Mild and catalyst-free petasis/decarboxylative domino reaction: Chemoselective synthesis of N -benzyl propargylamines

Article abstract of DOI:10.1021/jo502349a

Multicomponent domino reactions are attractive for assembling functionalized compounds. To this end, a one-pot catalyst-free chemoselective synthesis of N-benzyl propargylamines is reported with good functional group compatibility. This mild process involves in situ formation of an active amine through Petasis reaction of primary amines, formaldehyde solution, and boronic acids, which reacts with propiolic acids to give product in up to 94% yield via decarboxylative coupling reaction.

Full text of DOI:10.1021/jo502349a

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Note
Mild and Catalyst-Free Petasis/Decarboxylative Domino Reaction:
Chemoselective Synthesis of N-Benzyl Propargylamines
Huangdi Feng, Huihui Jia, and Zhihua Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502349a • Publication Date (Web): 19 Nov 2014
Downloaded from http://pubs.acs.org on November 21, 2014
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Mild and Catalyst-Free Petasis/Decarboxylative Domino
Reaction: Chemoselective Synthesis of N-Benzyl
Propargylamines
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Huangdi Feng, Huihui Jia and Zhihua Sun*
College of Chemistry and Chemical Engineering, Shanghai University of Engineering
Science, 333 Longteng Road, Shanghai 201620, China
*E-mail: sungaris@gmail.com
Table of Contents Graphic:
ABSTRACT
Multicomponent domino reactions are attractive for assembling functionalized
compounds. To this end, a one-pot catalyst-free chemoselective synthesis of N-benzyl
propargylamines is reported with good functional group compatibility. This mild
process involves in situ formation of an active amine through Petasis reaction of
primary amines, formaldehyde solution and boronic acids, which reacts with propiolic
acids to give product in up to 94% yield via decarboxylative coupling reaction.
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Propargylamines can be used as important building blocks for the generation of
functionalized five-1, six-2, seven-3 and eight-membered4 nitrogen heterocyclic
frameworks. In addition, they have been found within highly potent and irreversible
selective monoamine oxidase type-B inhibitors5. A common route to the synthesis of
propargylamines involves the reaction of an aldehyde with an amine and an alkyne,
known as the A3-coupling reaction6. However, examples for the constitution of
N-benzyl propargylamines have been rarely studied or reported owing to most of the
N-substituted benzylamines are not commercially available. As such, the development
of greener and more efficient approaches for the preparation of structurally diverse
propargylamines is highly desirable for synthetic organic chemistry.
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Currently, the transition-metal-catalyzed decarboxylative couplings have been
successfully used for C–C bond formation under relatively neutral conditions
compared to preformed organometallic reagents7, 8. In this regard, copper-catalyzed
decarboxylative couplings have been used as a valuable synthetic strategy for the
formation of propargylamines, employing amino acid9, 2-oxoacetic acid10, glyoxylic
acid11, propiolic acid12 as starting materials. However, those copper-catalyzed
methods usually suffer from some drawbacks in terms of environmental pollution and
complication in the purification processes. Recently, the group of Sunwoo Lee
reported a metal-free decarboxylative coupling reaction of propiolic acid with
secondary amine and paraformaldehyde13, similar to A3-coupling reaction. Although
this method provided a facile approach to propargylamines, no example with a
primary amine as starting material was reported due to primary amines are considered
as being difficult substrates in the A3-type coupling reaction14. Meanwhile, there are a
limited number of literature examples in which primary amines were employed in the
decarboxylative A3-coupling reaction15. To expand the decarboxylative coupling
reaction for the generation of propargylamines to a broad range of starting amines, we
envisioned a scenario wherein a primary amine might participate in a Petasis reaction
with an aldehyde and a boronic acid16, to form an active amine in situ, followed by
metal-free decarboxylative A3-coupling reaction of a propiolic acid (Figure 1).
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R3
COOH
R1
R3
R1 N
3
R1 NH2
+
HCHO + R2B(OH)2
R2
O
4
1
2
7
8
9
CO2
H2O
R1 N
R2
N
R2
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O
5
R1
R3
R2B(OH)2
H2O
OH
N
I
R2
IV
OH
R2
R2
R1 N
R1 N
R2B(OH)2
R3
CO2H
III
COO
II
2
3
R3
Figure 1. Petasis and decarboxylative domino reaction
Key to the success of this proposed reaction would be the addition of the aryl boronic
acid into imine I to produce N-benzyl hemiaminal II17, which in the presence of a
propiolic acid results in the formation of iminium salt III. It is noteworthy that the
related addition of another boronic acid into activated iminium salt III has been
desicribed to obtain amine 518. In this note, the alkynyl carbon next to the carboxylate
attacks iminium salt III to generate intermediate IV instead of the above process.
Subsequent extrusion of CO2 through decarboxylation pathway affords the desired
propargylamine in a process similar to the Eschweiler-Clarke methylation19. Herein,
we report the successful development of such a new catalyst-free one-pot
chemoselective synthesis of propargylamines through the Petasis/decarboxylative
domino reaction of a primary amine, a formaldehyde solution, an aryl boronic acid
and a propiolic acid.
We initiated our investigation using benzylamine (1a), formaldehyde solution,
phenylboronic acid (2a), and 3-phenylpropiolic acid (3a) in toluene at 60 oC for 10 h
(Table 1). To our delight, the desired product 4{1} was obtained in 31% yield (Table 1,
entry 1). To improve the yield, various ratios of the four starting materials were
examined (Table 1, entries 2 and 3). Among them, 3.2 equiv of formaldehyde solution
provided the best yield (Table 1, entry 2). When paraformaldehyde was used instead
of formaldehyde solution (Table 1, entries 4 and 5), only 46% and 40% of products
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were isolated, which is much lower than using formaldehyde solution (Table 1, entry
2). Subsequently, solvent screening showed that this reaction was sensitive to the
nature of solvents (Table1, entries 6–12), 1,2-dichloroethane (DCE) provided an
improved isolated yield of 83% for 4{1} (Table1, entry 6), whereas ethyl acetate,
water, acetonitrile, ethanol, dichloromethane and tetrahydrofuran gave lower yields of
the desired product. Eventually, different reaction time and temperatures were also
tested, but did not give much improvement of the yield (Table 1, entries 13–18).
Remarkably, using the reaction temperature of 45 oC was slightly more efficient than
60 oC to afford the optimal result (Table 1, entry 16). When the reaction was run at
room temperature for 10 h, a yield of 73% was obtained (Table 1, entry 17).
Prolonging the reaction time to 26 h, only produced a minor increase of yield (Table 1,
entry 18). In addition, the reaction yield under the optimal conditions can be
decreased from 84% to 65% after adding an acid to the reaction (Table 1, entry 19),
which could be explained by the adverse effect of an acid to the decarboxylative
pathway shown in Figure 1. When ethyl phenylpropiolate was used instead of
phenylboronic acid (Table 1, entry 20), no desired product was formed in the presence
of 1.5 equiv of acetic acid.
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Table 1: Optimization of Reaction Parametersa
entry
ratio
solvent
Toluene
temp [oC]
t [h]
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10
10
10
10
10
10
10
10
yield[%]b
1
2
1.0/2.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/4.0/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
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60
60
60
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60
60
60
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31
69
54
46
40
83
8
Toluene
3
Toluene
4c
5c
6
Toluene
H2O/Toluene (1:15)
DCE
7
AcOEt
8
H2O
33
14
9
CH3CN
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1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
1.0/3.2/1.1/1.2
EtOH
DCM
THF
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
60
45
60
60
80
80
45
rt
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10
10
24
5
6
68
trace
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65
84
73
74
65
0
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19d
20e
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rt
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aReactions conditions: 1a (0.5 mmol), formaldehyde solution (1.1-2 mmol), 2a (0.55 mmol), 3a (0.6 mmol) and
b
c
solvent (1.5 mL) in a sealed tube. Isolated yield. Paraformaldehyde was used instead of formaldehyde solution.
d1.5 equiv of acetic acid was added. Ethyl phenylpropiolate instead of phenylpropiolic acid with 1.5 equiv of
e
acetic acid
A variety of primary amines were subjected to the optimized conditions to evaluate
the scope of the Patisis/decarboxylative domino reaction. For substituted
benzylamines, the reaction afforded the corresponding products 4 in moderate to good
yield bearing electron-rich and electron-deficient groups (Table 2, 4{2}–4{12}). In
general, halo-substitution led to the cleanest and highest yielding reactions (Table 2,
4{2}–4{5}), and cyano-substitution also gave good yield (Table 2, 4{6}).
Methoxy-substitution usually afforded lower yield of the products compared to
methyl-substitution (Table 2, 4{7}–4{12}). The use of aliphatic amines also gave the
desired products in nice yields (Table 2, 4{13}–4{15}). Then, a number of boronic
acids were investigated. Both electron-poor and -rich aryl-substituted boronic acids
were effective, producing the desired compounds in 59–87% yields (Table 2, 4{16}–
4{19}). In addition, the reactions of aromatic naphthalen-1-ylboronic acid,
naphthalen-2-ylboronic acid and thiophen-3-ylboronic acid were also examined. The
corresponding coupling products were obtained in high yield (Table 2, 4{20}–4{22}).
It is noteworthy that 4-fluorophenyl boronic acid (2i), 4-tolylboronic acid (2g),
2-methoxyphenyl boronic acid (2k), and 4-methoxyphenyl boronic acid (2l) also
reacted well under standard conditions to give excellent yields in the formation of
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4{4}#, 4{9}#, 4{10}#, and 4{11}# when compared to the same structures 4{4}, 4{9},
4{10}, and 4{11} from alternative starting materials. Finally, our investigations were
focused on the use of various 3-substituted propiolic acids 3 (Table 2, 4{23}–4{30}).
Both aromatic and aliphatic propiolic acids were explored as reaction partners, and
the results clearly showed that aromatic propiolic acids worked well (Table 2, 4{23}–
4{27}) and alkyl propiolic acids afforded the target compounds only in low to
moderate yields (Table 2, 4{28}–4{30}). It seemed that substituents on the phenyl ring
of the aromatic propiolic acids played important roles in this process, as
electron-donating substituents (Table 2, 4{25}–4{27}) led to higher yields than
electron-withdrawing groups (Table 2, 4{23}–4{24}).
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Table 2: Substrate scope and limitationsa
Cl
N
84% 4{1}
88% 4{5}
65% 4{9}
49% 4{13}
93% 4{2}
76% 4{6}
60% 4{10}
54% 4{14}
90% 4{3}
91% 4{7}
63% 4{11}
73% 4{15}
78% 4{4}
86% 4{8}
68% 4{12}
59% 4{16}b
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N
7
F
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9
68 % 4{17}b
76% 4{18}c
86% 4{19}
87% 4{20}
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89% 4{21}
85% 4{22}
90% 4{4}#
94% 4{9}#
N
N
OMe
F3C
86% 4{10}#
94% 4{11}#
88% 4{26}
76% 4{23}
82% 4{27}
63% 4{24}
86% 4{25}
47% 4{28}
N
Me
53% 4{29}
31% 4{30}
aReactions conditions: amine (0.5 mmol), formaldehyde solution (1.6 mmol), boronic acid (0.55 mmol),
b
propiolic acid (0.6 mmol) and DCE (1.5 mL) in a sealed tube; reaction was monitored by TLC plate. This
reaction was carried out at 60 °C for 18 h. cThis reaction was carried out for 26 h.
Not surprisingly, when isobutylboronic acid was used in this protocol,
dipropargylamine 6 was obtained in 73% yield (Scheme 1). Only trace amounts of the
1
expected tertiary amine product was observed as indicated by H NMR spectroscopy
and LC–MS of the crude reaction mixtures since the Petasis reaction typically did not
work with inactive alkyl-boronic acid.
Scheme 1. Selective coupling reaction toward dipropargylamine
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In summary, we have described a catalyst free method for the synthesis of N-benzyl
propargylamines by multicomponent domino reaction of primary amines with
formaldehyde solution, boronic acids and propiolic acids. The reaction uses
commercially available reagents, and affords significant advantages over the related
transition-metal-catalyzed A3-coupling or decarboxylative A3-coupling, in that it
proceeds under much milder reaction conditions and displays a broad substrate scope
and high chemoselectivity.
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EXPERIMENTAL SECTION
General Information. All commercially available reagents were used without
purification unless otherwise noted. Column chromatography was performed using
silica gel (100–200 mesh). Visualization of the compounds was accomplished with
1
UV light (254 nm) and iodine. H NMR and 13C NMR spectra were recorded in
CDCl3 operating at 400 MHz and 100 MHz, respectively. Proton chemical shifts are
reported relative to the residual proton signals of the deuterated solvent CDCl3 (7.26
ppm) or TMS. Carbon chemical shifts were internally referenced to the deuterated
solvent signals in CDCl3 (77.00 ppm) and reported in δ (parts per million) values.
Coupling constants J are reported in Hz. Proton coupling patterns were described as
singlet (s), doublet (d), triplet (t), quartet (q), and multiple (m). High-resolution mass
spectra were recorded on a Liquid Chromatograph Mass Spectrometer
(LCMS-IT-TOF).
General Procedure for the Synthesis of Propagylamines 4. In a vial equipped with
a stirring bar, amixture of amine (0.5 mmol) and formaldehyde solution (1.6 mmol)
was dissolved in DCE (1.5 mL). Then boronic acid (0.55mmol) and propiolic acid
(0.6 mmol) were added. The reaction vessel was sealed and heated in an oil-bath for
o
10 h at a temperature of 45 C. The resulting reaction mixture was loaded on a silica
gel column and eluted with 2−5% ethyl acetate in hexane to afford the desired product
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4 as light yellow oil.
N,N-dibenzyl-3-phenylprop-2-yn-1-amine (4{1}). light yellow oil (131.1 mg, 84%
6
7
8
1
yield); H NMR (400 MHz, CDCl3) δ 7.57−7.54 (m, 2H), 7.50−7.48 (m, 4H),
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7.40−7.35 (m, 7H), 7.33−7.28 (m, 2H), 3.817 (s, 4H), 3.53 (t, 2H); C NMR (77
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MHz, CDCl3) δ 139.0, 131.8, 129.1, 128.3, 128.3, 128.0, 127.1, 123.5, 85.90, 84.8,
84.5, 57.8, 42.1; MS (ESI) m/z: 312.2 [M + H]+.
N-benzyl-N-(4-chlorobenzyl)-3-phenylprop-2-yn-1-amine (4{2}). light yellow oil
(160.9 mg, 93% yield); 1H NMR (400 MHz, CDCl3) δ 7.55−7.45 (m, 2H), 7.42−7.40
13
(m, 2H), 7.38−7.33 (m, 10H), 3.79 (s, 2H), 3.77 (s, 2H), 3.50 (s, 2H); C NMR (77
MHz, CDCl3) δ 138.7, 137.5, 132.9, 131.8, 130.4, 129.1, 128.6, 128.5, 128.4, 128.3,
128.2, 128.1, 127.2, 123.3, 86.0, 84.2, 57.8, 57.0, 42.1; HRMS (ESI) m/z calcd for
C23H20ClN [M + H]+ 346.1357, found 346.1347.
N-benzyl-N-(2-chlorobenzyl)-3-phenylprop-2-yn-1-amine (4{3}). light yellow oil
1
(155.7 mg, 90% yield); H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.2 Hz, 1H),
7.57−7.55 (m, 2H), 7.50−7.48 (m, 2H), 7.42−7.36 (m, 6H), 7.32−7.28 (m, 2H),
13
7.26−7.24 (m, 1H), 3.96 (s, 2H), 3.87 (s, 2H), 3.54 (s, 2H); C NMR (77 MHz,
CDCl3) δ 138.8, 136.5, 134.7, 131.8, 130.9, 130.0, 129.1, 128.3, 128.0, 127.2, 126.6,
123.4, 86.0, 84.4, 57.9, 54.9, 42.1; HRMS (ESI) m/z calcd for C23H20ClN [M + H]+
346.1357, found 346.1350.
N-benzyl-N-(4-fluorobenzyl)-3-phenylprop-2-yn-1-amine (4{4}). light yellow oil
(128.8 mg, 78% yield); 1H NMR (400 MHz, CDCl3) δ 7.61−7.58 (m, 2H), 7.53−7.41
(m, 9H), 7.37−7.33, (m, 1H) 7.13−7.10 (m, 2H), 3.84 (s, 2H), 3.81 (s, 2H), 3.55 (s,
13
2H); C NMR (77 MHz, CDCl3) δ 163.4, 161.0, 138.9, 134.7, 131.9, 130.7, 130.6,
129.1, 128.4, 128.1, 127.3, 123.5, 115.3, 115.1, 86.1, 84.3, 57.8, 57.0, 42.0; HRMS
(ESI) m/z calcd for C23H20FN [M + H]+ 330.1653, found 330.1651.
N-benzyl-N-(4-bromobenzyl)-3-phenylprop-2-yn-1-amine (4{5}). light yellow oil
(171.7mg, 88% yield);1H NMR (400 MHz, CDCl3) δ 7.60−7.53 (m, 6H), 7.45−7.34
(m, 8H)，3.83 (s, 2H), 3.79 (s, 2H), 3.55 (s, 2H); 13C NMR (77 MHz, CDCl3) δ 138.8,
138.1, 131.9, 131.5, 130.8, 129.1, 128.5, 128.4, 128.2, 127.3, 123.4, 121.0, 86.1, 84.2,
57.8, 57.1, 42.1; HRMS (ESI) m/z calcd for C23H20BrN [M + H]+ 390.0852, found
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390.0840.
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4-((benzyl(3-phenylprop-2-yn-1-yl)amino)methyl)benzonitrile (4{6}). light yellow oil
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(127.8mg, 76% yield); H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.4 Hz, 2H),
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2H), 3.54 (s, 2H); C NMR (77 MHz, CDCl3) δ 144.9, 138.4, 132.3, 131.9, 129.6,
129.1, 128.5, 128.3, 127.5, 123.2, 119.1, 111.0, 86.3, 83.8, 58.0, 57.3, 42.4; HRMS
(ESI) m/z calcd for C24H20N2 [M + H]+ 337.1699, found 337.1689.
N-benzyl-N-(2-methylbenzyl)-3-phenylprop-2-yn-1-amine (4{7}). light yellow oil
(148.4 mg, 91% yield); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.2 Hz, 2H), 7.41
(d, J = 4.8 Hz, 3H), 7.39−7.26 (m, 6H), 7.28−7.21 (m, 3H), 3.8 (s, 4H), 3.5 (s, 2H),
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2.5 (s, 3H); C NMR (77 MHz, CDCl3) δ 139.0, 137.8, 136.8, 131.8, 130.4, 130.2,
129.2, 128.4, 128.3, 128.0, 127.3, 127.1, 125.6, 123.6, 86.0, 84.6, 58.0, 56.0, 41.7,
19.3; HRMS (ESI) m/z calcd for C24H23N [M + H]+ 326.1903, found 326.1894.
N-benzyl-N-(3-methylbenzyl)-3-phenylprop-2-yn-1-amine (4{8}). light yellow oil
(140.3 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 7.61−7.50 (m, 4H), 7.45−7.29
(m, 9H), 7.18−7.16 (m, 1H), 3.86 (s, 2H), 3.83 (s, 2H)，3.58 (s, 2H), 2.46 (s, 3H); 13C
NMR (77 MHz, CDCl3) δ 139.0, 138.9, 137.9, 131.9, 129.9, 129.2, 128.4, 128.3,
128.0, 127.9, 127.2, 126.2, 123.6, 86.0, 84.6, 57.9, 57.8, 42.2, 21.5; HRMS (ESI) m/z
calcd for C24H23N [M + H]+ 326.1903, found 326.1896.
N-benzyl-N-(4-methylbenzyl)-3-phenylprop-2-yn-1-amine (4{9}). light yellow oil
(106.0 mg, 65% yield); 1H NMR (400 MHz, CDCl3) δ 7.56−7.54 (m, 2H), 7.49 (d, J =
7.2 Hz, 2H), 7.40−7.37 (m, 7H), 7.32−7.28 (m, 1H), 7.20 (d, J = 7.6 Hz, 2H), 3.81 (s,
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2H), 3.78 (s, 2H), 3.53 (s, 2H), 2.39 (s, 3H); C NMR (77 MHz, CDCl3) δ 139.0,
136.7, 135.8, 131.8, 129.1, 129.0, 128.3, 128.0, 127.12, 123.5, 86.0, 84.5, 57.7, 57.5,
42.0, 21.1; HRMS (ESI) m/z calcd for C24H23N [M + H]+ 326.1903, found 326.1893.
N-benzyl-N-(2-methoxybenzyl)-3-phenylprop-2-yn-1-amine (4{10}). light yellow oil
(102.7 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ 7.58−7.50 (m, 5H), 7.40−7.36
(m, 5H), 7.32−7.27 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 3.87 (s,
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3H), 3.86 (s, 4H), 3.59 (s, 2H); C NMR (77 MHz, CDCl3) δ 158.1, 139.2, 131.8,
130.5, 129.2, 128.3, 128.2, 128.1, 127.9, 127.2, 127.0, 123.7, 120.5, 110.7, 85.7, 85.2,
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58.1, 55.5, 51.5, 42.5; HRMS (ESI) m/z calcd forC24H23NO [M + H]+ 342.1852, found
342.1837.
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N-benzyl-N-(4-methoxybenzyl)-3-phenylprop-2-yn-1-amine (4{11}). light yellow oil
(107.8 mg, 63% yield); 1H NMR (400 MHz, CDCl3) δ 7.58−7.55 (m, 2H), 7.49 (d, J =
7.2 Hz, 2H), 7.42−7.38 (m, 7H), 7.34−7.28 (m, 1H), 6.94 (d, J = 8.4 Hz, 2H), 3.86 (s,
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3H), 3.81(s, 2H), 3.77(s, 2H), 3.53 (s, 2H); C NMR (77 MHz, CDCl3) δ 158.9,
139.1, 131.8, 131.0, 130.3, 129.1, 128.3, 128.0, 127.1, 123.5, 113.8, 85.9, 84.6, 57.7,
57.1, 55.3, 41.9; MS (ESI) m/z: 342.2 [M + H]+.
N-benzyl-N-(3,4-dimethoxybenzyl)-3-phenylprop-2-yn-1-amine (4{12}). light yellow
oil (126.5 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 7.57−7.55 (m, 2H), 7.49 (d,
J = 7.2 Hz, 2H), 7.41−7.28 (m, 5H), 7.07 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.88 (d, J
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= 8.4 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.80(s, 2H), 3.77 (s, 2H), 3.55 (s, 2H); C
NMR (77 MHz, CDCl3) δ 149.1, 148.3, 139.0, 131.8, 131.6, 129.1, 128.4, 128.0,
127.2, 123.5,121.3, 112.4, 111.1, 85.9, 84.6, 57.7, 57.5, 56.0, 55.9, 42.1; HRMS (ESI)
m/z calcd for C25H25NO2 [M + H]+ 372.1958, found 372.1942.
N-benzyl-N-(cyclohexylmethyl)-3-phenylprop-2-yn-1-amine (4{13}). light yellow oil
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(88.0 mg, 49% yield); H NMR (400 MHz, CDCl3) δ 7.52−7.50 (m, 2H), 7.48−7.43
(m, 2H), 7.38−7.28 (m, 6H), 3.74 (s, 2H), 3.55 (s, 2H), 2.47 (d, J = 7.2Hz, 2H),
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1.93−1.90 (m, 2H), 1.78−1.70 (m, 4H), 1.65−1.48 (m, 4H), 1.40−1.29 (m, 2H); C
NMR (77 MHz, CDCl3) δ 149.1, 148.3, 139.0, 131.8, 131.6, 129.1, 128.4, 128.0,
127.2, 123.5,121.3, 112.4, 111.1, 85.9, 84.6, 57.7, 57.5, 56.0, 55.9, 42.1; HRMS (ESI)
m/z calcd for C23H27N [M + H]+ 318.2216, found 318.2203.
N-benzyl-N-(3-methoxypropyl)-3-phenylprop-2-yn-1-amine (4{14}). light yellow oil
(79.4 mg, 54% yield); 1H NMR (400 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.42 (d, J =
7.2 Hz, 2H), 7.38−7.34 (m, 5H), 7.31−7.28 (m, 1H), 3.74 (s, 2H), 3.57 (s, 2H), 3.51 (t,
J = 6.4 Hz, 2H), 3.37 (s, 3H), 2.75 (t, J = 7.2 Hz, 2H), 1.91−1.85 (m, 2H); 13C NMR
(77 MHz, CDCl3) δ 139.0, 131.8, 129.1, 128.3, 128.0, 127.1, 123.4, 85.6, 84.5, 71.0,
58.6, 58.1, 50.1, 42.3, 27.9; HRMS (ESI) m/z calcd for C20H23NO [M + H]+ 294.1852,
found 294.1843.
N-benzyl-N-phenethyl-3-phenylprop-2-yn-1-amine (4{15}). light yellow oil (119.1 mg,
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73% yield); H NMR (400 MHz, CDCl3) δ 7.56−7.55 (m, 2H), 7.46−7.28 (m, 13H),
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3.85 (s, 2H), 3.69 (s, 2H), 2.98 (s, 4H); C NMR (77 MHz, CDCl3) δ 140.5, 138.8,
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131.8, 129.2, 128.8, 128.5, 128.4, 128.0, 127.2, 126.0, 123.5, 85.7, 84.5, 58.2, 55.4,
42.5, 34.3; MS (ESI) m/z: 326.2 [M + H]+.
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N-benzyl-N-(3-chlorobenzyl)-3-phenylprop-2-yn-1-amine (4{16}). light yellow oil
(102.1 mg, 59% yield); 1H NMR (400 MHz, CDCl3) δ 7.55−7.53 (m, 2H), 7.47 (d, J =
8.4 Hz, 3H), 7.40−7.28 (m, 9H), 3.80 (s, 2H), 3.77(s, 2H), 3.52(s, 2H); 13C NMR (77
MHz, CDCl3) δ 141.2, 138.6, 134.3, 131.8, 129.6, 129.1, 128.4, 128.3, 128.1, 127.4,
127.3, 127.2, 123.3, 86.1, 84.1, 57.8, 57.2, 42.1; HRMS (ESI) m/z calcd for
C23H20ClN [M + H]+ 346.1357, found 346.1341.
N-benzyl-N-(3-fluorobenzyl)-3-phenylprop-2-yn-1-amine (4{17}). light yellow oil
(112.3 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 7.56−7.54 (m, 4H), 7.50−7.02
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(m, 9H), 7.00−6.98 (m, 1H), 3.81 (s, 2H), 3.80 (s, 2H), 3.53(s, 2H); C NMR (77
MHz, CDCl3) δ 164.3, 161.9, 141.8, 141.7, 138.7, 131.8, 129.8, 129.7, 129.4, 129.1,
128.4, 128.3, 128.1, 127.3, 124.6, 124.5, 123.4, 115.8, 115.6, 114.2, 113.9, 86.1, 84.2,
57.8, 57.2, 42.1; HRMS (ESI) m/z calcd for C23H20FN [M + H]+ 330.1653, found
330.1645.
N-([1,1'-biphenyl]-4-ylmethyl)-N-benzyl-3-phenylprop-2-yn-1-amine (4{18}). light
yellow oil (147.5 mg, 76% yield); 1H NMR (400 MHz, CDCl3) δ 7.70−7.50 (m, 13H),
7.46−7.34 (m, 6H), 3.90 (s, 2H), 3.89 (s, 2H), 3.61(s, 2H); 13C NMR (77 MHz, CDCl3)
δ 164.3, 161.9, 141.8, 141.7, 138.7, 131.8, 129.8, 129.7, 129.4, 129.1, 128.4, 128.3,
128.1, 127.3, 124.6, 124.5, 123.4, 115.8, 115.6, 114.2, 113.9, 86.1, 84.2, 57.8, 57.2,
42.1; HRMS (ESI) m/z calcd for C29H26N [M + H]+ 388.2060, found 388.2054.
N-benzyl-N-(3-methoxybenzyl)-3-phenylprop-2-yn-1-amine (4{19}). light yellow oil
(147.1 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 7.59−7.57 (m, 2H), 7.53−7.51
(m, 2H), 7.43−7.39 (m, 5H), 7.35−7.28 (m, 2H), 7.11−7.10 (m, 2H), 6.88 (d, J =
7.2Hz, 1H), 3.88 (s, 3H), 3.84 (s, 2H), 3.83 (s, 2H), 3.57(s, 2H); 13C NMR (77 MHz,
CDCl3) δ 159.8, 140.7, 139.0, 131.8, 129.3, 129.1, 128.4, 128.1, 127.2, 123.5, 121.5,
114.6, 112.7, 86.0, 84.5, 57.8, 57.7, 55.2, 42.2; HRMS (ESI) m/z calcd for C24H23NO
[M + H]+ 342.1852, found 342.1835.
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N-benzyl-N-(naphthalen-1-ylmethyl)-3-phenylprop-2-yn-1-amine (4{20}). light yellow
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oil (157.6 mg, 87% yield); H NMR (400 MHz, CDCl3) δ 8.51−8.50 (d, J = 7.2 Hz,
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1H), 8.00−7.93 (m, 2H), 7.77−7.40 (m, 14H), 4.37 (s, 2H), 4.02 (s, 2H), 3.63 (s, 2H);
13C NMR (77 MHz, CDCl3) δ 139.0, 134.5, 134.2, 132.9, 132.0, 129.5, 129.4, 128.6,
128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.4, 125.9, 125.8, 125.3, 125.2, 123.7,
86.4, 84.7, 58.3, 56.4, 42.0; HRMS (ESI) m/z calcd for C27H23N [M + H]+ 362.1903,
found 362.1888.
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N-benzyl-N-(naphthalen-2-ylmethyl)-3-phenylprop-2-yn-1-amine (4{21}). light yellow
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oil (161.2 mg, 89% yield); H NMR (400 MHz, CDCl3) δ 7.99−7.94 (m, 4H), 7.76−
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7.55 (m, 7H), 7.50−7.38 (m, 6H), 4.06 (s, 2H), 3.95 (s, 2H), 3.66 (s, 2H); C NMR
(77 MHz, CDCl3) 139.0, 136.7, 133.6, 133.0, 131.9, 129.3, 128.5, 128.1, 127.9, 127.8,
127.5, 127.3, 126.0, 125.7, 123.6, 86.1, 84.6, 58.1, 57.9, 42.3; HRMS (ESI) m/z calcd
for C27H23N [M + H]+ 362.1903, found 362.1886.
N-benzyl-3-phenyl-N-(thiophen-3-ylmethyl)prop-2-yn-1-amine (4{22}). light yellow
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oil (135.2 mg, 85% yield); H NMR (400 MHz, CDCl3) δ 7.62−7.54 (m, 4H), 7.47−
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7.34 (m, 8H), 7.28−7.27 (m, 1H), 3.91 (s, 2H), 3.86 (s, 2H), 3.61 (s, 2H); C NMR
(77 MHz, CDCl3) 139.9, 139.0, 131.9, 129.2, 128.6, 128.4, 128.1, 127.3, 125.6, 123.5,
123.0, 86.0, 84.6, 57.7, 52.7, 42.3; HRMS (ESI) m/z calcd for C21H19NS [M + H]+
318.1311, found 318.1306.
N-benzyl-N-(4-fluorobenzyl)-3-phenylprop-2-yn-1-amine (4{4}#). light yellow oil
(148.6 mg, 90% yield); 1H NMR (400 MHz, CDCl3) δ 7.58−7.55 (m, 2H), 7.50−7.28
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(m, 10H), 7.10−7.06 (m, 2H), 3.82 (s, 2H), 3.78 (s, 2H), 3.53 (s, 2H); C NMR (77
MHz, CDCl3) δ 163.4, 161.0, 138.9, 134.7, 131.9, 130.7, 130.6, 129.1, 128.4, 128.1,
127.3, 123.5, 115.3, 115.1, 86.1, 84.3, 57.8, 57.0, 42.0; HRMS (ESI) m/z calcd for
C23H20FN [M + H]+ 330.1653, found 330.1640.
N-benzyl-N-(4-methylbenzyl)-3-phenylprop-2-yn-1-amine (4{9}#). light yellow oil
(153.3 mg, 94% yield); 1H NMR (400 MHz, CDCl3) δ 7.60−7.51 (m, 4H), 7.42−7.32
(m, 8H), 7.23 (d, J = 7.6 Hz, 2H), 3.84 (s, 2H), 3.82 (s, 2H), 3.56 (s, 2H), 2.43 (s, 3H);
13C NMR (77 MHz, CDCl3) δ 139.0, 136.7, 135.8, 131.8, 129.1, 129.0, 128.3, 128.0,
127.12, 123.5, 86.0, 84.5, 57.7, 57.5, 42.0, 21.1; HRMS (EI) m/z calcd for C24H23N
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[M]+ 326.1903, found 326.1889.
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N-benzyl-N-(2-methoxybenzyl)-3-phenylprop-2-yn-1-amine (4{10}#). light yellow oil
(147.1 mg, 86% yield); 1H NMR (400 MHz, CDCl3) δ 7.60−7.52 (m, 5H), 7.42−7.29
(m, 7H), 7.05−7.01 (m, 1H), 6.94 (d, J =8.4 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 4H), 3.60
(s, 2H); 13C NMR (77 MHz, CDCl3) δ 158.1, 139.2, 131.8, 130.5, 129.2, 128.3, 128.2,
128.1, 127.9, 127.2, 127.0, 123.7, 120.5, 110.7, 85.7, 85.2, 58.1, 55.5, 51.5, 42.5;
HRMS (ESI) m/z calcd for C24H23NO [M + H]+ 342.1852, found 342.1842.
N-benzyl-N-(4-methoxybenzyl)-3-phenylprop-2-yn-1-amine (4{11}#). light yellow oil
(160.9 mg, 94% yield); 1H NMR (400 MHz, CDCl3) δ 7.55−7.53 (m, 2H), 7.48−7.46
(m, 2H), 7.40−7.30 (m, 8H), 6.92 (d, J = 8.8Hz, 2H), 3.84 (s, 3H), 3.83 (s, 2H), 3.78
(s, 2H), 3.50 (s, 2H); 13C NMR (77 MHz, CDCl3) δ 158.9, 139.0, 131.8, 131.0, 130.3,
129.1, 128.3, 128.0, 127.1, 123.5, 113.8, 85.9, 84.6, 57.6, 57.1, 55.3, 41.9; MS (ESI)
m/z 342.2 [M + H]+.
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N,N-dibenzyl-3-(3-fluorophenyl)prop-2-yn-1-amine (4{23}). light yellow oil (125.5
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mg, 76% yield); H NMR (400 MHz, CDCl3) δ 7.54−7.50 (m, 4H), 7.45−7.27 (m,
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9H), 7.14−7.09 (m, 1H), 3.85 (s, 4H), 3.57 (s, 2H); C NMR (77 MHz, CDCl3) δ
163.7, 161.3, 138.8, 130.0, 129.9, 129.2, 128.8, 128.4, 128.3, 127.8, 127.7, 127.3,
125.4, 125.3, 118.8, 118.6, 115.6, 115.4, 85.7, 84.8, 57.8, 42.0; HRMS (ESI) m/z
calcd for C23H20FN [M + H]+ 330.1653, found 330.1638.
N,N-dibenzyl-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-amine (4{24}). light yellow oil
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(120.0 mg, 63% yield); H NMR (400 MHz, CDCl3) δ 7.67 (s, 4H), 7.50−7.47 (m,
4H), 7.42−7.31 (m, 6H), 3.83 (s, 4H), 3.56 (s, 2H); 13C NMR (77 MHz, CDCl3) δ
138.7, 132.1, 129.1, 128.4, 127.3, 125.4, 125.3, 125.2, 87.4, 84.7, 57.9, 42.0; HRMS
(ESI) m/z calcd for C24H20F3N [M + H]+ 380.1621, found 380.1609.
N,N-dibenzyl-3-(4-methoxyphenyl)prop-2-yn-1-amine (4{25}). light yellow oil (147.1
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mg, 86% yield); 1H NMR (400 MHz, CDCl3) H NMR (400 MHz, CDCl3) δ 7.51 (d,
J =8.4Hz, 4H), 7.42−7.31 (m, 4H), 6.93 (d, J = 8.8Hz, 6H), 3.88 (s, 3H), 3.83 (s, 4H),
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3.53 (s, 2H); C NMR (77 MHz, CDCl3) δ 159.5, 139.0, 133.2, 129.2, 128.4, 127.2,
115.6, 114.0, 85.8, 82.8, 57.7, 55.4, 42.2; HRMS (ESI) m/z calcd for C24H23NO [M +
H]+ 342.1852, found 342.1845.
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3-([1,1'-biphenyl]-4-yl)-N,N-dibenzylprop-2-yn-1-amine (4{26}). light yellow oil
(170.8 mg, 88% yield); 1H NMR (400 MHz, CDCl3) δ 7.74−7.69 (m, 6H), 7.61−7.54
(m, 6H), 7.50−7.45 (m, 5H), 7.42−7.39 (m, 2H), 3.93 (s, 4H), 3.65 (s, 2H); 13C NMR
(77 MHz, CDCl3) δ 140.9, 140.5, 139.1, 132.4, 129.3, 129.0, 128.5, 128.4, 127.8,
127.3, 127.2, 122.5, 85.9, 85.3, 57.9, 42.3; MS (ESI) m/z 388.2 [M + H]+.
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N,N-dibenzyl-3-(4-(tert-butyl)phenyl)prop-2-yn-1-amine (4{27}). light yellow oil
(151.0 mg, 82% yield); 1H NMR (400 MHz, CDCl3) δ 7.57−7.50 (m, 6H), 7.47−7.41
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(m, 6H), 7.37−7.33 (m, 2H), 3.86 (s, 4H), 3.57 (s, 2H), 1.43 (s, 9H); C NMR (77
MHz, CDCl3) δ 151.3, 139.0, 131.6, 129.2, 128.4, 128.3, 127.2, 125.4, 125.3, 120.5,
86.1, 83.7, 57.8, 42.1, 34.8, 31.3; HRMS (ESI) m/z calcd for C27H29N [M + H]+
368.2373, found 368.2360.
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N,N-dibenzylhept-2-yn-1-amine (4{28}). light yellow oil (68.7 mg, 47% yield); H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.2Hz, 4H), 7.35 (t, J = 7.2Hz, 4H), 7.30−7.26
(m, 2H), 3.27−3.26 (m, 4H), 2.33−2.30 (m, 2H), 1.64−1.30 (m, 2H), 1.01 (t, J =
7.2Hz, 2H); 13C NMR (77 MHz, CDCl3) δ 139.1, 129.1, 128.2, 127.0, 86.0, 74.3, 57.5,
41.7, 31.2, 22.0, 18.5, 13.7; MS (ESI) m/z: 292.2 [M + H]+.
1
N,N-dibenzylhex-2-yn-1-amine (4{29}). light yellow oil (73.7 mg, 53% yield); H
NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.2Hz, 4H), 7.37 (t, J = 7.4Hz, 4H),
7.31−7.28(m, 2H), 3.73 (s, 4H), 3.30 (s, 2H), 2.34−7.30(m, 2H), 1.67−1.64 (m, J =
7.2Hz, 2H), 1.12 (t, J = 7.2Hz, 3H); 13C NMR (77 MHz, CDCl3) δ 139.2, 129.1, 128.8,
128.2, 127.0, 85.7, 74.7, 57.6, 41.8, 22.6, 20.9, 13.6; HRMS (ESI) m/z calcd for
C20H23N [M + H]+ 278.1903, found 278.1885.
1
N,N-dibenzylbut-2-yn-1-amine (4{30}). light yellow oil (38.8 mg, 31% yield); H
NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.2Hz, 4H), 7.35 (t, J = 7.4Hz, 4H), 7.29−7.26
(m, 2H), 3.70 (s, 4H), 3.25 (s, 2H), 1.94(s, 3H); 13C NMR (77 MHz, CDCl3) δ 139.1,
129.1, 128.4, 128.2, 127.0, 81.0, 73.8, 57.5, 41.8, 29.7; MS (ESI) m/z: 250.2 [M +
H]+.
N-benzyl-3-phenyl-N-(3-phenylprop-2-yn-1-yl)prop-2-yn-1-amine (6). light yellow oil
(122.7 mg, 73% yield); 1H NMR (400 MHz, CDCl3) δ 7.52−7.48 (m, 6H), 7.41−7.31
(m, 9H), 3.89 (s, 2H), 3.74 (s, 4H); 13C NMR (77 MHz, CDCl3) δ 138.0, 131.8, 129.4,
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128.4, 128.3, 128.1, 127.4, 123.2, 85.5, 84.7, 57.4, 43.1; MS (ESI) m/z: 336.2 [M +
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H]+.
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ACKNOWLEDGMENTS
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The authors thank Professor Erkang Fan at the University of Washington for helpful
discussions, and are grateful for financial support from Shanghai Municipal Education
Commission (No.14ZZ159), Shanghai Municipal Science and Technology
Commission (No. 12430501300), Shanghai University of Engineering Science
(nhrc-2014-05), and the Program for Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Education.
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Supporting Information Available. NMR (1H and C) spectra of all compounds.
This material is available free of charge via the Internet at http://pubs.acs.org.
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