entry 17) and aliphatic alkynes (Table 2, entries
18À21), yielding the desired compounds in 82À87% yield. To
expand the scope of the protocol, a variety of 2-oxoacetic acids
were also evaluated. Aliphatic and heterocyclic 2-oxoacetic acids
gave good results (Table 2, entries 22À27).
1
by silica gel (200À300 mesh) column chromatography. H and 13C
NMR spectra were recorded on 300 or 600 MHz NMR instrument. The
1H chemical shifts are reported in parts per million relative to tetra-
methylsilane. High-resolution mass spectra were recorded by using ion
source temperature of 150À250 °C as required. High-resolution EI mass
spectra were performed with a resolution of 10 000.
General Procedure for the Synthesis of Propagylamines 4.
2-Oxoacetic acid 1 (1.1 mmol) was dissolved in toluene (1 mL),
applying a microwave vial along with a stirring bar, and then amine 2
(1.0 mmol), acetylene 3 (1.5 mmol), and copper bromide (0.15 mmol)
were added. The reaction vessel was sealed and irradiated in a CEM-
Discover for 25 min at a ceiling temperature of 100 °C. The resulting
reaction mixture was loaded on a column and flashed on silica gel
(8À10% EtOAc/heptane) to afford the desired product 4.
A tentative mechanism for this decarboxylative three-compo-
nent coupling is proposed in Scheme 1. The in situ formed
iminium salt A undergoes a Cu(I)-catalyzed decarboxylation to
afford the iminiumÀcopper species B.14 The latter undergoes
reaction with the alkyne 3, resulting in the formation of the
intermediate copper complex C. Further conversion results in
the generation of the desired propargylamine 4 with concomitant
regeneration of the Cu(I) catalyst.16
N-Benzyl-N-methyl-1,3-diphenylprop-2-yn-1-amine (Table 2,
entry 1): 1H NMR (300 MHz, CDCl3) δ 2.24 (s, 3H), 3.61À3.75 (m,
2H), 4.92 (s, 1H), 7.23À7.42 (m, 1H), 7.54À7.57 (m, 2H), 7.68 (d, J =
7.45 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 38.2, 59.1, 59.7, 84.9,
88.8, 123.5, 127.2, 127.7, 128.3, 128.5, 128.6, 129.2, 132.0, 132.6, 139.2,
139.4; HRMS (EI) m/z calcd for C23H21N [M + H] 311.1674, found
311.1694.
In conclusion, we have successfully developed a novel micro-
wave-assisted decarboxylative three-component coupling of a
2-oxoacetic acid, an amine, and an alkyne (OA2-coupling),
providing an efficient approach for the synthesis of polysubsti-
tuted propargylamines in the presence of a catalytic amount of
copper(I) catalyst. Interestingly, the reactions were also applic-
able to sterically hindered and primary amines as well as to
various aliphatic alkynes. Therefore, this new decarboxylative
4-(1,3-Diphenylprop-2-ynyl)morpholine (Table 2, entry
2): H NMR (300 MHz, CDCl3) δ 2.61 (s, 4H), 3.75 (s, 4H), 4.77
(s, 1H), 7.28À7.37 (m, 6H), 7.49À7.52 (m, 2H), 7.63 (d, J = 7.45 Hz,
2H); 13C NMR (75.5 MHz, CDCl3) δ 49.9, 62.1, 67.2, 85.2, 88.6, 123.1,
127.9, 128.3, 128.4, 128.7, 131.9, 137.9; HRMS (EI) m/z calcd for
C19H19ON [M + H] 277.1467, found 277.1462.
1
N-(1,3-Diphenylprop-2-ynyl)-N-methylprop-2-en-1-
amine (Table 2, entry 3): H NMR (300 MHz, CDCl3) δ 2.22
1
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NOTE
Table 2. Scope and Limitations of the Protocola
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NOTE
Table 2. Continued
a A mixture of 2-oxoacetic acid 1 (1.1 mmol), amine 2 (1.0 mmol), alkyne 3 (1.5 mmol), CuBr (15 mol %), and solvent (1 mL) was irradiated at a ceiling
temperature of 100 °C and a maximum power of 80 W for 25 min. b Isolated yields are reported.
(s, 3H), 3.18 (d, J = 6.18 Hz, 2H), 4.97 (s, 1H), 5.16 (d, J = 9.89 Hz, 1H),
5.28 (d, J = 16.69, 1H), 5.85À5.98 (m, 1H), 7.25À7.38 (m, 6H), 7.52 (d,
J = 3.57 Hz, 2H), 7.64 (d, J = 7.34 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 37.8, 57.9, 59.7, 84.9, 88.4, 117.7, 123.2, 127.5, 128.1, 128.3,
128.4, 131.8, 136.1, 138.9; HRMS (EI) m/z calcd for C19H19N [M + H]
261.1517, found 261.1502.
N-Allyl-N-(1,3-diphenylprop-2-ynyl)prop-2-en-1-amine
(Table 2, entry 4): 1H NMR (300 MHz, CDCl3) δ 3.02À3.09
(m, 2H), 3.25À3.31 (m, 2H), 5.12 (d, J = 11.00 Hz, 3H), 5.27 (d, J =
17.12 Hz, 2H), 5.79À5.92 (m, 2H), 7.23À7.36 (m, 6H), 7. 53 (t, J = 7.34
Hz, 2H), 7.69 (d, J = 7.57, 2H); 13C NMR (75.5 MHz, CDCl3) δ 53.5,
56.5, 85.3, 87.9, 117.3, 123.3, 127.4, 128.1, 128.2, 128.3, 131.8, 136.5, 139.3;
HRMS (EI) m/z calcd for C21H21N [M + H] 287.1674, found 287.1669.
N-Butyl-N-(1,3-diphenylprop-2-ynyl)butan-1-amine (Table 2,
entry 5): 1H NMR (300 MHz, CDCl3) δ 0.84 (t, J = 14.12 Hz, 6H),
1.22À1.47 (m, 8H), 2.50 (t, J = 13.60 Hz, 4H), 5.02 (s, 1H), 7.21À7.35
(m, 6H), 7. 50 (d, J = 4.19 Hz, 2H), 7.68 (d, J = 7.84 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3) δ 14.0, 20.5, 30.5, 50.6, 57.4, 86.1, 87.6, 117.3,
123.5, 127.2, 127.9, 128.3, 128.4, 131.8, 139.9; HRMS (EI) m/z calcd for
C23H29N [M + H] 319.2300, found 319.2315.
7611
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NOTE
1-(1,3-Diphenylprop-2-ynyl)piperidine (Table 2, entry 6):
1H NMR (300 MHz, CDCl3) δ 1.39À1.45 (m, 2H), 1.54À1.62
(m, 4H), 2.55 (d, J = 9.66 Hz, 4H), 4.78, (s, 1H), 7.22À7.35 (m, 6H), 7.
48À7.51 (m, 2H), 7.63 (d, J = 7.39 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 24.4, 26.2, 50.6, 62.3, 86.0, 87.9, 117.3, 123.3, 127.4, 128.0,
128.2, 128.4, 131.8, 138.6; HRMS (EI) m/z calcd for C20H21N [M + H]
275.1674, found 275.1681.
1-(1,3-Diphenylprop-2-ynyl)-4-methylpiperidine (Table 2,
entry 7): 1H NMR (300 MHz, CDCl3) δ 0.90 (d, J = 5.41 Hz, 3H),
1.10À1.34 (m, 3H), 1.53À1.68 (m, 2H), 2.15À2.22 (t, J = 21.09 Hz,
2H), 2.47À2.66 (m, 2H), 2.92 (d, J = 10.76 Hz, 1H) 4.81, (s, 1H),
7.24À7.37 (m, 6H), 7. 50 (d, J = 3.57 Hz, 2H), 7.62 (d, J = 7.32 Hz, 2H);
13C NMR (75.5 MHz, CDCl3) δ 21.9, 30.8, 34.3, 34.7, 47.4, 52.7, 62.0,
86.1, 87.9, 123.3, 127.4, 128.0, 128.2, 128.5, 131.8, 138.7; HRMS (EI)
m/z calcd for C21H23N [M + H] 289.1817, found 289.1830.
1-Benzyl-4-(1,3-diphenylprop-2-ynyl)piperazine (Table 2,
entry 8): 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 4H), 2.63 (s, 4H),
3.46 (m, 2H), 4.77 (s, 1H), 7.17À7.33 (m, 11H), 7. 48 (t, J = 6.94 Hz,
2H), 7.61 (d, J = 7.48 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 53.5,
61.8, 63.3, 85.9, 88.4, 123.4, 127.2, 127.8, 128.4, 128.5, 128.7, 129.4,
132.0, 138.3, 138.5; HRMS (EI) m/z calcd for C26H26N2 [M + H]
366.2096, found 366.2106.
(m, 10H), 7.51 (d, J = 7.87 Hz, 2H), 7.68 (d, J = 7.63 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3) δ 31.4, 34.9, 38.2, 59.1, 59.8, 84.2, 89.0, 120.5,
125.6, 127.3, 127.7, 128.3, 128.5, 128.6, 129.2, 131.9, 139.4, 139.5;
HRMS (EI) m/z calcd for C27H29N [M + H] 367.2300, found 367.2299.
N-Benzyl-3-(4-butoxyphenyl)-N-methyl-1-phenylprop-2-
yn-1-amine (Table 2, entry 15): 1H NMR (300 MHz, CDCl3) δ
0.96 (t, J = 14.12 Hz, 3H), 1.44À1.51 (m, 2H), 1.70À1.77 (m, 2H), 2.23
(s, 3H), 3.60À3.73 (m, 2H), 3.93 (t, J = 12.63 Hz, 2H), 4.90 (s, 1H),
6.85 (d, J = 8.17 Hz, 2H), 7.22À7.50 (m, 10H), 7.67 (d, J = 7.43 Hz,
2H); 13C NMR (75.5 MHz, CDCl3) δ 13.8, 19.2, 31.2, 38.0, 58.9, 59.6,
67.7, 83.0, 88.6, 114.5, 115.1, 127.0, 127.4, 128.1, 128.2, 128.3, 129.0,
133.2, 139.3, 139.5; HRMS (EI) m/z calcd for C27H29NO [M + H]
383.2249, found 383.2261.
N-Benzyl-3-(3-fluorophenyl)-N-methyl-1-phenylprop-2-yn-
1-amine (Table 2, entry 16): 1H NMR (300 MHz, CDCl3) δ 2.23
(s, 3H), 3.59À3.74 (m, 2H), 4.90 (s, 1H), 6.99 (t, J = 17.26 Hz, 1H),
7.19À7.41 (m, 11H), 7.65 (d, J = 7.43 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 38.0, 58.9, 59.5, 85.9, 87.5, 115.4, 115.6, 118.5, 118.8, 125.0,
125.1, 127.1, 127.6, 127.7, 127.8, 128.2, 128.3, 128.9, 129.8, 129.9, 138.7,
139.1; HRMS (EI) m/z calcd for C23H20NF [M + H] 329.1580, found
329.1570.
N-Benzyl-N-methyl-1-phenyl-3-(thiophen-2-yl)prop-2-yn-
1-amine (Table 2, entry 17): 1H NMR (300 MHz, CDCl3) δ 2.22
(s, 3H), 3.58À3.72 (m, 2H), 4.89 (s, 1H), 7.17À7.45 (m, 11H), 7.66 (d,
J = 7.53 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 38.3, 59.2, 60.0, 83.9,
84.6, 122.4, 125.6, 127.3, 127.8, 128.4, 128.6, 128.9, 129.2, 130.4, 139.2,
139.5; HRMS (EI) m/z calcd for C21H19NS [M + H] = 317.1238, found
317.1244.
N-Benzyl-1,3-diphenylprop-2-yn-1-amine (Table 2, entry
9): 1H NMR (300 MHz, CDCl3) δ 3.98 (s, 2H), 4.80 (s, 1H),
7.30À7.38 (m, 11H), 7. 48 (s, 2H), 7.61 (d, J = 6.76 Hz, 2H); 13C
NMR (75.5 MHz, CDCl3) δ 51.1, 53.6, 85.7, 89.2, 123.1, 127.1, 127.6,
127.7, 128.1, 128.3, 128.4, 128.5, 131.7, 139.8, 140.3; HRMS (EI) m/z
calcd for C22H19N [M + H] 297.1517, found 297.1506.
N-Benzyl-N-methyl-1,4-diphenylbut-2-yn-1-amine (Table 2,
N-(1,3-Diphenylprop-2-ynyl)hexan-1-amine (Table 2, en-
try 10): 1H NMR (300 MHz, CDCl3) δ 0.86 (d, J = 6.42 Hz, 3H), 1.29
(s, 6H), 1.48 (d, J = 6.18 Hz, 2H), 2.66À2.74 (m, 1H), 2.79À2.88 (m,
1H), 4.78 (s, 1H), 7.26À7.37 (m, 6H), 7. 45 (d, J = 3.21 Hz, 2H), 7.58
(d, J = 7.32 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 14.2, 22.7, 27.2,
30.1, 31.9, 47.5, 54.8, 85.4, 89.6, 123.3, 127.6, 127.7, 128.2, 128.3, 128.6,
131.8, 140.8; HRMS (EI) m/z calcd for C21H25N [M + H] 291.1987,
found 291.1977.
N-Benzyl-3-(4-methoxyphenyl)-N-methyl-1-phenylprop-2-
yn-1-amine (Table 2, entry 11): 1H NMR (600 MHz, CDCl3) δ
2.23 (s, 3H), 3.63 (d, J = 13.20 Hz, 1H), 3.70 (s, 3H), 3.71 (d, J = 13.20
Hz, 1H), 4.90 (s, 1H), 6.83 (d, J = 8.64 Hz, 2H), 7.19À7.34 (m, 6H),
7.40 (d, J = 7.56 Hz, 2H), 7.48 (d, J = 8.64 Hz, 2H), 7.68 (d, J = 7.92 Hz,
2H); 13C NMR (151 MHz, CDCl3) δ 38.2, 55.4, 59.1, 59.9, 83.4, 88.8,
114.2, 115.6, 127.3, 127.7, 128.3, 128.5, 128.6, 129.2, 133.5, 139.5, 139.6,
159.8; HRMS (EI) m/z calcd for C24H23NO [M + H] 341.1780, found
341.1768.
N-Benzyl-3-(4-ethylphenyl)-N-methyl-1-phenylprop-2-yn-
1-amine (Table 2, entry 12): 1H NMR (600 MHz, CDCl3) δ 1.20
(t, J = 15.42 Hz, 3H), 2.23 (s, 3H), 2.58À2.62 (m, 2H), 3.63 (d, J = 13.14
Hz, 1H), 3.71 (d, J = 13.14 Hz, 1H), 4.90 (s, 1H), 7.13(d, J = 7.92 Hz,
2H), 7.19À7.24 (m, 2H), 7.27À7.33 (m, 4H), 7. 40 (d, J = 7.33 Hz, 2H),
7.48 (d, J = 7.99 Hz, 2H), 7.68 (d, J = 7.99 Hz, 2H); 13C NMR (151
MHz, CDCl3) δ 15.8, 29.1, 38.3, 59.2, 59.9, 84.2, 89.1, 120.7, 127.3,
127.7, 128.2, 128.4, 128.5, 128.6, 129.3, 132.1, 139.5, 139.6, 144.8;
HRMS (EI) m/z calcd for C25H25N [M + H] 339.1987, found 339.1990.
N-Benzyl-N-methyl-1-phenyl-3-p-tolylprop-2-yn-1-amine
(Table 2, entry 13): 1H NMR (300 MHz, CDCl3) δ 2.23 (s, 3H), 2.29
(s, 3H), 3.60À3.73 (m, 2H), 4.90 (s, 1H), 7.09 (d, J = 7.78 Hz, 2H),
7.19À7.46 (m, 10H), 7.68 (d, J = 7.32 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 21.7, 38.3, 59.2, 59.9, 84.2, 89.1, 120.5, 127.3, 127.7, 128.4,
128.5, 128.6, 129.3, 129.4, 132.0, 138.4, 139.4, 139.5, 139.6; HRMS (EI)
m/z calcd for C24H23N [M + H] 325.1830, found 325.1824.
N-Benzyl-3-(4-tert-butylphenyl)-N-methyl-1-phenylprop-
2-yn-1-amine (Table 2, entry 14): 1H NMR (300 MHz, CDCl3) δ
1.30 (s, 9H), 2.23 (s, 3H), 3.61À3.74 (m, 2H), 4.91 (s, 1H), 7.21À7.42
1
entry 18): H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 3.54À3.75
(m, 2H), 3.75 (s, 2H), 4.75 (s, 1H), 7.18À7.42 (m, 13H), 7.64 (d, J =
7.53 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 25.6, 38.3, 59.2, 59.6,
77.8, 86.4, 126.9, 127.3, 127.7, 128.2, 128.4, 128.6, 128.8, 129.3, 137.4,
139.7; HRMS (EI) m/z calcd for C24H23N [M + H] 325.1830, found
325.1834.
N-Benzyl-3-cyclohexyl-N-methyl-1-phenylprop-2-yn-1-
amine (Table 2, entry 19): 1H NMR (300 MHz, CDCl3) δ
1.35À1.60 (m, 6H), 1.78À1.89 (m, 4H), 2.13 (s, 3H), 2.58 (s, 1H),
3.51À3.64 (m, 2H), 4.68 (s, 1H), 7.21À7.39 (m, 8H), 7.61 (d, J = 7.85
Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 24.8, 26.0, 29.2, 33.2, 37.8,
58.8, 59.1, 74.4, 93.2, 126.9, 127.2, 127.9, 128.2, 128.3, 129.0, 139.5,
139.7; HRMS (EI) m/z calcd for C23H27N [M + H] 317.2143, found
317.2129.
N-Benzyl-4-cyclopentyl-N-methyl-1-phenylbut-2-yn-1-amine
(Table 2, entry 20): 1H NMR (300 MHz, CDCl3) δ 1.36À1.42 (m,
2H), 1.54À1.69 (m, 4H), 1.85 (d, J = 6.78 Hz, 2H), 2.09À2.14 (m, 4H),
2.36 (d, J = 6.70 Hz, 2H), 3.51À3.65 (m, 2H), 4.68 (s, 1H), 7.17À7.39
(m, 8H), 7.62 (d, J = 7.43 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ
24.9, 25.7, 32.3, 38.1, 39.6, 59.0, 59.4, 75.0, 88.3, 127.1, 127.4, 128.1,
128.4, 128.5, 129.2, 139.7, 139.9; HRMS (EI) m/z calcd for C23H27N
[M + H] 317.2143, found 317.2134.
N-Benzyl-N-methyl-1-phenyloct-2-yn-1-amine (Table 2,
entry 21): H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 13.56 Hz,
1
3H), 1.31À1.52 (m, 4H), 1.57À1.64 (m, 2H), 2.14 (s, 3H), 2.35 (t, J =
13.56 Hz, 2H), 3.51À3.65 (m, 2H), 4.67 (s, 1H), 7.19À7.39 (m, 8H),
7.62 (d, J = 7.54 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ 14.3, 19.0,
22.4, 29.1, 31.3, 38.0, 59.0, 59.4, 75.0, 89.0, 127.1, 127.4, 128.1, 128.4,
128.5, 129.1, 139.7, 139.9; HRMS (EI) m/z calcd for C22H27N [M + H]
305.2143, found 305.2125.
N-Benzyl-N-methyl-1-phenylpent-1-yn-3-amine (Table 2,
entry 22): 1H NMR (300 MHz, CDCl3) δ 1.04 (t, J = 14.88 Hz, 3H),
1.71À1.80 (m, 2H), 2.27 (s, 3H), 3.46À3.56 (m, 2H), 3.73 (d, J = 13.77
Hz, 1H), 7.22À7.38 (m, 8H), 7.45À7.48 (m, 2H); 13C NMR (75.5
MHz, CDCl3) δ 11.3, 27.1, 37.8, 57.8, 59.2, 85.8, 87.4, 123.5, 126.9,
7612
dx.doi.org/10.1021/jo2013725 |J. Org. Chem. 2011, 76, 7608–7613

The Journal of Organic Chemistry
NOTE
127.8, 128.2, 129.0, 131.8, 139.4; HRMS (EI) m/z calcd for C19H21N
[M + H] 263.1674, found 263.1671.
111, 1808. (e) Hattoi, K.; Miyata, M.; Yamamoto, H. J. Am. Chem. Soc.
1993, 115, 1151. (f) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers,
H. P. L.; De Keersmaecker, S. C. J.; Van der Eycken, E. V. Angew. Chem., Int.
Ed. 2010, 49, 9465. Angew. Chem. 2010, 122, 9655. (g) Moura-Lettsa, G.;
DiBlasi, C. M.; Bauer, R. A.; Tan, D. S. Proc. Natl. Acad. Sci. U.S.A. 2011,
108, 6745.
N-Benzyl-N,5-dimethyl-1-phenylhex-1-yn-3-amine (Table 2,
entry 23): 1H NMR (300 MHz, CDCl3) δ 0.88À0.92 (m, 6H),
1.50À1.71 (m, 2H), 1.85À1.98 (m, 1H), 2.26 (s, 3H), 3.53 (d, J =
12.98 Hz, 1H), 3.65À3.74 (m, 2H), 7.20À7.47 (m, 10H); 13C NMR
(75.5 MHz, CDCl3) δ 14.3, 19.0, 22.4, 29.1, 31.3, 38.0, 59.0, 59.4, 75.0,
89.0, 127.1, 127.4, 128.1, 128.4, 128.5, 129.1, 139.7, 139.9; HRMS (EI)
m/z calcd for C21H25N [M + H] 291.1987, found 291.1970.
N-Benzyl-N-methyl-1-phenylnon-1-yn-3-amine (Table 2,
(2) For selected examples, see: (a) Wakefield, J. Organolithium
Methods in Organic Synthesis; Academic Press: London, 1988; p 32.
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Chem., Int. Ed. 2008, 47, 4358. Angew. Chem. 2008, 120, 4430.
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348, 1528. (b) Li, P.; Zhang, Y.; Wang, L. Chem.—Eur. J. 2009,
15, 2045. (c) Aschwanden, P.; Stephenson, C. R. J.; Carreira, E. M.
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Carreira, E. M. Angew. Chem., Int. Ed. 2002, 41, 3054. Angew. Chem.
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2004, 1472. (b) Zani, L.; Bolm, C. Chem. Commun. 2006, 4263.
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16, 9287.
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1
entry 24): H NMR (300 MHz, CDCl3) δ 0.88 (s, 2H), 1.28 (s,
6H), 1.48 (s, 2H), 1.72 (s, 2H), 2.27 (s, 3H), 3.53 (d, J = 13.56 Hz, 1H),
3.56 (s, 1H), 3.72 (d, J = 13.56 Hz, 1H), 7.27À7.45 (m, 10H); 13C NMR
(75.5 MHz, CDCl3) δ 14.2, 22.8, 26.6, 29.1, 31.9, 34.1, 37.9, 56.1, 59.4,
85.9, 87.8, 123.7, 127.0, 127.9, 128.3, 129.1, 131.9, 139.6; HRMS (EI)
m/z calcd for C23H29N [M + H] 319.2300, found 319.2320.
N-Benzyl-N-methyl-1,4-diphenylbut-3-yn-2-amine (Table 2,
entry 25): 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.00À3.04 (m,
2H), 3.57 (d, J = 13.17 Hz, 1H), 3.73À3.86 (m, 2H), 7.21 (s, 13H), 7.41
(s, 2H); 13C NMR (75.5 MHz, CDCl3) δ 38.1, 40.6, 58.1, 59.6, 87.0,
123.6, 126,6, 127.2, 128.2, 128.4, 128.5, 129.1, 129.7, 132.0, 138.9, 139.4;
HRMS (EI) m/z calcd for C24H23N [M + H] 325.1830, found 325.1820.
N-Benzyl-1-(furan-2-yl)-N-methyl-3-phenylprop-2-yn-1-amine
(Table 2, entry 26): 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 3H), 3.60
(d, J = 12.14 Hz, 1H), 3.73 (d, J = 12.14 Hz, 1H), 4.95 (s, 1H), 6.31 (s,
1H), 6.49 (s, 1H), 7.22À7.40 (m, 9H), 7.51 (s, 2H); 13C NMR (75.5
MHz, CDCl3) δ 38.3, 54.1, 58.4, 83.1, 86.7, 109.2, 110.0, 122.8, 127.1,
128.3, 129.0, 131.9, 138.7, 142.6; HRMS (EI) m/z calcd for C21H19NO
[M + H] 301.1467, found 301.1461.
N-Benzyl-N-methyl-3-phenyl-1-(thiophen-2-yl)prop-2-yn-
1-amine (Table 2, entry 27): 1H NMR (300 MHz, CDCl3) δ 2.32
(s, 3H), 3.57 (d, J = 13.17 Hz, 1H), 3.78 (d, J = 13.17 Hz, 1H), 5.06 (s,
1H), 6.93 (s, 1H), 7.25À7.53 (m, 12H); 13C NMR (75.5 MHz, CDCl3)
δ 38.6, 56.3, 58.4, 84.5, 87.6, 123.1, 125,7, 126.1, 126.4, 127.3, 128.5,
129.0, 132.1, 139.2, 144.6; HRMS (EI) m/z calcd for C21H19NS [M + H]
317.1238, found 317.1242.
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Lett. 2010, 12, 2638.
(11) Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V. Chem.—
’ ASSOCIATED CONTENT
Supporting Information. Copies of H NMR and 13C
1
S
b
Eur. J. 2010, 16, 3281.
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Authors
*E-mail: denis.ermolatev@chem.kuleuven.be; erik.vandereycken@
chem.kuleuven.be.
’ ACKNOWLEDGMENT
The authors wish to thank the FWO (Fund for Scientific
Research-Flanders (Belgium)) and the Research Fund of the
University of Leuven for financial support to the laboratory. D.S.
E. is grateful to the FWO for obtaining a postdoc fellowship. H.F.
thanks the China Scholarship Council for financial support.
(15) Giles, R. L.; Sullivan, J. D. S; Steiner, A. M.; Looper, R. E. Angew.
Chem. 2009, 121, 3162. Angew. Chem., Int. Ed. 2009, 48, 3116.
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Nagaiah, K. New J. Chem. 2004, 28, 335. (b) Wei, C.; Li, C. J. J. Am.
Chem. Soc. 2003, 125, 9584.
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