Efficient one-pot synthesis of propargylamines from Mannich bases through a retro-Mannich-type fragmentation

Article abstract of DOI:10.1055/s-0032-1316862

An efficient one-pot synthesis of propargylamines is achieved by copper-catalyzed coupling of phenylacetylenes with Mannich bases through a chlorine(1+) or bromine(1+) ion-initiated retro-Mannich-type fragmentation under mild conditions. The Mannich bases are easily prepared from an electron-rich phenol, formaldehyde, and an amine. The protocol provides an appealing alternative for the construction of propargylamines by a simple one-pot procedure. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1316862

952▌
PAPER
paper
Efficient One-Pot Synthesis of Propargylamines from Mannich Bases through
a Retro-Mannich-Type Fragmentation
One-Pot Synthesis of Propargylamines
Yefeng Zhu, Huishuang Zhao, Yunyang Wei*
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P. R. of China
Fax +86(25)84317078; E-mail: ywei@mail.njust.edu.cn
Received: 16.01.2013; Accepted after revision: 06.02.2013
organometallic reagents. The development of a new and
Abstract: An efficient one-pot synthesis of propargylamines is
efficient method for this synthesis is therefore an interest-
achieved by copper-catalyzed coupling of phenylacetylenes with
ing challenge.
Mannich bases through a chlorine(1+) or bromine(1+) ion-initiated
retro-Mannich-type fragmentation under mild conditions. The
Mannich bases are easily prepared from an electron-rich phenol,
formaldehyde, and an amine. The protocol provides an appealing al-
attracted a great deal of attention because of its high effi-
ternative for the construction of propargylamines by a simple one-
pot procedure.
The three-component coupling reaction of aldehydes, al-
kynes, and amines (the A3 coupling reaction) has recently
ciency and simple operations. Various A3 coupling reac-
tions have been reported to occur under homogeneous7 or
Key words: copper, catalysis, coupling, Mannich bases, alkynes,
amines
heterogeneous conditions.8 In addition, the catalytic enan-
tioselective addition of terminal alkynes to imines or en-
amines has been developed for the synthesis of chiral
propargylamines.9 The copper- and iron-catalyzed direct
The propargylamine group is a common skeletal motif in
oxidative alkynylation of C–H bonds in tertiary amines
various nitrogen-containing compounds, and propargyl-
has recently been shown to provide an attractive approach
amines are versatile synthetic intermediates for the syn-
to the synthesis of propargylamines. Iminium ions are
thesis of a variety of natural products.1,2 As a result, the
considered to be the key intermediates in these transfor-
synthesis of propargylamines has attracted considerable
mations. Generally, iminium ions are generated from al-
interest, and a number of methods have been devised.
dehydes
and
amines
or
through
oxidative
Propargylamines are usually synthesized by amination of
propargylic halides,3 propargylic phosphates,4 or propar-
gylic triflates,5 or through the reaction of lithium
acetylides or Grignard reagents with imines or their deriv-
atives.6 Such reactions require strictly controlled condi-
tions or the use of stoichiometric amounts of
dehydrogenation of tertiary amines10 in situ with an oxi-
dant such as tert-butyl hydroperoxide,11 N-bromosuccin-
imide,12 or di-tert-butyl peroxide.13 In 2010, Nakamura
and co-workers reported a copper-catalyzed substitution
reaction for the construction of propargylic amines in
which the iminium ions are generated through a C(sp)–
R1
N
Me
R2
OH
R1
R2
oxidant
CH2
N
R2
N
R1
previous work
this work
iminium ion
H
N
R2
[M]
R1
[M] = Cu, Fe, etc.
R1
N
R2
Scheme 1 Reactions of terminal alkynes with iminium ion intermediates
SYNTHESIS 2013, 45, 0952–0958
Advanced online publication: 27.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316862; Art ID: SS-2012-H0052-OP
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of Propargylamines
953
C(sp3) bond-cleavage reaction.14 More recently, they suc- In this transformation, an internal oxidant in the molecule
cessfully synthesized N-tethered 1,6-enynes by a zinc(II)- of the starting materials is used to provide the reactive im-
catalyzed redox dehydrogenative cross-coupling reaction. inium intermediate.
Table 1 Optimization of the Reaction Conditionsa
OH
Me
Me
N
[Cu], oxidant, base
solvent, 110 °C
N
+
Me
Me
1a
2a
3aa
Entry
Metal ion source
Oxidant
Base
Solvent
Yieldb (%)
1
2
CuI
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
–
NaHCO3
NaHCO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
61
68
71
82
63
0
CuBr
3
CuCl
NaHCO3
NaHCO3
4
CuCl2·2H2O
Cu(OAc)2·H2O
FeCl3
5
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
–
6
7
Co(acac)2
NiCl2·4H2O
Ni(OAc)2·2H2O
Pd(OAc)2
CuCl2·2H2O
CuCl2·2H2O
–
0
8
0
9
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26d
27
0
0
NCS
NCS
NBS
t-BuOOHc
(t-BuO)2
PhI(OAc)2
I2
0
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
NaOAc
Et3N
0
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2·2H2O
CuCl2
38
56
0
0
0
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
36
52
0
pyridine
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
0
0
H2O
0
1,4-dioxane
toluene
toluene
61
53
82
a Reaction conditions: [Cu] (20 mmol%), alkyne 1a (0.2 mmol), Mannich base 2a (0.3 mmol), oxidant (0.6 mmol), base (0.6 mmol), solvent
(2.0 mL), 110 °C, 6 h, under N2.
b Isolated yield based on 1a.
c 70% in H2O.
d Temperature 90 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 952–958

954
Y. Zhu et al.
PAPER
Here, we report an efficient copper-catalyzed coupling re- Therefore, the more inexpensive sodium bicarbonate was
action of phenylacetylene with a Mannich base under mild chosen for subsequent studies. Control experiments
conditions, in which iminium ions were generated in situ showed that the presence of an oxidant and a base was cru-
through a chlorine(1+) or bromine(1+) ion-initiated retro- cial for the reaction, and no product was detected in the
Mannich-type fragmentation (Scheme 1).15
absence of either the oxidant or the base (entries 11 and
12). We also tested the effects of various solvents on the
reaction (entries 23–25). Of the tested solvents, toluene
gave the best results (entry 4). Temperatures below than
110 °C dramatically decreased the reaction rate and con-
version (entry 26).
As part of our continued interest in investigating copper-
catalyzed coupling reactions,16 we found that the propar-
gylamine 3aa was obtained when phenylacetylene (1a)
was treated with Mannich base 2a in the presence of cop-
per(II) chloride dihydrate, N-chlorosuccinimide, and sodi-
um bicarbonate (Table 1, entry 4). This prompted us to To evaluate the potential of various Mannich bases in the
develop a new method for the synthesis of propargyl- reaction, other phenol-derived Mannich bases (2b–e)
amines from alkynes and Mannich bases.
were subjected to the reaction conditions optimized for
2a. As shown in Scheme 2, only the electron-rich
We selected phenylacetylene (1a) and Mannich base 2a as
model substrates for optimization of the reaction condi-
tions. In our preliminary studies, we were pleased to find
that when we used toluene as the solvent, N-chlorosuccin-
imide as the oxidant, and sodium bicarbonate as the base,
phenylacetylene (1a) reacted with Mannich base 2a at
110 °C in the presence of catalytic amount of copper(I) io-
dide to afford the propargylamine 3aa in 61% yield (Table
1, entry 1). By screening various metal compounds, we
found that copper salts are effective catalysts for the reac-
tion, and that copper(II) chloride dihydrate showed the
best catalytic activity, giving an 82% yield (entries 1–5).
Other metal salts including salts of iron, cobalt, nickel, or
palladium were not effective in this transformation (en-
tries 6–10). No product was detected in the absence of a
catalyst (entry 13).
Me
N
O
R =
R =
R =
R =
N
Me
2a
Et
2i
Me
N
N
OH
Ph
2j
Et
2f
R
Et
R =
R =
R =
R =
N
N
Ph
2k
2g
N
N
N Ph
2h
2l
Next, we examined various oxidants, bases, and solvents
with copper(II) chloride dihydrate as the catalyst. We
found that other oxidants, including N-bromosuccinimide,
tert-butyl hydroperoxide di-tert-butyl peroxide, (diacet-
oxyiodo)benzene, and iodine were either ineffective or
less effective than N-chlorosuccinimide (entries 14–18).
Investigation of a variety of bases revealed that sodium bi-
carbonate gave the best yield, whereas only trace amounts
of the product were detected when organic bases such as
triethylamine or pyridine were used (entries 19–22).
OH
OH
N
N
2m
Scheme 3 Various Mannich bases used in the reaction
OH
OH
Me
R1
R2
N
R1
Me
CuCl2·2H2O (20 mmol%)
N
Me
+
NaHCO3, NCS
PhMe, 110 °C, 6 h
or
Me
Me
R2
N
1a
2a–e
3aa–ae
Me
OH
OH
OH
OH
OH
Me
Me
N
N
Cl
Me
Me
N
N
Me
Me
Me
Me
Me
Cl
N
NO2
Me
2a
2b
47%
2c
0%
2d
0%
2e
63%
82%
Scheme 2 Results of copper-catalyzed coupling reactions of phenylacetylene and various Mannich bases
Synthesis 2013, 45, 952–958
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Propargylamines
955
Mannich bases 2b and 2e gave the corresponding propar- Having determined the optimal reaction conditions, we
gylamines; products 3ab and 3ae were obtained in yields extended our studies to various combinations of alkynes
of 47% and 82%, respectively. Electron-deficient 1a–e and 2,4-di-tert-butylphenol-type Mannich bases 2a
Mannich bases were ineffective, which clearly showed and 2f–m (Scheme 3). As shown in Scheme 4, most
that electronic effects are crucial to the reaction. The po- Mannich bases with cyclic, heterocyclic, or acyclic sec-
sition of the substituent groups also affected the reaction ondary aliphatic amine groups gave good yields of the
rate. When Mannich base 2e was used, product 3ae was corresponding products under the optimized conditions,
obtained in lower yield than that obtained from 2a. We the highest yields being obtained from Mannich base 2i.
therefore chose 2,4-di-tert-butylphenol-type Mannich When Mannich base 2l was used, only traces of the corre-
bases for our further studies on the reaction.
sponding product were obtained. It is noteworthy that
when N-bromosuccinimide was used instead of N-chloro-
OH
R1
N
R1
R1
N
R1
CuCl2·2H2O (20 mmol%)
+
R2
R2
NaHCO3, NCS
PhMe, 110 °C, 6 h
1a–e
3
2a,f–m
Me
N
Et
N
N
Me
Et
3aa, 82%
3af, 73%
3ai, 80%
3di, 71%
3ag, 76%
N
N
N
O
O
3ah, 71%
3bi, 82%
Me
N
N
N
O
O
Ph
MeO
F
3ci, 85%
3aj, 0%
Et
N
N
N
Ph
N
N
Br
Br
3ak, 0%
3al, 78%
3bl, 81%
N
N
N
N
F
Br
3dl, 81%
3am, 21%
Me
O
N
N
Me
3ea, < 5%
3ei, < 5%
Scheme 4 Results of copper-catalyzed coupling reactions of alkynes with 2,4-di-tert-butylphenol-type Mannich bases. Reagents and condi-
tions: CuCl2·2H2O (20 mmol%), aromatic alkyne (0.2 mmol), Mannich base (0.3 mmol), NCS (0.6 mmol), NaHCO3 (0.6 mmol), toluene (2.0
mL), 110 °C, 6 h, under N2. NBS was used instead of NCS in the preparations of 3al, 3bl, and 3dl. Yields of 3ea and 3el are based on GC/MS
studies.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 952–958

956
Y. Zhu et al.
PAPER
CuCl
CuCl2·2H2O
NaHCO3
3
1a
A
A
O
N
OH
Cl
OH
OH
Cl
O
R
Cl
R
N
R
N
R
CH2
[Cu]
R
+
N
R
2
B
C
D
Scheme 5 Possible mechanism for the copper-catalyzed coupling reaction of a Mannich base with a phenylacetylene to give a propargylamine
Chemicals were purchased from a commercial supplier (Shanghai
Chemical Co., Shanghai, China) and used without additional purifi-
cation. The Mannich bases were synthesized by the methods de-
scribed in the literature.18 Melting points were determined on a
Yamato melting apparatus Model MP-21. 1H NMR spectra were re-
corded in CDCl3 with TMS as internal standard by using a Bruker
DRX 500 (500 MHz) spectrometer. GC analysis was performed on
an Agilent GC-6820 chromatograph equipped with a 30 m × 0.32
mm × 0.5 μm HP-Innowax capillary column and a flame-ionization
detector. GC/MS spectra were recorded on Thermo TRACE DSQ
spectrometer equipped with a TRB-5MS column (30 m × 0.25 mm ×
0.25 μm). The progress of the reactions was monitored by TLC (sil-
ica gel polygrams SIL G/UV 254 plates). Column chromatography
was performed on Silicycle (40–60 mm) silica gel.
succinimide the products were obtained in good yields
with concomitant bromination of the benzene rings (3al,
3bl, and 3dl). However, Mannich bases with aromatic
secondary amine groups were less reactive in reactions
with phenylacetylene (1a), and none of the desired prod-
ucts 3aj and 3ak were isolated. The symmetrical Mannich
base 2m gave the symmetrical propargylamine 3am in
21% yield. Both electron-rich and electron-deficient aro-
matic alkynes were transformed into the corresponding
products (3bi, 3ci, and 3di). Hex-1-yne gave poor results,
with only traces of the products being detectable by
GC/MS (3ea and 3ei).
A possible mechanism for the copper-catalyzed coupling
of an alkyne and a Mannich base is shown in in Scheme 5.
In the presence of sodium bicarbonate, the reaction of
phenylacetylene (1a) with CuCl2·2H2O gives the cop-
per(II) acetylide A. The reaction of the Mannich base with
N-chlorosuccinimide gives intermediate B which is con-
verted into byproduct C17 and an iminium ion intermedi-
ate that reacts with a copper ion to form intermediate D.
Nucleophilic attack of A on D leads to the target product
3.
Propargylamines 3; General Procedure
NCS or NBS (0.6 mmol) was added to a mixture of CuCl2·2H2O (20
mmol%), the Mannich base 2 (0.3 mmol), the phenylacetylene 1
(0.2 mmol), and NaHCO3 (0.6 mmol) in toluene (2.0 mL) under N2
at r.t., and the soln was then stirred at 110 °C for 6 h. The mixture
was then cooled to r.t. and mixed with CHCl3 (10 mL) and H2O (10
mL). The organic phase was separated, dried (Na2SO4), and concen-
trated by rotary evaporation, and the residue was purified by column
chromatography.
1-(4-Bromophenyl)-4-(3-phenylprop-2-yn-1-yl)piperazine (3al)
Preparation by the general procedure from phenylacetylene (1a;
20.4 mg, 0.2 mmol), Mannich base 2l (114 mg, 0.3 mmol), and NBS
(0.6 mmol) with purification by flash chromatography [silica gel,
PE–EtOAc (3:1)] gave a white solid; yield: 50.2 mg (78%); mp
126–128 °C (MeOH).
This mechanism is in accordance with our experimental
results. In the reaction of Mannich base 2 with N-chloro-
succinimide to form intermediate B, the Mannich base
acts as a nucleophile and N-chlorosuccinimide acts as an
electrophile. Electron-withdrawing groups, such as chloro
or nitro groups, attached to the Mannich base decrease its
nucleophilicity and hinder the reaction. The benzene ring
of the copper(II) acetylide intermediate A can conjugate
with the double bond of the iminium ion intermediate D to
form a conjugated system, thereby stabilizing intermedi-
ate D. Aliphatic alkynes cannot stabilize intermediate D,
and are therefore inert in this reaction.
IR (KBr): 3064, 2844, 1596, 1421, 1384, 1164, 857, 814, 670, 589,
534 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H, ArH), 7.36–
7.30 (m, 5 H, ArH), 6.83–6.80 (m, 2 H, ArH), 3.61 (s, 2 H,
C≡CCH2), 3.25 (t, J = 4.9 Hz, 2 × 2 H, ArNCH2), 2.82 (t, J = 4.9
Hz, 2 × 2 H, NCH2).
13C NMR (125 MHz, CDCl3): δ = 150.3, 131.9, 131.8, 128.4, 128.3,
123.0, 117.8, 112.0, 85.7, 84.1, 52.0, 49.0, 47.8.
GC/MS (EI, 70 eV): m/z = 354.
In summary, we have developed a new and efficient meth-
od for synthesizing propargylamines by using 2,4-di-tert-
butylphenol type-Mannich bases through chlorine(1+) or
bromine(1+) ion-initiated retro-Mannich-type fragmenta-
tion. Investigations of the detailed mechanism of the reac-
tion and its synthetic applications are currently underway.
Anal. Calcd for C19H19BrN2: C, 64.23; N, 7.89; H, 5.39. Found: C,
64.36; N, 7.75; H, 5.59.
1-(4-Bromophenyl)-4-[3-(4-tolyl)prop-2-yn-1-yl]piperazine
(3bl)
Preparation by the general procedure from 1-ethynyl-4-methylben-
zene (23.2 mg, 0.2 mmol), Mannich base 2l (114 mg, 0.3 mmol),
and NBS (0.6 mmol) with purification by flash chromatography
Synthesis 2013, 45, 952–958
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Propargylamines
957
[silica gel, PE–EtOAc (3:1)] gave a white solid; yield: 59.6 mg
(81%); mp 135–137 °C (MeOH).
N,N-Diethyl-3-phenylprop-2-yn-1-amine (3af)
Preparation by the general procedure from phenylacetylene (1a;
20.4 mg, 0.2 mmol), Mannich base 2f (87.3 mg, 0.3 mmol), and
NCS (0.6 mmol) with purification by flash chromatography [silica
gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 27.3 mg (73%).
IR (KBr): 2939, 2845, 2819, 2771, 1605, 1400, 1152, 1012, 917,
817, 530 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.37–7.34 (m, 4 H, ArH), 7.14–
7.13 (m, 2 H, ArH), 6.83–6.80 (m, 2 H, ArH), 3.79 (s, 2 H,
C≡CCH2), 3.38 (br s, 2 × 2 H, ArNCH2), 3.03 (br s, 2 × 2 H, NCH2),
2.36 (s, 3 H, ArCH3).
1H NMR (500 MHz, CDCl3): δ = 7.43–7.41 (m, 2 H, ArH), 7.29–
7.28 (m, 3 H, ArH), 3.64 (s, 2 H, C≡CCH2), 2.63 (t, J = 4.8 Hz, 2 ×
2 H, NCH2), 1.12 (t, J = 4.8 Hz, 2 × 3 H, NCH2CH3).
GC-MS (EI, 70 eV): m/z = 187.
13C NMR (125 MHz, CDCl3): δ = 150.3, 138.3, 131.9, 131.7, 129.1,
The spectral data were in accordance with those reported in the lit-
erature.20
120.0, 117.8, 111.9, 85.8, 83.4, 52.0, 49.0, 47.9, 21.5.
GC/MS (EI, 70 eV): m/z = 368.
1-(3-Phenylprop-2-yn-1-yl)piperidine (3ag)
Anal. Calcd for C20H21BrN2: C, 65.05; N, 7.59; H, 5.73. Found: C,
64.88; N, 7.42; H, 5.89.
Preparation by the general procedure from phenylacetylene (1a;
20.4 mg, 0.2 mmol), Mannich base 2g (90.0 mg, 0.3 mmol), and
NBS (0.6 mmol) with purification by flash chromatography [silica
gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 30.2 mg (76%).
1-(4-Bromophenyl)-4-[3-(4-fluorophenyl)prop-2-yn-1-yl]piper-
azine (3dl)
Preparation by the general procedure from 1-ethynyl-4-fluoroben-
zene (24.0 mg, 0.2 mmol), Mannich base 2l (114 mg, 0.3 mmol),
and NBS (0.6 mmol) with purification by flash chromatography
[silica gel, PE–EtOAc (3:1)] gave a white solid; yield: 48.4 mg
(65%); mp 125–127 °C (MeOH).
1H NMR (500 MHz, CDCl3): δ = 7.45–7.42 (m, 2 H, ArH), 7.31–
7.28 (m, 3 H, ArH), 3.60 (s, 2 H, C≡CCH2), 2.71 (br s, 2 × 2 H,
NCH2), 1.78–1.73 (m, 2 × 2 H, NCH2CH2), 1.50 (s, 2 H,
NCH2CH2CH2).
GC/MS (EI, 70 eV): m/z = 199.
IR (KBr): 3038, 2835, 2814, 2771, 1599, 1400, 1230, 1157, 1012,
839, 814, 532 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.44–7.34 (m, 4 H, ArH), 7.02–
7.00 (m, 2 H, ArH), 6.99–6.80 (m, 2 H, ArH), 3.58 (s, 2 H,
C≡CCH2), 3.24 (t, J = 4.9 Hz, 2 × 2 H, ArNCH2), 2.80 (t, J = 4.9
Hz, 2 × 2 H, NCH2).
13C NMR (125 MHz, CDCl3): δ = 162.5 (d, JCF = 248.8 Hz), 150.3,
133.7 (d, JCF = 7.5 Hz), 132.0, 119.1, 117.8, 115.6 (d, JCF = 21.3
Hz), 112.0, 84.7, 83.8, 52.0, 49.0, 47.8.
The spectral data were in accordance with those reported in the lit-
erature.21
1-(3-Phenylprop-2-yn-1-yl)pyrrolidine (3ah)
Preparation by the general procedure from phenylacetylene (1a;
20.4 mg, 0.2 mmol), Mannich base 2h (86.7 mg, 0.3 mmol), and
NCS (0.6 mmol) with purification by flash chromatography [silica
gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 26.3 mg (71%).
1H NMR (500 MHz, CDCl3): δ = 7.44–7.42 (m, 2 H, ArH), 7.30–
7.29 (m, 3 H, ArH), 3.64 (s, 2 H, C≡CCH2), 2.72–2.69 (m, 2 × 2 H,
NCH2), 1.86–1.83 (m, 2 × 2 H, NCH2CH2).
GC/MS (EI, 70 eV): m/z = 372.
Anal. Calcd for C19H18BrFN2: C, 61.14; N, 7.51; H, 4.86. Found C,
61.01; N, 7.35; H, 5.09.
GC/MS (EI, 70 eV): m/z = 185.
The spectral data were in accordance with those reported in the lit-
erature.20
4-[3-(4-Methoxyphenyl)prop-2-yn-1-yl]morpholine (3ci)
Preparation by the general procedure from 1-ethynyl-4-methoxy-
benzene (26.4 mg, 0.2 mmol), Mannich base 2i (91.5 mg, 0.3
mmol), and NCS (0.6 mmol) with purification by flash chromatog-
raphy [silica gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 32.8 mg
(85%).
4-[3-(4-Tolyl)prop-2-yn-1-yl]morpholine (3bi)
Preparation by the general procedure from 1-ethynyl-4-methylben-
zene (23.2 mg, 0.2 mmol), Mannich base 2i (91.5 mg, 0.3 mmol),
and NCS (0.6 mmol) with purification by flash chromatography
[silica gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 35.3 mg
(82%).
IR (KBr): 3007, 2854, 2836, 2814, 2763, 1606, 1509, 1399, 1246,
1115, 1032, 832, 559 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.34–7.32 (m, 2 H, ArH), 7.12–
7.11 (m, 2 H, ArH), 3.83–3.81 (t, J = 4.9 Hz, 2 × 2 H, OCH2), 3.68
(s, 2 H, C≡CCH2), 2.74 (br s, 2 × 2 H, NCH3), 2.34 (s, 3 H, ArCH3).
1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 8.8 Hz, 2 H, ArH),
6.82 (d, J = 8.8 Hz, 2 H, ArH), 3.80 (s, 3 H, ArOCH3), 3.79 (t,
J = 4.6 Hz, 2 × 2 H, OCH2), 3.51 (s, 2 H, C≡CCH2), 2.67 (s, 2 × 2
H, NCH3).
13C NMR (125 MHz, CDCl3): δ = 159.6, 133.2, 115.0, 113.9, 85.7,
82.1, 66.8, 55.3, 52.4, 48.1.
GC/MS (EI, 70 eV): m/z = 215.
The spectral data were in accordance with those reported in the lit-
erature.22
GC/MS (EI, 70 eV): m/z = 231.
4-[3-(4-Fluorophenyl)prop-2-yn-1-yl]morpholine (3di)
Preparation by the general procedure from 1-ethynyl-4-fluoroben-
zene (24.0 mg, 0.2 mmol), Mannich base 2i (91.5 mg, 0.3 mmol),
and NCS (0.6 mmol) with purification by flash chromatography
[silica gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 39.3 mg
(71%).
1H NMR (500 MHz, CDCl3): δ = 7.43–7.40 (m, 2 H, ArH), 7.02–
6.98 (m, 2 H, ArH), 3.78 (t, J = 4.6 Hz, 2 × 2 H, OCH2), 3.50 (s, 2
H, C≡CCH2), 2.65 (t, J = 4.6 Hz, 2 × 2 H, NCH3).
Anal. Calcd for C14H17NO2: C, 72.70; N, 6.06; H, 7.41. Found: C,
72.58; N, 5.92; H, 7.51.
N,N-Dimethyl-3-phenylprop-2-yn-1-amine (3aa)
Preparation by the general procedure from phenylacetylene (1a;
20.4 mg, 0.2 mmol), Mannich base 2a (78.2 mg, 0.3 mmol), and
NBS (0.6 mmol) with purification by flash chromatography [silica
gel, PE–EtOAc (1:1)] gave a yellow oil; yield: 26.1 mg (82%).
1H NMR (500 MHz, CDCl3): δ = 7.46–7.45 (m, 2 H, ArH), 7.34–
7.30 (m, 3 H, ArH), 3.67 (s, 2 H, C≡CCH2), 2.54 (s, 2 × 3 H, NCH3).
GC/MS (EI, 70 eV): m/z = 219.
The spectral data were in accordance with those reported in the lit-
erature.21
GC/MS (EI, 70 eV): m/z = 159.
The spectral data were in accordance with those reported in the lit-
erature.19
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 952–958

958
Y. Zhu et al.
PAPER
1,4-Bis(3-phenylprop-2-yn-1-yl)piperazine (3am)
Chem. Commun. (Cambridge) 2005, 1315. (c) Kantam, M.
L.; Balasubrahmanyam, V.; Shiva Kumar, K. B.; Venkanna,
G. T. Tetrahedron Lett. 2007, 48, 7332. (d) Choudary, B.
M.; Sridhar, C.; Kantam, M. L.; Sreedhar, B. Tetrahedron
Lett. 2004, 45, 7319. (e) Wang, M.; Li, P.; Wang, L. Eur. J.
Org. Chem. 2008, 2255. (f) Zhang, X.; Corma, A. Angew.
Chem. Int. Ed. 2008, 47, 4358. (g) Kantam, M. L.; Prakash,
B. V.; Reddy, C. R. V.; Sreedhar, B. Synlett 2005, 2329.
(h) Maggi, R.; Bello, A.; Oro, C.; Sartori, G.; Soldi, L.
Tetrahedron 2008, 64, 1435. (i) Reddy, K. M.; Babu, N. S.;
Suryanarayana, I.; Prasad, P. S. S.; Lingaiah, N. Tetrahedron
Lett. 2006, 47, 7563. (j) Wang, S.; He, X.; Song, L.; Wang,
Z. Synlett 2009, 447.
Preparation by the general procedure from phenylacetylene (1a;
40.8 mg, 0.4 mmol), Mannich base 2m (313.2 mg, 0.6 mmol), and
NCS (0.6 mmol) with purification by flash chromatography [silica
gel, PE–EtOAc (5:1)] gave a yellow solid; yield: 13.2 mg (21%
yield); mp 102–104 °C (MeOH) (Lit.23 mp 103 °C).
1H NMR (500 MHz, CDCl3): δ = 7.48–7.46 (m, 4 H, ArH), 7.35–
7.31 (m, 6 H, ArH), 3.71 (s, 4 H, C≡CCH2), 3.02 (s, 4 × 2 H, NCH2).
GC/MS (EI, 70 eV): m/z = 314.
The spectral data were in accordance with those reported in the lit-
erature.23
2,4-Di-tert-butyl-6-chlorophenol (Byproduct C)
Colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.21 (d, J = 2.3 Hz, 1 H, ArH),
7.20 (d, J = 2.3 Hz, 1 H, ArH), 5.74 (s, 1 H, OH), 1.42 (s, 9 H, CH3),
1.29 (s, 9 H, CH3).
13C NMR (125 MHz, CDCl3): δ = 147.3, 143.1, 136.7, 123.3, 122.8,
120.4, 33.4, 34.5, 31.5, 29.4.
(9) (a) Gommermann, N.; Knochel, P. Chem. Commun.
(Cambridge) 2004, 2324. (b) Gommermann, N.; Knochel, P.
Synlett 2005, 2799. (c) Rueping, M.; Antonchick, A. P.;
Brinkmann, C. Angew. Chem. Int. Ed. 2007, 46, 6903.
(d) Wei, C.; Mague, J. T.; Li, C. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5749. (e) Ji, J. X.; Wu, J.; Chan, A. S. C.
Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 11196. (f) Bisai, A.;
Singh, V. K. Org. Lett. 2006, 8, 2405. (g) Gommermann, N.;
Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int. Ed.
2003, 42, 5763. (h) Blay, G.; Cardona, L.; Climent, E.;
Pedro, J. R. Angew. Chem. Int. Ed. 2008, 47, 5593.
(i) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. Int.
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Che, C. M. Org. Lett. 2006, 8, 1529.
GC/MS (EI, 70 eV): m/z = 240.
The spectral data were in accordance with those reported in the lit-
erature.24
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Synthesis 2013, 45, 952–958
© Georg Thieme Verlag Stuttgart · New York