synthesis of acetylenes, allenes and cumulenes || transformation of functional groups in acetylenic...

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E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-20.3d

20Transformation of Functional Groups in

Acetylenic and Allenic Compounds

20.1 ACETYLENIC HALOGEN COMPOUNDS

20.1.1 Propargyl bromide from propargyl alcohol andphosphorus tribromide

Scale: 3.0 molar; Apparatus: 1-litre round-bottomed, three-necked flask,

equipped with a dropping funnel, a mechanical stirrer and a reflux condenser.

The most convenient way to prepare 3-bromo-1-propyne on a laboratory

scale consists of converting the corresponding alcohol with phosphorus tribro-

mide in the presence of a small amount of pyridine. The formation of the bro-

mide proceeds through a number of intermediates. In the first step 2-propynyl

dibromophosphite, HC�CCH2OPBr2, and HBr are formed, which react

further to HC�CCH2Br and HOPBr2. The reaction with dibromophosphinous

acid, HOPBr2, proceeds in a way that is analogous to the first step. The nucleo-

philic attack of bromide on propargylic carbon in the bromophosphites, result-

ing in the formation of propargyl bromide, is catalysed by pyridine. This binds

part of the HBr, thus converting it into the more nucleophilic Br�. In addition

to propargyl bromide, appreciable amounts of 2,3-dibromo-1-propene,

H2C¼C(Br)CH2Br, are formed, especially when no solvent is used. The forma-

tion of this compound may be visualised as an electrophilic addition of HBr

to the triple bond in HC�CCH2OH or some intermediate, followed by reac-

tion with PBr3. Diethyl ether suppresses this electrophilic addition by forming

the oxonium complex Et2OþH �Br� with HBr. It is possible to obtain propar-

gyl bromide in high yields by slowly adding PBr3 to a strongly cooled mixture

of propargyl alcohol and diethyl ether and subsequently allowing the

369

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temperature to rise very slowly. In the procedure described below, the reaction

is carried out in refluxing ether, giving 3-bromo-1-propyne in � 70% yield. In

the published procedure [1] propargyl alcohol is added dropwise to phosphorus

tribromide containing a small amount of pyridine. We experienced this proce-

dure as inconvenient because much HBr escapes from the reaction mixture

during the addition of the alcohol.

Warning: Contact of 3-bromo-1-propyne (and homologues) with the skin

causes a painful irritation. It is absolutely necessary to wear protective

gloves and to work in a well-ventilated hood.

20.1.1.1 Procedure

A mixture of 3.0 mol of 2-propyn-1-ol, 400 ml of dry Et2O and 10 ml of

pyridine is placed in the flask. Phosphorus tribromide (1.1 mol) is added drop-

wise over 1.5 h without cooling, while stirring at a moderate rate. After the

addition, the reaction mixture is heated for an additional 1 h under reflux. The

greater part of the Et2O is then quickly distilled off (during � 45 min) at

atmospheric pressure through a 40-cm Vigreux column, keeping the bath tem-

perature below 100 �C. The remaining liquid is cooled to rt, after which the

volatile components are distilled off in a water-aspirator vacuum (10 to 20

Torr). The vapours are condensed in a single receiver, cooled in a bath at

�50 �C, or lower temperature (Figure 1.10). The distillation is stopped when

(at a pressure of 10–20 Torr) the temperature in the head of the column rises

above 35 �C. Redistillation at 760 Torr using an efficient column gives the main

portion of 3-bromo-1-propyne, passing over at 80–95 �C. The residue is mainly

2,3-dibromo-1-propene, H2C¼C(Br)CH2Br. Fractional distillation of the ethe-

real distillate (see above) gives an additional small amount of 3-bromo-1-pro-

pyne, bringing the yield at � 70%. Pure 3-bromo-1-propyne, bp 84 �C/760

Torr, is obtained by redistillation.

5-Bromo-3-penten-1-yne, HC�CCH¼CHCH2Br, bp�40 �C/15 Torr, ((E):(Z)

� 85:15), is obtained in� 70% yield by a similar procedure from the correspond-

ing alcohol (Chapter 4, exp. 4.5.14). During the addition of PBr3 the solution

turns very dark. 5-Bromo-3-penten-1-yne is a very lachrymatory compound.

Contact of the liquid or vapour with the skin has a similar effect as in the case

of 3-bromo-1-propyne and other acetylenic bromides.

20.1.2 Homologues of 3-bromo-1-propyne from propargylic alcoholsand phosphorus tribromide

370 20. TRANSFORMATION OF FUNCTIONAL GROUPS

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Scale: 0.90 molar; Apparatus: Figure 1.1, 1 litre

20.1.2.1 Procedure (for introduction and warning see exp. 20.1.1)

A mixture of 0.90 mol of the acetylenic alcohol, 250 ml of dry Et2O (Note 1)

and 5 ml of pyridine is cooled to �35 �C. Phosphorus tribromide (0.32 mol) is

added dropwise over 45 min, while keeping the temperature between �25 and

�35 �C (Note 2). The reaction mixture is stirred for an additional 2 h at �20 to

�25 �C, after which the temperature is allowed to rise over 2 h to rt. After

heating the reaction mixture for 30 min under reflux, a saturated aqueous

solution of NaCl is added with vigorous stirring. After separation of the

layers, one extraction with a small portion of Et2O is carried out. The organic

solution is dried over MgSO4, after which the greater part of the solvent is

distilled off at atmospheric pressure through a 40-cm Vigreux column or

removed under reduced pressure (in the case of less volatile bromo

compounds). Careful distillation of the remaining liquid gives the bromo

compounds 1-bromo-2-butyne, MeC�CCH2Br, bp � 60 �C/80 Torr;

1-bromo-2-pentyne, EtC�CCH2Br, bp 38 �C/10 Torr and 1-bromo-2-heptyne,

n-BuC�CCH2Br, bp 72 �C/12 Torr in high yields.

Notes

1. When smaller amounts of Et2O are used, yields are lower and more of the

dibromo compound (cf. exp. 20.1.1) is formed.

2. If the addition of PBr3 is carried out under reflux (cf. exp. 20.1.1), yields

are by 5 to 10% lower.

20.1.3 3-Bromo-3-methyl-1-butyne from 2-methyl-3-butyn-2-oland phosphorus tribromide

Scale: 0.30 molar; Apparatus: Figure 1.1, 500 ml

20.1.3.1 Procedure (cf. exps. 20.1.1 and 20.1.2)

Phosphorus tribromide (0.11 mol) is added dropwise over 20 min to 0.30 mol

of (neat) 2-methyl-3-butyn-2-ol, while keeping the temperature between 10 �C

20.1 ACETYLENIC HALOGEN COMPOUNDS 371

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and rt. During the addition, which is carried out over 15 min, the solid on the

glass wall (2-methyl-3-butyn-2-ol) gradually melts. Fifteen minutes after the

addition, 100 ml of water is added with vigorous stirring. The organic layer is

dried over a small amount of MgSO4 and subsequently transferred into a

500-ml round-bottomed flask which is equipped for a vacuum distillation

using an efficient column, a condenser and a single receiver cooled in a bath

at �10 �C (cf. Figure 1.10). The product passing over below 45 �C/15 Torr, a

mixture of 3-bromo-3-methyl-1-butyne and 2,3-dibromo-3-methyl-1-butene,

H2C¼ C(Br)Me2Br, is carefully redistilled in the same apparatus. The fraction

having bp up to 30 �C/15 Torr, is practically pure 3-bromo-3-methyl-1-butyne.

The yield is � 50% (Note).

Note

It should be possible to obtain higher yields by adding PBr3 at low tempera-

tures to a mixture of the alcohol and Et2O and gradually raising the tempera-

ture (cf. exp. 20.1.2).

20.1.4 3-Bromo-1-nonyne from the corresponding tosylate andlithium bromide

Scale: 0.30 molar; Apparatus: 1-litre two-necked, round-bottomed flask,

equipped with a mechanical stirrer and a reflux condenser.

The procedure for 3-bromo-1-nonyne illustrates an excellent method for the

preparation of primary and secondary propargylic bromides [2]. The prepara-

tion of the tosylates as well as the conversion into the bromides are very clean

reactions giving high overall yields. Purification by distillation is not necessary

if the proper conditions are applied for the preparation of the tosylates and

their conversion into the bromo compounds. For these reasons, this method

is more suitable than the PBr3-method for the preparation of propargylic bro-

mides with a low volatility or low thermal stability. Propargylic iodides may be

prepared similarly, using NaI in acetone or ethanol. It should be noted that the

substitution is regiospecific, i.e. 1,3-substitution (‘propargylic rearrangement’)

does not take place at all.


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20.1.4.1 Procedure

A solution of 0.40 mol of anhydrous lithium bromide in 150 ml of dry acetone

is added to a mixture of 0.30 mol of 1-hexyl-2-propynyl-4-methylbenzenesul-

phonate (cf. exp. 20.5.4) and 100 ml of acetone. After refluxing for 1 h, 600 ml

of ice water is added to the suspension and eight extractions with small

(1� 150 ml, 7� 50 ml) portions of pentane are carried out. The combined

extracts are washed with water and subsequently dried over MgSO4. After

removing the pentane under reduced pressure, the remaining liquid is distilled

through a 30-cm Vigreux column to give 3-bromo-1-nonyne, bp 82 �C/15 Torr,

in an excellent yield.

20.1.5 4-Bromo-1-butyne from the corresponding tosylate andlithium bromide in DMSO

Scale: 0.50 molar; Apparatus: Figure 1.10, 1 litre, a 40-cm Vigreux column

is used

This method for the conversion of tosylates into the corresponding bro-

mides, a variant of the preceding procedure, is more suitable for rather volatile

bromides (bp <55 �C/15 Torr) because the isolation is more convenient

(no frequent extraction, no time-consuming distillation). It should further be

noted that the PBr3 method fails for homopropargylic bromides, such as

4-bromo-1-butyne, HC�CCH2CH2Br.

20.1.5.1 Procedure

3-Butynyl-4-methylbenzenesulphonate (0.50 mol, freed from traces of Et2O by

evacuation, cf. exp. 20.5.4) is added with manual swirling to a solution (partly

suspension) of 0.70 mol of anhydrous lithium bromide in 250 ml of DMSO.

The apparatus is evacuated (water aspirator) and the flask heated in an oil

bath. The volatile acetylenic bromide is trapped in the strongly cooled (–40 �C)

receiver (Figure 1.10). The temperature of the bath is gradually raised until

DMSO begins to distil (bp � 80 �C/15 Torr). The distillation is stopped when

about 20 ml of DMSO has passed over. The contents of the receiver are washed

three times with 30-ml portions of water in a small dropping funnel and the

lower layer is subsequently dried over a small amount of MgSO4. Pure

4-bromo-1-butyne, HC�CCH2CH2Br, (distillation is not necessary) is


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obtained in a greater than 80% overall yield, starting from the acetylenic

alcohol.

3-Bromo-1-butyne, HC�CCH(Me)Br, is obtained in an excellent yield by a

similar procedure starting from 3-butyn-1-ol, HC�CCH(Me)OH. This alcohol

is commercially available as a 50% solution in water. The alcohol can be freed

from the water by saturating the aqueous solution with K2CO3 and subse-

quently drying the upper layer over K2CO3.

3-Chloro-1-butyne, HC�CCH(Me)Cl, bp 74 �C/760 Torr, can be prepared

analogously, using anhydrous lithium chloride.

For the preparation of 6-bromo-1-hexyne, HC�C(CH2)4Br, from 5-hexyn-

1-ol by the same method a more efficient column is used instead of the

Vigreux column. The distillation is stopped when about 50 ml of DMSO has

been collected in the receiver (cooled at 0 �C). The wash procedure gives

pure 6-bromo-1-hexyne in � 80% overall yield.

Acetylenic bromides with boiling points in the region of 80 �C/15 Torr or

higher may be prepared by heating the solution of LiBr and the tosylate in

DMSO for 1 h at 70–80 �C and subsequently adding water to the reaction

mixture. The bromo compound is then isolated via extraction with Et2O. It

is, however, also possible to prepare less volatile bromides by heating the cor-

responding tosylates with a 10 to 20% excess of anhydrous LiBr in refluxing

acetone or THF, as described in exp. 20.1.4.

20.1.6 1,4-Dichloro-2-butyne from 2-butyn-1,4-diol andthionyl chloride

Scale: 2.0 molar; Apparatus: Figure 1.1, 3-litre

The reaction of primary or secondary alcohols with thionyl chloride is a

general method for preparing the corresponding chloro compounds. In the

first step a chlorosulphite, ROSOCl, is formed, from which SO2 is eliminated

in a relatively slow step. This decomposition is facilitated by a tertiary amine,

e.g. pyridine. The ammonium salt RO-SONþCl�, formed from the chlorosul-

phite, e.g. 1,4-bis[chlorosulphinyloxy]-2-butyne, is subsequently attacked on

carbon (in R) by Cl�. Since nucleophilic substitutions on propargylic carbon


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proceed more easily than on carbon in saturated compounds, it may be

expected that the conversion of propargylic chlorosulphites into the chlorides

will take place under relatively mild conditions.

The thionyl chloride method can be applied successfully to prepare primary

and secondary acetylenic chlorides. The isolation and purification of volatile

chlorides is less convenient (contamination with SOCl2) than in the cases of

higher-boiling compounds (simple distillation from the reaction mixture).

The tosylate method (exp. 20.1.5) seems more attractive for the preparation

of chlorides such as 3-chloro-1-butyne, HC�CCH(Me)Cl, (bp 74 �C/760

Torr) and 1-chloro-2-butyne, MeC�CCH2Cl (bp 101 �C/760 Torr), on a

modest (up to � 0.5 molar) scale. For the preparation of ‘non-propargylic’

chlorides from the corresponding alcohols, e.g. 6-chloro-1-hexyne,

HC�C(CH2)4Cl from 5-hexyn-1-ol, HC�C(CH2)4OH, the reaction conditions

are expected to be comparable with those necessary for the formation of satu-

rated alkyl chlorides (refluxing for a few hours).

Warning: 1,4-Dichloro-2-butyne is a skin-irritating compound. It is advisa-

ble to wear protective gloves during the experiment.

20.1.6.1 Procedure

Powdered butynediol (2.0 mol, technical grade, light brown colour) and pyr-

idine (15 ml) are placed in the flask. Thionyl chloride (4.3 mol, pre-cooled at

�40 �C) is added in a number of portions over 30 min. During this addition,

the flask is cooled in a bath at �30 to �40 �C. The addition is accompanied

by abundant evolution of hydrogen chloride. As a result, the net heating

effect is very small. Temperature control in the first stage of the addition

is therefore not very essential. Stirring becomes more easy when the greater

part of the thionyl chloride has been added and part of the butynediol has

dissolved. After the addition, stirring at 0 to �10 �C is continued for an

additional 2 h, then the flask is placed in a large (10 to 15 litre if available)

bath with ice and ice water. The gas outlet is connected with a tube, loosely

filled with CaCl2-lumps. The stirrer is replaced with a stopper. After � 12 h

the brown reaction mixture is poured into a 1-litre round-bottomed flask,

which is equipped for a vacuum distillation, using an efficient column, a

condenser and a single receiver, cooled in an ice bath (cf. Figure 1.10).

The system is evacuated (water aspirator) and the temperature of the heating

bath (during the first hour of the evacuation rt) is gradually raised to

� 40 �C. When the pressure has dropped to below 40 Torr, the bath tempera-

ture is raised until dichlorobutyne begins to pass over. Exhaustive distillation

of the remaining viscous brown residue (partly pyridine�HCl) should not be

attempted because decomposition may ensue (Note). Careful redistillation


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affords 1,4-dichloro-2-butyne, bp 57 �C/12 Torr, in � 80% yield. If purified

butynediol (recrystallised from a 3:10 mixture of THF and Et2O) is used,

yields may be higher than 90%.

1,4-Dichloro-2-pentyne, MeCH(Cl)C�CCH2Cl, bp 60 �C/12 Torr, is pre-

pared in a similar way from 5-chloro-3-pentyn-2-ol, MeCH(OH)C�CCH2Cl.

This alcohol is obtained from lithiated propargyl chloride, LiC�CCH2Cl,

and acetaldehyde (Chapter 5, exp. 5.2.2).

Note

Treatment of the residue with water, followed by extraction with Et2O gives an

additional small amount of product.

20.1.7 1,6-Dichloro-2,4-hexadiyne from 2,4-hexadiyne-1,6-diol andthionyl chloride

Scale: 0.30 molar; Apparatus: Figure 1.1, 500-ml

20.1.7.1 Procedure (for warning see preceding experiment)

2,4-Hexadiyne-1,6-diol (0.30 mol, Chapter 15, exp. 15.1.1) and pyridine (3 ml)

are placed in the flask. Thionyl chloride (0.70 mol, pre-cooled to �30 �C) is

added in �10-g portions over 20 min, while cooling the flask in a bath at

�30 �C. Stirring is started as soon as possible. After the addition the cooling

bath is removed and the temperature of the reaction mixture is allowed to rise

over � 4 h (occasional cooling is applied if the temperature rises too fast) to

þ30 �C. The flask is then placed in a bath at 40�45 �C. The equipment is

removed and the flask is evacuated using a water aspirator. After about 1 h,

the evacuating operation is terminated and Et2O (200 ml) is added to the

remaining brown liquid. The solution is vigorously shaken with a mixture of

200 ml of ice water and 20 ml of pyridine. After separation of the layers, two

extractions with Et2O are carried out. The combined organic solutions are

successively washed with 3 N HCl and water and then dried over MgSO4.


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The Et2O is removed under reduced pressure and the remaining liquid distilled

through a short Vigreux column to give pure 1,6-dichloro-2,4-hexadiyne,

bp � 50 �C/0.2 Torr, in an excellent yield. The compound should be stored

at �20 �C.

20.1.8 5-Chloro-3-hexen-1-yne and 5-bromo-3-hexen-1-yne from4-hexen-1-yn-3-ol and concentrated aqueous HCl or HBr


20.1.8.1 Procedure [cf. 3]

4-Hexen-1-yn-3-ol (0.50 mol, Chapter 5, exp. 5.2.4) is added over 30 min to

250 ml of a concentrated aqueous solution of HCl (37%) or HBr (Note),

while keeping the temperature at 20 �C or 5–10 �C, respectively. The heating

effect is weak. After an additional 30 min (at the temperature indicated),

250 ml of ice water is added. The product is extracted six times with a 1:1

mixture of Et2O and pentane (a sufficient amount of solvent should be used

for the first extraction of the bromo compound in order to effect a satisfac-

tory separation of the layers). The combined organic solutions are washed

with water and subsequently dried over MgSO4. The greater part of the

solvent is then distilled off at atmospheric pressure through an efficient

column, keeping the bath temperature below 80 �C. Distillation of the

remaining liquid in vacuo through the same column gives the chloride

5-chloro-3-hexen-1-yne, HC�CCH¼CHCH(Cl)Me, ((Z)/(E) � 30:70), bp

55–60 �C/50 Torr, and the bromide 5-bromo-3-hexen-1-yne, HC�CCH¼

CHCH(Br)Me, ((Z)/(E) � 30:70), bp 44–50 �C/10 Torr, in yields of �70

and �90%, respectively.

1-Penten-4-yne-3-ol, H2C¼CHCH(OH)C�CH, and concentrated HBr give,

in 60% yield, a 30/70 mixture of 3-bromo-1-penten-4-yne, HC�CCH

(Br)CH¼CH2 and 5-bromo-3-penten-1-yne, HC�CCH¼CHCH2Br.

Note

The solution of HBr is obtained by stirring a mixture of 250 ml of 48% HBr

with 50 g of PBr3 at �20 �C until the solution has become homogeneous.


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20.1.9 3-Chloro-3-methyl-1-butyne from 2-methyl-3-butyn-2-oland concentrated aqueous HCl in the presence ofcopper(I) chloride

Scale: 0.50 molar; Apparatus: 1-litre wide-necked, conical flask and

thermometer.

20.1.9.1 Procedure [cf. 4]

Concentrated aqueous HCl (37%, 200 ml) powdered NH4Cl (50 g), copper(I)

chloride (10 g, technical grade) and copper bronze (2 g,Note 1) are placed in the

flask. The mixture is cooled to �20 �C and 0.50 mol of 2-methyl-3-butyn-2-ol

(commercially available) is added over a few minutes with manual swirling.

Subsequently gaseous HCl (40 g, weight increase) is introduced over 10 min

with manual swirling, while keeping the temperature below �10 �C (Note 2).

The flask is then placed in a bath at �10 �C. After 1 h (occasional swirling

by hand) 300 ml of ice water is added. The layers are separated as completely

as possible. The upper layer, crude 3-chloro-3-methyl-1-butyne, HC�

CCMe2Cl, (45 to 48 g), is swirled with � 10 g of anhydrous K2CO3 (Note 3) in

a 500-ml round-bottomed flask. This flask is equipped for a vacuum distillation

using a 40-cm Vigreux column, a condenser and a single receiver cooled in a

bath at �70 �C (Figure 1.10). A tube filled with CaCl2 lumps is placed between

the distillation apparatus and the water aspirator. The apparatus is evacuated

(10 to 20 Torr) and the flask containing the crude chloro compound and the

drying agent warmed in a bath at 30 to 40 �C. Careful redistillation of the

contents of the receiver through an efficient column gives 3-chloro-3-methyl-

1-butyne, bp 75–79 �C/760 Torr, in 70 to 75% yield, with a purity of � 95%.

Notes

1. We presume that the metal serves to re-convert CuCl2, formed by oxida-

tion, into CuCl.

2. At higher temperatures the tertiary chloride undergoes a rearrangement

under the influence of CuCl giving a chloride with a conjugated diene

system. This isomer has a considerably higher refractive index.

3. Traces of HCl or CuCl are neutralised or adsorbed.


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20.1.10 1-Chloro-1-ethynylcyclohexane from 1-ethynylcyclohexanoland concentrated aqueous HCl in the presence of copper(I)chloride

Scale: 0.50 molar; Apparatus: 1-litre three-necked, round-bottomed flask,

equipped with a mechanical stirrer, a powder funnel and a thermometer.

20.1.10.1 Procedure (for literature see exp. 20.1.9)

A mixture of concentrated HCl, CuCl, copper bronze (see Note 1 of exp.

20.1.9) and NH4Cl is prepared in a 1-litre conical flask as described in the

preceding experiment. Gaseous HCl (� 40 g, weight increase) is then quickly

introduced at �15 �C (see exp. 20.1.9). The cold mixture is poured into the

reaction flask. 1-Ethynylcyclohexanol (0.50 mol, commercially available) is

then added over 2 min with stirring and cooling between �5 and �10 �C.

Stirring at 0 to �5 �C is continued for an additional 1 h. Ice water (just

enough to effect dissolution of the salt) is then added, followed by � 50 ml

of pentane. After separation of the layers, one extraction with a small amount

of pentane is carried out. The combined organic solutions are dried over

MgSO4 and subsequently concentrated under reduced pressure. Careful distil-

lation of the remaining liquid through an efficient column gives 1-chloro-1-

ethynylcyclohexane, bp 55 �C/15 Torr, in high yields.

20.1.11 ‘Contrathermodynamic’ formation of propargyl iodide fromthe bromide and sodium iodide in absolute ethanol

Scale: 0.50 molar; Apparatus: 1-litre f1ask, provided with a mechanica1 stirrer

and a reflux condenser.

20.1.11.1 Procedure

A solution of 0.60 mol of dry sodium iodide in 350 ml of 100% ethanol (Note 1)

is heated to about 70 �C. Freshly distilled propargyl bromide (Note 2)


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(0.50 mol) is added over 10 min. After heating for 20 min at 70–75 �C, the white

suspension is cooled to rt and 500 ml of water is added, then the product is

extracted five times with 60-ml portions of high-boiling petroleum ether (bp

>190 �C). The combined extracts are washed with water and dried over mag-

nesium sulphate. The propargyl iodide is isolated from the extract by heating

this at 10–15 Torr in a distillation apparatus, using an efficient column and a

single receiver cooled at �30 �C (Figure 1.10). The distillation is stopped when

the temperature in the top of the column has risen above 50 �C. Redistillation

of the contents of the receiver in the same apparatus gives 3-iodo-1-propyne,

bp <25 �C/15 Torr, (receiver cooled at �30 �C), containing about 10% of

iodoallene.

Notes

1. In another experiment, performed on the same scale, 96% ethanol (instead

of 100%) and sodium iodide, containing 3–4% of water, was used.

Ethanol, 175 ml 96%, appeared to be sufficient to dissolve 90 g of this

quality of NaI. The reaction with propargyl bromide, HC�CCH2Br, gave

no trace of iodoallene, but instead some (� 10%) HC�CCH2Br was still

present in the crude product. This amount will probably increase if more

water is present since then the equilibrium cannot completely shift to the

right.

2. Propargyl chloride gives comparable amounts of propargyl iodide and

iodoallene. Propargyl tosylate will probably yield a product that is free

from the allene.

20.1.12 Zinc chloride-catalysed conversion of 2-alkynyl ethersinto the corresponding chlorides

Scale: 0.40 molar; Apparatus: Figure 1.1, 250 ml, magnetic stirring.

20.1.12.1 Procedure

Powdered anhydrous zinc chloride (1 g) is added to 0.40 mol of the 2-alkynyl

ether. Freshly distilled acetyl chloride (0.50 mol, excess) is added over 15 min.


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The mixture gradually turns brown, the temperature rises to 50–55 �C and is

maintained at this level by occasional cooling. After the exothermic reaction

has subsided, the mixture is heated for an additional 1.5 h at 50 �C. A

saturated aqueous solution of ammonium chloride (50 ml) is then added

with vigorous stirring. The upper layer is vigorously stirred at rt for 15 min

with a solution of 40 g of KOH in 150 ml of water in order to remove the

methyl acetate (this operation is not necessary when non-volatile acetylenic

chlorides are to be prepared). After drying the upper layer over a small

amount of magnesium sulphate, distillation is carried out, if R ¼ Me or

Et, under normal pressure. 1-Chloro-2-butyne, R ¼ Me, bp 101 �C/760

Torr, and 1-chloro-2-heptyne, R ¼ n-Bu, bp 55 �C/12 Torr, are obtained in

at least 80% yield.

Note

The chlorides are not accessible by reaction of the corresponding alcohols with

PCl3, since the intermediary phosphites do not readily react with HCl.

Alternative procedures for acetylenic chlorides are given in exps. 20.1.5 and

20.1.6.

20.2 ACETYLENIC AMINO AND IMINO COMPOUNDS

20.2.1 Propargylamine from propargyl bromide and liquid ammonia

Scale: 1.0 molar; Apparatus: Figure 1.1, 1 litre for the ammonolysis; 2-litre

round-bottomed, three-necked flask, equipped with a thermometer, a mechan-

ical stirrer and a powder funnel, for the addition to sodamide.

1-Amino-2-propyne (propargylamine) can be obtained in a fair overall yield

by alkylation of phthalimide with propargyl bromide in DMF followed by

20.2 ACETYLENIC AMINO AND IMINO COMPOUNDS 381

[13.1.2004–9:54pm] [369–426] [Page No. 382]


treatment of the product with dilute sulphuric acid and final addition of alkali

hydroxide [43]. The alternative syntheses may be summarised as conversion of

propargyl bromide or propargyl alcohol into some derivative (for example a

tosylate or hexamethylenetetramine salt [44]) and a subsequent treatment of

this intermediate, ultimately resulting in the formation of either the free

amine or some salt. Although in some cases impressive yields (of the final

step) have been reported, the syntheses are, in general, very laborious. The

use of reagents with relatively high molecular weights in some syntheses

makes performance on a larger scale inconvenient.

It may be expected that propargylamine is smoothly ammonolysed in liquid

ammonia. A qualitative experiment shows that this is indeed the case. Five

millilitres of the bromide are added to 50 ml of boiling ammonia. When

after 30 min the solution is poured onto 100 g of finely crushed ice, no

under layer is visible. Repetition of this operation after an interaction time

of ten minutes still does show the presence of some propargyl bromide.

These experiments give useful information with respect to the additional reac-

tion time in a synthetic procedure.

A serious problem is the subsequent reaction of propargyl bromide with

the corresponding amine presumed to occur in equilibrium with the primarily

formed propargylammonium bromide. This reaction, which affords dipropar-

gylamine, proceeds (like in the case of saturated-alkyl halides) much more

easily than the preceding reaction of propargyl bromide with ammonia. In

order to suppress this undesired reaction, the use of a large excess of

liquid ammonia seems desired. The next problem to be solved is to prevent

entraining of the volatile propargylamine with the evaporating ammonia.

In an earlier performed synthesis of propargylamine the ammonia was

allowed to evaporate completely. The amine was isolated in yields of

� 40% only [42]. In the procedure described below this problem is effectively

solved by reaction of propargyl bromide with liquid ammonia followed by

addition to an excess of sodamide in liquid ammonia. In this way, the

amine is fixed as the sodium compound. After complete evaporation of the

ammonia, the amine can be liberated by addition of water, just enough to

effect a smooth dissolution of the solid.

20.2.1.1 Procedure

Freshly distilled propargyl bromide (1.0 mol) is added dropwise over 1 h to

800 ml of anhydrous liquid ammonia in the 1-litre round-bottomed, three-

necked flask. During the addition the temperature of the reaction mixture is

kept between �33 (bp of ammonia) and �36 �C (bath with dry ice and

acetone), while nitrogen is introduced at a rate of � 100 ml/min. After an


[13.1.2004–9:54pm] [369–426] [Page No. 383]


additional 45 min (at � �36 �C) the resulting solution is cooled to between

�60 and �70 �C in a bath with liquid nitrogen. The solution is subsequently

poured in a number of portions over 10 min through the powder funnel to a

suspension of 2.2 mol of sodamide in � 500 ml of liquid ammonia. During

this addition the temperature is carefully kept below �50 �C by cooling with

liquid nitrogen. After this operation the cooling bath and the equipment are

removed. On the outer necks are placed stoppers. The middle neck is con-

nected with a drying tube filled with KOH pellets. In order to ensure the

constant presence of a protecting atmosphere of ammonia in the last stage of

the evaporation, the drying tube is placed on a level below the bottom of the

flask (cf. Figure 1.7). When, after one night, liquid ammonia is no longer

present, the flask is placed in a bath at � 30 �C and evacuated (water aspira-

tor) until the pressure has dropped to below 10–20 Torr (this operation takes

about 1 h). Inert gas (preferably argon) is then admitted and the flask is

equipped with a dropping funnel (on the middle neck), a reflux condenser

filled with dry ice and acetone (‘cold finger’-type) and a gas inlet. The flask is

placed in a bath at � 0 �C (or, preferably, at lower temperature). Nitrogen or

argon is slowly introduced and water (200 ml) is added over 30 minutes, in

the beginning dropwise, but in a later stage, when the intensity of reflux

(some ammonia) in the cold finger has subsided, portionwise. At the end,

the flask is vigorously swirled by hand for a few minutes in order to achieve

complete contact of the solid with the water. The flask is then equipped for a

distillation under atmospheric pressure (20-cm Vigreux column, condenser

and receiver cooled in a bath at 0 �C). The flask is immersed in an oil

bath and heated until the temperature in the head of the column has reached

100–102 �C. The distillate, a mixture of propargyl amine and water, is satu-

rated with KOH pellets (or, if available, machine-powdered KOH) and a

redistillation is carried out, now collecting all liquid passing over below

95 �C. After addition of KOH pellets and vigorous shaking, a final distilla-

tion is carried out giving the almost pure amine, distilling between 75 and

85 �C, n20D 1.4492. Yields are between 60 and 65%.

20.2.2 Propargylic tertiary amines from propargyl bromideand aliphatic or cycloaliphatic secondary amines

Scale: 0.50 molar (HC�CCH2Br); Apparatus: Figure 1.1 , 1 litre


[13.1.2004–9:54pm] [369–426] [Page No. 384]


Nucleophilic substitutions on propargylic or allylic carbon atoms generally

proceed more easily than substitutions with halides in which the unsaturated

system is absent or more remote from the halogen atom. This also holds for

reactions with amines. The initial product in the reaction of propargyl

bromides with an aliphatic or cycloaliphatic amine R2NH is the ammonium

salt HC�CCH2NR2 �HBr. Since secondary amines are stronger bases than

tertiary amines, it may be expected that HBr will be largely transferred to

the secondary amine. Thus, in order to achieve a complete conversion of pro-

pargyl bromide, it will be necessary to use an excess of at least 100 mol% of

the secondary amine. The reactions proceed at a convenient rate in diethyl

ether and the ethereal solutions of the propargylic tertiary amines can be

separated from the HBr salt of the secondary amine by filtration. If desired,

the secondary amine used in excess can be recovered by treating the salt with

concentrated aqueous KOH. Propargyl bromide reacts sluggishly with the

bulky diisopropylamine (yields are low).

20.2.2.1 Procedure [5,6]

Propargyl bromide (0.50 mol) is added over 20 min to an efficiently stirred

mixture of 1.10 mol of the amine (dried over KOH) and 500 ml of dry Et2O. A

suspension of salt is formed almost immediately. When the temperature of the

mixture has reached 35 �C, the thermometer is replaced with a reflux conden-

ser. The reaction is brought to completion by heating the suspension for an

additional hour under reflux. The suspension is then cooled to 0 �C, after which

the salt is filtered off on a sintered-glass funnel and rinsed well with dry Et2O.

In the case of pyrrolidine, an oily precipitate may be formed: instead of carry-

ing out the filtration, the supernatant solution is decanted and the precipitate is

thoroughly rinsed with pentane. In all cases, the greater part of the solvent is

distilled off at atmospheric pressure through a 40-cm Vigreux column (bath

temperature not higher than 100 �C), after which the remaining liquid is care-

fully fractionated through an efficient column. The following amines can be

prepared by this procedure.

N,N-diethyl-2-propyn-1-amine, HC�CCH2NEt2, bp � 60 �C/150 Torr,

yield >70%; 1-(2-propynyl)pyrrolidine, HC�CCH2–N(CH2)4, bp 42 �C/10

Torr, yield >70%; 1-(2-propynyl)piperidine, HC�CCH2–N(CH2)5, bp 62 �C/

10 Torr, yield >85%; 4-(2-propynyl)morpholine, HC�CCH2N(CH2)2O

(CH2)2, bp 75 �C/10 Torr, yield >85%.

(E)-N,N-Diethyl-2-penten-4-yn-1-amine, E-HC�CCH¼CHCH2NMe2, bp

70 �C/80 Torr, can be obtained in a high yield from (E)-5-bromo-3-penten-1-

yne, HC�CCH¼CHCH2Br, and dimethylamine (2.5 mol equivalents) in

Et2O by a similar procedure.


[13.1.2004–9:54pm] [369–426] [Page No. 385]


20.2.3 N,N-Dimethyl-2-propyn-1-amine from propargyl bromideand dimethylamine

Scale: 0.50 molar (HC�CCH2Br). Apparatus: Figure 1.1, 1 litre; stirrer:

Figure 1.2.

20.2.3.1 Procedure (for introduction see preceding exp.)

Dimethylamine (1.1 mol) is liquefied in a cold trap and subsequently poured

into 250 ml of high-boiling petroleum ether (bp >170 �C), pre-cooled at �5 �C.

Propargyl bromide (0.50 mol) is then added dropwise over 45 min, while

maintaining the temperature between 0 and 10 �C. A thick suspension is gra-

dually formed. After the addition, the temperature is allowed to rise to 35 �C

(occasional cooling may be necessary). After an additional 1.5 h (at 35 �C,

warming may be necessary) the dropping funnel and thermometer are replaced

with stoppers and the flask is equipped for a vacuum distillation (cf. Figure

1.10: 40-cm Vigreux column, condenser and single receiver, cooled in a bath at

�70 �C). A tube filled with KOH pellets is placed between the receiver and the

water aspirator. The system is evacuated (10–20 Torr) and the flask gradually

heated until the petroleum ether begins to pass over. The contents of the

receiver are carefully redistilled at atmospheric pressure through an efficient

column N,N-Dimethyl-2-propyn-1-amine, HC�CCH2NMe2, bp 82 �C/

760 Torr, is obtained in greater than 80% yield.

20.2.4 1,4-Bis(diethylamino)-2-butyne starting from1,4-dibromo-2-butyne

Scale: 0.25 molar; Apparatus: Figure 1.1, 500 ml for the preparation of dibro-

mobutyne; for the conversion into the amine the thermometer is replaced with

a reflux condenser.

Warning: Dibromobutyne is a skin-irritating and lachrymatory compound.

Protective gloves of suitable quality should be used; the experiment should

be carried out in a well-ventilated hood.


[13.1.2004–9:54pm] [369–426] [Page No. 386]


20.2.4.1 Procedure

2-Butyne-1,4-diol (0.25 mol, technical grade) is powdered and subsequently

placed in the flask, containing 100 ml of Et2O. Phosphorus tribromide (50 g,

slight excess) is added dropwise over � 45 min with cooling in a bath with ice

and ice water. After the addition, the cooling bath is removed and stirring is

continued for an additional 2 h (gentle refluxing may temporarily occur). Ice

water (300 ml) is then added and the lower (organic) layer is dried (without

washing) over MgSO4. The aqueous layer is extracted twice with 40-ml por-

tions of Et2O. The combined ethereal solutions are added over 30 min to a

mixture of 1.3 mol of diethylamine (dried over machine-powdered KOH) and

150 ml of Et2O. The thick suspension is heated for an additonal 1 h under

reflux, after which it is poured into 200 ml of an aqueous solution of 75 g of

KOH. The upper layer is dried (without washing) over K2CO3 together with

four ethereal extracts. The Et2O and excess of diethylamine are removed under

reduced pressure and the remaining liquid distilled from a 500-ml flask (a

relatively big flask is used in view of foaming during the distillation).

N1,N1,N4,N4-Tetramethyl-2-butyne-1,4-diamine, bp 110 �C/10 Torr, is obtained

in �65% yield based on butynediol.

20.2.5 N,N-Diethyl-5-hexyne-1-amine from the correspondingtosylate and diethylamine

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre, reflux condenser, stirrer and

thermometer

20.2.5.1 Procedure

5-Hexynyl-4-methylbenzenesulphonate (0.20 mol, prepared as described in exp.

20.5.4), dioxane (60 ml, dried over KOH) and diethylamine (0.5 mol, dried over

KOH) are placed in the flask. The mixture is heated for 2 h under reflux. The

temperature of the refluxing liquid rises by about 10 �C over the first period of

1 h, but remains constant during the rest of the time. After stopping the stirrer,

a two-layer system is visible. The mixture is cooled to rt and then cautiously

poured into a mixture of 50 ml of concentrated HCl and 50 ml of ice water.

Three extractions with Et2O are then carried out in order to remove impurities.

The extracts are washed twice with 10-ml portions of water, the washings being

added to the main portions of the aqueous solution. This is subsequently


[13.1.2004–9:54pm] [369–426] [Page No. 387]


heated and evacuated (rotary evaporator) in order to remove as much as

possible of the dioxane. This operation is terminated when the volume of the

solution has decreased to about 70 ml. After cooling to below 10 �C, NaOH

pellets (40 g) are added in ten equal portions with vigorous stirring and cooling

in a bath with ice water. The amine is then extracted five times with Et2O and

the extracts dried over K2CO3 (without preceding washing). After concentra-

tion of the ethereal solution under reduced pressure, the remaining liquid is

carefully distilled through an efficient column. N,N-Diethyl-5-hexyne-1-amine,

bp 73 �C/14 Torr, is obtained in greater than 80% yield.

20.2.6 2-Heptyne-1-amine from 1-bromo-2-heptyne andhexamethylenetetramine

The procedure [7] for 2-heptyne-1-amine, n-BuC�CCH2NH2, starting from

1-bromo-2-heptyne, n-BuC�CCH2Br, gives good results.

20.2.7 2-Methyl-3-butyne-2-amine from 3-chloro-3-methyl-1-butyneand sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre stirrer: Figure 1.2

The mechanism of this remarkable reaction, in which a halogen atom in an

acetylenic tertiary halide is substituted with high yields by the nucleophilic

group NH2, is not completely clear. Probably the ethynyl hydrogen atom is

abstracted in the first step by the strongly basic amide. The results from solvo-

lysis experiments carried out with tertiary acetylenic bromides suggest that

the intermediary sodium-3-chloro-3-methyl-1-butyne, NaC�C–CMe2Cl, loses

NaCl to give the carbene :C¼C¼CMe2. This species is attacked by NH3

or NaNH2.

20.2.7.1 Procedure [8] (cf. exp. 20.2.1 for the isolation)

To a suspension of 0.50 mol of sodamide in 400 ml of liquid ammonia

3-chloro3-methyl-1-butyne (0.20 mol, exp. 20.1.9) is added dropwise over

10 min. A thick brown suspension is formed. The ammonia is allowed to


[13.1.2004–9:54pm] [369–426] [Page No. 388]


evaporate overnight (see Figure 1.7). The last traces of ammonia are removed

by evacuating the flask for about half an hour. Nitrogen is then admitted and

the flask is equipped with a gas inlet (for introduction of N2), a dropping

funnel and an outlet, connected (via a plastic tube) to a cold trap (–70 �C).

Water (120 ml) is cautiously added over 15 min from the dropping funnel,

while N2 is passed through the apparatus. It is desired to immerse the flask in

a bath with ice water. After the addition of the water, the flask is swirled in

order to bring the aqueous mixture into contact with the solid on the glass

wall. After all solid material has dissolved, the contents of the trap are

poured into the flask. The flask is then equipped with a 40-cm Vigreux

column, which is connected to a condenser and a 250-ml receiver, cooled

at �20 �C. The flask is heated in an oil bath until the thermometer in the

head of the column indicates 100 �C. During this distillation, some gaseous

ammonia escapes from the receiver. The liquid in the receiver is saturated

with KOH (portionwise addition of pellets with manual swirling and cooling

in an ice-water bath). The receiver is then equipped for a vacuum distillation

(Figure 1.10) using a 30-cm Vigreux column, a condenser and a 250-ml

receiver cooled at �70 �C. The volatile amine is collected in this strongly

cooled receiver by subjecting the mixture of KOH, water and the amine to

a flash distillation at water-aspirator pressure (temperature of the heating

bath not higher than 60 �C). The liquid collected in the receiver still contains

small amounts of water. These can be removed by adding machine-powdered

KOH (15–20 g) and repeating the flash distillation operation. Redistillation

of the contents of the receiver gives 2-methyl-3-butyn-2-amine, bp 83 �C/760

Torr, in � 60% yield.

20.2.8 1-Ethynylcyclohexanamine from 1-chloro-1-ethynylcyclo-hexane and sodamide

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre stirrer: Figure 1.2

20.2.8.1 Procedure (cf. preceding exp.)

The tertiary chloride (0.20 mol, see exp. 20.1.10) is added dropwise over 15 min

to an efficiently stirred suspension of 0.50 mol of sodamide in 400 ml of liquid


[13.1.2004–9:54pm] [369–426] [Page No. 389]


ammonia. The reaction is very vigorous and occasional addition of small

amounts of Et2O may be necessary to suppress frothing (cooling of the reaction

mixture to below the bp of ammonia also is effective). The ammonia is allowed

to evaporate overnight (Figure 1.7), after which 200 ml of Et2O is added.

The mixture is then hydrolysed by cautiously adding (with swirling) 300 ml

of ice water. After dissolution of the solid material and separation of the layers,

three extractions with Et2O are carried out. The ethereal solutions are dried

(without preceding washing) over K2CO3 and subsequently concentrated under

reduced pressure. Distillation of the remaining liquid gives 1-ethynylcyclo-

hexanamine, bp 54 �C/15 Torr, in excellent yield.

20.2.9 1-Propargylpyrrole from pyrrole, potassium amideand propargyl bromide


20.2.9.1 Procedure [9]

Freshly distilled pyrrole (0.20 mol) is added over a few seconds to a solution of

0.20 mol of potassium amide (Chapter 2, exp. 2.3.1) in 150 ml of liquid ammo-

nia, cooled at � �60 �C. After 1 min 0.22 mol of propargyl bromide is added

over a few minutes, likewise at �60 �C. After this addition the reaction mixture

is stirred for 15 min at � �50 �C, then the cooling bath is removed and the

ammonia is removed by placing the flask in a bath at 40 �C (the equipment is

removed). The remaining mass is extracted five times with dry, warm Et2O.

The combined organic solutions are concentrated under reduced pressure.

Careful distillation through an efficient column gives 1-propargylpyrrole,

bp 60 �C/10 Torr, in 70% yield. The higher boiling fraction consists of 2-pro-

pargylpyrrole, 1,2- and 1,3-di(propargyl)pyrrole.

Using lithium amide or sodamide instead of potassium amide, the yield of

1-propargylpyrrole is moderate and the purity less.

1-Propargyl-1,3-imidazole and 1-propargylpyrazole can be prepared with

high yields from the azoles, potassium amide and propargyl bromide.


[13.1.2004–9:54pm] [369–426] [Page No. 390]


20.2.10 Acetylenic imines (general method, not checked) [48]

20.2.10.1 Procedure

To a solution of 0.03 mol of the acetylenic aldehyde in 10 ml of dry Et2O was

added dropwise an equimolar amount of the amine. Heat was evolved while the

reaction mixture became turbid. After an additional 10 min (at rt) the aqueous

layer was separated off and the ethereal solution was dried over magnesium

sulphate. After removal of the Et2O (water spirator), the remaining liquid was

distilled in vacuo or crystallised from benzene, Et2O or pentane. Yields were

generally higher than 70%.

20.3 ACETYLENIC AND ALLENIC NITRILES, THIOCYANATESAND ISOTHIOCYANATES

20.3.1 Preparation of 2-alkynenitriles from 1-bromo-1-alkynesand copper(I) cyanide in the presence of lithium bromide

Scale: 0.20 molar (RC�CBr); Apparatus: Figure 1.1, 250 ml, magnetic

stirring

20.3.1.1 Procedure

The 1-bromoalkyne (0.20 mol, Chapter 9, exps. 9.2.3–9.2.5), dry THF (80 ml)

and dry, powdered copper(I) cyanide (0.25 mol) are placed in the flask. The

mixture is warmed to 40 �C and a solution of 6 g of anhydrous lithium bromide

in 20 ml of THF is added. As a rule, the reaction starts within a few minutes

(heating to 50–55 �C may be necessary) and (with stirring at a moderate rate)

the temperature may rise above 60 �C. Occasional cooling is applied to keep

the temperature between 65 and 70 �C. After the reaction has subsided, the

mixture is heated for an additional half an hour at 65–70 �C. Most of the solid

has then passed into solution. The solution is poured into 200 ml of a cold

(0 �C) aqueous solution of 20 g of KCN (or 15 g of NaCN) and 30 g of NH4Cl.

After vigorous shaking, the solution is extracted four times with Et2O. The

combined ethereal solutions are washed with concentrated aqueous NH4Cl and

subsequently dried over MgSO4. After removal of the solvent under reduced


[13.1.2004–9:54pm] [369–426] [Page No. 391]


pressure, the remaining liquid is first subjected to a flash distillation in a high

vacuum and the distillate collected in a strongly cooled (<�30 �C, Figure 1.10)

receiver. Redistillation gives the nitriles in � 75% yield.

Examples of nitriles, which have been obtained by this procedure: 3-phenyl-

2-propynenitrile, PhC�CC�N, bp 95 �C/15 Torr, the distillate solidifies at

rt; 3-(1-cyclohexenyl)-2-propynenitrile, 1-cyclohexenyl–C�CC�N, bp 100 �C/

15 Torr; 2-heptynenitrile, BuC�CC�N, bp 56 �C/15 Torr.

Warning: The aqueous layers should not be poured into a waste container

for acids.

20.3.2 2,3-Decadienenitrile from corresponding bromo compoundand copper(I) cyanide in the presence of lithium bromide

Scale: 0.10 molar; Apparatus: 100-ml two-necked flask, provided with a

magnetic stirring bar and a reflux condenser

20.3.2.1 Procedure

A mixture of 0.15 mol of dry CuCN (commercially available), 6 g of anhydrous

LiBr, 0.10 mol of 1-bromo-1,2-nonadiene (Chapter 12, exp. 12.4.14 ) and 25 ml

of dry THF is heated to 90 �C and kept at that temperature for 30 min. The

reaction mixture gradually becomes homogeneous. After cooling to about

50 �C the brown solution is poured into a vigorously stirred solution of 30 g

of sodium cyanide and 30 g of ammonium chloride in 200 ml of water, to which

100 ml of Et2O has been added (for warning cf. preceding exp.). The reaction

flask is rinsed with warm (40 �C) THF and the solution obtained is also hydro-

lysed. After separation of the layers, the aqueous layer is extracted three

times with Et2O. The combined ethereal solutions are washed with concen-

trated ammonium chloride solution, dried over magnesium sulphate and

subsequently concentrated under reduced pressure. Rapid distillation of

the residue through a 25-cm Vigreux column gives 2,3-decadienenitrile,

bp 110 �C/15 Torr, in 62% yield. The nitrile dimerises or polymerises upon

prolonged heating.

1-Bromo-3-methyl-1,2-butadiene, Me2C¼C¼CHBr, and copper cyanide

give 4-methyl-2,3-pentadienenitrile under similar conditions.

20.3 ACETYLENIC AND ALLENIC NITRILES 391

[13.1.2004–9:54pm] [369–426] [Page No. 392]


20.3.3 3-Alkynenitriles from 1-bromo-2-alkynes andcopper(I) cyanide


Nitriles with the system –C�CCH2C�N cannot be prepared from the corre-

sponding propargylic bromides or tosylates and alkali cyanide, because the

basic cyanide causes a smooth isomerisation to allenic nitriles (C¼C¼

CHC�N). The use of copper(I) cyanide allows the substitution reaction to

be carried out under non-basic conditions. Since copper(I) cyanide is poorly

soluble in THF, the reaction proceeds sluggishly in this solvent and prolonged

heating at elevated temperatures presumably will be necessary. Anhydrous

LiBr forms a complex with CuCN that is soluble in THF, thus creating favour-

able conditions for the conversion. Indeed, a sub-stochiometrical amount of

LiBr appears to cause a smooth reaction. In addition to the main product, a

small amount of the 1,3-substitution product, the allenic cyanide,

RC(C�N)¼C¼CH2, is formed. The two isomers can be satisfactorily sepa-

rated by fractional distillation.

20.3.3.1 Procedure

Anhydrous lithium bromide (0.1 mol) is dissolved in 100 ml of dry THF. Dry,

powdered CuCN (0.47 mol) and the bromoalkyne (0.40 mol) are successively

added, after which the suspension is warmed to between 40 and 60 �C. An

exothermic reaction starts gradually and occasional cooling is necessary to

keep the reaction mixture between 70 and 80 �C. The greater part of the sus-

pension disappears and a brown solution is formed. After heating for an addi-

tional 30 min at 75–80 �C, the hot (cooling may result in partial solidification)

solution is cautiously poured into a vigorously stirred solution of 50 g of

NH4Cl in 250 ml of 4 N hydrochloric acid (in another three-necked flask),

which is kept between 0 and 5 �C. The first flask is rinsed with the aqueous

layer. The product is isolated by extraction with a 1:1 mixture of Et2O and

pentane (five to seven times). The combined organic solutions are washed with

saturated aqueous NH4Cl and subsequently dried over MgSO4. The liquid

remaining after removal of the solvent in vacuo is first subjected to a flash

distillation at <0.5 Torr, using a short Vigreux column and a single receiver

cooled in a bath at �50 �C (Figure 1.10). Redistillation of the contents of the

receiver through an efficient column gives 3-pentynenitrile, MeC�CCH2C�N,


[13.1.2004–9:54pm] [369–426] [Page No. 393]


bp 47 �C/15 Torr, in �60% yield (the small first fraction is mainly 2-methyl-

2,3-butadienenitrile, MeC(C�N)¼C¼CH2) and 3-octynenitrile, BuC�CCH2

C�N, bp 84 �C/15 Torr, in �70% yield (the first fraction of � 5 g consists

mainly of 2-butyl-2,3-butadienenitrile, BuC(C�N)¼C¼CH2).

20.3.4 4-Pentynenitrile from 3-butynyl tosylate andsodium cyanide in DMSO


20.3.4.1 Procedure

Dry, powdered sodium cyanide (40 g, excess; KCN is not sufficiently soluble),

DMSO (200 ml) and 3-butynyl tosylate (0.50 mol, cf. exp. 20.5.4) are placed in

the flask. The mixture is gradually heated to 70 �C. A rather strong exothermic

reaction occurs and occasional cooling may be necessary. After an additional

half hour (at 70 �C) the mixture is cooled to rt and then poured into 400 ml of

saturated aqueous NH4Cl. Twenty (Note) extractions with Et2O (2� 100 ml,

1� 50 ml, the other portions � 30 ml) are carried out. The combined organic

solutions are washed twice with 100-ml portions of saturated aqueous NH4Cl

and subsequently dried over K2CO3. The Et2O is then removed under reduced

pressure. Distillation of the remaining liquid through an efficient column gives

4-pentynenitrile, bp 60 �C/10 Torr, in high yields.

Note

The presence of DMSO enhances the solubility of the nitrile. The method

can also be applied to prepare other nitriles with the general structure RC�

C(CH2)nC�N (n>2). In these cases the extraction procedure is less laborious.

20.3.5 2-Heptynenitrile from the corresponding carboxamideand phosphorus pentoxide

Scale: 0.20 molar; Apparatus: 1-litre round-bottomed flask

20.3 ACETYLENIC AND ALLENIC NITRILES 393

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20.3.5.1 Procedure

The powdered crystalline 2-heptynamide (0.20 mol), paraffin oil (250 ml), some

drops of anti-foaming liquid and 130 g of P2O5 are successively placed in the

flask. The mixture is vigorously shaken during 1–2 min, so that a homogeneous

slurry is formed. The flask is then equipped for a distillation in vacuum (Figure

1.10), the receiver being cooled in a bath at –60 �C. After evacuating the

apparatus (<0.1 Torr), the flask is heated in an oil bath, initially at �150 �C,

later at 200 �C. When the distillation has stopped, inert gas is admitted and the

brown hot mass is cautiously (spatula) broken up in smaller particles. Repetition

of the heating operation gives an additional small amount of the nitrile.

Redistillation gives pure 2-heptynenitrile, bp 56 �C/15 Torr, in �70% yield.

20.3.6 2-Propynyl thiocyanate from propargyl bromide andpotassium thiocyanate

Scale: 0.20 molar; Apparatus: Figure 1.1, 250 ml; no dropping funnel, reflux

condenser instead of a thermometer.

20.3.6.1 Procedure

A vigorously stirred mixture of 0.30 mol of potassium thiocyanate, 30 ml of

water and 0.20 mol of propargyl bromide is heated for 30 min in a bath at

�90 �C. After cooling extraction with Et2O is carried out. The ethereal solution

is dried and concentrated under reduced pressure. 2-Propynyl thiocyanate,

bp 65 �C/15 Torr, is obtained in �90% yield.

20.3.7 Propargyl isothiocyanate from propargylamine andthiophosgene


The reaction of primary amines with (commercially available) thiophosgene

is a convenient preparative method for isothiocyanates. The reaction is


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quite general and gives good yields. The amino group attacks on the thiocar-

bonyl carbon atom with primary formation of a compound with the

structure RNHC(¼S)Cl. This intermediate may either eliminate HCl under

the influence of the amine with formation of the isothiocyanate or may under-

go a second substitution of Cl with formation of the thiourea derivative

S¼C(NHR)2. The latter compound can also be formed by addition of RNH2

to the heterocumulene system of the isothiocyanate. These undesired processes

can be largely avoided by keeping the concentration of the amine as low as pos-

sible during the reaction. Since part of the amine is inactivated by reaction with

the HCl liberated, it is necessary to carry out the reaction in the presence of a

basic reagent that neutralises the HCl, but does not react with thiophosgene.

In the procedure for propargyl isothiocyanate, which should be generally

applicable, we use aqueous potassium carbonate. At a later stage, aqueous

KOH is added to complete the elimination of HCl from the intermediary

N-(2-propynyl)carbamothioic chloride, HC�CCH2NHC(¼S)Cl.

20.3.7.1 Procedure

A mixture of 0.11 mol of thiophosgene and 75 ml of dichloromethane is cooled

to �5 �C. A solution of 0.10 mol of potassium carbonate in 100 ml of water

(5 �C) is added. A mixture of 0.10 mol of propargylamine (exp. 20.2.1) and

20 ml of water is added dropwise over 15 min with vigorous stirring and

maintaining of the temperature between 0 and 5 �C. After an additional

10 min a cold (0 �C) solution of 0.2 mol of KOH in 100 ml of water is

added in one portion with cooling below 0 �C and stirring is continued for

an additional 15 min. The organic layer and three extracts (Et2O) are dried

(without washing) over MgSO4 and subsequently concentrated under reduced

pressure. Distillation of the remaining liquid through a 20-cm Vigreux column

gives 2-propynyl isothiocyanate, HC�CCH2N¼C¼S, bp 55 �C/15 Torr, in

�70% yield. Like most isothiocyanates, the compound is a strong lachrymator.

Poor results are obtained when the addition is carried out in a reversed sense

(Cl2C¼S to HC�CCH2NH2, H2O, CH2Cl2 and KOH or K2CO3).

20.4 ACETYLENIC ALDEHYDES, KETONES ANDCARBOXYLIC ACIDS

20.4.1 Propiolaldehyde, HC�CCH¼O

A satisfactory procedure for propiolaldehyde, HC�CCH¼O, from propargyl

alcohol and chromic acid is described [10].

20.4 ACETYLENIC ALDEHYDES, KETONES AND . . . 395

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20.4.2 Ethynyl ketones from corresponding ethynyl carbinolsand chromic acid

Our experiences with the procedure described in the literature [45] were

satisfactory. For the preparation of 1-hexyn-3-one, HC�CCOn-Pr, the

original procedure is slightly modified: the solution of CrO3 is added over

45 min, while keeping the temperature between 10 and 15 �C. After an

additional 1.5 h (at 10 to 15 �C) the mixture is extracted 8 times with Et2O

and the combined extracts are washed with saturated aqueous ammo-

nium chloride. The conversion of HC�CCH(OH)Me into 3-butyn-2-one

is carried out in the absence of acetone. Our yields are the same as those

mentioned.

1-Phenyl-2-propyn-1-one, HC�CCOPh, is prepared as follows:

1-Phenyl-2-propyn-1-ol (0.20 mol, Chapter 5, exp. 5.2.2) is added to a mix-

ture of 200 ml of acetone, 60 ml of water and 23.1 g of 96% sulphuric acid

cooled at 10 �C. A solution of 14.7 g of CrO3 in 50 ml of water is added drop-

wise over 40 min, while maintaining the temperature between 10 and 15 �C.

After an additional 2 h (at rt) the greenish solution is poured into 1 litre of

ice water and the product is extracted with Et2O (five times). The combined

organic solutions are washed with concentrated aqueous ammonium chloride

and dried over MgSO4. The solid remaining after removal of the solvent

under reduced pressure is dissolved in �250 ml of refluxing pentane. The

clear solution is decanted from a small amount of brown product and put in

the refrigerator (�25 �C). Colourless crystals, mp 49–50 �C, are obtained.

The mother liquor is concentrated and cooled again, giving an additional

small amount of crystals. The yield is about 90%.

20.4.3 5-Hexyn-3-one from 5-hexyn-3-ol and chromic acid



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20.4.3.1 Procedure [11]

In the flask is placed acetone (90 ml), 5-hexyn-3-ol (0.30 mol, Chapter 5, exp.

5.2.9) and pentane (100 ml). To the vigorously stirred mixture is added over

�15 min a solution of 25 g of CrO3 in a mixture of 23 ml of 96% H2SO4 and

60 ml of water, while keeping the temperature between 0 and �5 �C. Stirring at

this temperature is continued for 30 min at 0 �C, then the mixture is cooled to

�10 �C and ten extractions with small portions of a 1:1 mixture of Et2O and

pentane are carried out. Care is taken to keep the temperature of the aqueous

layer below 0 �C. The combined extracts are washed twice with 50-ml portions

of 1 N H2SO4 saturated with ammonium chloride and dried over magnesium

sulphate. After removal of the solvents under reduced pressure, the remaining

liquid is distilled in the apparatus shown in Figure 1.10, the receiver being

cooled in a bath at 0 �C. 5-Hexyn-3-one, bp �38 �C/15 Torr, is obtained in

70% yield. The purity is �80%.

20.4.4 Propynoic acid, HC�CCOOH

The results mentioned in the procedure described in the literature [46], invol-

ving oxidation of propargyl alcohol with CrO3 in an acetone–water mixture,

could be reproduced.

20.5 ACETYLENIC ESTERS, DITHIOESTERS AND CARBOXAMIDES

20.5.1 General procedure for the preparation of acetylenic acetates


20.5.1.1 Procedure [12]

N,N-Diethylaniline (0.70 mol) and redistilled acetyl chloride (0.37 mol) are

placed in the flask. The acetylenic alcohol (0.30 mol) is added over a few

minutes while heating the mixture at �40 �C. An exothermic reaction starts

and the temperature rises to 120 �C in a few minutes. Occasional cooling is

20.5 ACETYLENIC ESTERS, DITHIOESTERS AND . . . 397

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necessary to keep the temperature at that level. After the exothermic reaction

has subsided, the mixture is heated for an additional 15 min at �130 �C

(immersion of the flask in the heating bath is necessary to prevent solidification

of the reaction mixture on the glass wall). After cooling to 50 �C (stirring has

been stopped), a mixture of 300 ml of ice water and 30 ml of 36% hydrochloric

acid is added. A small amount of Et2O is added, after which the mixture is

vigorously shaken (or stirred). After separation of the layers, two extractions

with Et2O are carried out. The combined organic solutions are washed with

water and then dried over MgSO4. The liquid remaining after concentration of

the solution under reduced pressure is distilled through a 30-cm Vigreux

column. 1,1-Dimetyl-2-propynyl acetate, R ¼ H, R1 ¼ R2 ¼ Me, bp 45 �C/

27 Torr, and R ¼ H, R1R2C ¼ cyclohexyl, bp 87 �C/15 Torr, are obtained in

excellent yields.

With primary and secondary alcohols the reaction presumably proceeds

much more easily and a sufficient amount of a solvent e.g. Et2O, may be

necessary. The reaction may be carried out in the refluxing solvent.

20.5.2 2-Propynyl propanedithioate from bromomagnesiumpropanedithioate and propargyl bromide


20.5.2.1 Procedure [13]

To a solution (partly suspension upon cooling) of ethylmagnesium bromide

prepared from 0.35 mol of ethyl bromide and 0.45 mol of magnesium in 300 ml

of THF is added with cooling at �0 �C 0.30 mol of carbon disulphide. This

addition is carried out over 30 min. After an additional 30 min at rt, 50 ml of

HMPT (instead of this co-solvent DMSO, DMF, N-methylpyrrolidinone, or

other strongly polar solvents may be tried) and 0.40 mol of propargyl bromide

are successively added. The temperature rises slowly. After heating for 2 h at

50 �C, the mixture is kept (without stirring) overnight at rt. Water (250 ml) is

then added. After dissolution of the salt and separation of the layers, two

extractions with pentane are carried out. The combined organic solutions are


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washed three times with saturated aqueous ammonium chloride and are sub-

sequently dried over magnesium sulphate. The red liquid remaining after

removal of the solvents under reduced pressure is distilled at the lowest possible

pressure (<1 Torr) to give 2-propynyl propanedithioate, bp �50 �C/0.5 Torr,

in �70% yield.

For distillation at >5 Torr higher bath temperatures are required and as a

result a 3,3-sigmatropic rearrangement to 1,2-propadienyl propanedithioate,

EtC(¼S)SCH¼C¼CH2, and subsequent decomposition of this allenic dithio-

ester take place.

20.5.3 General procedures for the preparation of acetylenicmethanesulphinates and methanesulphonates


Esters of acetylenic alcohols and methanesulphinic and methanesulphonic

acid have been used as synthetic intermediates in our laboratory, mainly for

SN20-like substitution reactions leading to allenic derivatives [14]. Although

pyridine is recommended as solvent for the preparation of these esters [15], the

procedure given in this experiment, which uses dichloromethane as solvent and

a relatively small excess of triethylamine or pyridine, seems more simple. Yields

are generally excellent as in the case of the acetylenic p-toluenesulphonic esters

(exp. 20.5.4). Also acetylenic tertiary alcohols RC�CC(R1)(R2)OH have been

successfully converted by this procedure into the 1,1-dialkyl-2-propynyl metha-

nesulphinates. The esters from tertiary alcohols and methanesulphonic acid,

MeSO2OC(R1)(R2)C�CR, are unstable at rt and can only be prepared at low

temperatures in an organic solvent from the lithium alkoxides and MeSO2Cl.

20.5.3.1 Procedure

Methanesulphinyl chloride [16] (0.25 mol), or methanesulphonyl chloride (0.25

mol, commercially available) is added dropwise over 10–15 min to a mixture


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of the acetylenic alcohol (0.20 mol), dry dichloromethane (300 ml) and dry

triethylamine (0.35 mol). After the addition, which is carried out at ��50 �C,

the temperature is allowed to rise to 0 �C. Ice water (200 ml) is added with

vigorous stirring to the white suspension. The aqueous layer is extracted twice

with small portions of dichloromethane. The combined organic solutions are

dried over MgSO4 and subsequently concentrated under reduced pressure,

while keeping the bath temperature below 70 �C. The last traces of solvent

may be removed in a high vacuum (bath temperature 30 to 40 �C). Yields of

the products (purity >95%) are usually greater than 90%. If not used directly,

the esters should be stored in the refrigerator (�20 �C).

20.5.4 General procedure for the preparation of acetylenic4-methylbenzenesulphonates

Scale: 0.20 molar; Apparatus: Figure 1.1, 1 litre; a powder funnel is used

instead of the dropping funnel

Esters of arenesulphonic acids are prepared by reaction of the corresponding

alcohol with the arenesulphonyl chloride in the presence of a basic reagent,

which has the function of activating the alcohol and binding the hydrogen

chloride. The reaction is often carried out with pyridine, which is used as

solvent. In the procedure for tosylates of primary aliphatic alcohols, described

in A. I. Vogel, A Textbook of Practical Organic Chemistry, an aqueous solution

of sodium hydroxide is used. Esters of primary alcohols are formed more easily

than secondary-alkyl esters, while tertiary alcohols cannot be esterified under

the usual conditions.

The procedure described below is quite general and uses finely, freshly

machine-powdered KOH, which is added to a solution of the primary or

secondary (acetylenic) alcohol and a 10–15% molar excess of tosyl chloride

in Et2O, kept around 0 �C. The excess of tosyl chloride is destroyed during

the reaction with the excess of KOH. Side- and subsequent reactions (‘saponi-

fication’ of the ester by KOH and 1,2-elimination of 4-methylbenzenesulphonic

acid from the ester) can be suppressed by keeping the temperature of


[13.1.2004–9:54pm] [369–426] [Page No. 401]


the reaction mixture below 5 �C. This procedure can be carried out within 2 h

and generally gives excellent (often almost quantitative) yields of the tosylates.

Purification of acetylenic tosylates by distillation, which is risky because of the

limited thermal stability of the esters, is not necessary because the ‘crude’

products have a satisfactory purity (>95%) for further synthetic work. If

not used immediately, the tosylates should be stored in the refrigerator,

where deterioration is negligible.

Warning: Tosyl chloride may irritate the skin; protective gloves should

be worn.

20.5.4.1 Procedure

4-Methylbenzenesulphonyl chloride (0.22 mol in the case of primary alcohols

or 0.24 mol for secondary alcohols) is dissolved in 400 ml of Et2O. The alcohol

(0.20 mol) is then added and the mixture is cooled to between �5 and �10 �C

(bath with dry ice and acetone). Freshly and finely machine-powdered

KOH (100 g) is added with efficient stirring. The addition is initially carried

out in 5-g portions with intervals of 2 min. The evolution of heat is consider-

able and efficient cooling is necessary to maintain the temperature between

�5 and 0 �C (for primary alcohols) or between 0 and þ5 �C (for secondary

alcohols). After about 20 g of KOH has been added over the first 20 min,

the remainder is added over an additional 10 min. The mixture is then

stirred for half an hour or 1 h at the temperature indicated in the cases of

primary or secondary alcohols, respectively. The work-up is carried out

by pouring the mixture into 500 ml of ice water (the solid remaining in the

flask is quickly hydrolysed with ice water) and subsequently added to the

bulk of the solution. After vigorous shaking, the layers are separated. The

organic layer and two ethereal extracts are dried over MgSO4, after which

the ether is thoroughly removed under reduced pressure, keeping the

temperature of the heating bath below 80 �C. Yields are usually greater

than 90%.

The following variant, which uses a very concentrated aqueous solution of

NaOH, also may be applied. Propargyl alcohol (0.10 mol) and tosyl chloride

(0.12 mol) are dissolved in 100 ml of Et2O. A solution of 7 g (excess) of

technical-grade KOH in the minimal amount (�4 ml) of water is added

dropwise over 15 min with vigorous magnetic stirring, while keeping the

temperature of the mixture at � �10 �C. After an additional 30 min at 0 �C

the work-up is carried out. Small amounts of tosyl chloride still may be present

in the product. The yield is almost quantitative.


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20.5.5 Conversion of ethyl 2-heptynoate into thecorresponding carboxamide

Scale: 0.20 molar; Apparatus: 250-ml round-bottomed, two-necked flask with

mechanical stirrer and thermometer-outlet combination.

20.5.5.1 Procedure

A mixture of 0.20 mol of ethyl 2-heptynoate, 200 ml of a concentrated solution

of ammonia in water and 100 ml of methanol is vigorously stirred at rt until it

becomes homogeneous. After standing for an additional period of about 4 h at

rt, methanol and water are removed under reduced pressure. The crystalline

residue is dissolved in 200 ml of a 1:4 mixture of pentane and Et2O. The lower

layer is extracted twice with small portions of this mixture. The combined

organic solutions are dried over magnesium sulphate and subsequently

concentrated under reduced pressure. The yield of pure crystalline 2-heptyna-

mide is quantitative.

20.6 ETHERS

20.6.1 3-Methoxy-1-propyne from propargyl alcohol,NaOH and dimethyl sulphate

Scale: 3.0 molar; Apparatus: 2-litre round-bottomed, three-necked flask,

equipped with a dropping funnel, a gas-tight mechanical stirrer, an efficient

reflux condenser and a thermometer, combined with the reflux condenser or

dropping funnel.

20.6.1.1 Procedure [17]

A cold (0–10 �C) solution of 180 g of sodium hydroxide (Note 1) in 300 ml of

water is placed in the flask. Propargyl alcohol (3.0 mol) is added over 10 min


[13.1.2004–9:54pm] [369–426] [Page No. 403]


at rt, after which dimethyl sulphate (250 g) is added at a rate such that the

temperature is maintained between 50 and 55 �C (some cooling may be neces-

sary). This addition takes about 2 h. After the addition the mixture is heated

under reflux for 2 h. The reflux condenser is then replaced with a 40-cm

Vigreux column, which is connected to an efficient condenser and a receiver,

cooled at 0 �C. The propargylic ether is distilled off as quickly as possible, while

the temperature of the heating bath is gradually raised. The distillation is

stopped when the thermometer in the head of the distillation column indicates

95 �C. In order to remove some methanol, the contents of the receiver are

washed three times with cold aqueous NH4Cl in a small separating funnel.

The upper layer is dried over a small amount of MgSO4. Yields are generally

higher than 70%. Redistillation (under N2) may be carried out (bp 61 �C/760

Torr, but is not necessary. The product must be stored under N2 in a perfectly

closed bottle, placed in the refrigerator (�20 �C) (Note 2).

3-Ethoxy-1-propyne, HC�CCH2OEt, bp 80 �C/760 Torr, is obtained in a

similar way (yields >70%) using Et2SO4. During the addition of this reagent,

the temperature of the reaction mixture is maintained between 60 and 70 �C.

The reaction is brought to completion by heating the reaction mixture for 2 h

under reflux.

Notes

1. The use of potassium hydroxide is less convenient since a very thick sus-

pension of K2SO4 is formed.

2. Auto-oxidation with formation of 1-methoxy-2-propynyl hydroperoxide,

HC�CCH(OOH)OMe takes place very readily. Samples that have been

stored for a few days at rt under air (instead of N2) contain detectable

amounts of the hydroperoxide. The presence of this compound appears

most convincingly by shaking 1 ml of the ether with an aqueous solution of

KI. A brown colour is developed immediately, but disappears when shak-

ing is continued (due to addition or some other reaction with I2). The

presence of much hydroperoxide (after prolonged storage at rt or even

in the refrigerator) appears from a considerably higher refractive index.

Samples that show a positive KI test, should never be redistilled at atmos-

pheric pressure. A good qualitative test consists of shaking 2 to 3 ml with

t-BuOK. If a dark brown colour is developed and much heat is evolved

(in that case the refractive index at rt is considerably higher than 1.40), the

sample should be poured into the waste container (after dilution with an

equal volume of acetone). One of the coworkers in our laboratory had an

extremely vigorous explosion during a distillation of a large (�500 g)

20.6 ETHERS 403

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amount of HC�CCH2OMe, which had been stored for a few weeks at

rt (not under N2). Samples that contain small amounts of hydroperoxide

(nD<1.403, slight evolution of heat upon shaking with t-BuOK) can

best be purified by adding a small amount of paraffin oil (20 ml on each

100 ml of HC�CCH2OMe) and subsequently ‘distilling’ the volatile ether

at 10 to 20 Torr. The vapour is condensed in a strongly cooled receiver

(cf. Figure 1.10).

20.6.2 1,4-Dimethoxy-2-butyne from 2-butyne-1,4-diol,NaOH and dimethyl sulphate


20.6.2.1 Procedure [18]

A solution of 1.0 mol of 2-butyne-1,4-diol in 160 ml of water is placed in the

flask. Sodium hydroxide pellets (100 g, Note) and dimethyl sulphate (2.5 mol)

are added in turn in �20 equal portions over 1.5 h. During the addition the

temperature of the reaction mixture is kept between 30 and 40 �C (occasional

cooling). After the addition, the mixture is heated for an additional 3 h in a

bath at 90 �C. Ice water (150 ml) is then added and, after cooling to rt, five

extractions with Et2O are carried out. The organic solutions are dried (without

washing) over K2CO3, after which they are concentrated in vacuo. Distillation

of the remaining liquid through a 40-cm Vigreux column gives 1,4-dimethoxy-

2-butyne, bp 54 �C/12 Torr, in yields of at least 80% (depending on the quality

of butynediol).

1,4-Diethoxy-2-butyne, EtOCH2C�CCH2OEt, bp 76 �C/12 Torr, is pre-

pared in a similar way, with comparable yields.

The bis-ethers should be stored under N2 in the refrigerator.

Note

If potassium hydroxide is used, a very thick suspension of potassium sulphate is

formed making efficient stirring difficult.


[13.1.2004–9:54pm] [369–426] [Page No. 405]


20.6.3 Di-(2-propynyl) ether from propargyl alcohol,propargyl bromide and NaOH

Scale: 0.50 molar; Apparatus: 1-litre three-necked, round-bottomed flask,

equipped with a powder funnel, a mechanical stirrer and a combination of

thermometer and outlet; after the addition of NaOH, the powder funnel is

replaced with a stopper

20.6.3.1 Procedure

Propargyl alcohol (0.70 mol) and propargyl bromide (0.50 mol) are placed in

the flask. Freshly and finely machine-powdered sodium hydroxide (30 g) is

added in small portions with vigorous stirring (small amounts of THF may

be added if stirring becomes difficult). The heating effect is rather strong so

that occasional cooling is necessary to keep the temperature between 60 and

70 �C. When the reaction has subsided, the mixture is heated for an additional

1 h in a bath at 70–80 �C. After cooling to rt, 500 ml of ice water is added with

vigorous stirring. The product is extracted with Et2O and the extract washed

with water. After drying the organic solution over MgSO4, most of the Et2O is

distilled off at normal pressure. The remaining liquid is distilled through a

30-cm Vigreux column to give di-(2-propynyl) ether , bp 67 �C/85 Torr, in an

excellent yield.

20.6.4 O-Methylation of an acetylenic tertiary alcohol withdimethyl sulphate


Tertiary and secondary alcohols are less acidic than primary alcohols.

Methylation of 2-methyl-3-butyn-2-ol, HC�CCMe2OH, with Me2SO4 and

alkali hydroxide in aqueous medium, analogous to the procedure for

HC�CCH2OMe (exp. 20.6.1), is therefore expected to give a poor result. In

the aprotic DMSO, however, the concentration of the alkoxide HC�CC

(Me)2OK will be sufficient, while the alkylation will proceed smoothly in this

20.6 ETHERS 405

[13.1.2004–9:54pm] [369–426] [Page No. 406]


strongly polar solvent. Undoubtedly, part of the dimethyl sulphate will react

with KOH to give methanol (which may further react to dimethyl ether).

Therefore, an excess of Me2SO4 and KOH is used.

The procedure for the tertiary propargylic ether seems to be generally

applicable. If alkyl groups other than methyl or ethyl are to be introduced,

modification of the reaction conditions will be necessary. For example, for

the preparation of 1-butoxy-2-propyne, HC�CCH2OBu, powdered KOH

may be added portionwise to a heated mixture of HC�CCH2OH (excess),

butyl bromide and DMSO. The volatile butyl propargyl ether can be isolated

from the reaction mixture by evacuation. In the cases of higher-boiling ethers,

isolation can be carried out after addition of water and extraction with Et2O or

pentane.

Methylation or ethylation of primary alcohols can also be performed in

Et2O.The procedure may consist of adding the alkylating reagent (MeI or

Me2SO4, EtI or Et2SO4) to a mixture of the primary alcohol, excess of finely

powdered KOH and Et2O (or THF, cf. exp. 20.6.11).

20.6.4.1 Procedure [19]

DMSO (technical grade, 250 ml) and machine-powdered KOH (1.5 mol) are

placed in the flask. 2-Methyl-3-butyn-2-ol (1.0 mol, commercially available) is

added over a few minutes. Subsequently 1.0 mol of dimethyl sulphate is added

dropwise with vigorous stirring, while keeping the temperature in the region of

60 �C (�45 min). After the exothermic reaction has ceased, stirring and heating

at �60 �C are continued for an additional half an hour. The flask is then

equipped for a vacuum distillation using a 40-cm Vigreux column, a condenser

and a single receiver cooled in a bath at �70 �C (Figure 1.10). The system is

evacuated (water aspirator) and the flask heated in a bath at 70 �C. The volatile

ether condenses in the strongly cooled receiver. The contents of the receiver are

washed twice with saturated aqueous ammonium chloride and are subse-

quently dried over MgSO4. Pure 3-methoxy-3-methyl-1-butyne, HC�CC

(Me)2OMe, is obtained in �65% yield. Distillation is not necessary.

20.6.5 O-Methylation of an O-lithiated acetylenic tertiary alcoholwith methyl iodide



[13.1.2004–9:54pm] [369–426] [Page No. 407]


Although the procedure for the O-methylation of 2-methyl-3-butyn-2-ol

(exp. 20.6.4) gives a fair yield, it is less suitable for the O-methylation of

alcohols that are not available in large amounts. In such cases there is need

for a very clean high-yield method. The procedure for the O-methylation of

ethynylcyclohexanol is illustrative. 1-Ethynylcyclohexanol is O-lithiated

quantitatively by BuLi in a mixture of THF and hexane. Since O-alkylations

of lithium alkoxides in solvents of moderate polarity proceed very sluggishly

(even in the case of methyl iodide), a sufficient amount of the polar

DMSO has to be added as a co-solvent. The methylation with methyl

iodide can then be accomplished under relatively mild conditions and there

is no indication for decomposition of the intermediary lithium alcoholate

into LiC�CH and cyclohexanone.

20.6.5.1 Procedure

THF (140 ml) is added to a solution of 0.21 mol of BuLi (Note) in 133 ml of

hexane with cooling below 0 �C. A mixture of 0.20 mol of 1-ethynylcyclohexanol

and 20 ml of THF is then added at �25 �C, followed by 75 ml of dry DMSO.

Five minutes later, 0.32 mol (excess) of methyl iodide is added in one portion at

�0 �C. The mixture is successively stirred for 1 h at 10 �C and 1 h at 45 �C, then

it is poured into 400 ml of a saturated aqueous solution of NaCl. The aqueous

layer is extracted three times with Et2O. The combined organic solutions are

washed four times with brine and are subsequently dried over MgSO4. The

greater part of the solvent is then distilled off at atmospheric pressure through

a 40-cm Vigreux column. Careful distillation of the remaining liquid through

an efficient column gives 1-ethynyl-1-methoxycyclohexane, bp 56 �C/18 Torr,

in an excellent yield.

Note

The excess of BuLi is used to compensate for losses due to the presence of

traces of oxygen and moisture.

20.6.6 Methylation of an in situ prepared acetylenic lithiumalcoholate with methyl iodide


20.6 ETHERS 407

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20.6.6.1 Procedure [20]

A suspension of 0.20 mol of MeC�CLi in 126 ml of hexane and 140 ml of THF

is prepared (Chapter 3, exp. 3.9.4). To this suspension is added at 0 �C a

solution of 0.10 mol of anhydrous lithium bromide (Note) in 40 ml of THF.

The mixture is then cooled to �40 �C and 0.20 mol of cyclohexanone is added

over 10 min, while maintaining the temperature between �35 and �45 �C.

After the addition, the cooling bath is removed and the temperature allowed

rising to �5 �C. Methyl iodide (0.28 mol) and dry DMSO (75 ml) are then

successively added. The temperature rises to about 35 �C, while salt separates

from the solution. After heating for an additional 1.5 h at 50 �C, two clear

layers have formed. Ice water (500 ml) is added and, after separation of the

layers, the aqueous layer is extracted four times with Et2O. The combined

organic solutions are washed four times with saturated aqueous NH4Cl and

are subsequently dried over MgSO4. Removal of the solvent in vacuo followed

by careful distillation through a 30-cm Vigreux column gives the 1-methoxy-1-

(1-propynyl)cyclohexane, bp 80 �C/12 Torr, in greater than 80% yield.

Note

The LiBr is added to solubilise part of the propynyllithium. If no LiBr is added,

the coupling with ketones is slower and part of the ketone is converted into the

enolate. In the cases of soluble lithium alkynylides, the addition of LiBr is not

necessary.

20.6.7 Protection of the OH group in alcohols with ethyl vinyl ether


Although many organic chemists still use 3,4-dihydro-2H-pyran for the pro-

tection of OH groups [21,22], protection with ethyl vinyl ether has distinct

advantages. Ethyl vinyl ether [23] is much cheaper than the cyclic ether, and

chemists working in a university will perhaps find the advantage of the

easier protection and deprotection more important. Furthermore, 1H NMR-

spectroscopic analysis of the addition products from ethyl vinyl ether in

many cases will be easier.

The reaction of alcohols (and phenols) with ethyl vinyl ether proceeds readily

at temperatures in the region of 0 �C. For obtaining good yields (often almost


[13.1.2004–9:54pm] [369–426] [Page No. 409]


quantitative) it is essential to use water-free alcohols and to keep the tempera-

ture below 0 �C during the protection reaction. The use of an excess of ethyl

vinyl ether allows the reaction to be completed within 30 min, irrespective of

whether primary, secondary or tertiary alcohols are used. It should be pointed

out that the reaction is by no means limited to acetylenic alcohols.

Traces of acid, which often adhere to the glass, should be neutralised.

This can be done most easily and effectively by rinsing the glass with gaseous

ammonia or a solution of an aliphatic amine in acetone.

20.6.7.1 Procedure

Freshly distilled ethyl vinyl ether (0.3 to 0.4 mol, excess) is cooled to �25 �C

and �70 mg of p-toluenesulphonic acid (monohydrate or anhydrous) dissolved

in 1 ml of THF is added with efficient stirring. The dry alcohol (0.20 mol)

is then added portionwise over about 15 min, while keeping the temperature

between �20 and �15 �C (a cooling bath at �70 �C is indispensable, since it

provides the necessary flexibility in controlling the temperature). After the

addition, the mixture is stirred for an additional 15 min at �5 to 0 �C. Then

an additional 50 mg of p-toluenesulphonic acid is added while watching the

temperature attentively. If, without external cooling, no significant rise of the

temperature is observed, a solution of 2 g of K2CO3 in 5 ml of water is added

with vigorous stirring (for 1 min). The organic layer is dried over K2CO3, 1 ml

of diethylamine is added, after which the solution is concentrated under

reduced pressure. As a rule, the remaining liquid needs not be distilled because

the purity is higher than 95%. Distillation (if desired) is often accompanied by

foaming; it is therefore advisable to use a distillation flask of 500 ml. Impure

or water-containing alcohols often react sluggishly (no distinct rise of the

temperature upon addition of �5 g of the alcohol in one portion to the vinyl

ether). It is then tempting to add more acid catalyst, but this may result in

a sudden rise of the temperature and development of a brown colour.

Purification by distillation is then difficult and yields are considerably lower.

Solid alcohols, for example 2-butyne-1,4-diol, HOCH2C�CCH2OH, can

best be added as a solution in a small amount of Et2O or THF.

20.6.8 3-(t-Butoxy)-1-propyne by acid-catalysed addition ofpropargyl alcohol to isobutene

20.6 ETHERS 409

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Scale: 1.5 molar; Apparatus: Figure 1.9, 500-ml; the gas inlet and outlet are

connected to a cylinder with isobutene and a washing bottle filled with paraffin

oil, respectively; all connections are made gas-tight

20.6.8.1 Procedure [24]

Concentrated sulphuric acid (1.5 to 2 ml) is added with efficient stirring to

1.5 mol of propargyl alcohol (freshly distilled under reduced pressure). The

alcohol is then warmed to 35 �C and isobutene is introduced at a rate such that

a weak flow (�10 to 20 ml/min) is emitted from the outlet. The temperature of

the vigorously agitated reaction mixture is kept between 40 and 45 �C (occa-

sional cooling, later occasional warming). The flow of isobutene should be

continuously controlled: in the beginning the rate of absorption increases

with the temperature due to the higher rate of reaction, when the reaction

subsides the rate of absorption decreases. After about 1.5 h (depending inter

alia upon the efficiency of stirring) the reaction begins to subside and the

temperature to drop. Stirring at 40 to 45 �C is then continued for another

1.5 h, while introducing isobutene at a rate of �50 ml/min. The light-brown

solution is poured into 500 ml of ice water, containing a sufficient amount of

KOH. After vigorous shaking in a small separating funnel, the upper layer

is dried over K2CO3 and subsequently distilled. 3-(t-Butoxy)-1-propyne,

bp �70 �C/90 Torr, is obtained in �70% yield. The compound should

be stored under nitrogen in a well-closed bottle at �20 �C (cf. note 2 of

exp. 20.6.1).

20.6.9 Conversion of acetylenic chlorohydrines into oxiranes

Scale: 0.20 molar; Apparatus: 1-litre round-bottomed flask, equipped

with a powder funnel, a mechanical stirrer and a thermometer-outlet com-

bination; after the addition of KOH, the powder funnel is replaced with a

stopper

20.6.9.1 Procedure

Freshly distilled chloroacetone (0.20 mol) is added over a few minutes to a

solution (or suspension) of 0.20 mol of the lithiated acetylene in 140 ml of


[13.1.2004–9:54pm] [369–426] [Page No. 411]


THF and 126 ml of hexane (Chapter 3, exp. 3.9.4) with cooling between �80

and �90 �C. Five minutes after the addition the mixture is poured into 300 ml

of an aqueous solution of 5 g of NH4Cl. In the cases of lithium alkynylides

with slight solubility, stirring is continued at �80 �C for an additional 15 min

before hydrolysing the mixture. After separation of the layers, extraction of

the aqueous layer with Et2O and drying of the organic solutions over MgSO4

the solvent is removed in vacuo and the remaining liquid distilled. The

distilled chlorohydrine (0.20 mol) is mixed with 200 ml of Et2O, and 50 g

of finely, freshly machine-powdered KOH is added over 30 min with

efficient stirring, while maintaining the temperature between 5 and 15 �C.

After an additional half an hour the mixture is poured into water. The organic

layer and the ethereal extract of the aqueous layer are dried over K2CO3,

after which the solvent is removed under reduced pressure. In the case of

the volatile 2-methyl-2-(1-propynyl)oxirane (bp 50 �C/60 Torr), the greater

part of the Et2O is distilled off under atmospheric pressure. Yields are

mostly excellent.

20.6.10 O-Silylation of acetylenic tertiary alcohols

Scale: 0.10 molar; Apparatus: 500-ml round-bottomed three-necked

flask, equipped with a dropping funnel, a mechanical stirrer and a reflux

condenser

20.6.10.1 Procedure [25]

In the flask are placed 0.10 mol of 1-ethynylcyclohexanol, 120 ml of dry Et2O,

0.11 mol of dry triethylamine and 5 ml of DMSO (or 3 ml of 1,5-diazabicy-

clo[5.4.0]undec-5-ene). Freshly distilled chloro(trimethyl)silane (0.12 mol,

mixed with 20 ml of Et2O) is added over 20 min with vigorous stirring. A

thick precipitate is formed. After the spontaneous reflux of the Et2O has sub-

sided, the mixture is heated for 1 h under reflux. Ice water is then added,

followed by extraction with Et2O, drying over magnesium sulphate and

removal of the solvents under reduced pressure. 1-Ethynylcyclohexyl trimethyl-

silyl ether, bp 76 �C/17 Torr, is obtained in an excellent yield.

Other tertiary alcohols can be silylated by a similar procedure.

20.6 ETHERS 411

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20.6.11 O-Methylation of alcohols with methyl iodideand potassium hydroxide

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

equipped with a powder funnel, a mechanical stirrer and a reflux condenser

20.6.11.1 Procedure

A mixture of 0.30 mol of 2-penten-4-yn-1-ol (Chapter 4, exp. 4.5.15), 0.60 mol

of methyl iodide and 50 ml of Et2O is warmed to �35 �C. Machine-powdered

KOH (60 g) is added in 5 portions (with temporary cooling below reflux

temperature) over 30 min with vigorous stirring. Immediately after addition

of each portion the powder funnel is replaced with a stopper. When the ensuing

gentle reflux has ceased, the next portion of KOH is added. After stirring for

an additional 1 h (with heating under reflux) ice water is added and two

extractions with small portions of Et2O or pentane are carried out. The

dried organic solution is concentrated under reduced pressure (bath tempera-

ture <25 �C) and the remaining liquid distilled to give 1-methoxy-2-penten-3-

yne, bp 38 �C/10 Torr, in a high yield.

This experimental procedure can also be applied to O-methylate or -ethylate

other primary alcohols. As alkylating reagents alkyl iodides or dialkyl sul-

phates can be used.

20.7 ACETYLENIC SULPHIDES AND THIOLS

20.7.1 Methyl 2-propynyl sulphide from sodium methanethiolateand propargyl chloride



[13.1.2004–9:54pm] [369–426] [Page No. 413]


20.7.1.1 Procedure [26]

Sodium hydroxide (0.60 mol) is dissolved in 40 ml of water and 150 ml of

methanol is added. Methanethiol (0.60 mol) is condensed (� �60 �C) in a

cold trap and 30 ml of cold (�20 �C or lower temperature) methanol is

added. This cold mixture is added over �15 min to the vigorously stirred

solution of sodium hydroxide while keeping the temperature between 0 and

10 �C. Subsequently 0.50 mol of propargyl chloride (or bromide) is added

dropwise over 20 min while keeping the temperature between 0 and 10 �C.

Salt separates immediately from the solution. After stirring for an additional

half an hour at �15 �C, 500 ml of an aqueous solution of 10 g of KOH is

added (to prevent stench due to hydrolysis of the excess of sodium metha-

nethiolate). The mixture is extracted ten times with small portions (total

amount �500 ml) of high-boiling (bp >170 �C/760 Torr) petroleum ether.

The combined extracts are washed twice with water and subsequently dried

over MgSO4. The solution is brought in a 1-litre round-bottomed flask,

which is equipped for a vacuum distillation using an efficient column

(Figure 1.10). The apparatus is evacuated using a water aspirator, the receiver

being cooled in a bath at �70 �C. The flask is heated in a water bath, which

is gradually brought at a temperature of 80 �C. The evacuation is terminated

when the petroleum ether begins to reflux in the top of the column. The

contents of the receiver are subjected again to the distillation-condensing

procedure, now keeping the temperature of the ‘heating’ bath below 15 �C.

Methyl 2-propynyl sulphide is collected in �85% yield.

Ethyl 2-propynyl sulphide and phenyl propargyl sulphide can be prepared

from the corresponding sodium thiolates and propargyl chloride or bromide.

In the case of EtSCH2C�CH, the reaction conditions are similar to those

described above. Pentane is used as extraction solvent. The greater part of

the solvent is distilled off at normal pressure through an efficient column,

after which the product is distilled at a pressure of 50 to 100 Torr. In the pre-

paration of phenyl 2-propynyl sulphide, PhSCH2C�CH, a 10% excess of pro-

pargyl halide is used. The product is extracted with a 1:1 mixture of Et2O and

pentane. The solvent is removed under reduced pressure and the sulphide

distilled at �0.5 to 1 Torr.

20.7.2 1,4-Bis(methylthio)-2-butyne from sodium methanethiolateand 1,4-dichloro-2-butyne


20.7 ACETYLENIC SULPHIDES AND THIOLS 413

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20.7.2.1 Procedure

A solution of 0.45 mol of MeSNa in �40 ml of water and 150 ml of methanol

is prepared as described in the preceding experiment. 1,4-Dichlorobutyne

(0.20 mol, exp. 20.1.6) is added over 15 min, while keeping the temperature

between 0 and 10 �C. After an additional period of 30 min, during which the

temperature is allowed to rise to rt, the suspension is poured into a solution of

5 g of KOH in 500 ml of water. The product is extracted with a 1:1 mixture of

Et2O and pentane, the extracts are washed with water, dried over MgSO4 and

subsequently concentrated under reduced pressure. 1,4-Bis(methylthio)-2-

butyne, bp 116 �C/14 Torr, is obtained in �80% yield.

20.7.3 (Z )-1-Ethylthio-1-buten-3-yne from ethanethiol and butadiyne


20.7.3.1 Procedure

Ethanethiol (0.20 mol, freshly distilled) is added over 10 min to a solution of

0.20 mol of butadiynylsodium (Chapter 3, exp. 3.9.26) in 300 ml of liquid

ammonia with cooling at��40 �C. After an additional 10 min the thermometer

is replaced with a powder funnel and 15 g of powdered ammonium chloride is

added in small portions over 15 min. After this addition the cooling bath is

removed. After standing for 2–3 h 150 ml of Et2O and 150 g of finely crushed

ice are successively added with stirring. After separation of the layers, three

extractions with Et2O are carried out. The organic solution is dried over magne-

sium sulphate and subsequently concentrated under reduced pressure. (Z)-1-

Ethylthio-1-buten-3-yne, bp 64 �C/12 Torr, is obtained in an excellent yield.

20.7.4 1,1-Bis(ethylthio)-2-butyne by zinc chloride-catalysedsubstitution of the ethoxy groups in the correspondingacetal by ethylthio groups

Scale: 0.10 molar; Apparatus: 250 ml two-necked round-bottomed flask

equipped with a mechanical stirrer and a reflux condenser


[13.1.2004–9:54pm] [369–426] [Page No. 415]


20.7.4.1 Procedure

In the flask are placed 0.10 mol of 1,1-diethoxy-2-butyne (Chapter 4, exp.

4.5.23) and 8 g of anhydrous zinc chloride. Freshly distilled ethanethiol (0.30

mol, large excess) is added in 5 portions over 20 min through the reflux con-

denser. After this addition a second portion of 8 g of zinc chloride is added and

the mixture is heated for 30 min in a bath at 45 �C. It is then poured into 100 ml

3 N hydrochloric acid. After vigorous shaking and separation of the layers one

extraction with Et2O is carried out. The organic solution is dried over magne-

sium sulphate and subsequently concentrated under reduced pressure. In order

to absorb the ethanethiol, a tube filled with KOH pellets and a trap cooled at

�70 �C are placed between the water aspirator and the flask containing the

ethereal solution (Note). 1,1-Bis(ethylthio)-2-butyne, bp 80 �C/0.6 Torr, is

obtained in �80% yield.

Note

Attempts to remove the excess of ethanethiol by shaking the ethereal extract

with a KOH solution are likely to result in isomerisation to 1,1-bis

(methylthio)-1,2-butadiene, MeCH¼C¼C(SEt)2.

20.7.5 2-Propyne-1-thiol from propargyl bromide and potassiumhydrosulphide

Scale: 0.30 molar; Apparatus: Figure 1.9, 500 ml; long inlet tube; after intro-

duction of hydrogen sulphide the reaction is carried out under inert gas.

20.7.5.1 Procedure

Hydrogen sulphide is introduced into a vigorously stirred solution of 60 g of

KOH in 60 ml of water. The temperature, initially between 0 and �10 �C, is

gradually lowered to �30 �C. After complete dissolution of the suspended

dipotassium sulphide at this temperature (formation of potassium hydrogen

sulphide) propargyl bromide (0.30 mol) and 200 mg of a radical inhibitor are

added and introduction of inert gas (�200 ml/min) is started. After very

vigorous stirring during 1.5–2 h at �2 to þ2 �C, 50 ml of water (saturated

with inert gas) is added. The layers are separated as completely as possible.

A radical inhibitor (�200 mg) is added to the upper layer and the liquid is

transferred into a 200 ml round-bottomed flask filled with inert gas and

20.7 ACETYLENIC SULPHIDES AND THIOLS 415

[13.1.2004–9:54pm] [369–426] [Page No. 416]


containing a few grams of magnesium sulphate. The flask is equipped for a

vacuum distillation (Figure 1.10), the receiver being cooled in a bath at �70 �C.

The system is evacuated (10–20 Torr) and the flask warmed in a bath gradually

heated to 70–80 �C. Almost pure 2-propyne-1-thiol is collected in the receiver.

The yield is between 40 and 50%. A considerable residue of di(2-propynyl)

sulphide is left behind. Some polymerisation takes place during storage at

�20 �C, even in the presence of a radical inhibitor.

2-Butyne-1-thiol, MeC�CCH2SH, is obtained in >70% yield by a

similar procedure. The mixture of KSH, water and 1-bromo-2-butyne,

MeC�CCH2Br, is stirred for 3 h at �35 �C. There is a small residue of

di(2-butynyl) sulphide.

20.7.6 2-(Propargylthio)thiophene from in situ prepared lithiummercaptothiophene and propargyl bromide

Scale: 0.10 molar; Apparatus: Figure 1.1, without dropping funnel, addition by

syringe.

20.7.6.1 Procedure

Thiophene (0.13 mol) is added in one portion to a solution of 0.10 mol of BuLi

in 63 ml of hexane and 70 ml of THF cooled at �10 �C, after which the cooling

bath is removed. After stirring for an additional 15 min at rt, the solution is

cooled to �35 �C and 3.2 g (0.10 mol) of powdered sulphur is added in a few

seconds. The mixture is stirred for an additional 30 min at �20 �C, then 20 ml

of methanol (Note 1) is added followed by 0.12 mol of propargyl bromide.

After having allowed the temperature rising to between 0� and rt, the reaction

mixture is heated for 30 min at 40 �C. Ice water (200 ml is added and two

extractions with Et2O are carried out. The organic solution is washed with

water and then dried over magnesium sulphate. The liquid remaining after

removal of the solvents under reduced pressure is distilled in a high vacuum,

keeping the temperature of the heating bath below 90 �C (Note 2). 2-Thienyl

propargyl sulphide, bp �50 �C/0.5 Torr, is obtained in an excellent yield.

The reaction with selenium gave the analogous 2-thienyl propargyl selenide,

but with tellurium the allenyl telluride H2C¼C¼CHTe-2-Thienyl was the only

product [47]. This compound is not the result of a base-catalysed isomerisation,

but is formed directly in a 1,3-substitution of bromine.


[13.1.2004–9:54pm] [369–426] [Page No. 417]


Notes

1. The desired product easily isomerises to the allenic sulphide under the

catalytic influence of the thiophenethiolate. This is solvated by methanol

making it less active as a catalyst.

2. At temperatures higher than 100 �C a 3,3-sigmatropic rearrangements sets

in, ultimately resulting in the formation of 2H-thieno[2,3-b]thiopyran [41].

20.8 ACETYLENIC AND ALLENIC SULPHOXIDES, SULPHONES,SULPHINAMIDES AND SULPHONAMIDES

20.8.1 Conversion of 1-ethylthio-1-propyne into the sulphoxide

Scale: 0.05 molar;Apparatus: Figure 1.1, 250 ml, the dropping funnel is omitted.

20.8.1.1 Procedure [27]

Sodium periodate (0.07 mol) is dissolved in 60 ml of water and a mixure of 0.05

mol of 1-ethylthio-1-propyne (Chapter 17, exp. 17.2.14) and 15 ml of MeOH

(Note) is added. The solution is agitated vigorously, while keeping the tem-

perature between 40 and 45 �C (initially rt). After one hour the white suspen-

sion is cooled to rt and 100 ml of water is added. The solution is extracted seven

times with chloroform and the combined extracts are dried (without washing)

over MgSO4. Concentration under reduced pressure (the last traces of CHCl3are removed at <0.1 Torr) gives pure ethyl 1-propynyl sulphoxide, in almost

quantitative yield.

Note

In the cases of the higher homologues, more methanol should be used or the

reaction should be carried out at a higher temperature.

20.8.2 Conversion of 1-ethylthio-1-propyne into the sulphone


20.8 ACETYLENIC AND ALLENIC SULPHOXIDES . . . 417

[13.1.2004–9:54pm] [369–426] [Page No. 418]


Warning: Contact of the skin with 33% H2O2 gives very painful white

spots. Rubber gloves should be worn and the face should be pro-

tected.

20.8.2.1 Procedure (cf. [28])

A mixture of 0.10 mol of 1-ethylthio-1-propyne (Chapter 17, exp. 17.2.14)

and 100 ml of glacial acetic acid is heated to 95 �C, then 36 ml of 33%

hydrogen peroxide is added over 15 min, while keeping the temperature

between 95 and 100 �C. After an additional 1 h the solution is cooled to

rt. Water (200 ml) is added and the solution is extracted ten times with

small portions of chloroform. The combined extracts are dried (without

washing) over MgSO4 and subsequently concentrated under reduced pressure

(see preceding exp.). Ethyl 1-propynyl sulphone is obtained in an excellent

yield.

Di(1-propynyl) sulphone, (MeC�C)2SO2 (mp 103–104.5 �C after crystallisa-

tion from a Et2O–pentane mixture), is prepared in a similar way from di(1-pro-

pynyl) sulphide with a yield of �75%.

20.8.3 Conversion of 1-methylthiopropadiene intomethyl propadienyl sulphoxide

Scale: 0.10 molar; Apparatus: Figure 1.1, 250 ml (without dropping tunnel)

20.8.3.1 Procedure

Amixture of 100 ml of water and 0.10 mol of methylthiopropadiene (Chapter 3,

exp. 3.9.39) is placed in the flask and 24 g of sodium periodate is added in

five portions at intervals of 4 min. The mixture is agitated vigorously and the

temperature is kept between 25 and 30 �C by occasional cooling. After 1 h

twenty extractions with 10-ml portions of chloroform are carried out. The

combined extracts are dried (without preceding washing) over magnesium

sulphate. Removal of the chloroform by evaporation under reduced pressure

gives the reasonably pure (>95%) methyl propadienyl sulphoxide in more

than 90% yield.


[13.1.2004–9:54pm] [369–426] [Page No. 419]


20.8.4 Conversion of 1-methylthio-1,2-pentadiene intomethyl 1,2-pentadienyl sulphoxide

Scale: 0.15 molar; Apparatus: Figure 1.1, 250 ml, without dropping funnel

20.8.4.1 Procedure

A mixture of 0.15 mol of 1-methylthio-1,2-pentadiene (Chapter 3, exp. 3.9.39),

100 ml of water, 40 ml of methanol (Note) and 0.18 mol of NaIO4 is vigorously

stirred. The temperature rises gradually, but is kept between 30 and 35 �C by

occasional cooling. After 1.5 h 500 ml of water is added to the white suspension

and ten extractions with 30-ml portions of chloroform are carried out. The

extracts are dried (without preceding washing) over magnesium sulphate. Eva-

poration of the solvent under reduced pressure (the last traces at 0.5–1 Torr)

gives methyl 1,2-pentadienyl sulphoxide as a viscous oil in almost quantitative

yield (purity �96%). The compound solidifies during storage in a refrigerator.

Note

This co-solvent is used in order to increase the solubility of the allenic sulphide.

20.8.5 Conversion of methyl propadienyl sulphoxideinto methyl propadienyl sulphone

Scale: 0.05 molar; Apparatus: 250-ml flask with a thermometer and a reflux

condenser

20.8.5.1 Procedure

A mixture of 100 ml of glacial acetic acid, 15 ml of 30% hydrogen peroxide and

0.05 mol of allenyl methyl sulphoxide (exp. 3) is heated for 30 min at 100 �C. The

colourless solution is cooled to rt and poured into 300 ml of ice water. The

sulphone is isolated by extracting the solution twelve times with 20-ml portions

of chloroform, drying the combined extracts over NaHCO3 and thoroughly

20.8 ACETYLENIC AND ALLENIC SULPHOXIDES . . . 419

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removing the solvent under reduced pressure. The residue is practically pure

sulphone, yield 80%. The product solidifies during storage for a few days at rt.

20.8.6 Oxidation of 1-alkyne-1-sulphinamideswith 3-chlorobenzenecarboperoxoic acid

Scale: 0.03 molar

20.8.6.1 Procedure [29]

3-Chlorobenzenecarboperoxoic acid (�0.10 mol, large excess) is added

portionwise to an ice-cold solution of N-phenyl-1-hexyne-1-sulphinamide-

(R ¼ n-Bu) in 70 ml of chloroform. After standing overnight at rt, the thick

precipitate of m-chlorobenzoic acid is filtered off. The clear orange solution is

washed with aqueous sodium bicarbonate. After drying over potassium carbo-

nate, the solvent is removed under reduced pressure. The crude N-phenyl-1-

hexyne-1-sulphonamide- is purified by chromatography (SiO2) to give a pale

yellow oil in �70% yield.

20.9 DIMETALLATED ACETYLENIC COMPOUNDS AND THEIRFUNCTIONALISATION

20.9.1 Preparation of dilithiated 2-methyl-1-buten-3-yneand its regioselective functionalisation withc-hexyl bromide and oxirane



[13.1.2004–9:54pm] [369–426] [Page No. 421]


Treatment of 2-methyl-1-buten-3-yne with an excess of BuLi or

BuLi �TMEDA does not give rise to double deprotonation, but to a slow addi-

tion with formation of an adduct. With the super basic reagent BuLi�t-BuOK

in a mixture of THF and hexane, dimetallation can be accomplished in a short

time at low temperatures [30,31]. The high efficiency of the dimetallation

appears from the excellent yield (>90%) of trimethyl[3-(trimethylsilyl)-

methyl]-3-buten-1-ynyl]silane, Me3SiC�CC(CH2SiMe3)¼CH2, obtained by

quenching with Me3SiCl. Addition of anhydrous lithium bromide converts

the dipotassium compound into the dilithio derivative, which can be used for

regiospecific functionalisations.

20.9.1.1 Procedure

A solution of 0.10 mol of freshly distilled 2-methyl-1-buten-3-yne (Chapter 19,

exp. 19.1.1) in 60 ml of THF is cooled to �80 �C (occasional cooling in a

bath with liquid N2). Solutions of 0.22 mol of BuLi in 140 ml of hexane and

0.22 mol of t-BuOK in 60 ml of THF, are successively added over 20 min with

cooling between �75 and �85 �C. A yellow suspension is formed. After stirring

for an additional 30 min at �70 �C, the cooling bath is removed and the

temperature allowed rising to þ5 �C. After an additional 10 min at 5 �C

(Note), a solution of 0.22 mol of anhydrous LiBr in 60 ml of THF is added

at �20 �C with vigorous stirring. The colour of the suspension changes into

light yellow.

Note

The 0.02 mol excess of BuLi�t-BuOK is destroyed by reaction with THF to give

ethene and H2C¼CHOK.

The reaction of dilithiated 2-methyl-1-buten-3-yne with cyclohexyl bromide

is an exceptional case of a successful alkylation with a cyclohexyl halide.

In reactions with most nucleophilic species, dehydrohalogenation is the main

process. Although the reaction conditions for the cyclohexylation are

similar to those of other alkylation reactions, the mechanism might differ

from the usual SN2 mechanism in that a single electron transfer (S.E.T.) is

involved. It is not possible to predict whether the reaction of a particular

nucleophilic species with cyclohexyl halide in an organic solvent or in

liquid ammonia will give a good yield of the cyclohexyl derivative or result

in dehydrohalogenation of the cycloalkyl halide. Reaction with acetylides,

RC�C�, and sp2-nucleophiles, C¼C� (vinylic, aromatic or hetero-aromatic

‘anions’) only give rise to elimination of hydrogen halide.

20.9 DIMETALLATED ACETYLENIC COMPOUNDS 421

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It is shown in Chapter 4 that lithium acetylides do not react at rt with

oxirane in a THF–hexane mixture. In contrast, the allylic site in dilithiated

2-methyl-1-buten-3-yne is smoothly hydroxyethylated at temperatures in the

region of �50 �C.

20.9.1.2 Procedure [40]

Cyclohexyl bromide (0.10 mol) or a mixture of 0.13 mol of oxirane and 30 ml

of THF is added dropwise over 15 min to the suspension of 0.10 mol of

dilithiated 2-methyl-1-buten-3-yne with cooling between �40 and �50 �C.

After an additional 15 min the cooling bath is removed and the temperature

is allowed to rise to 10 �C. Ice water (200 ml) is then added with vigorous

stirring and the layers are separated. The aqueous layer is extracted four and

eight times respectively, with Et2O. The organic solutions are dried (without

washing) over MgSO4 and subsequently concentrated in vacuo. Careful distil-

lation of the remaining liquid through a 30-cm Vigreux column gives: 1-(2-

methylene-3-butynyl)cyclohexane, HC�CC(CH2-c-C6H11)¼CH2, bp 70 �C/

10 Torr, in �70% yield, and 4-methylene-5-hexyn-1-ol, HC�CC(CH2CH2

CH2OH)¼CH2, bp 71 �C/10 Torr, in �90% yield.

20.9.2 Dilithiation of phenylacetylene and subsequentregioselective formylation


Abstraction of a proton remote from the ethynyl group is possible if this

proton is sufficiently activated. Examples are the dimetallations of phenylace-

tylene [32–34], 1-naphthylacetylene [35], 1-ethynylpyrrole [36] and isoprope-

nylacetylene [37,38]. Regioselective functionalisations at the most strongly


[13.1.2004–9:54pm] [369–426] [Page No. 423]


basic centre with a number of electrophiles have been successfully carried

out. Lithiated acetylenes react very slowly at �70 �C with DMF. However,

lithiated arene and hetarene derivatives in most cases add very quickly to

DMF at these low temperatures [39]. A difference in basicity may explain

the specific reaction of the ortho-aryl negative centre in dilithiated phenylace-

tylene with DMF.

20.9.2.1 Procedure

THF (100 ml) is added to a solution of 0.22 mol of butyllithium in 140 ml of

hexane, cooled to �50 �C. Phenylacetylene (0.10 mol) is added over 10 min to

the solution, while keeping the temperature below �20 �C. The solution is then

cooled to �65 �C and a solution of 0.12 mol of potassium tert-butoxide in

100 ml of THF is added dropwise over 30 min, while maintaining the tempera-

ture of the red suspension between �60 and �65 �C. After completion of the

addition, the cooling bath is removed and the temperature is allowed to rise to

0 �C. A solution of 0.13 mol of anhydrous lithium bromide in 40 ml of THF is

then added over a few seconds with vigorous stirring. The colour changes to

pink. The mixture is cooled to �90 �C and DMF (0.15 mol, excess) is added

over 5 min. The mixture is stirred for an additional 10 min at �65 �C, after

which the light-yellow to nearly white suspension is cautiously poured into a

vigorously stirred mixture of 1 litre of ice water and 40 ml of 36% aqueous

HCl. After standing for 15 min, the layers are separated and four extractions

with pentane are carried out. The combined organic solutions are washed with

a saturated solution of NH4Cl and subsequently dried over MgSO4. The light

yellow liquid remaining after removal of the solvent under reduced pressure is

distilled through a 20-cm Vigreux column at oil-pump pressure (1 Torr or less).

The use of an air condenser is recommended. The solid distillate is crystallised

from a 4:1 mixture of pentane and Et2O to give 2-ethynyl benzaldehyde,

mp 67 �C, in �55% yield.

20.10 COPPER(I) BROMIDE-CATALYSED FORMATION OF2-PROPARGYLHETARENES


20.10 COPPER(I) BROMIDE-CATALYSED FORMATION 423

[13.1.2004–9:54pm] [369–426] [Page No. 424]


20.10.1.1 Procedure [42]

A solution of 0.20 mol of 2-thienyllithium in 140 ml of THF and 126 ml of

hexane is prepared from thiophene and BuLi as described [19]. Magnesium

bromide etherate (0.25 mol, Chapter 2, exp. 2.3.10) is added at rt. A solution of

2 g of copper(I) bromide and 4 g of anhydrous lithium bromide in 15 ml of

THF is added at �0 �C, after which the mixture is cooled to �80 to �90 �C.

Propargyl bromide (0.25 mol ) is added dropwise over 15 min at � �90 �C,

then the cooling bath is removed and the temperature of the suspension is

allowed rising to 0 �C. A solution of 20 g of ammonium chloride in 100 ml

of water is cautiously added with vigorous stirring and cooling in an ice-water

bath. The aqueous layer is extracted once with pentane. After drying over

magnesium sulphate, the solvents are removed under reduced pressure (tem-

perature of the water bath not higher than 35 �C). Distillation of the remaining

liquid gives 2-(2-propynyl)thiophene, bp 60 �C/12 Torr, in �75% yield. The

product contains a few percent of the allenic isomer.

The analogous 2-furyl- and 1-methyl-2-pyrrolyl derivatives are prepared by

similar procedures. In the case of the furyl compound, the greater part of the

solvents is distilled off under atmospheric pressure prior to the vacuum distil-

lation. In both cases a small contamination of the allenic isomers is present.

The required Grignard compounds can be prepared via the lithium derivatives

[19] as described above.

Under similar conditions alkylmagnesium halides give practically pure alle-

nic derivatives, while in reactions with arylmagnesium halides comparable

amounts of acetylenic and allenic substitution product are obtained [42]. As

mentioned in Chapter 4, the Cu(I)-catalysed reaction between acetylenic

Grignard compounds and propargyl bromide or tosylate gives predominantly

acetylenic coupling products.

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synthesis of acetylenes, allenes and cumulenes || transformation of functional groups in acetylenic...

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