Tandem amine propargylation-Sonogashira reactions: New three-component coupling leading to functionalized substituted propargylic amines

Article abstract of DOI:10.1016/j.tetlet.2004.01.141

Three-component coupling reactions of propargyl halides, amines, and organic halides in the presence of palladium-copper catalysis produced efficiently highly functionalized propargylic amines in good to excellent yields at room temperature. Extension to

Full text of DOI:10.1016/j.tetlet.2004.01.141

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2607–2610
Tandem amine propargylation-Sonogashira reactions: new three-
component coupling leading to functionalized substituted
propargylic amines
*
€
^
Nathanael Olivi, Philippe Spruyt, Jean-Franßcois Peyrat, Mouad Alami and
Jean-Daniel Brion
Laboratoire de Chimie Thꢀerapeutique, BioCIS-CNRS (UMR 8076), Universitꢀe Paris Sud, Facultꢀe de Pharmacie,
rue J.B. Clꢀement, 92296 Cha^tenay-Malabry Cedex, France
Received 14 January 2004; revised 27 January 2004; accepted 28 January 2004
Abstract—Three-component coupling reactions of propargyl halides, amines, and organic halides in the presence of palladium–
copper catalysis produced efficiently highly functionalized propargylic amines in good to excellent yields at room temperature.
Extension to the synthesis of 2-(dialkylaminomethyl)benzo[b]furan or indole derivatives is described.
Ó 2004 Elsevier Ltd. All rights reserved.
Our recent results of various hydrostannylation of
disubstituted alkynes1 have resulted in a continual
requirement of substituted aryl propargylic amines 1
bearing various substituents on the aromatic ring. Such
structures are of great biological interest since they
display strong inhibitory activities toward several
enzymes.2 Moreover, they are synthetically key inter-
mediates for the preparation of allylic amines and var-
ious nitrogen heterocycles (e.g., pyrroles, b-lactams, and
pyrrolidines).3
able amines and aldehydes, the number of terminal
alkynes is limited (particularly functionalized terminal
arylalkynes) and their preparation requires multistep
sequence synthesis. Moreover, such terminal alkynes are
sensitive substrates when bearing an electron-with-
drawing substituent (NO2, CN, CF3. . .) on the aromatic
ring.9 From the standpoint of flexibility, a method
employing a common starting material as a precursor
would have obvious advantages. Herein, we wish to
report a three-component synthesis of highly function-
alized substituted aryl propargylic amines 1. The basic
concept of our process, illustrated in Scheme 1 is based
on a tandem amine propargylation-Sonogashira reac-
tion using amines, propargyl bromide, and functional-
ized aryl halides under palladium–copper catalysis. The
commercial availability of such compounds makes this
approach sufficiently diversity oriented, thus fulfilling
the recent demand for the generation of large combi-
natorial chemical libraries.10
In recent years, great efforts have been made to devise
new routes to propargylic amines including amination of
propargylic electrophiles (halides, triflates, or phos-
phates),4 TiCl4 mediated amination of propargyl ester,5
addition of 1-alkynes to pre-formed imines,6 or Sono-
gashira coupling of aryl halides with propargyl amines.7
While these reactions are suitable methods, they require
the preparation of either or both reagents. The most
obvious and certainly the most popular way to prepare
propargylic amines is the Mannich three-component
condensation of 1-alkynes, aldehydes, and amines
(Scheme 1).8 While there are many commercially avail-
H C=O
2
+
Ar
R
H
Mannich
R
N
R
N
R
1
Ar
Keywords: Sonogashira; Propargyl halides; Propargylic amines; Palla-
dium; 2-(Dialkylaminomethyl)indoles; 2-(Dialkylaminomethyl)benzo-
furanes.
+
X-Ar
Br
this work
* Corresponding author. Tel.: +33-146835887; fax: +33-146835828;
e-mail: mouad.alami@cep.u-psud.fr
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.141

2608
N. Olivi et al. / Tetrahedron Letters 45 (2004) 2607–2610
Typically the reaction of aryl halides (1 equiv), propar-
gyl bromide (1.2 equiv) and amine in the presence of
PdCl2(PPh3)2 (5 mol %) and CuI (10 mol %) resulted in
the formation of the propargylic amines 1 in excellent
yields. As shown in Table 1, this process can be applied
to a broad range of secondary amines and functional-
ized aryl iodides or aryl bromides. For the aryl iodides,
the reactions proceeded at ambient temperature and
were completed in a short period time (15–30 min). Both
aromatic iodides bearing an ortho or a para electron-
donating or electron-withdrawing substituents afforded
the coupling product in excellent yields (entries 1–7).
For the aryl bromides, the reaction required heating and
proceeded at 60 °C for several hours to give the desired
coupling product efficiently. In contrast to 1,4-diiodo-
benzene11 (entry 8), the reaction of 1,2-dibromobenzene
Table 1. Synthesis of functionalized propargylic amines 1 by a three-component assembling process under palladium–copper catalysis
Entry
1
Amine
Propargyl halide
RX
Propargylic amine 1
Yield (%)a
Br
NH
I
OMe
80b
N
OMe
87c
83
Br
Br
2
3
I
I
OMe
N
OMe
NH
O
N
O
NH
NHBoc
NHBoc
AcHN
I
AcHN
Br
Et2N
Et2N
iPr2N
4
95
NH
Br
Br
5
6
I
I
NO2
NO2
94
69
NH
NH
NO2
NO2
O
N
OEt
EtOOC
I
O
Br
Br
7
8
O
O
NH
78
98
O
N
O
NH
I
I
N
Br
Br
Br
Br
Br
NH
NH
N
9
69
93
O
N
10
O
O
Br
Br
COOEt
COOEt
NO2
O
N
Br
Br
11
NH
NO2
86d
N
Et2N
N
12
13
74
74
NH
Br
Cl
Et2N
COOMe
I
COOMe
CN
NH
C5H11
C5H11
Cl
N
NH
14
89
I
CN
Cl
C5H11
C5H11
Cl
E/Z 1/1
15
16
63e
76f
Br
Br
Cl
NH
NH
N
E/Z 9/1
N
Cl
a Isolated yield based on arylhalide. Propargylic amines 1 synthesized are new compounds except those of entries 5, 8, 11, and 12. All new compounds
exhibited satisfactory spectral properties. For a general procedure, see Ref. 15.
b Reaction performed without copper iodide; see Ref. 16.
c Reaction performed at 60 °C.
d Reaction performed at room temperature.
e Isolated yield based on propargyl bromide (1 equiv). Reaction performed in the presence of an excess (10 equiv) of 1,2-dichloroethylene (E/Z 1/1),
see Ref. 12.
f PdCl2(PhCN)2 was used instead of PdCl2(PPh3)2, see Ref. 13.

N. Olivi et al. / Tetrahedron Letters 45 (2004) 2607–2610
2609
(entry 9) allows the selective obtention of the mono-
coupling product even when using an excess of propar-
gyl bromide (3 equiv). Under similar conditions,
heteroaromatic bromides such as 2-bromopyridine
underwent the three-component reaction and afforded
the coupling product in 74% yield (entry 12). On the
other hand, this process is also effective even when using
the less reactive vinyl chlorides including 1,2-dichloro-
ethylene12 (entry 15) or chloroenynes (entry 16). In the
process to the preparation of other heteroatom-con-
taining cyclic compounds is already underway.
Acknowledgements
The CNRS is gratefully thanked for support of this
research and for a doctoral fellowship to N.O.
13
latter case, PdCl2(PhCN)2 was used as catalyst instead
of PdCl2(PPh3)2. It should be noted that this three-
component procedure with substituted propargyl chlor-
ides such as 3-chloro-oct-1-yne is also effective to give
the expected products. Its coupling with methyl 4-
iodobenzoate (entry 13) or 4-iodobenzonitrile (entry 14)
provided the desired three-component coupling com-
pound in 74% and 89%, respectively.
References and notes
1. (a) Liron, F.; Le Garrec, P.; Alami, M. Synlett 1999, 246–
248; (b) Alami, M.; Liron, F.; Gervais, M.; Peyrat, J. F.;
Brion, J. D. Angew. Chem., Int. Ed. 2002, 41, 1578–1580.
2. (a) Shirota, F. N.; DeMaster, E. G.; Nagasawa, H. T. J.
Med. Chem. 1979, 22, 463–464; (b) Yu, P. H.; Davies, B.
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dron Lett. 1991, 32, 4121–4124; (b) Campi, E. M.; Jackson,
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Tetrahedron Lett. 1991, 32, 7683–7686; (d) Clive, D. L.
J.; Cole, D. C.; Tao, Y. J. Org. Chem. 1994, 59, 1396–
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Chem. 1980, 45, 4616–4622; (b) Imada, Y.; Yuassa, M.;
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Chem. 1990, 9, 767–770; (d) Basak, A.; Rudra, K. R.
Tetrahedron Lett. 2000, 41, 7231–7234; (e) Basak, A.;
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Glase, S. A.; Akunne, H. C.; Heffner, T. G.; Jaen, J. C.;
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7. (a) Mladenova, M.; Alami, M.; Linstrumelle, G. Synth.
Commun. 1995, 25, 1401–1410; (b) Bleicher, L. S.;
Cosford, N. D. P.; Herbaut, A.; McCallum, J. S.;
McDonald, I. A. J. Org. Chem. 1998, 63, 1109–1118.
8. (a) Tramontini, M. Synthesis 1973, 703–775. For recent
communications, see: (b) Li, C. J.; Wei, C. Chem.
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Org. Lett. 2003, 5, 4473–4475; (d) Wie, C.; Li, C. J. J. Am.
Chem. Soc. 2003, 125, 9584–9585.
Finally, under these reaction conditions, it was also
possible to extend the scope of this three-component
assembling process to perform a tandem amine prop-
argylation-Sonogashira-cyclization sequence to obtain
2-(dialkylaminomethyl)benzo[b]furan or indole deriva-
tives, an important class of heterocycles that exhibit a
wide range of activity14 (Scheme 2). Thus, when ortho
iodophenol was used as substrate, the cyclized benzo-
furan was obtained in a 75% yield. Similarly, 2-iodo
substituted aniline yielded 2-substituted indole deriva-
tive quantitatively. It should be noted, that the effect of
the functional group on the nitrogen atom toward the
cyclization step is crucial since no cyclization reaction
occurred from the compound having an acetyl function
on the nitrogen atom (Table 1, entry 4).
In conclusion, we have successfully developed a new
three-component assembling of amines, organic halides
and propargyl halides for the preparation of function-
alized propargylic amine, indole, and benzofuran
derivatives in high yields. Variation is allowed in each of
the three components, thus making a wide range of
accessible products. This process is not only of interest
for combinatorial synthesis of propargylic amines and
heterocycles, but in many cases also offers considerable
synthetic advantages in terms of yield, selectivity, and
simplicity of the reaction procedure. Extension of this
Br
5% PdCl2(PPh3)2
10% CuI
I
9. Kwatra, M. M.; Simon, D. Z.; Salvador, R. L.; Cooper,
P. D. J. Med. Chem. 1978, 21, 253–257.
10. Youngman, M. A.; Dax, S. L. J. Comb. Chem. 2001, 3,
469–472.
N
+
0°C then 50°C
O
OH
75%
HN
11. Unroe, M. R.; Reinhardt, B. A. Synthesis 1987, 981–985.
12. Alami, M.; Peyrat, J. F.; Brion, J. D. Tetrahedron Lett.
2002, 43, 3007–3009, and references cited therein.
13. For a review, see: (a) Alami, M.; Peyrat, J. F.; Brion, J. D.
Synthesis 2000, 1499–1518; (b) Alami, M.; Linstrumelle,
G. Tetrahedron Lett. 1991, 32, 6109–6112; (c) Alami, M.;
Crousse, B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114–
123.
Br
5% PdCl2(PPh3)2
10% CuI
I
N
+
0°C then 50°C
N
97%
NHTs
HN
Ts
14. For a review, see: (a) Cacchi, S.; Fabrizi, G.; Goggiomani,
A. Heterocycles 2001, 56, 613–632; (b) Seefeld, M. A.;
Miller, W. H.; Newlander, K. A.; Burgess, W. J.; Payne,
Scheme 2.

2610
N. Olivi et al. / Tetrahedron Letters 45 (2004) 2607–2610
D. J.; Rittenhouse, S. F.; Moore, T. D.; DeWolf, W. E.,
Ethyl 4-(3-morpholin-4-ylprop-1-ynyl)benzoate (entry 10):
1H NMR (200 MHz, CDCl3, d ppm) 7.86 (d, J ¼ 8:5 Hz,
2H), 7.37 (d, J ¼ 8:5 Hz, 2H), 4.25 (q, J ¼ 7:1 Hz, 2H),
3.64 (t, J ¼ 4:7 Hz, 4H), 3.40 (s, 2H), 2.51 (t, J ¼ 4:7 Hz,
4H), 1.26 (t, J ¼ 7:1 Hz, 3H). 13C NMR (50 MHz, CDCl3,
d ppm) 165.5, 131.2, 129.6, 129.1, 127.2, 87.0, 84.6, 66.5,
60.7, 52.1, 47.7, 14.0.
Jr.; Keller, P. M.; Qiu, X.; Janson, C. A.; Vaidya, K.;
Fosberry, A. P.; Smyth, M. G.; Joworski, D. D.; Slater-
Radosti, C.; Huffman, W. F. Bioorg. Med. Chem. Lett.
2001, 11, 2241–2244; (c) Kabalka, G. W.; Wang, L.; Pagni,
R. M. Tetrahedron Lett. 2001, 42, 6049–6051.
15. General procedure: Under an inert atmosphere, propargyl
bromide (1.2 equiv) purchased from Aldrich was slowly
added, at 0 °C, to a solution containing aryl iodide
(1 equiv), PdCl2(PPh3)2 (5 mol %), CuI (10 mol %), and
amine (used as a solvent). The reaction mixture was stirred
at room temperature (or heated at 60 °C when using an
aryl bromide) and monitored by TLC until complete
consumption of starting materials then concentrated in
vacuo. Purification by chromatography on silica gel
afforded pure propargylic amine 1.
Methyl 4-(3-diethylaminooct-1-ynyl)benzoate (entry 13):
1H NMR (200 MHz, CDCl3, d ppm) 7.94 (d, J ¼ 8:0 Hz,
2H), 7.44 (d, J ¼ 8:0 Hz, 2H), 3.88 (s, 3H), 3.67 (t,
J ¼ 7:3 Hz, 1H), 2.80 to 2.35 (m, 4H), 1.70 to 1.30 (m, 8H),
1.08 (t, J ¼ 7:2 Hz, 6H), 0.89 (t, J ¼ 7:0 Hz, 3H). 13C NMR
(50 MHz, CDCl3, d ppm) 166.4, 131.5, 129.3, 129.0, 128.4,
92.7, 84.0, 53.7, 52.0, 44.9, 34.0, 31.5, 26.4, 22.5, 13.9, 13.7.
16. Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett.
1993, 34, 6403–6406.