Base-catalyzed, three-component coupling of aldehydes, terminal aryl acetylenes, and amines: Application to synthesis of propargylamines

Article abstract of DOI:10.1055/s-0030-1259916

Propargylamines are formed in high yield by three-component coupling reaction of aldehydes, terminal aryl acetylenes, and amines in DMSO in the presence of catalytic tetraalkylammonium hydroxide. This reaction does not require a transition-metal catalyst.

Full text of DOI:10.1055/s-0030-1259916

LETTER
1157
Base-Catalyzed, Three-Component Coupling of Aldehydes, Terminal Aryl
Acetylenes, and Amines: Application to Synthesis of Propargylamines
A
pplication to
a
Synthesis
o
c
f
Propargy
h
lamines in S. Patil,* Sachin V. Patil, Vivek D. Bobade*
Department of Chemistry, HPT Arts and RYK Science College, Nasik 422005, India
Fax +91(253)2574682; E-mail: spatilsachin@yahoo.co.in; E-mail: v_bobade31@rediffmail.com
Received 18 December 2010
sis to the three-component coupling reaction of aldehydes,
terminal aryl acetylenes, and amines in DMSO for synthe-
sis of propargylamines.
Abstract: Propargylamines are formed in high yield by three-com-
ponent coupling reaction of aldehydes, terminal aryl acetylenes, and
amines in DMSO in the presence of catalytic tetraalkylammonium
hydroxide. This reaction does not require a transition-metal cata-
lyst.
In the initial study, piperidine, benzaldehyde, and phenyl-
acetylene were chosen to optimize the reaction conditions.
Following optimization, 10 mol% of tetrabutylammoni-
um hydroxide (TBAOH) was found to be effective for the
formation of propargylamines in DMSO at room temper-
ature.
Key words: three-component coupling, aldehydes, aryl acetylenes,
amines, tetraalkylammonium hydroxide
One-pot multicomponent coupling reactions (MCR) have
attracted significant research interest in recent years.1
Multicomponent reactions can provide ideal protocols for
the development of environmentally friendly and eco-
nomically advantageous chemical processes.2 Recently, a
Barbier–Grignard-type addition of alkynes to imines to
generate propargylamines in water/organic solvent by us-
ing a transition-metal catalyst has been reported
(Scheme 1).
The mechanistic pathway of this TBAOH-catalyzed syn-
thesis of propargylamines in DMSO is proposed in
(Scheme 2). Reversible activation of the C–H bond of
phenylacetylene (III) by the base generates acetylide in-
termediate (IV) which reacts with imminium ion (II) gen-
erated in situ from the aldehyde and secondary amine (I)
to give the corresponding propargylamine and regenerate
catalyst for further reaction.
–
NR3
catalyst [M]
R1CHO +
R2
+
R3NH
RCHO
solvent
+
N
R1
N
H
R2
–OH
IV
R
I
II
Scheme 1
B
Transition metals such as silver,3 ruthenium,4 copper,5 in-
dium,6a nickel,6b iron,7 and gold8 have been used to cata-
lyze the addition of terminal alkynes to imines to afford
propargylamines in high yield. The microwave-promoted
Mannich condensation of terminal alkynes and secondary
amines has also been reported.9 However, all these meth-
ods have the drawback of requiring catalyst separation to
limit the metallic impurity.
B–
N
R
III
Scheme 2
Propargylamines are versatile building blocks in organic
synthesis and important structural elements of natural
products and therapeutic drug molecules.10 Recently, it
was reported that the high acidity of aryl acetylenes in
dimethylsulfoxide11–15 should allow formation of the reac-
tive acetylide species by treatment of the terminal alkynes
with a hydroxide or alkoxide base in dimethylsulfoxide.
In fact, formation of acetylide intermediates has been pro-
posed by Ishikawa and co-workers in their studies of the
alkynylation of ketones.15 We have applied this hypothe-
The scope of the process was examined as illustrated by
the examples in Table 1. Aromatic and aliphatic alde-
hydes bearing functional groups such as alkoxy, chloro,
and trifluromethyl were found to undergo the three-com-
ponent coupling reaction. Aryl aldehydes bearing the
electron-donating methoxy group reacted smoothly but
required longer reaction time; whereas aryl aldehydes
bearing electron-withdrawing groups displayed high reac-
tivity and higher conversion with shorter reaction time.
The coupling of cyclohexylcarboxaldehyde was also fac-
ile (entries 11 and 12). Pyridine-4-carboxaldehyde (entry
6) gave an excellent yield, while pyridine-2-carboxalde-
SYNLETT 2011, No. 8, pp 1157–1159
x
x.
x
x.
2
0
1
1
Advanced online publication: 22.03.2011
DOI: 10.1055/s-0030-1259916; Art ID: D27510ST
© Georg Thieme Verlag Stuttgart · New York

1158
S. S. Patil et al.
LETTER
hyde (entry 5) formed the requisite propargylpyridine
with a small amount of byproduct (20% isolated based on
aldehyde), identified as 3-phenyl-1-(piperidin-1-yl)in-
dolizine (Figure 1), which is formed by isomerization of
the propargylpyridine. In addition, 2-furaldehyde (entries
9 and 10) also gave good yields (82% and, 85% respec-
tively). The reaction involving phenylacetylene gave both
higher conversions and better yields, while 4-nitrophenyl-
acetylene gave a lower yield (entry 13), which could be a
reflection of the reduced nucleophilicity of the acetylide
anion. Alkyl acetylenes (entry 14) failed to react under the
optimized conditions, probably due to their lower acidity.
To expand the scope of amine substrates, we used various
aldehydes and phenylacetylene as model substrates and
examined various primary and secondary amines. It was
found that dialkylamines reacted smoothly under the opti-
mized conditions, however, use of a bulky amine led to
lower yield of product (entry 16).
Table 1 Coupling of Aldehydes, Amines, and Alkynes Catalyzed
by Tetrabutylammonium Hydroxide in DMSO
TBAOH
(10 mol%)
NR3
R1CHO +
R3
NH
R2
+
DMSO, r.t.
R1
R2
Entry 1 (R1)
2 (R2)
Amine
Product Yield Time
3
(%)a (min)
1
2
Ph
Ph
piperidine
piperidine
piperidine
piperidine
piperidine
piperidine
3a
3b
3c
3d
3e
3f
90
89
76
84
45
75
82
92
82
85
73
70
37
0
30
230
20
4-MeOC6H4 Ph
4-F3CC6H4 Ph
3
4
4-ClC6H4
2-pyridine
4-pyridine
Ph
Ph
Ph
20
5
120
20
6
7
4-O2NC6H4 Ph
Ph Ph
morpholine 3g
pyrrolidine 3h
30
8
40
N
9
furaldehyde Ph
furaldehyde Ph
cyclohexyl Ph
cyclohexyl Ph
piperidine
morpholine 3j
piperidine 3k
morpholine 3l
4-O2NC6H4 morpholine 3m
3i
45
N
10
11
12
13
14
15
16
45
30
30
Figure 1
Ph
Ph
Ph
Ph
240
360
30
Bu
Ph
Ph
morpholine 3n
In conclusion, we have developed a TBAOH-catalyzed
three-component coupling of aldehydes, terminal aryl
acetylenes, and amines via C–H activation in DMSO un-
der transition-metal-free conditions. The process is simple
and has been shown to generate a diverse range of propar-
gylamines in excellent yields. The experimental simplici-
ty, ease of product isolation, low cost, and ready
availability of reagents should make this process useful
for the synthesis of propargylamines.
Et2NH
Et2NH
3o
3p
75
20
360
a Isolated yield with respect to aldehyde.
(3) (a) Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472. (b)Wei, C.;
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Acknowledgment
The author thanks to UGC, New Delhi, India, for financial support
and Principal HPT Arts and RYK Science College for providing
help throughout research.
Reference and Notes
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Synlett 2011, No. 8, 1157–1159 © Thieme Stuttgart · New York

LETTER
Application to Synthesis of Propargylamines
1159
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by silica gel column chromatography (hexane–EtOAc) gave
pure materials.
Representative Spectroscopic Data
N-(1,3-Diphenyl-2-propynyl)piperidine (3a)
1H NMR (400 MHz, CDCl3): d = 7.62–7.60 (m, 2 H), 7.53–
7.50 (m, 2 H), 7.37–7.27 (m, 6 H), 4.79 (s, 1 H), 2.56 (m, 4
H), 1.61–1.56 (m, 4 H), 1.45–1.44 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 138.3, 131.6, 128.5, 128.2, 128.0, 127.4,
123.2, 87.6, 86.0, 62.3, 26.8, 26.1, 24.4. MS: m/z (%) = 275
(20) [M+], 198 (81), 191 (100), 115 (14).
N-[1-(4-Methoxyphenyl)-3-phenyl-2-propynyl]-
piperidine (3b)
1H NMR (400 MHz, CDCl3): d = 7.55–7.50 (m, 4 H), 7.33–
7.30 (m, 3 H), 6.90–6.87 (m, 2 H), 4.74 (s, 1 H), 3.80 (s, 3
H), 2.56–2.54 (m, 4 H), 1.64–1.53 (m, 4 H), 1.46–1.42 (m, 2
H). 13C NMR (100 MHz, CDCl3): d = 158.9, 131.7, 130.6,
129.6, 128.2, 128.0, 123.3, 113.3, 87.6, 86.3, 61.7, 55.2,
50.6, 26.1, 24.4. MS: m/z (%) = 307 (4) [M+], 221 (38), 135
(30), 87 (100), 43 (73).
(11) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell,
F. G.; Cornforth, F. J.; Drucker, G. E.; Margolin, Z.;
McCallum, R. J.; McCollum, G. J.; Vanier, N. R. J. Am.
Chem. Soc. 1975, 97, 7006.
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Chem. 1980, 45, 3295.
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Perkin Trans. 2 1979, 726.
(14) Kwok, S. N.; Fosting, J. R.; Fraster, R. J.; Rodionov, V. O.;
Fokin, V. V. Org. Lett. 2010, 12, 4217.
(15) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo,
T.; Saito, S. J. Org. Chem. 2003, 68, 3702; and references
cited therein.
(16) General Procedure for the Synthesis of Propargylamines
A 25 mL round-bottom flask was charged with DMSO (3
mL), aldehyde (1.0 mmol), amine (1.3 mmol), alkyne (1.3
mmol), and TBAOH (0.1 mmol). The resulting solution was
stirred at r.t., for the time indicated in Table 1. The reaction
mixture was poured into H2O (60 mL), and the suspension
was stirred for 30 min. Then, it was extracted with EtOAc
(2 × 25 mL), and the combined organic extracts were dried
over anhyd Na2SO4, filtered, and concentrated under
reduced pressure to obtain the crude products. Purification
N-(1,3-Diphenyl-2-propynyl)pyrrolidine (3h)
1H NMR (400 MHz, CDCl3): d = 7.68–7.66 (m, 2 H), 7.56–
7.53 (m, 2 H), 7.37–7.30 (m, 6 H), 4.90 (s, 1 H), 2.72 (m, 4
H), 1.81 (m, 4 H). 13C NMR (100 MHz, CDCl3): d = 138.3,
131.5, 128.2, 128.1, 127.5, 123.1, 86.8, 86.6, 59.0, 50.2,
23.4. MS: m/z (%) = 261 (8) [M+], 184 (61), 115 (13).
N-1[(4-Cyclohexyl-3-phenyl-2-propynyl)]morpholine
(3l)
1H NMR (400 MHz, CDCl3): d = 7.45–7.44 (m, 2 H), 7.29–
7.28 (m, 3 H), 3.79–3.74 (m, 4 H), 3.13 (d, J = 9.9 Hz, 1 H),
2.70–2.69 (m, 2 H), 2.53–2.50 (m, 2 H), 2.14–2.04 (m, 2 H),
1.77–1.59 (m, 4 H), 1.32–0.96 (m, 5 H). 13C NMR (100
MHz, CDCl3): d = 131.6, 128.1, 127.7, 123.3, 86.7, 86.5,
67.0, 63.8, 49.8, 38.9, 30.9, 30.2, 26.6, 26.1, 25.9. MS:
m/z (%) = 283 (5) [M+], 200(100), 115 (20), 77 (2), 55 (9),
41 (10).
Synlett 2011, No. 8, 1157–1159 © Thieme Stuttgart · New York

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