synthesis of acetylenes, allenes and cumulenes || aminoalkylation of acetylenic compounds

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E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-13.3d

13Aminoalkylation of Acetylenic

Compounds

13.1 INTRODUCTION

The reaction of phenylacetylene with formaldehyde and secondary amines was

reported in 1933 [1]. Aliphatic 1-alkynes, which are less acidic than pheny-

lacetylene, react sluggishly.

The formation of the acetylenic tertiary amines may be visualised as a

nucleophilic attack of the acetylide anion on the imonium ion R12N

þCH2,

which is in equilibrium with the (dialkylamino)methanol R12NCH2OH. These

compounds are easily formed at room temperature or slightly elevated tem-

peratures from secondary amines and polymeric formaldehyde (paraformalde-

hyde). The reaction of R12NCH2OH with acetylenes is usually carried out at

� 100 �C in an organic solvent such as dioxane. Acetylenes with a conjugated

unsaturated system, RCH¼CHC�CH or RC�CC�CH, arylacetylenes,

ArC�CH, and ethynyl sulphides, HC�CSR, react more easily than do alkyla-

cetylenes. In the latter compounds the ethynyl proton is less ‘mobile’. The

reaction times, which are quite long for alkylacetylenes, can be shortened to

one or a few hours by using a small amount of a copper salt (Cu(OAc)2,

CuCl, CuBr) [2]. This forms a copper(I) compound with the acetylene. The

copper acetylide is often visible as a yellow solid during the reaction. This

solid disappears or is replaced by a red suspension of copper, when the conver-

sion has finished. It is advisable to use no, or only a slight excess of the second-

ary amine and paraformaldehyde, because the presence of R12NCH2OH may

give rise to difficulties during the purification of the aminoacetylenes (partial

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decomposition of the aminomethanol during distillation) especially in the cases

of more volatile representatives. The yields of the copper-catalysed Mannich

reactions with acetylenic derivatives are usually high. The reactions with vola-

tile acetylenes (especially gases) require a more careful performance than the

ones with boiling points higher than 60 �C. A too quick addition may lead

to incomplete conversion due to lowering of the attainable temperature in

the reaction mixture. Acetylene and (dialkylamino)methanol react under pres-

sure to give N,N-dialkyl 2-butyne-1,4-diamines, R2NCH2C�CCH2NR2, as the

main product [2]. If the usual procedure is followed with acetylenic alcohols,

yields are often low due to preferential reaction of the hydroxyl group [3,4]

or formation of N,N-acetals, H2C(NR)2 [5]. An efficient procedure for

Mannich coupling with acetylenic alcohols has been developed in the author’s

laboratory [6]. Ethoxyacetylene, HC�COEt, does not give the normal

Mannich reaction [7].

Many examples of dialkylaminoalkylation can be found in the monographs

[8,9] and in a review [10].

13.2 EXPERIMENTAL SECTION

13.2.1 Preparation of (dimethylamino)methanoland (diethylamino)methanol

Scale: 0.30 molar; Apparatus: 250-ml two-necked, round-bottomed flask,

equipped with a stopper (which is temporarily removed during the addition

of the amine) and a combination of a thermometer and an outlet; magnetic

stirring.

13.2.1.1 Procedure

Pure dioxane (25 ml) and powdered paraformaldehyde (9 g, corresponding to

0.30 mol of the monomer) are placed in the flask. Liquefied dimethylamine

(� 0.10 mol, mixed with 10 ml of dioxane and cooled to � 0 �C), or diethyla-

mine (� 0.10 mol) is added at rt. The temperature of the mixture rises gradually

to � 45 �C. After cooling to rt, a second portion of � 0.10 mol of the amine is

added. When the ensuing exothermic reaction has subsided, the remaining

� 0.10 mol of the amine is added at rt. The conversion is completed by heating

the mixture for 30 min at � 50 �C. A slightly turbid solution is formed.

268 13. AMINOALKYLATION OF ACETYLENIC COMPOUNDS

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Other aliphatic or cycloaliphatic secondary amines are converted into the

condensation products by a similar procedure.

13.2.2 Mannich reactions with gaseous acetylenes

Scale: 0.30 molar; Apparatus: 500-ml three-necked, round-bottomed flask,

equipped with a long gas inlet tube, a gas-tight mechanical stirrer and

a reflux condenser. The inlet tube is connected with a trap containing the

liquefied acetylene, and the top of the condenser with a trap placed in a bath

at –78 �C. All connections are fixed well and are made gas-tight.

13.2.2.1 Procedure

Powdered copper(I) bromide (2 g) is added to the solution prepared in

exp. 13.2.1. The flask is heated in an oil bath at 100–105 �C. The trap contain-

ing the acetylene (0.40 mol, excess) is placed in a bath at 0–5 �C (in the case of

propyne) or rt (in the case of butyne and vinylacetylene). During the introduc-

tion of the acetylene, which takes � 30 min, the mixture is agitated vigorously

in order to achieve efficient absorption of the gaseous acetylene. As soon as the

trap has become empty, the two traps are interchanged. As a rule, only a small

amount of unconverted alkyne appears to be present in the second trap. The

introduction of gas and heating at � 100 �C are continued until the amount of

condensed acetylene in the second trap has become very small (<0.1 mol). The

brown suspension (in some cases yellow) is then cooled to rt. Although it is

possible to isolate the product via an aqueous work-up (Note 1), we prefer the

following procedure. The reaction flask is equipped for a vacuum distillation,

using a short Vigreux column, condenser and single receiver cooled in a bath at

<–40 �C (cf. Figure 1.10). The apparatus is evacuated using a water aspirator

(10–20 Torr) and the reaction flask warmed in an oil bath (initially rt), until the

distillation has stopped completely. After some cooling, nitrogen is admitted.

A small brown residue remains in the reaction flask. The distillate, a mixture

of dioxane, water (� 0.3 mol) and the desired product, is vigorously shaken

with � 15 g of K2CO3 in order to absorb the water. After suction

filtration through sintered glass and thorough rinsing of the K2CO3 with

Et2O, a very careful distillation (Note 2) through an efficient column is carried

out. The amines N,N-diethyl-2-butyn-1-amine, R1¼Et, R¼Me, bp 45 �C/12

Torr; N,N-diethyl- 2-pentyn-1-amine, R¼R1¼Et, bp 63 �C/10 Torr; and

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N,N-diethyl-4-penten-2-yn-1-amine, R¼H2C¼CH, R1¼Et, bp 68 �C/10 Torr,

are obtained in high yields (mostly >70%).

Notes

1. In the case of the lower homologues, which have a reasonably good solu-

bility in water, several extractions with Et2O have to be carried out. The

presence of insoluble copper compounds may give rise to difficulties with

the separation of the layers.

2. In view of serious foaming, a relatively big distillation flask is used.

13.2.3 Mannich reactions with liquid acetylenes

Scale: 0.30 molar; Apparatus: 250-ml two-necked round-bottomed flask

equipped with a dropping funnel and a reflux condenser and a magnetic

stirring bar.

13.2.3.1 Procedure

After addition of 2 g of finely powdered CuBr, the solution of R12NCH2OH

(exp. 13.2.1) is heated up to � 70 �C (bath temperature). The reactive acetylenic

compound (HC�CC�CR, HC�CCH¼CHR, (Het)arylC�CH, HC�CSR,

0.31 mol) is added over � 20 min, while keeping the temperature between

70 and 80 �C. The conversion is completed by heating the mixture (brown

suspension) for 30 min at 90 �C, after which it is cooled to rt.

In the other cases, the mixture of R12NCH2OH and dioxane is heated in

a bath at 85 �C and the acetylene is added in portions over 30 min.

Subsequently, the bath temperature is raised to 100–110 �C. After an additional

period of 2–2.5 h the reaction mixture is cooled to rt.

In all cases the reaction mixture is poured into 500 ml of water, after which a

sufficient number of extractions with Et2O are carried out. The organic solu-

tions (washing is not carried out) are dried well over K2CO3 (shaking or

stirring with � 20 g of K2CO3 for 15 min, then suction filtration and rinsing

of the drying agent with Et2O). The isolation is carried out as described in

the preceding procedure. Yields are generally higher than 70%.


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Examples of compounds prepared by this method:N,N-dimethyl-2-heptyn-1-

amine, n-BuC�CCH2NMe2, bp 60 �C/12 Torr; N,N-diethyl-2-heptyn-1-amine,

n-BuC�CCH2NEt2, bp 86 �C/12 Torr; N,N-diethyl-4-hepten-2-yn-1-amine,

EtCH¼CHC�CCH2NEt2, bp 92–98 �C/12 Torr ((E):(Z) �1:1); (Z)-N,N-

diethyl-5-ethylthio-4-penten-2-yn-1-amine, EtSCH¼CHC�CCH2NEt2, bp

142 �C/12 Torr (short Vigreux column); N,N-diethyl-2,4-nonadiyn-1-amine,

n-BuC�CC�CCH2NEt2, bp � 90 �C/0.5 Torr (20-cm Vigreux column); 4-

methoxy-N,N-dimethyl-2-butyn-1-amine, MeOCH2C�CCH2NMe2, bp 60 �C/

15 Torr; N,N-diethyl-4-methoxy-2-butyn-1-amine, MeOCH2C�CCH2NEt2,

bp 77 �C/15 Torr.

Note

Volatile acetylenes, such as 1-pentyne and methyl propargyl ether, should be

added in small portions, especially in the beginning, otherwise it takes rather

long before the required reaction temperature of � 90 �C is reached.

13.2.4 Mannich reactions with acetylenic alcohols

Scale: 0.30 molar (acetylenic alcohol); Apparatus: 500 ml round-bottomed flask

with reflux condenser and thermometer; mechanical or magnetic stirring.

13.2.4.1 Procedure [6]

A solution of (dialkylamino)methanol, R1NCH2OH, in 35 ml of dioxane,

prepared on 0.40 molar scale (excess, exp. 13.2.1) is cooled to –10 �C, after

which 10 ml of a 1:1 (by weight) mixture of 96% sulfuric acid and water is

added with manual swirling (lower yields are obtained if more is added).

Subsequently 1 g of powdered CuBr and 0.30 mol of the acetylenic alcohol

are added. The mixture is heated under gentle reflux for � 20 min. The green-

ish-yellow slurry soon disappears and the reaction mixture turns dark red to

brown. After cooling to rt, 120 ml of Et2O is added followed by 20 g of

anhydrous potassium carbonate. After vigorous shaking, the brown superna-

tant layer is decanted from the brown slurry. The extraction operation is

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repeated at least 10 times with small amounts of Et2O (cf. hint in Chapter 1,

Section 1.3). The combined extracts are dried over a smaller amount of potas-

sium carbonate and subsequently concentrated under reduced pressure.

Distillation of the rather viscous liquids through a short column gives

4-(dimethylamino)-2-butyn-1-ol, Me2NCH2C�CCH2OH, bp 110 �C/15 Torr,

and 5-(dimethylamino)-3-pentyn-1-ol, Me2NCH2C�CCH2CH2OH, bp 115 �C/

15 Torr, in excellent yields.

Good results are obtained also with other R12NCH2OH.

REFERENCES

1. C. Mannich and F. T. Chang, Chem. Ber. 66, 418 (1933).

2. W. Reppe et al., Liebigs Ann. Chem. 596, 1 (1955); 601, 81 (1956).

3. C. M. McLeod and G. M. Robinson, J. Chem. Soc. 1470 (1921).

4. J. E. Fernandez, C. Powell and J. S. Fowler, J. Chem. Eng. Data 7, 600 (1963).

5. R. L. Salvador and D. Simon, Can. J. Chem. 44, 2570 (1966).

6. Unpublished results from the author’s laboratory.

7. J. F. Arens, D. H. Koerts and P. Plieger, Recl. Trav. Chim., Pays-Bas 750, 1454 (1956).

8. H. Hellmann and G. Opitz, �-Aminalkylirung. Verlag-Chemie, Weinheim, 1960, p. 95.

9. B. Reichert, Die Mannich Reaktion. Springer-Verlag, Berlin, 1959, p. 39.

10. V. Jager, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag,

Stuttgart, 1977, p. 545.


synthesis of acetylenes, allenes and cumulenes || aminoalkylation of acetylenic compounds

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