Microwave assisted Mannich reaction of terminal alkynes on alumina

Article abstract of DOI:10.1007/s706-002-8251-8

Terminal alkynes, secondary amines, and formaldehyde undergo a Mannich reaction at room temperature in the presence of CuCl on Al₂O₃ without any organic solvent as reaction medium. The reaction can be promoted by microwave irradiatio

Full text of DOI:10.1007/s706-002-8251-8

Monatshefte fuÈr Chemie 133, 199±204 ꢀ2002)
Microwave Assisted Mannich Reaction
of Terminal Alkynes on Alumina
Ã
and M. R. Naimi-Jamal
Ali Shari® , Hossein Farhangian, Farshid Mohsenzadeh,
Ã;a
Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Summary. Terminal alkynes, secondary amines, and formaldehyde undergo a Mannich reaction at
room temperature in the presence of CuCl on Al2O3 without any organic solvent as reaction medium.
The reaction can be promoted by microwave irradiation and is complete within one minute.
Keywords. Alkynes; Alumina; Mannich bases; Microwave irradiation.
Introduction
The Mannich reaction is one of the most important multicomponent reactions in
organic chemistry [1]. Mannich bases are of considerable interest and have found
applications in chemical and pharmaceutical industry [1g, 2].
A large variety of compounds such as ketones, nitro compounds [1b], amines
[3], amides [4], and electron-rich aromatic compounds [1c, 5] can serve as sub-
stratesinMannichreactions. Terminal alkynesalsocantakepartinMannichreactions
to give the corresponding propargylamines which can be further transformed to
ꢀ-aminoketones [6], aminoalkenes [6b, 7], or aminoalkanes [6b].
Some propargylamines exhibit biological activities. For example, substituted
1-aryl-3-aminopropynes have antiulceration, sedative, hypnotic, antispasmodic,
analgesic, and anti-in¯ammatory effects [8]. Also, a number of 3-phenylpropyn-
2-amines ꢀ1) have been previously prepared and shown some monoamine oxidase
inhibitory, anorexigenic, and blood lipid lowering activity as well as tryptamine-
like behavioural effects without any interaction with tryptamine receptors [9].
There are several methods for the preparation of propargylamines, e.g. reaction
of 1-ꢀꢁ-aminoalkyl)-benzotriazoles with lithium alkenydes [10] or with sodium
Ã
Corresponding authors. E-mail: m.r.naimi@gmx.net
È
Current address: Fachbereich Chemie, OC I, Universitat Oldenburg, D-26111 Oldenburg, Germany
a

200
A. Shari® et al.
dialkynyldiethylaluminates [11], reaction of propargyl bromides with secondary
amines [12], or reaction of geminal aminoethers with terminal acetylenes [13].
However, the most convenient method for the preparation of 1 is re¯uxing a
solution of a terminal acetylene, a suitable amine, and formaldehyde in a polar
solvent, mostly dioxane, in the presence of a catalytic amount of a copper salt
ꢀusually CuCl or CuꢀOAc)2) [6±8, 14]. Copper salts are frequently used in the reac-
tion, since they have been found to increase the nucleophilicity of the acetylenic
substrates towards the Mannich reactants [15]. Recently, Dax et al. have shown that
any member of the three components can be immobilized on a resin and subsequently
reacted with the other two in the presence of a copperꢀI) salt to afford the desired
Mannich adducts [16].
Here, we report an environmentally benign preparation of propargylamines via
a Mannich reaction on Al2O3 without any organic solvent as reaction medium
ꢀScheme 1).
Scheme 1
Results and Discussion
We have previously shown that electron-rich aromatic compounds can be
aminoalkylated by a Mannich reaction with appropriate adducts on solid supports
assisted by microwave irradiation [5b]. In continuation of our interest in Mannich
base synthesis, in peculiar with those assisted by microwave irradiation, we
examined the extension of this method to the aminomethylation of terminal
alkynes with two different methods.
In method A, a terminal acetylene ꢀ2), a secondary amine ꢀ3), formaldehyde
ꢀused as 37% aqueous solution), CuCl, and neutral alumina were mixed together
and stirred at room temperature. The progress of the reaction was monitored with
TLC. After 6 h, the products were obtained in good to excellent yields ꢀTable 1).
This method can also be applied to bulky secondary amines, such as dibenzylamine
and diisopropylamine ꢀTable 1, entries 6 and 7). In the absence of CuCl, the yield
of the reaction is negligible.
Method B is basically similar to method A, but the reaction was promoted by
microwave irradiation in a domestic microwave oven. The reaction was complete
in about one minute. The yields of the products were in the range of 70±94%, i.e.
comparable to those obtained from method A ꢀTable 1). The products 4a±i are
known compounds; the new products 4j±m were characterized by their NMR
spectra and HRMS.
To investigate solid supports other than neutral alumina, we also examined
basic and acidic alumina, silica gel, and montmorillonite K-10, but the best results
were obtained with neutral alumina.

Mannich Reaction of Terminal Alkynes
201
Table 1. Aminomethylation of terminal alkynes on alumina at room temperature ꢀA) or assisted by
microwave irradiation ꢀB)
Entry Alkyne 2
ꢀR)
Amine 3
ꢀHNR02)
Product
Yield/%
A
B
1
2
Ph
HNEt2
4a
4b
4c
4d
4e
4f
83
86
92
95
86
86
73
83
88
77
80
85
84
87
81
94
92
91
88
70
80
90
85
91
87
90
Ph
HNBu2
3
Ph
pyrrolidine
piperidine
morpholine
HNꢀCH2Ph)2
HNꢀi-Pr)2
HNMePh
Piperidine
HNEt2
4
Ph
5
Ph
6
Ph
7
Ph
4g
4h
4i
8
Ph
9
PhMeNCH2
1-Naphthyl-OCH2
1-Naphthyl-OCH2
1-Naphthyl-OCH2
1-Naphthyl-OCH2
10
11
12
13
4j
pyrrolidine
piperidine
morpholine
4k
4l
4m
In conclusion, we report herein a new method for the preparation of pro-
pargylamines using Al2O3, in a solvent-free and environmentally friendly reaction.
The reaction time is dramatically reduced from several hours to one minute
using microwave irradiation. Extending this method to the preparation of other
classes of Mannich bases is under investigation.
Experimental
1H NMRꢀ80 MHz or 300 MHz) and 13C NMRꢀ75 MHz) spectra were recorded on a Bruker 80 MHz
or Bruker WP 300 MHz spectrometer in CDCl3 using TMS as internal standard. HRMS were
obtained on a Finnigan MAT system MAT 212. Microwave induced reactions were carried out in
a domestic microwave oven Moulinex Micro-Chef ꢀ900 W) at 2450 MHz. The aluminum oxide
employed was Fluka type 507 C neutral, pH 7.0 Æ 0.5, particle size 0.05±0.15 mm.
General procedure for the preparation of propargylamines on neutral alumina at room
temperature ꢀmethod A)
A mixture of 2 mmol terminal acetylene, 2.1 mmol secondary amine, 2 mmol formaldehyde ꢀused as
37% aqueous solution), 0.2 mmol CuCl, and 3 g neutral alumina was stirred at room temperature for
6 h. The progress of the reaction was monitored by TLC. Then, the mixture was extracted with ethyl
acetate ꢀ3 Â 20 cm3) and ®ltered. Evaporation of the solvent under reduced pressure afforded the crude
product which was puri®ed by chromatography over a short column of silica gel ꢀeluent : petroleum
ether : ethyl acetate ˆ 5 : 1).
General procedure for the preparation of propargylamines on neutral alumina under microwave
irradiation ꢀmethod B)
2 mmol terminal acetylene, 2.1 mmol secondary amine, 2 mmol formaldehyde ꢀused as 37% aqueous
solution), 0.2 mmol CuCl, and 3 g neutral alumina were mixed together, put in a 25 cm3 beaker, and

202
A. Shari® et al.
irradiated in a microwave oven three times ꢀeach time for 20 s 3 min intervals). After cooling, the
mixture was extracted with ethyl acetate ꢀ3 Â 20 cm3) and ®ltered. Evaporation of the solvent under
reduced pressure afforded the crude product which was puri®ed as given above.
Diethyl-ꢀ3-phenyl-prop-2-ynyl)-amine ꢀ4a) [11]
1H NMRꢀCDCl 3, ꢂ, 80 MHz): 1.0 ꢀt, 2CH3), 2.4 ꢀq, 2CH2), 3.5 ꢀs, CH2), 7.1±7.4 ꢀm, 5Harom) ppm.
Dibutyl-ꢀ3-phenyl-prop-2-ynyl)-amine ꢀ4b) [17]
1H NMRꢀCDCl 3, ꢂ, 80 MHz): 0.9±1.1 ꢀm, 14H), 2.1±2.4 ꢀt, 2CH2), 3.5 ꢀs, CH2), 7.1±7.4
ꢀm, 5Harom) ppm.
1-ꢀ3-Phenyl-prop-2-ynyl)-pyrrolidine ꢀ4c) [10]
1H NMRꢀCDCl 3, ꢂ, 80 MHz): 1.5±1.7 ꢀm, 2CH2), 2.5±2.7 ꢀm, 2CH2), 3.5 ꢀs, CH2), 7.1±7.4
ꢀm, 5Harom) ppm.
1-ꢀ3-Phenyl-prop-2-ynyl)-piperidine ꢀ4d) [14a]
1H NMRꢀCDCl , ꢂ, 80 MHz): 1.1±1.7 ꢀm, 3CH2), 2.2 ꢀt, 2CH2), 3.5 ꢀs, CH2), 7.1±7.5 ꢀm, 5Harom
ppm.
)
3
4-ꢀ3-Phenyl-prop-2-ynyl)-morpholine ꢀ4e) [14a]
1H NMRꢀCDCl 3, ꢂ, 80 MHz): 2.4±2.6 ꢀt, 2CH2), 3.0±3.6 ꢀt, 2CH2), 3.5 ꢀs, CH2), 7.1±7.5
ꢀm, 5Harom) ppm.
Dibenzyl-ꢀ3-phenyl-prop-2-ynyl)-amine ꢀ4f) [10]
1H NMRꢀCDCl , ꢂ, 80 MHz): 3.4 ꢀs, CH2), 3.7 ꢀs, 2CH2), 7.2±7.4 ꢀm, 15Harom) ppm.
3
Diisopropyl-ꢀ3-phenyl-prop-2-ynyl)-amine ꢀ4g) [9]
1H NMRꢀCDCl , ꢂ, 80 MHz): 1.1 ꢀd, 4CH3), 3.3 ꢀhept, 2CH), 3.7 ꢀs, CH2), 7.1±7.3 ꢀm, 5Harom
ppm.
)
3
Methyl-phenyl-ꢀ3-phenyl-prop-2-ynyl)-amine ꢀ4h) [11]
1H NMRꢀCDCl , ꢂ, 80 MHz): 3.1 ꢀs, CH3), 4.4 ꢀs, CH2), 7.0±7.4 ꢀm, 10Harom) ppm.
3
Methyl-phenyl-ꢀ4-piperidin-1-yl-but-2-ynyl)-amine ꢀ4i) [14c]
1H NMRꢀCDCl 3, ꢂ, 80 MHz): 1.4±1.5 ꢀm, 3CH2), 2.2±2.3 ꢀt, 2CH2), 2.9 ꢀs, CH3), 3.1 ꢀt, CH2), 4.0
ꢀt, CH2), 6.6±7.3 ꢀm, 5Harom) ppm.
Diethyl-ꢀ4-ꢀnaphthalen-2-yloxy)-but-2-ynyl)-amine ꢀ4j; C18H21NO)
1H NMRꢀCDCl , ꢂ, 300 MHz): 0.95±1.05 ꢀt, 2CH3), 2.40±2.50 ꢀq, 2CH2), 3.42 ꢀs, CH2), 4.84
ꢀs, CH2), 6.84±6.95 ꢀd, 1Harom), 7.25±7.35 ꢀt, 1Harom), 7.36±7.49 ꢀm, 3Harom), 7.69±7.79 ꢀm, 1Harom),
3

Mannich Reaction of Terminal Alkynes
203
8.21±8.31 ꢀm, 1Harom) ppm; 13C NMRꢀCDCl 3, ꢂ, 75 MHz): 12.3, 40.8, 47.0, 56.4, 79.5, 82.4, 105.6,
120.7, 121.9, 125.0, 125.4, 125.7, 126.2, 127.2, 134.4, 153.3 ppm; HRMS ꢀEI): calcd. 267.1623,
found 267.1624.
1-ꢀ4-ꢀNaphthalen-2-yloxy)-but-2-ynyl)-pyrrolidine ꢀ4k; C18H19NO)
1H NMRꢀCDCl , ꢂ, 300 MHz): 1.70±1.78 ꢀm, 2CH2), 2.51±2.60 ꢀm, 2CH2), 3.43 ꢀs, CH2), 4.90
3
ꢀs, CH2), 6.89±6.96 ꢀd, 1Harom), 7.29±7.39 ꢀt, 1Harom), 7.39±7.51 ꢀm, 3Harom), 7.70±7.83 ꢀm, 1Harom),
8.20±8.32 ꢀm, 1Harom) ppm; 13C NMRꢀCDCl 3, ꢂ, 75 MHz): 23.7, 43.2, 52.4, 56.5, 79.0, 83.5, 105.7,
120.8, 122.0, 125.2, 125.5, 125.7, 126.3, 127.3, 134.4, 153.4 ppm; HRMS ꢀEI): calcd. 265.1467,
found 265.1465.
1-ꢀ4-ꢀNaphthalen-2-yloxy)-but-2-ynyl)-piperidine ꢀ4l; C19H21NO)
1H NMRꢀCDCl , ꢂ, 300 MHz): 1.27±1.39 ꢀm, CH2), 1.48±1.63 ꢀm, 2CH2), 2.32±2.45 ꢀt, 2CH2),
3
3.25 ꢀs, CH2), 4.85 ꢀs, CH2), 6.85±6.95 ꢀd, 1Harom), 7.26±7.35 ꢀt, 1Harom), 7.36±7.48 ꢀm, 3Harom),
7.68±7.79 ꢀm, 1Harom), 8.21±8.31 ꢀm, 1Harom) ppm; 13C NMRꢀCDCl 3, ꢂ, 75 MHz): 23.5, 25.6, 47.6,
53.0, 56.3, 79.4, 83.0, 105.5, 120.6, 121.8, 124.9, 125.2, 125.5, 125.7, 126.0, 127.1, 134.2,
153.2 ppm; HRMS ꢀCI, isobutane): calcd. 280.1701, found 280.1697.
4-ꢀ4-ꢀNaphthalen-2-yloxy)-but-2-ynyl)-morpholine ꢀ4m; C18H19NO2)
1H NMRꢀCDCl 3, ꢂ, 300 MHz): 2.37±2.46 ꢀt, 2CH2), 3.22 ꢀs, CH2), 3.57±3.70 ꢀt, 2CH2), 4.84
ꢀs, CH2), 6.80±6.90 ꢀd, 1Harom), 7.25±7.35 ꢀt, 1Harom), 7.35±7.50 ꢀm, 3Harom), 7.70±7.80 ꢀm, 1Harom),
8.20±8.30 ꢀm, 1Harom) ppm; 13C NMRꢀCDCl , ꢂ, 75 MHz): 47.0, 51.9, 56.1, 66.4, 79.9, 82.2,
3
105.4, 120.6, 121.7, 124.9, 125.2, 125.4, 125.8, 126.1, 127.1, 134.2, 153.1 ppm; HRMS ꢀEI): calcd.
281.1416, found 281.1416.
References
[1] a) Volkmann RA ꢀ1991) In: Trost BM, Fleming I ꢀeds) Comprehensive Organic Synthesis, vol 1.
Pergamon Press, Oxford, chapter 1.12, p 355; b) Kleinman EF, ibid, vol 2, chapter 4.1, p 893; c)
Heaney H, ibid, vol 2, chapter 4.2, p 953; d) Kleinman EF, Volkmann RA, ibid, vol 2, chapter
4.3, p 975; e) Overman LE, Ricca DJ, ibid, vol 2, chapter 4.4, p 1007; f) Tramontini M,
Angiolini L ꢀ1990) Tetrahedron 46: 1791; g) Tramontini M, Angiolini L ꢀ1994) Mannich Bases,

Chemistry and Uses. CRC, Boca Raton, FL; h) Bohme H, Haake M ꢀ1976) In: Taylor EC ꢀed)
Advances in Organic Chemistry, vol 9, part 1. Wiley, New York, p 108
[2] a) Karlen B, Lindeke B, Lindgren S, Svensson KG, Dahlbom R, Jenden DJ, Giering JE ꢀ1970)
J Med Chem 13: 651; b) Cook SC, Dax SL ꢀ1996) Bioorg Med Chem Lett 6: 797; c) Dahlbom R,
Karlen B, George R, Jenden DJ ꢀ1966) J Med Chem 9: 843; d) Neumeyer JL, Moyer UV,
Richman JA, Rosenberg FJ, Teiger DG ꢀ1967) J Med Chem 10: 615
[3] Knapp S, Hale JJ, Bastos M, Gibson FS ꢀ1990) Tetrahedron Lett 31: 2109
[4] a) Shari® A, Mohsenzadeh F, Naimi-Jamal MRꢀ2000) J Chem Res ꢀS) 394; b) Hamlet AB,
Durst T ꢀ1983) Can J Chem 61: 411
[5] a) Mojtahedi MM, Shari® A, Mohsenzadeh F, Saidi MRꢀ2000) Synth Commun 3031): 69;
b) Shari® A, Mirzaei M, Naimi-Jamal MRꢀ2001) Monatsh Chem 132: 875
[6] a) Mistryukov EA, Aronova NI, Kucherov VF ꢀ1962) Izv Akad Nauk SSSR, Otd Khim Nauk
870, CA ꢀ1962) 12421c; b) Mannich C, Chang FT ꢀ1933) Chem Ber 66: 418

[7] Stutz A, Granitzer W, Roth S ꢀ1985) Tetrahedron 41323): 5685
[8] Aziende Chimiche Riunite Angelini Francesco ꢀ1967) British patent 1055548, CA 66: 105003u

204
A. Shari® et al.: Mannich Reaction of Terminal Alkynes
[9] Kwatra MM, Simon DZ, Salvador RL, Cooper PD ꢀ1978) J Med Chem 21: 253 and Ref. [2b]
therein
[10] Katritzky AR, Gallos JK, Yannakopoulou K ꢀ1989) Synthesis 31
[11] Ahn JH, Joung MJ, Yoon NM, Oniciu DC, Katritzky ARꢀ1999) J Org Chem 64: 488
[12] a) Al-Iraqi MA, Al-Rawi JMA, Khuthier AH ꢀ1980) Org Magn Reson 14: 161; b) Al-Rawi
JMA, Khuthier AH ꢀ1981) Org Magn Reson 15: 285; c) Khuthier AH, Sheat MA, Al-Rawi
JMA, Salih ZS ꢀ1987) J Chem Res ꢀS) 184
[13] Epsztein R, Le Goff N ꢀ1985) Tetrahedron Lett 26: 3203
[14] a) Khuthier AH, Sheat MA ꢀ1989) J Prakt Chemie 331: 187; b) Bardamova MI, Myasnikova
RN, Kotlyarevskii IL ꢀ1967) Izv Akad Nauk SSSR Ser Khim ꢀ2) 443, CA ꢀ1967) 67: 21541a;
c) Miocque M, Vierfond JM ꢀ1973) C RAcad Sci Ser C 277: 387, CA ꢀ1974) 80: 47570c
[15] a) Salvador RL, Simon D ꢀ1966) Can J Chem 44: 2570; b) Tramontini M ꢀ1973) Synthesis 703
[16] a) McNally JJ, Youngman MA, Dax SL ꢀ1998) Tetrahedron Lett 39: 967; b) Youngman MA,
Dax SL ꢀ1997) Tetrahedron Lett 38: 6347
[17] Chukhadzhyan EO, Gabrielyan GL, Babayan AT ꢀ1976) Arm Khim Zh 29: 71, CA ꢀ1976) 85:
77965f
Received May 2, 2001. Accepted ꢀrevised) June 25, 2001