[bmim]PF6/CuBr: A novel and recyclable catalytic system for the synthesis of propargyl amines

Article abstract of DOI:10.1039/b312785k

A novel and efficient method has been developed for the synthesis of propargyl amines in a one-pot operation from aldehydes, amines and alkynes by using copper(i) bromide immobilized in ionic liquids. The ionic liquid containing catalyst can be recovered and recycled in three to four subsequent runs with gradual decrease in activity.

Full text of DOI:10.1039/b312785k

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L E T T E R
[bmim]PF6/CuBr: a novel and recyclable catalytic system for the
synthesis of propargyl amines
Jhillu S. Yadav,* Basi V. Subba Reddy, Veerjala Naveenkumar, Ramisetti Srinivasa Rao and
Kommu Nagaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007,
India. E-mail: yadav@iict.ap.nic.in; Fax: +91-40-2716 0512
Received (in Montpellier, France) 9th October 2003, Accepted 16th January 2004
First published as an Advance Article on the web 16th February 2004
A novel and efficient method has been developed for the synthesis
of propargyl amines in a one-pot operation from aldehydes,
amines and alkynes by using copper(I) bromide immobilized
in ionic liquids. The ionic liquid containing catalyst can be
recovered and recycled in three to four subsequent runs with
gradual decrease in activity
Scheme 1
The stereoselective addition of organometallic reagents to
aldehydes and imines is one of the most important carbon-
aniline with phenyl acetylene in the presence of 30 mol % of
carbon bond-forming reactions in organic synthesis.1 Propar-
gyl amines are important synthetic intermediates for the
synthesis of various polyfunctional amino derivatives and also
for the synthesis of many biologically active compounds.2 The
simplest and most straightforward method for the synthesis of
propargyl amines involves the addition of alkynyl metal
reagents to imines.3 Addition of alkynes to imines, enamines,
nitrones and acyliminium ions using copper salts has been
reported to produce propargyl amines.4 Asymmetric versions
of enamine-alkyne and imine-alkyne additions have also been
reported to produce enantiomerically pure propargyl amines.5
Recently, ionic liquids have emerged as a set of green sol-
vents with unique properties such as tunable polarity, high
thermal stability, and immiscibility with a number of organic
solvents, negligible vapor pressure and recyclability.6 Their
non-volatile character and thermal stability makes them poten-
tially attractive alternatives to environmentally unfavorable
organic solvents, notably chlorinated hydrocarbons. They are
particularly promising as solvents for the immobilization
of transition metal catalysts, Lewis acids and enzymes
(Fig 1).7 As a result of their green credentials and potential
to enhance reaction rates and selectivities, ionic liquids are
finding increasing applications in organic synthesis.8
CuBr in [bmim]PF6 at 60 ꢀC afforded the corresponding
N-(1,3-diphenyl-2-propynyl)aniline in 89% yield. In a similar
fashion, various imines (formed in situ from aldehydes and
amines in the ionic liquid) reacted smoothly with alkynes to
produce the corresponding propargylic amines. The reactions
proceeded efficiently in ionic liquids and were complete within
3.5–6.0 h. Both electron-rich and electron-deficient aldehydes
and amines afforded the corresponding propargylic amines in
excellent yields (75–89%) with high selectivity, whereas ketones
did not give the desired product under these reaction condi-
tions. From the results are presented in Table 1, the scope
and generality of this process is illustrated with respect to
various aldehydes, amines and alkynes.
Acid-sensitive aldehydes such as cinnamaldehyde worked
well without any decomposition or polymerization under these
reaction conditions (4h, Table 1). Even sterically hindered
amines and alkynes also gave the corresponding propargylic
amines in high yields (4h, 4i, 4l and 4m, Table 1). In all cases,
no propargylic alcohol (an adduct between the aldehyde and
alkyne) was obtained under similar reaction conditions. This
is because of the rapid formation of imines from aldehydes
and amines in ionic liquids. The reactivity of alkynes and aldi-
mines was studied in both hydrophilic (i.e., [bmim]BF4) and
hydrophobic (i.e., [bmim]PF6) ionic liquids. [bmim]BF4 was
also equally effective for this conversion. Among the various
copper salts, such as CuCl, CuBr, Cu(OAc)2 and Cu(OTf)2 ,
tested, CuBr was found to be the most effective catalyst in
terms of conversion reaction rates. Compared to conventional
solvents, enhanced reaction rates, improved yields and high
selectivity are the features obtained in ionic liquids. For exam-
ple, treatment of benzaldehyde and p-anisidine with phenyl
acetylene in the presence of 30 mol % copper bromide in
[bmim]PF6 at 60 ꢀC for 3.5 h afforded the corresponding N-
(1,3-diphenyl-2-propynyl)-4-methoxyaniline (4c) in 85% yield
whereas the same reaction in refluxing THF after 8.0 h gave
the product in 60% yield as a mixture of propargyl amine
and 2,4-disubstituted quinoline in an 8:2 ratio.
In view of the emerging importance of imidazolium based
ionic liquids as novel reaction media, we wish to explore the
use of ionic liquids as a recyclable solvent system for the
three-component coupling reaction of aldehydes, amines and
alkynes to produce propargylic amines in excellent yields
(Scheme 1). Accordingly, treatment of benzaldehyde and
Similar results were also obtained using ionic liquids having
longer alkyl chains such as 1-hexyl-3-methylimidazolium hexa-
fluorophosphate ([hmim]PF6) or 1-octyl-3-methylimidazolium
Fig. 1 Chemical structures of ionic liquids.
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 3 3 5 – 3 3 7
335

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Table 1 Synthesis of propargylic amines using copper(I) bromide in ionic liquid [bmim]PF6
Producta
=
Alkyne R’’–
=
Aldehyde R–CHO
R
Amine R’–NH2
R’
R’’
Time/h
% Yieldb
C6H5
C6H5
C6H5
n-CH3(CH2)2
n-CH3(CH2)5
n-CH3(CH2)5
HO(CH2)2
4a
4b
4c
4d
4e
4f
4.0
5.0
3.5
5.5
6.0
4.5
89
83
85
81
88
85
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
n-CH3(CH2)3
3,5-(F,F)C6H3
3,4-(MeO)2C6H3
3,5-(F,F)C6H3
Allyl-O(CH2)6
BnOCH2
4-BnOC6H4
3,4-(MeO)2C6H3
4g
5.0
87
=
Ph–CH CH
C6H5
3-NO2C6H4
4-MeOC6H4
3,4-(OCH2O)C6H3
4-FC6H4
2,6-(CH3)2C6H3OCH2
4h
4i
6.5
4.5
5.5
5.0
4.5
5.5
89
87
84
82
89
85
C6H5
C6H5
C6H5
C6H5
C6H5
4-BrC6H4
3,4-(MeO)2C6H3
C6H5
4j
4k
4l
C6H5
C6H5CH2
n-CH3(CH2)6
4m
a
b
All products were characterized by 1HNMR, IR and mass spectroscopy Isolated and unoptimized yields
hexafluorophosphate ([octmim]PF6). However, the products
were obtained in low yields (30–55%) when 1-n-butyl-3-methyl-
imidazolium chloride ([bmim]Cl) was used as a solvent. These
results clearly indicate that the efficiency of the ionic liquid is
strongly influenced by the nature of the anion only.
and reaction rates, cleaner reaction profiles and recyclability
of the ionic liquids, making this method useful and attractive
for the synthesis of propargylic amines.
Another advantage in the use of ionic liquids as a novel reac-
tion medium for this transformation is that these ionic solvents
can be easily recovered after completion of the reaction and
can be reused in successive runs. The products were easily
separated by simple extraction with diethyl ether and the
remaining ionic liquid was thoroughly washed with ether and
recycled in further reactions with gradual decrease in activity.
For instance, benzaldehyde, aniline and phenyl acetylene in
[bmim]PF6 ionic liquid afforded 89%, 85%, and 80% yields
over three cycles. However, on the addition of more catalyst
to the fourth run, no decrease in yield was obtained in runs
carried out using a recycled ionic liquid and the results are
presented in Table 2.
The simple experimental and product isolation procedures,
combined with ease of recovery and reuse of this novel reac-
tion media, are expected to contribute to the development of
a clean process for the synthesis of propargylic amines.
Furthermore, the recovery and reuse of the catalyst is espe-
cially easy in ionic liquids compared to organic solvents.
In summary, this paper demonstrates the successful use of
ionic liquids as a novel and convenient reaction media for
the three-component coupling reaction of aldehydes, amines
and alkynes to produce propargylic amines in excellent yields
in a single-step operation. This method is very useful for the
synthesis of propargylic amines, especially from acid-sensitive
substrates. The notable features of this procedure are the mild
reaction conditions, simplicity in operation, improved yields
Experimental
Melting points were determined on a Fisher–John melting
point apparatus and are uncorrected. IR spectra were recorded
on a Shimadzu 470 IR spectrometer. Silica gel (60–120 mesh)
1
was used for column chromatography. H NMR spectra were
recorded in CDCl3 on Varian FT-200 (200 MHz) and Bruker
Avance (300 MHz) machines using TMS as internal standard.
Mass spectra were taken on a Finnigan Mat-1210 double
focusing spectrometer.
General procedure
A mixture of aldehyde (1 mmol), amine (1 mmol) and alkyne
(1 mmol) and CuBr (30 mol %) in [bmim]PF6 (2.0 mL) was
stirred at 60 ꢀC for the appropriate time (see Table 1). After
completion of the reaction, as indicated by TLC, the reaction
mixture was washed with diethyl ether (3 ꢁ 10 mL). The com-
bined ether extracts were concentrated in vacuo and the result-
ing product was directly charged onto a small silica gel column
and eluted with a mixture of ethyl acetate–n-hexane (2:8) to
afford pure propargylic amine. The rest of the ionic liquid
was further washed with ether and recycled in subsequent runs.
Spectral data for all products (Table 1) follow.
4a. Yellow oil; IR (neat): nmax : 3400 , 3056, 2976, 2944,
1584, 1488, 1328, 752 cmꢂ1; H NMR (300 MHz, CDCl3): d
1
0.95 (t, J ¼ 6.7 Hz, 3H), 1.45–1.60 (m, 2H), 2.20 (t, J ¼ 6.5
Hz, 2H), 3.90–4.00 (br s, NH, 1H), 5.20 (s, 1H), 6.65–6.75
(m, 3H), 7.10–7.20 (m, 2H), 7.45 (m, 1H), 7.50–7.60 (m, 2H),
7.85–7.95 (m, 2H); EI-MS: m/z (%) 249 [M]þ (12), 157 (100),
129 (37), 115 (25), 91 (27), 51 (6).
Table 2 Recyclability of the CuBr/[bmim]PF6 system for the
coupling of aniline, benzaldehyde and phenylacetylenea
Run
CuBr/mol %
Time/h
% Yield
4b. Yellow oil, IR (neat): nmax : 3408 (br s), 2928, 2864, 1600,
1
2
3
4
5
30
0
4.5
5.0
6.0
3.5
5.5
89
85
80
92
87
1
1488, 1424, 1232, 1152, 1008, 832 cmꢂ1; H NMR (200 MHz,
0
CDCl3): d 0.98 (t, J ¼ 6.7 Hz, 3H), 1.30–1.50 (m, 4H), 1.55–
1.78 (m, 4H), 2.40 (t, J ¼ 6.5 Hz, 2H), 3.78 (s, 3H), 4.56 (s,
1H), 6.80 (d, J ¼ 8.0 Hz, 2H), 7.10–7.30 (m, 5H), 7.40 (d,
J ¼ 8.0 Hz, 2H); EI-MS: m/z (%) 321 [M]þ (15), 230 (100),
197 (7), 159 (31), 147 (20), 121 (100), 91 (87), 43 (20).
30
0
a
Aldehyde:amine:alkyne ¼ 1:1:1; 1 mmol of each compound used
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
336
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 3 3 5 – 3 3 7

View Article Online
MHz): d 3.80–3.90 (br s, NH, 1H), 5.30 (s, 1H), 5.85 (s, 2H),
6.30 (s, 1H), 6.60 (d, J ¼ 7.8 Hz, 1H), 7.25 (m, 3H), 7.35 (m,
2H), 7.45–7.50 (m, 5H). EI-MS: m/z (%) 396 [M]þ (15), 304
(7), 270 (6), 217 (2), 190 (2), 166 (2), 137 (2), 121 (31), 119
(95), 117 (100), 82 (25), 47 (36), 35 (28).
4c. Pale yellow oil, IR (neat): nmax : 3440 (br s), 2928, 2848,
1
1616, 1520, 1456, 1232, 1152, 1024, 736 cmꢂ1; H NMR (200
MHz, CDCl3): d 0.80–1.00 (m, 6H), 1.20–1.40 (m, 12H),
1.50–1.60 (m, 2H), 2.30–2.40 (t, J ¼ 6.5 Hz, 2H), 3.78 (s,
3H), 4.70 (s, 1H), 6.80 (d, J ¼ 8.0 Hz, 2H), 7.40 (d, J ¼ 8.0
Hz, 2H); EI-MS: m/z (%) 301 [M]þ (20), 252 (6), 244 (10),
230 (19), 215 (63), 187 (6), 167 (6), 161 (100), 135 (53), 134
(16), 121 (81), 105 (10), 91 (11), 77 (25), 57 (26), 43 (42), 36 (7).
4k. Yellow oil; IR (neat): nmax : 3344 (br s), 2912, 2848, 1616,
1504, 1264, 1136, 960, 832 cmꢂ1 1H NMR (CDCl3 , 300
;
MHz): d 3.50 (s, 6H), 4.45–4.55 (br s, NH, 1H), 5.40 (s, 1H),
6.20 (m, 1H), 6.80–6.85 (m, 1H), 6.90–7.00 (m, 3H), 7.20 (m,
3H), 7.35 (m, 2H), 7.65–7.70 (m, 2H). EI-MS: m/z (%) 361
[M]þ (10), 156 (7), 142 (26), 124 (67), 122 (61), 105 (100), 95
(25), 84 (36), 77 (80), 49 (70).
4d. Yellow oil, IR (neat): nmax : 3376 (br s), 2972, 2832, 1616,
1504, 1264, 1136, 1056, 848 cmꢂ1 1H NMR (200 MHz,
;
CDCl3): d 1.80–2.00 (br s, OH, 1H), 2.42 (t, J ¼ 6.9 Hz,
2H), 3.62 (t, J ¼ 6.9 Hz, 2H), 5.18 (s, 1H), 6.60–6.80 (m,
3H), 7.30 (d, J ¼ 7.8 Hz, 2H), 7.50 (d, , J ¼ 7.8 Hz, 2H);
EI-MS: m/z (%) 319 [M]þ (10), 287 (19), 218 (29), 155 (12),
142 (45), 129 (60), 105 (90), 77 (100), 43 (37).
4l. Pale yellow solid, m.p. 85 ꢀC; IR (neat): nmax : 3424 (br s),
3088, 3040, 1600, 1488, 1308, 1280, 1055 cmꢂ1 1H NMR
;
4e. Pale yellow oil, IR (neat): nmax : 3456 (br s), 2944, 2864,
(CDCl3 , 200 MHz): d 3.98–4.05 (br s, NH, 1H), 5.42 (s,
1H), 6.65–6.78 (m, 3H), 7.10–7.40 (m, 10H), 7.55–7.60 (m,
2H). FAB-MS: m/z (%) 283 [M]þ (11), 206 (7), 191 (100),
165 (3), 109 (7), 69 (23), 55 (31).
1
1616, 1520, 1456, 1200, 1040, 848 cmꢂ1; H NMR (200 MHz,
CDCl3): d 1.30–1.60 (m, 8H), 2.20 (m, 2H), 3.40 (t, 2H, J ¼
6.7 Hz), 3.58 (s, 3H), 3.60 (s, 3H), 3.98 (d, 2H, J ¼ 6.7 Hz),
4.40–4.60 (br s, NH, 1H), 5.10–5.20 (m, 2H), 5.30 (s, 1H),
5.80–5.60 (m, 1H), 6.30 (m, 2H), 6.90 (d, J ¼ 8.0 Hz, 1H),
7.30 (dd, J ¼ 8.0 and 2.3 Hz, 1H), 7.45–7.55 (m, 3H); FAB-
MS: m/z (%) 486 [M]þ (5), 320 (3), 207 (3), 185 (5), 109 (15),
95 (31), 83 (36), 161 (35), 69 (53), 55 (100).
4m. Pale yellow solid, m.p. 83 ꢀC; IR (neat): nmax : 3456 (br
s), 3088, 2944, 2848, 1600, 1488, 1424, 1055, 880 cmꢂ1 1H
;
NMR (CDCl3 , 200 MHz): d 0.98 (t, J ¼ 6.7 Hz, 3H), 1.20–
1.40 (m, 8H), 1.45–1.55 (m, 2H), 1.65–1.80 (m, 2H), 3.50 (t,
J ¼ 6.5 Hz, 1H), 3.80–4.10 (m, 2H), 7.20–7.50 (m, 10H). EI-
MS: m/z (%) 319 [M]þ (5), 203 (100), 151 (5), 102 (3), 39 (10).
4f. Yellow oil; IR (neat): nmax : 3410 (br s), 3034, 2858, 1603,
1514, 1453, 1227, 1093, 846 cmꢂ1 1H NMR (200 MHz,
;
CDCl3): d 4.00–4.10 (br s, NH, 1H), 4.15 (s, 2H), 4.44 (s,
2H), 5.22 (s, 1H), 6.60–6.80 (m, 3H), 7.05 (m, 1H), 7.20–7.40
(m, 5H), 7.50 (m, 2H); EI-MS: m/z (%) 380 [M]þ (15), 377
(3), 230 (22), 223 (31), 141 (8), 91 (100), 51 (10).
Acknowledgements
BVS and RSR thank CSIR, New Delhi, for the award of
fellowships.
4g. Yellow oil; IR (neat): nmax : 3420 (br s), 2935, 2865, 1680,
1
1632, 1504, 1456, 1236, 1216, 1168, 1120, 1040, 992 cmꢂ1; H
NMR (CDCl3 , 200 MHz): d 1.42 (s, 9H), 2.40 (t, 4H, J ¼ 6.5
Hz), 3.36 (s, 2H), 3.40 (t, 4H, J ¼ 6.5 Hz), 3.72 (s, 3H), 3.80 (s,
3H), 4.40–4.50 (br s, 1H, NH), 5.05 (s, 2H), 5.20 (m, 1H), 6.18
(dd, J ¼ 8.0 and 2.3 Hz, 1H), 6.38 (d, J ¼ 2.3 Hz, 1H), 6.62 (d,
J ¼ 8.0 Hz, 1H), 6.98 (d, J ¼ 8.0, 2H), 7.38–7.55 (m, 5H), 7.58
(d, J ¼ 8.0 Hz, 2H). FAB-MS: m/z (%) 571 [M]þ (12), 551 (5),
524 (3), 417 (3), 207 (3), 123 (10), 109 (18), 95 (37), 83 (35), 55
(100).
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4h. Yellow oil; IR (neat): nmax : 3376 (br s), 2928, 2864, 1600,
1520, 1360, 1168, 1040, 832 cmꢂ1 1H NMR (CDCl3 , 300
;
MHz): d 2.30 (s, 6H), 4.15–4.25 (br s, NH, 1H), 4.70 (s, 2H),
5.00 (s, 1H), 6.20–6.25 (dd, J ¼ 15.0 and 2.3 Hz, 1H), 6.50
(s, 1H), 6.60 (s, 1H), 6.80–6.85 (d, J ¼ 15.0 Hz, 1H), 6.90–
6.95 (dd, J ¼ 7.8 and 2.3 Hz, 1H), 7.20–7.35 (m, 7H), 7.50
(s, 1H), 7.60 (d, J ¼ 7.8 Hz, 1H). EI-MS: m/z (%) 412 [M]þ
(16), 136 (77), 118 (100), 91 (100), 77 (12), 65 (35), 51 (16),
39 (30).
4i. Yellow oil, IR (neat): nmax : 3344 (brs), 3056, 2928, 2832,
5
6
1600, 1504, 1232, 1040, 832 cmꢂ1 1H NMR (CDCl3 , 200
;
MHz): d 3.70 (s, 3H), 3.65–3.75 (brs, NH,1H), 5.38 (s, 1H),
6.60–6.80 (m, 4H), 7.20–7.30 (m, 4H), 7.35–7.40 (m, 4H),
7.60 (d, J ¼ 8.0 Hz, 2H). EIMS: m/z: 313 (Mþ 8), 236 (10),
191 (96), 165 (3), 121 (31), 119 (96), 117 (100), 84 (32), 55
(47), 37 (6).
7
8
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4j. Yellow oil, IR (neat): nmax : 3392 (br s), 3040, 2896, 2832,
1632, 1472, 1200, 1056, 832 cmꢂ1 1H NMR (CDCl3 , 300
;
T h i s j o u r n a l i s Q T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 4
N e w . J . C h e m . , 2 0 0 4 , 2 8 , 3 3 5 – 3 3 7
337