Synthetic access to secondary propargylamines via copper-catalyzed oxidative deamination-alkynylation cascade

Article abstract of DOI:10.1021/acs.joc.9b01431

A novel and selective cascade reaction of primary amines and alkynes for the synthesis of the corresponding secondary propargylamines is described. This protocol proceeds with a CuBr₂/TBHP system through a process of oxidative deamination of primary amines to imine and alkynylation, featuring a wide scope of substrates with good functional-group tolerance and operational-simplicity. Additionally, the use of two different primary amines could also work smoothly using this protocol.

Full text of DOI:10.1021/acs.joc.9b01431

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Note
Synthetic Access to Secondary Propargylamines via Copper-
Catalyzed Oxidative Deamination-Alkynylation Cascade
Huiqiong Li, Huangdi Feng, Jingxian Zhang, Erik V. Van der Eycken, and Liliang Huang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01431 • Publication Date (Web): 26 Jul 2019
Downloaded from pubs.acs.org on July 27, 2019
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Synthetic Access to Secondary Propargylamines via Copper-Catalyzed
Oxidative Deamination-Alkynylation Cascade
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Huiqiong Li,† Huangdi Feng,*† Jingxian Zhang † Erik V. Van der Eycken‡,§ and Liliang Huang†
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†College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
333 Longteng Road, Shanghai, 201620, China
‡Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of
Chemistry, KU Leuven, Celestijnenlaan 200F, Leuven 3001, Belgium
§Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street,
Moscow 117198, Russia.
*E-mail: hdfeng@sues.edu.cn;
Graphical Abstract
R1
H2N
NH2
NH2
Homo Deamination
Cross Deamination
ii
Cu
R1
R2
+
+
i
( )
( )
TBHP
R1
H2N
R3
NH
NH
R1
R2
R3
R3
R1
R1
25 examples
9 examples
Abstract
A novel and selective cascade reaction of primary amines and alkynes for the synthesis of the
corresponding secondary propargylamines is described. This protocol proceeds with a CuBr2/TBHP
system through a process of oxidative deamination of primary amines to imine and alkynylation,
featuring a wide scope of substrates with good functional-group tolerance and operational-simplicity.
Additionally, the use of two different primary amines could also work smoothly using this protocol.
Introduction
Propargylamines are robust substrates widely valued for the generation of diverse heterocycles in
organic synthesis.1 A number of these compounds also exhibit intrinsic biological activities in the
treatment of neurodegenerative diseases.2 Owing to their apparent importance, significant efforts
have been done for the synthesis of propargylamines. In particular, the transition metal-catalyzed
three-component coupling of an amine, an aldehyde, and a terminal alkyne, known as the A3-
coupling, is now broadly employed for the synthesis of propargylamines (Scheme 1, eq 1).3 Also, a
decarboxylative A3-coupling process has been developed as an alternative approach for accessing
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propargylamines.4 In addition, transition metal-catalyzed tandem hydroamination of
alkynes/alkynylation has been firmly established by Li, Hammond, Dyson, Blecherta, Larsen and
others, leading to the construction of functionalized propargylamines (Scheme 1, eq 2).5 At the same
time, tertiary amines have emerged as direct precursors that can undergo oxidative cross-
dehydrogenative coupling (CDC) with alkynes to produce a series of tertiary propargylamines
(Scheme 1, eq 3).6,7 However, the lower reactivity of primary amines mostly makes the reported
strategies not ideally suitable for the yielding of secondary propargylamines which have revealed a
broader range of transformations than tertiary propargylamines.8 Therefore, the exploration of a new
and efficient protocol for the synthesis of secondary propargylamines is still highly desirable.
R1
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R2
R2
R2
R1
O
N
transition metal
(1)
+
+
R4
R4
R3
R4
NH
R2
R3
R3
R1
N
R1
N
R1
R2
R3
R3
R3
+
R3
or
(2)
NH
R2
Cu, Zn, etc
R3
Me
R1
N
R1
N
Cu, Fe, Zn
oxidants
(3)
R1
R3
+
R4
R2
R3
NH
R1
or
NH2
+
NH
R1
R3
R
R3
R3
R1 NH2
(4)
Cu, oxidant
NH2
R
Homo-
Cross-
(this work)
R3
R
R1
N
R
Scheme 1. Representative routes to propargylamines: (1) Transition metal-catalyzed A3-coupling,
(2) Cross-dehydrogenative coupling, (3) Tandem hydroamination/alkynylation; (4) Present work:
deamination/alkynylation cascade.
It has been well established that oxidative deamination of amines can be performed to form imines
in the presence of metal catalysts.9 For example, the copper/oxidant dual system was successfully
applied for the reaction of a primary amine.10 In pursuit of expanding our knowledge about A3-
coupling reactions,11 we speculated that the imines resulting from direct oxidation of primary
amines, could be trapped by alkynes in the presence of a copper catalyst (Scheme 1, eq 4). To the
best of our knowledge this is the first report of an efficient synthesis of secondary propargylamines
from primary amines and alkynes, through a catalytic oxidative deamination/alkynylation cascade
process. This strategy poses significant challenges, not just because of the propensity of over-
oxidation of the imine to the nitrile,12 but also because of the rapid homocoupling of alkynes under
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oxidative conditions13 Moreover, another impediment is the competing over-oxidation of the final
propargylamines.
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Results and Discussion
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An optimization campaign ascertained suitable reaction conditions opting for a model reaction of
benzylamine 1a and phenylacetylene 2a in the presence of CuBr2. Employing 12.5 mol% Cu with
1.25 equiv tert-butyl hydroperoxide (70% TBHP) in toluene, a 70% yield of propargylamine 3a was
obtained after 3 h at 100 °C (Table 1, entry 1). The importance of water for the yield was pronounced
when TBHP-decane was introduced instead of aqueous 70% TBHP (entry 2). Using H2O2, no
desired product was observed (entry 3). Different copper catalysts such as CuCl2, Cu(OTf)2, CuI
and CuBr as well as various catalyst loadings showed lower catalytic efficacy, giving 3a in 18−58%
yields (entries 4−9). Switching the solvent to DCE, CH3CN or omitting it, resulted in lower yields
(entries 10−12). Further, tuning the reaction parameters such as ratio of substrates, temperature and
time had a positive effect on the yield (entries 13−16). A 79% yield of product was observed when
2.5 equiv of phenylacetylene 2a was applied at 110 oC for 4 h (entry 16).
Table 1. Oxidative Deaminative Reaction with Alkynes
Ph
12.5 mol% CuBr2
70% TBHP (12.5 equiv)
HN
NH2
+
toluene (1 mL), 100 oC, 3 h
1a
(0.8 mmol)
2a
(0.8 mmol)
3a
standard conditions
entry
deviation from the “standard conditions”
yielda (%)
1
none
70
53
NDb
46
18
51
58
56
39
55
28
64
69
74
76
79
2
TBHP-decane instead of 70% TBHP
H2O2 instead of 70% TBHP
CuCl2 instead of CuBr2
Cu(OTf)2 instead of CuBr2
CuI instead of CuBr2
3
4
5
6
7
CuBr instead of CuBr2
8 mol% of CuBr2
8
9
20 mol% of CuBr2
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12
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15
16
DCE instead of toluene
CH3CN instead of toluene
omit toluene
1a (1.0 mmol)
2a (1.0 mmol)
2a (1.0 mmol), reaction time prolonged to 4 h
2a (1.0 mmol), temperature increased to 110 °C, 4 h
aIsolated yields. bND = not detected
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With the optimized reaction conditions in hand, a series of propargylamines 3 were generated from
their corresponding amines and alkynes (Table 2). Firstly, a range of benzylamines was examined
demonstrating that both electron-donating and electron-withdrawing substrates could react with 2a
smoothly to deliver the corresponding products (3a−3e, 3g−3j) in good to excellent yields.
Surprisingly, meta-substituted benzylamines provided lower yields (3c and 3e) than ortho-and para-
substituted ones (3b and 3d) together with the corresponding aldehydes as byproducts (monitored
by GC-MS). However, when the 3,4-dimethoxybenzylamine was used, no desired product (3f) was
obtained. Remarkably, for aliphatic primary amines involving cyclohexylmethanamine, n-butylamine
and phenethylamine, only cyclohexylmethanamine could be successfully converted into the desired
product (3k). This might be owing to the fact that most aliphatic amines are more difficult converted
into the corresponding imine as compared to benzylamine employing the standard conditions.14 It
is also worth noting that a secondary amine tolerates the reaction conditions, giving the tertiary
propargylamine 3n. The result suggests that the final secondary propargylamine is potential to
further transformation. Furthermore, the scope of alkynes was evaluated using benzylamine 1a. To
our delight, all the target products (3aa−3an) were obtained with very good yields when reacted
with different phenylacetylenes. However, it turned out that the reaction efficiency was susceptible
to electronic effects. In general, phenylacetylenes containing electron-donating groups including
methyl, methoxy, ethyl, butyl, amyl and t-butyl afforded higher yields (3aa−3ag) than those with
electron-withdrawing groups, including Cl, F, CF3 (3ah−3an). No product (3ao) was obtained with
ethynylcyclopropane.
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Table 2. Applicable Amines and Alkynes to Homo-Deaminative Couplinga.
R1
CuBr2(12.5 mol%),TBHP(1.25 equiv)
R2
HN
R1 NH2
+
R2
toluene,110 oC, 4 h
R1
1
2
3
Amines
OMe
HN
HN
HN
HN
HN
MeO
3a, 79% yield
3b, 87% yield
3c, 63% yield
3d, 81% yield
3e, 57% yield
OMe
Cl
Cl
F
Br
OMe
HN
HN
HN
HN
HN
Cl
MeO
MeO
Br
F
Cl
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3f, 0% yield
3g, 59% yield
3h, 70% yield
3i, 61% yield
3j, 72% yield
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HN
N
HN
HN
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3k, 57% yield
3l, 0% yield
3m, 0% yield
3n, 66% yield
Alkynes
HN
HN
HN
HN
OMe
nAm
F
Et
3aa, 88% yield
3ab, 82% yield
3ac, 90% yield
3ag, 86% yield
3ad, 79% yield
HN
HN
HN
HN
nBu
tBu
Cl
3ae, 87% yield
3af, 86% yield
3ah, 73% yield
HN
HN
HN
HN
F
F
F3C
3ai, 73% yield
3aj, 78%yield
3ak, 71% yield
3al, 51% yield
HN
HN
HN
CF3
CF3
3am, 84% yield
3an, 67% yield
3ao, 0% yield
aReaction scale: 0.8 mmol of amine 1, 1.0 mmol of alkyne 2, 12.5 mmol% of CuBr2, 1.25 equiv of
70% TBHP, 1 mL toluene. Reported yields are isolated yields.
It is well-known that the cross-deamination of two different amines is more difficult. In order to
further demonstrate the synthetic practicality of our protocol, a three-component tandem reaction of
a benzylamine, an amine and a phenylacetylene was tested under slightly improved conditions. The
initial study started using benzylamine 1a and n-butylamine under the standard conditions, but only
39% yield of the corresponding products 4a was isolated. An increased yield to 48% was obtained
when 2.0 equiv. TBHP was introduced. (Table 3). Subsequently, different amines 1’ were evaluated,
and moderate yields of the desired products (4b−4e) were obtained, because the homo-deamination
of benzylamine 1a could not be fully avoided, giving 3a as a main isolated byproduct. Notably,
when two different benzylamines were employed in the reaction, the desired product 4b was isolated
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in 56% yield. Furthermore, various benzylamines 1 and phenylacetylenes 2 with common functional
groups could also be applied, resulting in the formation of the corresponding propargylamines
(4f−4i) in moderate yields.
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Table 3. Applicable Amines and Alkynes to Cross-Deaminative Couplinga.
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R3
N
R2
R1
R3
NH
1'
CuBr2(15 mol%), TBHP(2.0 equiv)
toluene,110 oC, 4 h
NH2
R1
+
+
R4
R4
R2
4
1
2
OMe
OMe
O
OMe
N
HN
N
HN
HN
4a, 48% yield
4b, 50% yield
4c, 49% yield
4d, 30% yield
4e, 39% yield
HN
HN
HN
HN
OMe
CF3
F
4f, 41% yield
4g, 40% yield
4h, 46% yield
4i, 43% yield
aReaction scale: 0.5 mmol of benzylamine 1, 0.3 mmol of amine 1’, 1.0 mmol of phenylacetylenes
2, 1 mL toluene. Reported yields are isolated yields.
A plausible mechanism is depicted in Scheme 2. Key intermediate methanimine A2 is generated
with the regeneration of the copper catalyst via CuBr2/TBHP initiated dehydrogenative oxidation of
primary amine 1 through the intermediate A1.15 Subsequently, the imine A3 could be produced
through two pathways:8 1) partial hydrolysis of intermediate A2 resulting in the corresponding
aldehyde, followed by a condensation reaction with another molecule of amine 1 or 1’, 2) direct
deaminative reaction of A2 with another molecule of amine 1 or 1’. Meanwhile, the copper acetylide
B2 is in situ formed from an alkyne 2 and a copper catalyst through the intermediate B1, followed
by the reaction with the imine intermediate A3, leading to the desired homo-deamination product 3
or cross-deamination product 4.
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CuII
CuII
HN
NH2
R1
R3
1 A1
1
R
B1
TBHP
R3
NH
2
CuII
R3
CuII
B2
A2
R1
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R2
HN
R1
NH2
1'
R3
R2
R2
N
R1
A3
3
4
or
Scheme 2. Mechanistic Hypothesis.
Conclusion
In summary, we have developed a novel protocol to generate a diverse array of secondary propargyl
amines starting from two amines and an alkyne. The reaction proceeds via a copper-catalyzed
aerobic deamination/alkynylation cascade, in which the [Cu]-acetylide is postulated to capture the
imine intermediate. This homo- or cross-deaminative coupling reaction complements
disconnections in traditional synthetic routes to secondary propargyl amines.
Experimental Sections
General information. Unless otherwise noted, all commercial reagents were used directly as
purchased. All work-up and purification procedures were carried out with reagent-grade solvents
that had not been pre-dried under ambient atmosphere. Thin-layer chromatography (TLC) was
performed and visualization of the compounds was accomplished with UV light (254 nm) or iodine.
Flash column chromatography was performed on silica gel (200–300 mesh).
All 1H and 13C NMR spectra were recorded on a Bruker Avance III instrument (400 MHz and 100
MHz, respectively). Chemical shifts (δ) are reported in ppm relative to the tetramethylsilane (TMS)
signal or residual protio solvent signal. Data for 1H NMR are recorded as follows: chemical shift (δ,
ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, coupling constant
(s) in Hz, integration). Data for 13C NMR is reported in terms of chemical shift (δ, ppm). High
resolution mass spectra were obtained on a Waters GC-TOFMS mass spectrometer with an electron
impact ionization (EI) probe.
General Procedure for the synthesis of secondary propargylamines 3. Amines 1 (0.8 mmol),
CuBr2 (11.16 mg, 12.5 mol%), 70% TBHP (64 mg, 0.5 mmol) and toluene (1 mL) were charged
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into a 10 mL tube along with a magnetic stir bar. The mixture was stirred in oil bath at 110 oC for
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4-5 min, then alkynes 2 (1.0 mmol) were added into the reaction system, and the resulting mixture
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o
was stirred at 110 C for another 4 h until amines 1 were completely consumed, monitoring with
9
TLC. Subsequently, the mixture was cooled to room temperature), and purified by running column
chromatography on silica gel using petroleum ether/ethyl acetate (v/v, 30:1) as eluent to afford the
desired products 3.
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General Procedure for the synthesis of secondary propargylamines 4. Benzylamine 1 (0.5
mmol), another amines (0.3 mmol), CuBr2 (10 mg, 15 mol%), 70% TBHP (77 mg, 0.6 mmol) and
toluene (1 mL) were charged into a 10 mL tube along with a magnetic stir bar. The mixture was
stirred in oil bath at 110 ℃ for 4-5 min, phenylacetylenes 2 (1.0 mmol) was then added into the
o
reaction system. After that, the reaction was performed again and refluxed at 110 C for 4 h.
Subsequently, the mixture was cooled to room temperature, and purified by running column
chromatography on silica gel using petroleum ether/ethyl acetate (v/v, 30:1-20:1) as eluent to afford
the desired products 4.
N-benzyl-1, 3-diphenylprop-2-yn-1-amine (3a)16. yellow oil; 94.1 mg; 79% yield. 1H NMR (400
MHz, CDCl3) δ 7.62–7.60 (m, 2H), 7.50–7.47 (m, 2H), 7.44–7.27 (m, 10H), 7.27–7.21 (m, 1H),
4.80 (s, 1H), 4.09–3.86 (m, 2H), 1.77 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.4, 139.9,
131.8, 128.6, 128.5, 128.3, 128.2, 127.8, 127.7, 127.1, 123.2, 89.3, 85.8, 77.4, 53.7, 51.2.
N-(2-methylbenzyl)-3-phenyl-1-(o-tolyl)prop-2-yn-1-amine (3b). yellow oil; 113.2 mg; 87%
yield. 1H NMR (400 MHz, CDCl3) δ 7.82–7.67 (m, 1H), 7.57–7.43 (m, 2H), 7.41–7.26 (m, 4H),
7.24–7.18 (m, 2H), 7.18–7.15 (m, 4H), 4.93 (s, 1H), 4.07 (d, J = 12.6 Hz, 1H), 3.94 (d, J = 12.6 Hz,
1H), 2.38 (d, J = 7.0 Hz, 6H), 1.53 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.3, 137.8, 137.0,
136.4, 131.8, 130.7, 130.4, 129.3, 128.4, 128.2, 127.8, 127.5, 127.3, 126.1, 125.9, 123.4, 89.6, 85.7,
51.5, 49.5, 19.0, 18.9. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found 325.1828.
N-(3-methylbenzyl)-3-phenyl-1-(m-tolyl)prop-2-yn-1-amine (3c). milk white oil; 82.0 mg; 63%
yield. 1H NMR (400 MHz, CDCl3) δ 7.57–7.55 (m, 2H), 7.46 (s, 2H), 7.40–7.35 (m, 3H), 7.34–7.25
(m, 4H), 7.18–7.12 (m, 2H), 4.85 (s, 1H), 4.10–3.93 (m, 2H), 3.04 (s, 1H), 2.41 (d, J = 9.5 Hz, 6H).
13C{1H} NMR (100 MHz, CDCl3) δ 139.6, 138.9, 138.3, 138.1, 131.8, 129.4, 128.8, 128.5, 128.5,
128.4, 128.3, 128.3, 128.1, 125.7, 124.9, 123.2, 88.8, 86.1, 53.7, 51.0, 21.5, 21.4. HRMS (EI) m/z
calcd for C24H23N [M]+ 325.1830, found 325.1829.
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N-(4-methylbenzyl)-3-phenyl-1-(p-tolyl)prop-2-yn-1-amine (3d). milk white oil; 105.0 mg; 81%
yield. 1H NMR (400 MHz, CDCl3) δ 7.59–7.51 (m, 4H), 7.40–7.35 (m, 5H), 7.26–7.21 (m, 4H),
4.83 (s, 1H), 4.06–3.97 (m, 2H), 2.42 (d, J = 5.0 Hz, 6H), 1.95 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 137.5, 137.4, 136.8, 136.6, 131.8, 129.2, 129.1, 128.4, 128.3, 128.1, 127.6, 123.3, 89.6,
85.5, 53.3, 50.8, 21.1, 21.1. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found 325.1830.
N-(3-methoxybenzyl)-1-(3-methoxyphenyl)-3-phenylprop-2-yn-1-amine (3e). milk white oil;
81.4 mg; 57% yield. 1H NMR (400 MHz, CDCl3) δ 7.58–7.52 (m, 2H), 7.41–7.29 (m, 5H), 7.29–
7.24 (m, 2H), 7.09–7.02 (m, 2H), 6.94–6.84 (m, 2H), 4.86 (s, 1H), 4.08–4.00 (m, 2H), 3.88 (d, J =
7.8 Hz, 6H), 2.15 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.8, 141.8, 141.3, 131.8, 129.5,
129.4, 128.3, 128.2, 123.1, 120.8, 120.1, 113.9, 113.4, 112.7, 89.1, 85.8, 55.3, 55.2, 53.6, 51.1.
HRMS (EI) m/z calcd for C24H23NO2 [M]+ 357.1729, found 357.1728.
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N-(2-chlorobenzyl)-1-(2-chlorophenyl)-3-phenylprop-2-yn-1-amine (3g). yellow oil; 86.6 mg;
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59% yield. H NMR (400 MHz, CDCl3) δ 7.86–7.83 (m, 1H), 7.50–7.47 (m, 3H), 7.38–7.30 (m,
6H), 7.25–7.18 (m, 3H), 5.22 (s, 1H), 4.14 (d, J = 13.5 Hz, 1H), 4.05 (d, J = 13.5 Hz, 1H), 2.04 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 137.6, 137.0, 134.1, 133.4, 131.8, 131.8, 130.7, 129.8,
129.5, 129.2, 128.6, 128.3, 127.7, 127.2, 126.9, 123.0, 88.2, 85.7, 51.3, 49.2. HRMS (EI) m/z calcd
for C22H17Cl2N [M]+ 365.0738, found 365.0730.
N-(4-chlorobenzyl)-1-(4-chlorophenyl)-3-phenylprop-2-yn-1-amine (3h). yellow soild; 102.3
mg; 70% yield; MP: 64.1–67.2 oC. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 8.4 Hz, 2H), 7.49–
7.46 (m, 2H), 7.35–7.30 (m, 7H), 7.30–7.26 (m, 2H), 4.73 (s, 1H), 3.93 (d, J = 9.8 Hz, 2H), 1.74 (s,
1H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.8, 138.2, 133.6, 132.9, 131.8, 129.8, 129.1, 128.7,
128.6, 128.5, 128.4, 122.9, 88.5, 86.3, 53.0, 50.4. HRMS (EI) m/z calcd for C22H17Cl2N [M]+
365.0738, found 365.0726.
N-(4-bromobenzyl)-1-(4-bromophenyl)-3-phenylprop-2-yn-1-amine (3i). white soild; 110.4 mg;
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61% yield; MP: 86.8–87.6 C. 1H NMR (400 MHz, CDCl3) δ 7.58–7.39 (m, 8H), 7.35–7.32 (m,
3H), 7.29–7.22 (m, 2H), 4.72 (s, 1H), 3.92 (d, J = 10.8 Hz, 2H), 1.78 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 139.2, 138.6, 131.8, 131.6, 131.6, 130.2, 129.4, 128.5, 128.4, 122.8, 121.8, 121.0,
88.3, 86.4, 53.0, 50.4. HRMS (EI) m/z calcd for C22H17Br2N [M]+ 452.9728, found 452.9729.
N-(4-fluorobenzyl)-1-(4-fluorophenyl)-3-phenylprop-2-yn-1-amine (3j). colorless oil; 96.0 mg;
72% yield. 1H NMR (400 MHz, CDCl3) δ 7.60–7.55 (m, 2H), 7.54–7.44 (m, 2H), 7.39–7.30 (m,
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5H), 7.09–6.98 (m, 4H), 4.75 (s, 1H), 4.02–3.87 (m, 2H), 1.77 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3) δ 163.6, 163.3, 161.0 (d, J C, F = 30.9 HZ), 136.1 (d, J C, F = 2.5 HZ), 135.5 (d, J C, F = 2.7
HZ), 131.8, 130.0 (d, J C, F = 7.8 HZ), 129.3 (d, J C, F =8.1 HZ), 128.4, 123.0, 115.4 (d, J C, F = 5.7
HZ), 115.2 (d, J C, F = 5.5 HZ), 88.8, 86.1, 52.9, 50.4. HRMS (EI) m/z calcd for C22H17F2N [M]+
333.1329, found 333.1327.
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1-cyclohexyl-N-(cyclohexylmethyl)-3-phenylprop-2-yn-1-amine (3k). yellow oil; 70.2 mg; 57%
yield. 1H NMR (400 MHz, CDCl3) δ 7.44–7.41 (m, 2H), 7.32–7.27 (m, 3H), 3.36 (d, J = 5.7 Hz,
1H), 2.75–2.70 (m, 1H), 2.51–2.46 (m, 1H), 1.78–1.56 (m, 8H), 1.55–1.39 (m, 3H), 1.33–1.15 (m,
10H), 0.99–0.88 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 131.9, 128.8, 128.4, 122.0, 56.4,
52.7, 40.3, 35.1, 31.2, 30.4, 30.1, 27.9, 26.1, 26.0, 25.8, 25.6, 25.5. HRMS (EI) m/z calcd for
C22H31N [M]+ 309.2457, found 309.2450.
N-benzyl-N-methyl-1, 3-diphenylprop-2-yn-1-amine (3n)17. yellow oil; 82.1 mg; 66% yield. 1H
NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.7 Hz, 2H), 7.58–7.56 (m, 2H), 7.42 (d, J = 7.2 Hz, 2H),
7.39–7.22 (m, 9H), 4.92 (s, 1H), 3.73 (d, J = 13.1 Hz, 1H), 3.64 (d, J = 13.1 Hz, 1H), 2.24 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 139.4, 139.1, 132.0, 129.1, 128.4, 128.4, 128.3, 128.2, 127.6,
127.2, 123.4, 88.8, 84.8, 77.4, 59.7, 59.0, 38.1.
N-benzyl-1-phenyl-3-(m-tolyl)prop-2-yn-1-amine (3aa)18. colorless oil; 109.5 mg; 88% yield. 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.40 (d, J = 7.3 Hz, 2H), 7.37–7.26 (m, 7H),
7.26–7.21 (m, 1H), 7.20–7.14 (m, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.78 (s, 1H), 4.04–3.89 (m, 2H),
2.31 (s, 3H), 1.79 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.6, 140.0, 138.1, 132.5, 129.2,
129.0, 128.6, 128.6, 128.6, 128.3, 127.9, 127.8, 127.2, 123.1,89.1, 86.5, 53.8, 51.3, 21.3.
N-benzyl-1-phenyl-3-(p-tolyl)prop-2-yn-1-amine (3ab). colorless oil; 102.5 mg; 82% yield. 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.3 Hz, 2H), 7.43–7.37 (m, 3H), 7.37–7.19 (m, 7H), 7.10
(d, J = 7.9 Hz, 2H), 4.78 (s, 1H), 4.03–3.92 (m, 2H), 2.32 (s, 3H), 1.77 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 140.6, 140.0, 138.3, 131.7, 129.1, 128.6, 128.5, 127.8, 127.1, 120.2, 88.6, 85.9, ,
53.8, 51.2, 21.5. HRMS (EI) m/z calcd for C23H21N [M]+ 311.1674, found 311.1673.
N-benzyl-3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-amine (3ac)18. colorless oil; 117.8 mg; 90%
yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.43–7.37 (m, 4H), 7.36–7.21 (m,
6H), 6.86–6.78 (m, 2H), 4.78 (s, 1H), 4.03–3.91 (m, 2H), 3.76 (s, 3H), 2.21 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 159.6, 140.6, 139.9, 133.2, 128.6, 128.5, 128.5, 127.8, 127.7, 127.1, 115.4,
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N-benzyl-3-(4-ethylphenyl)-1-phenylprop-2-yn-1-amine (3ad). yellow oil; 102.8 mg; 79% yield.
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz, 2H), 7.44–7.19 (m, 10H), 7.13 (d, J = 8.1 Hz,
2H), 4.78 (s, 1H), 4.05–3.89 (m, 2H), 2.64–2.59 (m, 2H), 1.80 (s, 1H), 1.23–1.19 (m, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 144.7, 140.6, 140.0, 131.9, 128.6, 128.6, 128.6, 128.0, 127.8, 127.2,
120.5, 88.7, 86.1, 53.8, 51.3, 29.0, 15.6. HRMS (EI) m/z calcd for C24H23N [M]+ 325.1830, found
325.1829.
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N-benzyl-3-(4-butylphenyl)-1-phenylprop-2-yn-1-amine (3ae). yellow oil; 122.9 mg; 87% yield.
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.7 Hz, 2H), 7.41–7.38 (m, 4H), 7.37–7.19 (m, 6H), 7.11
(d, J = 7.9 Hz, 2H), 4.78 (s, 1H), 4.08–3.89 (m, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.77 (s, 1H), 1.64–
1.48 (m, 2H), 1.37–1.28 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
143.4, 140.7, 140.1, 131.8, 128.6, 128.6, 128.6, 128.5, 127.8, 127.2, 120.5, 88.7, 86.1, 53.8, 51.3,
35.7, 33.5, 22.4, 14.1. HRMS (EI) m/z calcd for C26H27N [M]+ 353.2143, found 353.2143.
N-benzyl-3-(4-(tert-butyl)phenyl)-1-phenylprop-2-yn-1-amine (3af). yellow oil; 121.5 mg; 86%
yield. 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J =
7.4 Hz, 2H), 7.37–7.18 (m, 8H), 4.79 (s, 1H), 4.07–3.91 (m, 2H), 1.77 (s, 1H), 1.30 (s, 9H). 13C{1H}
NMR (100 MHz, CDCl3) δ 151.5, 140.6, 140.1, 131.6, 128.6, 128.5, 127.8, 127.2, 125.4, 120.3,
88.7, 86.0, 53.8, 51.3, 34.8, 31.3. HRMS (EI) m/z calcd for C26H27N [M]+ 353.2143, found 353.2145.
N-benzyl-3-(4-pentylphenyl)-1-phenylprop-2-yn-1-amine (3ag). yellow oil; 125.8 mg; 86%
yield. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.4 Hz, 2H), 7.41–7.38 (m, 4H), 7.36–7.21 (m,
6H), 7.12 (d, J = 8.0 Hz, 2H), 4.78 (s, 1H), 4.08–3.89 (m, 2H), 2.68–2.47 (m, 2H), 1.77 (s, 1H),
1.68–1.47 (m, 2H), 1.36–1.21 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 143.4, 140.6, 140.0, 131.8, 128.6, 128.6, 128.5, 127.8, 127.2, 120.5, 88.7, 86.1, 53.8, 51.3, 36.0,
31.5, 31.1, 22.7, 14.2. HRMS (EI) m/z calcd for C27H29N [M]+ 367.2300, found 367.2303.
N-benzyl-3-(4-chlorophenyl)-1-phenylprop-2-yn-1-amine (3ah). colorless oil; 97.1 mg; 73%
yield. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.4 Hz, 2H), 7.42–7.21 (m, 12H), 4.78 (s, 1H),
4.03–3.88 (m, 2H), 1.84 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.2, 139.8, 134.3, 133.1,
128.7, 128.7, 128.6, 128.5, 128.0, 127.7, 127.2, 121.7, 90.4, 84.7, 53.7, 51.3. HRMS (EI) m/z calcd
for C22H18ClN [M]+ 331.1128, found 331.1124.
N-benzyl-3-(2-fluorophenyl)-1-phenylprop-2-yn-1-amine (3ai). Colorless oil; 92.5 mg; 73%
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yield. 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 2H), 7.50–7.24 (m, 10H), 7.11–7.06 (m,
2H), 4.83 (s, 1H), 4.08–3.95 (m, 2H), 1.80 (s, 1H).13C{1H} NMR (100 MHz, CDCl3) δ 164.3, 161.8,
139.8 (d, J C, F = 21.4 HZ), 133.6, 129.9 (d, J C, F = 7.9 HZ), 128.6, 128.5, 128.5, 127.9, 127.7, 127.1,
123.9 (d, J C, F = 37.1 HZ), 115.5 (d, J C, F = 20.8 HZ), 111.8 (d, J C, F = 16.7 HZ), 94.6 (d, J C, F = 3.0
HZ), 79.3, 53.8, 51.1. HRMS (EI) m/z calcd for C22H18FN [M]+ 315.1423, found 315.1422.
N-benzyl-3-(3-fluorophenyl)-1-phenylprop-2-yn-1-amine (3aj). yellow oil; 98.2 mg; 78% yield.
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.5 Hz, 2H), 7.40–7.29 (m, 7H), 7.27–7.21 (m, 3H), 7.17
(d, J = 8.8 Hz, 1H), 7.03–6.95 (m, 1H), 4.78 (s, 1H), 4.05–3.86 (m, 2H), 1.79 (s, 1H). 13C{1H} NMR
(100 MHz, CDCl3) δ 163.7, 161.2, 140.0 (d, J C, F = 35.5 HZ), 130.0 (d, J C, F = 8.5 HZ), 128.7,
128.6, 128.5, 128.0, 127.8, 127.7, 127.2, 125.1 (d, J C, F = 9.5 HZ), 118.7 (d, J C, F = 22.6 HZ), 115.6
(d, J C, F = 21.0 HZ), 90.5, 84.6 (d, J C, F = 3.3 HZ), 53.7, 51.3. HRMS (EI) m/z calcd for C22H18FN
[M]+ 315.1423, found 315.1421.
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N-benzyl-3-(4-fluorophenyl)-1-phenylprop-2-yn-1-amine (3ak). yellow oil; 89.5 mg; 71% yield.
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.7 Hz, 2H), 7.46–7.43 (m, 2H), 7.40–7.23 (m, 8H), 6.99
(t, J = 8.5 Hz, 2H), 4.78 (s, 1H), 4.04–3.86 (m, 2H), 1.86 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3)
δ 163.7, 161.3, 140.1 (d, J C, F = 50.3 HZ), 133.6 (d, J C, F = 8.2 HZ), 128.6, 128.5, 128.4, 127.8,
127.7, 127.2, 119.3 (d, J C, F = 3.5 HZ), 115.6 (d, J C, F = 21.9 HZ), 89.0, 84.7, 53.7, 51.2. HRMS
(EI) m/z calcd for C22H18FN [M]+ 315.1423, found 315.1420.
N-benzyl-1-phenyl-3-(2-(trifluoromethyl)phenyl)prop-2-yn-1-amine (3al). yellow oil; 74.5 mg;
51% yield. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.8 Hz, 1H), 7.64–7.59 (m, 3H), 7.48 (t, J =
7.4 Hz, 1H), 7.43–7.25 (m, 9H), 4.84 (s, 1H), 4.11–3.96 (m, 2H), 1.79 (s, 1H). 13C{1H} NMR (100
MHz, CDCl3) δ 140.0, 139.9, 134.3, 131.4, 128.5, 128.5, 128.0, 127.9, 127.7, 127.1, 126.5, 125.9
(q, J C, F = 15.1 HZ), 125.1, 122.4, 121.5 (dd, J C, F = 6.0 HZ), 95.4, 81.8, 53.8, 51.1. HRMS (EI) m/z
calcd for C23H18F3N [M]+ 365.1391, found 365.1390.
N-benzyl-1-phenyl-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-amine (3am). yellow oil; 122.1
mg; 84% yield. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.63–7.58 (m, 3H), 7.53 (d, J = 7.9 Hz,
1H), 7.42–7.34 (m, 6H), 7.33–7.29 (m, 2H), 7.28–7.23 (m, 1H), 4.80 (s, 1H), 4.05–3.92 (m, 2H),
1.82 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.1, 139.8, 135.0, 131.0 (d, J C, F = 32.4 HZ),
128.9, 128.7, 128.6, 128.5, 128.0, 127.7, 127.3, 125.2, 124.8 (q, J C, F =10.9 HZ), 124.2, 122.5, 91.2,
84.3, 53.7, 51.3. HRMS (EI) m/z calcd for C23H18F3N [M]+ 365.1391, found 365.1393.
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N-benzyl-1-phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-amine (3an). colorless oil; 98.1
mg; 67% yield. 1H NMR (400 MHz, CDCl3) δ 7.63–7.53 (m, 6H), 7.41–7.31 (m, 7H), 7.30–7.24
(m, 1H), 4.81 (s, 1H), 4.08–3.88 (m, 2H), 1.81 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.0,
139.7, 132.1, 130.2 (d, J C, F = 32.8 HZ), 128.7, 128.6, 128.5, 128.0, 127.7, 127.3, 127.0, 125.4-
125.2 (m), 122.7, 92.0, 84.5, 53.7, 51.3. HRMS (EI) m/z calcd for C23H18F3N [M]+ 365.1391, found
365.1391.
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N-(1,3-diphenylprop-2-yn-1-yl)butan-1-amine (4a)19. yellow oil; 38.2 mg; 48% yield. 1H NMR
(400 MHz, CDCl3) δ 7.59 (d, J = 7.3 Hz, 2H), 7.48–7.45 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.34–
7.28 (m, 4H), 4.80 (s, 1H), 2.93–2.79 (m, 1H), 2.79–2.64 (m, 1H), 1.61 (s, 1H), 1.57–1.46 (m, 2H),
1.41–1.35 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.7, 131.7, 128.5,
128.2, 128.1, 127.7, 127.6, 123.3, 89.7, 85.3, 54.8, 47.0, 32.1, 20.5, 14.0.
N-(3, 4-dimethoxybenzyl)-1, 3-diphenylprop-2-yn-1-amine (4b). yellow oil; 53.6 mg; 50% yield.
1H NMR (400 MHz, CDCl3) δ 7.70–7.61 (m, 2H), 7.54 (d, J = 3.4 Hz, 2H), 7.46–7.31 (m, 6H),
6.96–7.01 (m, 2H), 6.85–6.88 (m, 1H), 4.83 (d, J = 3.4 Hz, 1H), 3.98 (s, 2H), 3.90–3.94 (m, 6H),
1.78 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 149.1, 148.3, 140.5, 132.5, 131.7, 128.5, 128.3,
128.2, 127.7, 127.6, 123.2, 120.6, 111.8, 111.3, 89.3, 85.7, 56.0, 55.9, 53.6, 51.0. HRMS (EI) m/z
calcd for C24H23NO2 [M]+ 357.1729, found 357.1728.
N-(3-methoxyphenethyl)-1, 3-diphenylprop-2-yn-1-amine (4c). yellow oil; 50.1 mg; 49% yield.
1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.2 Hz, 2H), 7.49–7.42 (m, 2H), 7.36 (t, J = 7.3 Hz, 2H),
7.31–7.27 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.79–6.67 (m, 2H), 4.83 (s,
1H), 3.76 (s, 3H), 3.16–3.09 (m, 1H), 3.04–2.98 (m, 1H), 2.90–2.77 (m, 2H), 1.58 (s, 1H). 13C{1H}
NMR (100 MHz, CDCl3) δ 159.7, 141.5, 140.4, 131.7, 129.4, 128.5, 128.3, 128.1, 127.7, 127.6,
123.1, 121.2, 114.4, 111.6, 89.3, 85.4, 55.1, 54.6, 48.2, 36.3. HRMS (EI) m/z calcd for C24H23NO
[M]+ 341.1780, found 341.1778.
1-(1, 3-diphenylprop-2-yn-1-yl)pyrrolidine (4d)17. yellow oil; 23.0 mg; 30% yield. 1H NMR (400
MHz, CDCl3) δ 7.61 (d, J = 7.2 Hz, 2H), 7.48 (d, J = 1.5 Hz, 2H), 7.38–7.31 (m, 6H), 4.88 (s, 1H),
2.69 (s, 4H), 1.80 (s, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 139.2, 131.8, 128.4, 128.3, 128.1,
128.0, 127.7, 123.2, 87.0, 86.8, 59.1, 50.2, 23.5.
4-(1, 3-diphenylprop-2-yn-1-yl)morpholine (4e)17. yellow oil; 32.3 mg; 39% yield. 1H NMR (400
MHz, CDCl3) δ 7.63 (d, J = 7.3 Hz, 2H), 7.54–7.48 (m, 2H), 7.39–7.29 (m, 6H), 4.79 (s, 1H), 3.79–
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3.66 (m, 4H), 2.63 (d, J = 4.0 Hz, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ 137.9, 131.8, 128.6,
128.3, 128.3, 128.2, 127.8, 123.0, 88.5, 85.1, 67.2, 62.1, 49.9.
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N-(1-(4-fluorophenyl)-3-phenylprop-2-yn-1-yl)butan-1-amine (4f)19. yellow oil; 35.2 mg; 41%
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yield. H NMR (400 MHz, CDCl3) δ 7.62–7.52 (m, 2H), 7.47–7.45 (m, 2H), 7.41–7.27 (m, 4H),
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7.05 (t, J = 8.7 Hz, 1H), 4.79 (d, J = 8.0 Hz, 1H), 2.90–2.78 (m, 1H), 2.76–2.65 (m, 1H), 1.58–1.45
(m, 3H), 1.38 (t, J = 11.1 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
162.3 (d, J C, F = 244.3 HZ), 136.5 (d, J C, F = 3.0 HZ), 131.7, 129.2 (d, J C, F = 8.1 HZ), 128.3, 127.6,
123.1, 115.2 (d, J C, F = 21.3 HZ), 89.3, 85.5, 54.0, 47.0, 32.1, 20.5, 14.0.
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N-(3-phenyl-1-(o-tolyl)prop-2-yn-1-yl)butan-1-amine (4g). yellow oil; 33.3 mg; 40% yield. H
NMR (400 MHz, CDCl3) δ 7.70–7.64 (m, 1H), 7.48–7.42 (m, 2H), 7.32–7.27 (m, 3H), 7.24–7.14
(m, 3H), 4.90 (s, 1H), 2.99–2.87 (m, 1H), 2.79–2.66 (m, 1H), 2.47 (s, 3H), 1.54–1.50 (m, 3H), 1.42–
1.34 (m, 2H), 0.92 (d, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 138.7, 136.1, 131.7,
130.7, 128.2, 128.0, 127.6, 127.2, 126.1, 123.4, 89.8, 84.9, 52.0, 47.6, 32.2, 20.6, 19.0, 14.0. HRMS
(EI) m/z calcd for C20H23N [M]+ 277.1830, found 277.1829.
N-(1-phenyl-3-(3-(trifluoromethyl)phenyl)prop-2-yn-1-yl)butan-1-amine (4h). yellow oil; 46.2
mg; 46% yield. 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2
Hz, 3H), 7.44 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.32 (d, J = 7.2 Hz, 1H), 4.80 (s, 1H),
2.88–2.82 (m, 1H), 2.75–2.68 (m, 1H), 1.58 (s, 1H), 1.56–1.48 (m, 2H), 1.42–1.35 (m, 2H), 0.92 (t,
J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 140.3, 134.8 (d, J C, F = 0.8 HZ), 130.9 (d, J
C, F = 32.5 HZ), 128.8, 128.6, 128.5, 128.5, 127.8, 127.5, 124.7 (dd, J C, F = 7.1 HZ), 124.2, 91.4,
83.7, 54.7, 47.1, 32.1, 20.5, 14.0. HRMS (EI) m/z calcd for C20H20F3N [M]+ 331.1548, found
331.1551.
N-(3-(4-methoxyphenyl)-1-phenylprop-2-yn-1-yl)butan-1-amine (4i). yellow oil; 37.8 mg, 43%
1
yield. H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.3 Hz, 2H), 7.40–7.36 (m, 3H), 7.33–7.27(m,
2H), 6.84 (d, J = 2.7 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.78 (s, 1H), 3.80 (s, 3H), 2.87–2.81 (m,
1H), 2.74–2.67 (m, 1H), 1.54–1.49 (m, 3H), 1.43–1.34 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 159.5, 140.9, 133.1, 128.5, 128.4, 128.4, 127.6, 113.9, 88.1, 85.1, 55.3,
54.8, 47.1, 32.1, 20.5, 14.0. HRMS (EI) m/z calcd for C20H23NO [M]+ 293.1780, found 293.1776.
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
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NMR spectra for compounds 3a−3e, 3g−3k, 3n, 3aa−3an, 4a-4i (PDF)
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Author Information
Corresponding Authors
*E-mail: hdfeng@sues.edu.cn.
ORCID
Huangdi Feng: 0000-0002-5500-8283
Notes
The authors declare no competing financial interest.
Acknowledgements
The authors would like to thank Hua Wei for assistance. This research was supported by the
Innovation Research Projects of Shanghai University of Engineering Science (201810856017,
cs1704006, A1-0601-19-01017), and the Opening Project of Shanghai Key Laboratory of Chemical
Biology for financial support. We also acknowledge the support of the RUDN University Program
5-100.
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