Copper- and amine-free Sonogashira reaction of N,N-disubstituted propargylamine: Synthesis of substituted aryl propargylamine

Article abstract of DOI:10.1080/00397910600632070

A copper- and amine-free Sonogashira reaction of N,N -disubstituted propargylamine (DEP) is reported. The procedure was mild and tolerated a series of aryl bromides, affording the substituted aryl propargylic amines in good to excellent yield. Copyright T

Full text of DOI:10.1080/00397910600632070

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Copper‐ and Amine‐Free Sonogashira
Reaction of N,N‐Disubstituted
Propargylamine: Synthesis of Substituted Aryl
Propargylamine
Weiwei Zhang a , Jiang Cheng a , Linya Ding a , Ping Zhong a , Li Zhao a &
Huayue Wu a
a Department of Chemistry , Wenzhou University , Wenzhou, China
Published online: 20 Aug 2006.
To cite this article: Weiwei Zhang , Jiang Cheng , Linya Ding , Ping Zhong , Li Zhao & Huayue Wu (2006)
Copper‐ and Amine‐Free Sonogashira Reaction of N,N‐Disubstituted Propargylamine: Synthesis of Substituted
Aryl Propargylamine, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 36:14, 2001-2007
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Synthetic Communicationsw, 36: 2001–2007, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600632070
Copper- and Amine-Free Sonogashira
Reaction of N,N-Disubstituted
Propargylamine: Synthesis of Substituted
Aryl Propargylamine
Weiwei Zhang, Jiang Cheng, Linya Ding, Ping Zhong,
Li Zhao, and Huayue Wu
Department of Chemistry, Wenzhou University, Wenzhou, China
Abstract: A copper- and amine-free Sonogashira reaction of N,N-disubstituted propar-
gylamine (DEP) is reported. The procedure was mild and tolerated a series of aryl
bromides, affording the substituted aryl propargylic amines in good to excellent yield.
Keywords: Aryl bromide, copper free, palladium, propargylamine, Sonogashira reaction
Palladium-catalyzed coupling of terminal alkynes with aryl or alkenyl iodides,
which was described for the first time by Sonogashira et al. in 1975, is one of
the most straightforward methods for the preparation of aryl alkynes and con-
jugated enynes.[1] Usually the Sonogashira coupling is carried out in the
presence of catalytic amounts of a palladium complex as well as copper
iodide in an amine as solvent to obtain good yield.[2]
Propargyl amines are not only synthetically important intermediates for
preparation of various nitrogen compounds such as (E)-allylamines, pyrroles,
b-lactams, and pyrrolidines[3] but are also biologically important.[4] Substituted
aryl propargylic amines bearing various substituents in the aromatic ring display
strong inhibitory activities toward several enzymes. There are some routes to
propargylamine, including amination of propargylic electrophiles,[5] TiCl4-
mediated amination of propargyl ester,[6] addition of 1-alkynes to preformed
imines,[7] or Sonogashira reaction of aryl halides with propargylamine.[8]
Received in Japan November 2, 2005
Address correspondence to Huayue Wu, Department of Chemistry, Wenzhou
University, Mid. Xueyuan Rd., Wenzhou 32502, China. Tel.: 0086-577-88156826;
Fax: 0086-577-88156826; E-mail: shchengjiang@yahoo.com.cn
2001

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W. Zhang et al.
However, the copper-free Sonogashira reaction of propargylamine was rarely
reported. The Cu(I) acetylides formed in situ could undergo oxidative dimeriza-
tion to give diaryldiacetylenes when they are exposed to air or an oxidant (a
reaction known as the Glaser coupling).[9] These by-products are generally
difficult to separate from the desired products. Moreover, only a few results
were reported using less reactive aryl bromides.[10]
Cheng et al. reported that aminophosphine L1, which is air-stable and facile
to prepare was a highly efficient ligand in the Suzuki cross-coupling reaction and
Sonogashira reaction.[11] Accordingly, we envisioned enlarging the application
scope of the ligand in the Sonogashira reaction. Herein, we report a copper-
and amine-free Sonogashira reaction between aryl bromides and N,N-diethyl
propargylamine (DEP) employing aminophosphine ligands (Scheme 1).
For the study, based on Zhang’s results,[11] THF was chosen as the solvent
and potassium carbonate as the base. The reaction was run at 658C under
nitrogen in the presence of a combination of Pd(OAc)2 and L1 as catalyst.
Treatment of a mixture of 1 (334 mg, 3 mmol), 4-bromoanisole 2a (374 mg,
2 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol), and L1 (8.6 mg, 0.03 mmol) in dry
THF (5 mL) at 658C under an inert atmosphere for 8 h produced the desired
product 3a in 86% yield. This is a promising result, because no copper salt
and amine was required. Then a series of aryl bromides were tested in the
reaction conditions. Results are summarized in Table 1.
All of the aryl bromides substrates processing electron-donating and
electron-withdrawing groups worked well under the reaction conditions in
the absence of CuI or amine. For example, the aryl bromides, which contain
electron-donating substituents, were considered reluctant to oxidative
addition to Pd(0); however, 86% and 90% of isolated product (3a, 3b) were
obtained for the coupling reaction, respectively (Table 1, entries 1, 2). The
ortho group in the aryl bromide had some effect in the reaction, although
the yield slightly decreased to 81% for 2-bromo-m-xylene (2h) (Table 1,
entry 8), the reaction became sluggish, and more catalyst load was required.
For the 1-bromonaphthalene (2d), which is electron rich and a hindrance
in the ortho position, the yield reached 78% (Table 1, entry 4). The
4-bromobenzaldehyde (2f) and 3-bromobenzaldehyde (2g) were not
Scheme 1.

Copper- and Amine-Free Sonogashira Reaction
Table 1. Sonogashira reaction of N,N-disubstituted
propargylamine
2003
Entry
1
Aryl bromide
4-Bromoanisole
2a
Yield (%)a
86
3a
90
3b
88
3c
2
3
3-Bromoanisole
2b
Bromobenzene
2c
4
1-Bromonaphthalene
2d
78b
3d
76
3e
5
4-Bromotoluene
2e
4-Bromobenzaldehyde
6
89
3f
2f
3-Bromobenzaldehyde
7
86
3g
81b
3h
63b
3i
2g
2-Bromo-m-xylene
8
2h
2-Bromomesitylene
9
2i
2-Bromopyridine
10
59b
3j
2j
aIsolated yield, all reactions were run with aryl bromide
(2 mmol), DEP (3 mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol),
K2CO3 (828 mg, 6 mmol), and L1 (8.6 mg, 0.03 mmol) in
5 ml of THF at 658C for 8 h.
bPd(OAc)2 (11.2 mg, 0.05 mmol) and L1 (43.1 mg,
0.15 mmol).
sensitive in the reaction conditions, affording the desired products in 89% and
86% yield, respectively (Table 1, entries 6, 7).
In conclusion, we developed a copper- and amine-free Sonogashira
reaction of N,N-disubstituted propargylamine. It is a facile and mild way to
synthesis substituted aryl propargylamine. Aminophosphine was used as the
ligands. The ligand is facile to be prepared from commercial available
material and is air stable.
EXPERIMENTAL
General
All reactions and manipulations were conducted under a nitrogen atmosphere
using standard Schlenk techniques. Column chromatography was performed

2004
W. Zhang et al.
1
using EM silica gel 60 (300–400 mesh) or Al2O3; H NMR, and 13C NMR
were recorded on a 300 MHz spectrometer. Chemical shifts were reported
in ppm downfield from tetramethylsilane with the solvent resonance as the
internal standard.
Materials
THF was distilled from sodium-diphenylacetone prior to use. K2CO3, aryl
bromides, and DEP were used directly as obtained commercially unless
otherwise noted.
General Procedure for the Sonogashira Reaction
Under a nitrogen atmosphere, a Schlenk reaction tube was charged with DEP
(334 mg, 3 mmol), aryl bromide (2 mmol), K2CO3 (828 mg, 6 mmol),
Pd(OAc)2 (2.2 mg, 0.01 mmol), L1 (8.6 mg, 0.15 mmol), and THF (5 mL).
The reaction tube was purged with N2 under a dry ice bath. After the
mixture was heated at 658C for 8 h, the solvent was evaporated under
reduced pressure and the residue was purified by flash column chromato-
graphy on a silica gel (pre-eluted with 5% trimethylamine in petroleum) to
give the product 3.
Data
3a 1-(p-Anisyl)-3-(diethylamino)propyne[10a]
1H NMR (300 MHz, CDCl3) d 7.33 (d, J ¼ 8.7 Hz, 2H), 6.78 (d, J ¼ 8.7 Hz,
2H), 3.76 (s, 3H), 3.59 (s, 2H), 2.58 (q, J ¼ 7.2 Hz, 4H), 1.08 (t, J ¼ 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3): d 159.2, 133.3, 115.4, 113.7, 84.6, 82.7,
55.1, 47.1, 41.4, 23.0.
3b 1-(m-Anisyl)-3-(diethylamino)propyne
1H NMR (300 MHz, CDCl3) d 7.25–7.21 (m, 1H), 7.19–7.16 (m, 1H), 7.02–
6.99 (m, 1H), 6.95–6.83 (m, 1H), 3.76 (s, 3H), 3.62 (s, 2H), 2.62
(q, J ¼ 7.2 Hz, 4H), 1.11 (t, J ¼ 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d 159.2, 129.2, 124.2, 120.1, 116.7, 114.6, 84.8, 82.3, 55.1, 47.1, 41.7, 12.5.
MS (EI): m/z 217 (Mþ), IR (neat, cm21): 3067 (w), 2967 (s), 2823 (s),
2358 (m), 1590 (s), 1474 (s), 1120 (m), 1124 (s), 1094 (s). Anal. calcd for
C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.14; H, 8.66; N, 6.64.

Copper- and Amine-Free Sonogashira Reaction
2005
3c 1-Phenyl-3-(diethylamino)propyne[10a]
1H NMR (300 MHz, CDCl3) d 7.43–7.40 (m, 2H), 7.29–7.25 (m, 3H), 3.64
(s, 2H), 2.63 (q, J ¼ 7.2 Hz, 4H), 1.11 (t, J ¼ 7.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d 131.7, 128.2, 127.9, 123.4, 84.9, 84.5, 47.3, 41.5, 12.6.
3d 1-Naphthalenyl-3-(diethylamino)propyne[10a]
1H NMR (300 MHz, CDCl3): d 8.34 (d, J ¼ 8.1 Hz, 1H), 7.85–7.81 (m, 2H),
7.67–7.65 (m, 1H), 7.57–7.50 (m, 2H), 7.43–7.40 (m, 1H), 3.82 (s, 2H), 2.73
(q, J ¼ 7.2 Hz, 4H), 1.18 (t, J ¼ 7.2 Hz, 6H);. 13C NMR (75 MHz, CDCl3): d
133.3, 133.1, 130.5, 128.3, 128.2, 126.6, 126.3, 126.2, 125.1, 89.3, 83.1, 47.5,
41.7, 12.7.
3e 3-(Diethylamino)-1-(p-tolyl)propyne[10a]
1H NMR (300 MHz, CDCl3) d 7.30 (d, J ¼ 8.1 Hz, 2H), 7.08 (d, J ¼ 8.1 Hz,
2H), 3.63 (s, 2H), 2.63 (q, J ¼ 7.2 Hz, 4H), 2.33 (s, 3H), 1.11 (t, J ¼ 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3): d 137.9, 131.6, 128.9, 120.3, 85.0, 83.6,
47.3, 41.5, 21.4, 12.6.
3f 4-(3-(Diethylamino)prop-1-ynyl)benzaldehyde[10a]
1H NMR (300 MHz, CDCl3) d 9.97 (s, 1H), 7.79 (d, J ¼ 8.3 Hz, 2H), 7.53
(d, J ¼ 8.3 Hz, 2H), 3.65 (s, 2H), 2.61 (q, J ¼ 7.2 Hz, 4H), 1.11
(t, J ¼ 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 191.3, 135.3, 132.2,
129.7, 129.4, 89.2, 84.3, 47.3, 41.6, 12.5.
3g 3-(3-(Diethylamino)prop-1-ynyl)benzaldehyde
1H NMR (300 MHz, CDCl3) d 9.98 (s, 1H), 7.91 (s, 1H), 7.80–7.78 (m, 1H),
7.67–7.64 (m, 1H), 7.49–7.46 (m, 1H), 3.65 (s, 2H), 2.64 (q, J ¼ 7.2 Hz, 4H),
1.12 (t, J ¼ 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 191.5, 137.2, 136.4,
132.9, 128.9, 128.7, 124.6, 91.3, 83.4, 47.3, 41.4, 12.5. MS (EI): m/z 215
(Mþ), IR (neat, cm21): 3067 (w), 2971 (m), 2819 (m), 2357 (m), 1707 (s),
785 (s). Anal. calcd for C14H17NO: C, 77.10; H, 7.96; N, 6.51. Found: C,
77.02; H, 7.74; N, 6.57.
3h 3-(2,6-Dimethylphenyl)-N,N-diethylprop-2-yn-1-amine
1H NMR (300 MHz, CDCl3) d 7.06–7.03 (m, 3H), 3.77 (s, 2H), 2.66
(q, J ¼ 7.2 Hz, 4H), 2.43 (s, 6H), 1.14 (t, J ¼ 7.2 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d 140.1, 127.3, 126.6, 123.2, 92.5, 82.5, 47.4, 41.4, 21.3,
12.7. MS (EI): m/z 215 (Mþ), IR (neat, cm21): 3064 (w), 2966 (s), 2819

2006
W. Zhang et al.
(m), 2926 (m), 2357 (s), 1677 (m), 1460 (s). Anal. calcd for C15H21NO: C,
83.67; H, 9.83; N, 6.50. Found: C, 83.51; H, 9.62; N, 6.64.
3i N,N-Diethyl-3-mesitylprop-2-yn-1-amine[10a]
1H NMR (300 MHz, CDCl3) d 6.85 (s, 2H), 3.75 (s, 2H), 2.63 (q, J ¼ 7.2 Hz,
4H), 2.39 (s, 6H), 2.27 (s, 3H), 1.13 (t, J ¼ 7.2 Hz, 6H); 13C NMR (75 MHz,
CDCl3): d 140.0, 137.2, 127.5, 120.2, 91.6, 82.6, 47.4, 41.4, 21.2, 21.1, 12.8.
3j N,N-Diethyl-3-(pyridin-2-yl)prop-2-yn-1-amine[10a]
1H NMR (300 MHz, CDCl3) d 8.54–8.52 (m, 1H), 7.59–7.57 (m, 1H), 7.39–
7.36 (m, 1H), 7.19–7.15 (m, 1H), 3.65 (s, 2H), 2.62 (q, J ¼ 7.2 Hz, 4H), 1.14
(t, J ¼ 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 149.8, 143.3, 136.0, 127.1,
122.6, 84.9, 84.6, 47.4, 41.3, 12.6.
ACKNOWLEDGMENT
We thank the National Natural Science Foudation of China (20504023,
20572079) and the Natural Science Foundation of Zhejiang Province (No.
Y404039, No. Y405015) for financial support.
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