synthesis of acetylenes, allenes and cumulenes || cross-coupling between 1-alkynes and...

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E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d

14Cross-coupling between 1-Alkynes and

1-Bromo-1-alkynes

14.1 INTRODUCTION

The Cu(I)-catalysed cross-coupling between 1-alkynes and 1-bromoalkynes

was published for the first time in 1957 [1].

This synthesis of unsymmetrically substituted butadiynes is one of the most

useful and versatile methods in acetylenic chemistry [2–5]. This reaction, usually

referred to as Cadiot–Chodkiewicz coupling, has been found particularly

useful in syntheses of naturally occurring poly-unsaturated compounds [6].

About the mechanism little is known. Copper acetylides are likely inter-

mediates.

The present chapter is mainly based on the reviews [1–5] and own experimen-

tal data.

The Cadiot–Chodkiewicz coupling gives access to a wide variety of unsym-

metrically substituted butadiynes, RC�C–C�CR1.

Some hetero-substituted acetylenes do not survive the conditions of the cou-

pling. For example, ethynyl(trimethyl)silane, Me3SiC�CH, and ethynyl(tri-

alkyl)stannanes, R3SnC�CH, undergo C-heteroatom cleavage under the

influence of the amine present in the coupling mixture. However couplings

with 2-bromoethynyl(triethyl)silane, BrC�C–Si(Et)3, have been successfully

carried out [9]. Acetylenic phosphines, R2PC�CH, cannot be used, because

of strong P–Cu complexation.

In the review on this cross-coupling [2] a number of representative asym-

metric couplings reported in literature are arranged according to the nature

of the acetylene RC�CH.

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The thermodynamic acidity of the acetylene (pK) and the ease with which it

couples with the bromoalkyne seem to be related. Acetylenic hydrocarbons

with a non-conjugated triple bond, e.g. 1-hexyne, HC�Cn-Bu, are less reactive

than arylacetylenes, e.g. ethynylbenzene, PhC�CH, presumably because the

intermediary copper alkynylides, e.g. n-BuC�CCu, are formed less easily.

Whereas PhC�CH and 1-bromo-1-butyne, EtC�CBr, gave the unsymmetrical

acetylene 1-phenyl-1,3-hexadiyne, PhC�CC�CEt, in a good (� 70%) yield,

1-(2-bromoethynyl)benzene, PhC�CBr, and 1-butyne, EtC�CH, reacted

under similar conditions to give the unsymmetrical and symmetrical product

diphenylbutadiyne, PhC�CC�CPh, in comparable amounts. From the

reaction (at �30 �C) between 1-octyne, C6H13C�CH, and 1-bromo-1-butyne,

EtC�CBr, the coupling product 3,5-dodecadiyne, C6H13C�CC�CEt, was

isolated in a modest (� 50%) yield [10]. The formation of appreciable amounts

of homo-coupling products may become a serious problem in larger-scale

preparations of RC�CC�CR1 in which both R and R1 contain long carbon

chains.

We succeeded in obtaining good (>65%) yields of cross-coupling products

from EtC�CBr and the alcohols HC�C(CH2)nOH with n ¼ 1, 2, 4, 5 and 7 by

carrying out the reactions at suitable temperatures (see Table 14.1). However

10-undecyn-1-ol, HC�C(CH2)9OH, and bromobutyne gave yields of maxi-

mally 45% and � 25% of 10,12-pentadecadiyn-1-ol, EtC�CC�C(CH2)9OH,

when performed at 30 to 35 �C and 15 to 20 �C, respectively, homo-coupling

of EtC�CBr being the main reaction. An unfavourable factor in the case of

HC�C(CH2)9OH might be the slight solubility of the copper derivative,

which appears as a white suspension upon addition of copper(I) halide.

Most of the other acetylenic derivatives investigated form almost colourless

solutions with copper(I) halide.

The presence of an alcoholic function in the acetylene is said to be favour-

able, whereas variations in the structure of the bromoacetylene, R1C�CBr, are

reported to have little influence upon the results.

In the general procedure the bromoacetylene (mixed with a solvent) is

added dropwise to a well-stirred mixture of the acetylene, water or an organic

solvent, aqueous ethylamine, hydroxylamine �HCl and a catalytic quantity

(1 to 5 mol%) of copper(I)chloride or bromide. The ethylamine serves to neu-

tralise the hydrobromic acid produced in the coupling. The use of a large

(� 70 mol%) excess is recommended [2]. If the acetylene contains a COOH

group, more ethylamine has to be used. Bromoacetylenes containing a

COOH group are most conveniently added as a solution of their sodium

or ethylamine salts.

The function of the hydroxylamine salt is to reduce any Cu(II), which might

be formed by the presence of traces of oxygen, to Cu(I), and which may give

rise to oxidative dimerisation of the acetylene RC�CH.

274 14. CROSS-COUPLING BETWEEN 1-ALKYNES . . .

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Methanol, ethanol and water are the most frequently used solvents. For

reactions with compounds that are slightly soluble in these solvents, diethyl

ether, tetrahydrofuran, N,N-dimethylformamide or N-methyl-2-pyrrolidinone

may be used.

The coupling reaction is usually very fast at concentrations of the order of

0.5 to 1 mol/litre and can be easily followed by observation of the heating

effect. Most couplings in the presence of ethylamine proceed at a convenient

rate within the temperature range 10–35 �C, but the rate may decrease strongly

if the temperature is lowered by 10 to 20 degrees. ‘Optimum temperatures’

depending upon the nature of the acetylene are recommended [2]. These are

15–25 �C for non-conjugated acetylenes, RC�CH, and 30 �C for enynes,

RCH¼CHC�CH, and diynes, RC�CC�CH.

If the product is neutral or contains weakly basic groups (NH2, R2N), a

small amount of alkali cyanide is added prior to carrying out the work-up.

This converts Cu(I) into the inactive complex. If relatively much methanol

or ethanol has been used, it seems practical to remove these solvents under

reduced pressure before carrying out the extraction procedure. Carboxylic

acids can be isolated after treatment with mineral acid. After addition of the

bromoacetylene (no cyanide should be added!) methanol or ethanol are

removed in vacuo, the neutral by products that might have formed are removed

by extraction. Finally, dilute acid is added to liberate the coupling product.

1-Bromo-1-acetylenes are far more reactive than 1-chloro-1-acetylenes, while

1-iodo-1-acetylenes have not been used because they very readily undergo

homo-coupling. However, some examples of successful cross-couplings

between 1-iodoacetylenes and acetylenic compounds have been reported

more recently [7,8]. Conditions similar to the ones applied for coupling

between acetylenes and sp2 halides (Chapter 16) were applied.

An unsymmetrically substituted compound RC�CC�CR1 can, in principle,

be obtained by two alternative couplings:

The decision about the alternative to be followed depends upon a number of

factors, such as yield, accessibility and stability of the reaction partners and

ease of purification of the product. If, for example, 1-phenyl-1,3-hexadiyne,

PhC�CC�CEt, is to be prepared, route a is preferred (PhC�CHþ

BrC�CEt), since couplings with more acidic acetylenes give better results.

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For the preparation of, for example HOCMe2CC�C�CCH2NMe2, the

combination of BrC�CCMe2OH and HC�CCH2NMe2 is better than

HC�CCMe2OHþBrC�CCH2NMe2, since the latter bromide is expected to

be very unstable.

Under the catalytic influence of Cu(I) the bromoacetylene may be converted

into the symmetrical product (homo-coupling):

Cu2þ is reduced to Cuþ by the hydroxylamine present in the solution.

Ammonia is said to favour this homo-coupling, whereas primary amines

repress it. The possibility of this undesired reaction can be further reduced

by using Cu(I) salts in small amounts, by slow addition of the bromoacetylene

with efficient stirring and by a careful control of the operating temperature

(low is better, but not always).

The use of large amounts of primary amine (more than the usual excess)

involves the risk of addition across the triple bond of the bromoacetylene [3].

14.2 EXPERIMENTAL SECTION

Note: All reactions are carried out under inert gas.

14.2.1 General remarks and some observations

We have carried out several couplings on a 0.05 to 0.10 molar and in some

cases larger scale with readily available 1-bromo-1-alkynes and acetylenes

(Table 14.1). The amount of copper halide (we always used copper(I) bromide)

was ca. 5 mol%, while ethylamine was used in a large excess (15 g 70%

aqueous solution for 0.10 molar-scale reactions). The solvent for our reactions

was methanol. For the coupling of propargyl alcohol with the lower bromo-

alkynes we also did experiments with water–methanol mixtures, but the results

were similar to those obtained with methanol as the only solvent. The

bromoalkyne was added as a solution in methanol.

The reaction can be easily followed by temperature observation, provided

that the concentration of the acetylene, R1C�CH, is not too low (between

0.5 and 1 mol/litre). Addition of a few drops of a methanolic solution of

bromoalkyne to a mixture of the acetylenic partner, methanol and the other


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reagents usually causes the temperature to rise by several degree celsius within

the temperature range 10–40 �C. When the addition is stopped, the

temperature does not further rise. The couplings with propargyl alcohol are

exceptions on this rule: the heating effect during addition of the bromoalkyne

is weak below 40 �C. This lower reactivity might be due to a poor solubility of

the copper acetylide, CuC�CCH2OH. It appears as a yellow suspension upon

addition of the copper halide. In couplings with 1-butyne and its homologues

also a yellow suspension or tubidity was visible, but in these cases the heating

effect was strong. It is, in general, advisable to carry out the reactions at

temperatures as low as possible, but with maintenance of the prompt tempera-

ture response after addition of a small amount of the bromoalkyne or after

interruption of the addition. It seems furthermore important to stir efficiently

during the addition of the acetylenic bromide, as too high concentrations of

this may give rise to homo-coupling. It may be noted from the table that the

results of some couplings can be considerably improved if carried out at

lower temperatures. Higher temperatures may be more favourable when the

intermediary copper acetylide has a low solubility.

Another possibility to improve results is to use excess of the bromoalkyne, or

of the acetylene if this is readily accessible or cheap, e.g. 2-propyn-1-ol,

HC�CCH2OH, and 2-methyl-3-butyn-2-ol, HC�CC(Me)2OH. In the case of

acetylenic alcohols with a long carbon chain one may decide to use an excess

of the bromoalkyne in the hope that the alcohol will be completely converted

into the desired product, thus circumventing a laborious purification procedure.

14.2.2 General procedure for the Cadiot–Chodkiewicz coupling

Scale: 0.10 molar; Apparatus: 250-ml round-bottomed, three-necked flask

equipped with a dropping funnel, gas inlet and thermometer-outlet combina-

tion; magnetic stirring.

14.2.2.1 Procedure

In the flask are placed 0.10 mol of the acetylenic derivative, 15 g of a 70%

aqueous solution of ethylamine (EtNH2), 5 g of hydroxylamine �HCl and 50 ml

of methanol. The air in the flask is thoroughly replaced by inert gas, then 0.7 g

of finely powdered copper(I) bromide is added. In the case of propargyl alcohol

and aliphatic 1-alkynes and some other acetylenes a yellow suspension is

formed, while 1,3-diynes may give a red suspension. A mixture of 0.10 mol

of the bromoalkyne (Chapter 9) and 25 ml of methanol is added dropwise over

40 min with efficient stirring and maintaining the temperature at the level

indicated in Table 14.1 (occasional cooling in ice). Ten minutes after the

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addition, a solution of 2 g of NaCN or KCN in 10 ml of water is introduced.

After removing the greater part of the methanol on the rotary evaporator, the

remaining liquid is extracted with Et2O. After drying over magnesium sulphate

or potassium carbonate (in the case of amino compounds) and concentration

of the solution under reduced pressure, the remaining liquids are distilled in a

vacuum. Products with systems of more than two conjugated triple bonds

should not be distilled.

Table 14.1

Cadiot–Chodkiewicz cross-couplingsa

Reactants Temp.

(in �C)

Yield

(in %)

Add. time

(in hours)

% Excess

RC�CH

C6H13C�CH, BrC�CEt 30–35 or 55

15–20

PhC�CH, BrC�CEt 44–48 70 1 20

EtC�CH, BrC�CPh 25–30 45

HOCH2C�CH, BrC�CEt 45–50 86 1 20

HOCH2C�CH, BrC�CEt 25–45 71 0.75 20

HOC(Me)2C�CH, BrC�CEt 20–25 81 20

HO(CH2)2C�CH, BrC�CEt 25–28 74 20

HO(CH2)2C�CH, BrC�CEt 9–11 87 20

HO(CH2)4C�CH, BrC�CEt 15–17 69 15

HO(CH2)4C�CH, BrC�CEt 28–32 57 15

HO(CH2)4C�CH, BrC�CEt 42–47 45


HO(CH2)9C�CH, BrC�CEt 45–50 36 15



ROCH2C�CH, BrC�CC5H11b 30–35 >80

EtSCH2C�CH, BrC�CEt 15–18 80 1

EtSCH2C�CH, BrC�CEt 40–45 70 1

Et2NCH2C�CH, BrC�CEt 30–35 >80

RO(CH2)2C�CH, BrC�CEtb 17–20 74

5% excess EtC�CBr

RO(CH2)4C�CH, BrC�CEt 17–20 80

Et2N(CH2)2C�CH, BrC�CEt 25–30 <10 15

Et2N(CH2)2C�CH, BrC�CEt 10–13 55 15

(EtO)2CHC�CH, BrC�CEt 24–27 77 20

EtSCH¼CHC�CH, BrC�C–t-Bu 30–35 >80c

H2NC(Me)2C�CH, BrC�CEt 37–40 43c 1.2

H2NC(Me)2C�CH, BrC�CEt 11–13 67c 1.2

aReactions carried out in the author’s laboratory on a scale of at least 50 mmol;

products were isolated by fractional distillation at 10 to 15 Torr, products with long

carbon chains in a high vacuum. For other couplings see the Refs. [1,2].bR ¼ OCH(Me)OEt.cUndistilled products, purity � 95%.


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REFERENCES

1. W. Chodkiewicz, Ann. de Chimie (Paris), 819 (1957).

2. P. Cadiot and W. Chodkiewicz, in Chemistry of Acetylenes (ed. H. G. Viehe). Marcel Dekker,

New York, 1969, p. 597.

3. G. Eglinton andW. McCrae, in Adv. in Org. Chem. Interscience Publ., New York, 1963, Vol. 4,

p. 252.

4. T. F. Rudledge, Acetylenic Compounds. Reinhold Book Corp., New York, 1968, p. 256.

5. U. Niedballa, in Houben-Weyl, Methoden der Organischen Chemie, Band 5/2a. Thieme-Verlag,

Stuttgart, 1977, p. 931.

6. F. Bohlmann, C. Zdero, H. Bethke and D. Schumann, Chem. Ber. 100, 1553 (1968).

7. J. Wityak and J. B. Chan, Synth. Commun. 21, 977 (1991).

8. G. Linstrumelle, personal communication.

9. R. Eastmond, D. R. M. Walton, J. Chem. Soc., Chem. Comm., 204 (1968).

10. Unpublished results and observations from the author’s laboratory.

REFERENCES 279

synthesis of acetylenes, allenes and cumulenes || cross-coupling between 1-alkynes and...

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