Activation of primary amines by copper(i)-based lewis acid promoters in the solventless synthesis of secondary propargylamines

Article abstract of DOI:10.1055/s-0037-1612253

Primary amines are activated by copper(I)-based Lewis acid promoters in an A ³ -coupling one-pot solventless reaction with aldehydes and phenylacetylene for the synthesis of secondary propargylamines. The reaction is promoted by a CuSO ₄ /NaI system, a practical precursor of the in situ generated effective CuI/I ₂ system, that worked well, but only in a restricted number of examples. Substitution of I ₂ with CeCl ₃ ·7H ₂ O in a one-pot two-step reaction provided good yields and a wider applicability, with the added value given by a safer procedure.

Full text of DOI:10.1055/s-0037-1612253

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
C. Cimarelli et al.
Paper
Synthesis
Activation of Primary Amines by Copper(I)-Based Lewis Acid Promoters
in the Solventless Synthesis of Secondary Propargylamines
Cristina Cimarelli*a
Federica Navazioa
Federico V. Rossia
Fabio Del Bellob
0
0
0
0-0
0
0
2-7
2
8
9-0
9
4
1
R1NH2
1a–f
+
R1NH2
1a–f
R1
R1
HN
N
ii)
i)
iii)
Ph
+
R2
H
R2
Method A
Ph
Method B
O
O
Ph
Enrico Marcantonia
R2
2a–p
H
R2
2a–p
H
a School of Science and Technology, Chemistry
Division, University of Camerino, Via S. Agostino
1, 62032 Camerino, Italy
Method A: 9 examples up to 62% yield
i) CuSO4 (30 mol%)/NaI (60 mol%),
PhCOOH (5 mol%), solventless, N2, 80 °C
Method B: 20 examples up to 95% yield
ii) MgSO4, CeCl3•7H2O (30 mol%), solventless, N2, r.t., 0.25 h
iii) CuI (30 mol%), solventless, N2, 40 °C
cristina.cimarelli@unicam.it
b School of Pharmacy, Medicinal Chemistry Unit,
University of Camerino, Via S. Agostino 1, 62032
Camerino, Italy
Received: 12.11.2018
Accepted after revision: 24.01.2019
Published online: 11.03.2019
Since the pioneering work of Li and Wei25 the issue of
the synthesis of propargylamines by direct addition of ter-
minal alkynes to imines, defined in short as A3 coupling, has
been addressed in different ways, under solvent or solvent-
less conditions, by metal catalysis or organocatalysis, and
also in an enantioselective manner.26–29
Our goal was the development of a green and simple
Lewis acid catalyzed or promoted A3 reaction with alde-
hydes and alkynes for the activation of primary amines that
are, in general, less applied in such reactions due to their
lower reactivity. In particular, many synthetic methods
based on Lewis acid catalysis have been developed, and
copper(I) or copper(II) revealed as the most useful and fre-
quently applied metal in A3 reactions. In general, the coor-
dination of Lewis acids with the final propargylamine is
stronger than with the intermediate imine, so a catalytic
amount of Lewis acid may not be enough for the reaction. A
second Lewis acid may offset this unfavorable factor.
With this aim, we explored the effect of the use of io-
dine, because it possesses a strong C–C multiple bond coor-
dination ability and may be both a σ- and a π-electrophilic
Lewis acid. Reactions catalyzed by this element are very
similar to ones catalyzed by transition metals, but it is
cheaper than, for example, Pt, Pd and Os, and more environ-
mentally friendly.30 Iodides of cations at high charge are un-
stable, due to the propensity of iodine to lose an electron to
transform into its stable form, I2, that in turn tends to break
down heterolytically to form iodide in the presence of
strong organic nucleophiles, such as amines.31 Furthermore,
iodine has been used as a mild Lewis acid to activate imines
in the synthesis of quinolines via a three-component reac-
tion of amines, aldehydes and alkynes.32 At the same time,
molecular iodine is corrosive and toxic, so attempts to gen-
erate it in situ in copper-catalyzed reactions have been
DOI: 10.1055/s-0037-1612253; Art ID: ss-2018-t0759-op
Abstract Primary amines are activated by copper(I)-based Lewis acid
promoters in an A3-coupling one-pot solventless reaction with alde-
hydes and phenylacetylene for the synthesis of secondary propargyl-
amines. The reaction is promoted by a CuSO4/NaI system, a practical
precursor of the in situ generated effective CuI/I2 system, that worked
well, but only in a restricted number of examples. Substitution of I2 with
CeCl3·7H2O in a one-pot two-step reaction provided good yields and a
wider applicability, with the added value given by a safer procedure.
Key words propargylamines, A3 coupling, primary amines, copper,
cerium trichloride, Lewis acids
Propargylamines are a class of building blocks involved
in the synthesis of several important heterocyclic scaffolds,
as direct precursors or as starting materials for the prepara-
tion of key intermediates. These compounds are susceptible
to many different chemical transformations because of
their characteristic structure that encompasses an amine
group suitable for nucleophilic reactions, placed at the β-
position to an alkyne moiety that in turn can act both as an
electrophile and as a source of electrons in nucleophilic re-
actions.
Many synthetic methods have been developed for the
synthesis of different classes of heterocycles1–10 starting
from propargylamines. At the same time, propargylamines
are direct precursors of propargylureas that can undergo
silver- or gold-catalyzed cycloisomerization to produce a
series of other nitrogen-containing heterocyclic com-
pounds.11–15 Furthermore, the synthesis of oxazolidi-
nones16–23 and oxazolones24 through carboxylative cycliza-
tion of propargylic amines with CO2 is a clean and atom-
economic reaction for CO2 fixation in the field of green
chemistry.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
C. Cimarelli et al.
Paper
Synthesis
made, with the CuI/I2 system obtained by direct reaction of
copper(II) perchlorate33 or sulfate34 with NaI, in the last case
according to Equation 1.
(1a), benzaldehyde (2a) and phenylacetylene (3) in dioxane
at reflux and under nitrogen atmosphere, as depicted in
Scheme 1. The results obtained are reported in Table 1.
It is clear that the CuI/I2-promoting system is active in
the reaction and that its action results from the synergy of
both copper(I) and iodine, as shown by the very poor re-
sults obtained when one or the other of the two compo-
nents was used independently (Table 1, entries 1–3). On the
other hand, also CeCl3·7H2O, alone or in combination with
other Lewis acids, proved to be a good promoter for the
synthesis of imine 5, as previously known,40 but in solution
it did not afford the product, except with CuI, with compa-
rable results (Table 1, entries 5–10). Copper(I) gave a much
better performance than copper(II) (Table 1, entries 1, 11).
The CuSO4/NaI couple has been revealed as a good way to
generate the actual promoting system CuI/I2 in situ by di-
rect mixing, through a quick, quantitative and spontaneous
reaction. The lower cost, the major commercial availability
and the ease of use of CuSO4 and NaI make them an inter-
esting alternative. In situ generated CuI/I2 was more reac-
tive than the catalyst obtained by direct mixing of CuI and I2
in the same ratio in the synthesis of 5-iodotriazoles.33
Solvent screening (Table 2) showed that propargylamine
4a is obtained in water and also in water/ethanol mixtures
in higher yields (11–43%) than in dioxane (see Table 1), but
with a consistent parallel dimerization of phenylacetylene
(10–40%). We found also that a higher yield of 4a was ob-
tained under solventless conditions, where the formation of
dimer was reduced.
(1)
2 CuSO4 + 4 NaI
2 CuI + I2 + 2 Na2SO4
Equation 1
On the basis of these considerations, we studied the ap-
plication of the CuI/I2-promoting system in the A3 reaction
of primary amines, aldehydes and phenylacetylene, and
also the in situ formation of the promoting system by using
a CuSO4/NaI couple that avoids the direct manipulation of
iodine. Unfortunately, the reactions promoted by the Cu-
SO4/NaI system gave good results only in a limited number
of examples. A partial result obtained in a preliminary cata-
lyst screening when using a CeCl3·7H2O/CuI-promoting sys-
tem prompted us to also explore the A3 coupling with this
Lewis acid, under the same conditions developed for the
CuSO4/NaI system.
Lanthanides have played an important role in the search
for affordable and environmentally benign synthetic meth-
odologies. In particular, numerous reactions and synthetic
procedures have been developed based on cerium(III) as key
component, through its more available source CeCl3·7H2O.
The salt is interesting because of its high efficiency, and low
toxicity and cost, and for the ease of application also under
non-anhydrous conditions.35 While CeCl3·7H2O has been
used as a catalyst in multicomponent reactions,36 to gener-
ate new products in a single step and to avoid large
amounts of solvents and expensive purification techniques,
to the best of our knowledge there are no reports on its use
in the synthesis of propargylamines.
Table 1 Catalyst Screening for the Synthesis of Secondary Propargyl-
aminesa
Often reactions catalyzed by CeCl3·7H2O require a stoi-
chiometric amount of catalyst and long reaction times. A
more reactive Lewis acid is represented by the mixture Ce-
Cl3·7H2O/metal iodides in a 1:1 ratio,37 also in supported
form,38 and with copper being the transition metal of
choice for A3 reactions, CuI was chosen also to widen the
application of a promoting system used experimentally be-
fore only in the synthesis of 2-substituted benzimidaz-
oles.39
Entry
Catalyst
Yield (%)
4a
5
1b
2
CuI/I2
27
2
29
92
70
94
>99
20
43
30
25
41
22
CuI
3c
4
I2
–
NaI
–
5
CeCl3·7H2O/NaI
CeCl3·7H2O/CuI
CeCl3·7H2O
dry CeCl3
CeCl3·7H2O/NaI/I2
CeCl3·7H2O/CuI/I2
CuSO4/I2
–
To find the best conditions for the synthesis of second-
ary propargylamines, we began by screening a series of
Lewis acids, performing the pilot reaction of benzylamine
6
28
–
7
8
–
9d
10
11
–
O
Ph
NH
N
Ph
–
Ph
NH2
H
Ph
Ph
<2
Ph
1a
2a
Cat. (30 mol%)
4a
Ph
5
a Reaction conditions: 1a (1 mmol), 2a (1 mmol) and 3 (1 mmol) were
mixed together with the Lewis acid (0.30 mmol), in dioxane (5 mL) under
N2 atmosphere, and left at reflux until a constant composition of the mix-
ture was reached. Chromatographic yields.
+
+
Ph
dioxane, reflux, N2
Ph
b 4% diiodostyrene was formed.
Ph
3
6
c 23% diiodostyrene was formed.
d 44% diiodostyrene was formed.
Scheme 1 Catalyst screening in the pilot A3-coupling reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

C
C. Cimarelli et al.
Paper
Synthesis
Table 2 Solvent Screening for the Synthesis of Secondary Propargyl-
The best results were obtained under solventless condi-
tions, at 80 °C, using a mixture of dry CuSO4 and NaI to pre-
pare the CuI/I2 system in situ and with the formation of a
reduced amount of phenylacetylene dimer 6 (Table 3, entry
7).
aminesa
Entry
Solvent
Catalyst
Yield (%)
4a
5
6
Beyond Equation 1, the reactions of Cu2+ and I2/I– may
produce different ions, depending also on their relative
amounts, as depicted in Equations 2 and 3.
1
2
CH3CN
CuI/I2
CuI/I2
CuI/I2
CuI/I2
CuI/I2
CuI/I2
CuI/I2
CuI/I2
CuI/I2
CuI/I2
29
–
45
49
53
81
90
80
6
13
–
EtOAc
3
i-PrOH
1
–
CuI + I–
I2 + I–
[CuI2]–
[I3]–
(2)
(3)
4
anhydrous EtOH
MeOH
–
–
5
–
10
8
Equations 2 and 3
6
EtOH
–
7
H2O
33
11
–
40
25
22
26
8
EtOH/H2Ob
EtOH/H2Oc
EtOH/H2Od
62
77
30
The reaction outlined in Scheme 1 was then performed
under conditions that allow the formation of [I3]– only or of
[CuI2]– and CuI/I2. The results clearly indicate that [I3]– acts
only as an iodinating agent of phenylacetylene, as expected
(Table 3, entry 9). The addition of an equimolecular amount
of NaI to CuI improved the yield more than the same
amount of iodine (Table 3, entries 2, 4). The CuSO4/NaI sys-
tem worked as a good precursor of the CuI/I2 promoter (Ta-
ble 3, entries 2, 7). An increase in the NaI/CuSO4 ratio to 3:1
did not improve the yield of 4a (Table 3, entry 8). In particu-
lar, a lack of NaI with respect to the stoichiometric 1:2 ratio
of Equation 1 afforded a lower yield (Table 3, entry 6),
showing that the effective promoting agent is the CuI/I2
system, formed as per Equation 1. In almost all the reac-
tions we found an amount of 1,4-diphenylbuta-1,3-diyne
(6) ranging from 4% to 15%, formed from phenylacetylene
(3) through Glaser coupling.41 This side reaction diverts re-
agent 3 towards an undesired product, decreasing the final
yield of the propargylamine, and can be suppressed by the
addition of a small percentage of benzoic acid.42
9
10
43
a Reaction conditions: 1a (1 mmol), 2a (1 mmol) and 3 (1 mmol) were
mixed together in solvent (5 mL) at 80 °C, with catalyst (0.30 mmol, 1:1
molar ratio) under N2 atmosphere, until a constant composition of the mix-
ture was reached. Chromatographic yields.
b EtOH/H2O, 50:50 v/v.
c EtOH/H2O, 75:25 v/v.
d EtOH/H2O, 25:75 v/v.
Table 3 summarizes the temperature effect on the
CuI/I2-promoted reaction, the comparison with in situ pre-
pared promoter from CuSO4 and NaI, and the optimization
of the CuSO4/NaI ratio under solventless conditions.
At room temperature the reaction did not take place
(Table 3, entry 1), and a temperature increase from 80 °C to
100 °C had no effect on the reaction (Table 3, entries 2, 3).
Table 3 Catalyst Composition and Temperature Screening for the Sol-
ventless Synthesis of Secondary Propargylaminesa
The reaction was then explored with different amines
and aldehydes. Aldehydes 2a–i and phenylacetylene (3)
were mixed in the reaction vessel under inert atmosphere,
then NaI and CuSO4 were added. As the two salts get mixed,
a deep brown color develops, indicating that the reaction in
Equation 1 has gone to completion, then amines 1a–c were
added. The mixture was stirred at 80 °C until a constant
composition was reached (2–5 h); the final propargyl-
amines 4a, 4c–i, 4q were obtained in yields from acceptable
to good, with slightly better results starting from aliphatic
aldehydes (Scheme 2 and Table 4).
Entry
Promoter (mol%)
Yield (%)
4a
5
6
1b
2
CuI (30)/I2 (30)
–
87
50
56
33
78
41
15
29
73
–
1
CuI (30)/I2 (30)
40
39
60
10
39
69
55
–
3c
4
CuI (30)/I2 (30)
1
CuI (30)/NaI (30)
CuSO4·5H2O (30)/NaI (30)
CuSO4 (30)/NaI (30)
CuSO4 (30)/NaI (60)
CuSO4 (30)/NaI (90)
I2 (30)/NaI (30)
0
5
11
15
4
6
7
R1
R2
8
4
CuSO4 (30 mol%),
NaI (60 mol%)
HN
O
9d
–
R1 NH2
+
+
Ph
PhCOOH (5 mol%)
solventless, N2, 80 °C
H
R2
2a–i
a Reaction conditions: 1a (1 mmol), 2a (1 mmol) and 3 (1 mmol) were
mixed together with the promoter, at 80 °C unless differently reported, un-
der N2 atmosphere, until a constant composition of the mixture was
reached. Chromatographic yields.
Ph
1a–c
3
4a, 4c–i, 4q
Scheme 2 CuSO4/NaI-promoted synthesis of secondary propargyl-
amines
b At r.t.
c At 100 °C.
d 18% diiodostyrene was formed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

D
C. Cimarelli et al.
Paper
Synthesis
Table 4 CuSO4/NaI-Promoted Synthesis of Secondary Propargyl-
amines
The conditions for the CeCl3·7H2O/CuI-promoted reac-
tion were optimized with respect to temperature and
amount of promoting system (Table 5), with the finding
that the reaction already had a good performance at room
temperature, comparable with the results obtained at 40 °C,
that are reached in shorter reaction times. At 80 °C, de-
creased yields were observed, although the reaction is com-
pleted in a much shorter time. So, the best results were
found at 40 °C, in 15 hours, with 30 mol% of the promoting
system.
Entry
1
R1
Bn
2
R2
Ph
4
Yielda (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
39
n.r.
30
37
42
40
11
50
62b
53
n.r.
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
i-Pr
4-t-BuC6H4
4-ClC6H4
4-MeOC6H4
Pr
3
4
5
The reactions with CeCl3·7H2O were performed by also
pre-forming the imine: the formation of imines 5 catalyzed
6
i-Pr
7
2g
2h
2i
t-Bu
4g
4h
4i
8
cyclohexyl
2-butyl
Ph
Table 6 CeCl3·7H2O/CuI-Promoted Synthesis of Secondary Propargyl-
amines
9
10
11
2a
4q
4r
Entry
1
R1
2
R2
4
Yielda
(%)
1-phenylethyl 2a
Ph
a Isolated yields.
b d.r. 21:79.
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Bn
2a
2b
2c
2d
2e
2f
Ph
4a
4b
4c
4d
4e
4f
85
81
67
50
52
76
50
75
95c
57
78
60
Bn
4-t-BuC6H4
b
3
Bn
4-ClC6H4
4
Bn
4-MeOC6H4
Pr
Table 5 Optimization of the Catalyst Amount and Temperature in the
CeCl3·7H2O/CuI-Promoted Synthesis of Secondary Propargylaminesa
5
Bn
6
Bn
i-Pr
Entry
Promoterb
Conditions
25 °Cc
7
Bn
2g
2h
2i
t-Bu
4g
4h
4i
40 °Cd
80 °Ce
8
Bn
cyclohexyl
2-butyl
4-MeC6H4
4-n-PrC6H4
4-i-PrC6H4
4-FC6H4
Yield (%) of 4a
9
Bn
1
2
3
4
10 mol%
30 mol%
60 mol%
100 mol%
70
87
60
55
80
85
78
60
49
70
65
62
10
11
12
13
14
15
16
17
18
19
20
21
Bn
2j
4j
Bn
2k
2l
4k
4l
Bn
Bn
2m
2n
2o
2p
2a
2a
2a
4m 54
a Reaction conditions: benzylamine (1a, 1 mmol) and benzaldehyde (2a, 1
mmol) were stirred in the presence of CeCl3·7H2O and MgSO4 and then, af-
ter formation of the imine, phenylacetylene (3, 1.6 mmol) and CuI were
added. The reactions were stopped when a constant composition of the
mixture was reached. Isolated yields.
b
Bn
4-BrC6H4
4n
4o
4p
4q
4r
55
70
45
72
64d
71
62
47
Bn
3-formylphenyl
Bn
2-furyl
Ph
b mol% of each Lewis acid.
i-Pr
c Constant composition reached in 24 h.
d Constant composition reached in 15 h.
1-phenylethyl
Ph
e Constant composition reached in 5 h.
i-Bu
Ph
4s
4t
4-MeOC6H4CH2 2d
2-furylmethyl 2p
4-MeOC6H4
2-furyl
4u
In the second stage of this study, the application of
CeCl3·7H2O instead of iodine was examined, in order to ob-
tain better yields and a more general applicability of the re-
action, with the added value which would be given by a saf-
er procedure.
a Isolated yields.
b Solid imines. The reaction was performed in CH3CN (2 mL).
c d.r. 68:32.
d d.r. 72:28.
R1
R1
HN
O
, CuI (30 mol%)
solventless, N2, 40 °C
N
Ph
CeCl3•7H2O (30 mol%), MgSO4
R1 NH2
+
solventless, N2, r.t., 0.25 h
R2
R2
2a–p
H
R2
H
Ph
1a–f
5
4a–u
Scheme 3 CeCl3·7H2O/CuI-promoted synthesis of secondary propargylamines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

E
C. Cimarelli et al.
Paper
Synthesis
Mechanism A
H2N Bn
+ CuI +
H
Ph
Bn
Ph
HN
Ph
aggregates
Cu
Ph
HN Bn
Ph
NH2Bn
Cu NH2Bn
Ph
BnH2N Cu
Ph
BnH2N Cu
BnH2N
Ph
Ph
O
I2
Bn
I2
Ph
+
NH2Bn
N
N
I2
Bn
Ph
Cu
– H2O
Ph
H2N Bn
– CuNH2Bn
BnH2N Cu
Ph
Ph
Mechanism B
Bn NH2
Cl3Ce
Ph
Bn
N
Bn
Ph
Cl3Ce
Ph
Bn
HN
O
Ph
H
CeCl3•7H2O
– H2O
Cu
N
+
CuI
Ph
Ph
Ph
Scheme 4 Mechanism hypotheses for the copper-based Lewis acid promoted synthesis of secondary propargylamines. Mechanism A: CuSO4/NaI-pro-
moted A3 coupling. Mechanism B: CeCl3·7H2O/CuI-promoted synthesis.
by the first Lewis acid was monitored by GC-MS or 1H NMR
spectroscopy in some cases, then phenylacetylene (3) and
the second Lewis acid were added. After the reaction time,
the final propargylamine 4 was isolated. When the reaction
of 1a, 2a and 3 was performed by mixing together all the
reagents and catalysts, only a 50% yield of product 4a was
obtained vs the 85% yield observed with imine pre-forma-
tion.
The order of addition of the two Lewis acids was investi-
gated and the results are very similar one another either
when we change the order of addition of the two acids: 90%
yield of 4a after 24 hours starting from CuI and 85% starting
from CeCl3·7H2O. In any case, the reaction mixtures ob-
tained using CuI first and then CeCl3·7H2O resulted in more
viscous mixtures and were therefore difficult to work up, so
the procedure that uses CeCl3·7H2O in the first step and CuI
in the subsequent step was chosen to prepare a series of
secondary propargylamines.
til a constant composition was reached (12–15 h), then
worked up. The final propargylamines 4a–u were isolated
in good yields (Scheme 3 and Table 6).
Generally, the CuSO4/NaI-promoted reactions are faster
and better yields were obtained with aliphatic aldehydes
than with aromatic aldehydes. The reactions promoted by
the CuSO4/NaI system gave good results only in a limited
number of examples and the yields were generally lower
than the corresponding reactions promoted by
CeCl3·7H2O/CuI. Using the latter promoting system, the re-
action showed wider applicability and resulted in better
yields both with aliphatic and aromatic aldehydes; Glaser
coupling was not observed. The reaction was also applied to
chiral starting materials and, interestingly, the diastereo-
meric ratio of product 4i from the reaction of chiral alde-
hyde 2i promoted by CuSO4/NaI was reversed with respect
to the same reaction promoted by CeCl3·7H2O/CuI (Tables 4
and 6).
Amines 1a–f and aldehydes 2a–p were mixed in the
presence of CeCl3·7H2O and MgSO4 at room temperature
under inert atmosphere, and the formation of the corre-
sponding imines, monitored by GC and NMR spectroscopy
in some cases, took place generally in 85–90% yield after 15
minutes. Then, phenylacetylene (3) and CuI were added,
and the reaction mixture was warmed and left at 40 °C un-
Some facts allow us to hypothesize that the CuSO4/NaI-
promoted reaction proceeds according to a different mech-
anism than the one promoted by the CeCl3·7H2O/CuI sys-
tem. First of all, the noted change in the stereochemistry of
the reaction suggests the said difference. The reaction pro-
moted by CuSO4/NaI clearly takes place under oxidative
coupling conditions (Scheme 4, Mechanism A), as demon-
strated by the dimerization of phenylacetylene (3) and by
the presence of small percentages of derivatives obtained
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

F
C. Cimarelli et al.
Paper
Synthesis
by oxidative coupling of the starting amine. Such products
are absent in the reaction promoted by CeCl3·7H2O/CuI, that
instead gives better results upon pre-forming the imine, in
a two-step one-pot reaction. This fact prompts us to think
that in these reactions the promoter activates the imine to-
wards attack by the copper acetylide (Scheme 4, Mecha-
nism B). In Scheme 4, both mechanistic hypotheses are de-
picted. Further studies on this aspect are underway.
In summary, two different Lewis acid based promoting
systems, CuI/I2 and CeCl3·7H2O/CuI, were applied for the
synthesis of secondary propargylamines by A3 reaction of
less studied primary amines, aldehydes and phenylacety-
lene, both systems characterized by ease of use, low toxicity
and cost. The CuSO4/NaI couple revealed itself as a good and
practical precursor for the in situ generation of CuI and I2.
The CeCl3·7H2O/CuI promoter represents an improvement
with respect to CuSO4/NaI due to the increased perfor-
mance of the reaction in terms of yields, although at the ex-
pense of longer reaction times, and with the added value of
a lower toxicity of the promoting system itself, that avoids
the use of toxic and corrosive molecular iodine. The desired
propargylamines were obtained in yields ranging from
moderate to good and in some cases unprecedented prod-
ucts were synthesized.
and the solvent was evaporated under reduced pressure. The crude
was purified by flash chromatography (hexane/EtOAc, 9:1) to afford
the desired propargylamine 4a, 4c–i, 4q.
CeCl3·7H2O/CuI-Promoted Synthesis of Propargylamines 4; Method
B General Procedure
Aldehyde 2a–p (1 mmol) and amine 1a–f (1 mmol) were put in a
three-necked flask equipped with magnetic stirring and under N2 at-
mosphere. MgSO4 (0.050 g) and CeCl3·7H2O (0.112 g, 0.3 mmol) were
added and the mixture was stirred at r.t. for 15 min, checking for the
complete formation of the corresponding imine by TLC and GC-MS.
Phenylacetylene (3; 0.163 g, 1.6 mmol) and CuI (0.057 g, 0.3 mmol)
were added and the mixture was heated at 40 °C under N2 atmo-
sphere for 15 h. Then, the mixture was diluted with CH2Cl2 and
washed with 0.5 M ammonia/ammonium chloride buffer solution.
The organic layer was separated and dried over Na2SO4, then the sol-
vent was evaporated under reduced pressure. The crude was purified
by flash chromatography (hexane/EtOAc, 9:1) to afford the desired
propargylamine 4a–u.
N-Benzyl-1,3-diphenylprop-2-yn-1-amine (4a)
Method A: yield: 0.116 g (39%); Method B: yield: 0.253 g (85%); oil.
Spectroscopic data in agreement with literature.43
IR: 3065, 3024, 1595, 1492, 1448, 1065, 1028, 755, 689 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.65 (d, J = 7.5 Hz, 2 H), 7.55–7.50 (m, 2
H), 7.47–7.29 (m, 11 H), 4.84 (s, 1 H), 4.03 (s, 2 H), 1.71 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 140.2, 139.6, 132.0, 129.09, 128.8,
128.7, 128.5, 128.4, 128.1, 128.0, 127.4, 123.3, 89.1, 86.0, 53.8, 51.2.
GC-MS (EI, 70 eV): m/z (%) = 297 (M+, 19), 296 (39), 220 (52), 191
(100), 91 (66).
All reagents and solvents were purchased from commercial suppliers
and used without further purification, unless mentioned otherwise.
Dry CuSO4 was freshly prepared by heating CuSO4·5H2O in an oven at
200 °C for 3 h, until the blue powder became white. Chiral reagents
were used as racemates. All reactions were monitored by TLC using
EMD/Merck silica gel 60 pre-coated plates (0.25 mm), and the com-
pounds were visualized by using UV light (254 nm) or iodine vapors
as developing agent. Purification of the reaction products was carried
out by column flash chromatography using silica gel (0.25 mm). IR
specra were recorded on a Perkin Elmer UATR two instrument. 1H and
13C NMR spectra were recorded on a Varian Mercury 400 spectrome-
ter (400 MHz and 100 MHz, respectively). Chemical shifts are given in
ppm with reference to residual H in deuterated solvents as the inter-
nal standard. Coupling constants J are reported in Hz. Diastereomeric
ratios were determined by integration of the respective 1H NMR sig-
nals of the diastereomers isolated as a mixture by column chromatog-
raphy. Mass spectra were obtained using an Agilent 6850 gas chro-
matograph equipped with a HP5MS column (0.25 mm diameter) and
an Agilent 5973N mass selective detector. Microanalyses were per-
formed with an EA1108 CHNS D Fisons instrument.
Anal. Calcd for C22H19N: C, 88.85; H, 6.44; N, 4.71. Found: C, 89.15; H,
6.24; N, 5.01.
N-Benzyl-1-(4-tert-butylphenyl)-3-phenylprop-2-yn-1-amine (4b)
Method B: yield: 0.286 g (81%); oil.
IR: 3028, 2958, 2869, 1492, 1455, 1274, 1109, 829, 752, 689 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 8 Hz, 2 H), 7.58–7.56 (m, 2
H), 7.48 (t, J = 8 Hz, 4 H), 7.43–7.37 (m, 5 H), 7.33 (d, J = 7.4 Hz, 1 H),
4.86 (s, 1 H), 4.11 (d, J = 13.0 Hz, 1 H), 4.07 (d, J = 13.0 Hz, 1 H), 2.05
(br s, 1 H), 1.40 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 151.0, 140.1, 137.6, 132.1, 128.8,
128.7, 128.6, 128.4, 127.6, 127.4, 125.8, 123.5, 89.7, 85.9, 53.6, 51.5,
34.8, 31.7.
GC-MS (EI, 70 eV): m/z (%) = 353 (M+, 63), 352 (76), 296 (78), 247
(100), 217 (62), 91 (78).
Anal. Calcd for C26H27N: C, 88.34; H, 7.70; N, 3.96. Found: C, 88.17; H,
7.57; N, 4.32.
CuSO4/NaI-Promoted Synthesis of Propargylamines 4; Method A
General Procedure
N-Benzyl-1-(4-chlorophenyl)-3-phenylprop-2-yn-1-amine (4c)
Aldehyde 2a–i (1 mmol), phenylacetylene (3; 0.306 g, 3 mmol), NaI
(0.090 g, 0.6 mmol), dry CuSO4 (0.048 g, 0.3 mmol), MgSO4 (0.050 g),
benzoic acid (0.006 g, 0.05 mmol) and amine 1a–c (1 mmol) were put
in this order, under an inert atmosphere, in a three-necked flask
equipped with magnetic stirring. The mixture was heated at 80 °C
and the reaction monitored by TLC and GC-MS until a constant com-
position was reached (2–5 h). The mixture was then diluted with
CH2Cl2 and washed with 0.5 M ammonia/ammonium chloride buffer.
The organic phase was separated and dried over Na2SO4, then filtered,
Method A: yield: 0.100 g (30%); Method B: yield: 0.222 g (67%); oil.
IR: 3027, 2843, 1488, 1444, 1090, 1013, 829, 752, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.26 (m, 14 H), 4.82 (s, 1 H), 4.02
(s, 2 H), 1.94 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 139.8, 139.1, 132.0, 129.4, 128.9,
128.8, 128.7, 128.6, 128.5, 128.0, 127.5, 123.1, 88.8, 86.4, 53.2, 51.3.
GC-MS (EI, 70 eV): m/z (%) = 331 (M+, 25), 330 (45), 254 (25), 225
(100), 189 (41), 128 (11), 91 (70).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

G
C. Cimarelli et al.
Paper
Synthesis
Anal. Calcd for C22H18ClN: C, 79.63; H, 5.47; Cl, 10.68; N, 4.22. Found:
C, 79.57; H, 5.39; Cl, 10.91; N, 4.36.
GC-MS (EI, 70 eV): m/z (%) = 277 (M+, 66), 276 (17), 262 (19), 220
(100), 173 (16), 144 (42), 117 (87), 91 (86).
Anal. Calcd for C20H23N: C, 86.59; H, 8.36; N, 5.05. Found: C, 86.47; H,
8.21; N, 5.23.
N-Benzyl-1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-amine (4d)
Method A: yield: 0.121 g (37%); Method B: yield: 0.164 g (50%); oil.
IR: 2895, 2832, 1610, 1506, 1241, 1171, 1035, 821, 759, 693 cm–1
.
N-Benzyl-1-cyclohexyl-3-phenylprop-2-yn-1-amine (4h)
Method A: yield: 0.152 g (50%); Method B: yield: 0.227 g (75%); oil.
Spectroscopic data in agreement with literature.45
1H NMR (500 MHz, CDCl3): δ = 7.57 (d, J = 8.6 Hz, 2 H), 7.54–7.52 (m, 2
H), 7.47 (d, J = 7.4 Hz, 2 H), 7.38–7.28 (m, 6 H), 6.93 (d, J = 8.7 Hz, 2 H),
4.80 (s, 1 H), 4.01 (s, 2 H), 3.82 (s, 3 H), 2.08 (br s, 1 H).
IR: 2924, 2845, 1492, 1451, 1070, 752, 690 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 159.4, 131.8, 129.4, 129.1, 128.8,
128.5, 128.3, 127.4, 126.6, 122.9, 114.15, 113.9, 88.4, 86.3, 55.3, 52.8,
50.6.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.26 (m, 10 H), 4.14 (d, J = 13.4
Hz, 1 H), 3.93 (d, J = 13.4 Hz, 1 H), 3.43 (d, J = 5.8 Hz, 1 H), 2.00–1.60
(m, 7 H), 1.35–1.19 (m, 5 H).
GC-MS (EI, 70 eV): m/z (%) = 327 (M+, 17), 326 (25), 236 (41), 221
(100), 178 (21), 91 (44).
13C NMR (100 MHz, CDCl3): δ = 140.4, 132.0, 128.7, 128.6, 128.5,
128.1, 127.2, 123.8, 90.4, 85.0, 55.7, 52.0, 42.9, 30.5, 29.1, 26.8, 26.5,
26.4.
Anal. Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28. Found: C, 84.78;
H, 6.74; N, 4.12.
GC-MS (EI, 70 eV): m/z (%) = 303 (M+, 1), 302 (1), 220 (100), 91 (35).
Anal. Calcd for C22H25N: C, 87.08; H, 8.30; N, 4.62. Found: C, 87.23; H,
8.22; N, 4.46.
N-Benzyl-1-phenylhex-1-yn-3-amine (4e)
Method A: yield: 0.110 g (42%); Method B: yield: 0.137 g (52%); oil.
Spectroscopic data in agreement with literature.14
N-Benzyl-4-methyl-1-phenylhex-1-yn-3-amine (4i)
IR: 2059, 1597, 1491, 1458, 1325, 1031, 755, 736, 589 cm–1
.
Method A: yield: 0.173 g (62%); d.r. 21:79; Method B: yield: 0.264 g
(95%); d.r. 68:32; oil.
1H NMR (400 MHz, CDCl3): δ = 7.49–7.23 (m, 10 H), 4.11 (d, J = 13.0
Hz, 1 H), 3.92 (d, J = 13.0 Hz, 1 H), 3.62 (dd, J = 6.3, 7.4 Hz, 1 H), 1.90
(br s, 1 H), 1.80–1.65 (m, 2 H), 1.64–1.50 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3
H).
13C NMR (100 MHz, CDCl3): δ = 140.1, 131.9, 128.7, 128.6, 128.5,
128.2, 127.3, 123.6, 91.1, 84.3, 51.7, 50.0, 38.4, 19.7, 14.2.
IR: 3027, 2961, 1735, 1584, 1488, 1451, 1381, 1028, 748, 685, 527
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.23 (m, 20 H), 4.14 (d, J = 13.0
Hz, 2 H), 3.92 (d, J = 13.0 Hz, 2 H), 3.56 (d, J = 5.0 Hz, 1 H), 3.49 (d, J =
5.0 Hz, 1 H), 1.81–1.59 (m, 6 H), 1.43–1.29 (m, 2 H), 1.08 (d, J = 6.6 Hz,
6 H), 0.95 (t, J = 7.4 Hz, 3 H), 0.94 (t, J = 7.2 Hz, 3 H). Diastereomers
isolated as a mixture; the d.r. was determined by comparing the rela-
tive areas of the proton signals at δ 3.56 and 3.49.
13C NMR (100 MHz, CDCl3): δ = 140.1, 131.9, 128.7, 128.6, 128.5,
128.1, 128.0, 127.9, 127.3, 123.7, 89.6, 85.1, 55.1, 54.9, 53.9, 52.0,
51.4, 39.9, 39.7, 29.9, 27.1, 25.5, 16.1, 15.1, 11.9.
GC-MS (EI, 70 eV): m/z (%) = 263 (M+, 1), 262 (2), 220 (100), 115 (10),
91 (44).
Anal. Calcd for C19H21N: C, 86.64; H, 8.04; N, 5.32. Found: C, 86.48; H,
7.88; N, 5.44.
N-Benzyl-4-methyl-1-phenylpent-1-yn-3-amine (4f)
GC-MS (EI, 70 eV): m/z (%) = 277 (M+, 71), 262 (22), 249 (60), 220 (65),
200 (25), 186 (29), 144 (38), 117 (47), 91 (100).
Method A: yield: 0.105 g (40%); Method B: yield: 0.200 g (76%); oil.
Spectroscopic data in agreement with literature.44
Anal. Calcd for C20H23N: C, 86.59; H, 8.36; N, 5.05. Found: C, 86.84; H,
8.23; N, 4.77.
IR: 2926, 2852, 1487, 1443, 1068, 1027, 755, 683 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.26 (m, 10 H), 4.17 (d, J = 13.0
Hz, 1 H), 3.95 (d, J = 13.0 Hz, 1 H), 3.46 (d, J = 5.4 Hz, 1 H), 2.01 (d hept,
J = 6.5, 6.5 Hz, 1 H), 1.59 (br s, 1 H), 1.13 (d, J = 6.7 Hz, 3 H), 1.12 (d, J =
6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 140.3, 131.8, 128.5, 128.4, 128.3,
127.9, 127.0, 123.6, 89.9, 84.8, 56.3, 51.9, 33.0, 19.9, 18.2.
N-Benzyl-3-phenyl-1-(p-tolyl)prop-2-yn-1-amine (4j)
Method B: yield: 0.177 g (57%); oil. Spectroscopic data in agreement
with literature.45
IR: 3024, 2921, 1488, 1444, 1025, 814, 755, 685 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.21 (m, 14 H), 4.82 (s, 1 H), 4.03
(s, 2 H), 2.39 (s, 4 H).
13C NMR (100 MHz, CDCl3): δ = 137.6, 131.8, 129.2, 128.6, 128.5,
128.3, 128.2, 127.7, 127.6, 127.2, 123.2, 89.0, 85.8, 53.3, 51.0, 21.2.
GC-MS (EI, 70 eV): m/z (%) = 263 (M+, 69), 262 (23), 248 (15), 220 (91),
162 (16), 91 (100).
Anal. Calcd for C19H21N: C, 86.64; H, 8.04; N, 5.32. Found: C, 86.57; H,
8.29; N, 5.47.
GC-MS (EI, 70 eV): m/z (%) = 311 (M+, 30), 310 (49), 220 (62), 205
(100), 91 (52).
N-Benzyl-4,4-dimethyl-1-phenylpent-1-yn-3-amine (4g)
Anal. Calcd for C23H21N: C, 88.71; H, 6.80; N, 4.50. Found: C, 88.97; H,
6.98; N, 4.33.
Method A: yield: 0.030 g (11%); Method B: yield: 0.138 g (50%); oil.
Spectroscopic data in agreement with literature.44
IR: 2955, 2863, 1480, 1439, 1097, 1031, 755, 692 cm–1
.
N-Benzyl-3-phenyl-1-(4-propylphenyl)prop-2-yn-1-amine (4k)
1H NMR (400 MHz, CDCl3): δ = 7.50–7.44 (m, 4 H), 7.37–7.26 (m, 6 H),
4.19 (d, J = 13.3 Hz, 1 H), 3.92 (d, J = 13.3 Hz, 1 H), 3.19 (s, 1 H), 1.45
(br s, 1 H), 1.10 (s, 9 H).
Method B: yield: 0.265 g (78%); oil.
IR: 2961, 2924, 2862, 1488, 1448, 1090, 755, 685 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 134.6, 131.9, 128.6, 128.5, 128.4,
128.0, 127.2, 127.1, 90.5, 84.8, 60.3, 52.5, 35.4, 26.9.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

H
C. Cimarelli et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 7.5 Hz, 2 H), 7.57–7.25 (m,
10 H), 7.21 (d, J = 8.0 Hz, 2 H), 4.82 (s, 1 H), 4.07 (d, J = 12.0 Hz, 1 H),
4.03 (d, J = 12.0 Hz, 1 H), 2.63 (t, J = 7.6 Hz, 2 H), 2.03 (br s, 1 H), 1.68
(sext, J = 7.5 Hz, 2 H), 0.99 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 142.6, 140.0, 137.8, 132.0, 128.9,
128.8, 128.7, 128.6, 128.4, 127.8, 127.4, 123.5, 89.7, 85.9, 53.6, 51.4,
38.0, 24.9, 14.2.
IR: 3024, 2836, 2729, 1694, 1595, 1488, 1440, 1138, 755, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.06 (s, 1 H), 8.17 (s, 1 H), 7.95 (d, J =
7.6 Hz, 1 H), 7.85 (d, J = 6.6 Hz, 1 H), 7.57–7.10 (m, 11 H), 4.90 (s, 1 H),
4.03 (s, 2 H), 2.15 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 192.5, 141.6, 139.5, 136.9, 134.2,
132.3, 132.1, 129.5, 129.4, 129.3, 128.8, 128.7, 128.6, 127.6, 123.0,
88.3, 86.8, 53.4, 51.4.
GC-MS (EI, 70 eV): m/z (%) = 339 (M+, 48), 338 (64), 296 (39), 262 (25),
248 (49), 233 (100), 204 (58), 91 (63).
GC-MS (EI, 70 eV): m/z (%) = 325 (M+, 44), 324 (55), 298 (15), 248 (43),
234 (51), 219 (100), 218 (74), 189 (43), 91 (69).
Anal. Calcd for C25H25N: C, 88.45; H, 7.42; N, 4.13. Found: C, 88.39; H,
7.47; N, 4.06.
Anal. Calcd for C23H19NO: C, 84.89; H, 5.89; N, 4.30. Found: C, 84.76;
H, 5.94; N, 4.22.
N-Benzyl-1-(4-isopropylphenyl)-3-phenylprop-2-yn-1-amine (4l)
N-Benzyl-1-(furan-2-yl)-3-phenylprop-2-yn-1-amine (4p)
Method B: yield: 0.203 g (60%); oil.
IR: 2960, 1697, 1489, 1215, 830, 754, 693 cm–1
Method B: yield: 0.130 g (45%); oil. Spectroscopic data in agreement
with literature.46
.
1H NMR (400 MHz, CDCl3): δ = 7.60–7.25 (m, 14 H), 4.83 (s, 1 H), 4.08
(d, J = 13.1 Hz, 1 H), 4.03 (d, J = 13.1 Hz, 1 H), 2.96 (sept, J = 6.9 Hz, 1
H), 1.94 (br s, 1 H), 1.30 (d, J = 6.9 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 148.7, 140.0, 137.9, 132.0, 128.8,
128.7, 128.6, 128.4, 127.9, 127.4, 126.9, 123.5, 89.7, 85.8, 53.6, 51.4,
34.1, 24.3.
IR: 3061, 3026, 2843, 1489, 1144, 1073, 1007, 754, 728, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.25 (m, 11 H), 6.48–6.44 (m, 1
H), 6.38–6.35 (m, 1 H), 4.93 (s, 1 H), 4.02 (d, J = 13.0 Hz, 1 H), 3.98 (d,
J = 13.0 Hz, 1 H), 2.61 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 152.6, 142.8, 139.2, 132.1, 128.8,
128.7, 128.6, 128.5, 127.5, 122.9, 110.5, 108.0, 86.5, 85.2, 50.8, 47.9.
GC-MS (EI, 70 eV): m/z (%) = 339 (M+, 38), 338 (52), 296 (48), 250 (40),
233 (100), 218 (48), 91 (95).
GC-MS (EI, 70 eV): m/z (%) = 287 (M+, 12), 286 (20), 258 (11), 196 (49),
181 (100), 152 (50), 91 (42).
Anal. Calcd for C25H25N: C, 88.45; H, 7.42; N, 4.13. Found: C, 88.33; H,
7.49; N, 4.02.
Anal. Calcd for C20H17NO: C, 83.59; H, 5.96; N, 4.87. Found: C, 83.72;
H, 5.83; N, 4.63.
N-Benzyl-1-(4-fluorophenyl)-3-phenylprop-2-yn-1-amine (4m)
N-Isopropyl-1,3-diphenylprop-2-yn-1-amine (4q)
Method B: yield: 0.170 g (54%); oil.
IR: 3027, 2847, 1602, 1506, 1219, 1153, 832, 759, 689 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.64–7.60 (m, 2 H), 7.53–7.51 (m, 2 H),
7.48–7.26 (m, 8 H), 7.11–7.05 (m, 2 H), 4.81 (s, 1 H), 4.01 (s, 2 H), 1.97
(br s, 1 H).
Method A: yield: 0.132 g (53%); Method B: yield: 0.180 g (72%); oil.
.
IR: 2959, 1594, 1491, 1167, 753, 692 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.64–7.32 (m, 10 H), 4.88 (s, 1 H), 3.28
(hept, J = 6.2 Hz, 1 H), 1.60 (br s, 1 H), 1.19 (d, J = 6.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 141.2, 132.0, 128.9, 128.7, 128.4,
128.0, 127.8, 123.5, 89.9, 85.4, 52.5, 46.6, 23.9, 22.4.
GC-MS (EI, 70 eV): m/z (%) = 249 (M+, 7), 248 (9), 234 (16), 206 (11),
13C NMR (100 MHz, CDCl3): δ = 162.6 (d, JC–F = 248.6 Hz), 139.8,
1
3
4
136.2, 132.0, 129.6 (d, JC–F = 8.2 Hz), 128.7 (d, JC–F = 2.2 Hz), 128.6,
2
128.5, 128.0, 127.4, 123.2, 115.5 (d, JC–F = 22.4 Hz), 89.0, 86.3, 53.1,
51.3.
191 (100), 172 (13), 130 (9), 128 (9), 77 (10).
Anal. Calcd for C18H19N: C, 86.70; H, 7.68; N, 5.62. Found: C, 86.91; H,
7.47; N, 5.68.
GC-MS (EI, 70 eV): m/z (%) = 315 (M+, 20), 314 (34), 238 (21), 224 (54),
209 (100), 91 (40).
Anal. Calcd for C22H18FN: C, 83.78; H, 5.75; F, 6.02; N, 4.44. Found: C,
84.11; H, 6.03; F, 5.87; N, 4.77.
1,3-Diphenyl-N-(1-phenylethyl)prop-2-yn-1-amine (4r)
Method B: yield: 0.200 g (64%); d.r. 72:28; oil.
IR: 3054, 3028, 2970, 2863, 2250, 1491, 1443, 1104, 1031, 751, 696
N-Benzyl-1-(4-bromophenyl)-3-phenylprop-2-yn-1-amine (4n)
cm–1
.
Method B: yield: 0.206 g (55%); oil.
1H NMR (400 MHz, CDCl3): δ = 7.65–7.25 (m, 30 H), 4.72 (s, 1 H), 4.51
(s, 1 H), 4.42 (q, J = 6.5 Hz, 1 H), 3.96 (q, J = 6.5 Hz, 1 H), 1.75 (br s, 2 H),
1.46 (d, J = 6.5 Hz, 3 H), 1.43 (d, J = 6.5 Hz, 3 H). Diastereomers isolated
as a mixture; the d.r. was determined by comparing the relative areas
of the proton signals at δ 4.72 and 4.51. Data in agreement with liter-
ature.47
IR: 3061, 3028, 2843, 1484, 1455, 1072, 1009, 821, 755, 693 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.54–7.48 (m, 6 H), 7.43–7.26 (m, 8 H),
4.78 (s, 1 H), 3.99 (s, 2 H), 2.11 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 139.5, 139.4, 132.0, 131.8, 129.7,
.
128.8, 128.7, 128.6, 128.5, 127.5, 123.0, 122.0, 88.6, 86.4, 53.2, 51.2.
GC-MS (EI, 70 eV): m/z (%) = 376 ([M + 1]+, 31), 374 (M+, 30), 286 (33),
284 (34), 271 (75), 269 (74), 220 (32), 189 (78), 91 (100).
13C NMR (100 MHz, CDCl3): δ = 144.9, 141.0, 132.0, 128.9, 128.7,
128.5, 128.4, 128.0, 127.8, 127.5, 127.2, 123.5, 56.4, 55.5, 52.4, 25.3,
23.8.
Anal. Calcd for C22H18BrN: C, 70.22; H, 4.82; Br, 21.23; N, 3.72. Found:
C, 70.11; H, 4.93; Br, 21.31; N, 3.56.
GC-MS (EI, 70 eV): m/z (%) = 311 (M+, 8), 310 (7), 296 (32), 234 (12),
206 (24), 191 (100), 105 (13), 77 (6).
3-[1-(Benzylamino)-3-phenylprop-2-yn-1-yl]benzaldehyde (4o)
Anal. Calcd for C23H21N: C, 88.71; H, 6.80; N, 4.50. Found: C, 88.54; H,
6.97; N, 4.31.
Method B: yield: 0.228 g (70%); oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

I
C. Cimarelli et al.
Paper
Synthesis
N-(2-Methylpropyl)-1,3-diphenylprop-2-yn-1-amine (4s)
Supporting Information
Method B: yield: 0.187 g (71%); oil.
IR: 2961, 1492, 1448, 1098, 755, 685 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 7.6 Hz, 2 H), 7.51–7.25 (m, 8
H), 4.84 (s, 1 H), 2.65 (dd, J = 11.4, 7.0 Hz, 1 H), 2.58 (dd, J = 11.4, 6.5
Hz, 1 H), 2.02 (br s, 1 H), 1.83 (hept, J = 6.5 Hz, 1 H), 0.98 (dd, J = 3.5,
6.6 Hz, 6 H).
Supporting information for this article is available online at
.
https://doi.org/10.1055/s-0037-1612253.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
References
(1) Ermolat’ev, D. S.; Bariwal, J. B.; Steenackers, H. P. L.; De Keers-
maecker, S. C. J.; Van der Eycken, E. V. Angew. Chem. Int. Ed.
2010, 49, 9465.
(2) Fedoseev, P.; Sharma, N.; Khunt, R.; Ermolat’ev, D. S.; Van der
Eycken, E. V. RSC Adv. 2016, 6, 75202.
13C NMR (100 MHz, CDCl3): δ = 140.1, 131.7, 128.5, 128.3, 128.1,
127.8, 127.7, 123.2, 89.2, 85.5, 55.1, 54.7, 28.3, 20.9, 20.7.
GC-MS (EI, 70 eV): m/z (%) = 263 (M+, 4), 262 (3), 220 (24), 191 (100),
165 (7).
(3) Yuan, B.; Zhang, F.; Li, Z.; Yang, S.; Yan, R. Org. Lett. 2016, 18,
5928.
Anal. Calcd for C19H21N: C, 86.64; H, 8.04; N, 5.32. Found: C, 86.43; H,
7.85; N, 5.39.
(4) Weng, J.; Chen, Y.; Yue, B.; Xu, M.; Jin, H. Eur. J. Org. Chem. 2015,
3164.
(5) Kwon, K.-H.; Serrano, C. M.; Koch, M.; Barrows, L. R.; Looper, R.
E. Org. Lett. 2014, 16, 6048.
(6) Grishina, A. A.; Polyakova, S. M.; Kunetskiy, R. A.; Císařová, I.;
Lyapkalo, I. M. Chem. Eur. J. 2011, 17, 96.
N-(4-Methoxybenzyl)-1-(4-methoxyphenyl)-3-phenylprop-2-yn-
1-amine (4t)
Method B: yield: 0.221 g (62%); oil.
IR: 2833, 1608, 1505, 1244, 1027, 828, 751, 692 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.53 (m, 4 H), 7.36–7.33 (m, 5 H),
6.93–6.89 (m, 4 H), 4.76 (s, 1 H), 3.94 (s, 2 H), 3.82 (s, 3 H), 3.81 (s, 3
H), 2.14 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.4, 159.0, 132.6, 132.0, 130.0,
129.1, 128.5, 128.4, 123.4, 114.3, 114.1, 114.0, 89.6, 85.9, 55.6, 55.5,
53.1, 50.6.
(7) Ranjan, A.; Yerande, R.; Wakchaure, P. B.; Yerande, S. G.; Dethe,
D. H. Org. Lett. 2014, 16, 5788.
(8) Nechaev, A. A.; Peshkov, A. A.; Van Hecke, K.; Peshkov, V. A.; Van
der Eycken, E. V. Eur. J. Org. Chem. 2017, 1063.
(9) Ying, J.; Wang, H.; Qi, X.; Peng, J.; Wu, X. Eur. J. Org. Chem. 2018,
688.
(10) Wang, H.; Ying, J.; Lai, M.; Qi, X.; Peng, J.; Wu, X. Adv. Synth.
Catal. 2018, 360, 1693.
(11) Peshkov, V. A.; Pereshivko, O. P.; Sharma, S.; Meganathan, T.;
Parmar, V. S.; Ermolat’ev, D. S.; Van der Eycken, E. V. J. Org.
Chem. 2011, 76, 5867.
GC-MS (EI, 70 eV): m/z (%) = 357 (M+, 22), 356 (19), 280 (22), 250 (17),
236 (34), 221 (100), 178 (20), 121 (55).
Anal. Calcd for C24H23NO2: C, 80.64; H, 6.49; N, 3.92. Found: C, 80.51;
H, 6.67; N, 3.78.
(12) Pereshivko, O. P.; Peshkov, V. A.; Jacobs, J.; Van Meervelt, L.; Van
der Eycken, E. V. Adv. Synth. Cat. 2013, 355, 781.
(13) Campbell, M. J.; Toste, F. D. Chem. Sci. 2011, 2, 1369.
(14) Wang, G.; Liu, C.; Li, B.; Wang, Y.; Van Hecke, K.; Van der Eycken,
E. V.; Pereshivko, O. P.; Peshkov, V. A. Tetrahedron 2017, 73,
6372; and references cited therein.
(15) Pereshivko, O. P.; Peshkov, V. A.; Peshkov, A. A.; Jacobs, J.; Van
Meervelt, L.; Van der Eycken, E. V. Org. Biomol. Chem. 2014, 12,
1741.
1-(Furan-2-yl)-N-(furan-2-ylmethyl)-3-phenylprop-2-yn-1-amine
(4u)
Method B: yield: 0.130 g (47%); oil.
IR: 3014, 1664, 1597, 1487, 1439, 1222, 1009, 747, 692 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.26 (m, 7 H), 6.49–6.47 (m, 1 H),
6.37–6.28 (m, 3 H), 4.97 (s, 1 H), 4.03 (d, J = 14.2 Hz, 1 H), 4.00 (d, 14.2
Hz, 1 H), 2.70 (br s, 1 H).
(16) Sadeghzadeh, S. M.; Zhiani, R.; Emrani, S. Appl. Organomet.
Chem. 2018, 32, e3941.
(17) Sadeghzadeh, S. M. Appl. Organomet. Chem. 2016, 30, 835.
(18) Sadeghzadeh, S. M. J. Mol. Catal. A: Chem. 2016, 423, 216.
(19) Liu, X.; Wang, M. Y.; Wang, S. Y.; Wang, Q.; He, L. N. ChemSus-
Chem 2017, 10, 1210.
(20) Kikuchi, S.; Yoshida, S.; Sugawara, Y.; Yamada, W.; Cheng, H.;
Fukui, K.; Sekine, K.; Iwakura, I.; Ikeno, T.; Yamada, T. Bull. Chem.
Soc. Jpn. 2011, 84, 698.
13C NMR (100 MHz, CDCl3): δ = 152.6, 152.0, 142.9, 142.4, 132.1,
128.7, 128.5, 122.8, 110.6, 110.5, 108.3, 108.1, 85.9, 85.4, 47.7, 43.3.
GC-MS (EI, 70 eV): m/z (%) = 277 (M+, 6), 276 (21), 260 (11), 248 (26),
200 (32), 181 (100), 152 (51), 109 (63), 81 (34).
Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 78.21;
H, 5.37; N, 5.31.
(21) Zhao, Y.; Qiu, J.; Li, Z.; Wang, H.; Fan, M.; Wang, J. ChemSusChem
2017, 10, 2001.
Funding Information
This work was carried out under the framework of the University Re-
search Project ‘Chemical Swiss tools to treat tumors, metastases and
infections’ supported by the University of Camerino (FAR 2014-2015).
(22) Hu, J.; Ma, J.; Zhu, Q.; Zhang, Z.; Wu, C.; Han, B. Angew. Chem. Int.
Ed. 2015, 54, 5399.
(23) Wang, M.; Song, Q.; Ma, R.; Xie, J.; He, L. Green Chem. 2016, 18,
282.
U
n
i
v
ersità
d
e
g
l
iStu
d
idiC
a
m
eri
n
o
(F
A
R
2
0
1
4-2
0
1
5)
(24) Hu, J.; Ma, J.; Zhang, Z.; Zhu, Q.; Zhou, H.; Lua, W.; Han, B. Green
Chem. 2015, 17, 1219.
Acknowledgment
(25) Li, C. J.; Wei, C. Chem. Commun. 2002, 268.
(26) Peshkov, V. A.; Pereshivko, O. P.; Van der Eycken, E. V. Chem. Soc.
Rev. 2012, 41, 3790; and references cited therein.
(27) Lauder, K.; Toscani, A.; Scalacci, N.; Castagnolo, D. Chem. Rev.
2017, 117, 14091; and references cited therein.
We thank Pfizer Global Supply – Ascoli Piceno Site for granting doc-
toral fellowships to F.N. and F.V.R.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

J
C. Cimarelli et al.
Paper
Synthesis
(28) Saha, T. K.; Das, R. ChemistrySelect 2018, 3, 147.
(29) Shehzadi, S. A.; Saeed, A.; Lemière, F.; Maes, B. U. W.; Tehrani, K.
A. Eur. J. Org. Chem. 2018, 78.
(38) Bartoli, G.; Fernández-Bolaños, J. G.; Di Antonio, G.; Foglia, G.;
Giuli, S.; Gunnella, R.; Mancinelli, M.; Marcantoni, E.; Paoletti,
M. J. Org. Chem. 2007, 72, 6029.
(30) Yusubov, M. S.; Zhdankin, V. V. Resour.-Effic. Technol. 2015, 1,
49.
(39) Cimarelli, C.; Di Nicola, M.; Diomedi, S.; Giovannini, R.;
Hamprecht, D.; Properzi, R.; Sorana, F.; Marcantoni, E. Org.
Biomol. Chem. 2015, 13, 11687.
(40) Ravishankar, L.; Patwe, S. A.; Gosarani, N.; Roy, A. Synth.
Commun. 2010, 40, 3177.
(31) Küpper, F. C.; Feiters, M. C.; Olofsson, B.; Kaiho, T.; Yanagida, S.;
Zimmermann, M. B.; Carpenter, L. J.; Luther, G. V. III.; Lu, Z.;
Jonsson, M.; Kloo, L. Angew. Chem. Int. Ed. 2011, 50, 11598.
(32) Li, X.; Mao, Z.; Wang, Y.; Chen, W.; Lin, X. Tetrahedron 2011, 67,
3858.
(41) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem. Int. Ed.
2000, 39, 2632.
(33) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, 77,
6443; and references cited therein.
(42) Lu, Y.; Johnstone, T. C.; Arndtsen, B. A. J. Am. Chem. Soc. 2009,
131, 11284.
(34) Bailey, A. D.; Cherney, S. M.; Anzalone, P. W.; Anderson, E. D.;
Ernat, J. J.; Mohan, R. J. Synlett 2006, 215.
(43) Feng, H.; Ermolat’ev, D. S.; Song, G.; Van der Eycken, E. V. J. Org.
Chem. 2011, 76, 7608.
(35) Bartoli, G.; Marcantoni, E.; Marcolini, M.; Sambri, L. Chem. Rev.
2010, 110, 6104; and references cited therein.
(44) Wachenfeldt, H. v.; Paulsen, F.; Sundin, A.; Strand, D. Eur. J. Org.
Chem. 2013, 4578.
(36) Multicomponent Reactions: Concepts and Applications for Design
and Synthesis; Herrera, R. P.; Marqués-López, E., Ed.; John Wiley
& Sons: Hoboken, New Jersey, 2015.
(45) Bariwal, J. B.; Ermolat’ev, D. S.; Van der Eycken, E. V. Chem. Eur. J.
2010, 16, 3281.
(46) Tong, S.; Wang, Q.; Wang, M. X.; Zhu, J. Angew. Chem. Int. Ed.
2015, 54, 1293.
(37) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003, 2101.
(47) Shi, L.; Tu, Y. Q.; Wang, M.; Zhang, F. M.; Fan, C. A. Org. Lett.
2004, 6, 1001.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J