A simple method for the preparation of propargylamines using molecular sieve modified with copper(II)

Article abstract of DOI:10.1039/c0ob00224k

A new, heterogeneous, 4 A molecular sieve-supported copper(ii) catalyst was developed and was used successfully in the A³ coupling of alkynes, aldehydes and amines under simple reaction conditions.

Full text of DOI:10.1039/c0ob00224k

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A simple method for the preparation of propargylamines using molecular sieve
modified with copper(II)
a
a
a
a
b
´
Anna Fodor, Arpa´d Kiss, No´ra Debreczeni, Zolta´n Hell* and Iva´n Gresits
Received 7th June 2010, Accepted 29th June 2010
DOI: 10.1039/c0ob00224k
˚
A new, heterogeneous, 4 A molecular sieve-supported copper(II) catalyst was developed and was used
successfully in the A3 coupling of alkynes, aldehydes and amines under simple reaction conditions.
Introduction
Results and discussion
The metal-catalyzed carbon–carbon bond formation has become
one of the most important reactions in preparative organic
chemistry, even on an industrial scale. From this point of view,
some metals have a large literature background e.g. Pd in the
Heck, Sonogashira, Stille, or Suzuki–Miyaura couplings, or Ru in
metathesis, but other metals such as nickel, iron, copper, etc. also
have an increasing synthetic importance.
Recently our research group developed a new, heterogeneous Pd
catalyst, Pd0 on Mg–La mixed oxide, which was used successfully
in the Heck,16 Sonogashira,17 and Suzuki reactions.18 Then, good
results were obtained with NiII on the same support in the Kumada
coupling.19 Continuing this work, we examined the possibility of
the applicability of a heterogeneous copper catalyst in the A3
coupling.
Propargylamines are versatile synthons in the preparation
of organic compounds, especially different N-heterocycles. The
conventional methods for their synthesis involve the amination
of propargylic halides, phosphates or triflates.1 Another possible
way is the reaction of lithium acetylides or Grignard reagents
with imines or their derivatives.2,3 However, these methods require
the use of stoichiometric amounts of organometallic reagents and
strictly controlled reaction conditions. Furthermore, protection
of sensitive functional groups, such as aldehyde, is also necessary.
Thus, the development of a new efficient method has been an inter-
esting synthetic challenge. In the course of this research transition
metal complex catalysts were developed for the activation of the C–
H bond of the terminal alkyne containing iridium,4 indium,5 zinc,6
silver,7 or copper.8 Wei and Li have reported the highly efficient
three-component coupling reaction (alkyne–amine–aldehyde or
A3 reaction) through C–H activation in water using gold,9 but
the use of these homogeneous catalysts have some disadvantages,
as they are expensive, not recyclable, and their separation from
the reaction mixture is tedious. This led to the elaboration of
different heterogeneous, recyclable catalysts. Lo and co-workers10
developed a gold-based complex, which was successfully used in
aqueous media for the preparation of propargylamines with good
yield. Other metal-based heterogeneous catalysts were also used
successfully in the A3-reaction, e.g. AgI-tungstophosphoric acid,11
CuI anchored on a silica gel support12 or on USY-zeolite,13 CuII
salt on a hydroxyapatite support,14 or N-heterocyclic carbene–CuI
on a silica support.15 The main disadvantages of these methods are
the high price of the catalyst,11,15 the tedious preparation of it,12,15
the sensitivity of copperI compounds,12,13,15 or problems with the
reusability/recyclability.13
First, we tested different basic materials as supports. These
were Mg:La 3 : 1 mixed oxide (MgLaO), Mg:Al 2 : 1 hydrotalcite
(HT), and 4 A molecular sieves (4A). These solid bases were
˚
treated with CuCl2 in deionized water at room temperature for
12 h. The copper content of the catalysts thus obtained was 0.77,
0.67, and 1.00 mmol g-1, respectively (determined by ICP-OES).
These catalysts were examined in the reaction of formaldehyde,
phenylacetylene and morpholine (Scheme 1) under solvent-free
conditions. The results are summarized in Table 1. After the
reaction time indicated in the table, the reaction mixture was
diluted with methyl-tert-butyl ether, the solid was filtered out, the
solvent was evaporated, and then the residues were examined with
both 1H NMR spectroscopy and GC-MS.
Scheme 1
As is shown, the best result was obtained with CuII on 4A as
basic support (Table 1, entry 4). In the case of CuII–MgLa and
CuII–HT, the main product was N-hydroxymethyl-morpholine, the
known intermediate of the A3 coupling. Based on these results
Table 1 Selection of the catalyst for the A3 couplinga
Catalyst
Reaction time/h
Yield (%)b
1
2
3
4
5
6
CuII–HT
14
24
14
24
24
24
12 (26)c
14 (42)c
56
92
90
CuII–MgLa (3 : 1)
CuII–4A
CuII –4A
CuII–4Ad
CuII–4Ae
33
aDepartment of Organic Chemistry and Technology, Budapest Univer-
sity of Technology and Economics, H-1521 Budapest, Hungary. E-mail:
zhell@mail.bme.hu; Fax: (+36 1) 463-3648; Tel: (+36 1) 463-1414
a 5 mmol morpholine, 5 mmol paraformaldehyde, 6 mmol phenylacetylene,
0.5 g catalyst. b Isolated yield, corrected with the results of GC-MS.
c The main product is hydroxymethyl-morpholine (its yield is shown in
parentheses). d 0.2 g catalyst was used. e 0.2 mmol Cu/g support.
bDepartment of Chemical and Environmental Process Engineering, Budapest
University of Technology and Economics, H-1521 Budapest, Hungary.
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Scheme 2
we investigated the reaction of different alkynes, amines and
aldehydes in the presence of CuII–4A (Scheme 2). The results are
summarized in Table 2.
Scheme 4
Generally, after 24 h stirring at room temperature pheny-
lacetylene, formaldehyde and secondary amines gave the desired
products in high isolated yield (see entries 1–6). The primary
n-butylamine gave significantly lower yield (entry 7). Aromatic
amines failed to react (entries 8–9). In the case of dipheny-
lamine, because of its melting point (54 ◦C) the reaction was
significantly better. The Glaser coupling strongly consumes the
phenylacetylene—this was shown by the presence of a significant
amount of unreacted aldehyde in the reaction mixture. Thus,
instead of 20 mol%, 50 mol% excess of phenylacetylene was
added, and the desired propargylamine was obtained in nearly
quantitative yield and with formation of less than 10% dimeric
product. Based on these results the reaction was repeated with
several aldehydes. The results are summarized in Table 4
The big disadvantage of the transition metal-catalyzed reactions
is that the metal often contaminates the product, or its separation
is very tedious. Copper is known to form complexes with amines.
This could mean that during such a long reaction, either at room
temperature or by heating, a remarkable amount of copper would
be detectable in the liquid phase. We investigated the products
isolated in the reactions and the X-ray fluorescence analysis
showed that in most of the cases the copper content of the products
was less than 1 ppm. Thus, we could consider that our catalyst
system is stable enough to avoid the copper contamination of the
product.
◦
conducted at 60 C. In the reaction of aniline, the main product
was N-methylene aniline, formed from N-hydroxymethyl-aniline
by dehydration. Butyraldehyde gave the desired product with
quantitative yield (entry 10). The aliphatic 1-heptyne failed to
react under solvent-free conditions at room temperature, probably
due to the high viscosity of the mixture. While using acetonitrile
as solvent15 the appropriate propargylamine was obtained in
moderate yield (entry 11). Methyl acetylenecarboxylate showed
violent reaction with both morpholine and dibutylamine, but
instead of the formation of propargylamines, an addition of the
amine to the C C bond occurred together with the formation
of some polymeric products. This could be concluded from the
1H NMR spectra (olefinic protons of the morpholine adduct—see
Scheme 3—were found at 4.70 and 7.35 ppm) and from GC-MS
examination of the product mixture. The addition of an amine to
the C C bond is known in the literature,20 the E adduct is formed
even without the addition of any catalyst.
The catalyst can be easily recovered from the reaction mixture
and it is reusable without any purification. In the reaction of
phenylacetylene, paraformaldehyde and morpholine, the same
catalyst gave 92, 89 and 81% yields in the 1st, 2nd and 3rd cycle,
respectively.
Although A3 coupling is described with aldehydes, we examined
ketones, too, namely acetone and acetophenone. In these cases,
instead of an A3-type reaction, the Glaser-type self coupling
of phenylacetylene occurred and 1,3-diphenyl-but-1,3-diyn was
obtained in good yield (95 and 50%, respectively) (Scheme 5).
The original Glaser method described the use of ammonium
chloride and cuprous salt in the presence of atmospheric oxygen
for the coupling. When we reacted phenylacetylene in the presence
of ammonium chloride, acetone, and CuII–4A, the yield of
1,3-diphenyl-but-1,3-diyn decreased to 34%. We examined the
possibility of a cross-coupling Glaser reaction. Phenylacetylene
and meparfynol were reacted with acetone and morpholine in the
presence of CuII–4A. After 24 h stirring at room temperature the
reaction mixture was examined by GC-MS. The results showed
that phenylacetylene is more reactive than meparfynol, since the
amount of the phenylacetylene dimer was predominant in the
mixture, the amount of meparfynol dimer was almost negligible
(Scheme 6). This is in good correlation with the results obtained
in the A3 coupling, i.e. both meparfynol and heptyne gave weaker
yield than phenylacetylene.
Scheme 3
Meparfynol (3-methylpent-1-yn-3-ol) showed no reactivity at
room temperature, but in refluxing toluene the desired propar-
gylamine was obtained with excellent yield (entry 15). trans-
Cinnamaldehyde under the same conditions gave the desired
product in quantitative preparative yield (entry 16).
Reaction of aromatic aldehydes such as veratraldehyde, 3,4,5-
trimethoxybenzaldehyde or 4-chlorobenzaldehyde (in acetonitrile)
at room temperature (entries 17–19) gave no, or poor results; the
aldehydes could be recovered from the reaction mixture. Thus,
experiments were performed to determine the optimal reaction
conditions for aromatic aldehydes (see Table 3). The reaction of
p-chlorobenzaldehyde, phenylacetylene and morpholine was used
for this purpose.
In acetonitrile at 60 ◦C 60%, while at 80 ◦C 78% of product
was obtained, but with increasing temperature, the amount of the
phenylacetylene dimer 1,3-diphenyl-but-1,3-diyn (Scheme 4) also
increased significantly. This dimer is produced in a Glaser-type
self coupling.21
Conclusion
By changing acetonitrile to toluene at 110 ◦C the yield in-
creased to 89%, and the propargylamine/Glaser-dimer ratio was
Thus, copper supported on 4 A molecular sieves is a good, easily
recoverable and reusable catalyst for the A3 coupling of aliphatic
II
˚
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Table 2 A3 coupling in the presence of CuII–4Aa
Table 3 Effect of the reaction conditions to the A3 coupling of p-
chlorobenzaldehyde
Alkyne
Aldehyde
CH2O
Amine
Yield (%)b
92
1
2
3
CH2O
CH2O
93
76
Solvent
T/◦C
Molar ratioa
Yield (%)
1
2
3
4
5
acetonitrile
acetonitrile
acetonitrile
toluene
rt
60
80
110
110
1.2 : 1
1.2 : 1
1.2 : 1
1.2 : 1
1.5 : 1
10b
60bc
78 bc
89c
4
CH2O
96
toluene
96c
5
6
7
8
CH2O
CH2O
CH2O
CH2O
70
72
40
1c,d
a Phenylacetylene : aldehyde ratio. b Based on the 1H NMR spectra. c Based
on GC-MS
Table 4 A3 coupling of aromatic aldehydes with phenylacetylenea
9
CH2O
7d
10
98
Aldehyde
Yield (%)
96
1
2
11
CH2O
2d (27)e
70
99
12
13
CH2O
CH2O
4d
3
f
—
4
5
90
89
f
14
15
CH2O
CH2O
—
— (94g)
6
7
70
54
16
17
18
19
99g
1e,h
3e,h
10e,h
a 5 mmol amine, 5 mmol aldehyde, 7.5 mmol phenylacetylene, 0.5 g catalyst,
toluene, reflux, 15 h. Isolated yields, corrected with the results of GC-MS
and 1H NMR spectra
aldehydes, alkynes and secondary amines at room temperature
under solvent-free conditions. Aromatic aldehydes in boiling
toluene yielded the desired propargylamines almost quantitatively.
Experimental
a 5 mmol amine, 5 mmol aldehyde, 6 mmol phenylacetylene, 0.5 g catalyst.
b Isolated yield, corrected with the results of GC-MS. c At 60 ◦C d Based
on GC-MS. e In acetonitrile. f Instead of A3 coupling an addition of the
amine to the C C bond occurred (see text). g In refluxing toluene. h Based
on the 1H NMR spectra.
1H NMR spectra were made on BRUKER Avance-300 or 500
instruments using TMS as internal standard in CDCl3.
GC-MS spectra were made on Shimadzu GC-2010, GC-MS
QP2010S instrument, column: HP-5MS, 30 m ¥ 0.25 mm ¥
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Scheme 5
Scheme 6
0.25 mm, Temperature program: 40 ◦C (10 min) → 10 ◦C min-1
300 ◦C (26 min).
→
666 cm-1. Anal. Calcd. for C13H15NO: C 77.61, H 7.46, N 6.97%,
found: C 77.53, H 7.49, N 7.02%.
IR spectra were made on BRUKER Tensor 37 instrument.
N -(3-Phenylprop-2-ynyl)-N -methyl-benzylamine. Yellowish
oil, H NMR (300 MHz, CDCl3) d (ppm): 2.39 (s, 3H, CH3);
1
XRF examinations
3.50 (s, 2H, PhCH2); 3.63 (s, 2H, C C–CH2); 7.28–7.29 (m, 7H,
ArH); 7.36–7.47 (m, 3H, ArH). 13C NMR (CDCl3): spectral data
are in agreement with the reported ones.23 GC: Rt: 29.17 min. MS
m/z(%): 235(M+, 25), 158(45), 144(30), 115(100), 91(70). Anal.
Calcd. for C17H17N: C 86.81, H 7.23, N 5.96%, found: C 86.79, H
7,31, N 6.02%.
Canberra isotope excitation instrument with SCD, exciting source:
125I.
TLC
Merck Kieselgel 60 F254 plates, hexane–acetone 4 : 1 eluent,
detection either by UV light at 254 nm or by heating after spraying
with phosphoromolybdic acid solution.
N-(3-Phenylprop-2-ynyl)pyrrolidine. Yellow oil, 1H NMR
(300 MHz, CDCl3) d (ppm): 1.83 (m, 4H, 2¥CH2); 2.70 (m, 4H,
2¥N–CH2); 3.63 (s, 2H, C C–CH2); 7.27–7.29 (m, 4H, ArH);
7.43 (m, 1H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm): 131.5,
128.4, 128.0, 123.0, 84.7, 77.3, 53.2, 48.2, 25.3. GC: Rt: 25.25 min.
MS m/z(%): 185(M+, 30), 156(50), 115(100), 89(15), 70(20). Anal.
Calcd. for C13H15N: C 84.32, H 8.11, N 7.57%, found: C 84.39, H
8.04, N 7.64%.
Preparation of the catalysts
2 g of support and 0.34 g (2 mmol) of CuCl2·2H2O in 200 ml
deionized water were stirred at room temperature for 12 h. Then
the solid was filtered out, washed with deionized water and then
with acetone, and dried in an oven at 120 ◦C for 1 h.
N,N-Dibutyl-N-(3-phenylprop-2-ynyl)-amine. Yellow oil, 1H
NMR (500 MHz, CDCl3) d (ppm): 0.93 (t, 6H, 2¥CH3); 1.34–
1.36 (sex, 4H, 2¥CH2–CH3); 1.48 (qui, 4H, 2¥CH2); 2.53 (t, 4H,
2¥NCH2); 3.61 (s, 2H, C C–CH2); 7.28 (m, 3H, ArH); 7.42 (m,
2H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm): 131.5, 128.7,
128.1, 122.7, 84.4, 77.2, 49.3, 33.5, 20.2, 17.5. GC: Rt: 27.46 min.
MS m/z(%): 243(M+, 5), 200(55), 115(100). IR(film): n 2957, 2931,
2871, 2817, 1598, 1489, 1458, 1376, 1320, 1094, 755, 690 cm-1.
Anal. Calcd. for C17H25N: C 83.95, H 10.29, N 5.76%, found: C
84.03, H 10.32, N 5.69%.
Typical procedure for the reaction of aliphatic aldehydes
6 mmol (660 ml) of phenylacetylene, 5 mmol of aldehyde, 5 mmol
of amine and 0.5 g CuII–4A were stirred at room temperature for
24 h. Then the mixture was diluted with methyl-tert-butyl ether,
the solid was filtered out, washed with the same solvent, the filtrate
was evaporated and the product was characterized.
1
N-(3-Phenylprop-2-ynyl)morpholine. Yellowish oil, H NMR
(300 MHz, CDCl3) d (ppm): 2.62 (m, 4H, 2¥N–CH2); 3.48 (s, 2H,
C
C–CH2); 3.75 (m, 4H, 2¥O–CH2); 7.29 (m, 3H, ArH); 7.42 (m,
N-(3-Phenylprop-2-ynyl)piperidine. Yellowish oil, 1H NMR
(300 MHz, CDCl3) d (ppm): 1.44–1.66 (m, 6H, CH2–CH2–CH2);
2.41–2.66 (m, 4H, 2¥N–CH2); 3.47 (s, 2H, C C–CH2); 7.28 (m,
3H, ArH); 7.42 (m, 2H, ArH). 13C NMR (CDCl3): spectral data
are in agreement with the reported ones.22 GC: Rt: 26.33 min. MS
2H, ArH). 13C NMR (CDCl3): spectral data are in agreement with
the reported ones22 GC: Rt: 26.65 min. MS m/z(%): 201(M+,25),
170(25), 143(40), 115(100). IR(film): n 3056, 2959, 2855, 2813,
2762, 1682, 1598, 1489, 1453, 1331, 1116, 1006, 862, 758, 692,
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m/z(%): 199 (M+, 30), 170(10), 156(40), 115(100). Anal. Calcd.
for C14H17N: C 84.42, H 8.54, N 7.04%, found: C 84.42, H 8.61, N
7.11%.
Methyl (E)-3-(N,N-dibutylamino)-2-propenoate. Yellowish
oil, H NMR (300 MHz, CDCl3) d (ppm): 0.93 (t, 6H, 2¥CH3);
1.33 (m, 4H, 2¥CH2); 1.51 (m, 4H, 2¥CH2); 2.62 (t, 4H, 2¥CH2);
3.66 (s, 3H, O–CH3); 4.53 (d, 1H, = CH–N); 7.43 (dd, 1H, =
CH–CO). 13C NMR (CDCl3): spectral data are in agreement with
the reported ones.25 GC: Rt: 26.13 min. MS m/z(%): 213(M+, 20),
182(45), 170(65), 140(75), 128(90), 98(65), 84(100).
1
1
N¢-Methyl-N-(3-phenylprop-2-ynyl)piperazine. Yellow oil, H
NMR (300 MHz, CDCl3) d (ppm): 2.26 (s, 3H, N-CH3); 2.40-
2.69 (m, 8H, 2¥N-CH2–CH2–N); 3.50 (s, 2H, C C–CH2); 7.26–
7.30 (m, 3H, ArH); 7.46-7.47 (m, 2H, ArH). 13C NMR (75 MHz,
CDCl3) d (ppm): 131.8, 128.6, 128.2, 123.1, 84.3, 77.3, 55.2, 53.7,
48.3, 47.5. GC: Rt: 27.43 min. MS m/z(%): 214(M+, 10), 158(25),
143(25), 115(55), 97(100), 56(55). Anal. Calcd. for C14H18N2: C
78.50, H 8.41, N 13.08%, found: C 78.57, H 8.39, N 13.03%.
N-(4-Hydroxy-4-methyl-hex-2-ynyl)morpholine. Yellow oil,
1H NMR (500 MHz, CDCl3) d (ppm): 1.04 (t, 3H, CH3); 1.47 (s,
3H, CH3); 1.70 (q, 2H, CH2); 2.57 (m, 5H, 2¥N–CH2, OH); 3.32
(s, 2H, CH2–C C); 3.75 (t, 4H, 2¥O–CH2). 13C NMR (75 MHz,
CDCl3) d (ppm): 89.6, 77.4, 68.6, 66.7, 52.2, 47.4, 36.6, 29.5, 9.1.
GC: Rt: 23.59 min. MS m/z(%): 197(M+, 10), 179(10), 168(15),
96(25), 86(55), 56(35), 43(100). IR(film): n 3410, 2971, 2933, 2860,
1658, 1455, 1290, 1206, 1163, 1116, 1002, 915, 863, 775 cm-1.
Anal. Calcd. for C11H19NO2: C 67.01, H 9.64, N 7.11%, found: C
67.09, H 9.69, N 7.12%.
N-(3-Phenylprop-2-ynyl)-butylamine. Yellow oil, 1H NMR
(300 MHz, CDCl3) d (ppm): 0.93 (t, 3H, CH3); 1.32–1.34 (m,
2H, CH2–CH3); 1.42–1.44 (m, 2H, CH2); 2.40 (m, 2H, N–CH2);
3.07 (s, 1H, NH); 3.22 (s, 2H, C C–CH2); 7.30–7.34 (m, 3H,
ArH); 7.47–7.50 (m, 2H, ArH). 13C NMR (CDCl3): spectral data
are in agreement with the reported ones.24 MS m/z(%): 187(M+,
7), 144(60), 115(100). IR(film): n 2957, 2929, 2871, 1490, 1442,
1327, 1142, 755, 691 cm-1. Anal. Calcd. for C13H17N: C 83.42, H
9.09, N 7.49%, found: C 83.38, H 9.12, N 7.41%.
N-[3-Phenyl-1-((E)-2-phenylethenyl)-prop-2-ynyl]-morpholine.
1
yellow oil, H NMR (300 MHz, CDCl3) d (ppm): 2.70 (m, 2H,
N–CH2); 2.82 (m, 2H, N–CH2); 3.82 (m, 4H, 2¥O–CH2); 4.42
(d, 1H, CH–C C); 6.33 (dd, 1H, = CH–CH); 6.94 (d, 1H,
CH CH), 7.20 (d, 1H, ArH); 7.27–7.38 (m, 5H, ArH); 7.46–7.49
(m, 2H, ArH); 7.52–7.57 (m, 2H, ArH). 13C NMR (75 MHz,
CDCl3) d (ppm): 136.5, 133.6, 132.0, 128.7, 128.4, 128.0, 126.7,
123.0, 88.6, 84.4, 77.3, 67.2, 60.0, 50.1. GC: Rt: 34.69 min. MS
m/z(%): 303(M+, 25), 217(95), 202(65), 115(100), 86(40), 56(50).
IR(film): n 3288, 3058, 3029, 2957, 2854, 2690, 2222, 1953, 1679,
1598, 1490, 1451, 1321, 1118, 1071, 1003, 970, 865, 757, 725,
692 cm-1. Anal. Calcd. for C21H21NO: C 83.17, H 6.93, N 4.62%,
found: C 83.10, H 6.90, N 4.68%.
N,N-Diphenyl-N-(3-phenylprop-2-ynyl)-amine. GC: Rt: 33.38
min. MS m/z(%): 283(M+, 90), 206(20), 168(65), 115(100), 77(30).
N-Phenyl-N-(3-phenylprop-2-ynyl)-amine. GC: Rt: 29.33 min.
MS m/z(%): 207(M+, 50), 178(10), 130(15), 115(100).
N-Methylene-aniline. GC: Rt: 13.60 min. MS m/z(%):
105(M+, 100), 77(90), 51(45).
1
N-(3-Phenyl-1-propyl-prop-2-ynyl)morpholine. Yellow oil, H
NMR (300 MHz, CDCl3) d (ppm): 0.97 (t, 3H, CH3); 1.55 (sex, 2H,
CH2–CH3); 1.66 (q, 2H, CH2); 2.56 (m, 2H, N–CH2); 2.72 (m, 2H,
N–CH2); 3.50 (t, 1H, C C–CH2); 3.74 (m, 4H, 2¥O–CH2); 7.28–
7.30 (m, 3H, ArH); 7.42–7.51 (m, 2H, ArH). 13C NMR (75 MHz,
CDCl3) d (ppm): 131.5, 128.3, 128.1, 123.1, 84.7, 77.6, 66.2, 52.7,
48.1, 33.8, 21.3, 16.1. GC: Rt: 28.44 min. MS m/z(%): 243(M+, 5),
200(100), 128(15), 115(45). Anal. Calcd. for C16H21NO: C 79.01,
H 8.64, N 5.76%, found: C 78.98, H 8.66, N 5.71%.
N-(3-Phenyl-1-(3,4,5-trimethoxyphenyl)-prop-2-ynyl)-morpho-
line. 1H NMR (300 MHz, CDCl3) d (ppm): 4.66 (s, 1H, CH–
C
C).
Typical procedure for the reaction of aromatic aldehydes
7.5 mmol (660 ml) of phenylacetylene, 5 mmol of aldehyde,
5 mmol of amine and 0.5 g CuII–4A in 2 ml toluene were stirred
under reflux for 15 h. Then the mixture was cooled, diluted with
methyl-tert-butyl ether, the solid was filtered out, washed with
the same solvent, the filtrate was evaporated and the product was
characterized.
N-(Oct-2-ynyl)morpholine. Yellowish
oil,
1H
NMR
(300 MHz, CDCl3) d (ppm): 0.86 (t, 3H, CH3); 1.31 (m,
4H, CH2–CH2); 1.48 (m, 2H, CH2); 2.16 (t, 2H, CH2–C C);
2.51 (m, 4H, 2¥N–CH2); 3.66 (m, 6H, 2¥O–CH2, C C–CH2).
13C NMR (75 MHz, CDCl3) d (ppm): 84.5, 77.2, 65.4, 52.6,
48.2, 31.1, 28.7, 22.1, 18.5, 14.1. GC: Rt: 23.94 min. MS m/z(%):
195(M+, 25), 138(20), 122(20), 108(100), 86(75), 67(45), 42(70).
Anal. Calcd. for C12H21NO: C 73.85, H 10.77, N 7.18%, found: C
73.88, H 10.71, N 7.12%.
N-(3-Phenyl-1-(4-chlorophenyl)-prop-2-ynyl)morpholine. Ye-
1
llow oil, H NMR (300 MHz, CDCl3) d (ppm): 2.40 (m, 2H,
N–CH2); 2.61 (m, 2H, N–CH2); 3.72 (d, 4H, 2¥O–CH2); 4.76 (s,
1H, CH–C C); 7.13 (d, 2H, ArH); 7.33–7.35 (m, 3H, ArH); 7.50–
7.52 (m, 2H, ArH); 7.58 (d, 2H, ArH). 13C NMR (CDCl3): spectral
data are in agreement with the reported ones.26 GC: Rt: 33.85 min.
MS m/z(%): 311(M+, 15), 225(100), 189(35), 86(40), 56(65). Anal.
Calcd. for C19H18ClNO: C 73.19, H 5.78, N 4.49%, found: C 73.11,
H 5.74, N 4.41%.
N,N-Dibutyl-(oct-2-ynyl)amine. GC: Rt: 24.96 min. MS
m/z(%): 237(M+, 5), 194(100), 152(40), 41(30).
1
Methyl (E)-3-(4-morpholinyl)-2-propenoate. Yellowish oil, H
NMR (300 MHz, CDCl3) d (ppm): 2.41 (m, 2H, N–CH2); 2.50 (m,
2H, N–CH2); 3.66 (s, 3H, O–CH3); 3.71 (m, 4H, 2¥O–CH2); 4.70
(d, 1H, = CH–N); 7.35 (dd, 1H, = CH–CO). 13C NMR (CDCl3):
spectral data are in agreement with the reported ones.25 GC: Rt:
24.30 min. MS m/z(%): 171(M+, 65), 156(30), 140(80), 112(100),
82(90), 55(60), 42(70).
N-(3-Phenyl-1-(3,4-dimethoxyphenyl)-prop-2-ynyl)-morpholine.
Yellow oil, H NMR (300 MHz, CDCl3) d (ppm): 2.65 (m, 4H,
2¥N–CH2); 3.75 (m, 4H, 2¥O–CH2); 3.90 (s, 3H, O–CH3); 3.93
(s, 3H, O–CH3); 4.74 (s, 1H, CH–C C); 6.87 (d, 1H, ArH); 7.00
(d, 1H, ArH), 7.19–7.21 (m, 2H, ArH); 7.34–7.41 (m, 2H, ArH);
7.50–7.56 (m, 2H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm):
1
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149.1, 148.8, 132.0, 130.6, 128.5, 128.4, 127.0, 123.2, 122.0, 121.0,
88.5, 85.5, 67.4, 62.0, 56.4, 56.2, 50.1. GC: Rt: 35.44 min. MS
m/z(%): 337(M+, 5), 251(100), 207(20), 165(15), 115(100), 55(15).
Anal. Calcd. for C21H23NO3: C 74.78, H 6.82, N 4.15%, found: C
74.71, H 6.91, N 4.21%.
were stirred at room temperature for 24 h. Then the solid was
filtered off, washed with acetone, and the filtrate was evaporated.
1,3-Diphenyl-but-1,3-diyne. White solid, m.p. 84–85 ◦C (lit.:
86–88 ◦C27), 1H NMR (300 MHz, CDCl3) d (ppm): 7.32–7.37 (m,
6H, ArH); 7.51–7.55 (m, 4H, ArH). 13C NMR (75 MHz, CDCl3)
d (ppm): 74.11, 81.72, 122.03, 128.52, 129.43, 132.35. GC: Rt:
29.58 min. MS m/z(%): 202(M+, 100), 174(5), 150(10), 101(10),
88(10). Anal. Calcd. for C16H10: C 95.05, H 4.95%, found: C 95.08,
H 4.92%.
N-(3-Phenyl-1-(3-nitrophenyl)-prop-2-ynyl)morpholine. Ora-
1
nge oil, H NMR (300 MHz, CDCl3) d (ppm):): 2.64 (m, 4H,
2¥N–CH2); 3.75 (m, 4H, 2¥O–CH2); 4.88 (s, 1H, CH–C C); 7.16
(d, 1H, ArH); 7.23 (d, 1H, ArH); 7.33–7.37 (m, 2H, ArH); 7.52–
7.57 (m, 2H, ArH); 8.00 (d, 1H, ArH); 8.17 (d, 1H, ArH); 8.54
(s, 1H, ArH). 13C NMR (75 MHz, CDCl3) d (ppm): 148.5, 140.6,
134.6, 132.0, 129.3, 128.8, 128.4, 128.3, 123.6, 123.0, 122.5, 90.0,
83.8, 83.3, 67.1, 61.4. GC: Rt: 35.64 min. MS m/z(%): 322(M+,
10), 236(45), 200(45), 190(40), 86(45), 56(100). IR(film): n 3288,
3079, 2959, 2856, 2825, 2219, 1682, 1531, 1490, 1453, 1349, 1116,
1004, 907, 862, 758, 730, 692 cm-1. Anal. Calcd. for C19H18N2O3:
C 70.81, H 5.59, N 8.70%, found: C 70.84, H 5.51, N 8.76%.
5-Hydroxy-5-methyl-1-phenyl-hept-1,3-diyne. GC: Rt: 26.55
min. MS m/z(%): 198(M+, 10), 169(45), 126(15), 115(10), 43(100).
3,8-Dihydroxy-3,8-dimethyl-dec-4,6-diyne. GC: Rt: 23.48 min.
MS m/z(%): 165(M+, 20), 93(20), 43(100).
Acknowledgements
N-(1,3-Diphenyl-prop-2-ynyl)morpholine. Yellow oil, 1H
NMR (300 MHz, CDCl3) d (ppm): 2.68 (m, 4H, 2¥N–CH2); 3.77
(m, 4H, 2¥O–CH2); 4.83 (s, 1H, CH–C C); 7.34–7.41 (m, 5H,
ArH); 7.52–7.57 (m, 3H, ArH); 7.68 (d, 2H, ArH). 13C NMR
(CDCl3): spectral data are in agreement with the reported ones.26
GC: Rt: 32.15 min. MS m/z(%): 277(M+, 15), 200(25), 191(100),
86(30), 56(45). Anal. Calcd. for C19H19NO: C 82.31, H 6.86, N
5.05%, found: C 82.27, H 6.81, N 5.09%.
The authors are grateful to Merck Hungary Ltd. for the financial
support and to Chinoin Pharmaceutical and Chemical Works
Ltd., member of the Sanofi-Aventis Group for the technical
´
support, A. K. for the financial support as well.
Notes and references
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llow oil, H NMR (300 MHz, CDCl3) d (ppm):): 2.61 (m, 4H,
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1
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ArH); 6.72 (s, 1H, CH–C C); 7.18–7.35 (m, 3H, ArH); 7.44–7.58
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N-(3-Phenyl-1-(3-hydroxyphenyl)-prop-2-ynyl)morpholine. Ye-
1
llow oil, H NMR (300 MHz, CDCl3) d (ppm): 2.63 (m, 4H,
2¥N–CH2); 3.73 (m, 4H, 2¥O–CH2); 4.67 (s, 1H, OH); 4.72 (s, 1H,
CH–C C); 7.16–7.18 (m, 3H, ArH); 7.23–7.25 (m, 2H, ArH);
7.31–7.33 (m, 3H, ArH); 7.48–7.50 (m, 1H, ArH). 13C NMR
(75 MHz, CDCl3) d (ppm): 138.5, 131.7, 130.6, 128.3, 128.2,
122.8, 123.3, 121.3, 115,4, 84.3, 81.6, 66.2, 52.7, 48.2. GC: Rt:
34.65 min. MS m/z(%): 293(M+, 20), 207(100), 178(20), 115(15),
86(55), 56(65). Anal. Calcd. for C19H19NO2: C 77.82, H 6.48, N
4.78%, found: C 77.89, H 6.48, N 4.72%.
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