Highly Efficient One-Pot Synthesis of Novel Propargylamine-Based Sulfonamides by an A3-Coupling Reaction

Article abstract of DOI:10.1055/s-0035-1562602

Novel propargylamine-based sulfonamides were synthesized in excellent yields by the copper(I) iodide catalyzed three-component coupling of propargylsulfonamides, morpholine, and aldehydes.

Full text of DOI:10.1055/s-0035-1562602

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
M. Abdoli et al.
Letter
Synlett
Highly Efficient One-Pot Synthesis of Novel Propargylamine-
Based Sulfonamides by an A3-Coupling Reaction
Morteza Abdolia
Hamid Saeidian*b
Me
R2
R2
Me
Ali Kakanejadifard*a
CuI (10 mol%), K2CO3 (10 mol%)
O
a Department of Chemistry, Faculty of Science, Lorestan
University, Khorramabad, Iran
H
NH
toluene, reflux
48 h
N
N
S
O
N
S
O
R1
O
b Department of Science, Payame Noor University
(PNU), P.O. Box: 19395-4697, Tehran, Iran
Saeidian1980@gmail.com
R1
R1 = Ph, Bn, (S)-CH2(Me)Ph
2 = H, 4-Me, 4-OMe, 4-i-Pr, 2-Cl, 2-OH, 2,4-Cl2
O
O
O
Novel propargylamine-based sulfonamides
as raw chemicals
R
10 examples (67–87%)
kakanejadi.a@lu.ac.ir
Received: 12.05.2016
Accepted after revision: 28.06.2016
Published online: 28.07.2016
To the best of our knowledge, no general method for the
synthesis of propargylamine-based sulfonamide derivatives
has been reported in the literature. We proposed that the
target compounds might be produced by an efficient cop-
per(I)-catalyzed one-pot coupling of a secondary amine
with an N-propargylsulfonamide, and an aromatic alde-
hyde, and this communication presents our results based
on this approach. The starting N-propargyl-4-toluenesul-
fonamides 5 are readily prepared. Treatment of tosyl chlo-
ride (1) with an amine 2 in pyridine at room temperature
for two hours affords the corresponding sulfonamide 3 in
good to excellent yield. The N-propargylsulfonamides 5 can
then be prepared in high yields by the treatment of sulfon-
amide 3 with propargyl bromide (4) in the presence of
K2CO3 in refluxing acetonitrile for 8 hours (Scheme 2).
DOI: 10.1055/s-0035-1562602; Art ID: st-2016-d0337-l
Abstract Novel propargylamine-based sulfonamides were synthesized
in excellent yields by the copper(I) iodide catalyzed three-component
coupling of propargylsulfonamides, morpholine, and aldehydes.
Key words propargylsulfonamides, multicomponent reaction, cou-
pling, copper catalysis
The design and synthesis of novel molecular scaffolds
with unique structural and biological properties is always
an interesting challenge.1–4 Propargylamines exhibit biolog-
ical properties such as anti-Alzheimer, anti-Parkinsonian,
and antidepressant activities.5–8 Moreover, sulfonamide de-
rivatives are also well-known important biological compo-
nents.9–12
We became interested in developing a method that pro-
vides access to propargylamine-based sulfonamide deriva-
tives. Methods for the preparation of propargylamines in-
clude amination of propargylic electrophiles,13–16 nucleo-
philic addition of alkynes to imines or enamines,17–20 and
three-component (amine, aldehyde, terminal alkyne) cou-
pling reactions through C–H activation. Among these syn-
thetic strategies, the A3-coupling is efficient and permits
the construction of complex structures from simple start-
ing materials with water as a byproduct of the reaction
(Scheme 1).21–25
O
S
O
S
R
pyridine
r.t, 2 h
Me
Cl
+
RNH2
Me
NH
O
O
1
2
3a, R = Bn (95%)
3b, R = (S)-CH2(Me)Ph (91%)
3c, R = Ph (80%)
O
S
R
K2CO3
Br
3 +
Me
N
4
MeCn, reflux
8 h
O
5a, 91%
5b, 90%
5c, 78%
Scheme 2 Synthesis of N-propargylsulfonamides 5 from tosyl chloride
(1)
With the propargylsulfonamides 5 in hand, we turned
our attention to the A3-coupling. We started our studies
with the optimization of the catalytic system and the reac-
tion conditions for the model reaction of sulfonamide 5a,
benzaldehyde (6a), and morpholine (7). First, we surveyed
various copper catalysts in refluxing MeCN (Table 1, entries
1–7). With CuO as the catalyst, only a low conversion to the
desired product was observed (entry 1). Likewise, the mod-
R1
H
R2
R1
R2
N
N
H
O
conditions
H
R
R
R3
R3
Scheme 1 Synthesis of propargylamines by an A3-coupling reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
M. Abdoli et al.
Letter
Synlett
Table 1 Optimization of the Conditions for the Model Reaction of Sulfonamide 5, Benzaldehyde (6a), and Morpholine (7)
Me
O
O
O
Cu source
H
N
S
Me +
+
solvent, reflux
48 h
N
H
N
N
S
O
O
O
6a
5
7
8a
O
Entry
Catalyst (mol%)
K2CO3 (mol%)
Solvent
Yield (%)
1
2
CuO (10)
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
trace
31
25
33
15
41
75
87
67
24
79
76
CuCl2 (10)
Cu(SO4)2 (10)
CuBr2 (10)
–
3
–
4
–
5
Cu powder (10)
CuI (10)
–
6
–
7
CuI (10)
10
10
10
10
10
10
8
CuI (10)
CuI (10)
toluene
CH2Cl2
H2O
9
10
11
12
CuI (10)
CuI (5)
toluene
toluene
CuI (2.5)
el reaction in the presence of CuCl2 failed to give satisfacto-
ry results (entry 2), as did the reactions in the presence of
Cu(SO4)2, CuBr2, or Cu powder (entries 3–5). The reaction in
the presence of CuI gave the desired product in moderate
yield (entry 6), which improved in the presence of K2CO3 as
a base (entry 7). The base might play two roles in the reac-
tion: deprotonation of the presumed copper(I)-coordinated
propargylsulfonamides 5 and increasing the rate of imini-
um ion formation (see Scheme 4 below). We also investigat-
ed the effects of various solvents under reflux conditions
(entries 8–10). The best yield was achieved by using toluene
as the solvent (entry 8). When we examined the amount of
catalyst required, we were unable to reduce the catalyst
loading below 10 mol% without adversely affecting the
yield (entries 11 and 12). Thus, the optimal reaction condi-
tions were determined to be CuI (10 mol%) as the catalyst,
K2CO3 (10 mol%) as the base, and toluene as the solvent at
reflux for 48 hours.
To explore the scope of the reaction, we used various
benzaldehydes and N-propargylsulfonamides with mor-
pholine as the amine (Scheme 3). Generally, the coupling
proceeded smoothly to afford the corresponding substitut-
ed N-propargylsulfonamides in good yields under the opti-
mized conditions.27 The electronic character of the substit-
uents on the aldehydes had little effect, as both electron-
rich and electron-deficient aromatic aldehydes reacted effi-
ciently. Furthermore, the reaction was tolerant towards a
variety of functional groups, such as chloro, alkoxy, or hy-
droxy. The reaction was readily performed on a gram scale
to give isolated yields comparable to those obtained from
small-scale reactions.
The structures of the desired products 8 were con-
firmed by 1H NMR, and 13C NMR spectroscopy (see the Sup-
porting Information and ref. 27).
A mechanism for this copper-catalyzed A3-coupling is
proposed in Scheme 4.26 The reaction proceeds by genera-
tion of an iminium ion II by condensation of morpholine (7)
with the aldehyde 6. Intermediate II then reacts with the
copper acetylide I generated in situ from the sulfonamide 5,
to give the corresponding N-propargylsulfonamide 8 with
concomitant regeneration of the copper (I) catalyst.
In summary, an efficient method has been developed for
the preparation of a new class of propargylamine-based
sulfonamides through the A3-coupling reaction of an aro-
matic aldehyde, morpholine, and an N-propargylarenesul-
fonamide in the presence of CuI as catalyst. The process is
simple and permits the synthesis of a diverse range of prop-
argylamine-based sulfonamides in high yields.
Acknowledgment
We wish to acknowledge financial support from Lorestan University
and Payame Noor University (PNU).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
M. Abdoli et al.
Letter
Synlett
Me
R2
O
O
O
CuI (10 mol%), K2CO3 (10 mol%)
H
R2
+
N
S
Me
+
toluene, reflux
48 h
R1
N
H
O
N
N
S
O
R1
8b–g
O
6b–e
7
5
O
Me
Me
Me
Me
Me
O
O
O
O
O
S
S
S
S
S
O
O
O
O
O
N
N
N
N
N
Cl
N
O
N
O
N
O
N
O
N
O
8a, (87%)
8b, (83%)
8d, (82%)
8e, (80%)
8c, (77%)
Me
MeO
Me
i-Pr
Me
Me
Me
Me
O
O
O
O
O
S
S
S
S
S
O
O
O
O
O
N
N
N
N
N
Me
Me
HO
N
O
Cl
Cl
N
O
N
O
N
O
N
O
8g, (74%)
8h, (85%)
8i, (80%)
8j (73%)
8f, (67%)
Me
Scheme 3 The synthesis of propargylamine-based sulfonamide derivatives by using a variety of aldehydes
O
Cu
H
R1
N
R1
N
O
OH
N
S
O
O
S
O
H
R2
II
Me
copper acetylide I
R2
O
5
Me
O
Me
H
Cu+
R2
+
N
H
7
6
N
N
R1
S
O
O
8
O
Scheme 4 A proposed mechanism for the formation of propargylamine-based sulfonamides 8
Supporting Information
References and Notes
Supporting information for this article is available online at
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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18.6, 2.0 Hz, 2 H), 4.41 (br s, 1 H), 4.43 (ABd, J = 14.0 Hz, 1 H),
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toluenesulfonamide (8b)
Yellow oil; yield: 405 mg (83%). 1H NMR (400 MHz, CDCl3): δ =
2.33–2.36 (m, 7 H), 2.39 (s, 3 H), 3.68–3.76 (m, 4 H), 4.13–4.19
(ABdd, J = 18.8, 2.0 Hz, 2 H), 4.28–4.35 (br s, 1 H), 4.41 (ABd, J =
14.0 Hz, 1 H), 4.47 (ABd, J = 14.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 2 H),
7.21–7.26 (m, 4 H), 7.33–7.40 (m, 5 H), 7.83 (d, J = 8.4 Hz, 2 H).
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61.20, 66.93, 80.44, 81.85, 127.78, 128.16, 128.30, 128.31,
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D