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Cross-coupling between 1-Alkynes and 1-Bromo-1-alkynes
14 Cross-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 intermediates. The present chapter is mainly based on the reviews [1–5] and own experimental data. The Cadiot–Chodkiewicz coupling gives access to a wide variety of unsymmetrically substituted butadiynes, RCC–CCR1. Some hetero-substituted acetylenes do not survive the conditions of the coupling. For example, ethynyl(trimethyl)silane, Me3SiCCH, and ethynyl(trialkyl)stannanes, R3SnCCH, undergo C-heteroatom cleavage under the influence of the amine present in the coupling mixture. However couplings with 2-bromoethynyl(triethyl)silane, BrCC–Si(Et)3, have been successfully carried out [9]. Acetylenic phosphines, R2PCCH, cannot be used, because of strong P–Cu complexation. In the review on this cross-coupling [2] a number of representative asymmetric couplings reported in literature are arranged according to the nature of the acetylene RCCH. 273
274
14.
CROSS-COUPLING BETWEEN 1-ALKYNES . . .
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, HCCn-Bu, are less reactive than arylacetylenes, e.g. ethynylbenzene, PhCCH, presumably because the intermediary copper alkynylides, e.g. n-BuCCCu, are formed less easily. Whereas PhCCH and 1-bromo-1-butyne, EtCCBr, gave the unsymmetrical acetylene 1-phenyl-1,3-hexadiyne, PhCCCCEt, in a good ( 70%) yield, 1-(2-bromoethynyl)benzene, PhCCBr, and 1-butyne, EtCCH, reacted under similar conditions to give the unsymmetrical and symmetrical product diphenylbutadiyne, PhCCCCPh, in comparable amounts. From the reaction (at 30 C) between 1-octyne, C6H13CCH, and 1-bromo-1-butyne, EtCCBr, the coupling product 3,5-dodecadiyne, C6H13CCCCEt, 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 RCCCCR1 in which both R and R1 contain long carbon chains. We succeeded in obtaining good (> 65%) yields of cross-coupling products from EtCCBr and the alcohols HCC(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, HCC(CH2)9OH, and bromobutyne gave yields of maximally 45% and 25% of 10,12-pentadecadiyn-1-ol, EtCCCC(CH2)9OH, when performed at 30 to 35 C and 15 to 20 C, respectively, homo-coupling of EtCCBr being the main reaction. An unfavourable factor in the case of HCC(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 favourable, whereas variations in the structure of the bromoacetylene, R1CCBr, 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 neutralise 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 RCCH.
14.1
INTRODUCTION
275
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, RCCH, and 30 C for enynes, RCH¼CHCCH, and diynes, RCCCCH. 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 RCCCCR1 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, PhCCCCEt, is to be prepared, route a is preferred (PhCCH þ BrCCEt), since couplings with more acidic acetylenes give better results.
276
14.
CROSS-COUPLING BETWEEN 1-ALKYNES . . .
For the preparation of, for example HOCMe2CCCCCH2NMe2, the combination of BrCCCMe2OH and HCCCH2NMe2 is better than HCCCMe2OH þ BrCCCH2NMe2, 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 bromoalkynes 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, R1CCH, 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
14.2
EXPERIMENTAL SECTION
277
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, CuCCCH2OH. 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 temperature 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, HCCCH2OH, and 2-methyl-3-butyn-2-ol, HCCC(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 combination; 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
278
14.
CROSS-COUPLING BETWEEN 1-ALKYNES . . . Table 14.1
Cadiot–Chodkiewicz cross-couplingsa Reactants C6H13CCH, BrCCEt PhCCH, BrCCEt EtCCH, BrCCPh HOCH2CCH, BrCCEt HOCH2CCH, BrCCEt HOC(Me)2CCH, BrCCEt HO(CH2)2CCH, BrCCEt HO(CH2)2CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)7CCH, BrCCEt HO(CH2)9CCH, BrCCEt HO(CH2)9CCH, BrCCEt HO(CH2)9CCH, BrCCEt ROCH2CCH, BrCCC5H11b EtSCH2CCH, BrCCEt EtSCH2CCH, BrCCEt Et2NCH2CCH, BrCCEt RO(CH2)2CCH, BrCCEtb 5% excess EtCCBr RO(CH2)4CCH, BrCCEt Et2N(CH2)2CCH, BrCCEt Et2N(CH2)2CCH, BrCCEt (EtO)2CHCCH, BrCCEt EtSCH¼CHCCH, BrCC–t-Bu H2NC(Me)2CCH, BrCCEt H2NC(Me)2CCH, BrCCEt
Temp. (in C) 30–35 or 15–20 44–48 25–30 45–50 25–45 20–25 25–28 9–11 15–17 28–32 42–47 25–30 45–50 35–40 15–20 30–35 15–18 40–45 30–35 17–20 17–20 25–30 10–13 24–27 30–35 37–40 11–13
Yield (in %)
Add. time (in hours)
% Excess RCCH
1
20
1 0.75
20 20 20 20 20 15 15
55 70 45 86 71 81 74 87 69 57 45 64 36 45 25 >80 80 70 >80 74 80 <10 55 77 >80c 43c 67c
15
1 1
15 15 20 1.2 1.2
a Reactions 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]. b R ¼ OCH(Me)OEt. c Undistilled products, purity 95%.
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.
REFERENCES
279 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 and W. 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.
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 intermediates. The present chapter is mainly based on the reviews [1–5] and own experimental data. The Cadiot–Chodkiewicz coupling gives access to a wide variety of unsymmetrically substituted butadiynes, RCC–CCR1. Some hetero-substituted acetylenes do not survive the conditions of the coupling. For example, ethynyl(trimethyl)silane, Me3SiCCH, and ethynyl(trialkyl)stannanes, R3SnCCH, undergo C-heteroatom cleavage under the influence of the amine present in the coupling mixture. However couplings with 2-bromoethynyl(triethyl)silane, BrCC–Si(Et)3, have been successfully carried out [9]. Acetylenic phosphines, R2PCCH, cannot be used, because of strong P–Cu complexation. In the review on this cross-coupling [2] a number of representative asymmetric couplings reported in literature are arranged according to the nature of the acetylene RCCH. 273
274
14.
CROSS-COUPLING BETWEEN 1-ALKYNES . . .
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, HCCn-Bu, are less reactive than arylacetylenes, e.g. ethynylbenzene, PhCCH, presumably because the intermediary copper alkynylides, e.g. n-BuCCCu, are formed less easily. Whereas PhCCH and 1-bromo-1-butyne, EtCCBr, gave the unsymmetrical acetylene 1-phenyl-1,3-hexadiyne, PhCCCCEt, in a good ( 70%) yield, 1-(2-bromoethynyl)benzene, PhCCBr, and 1-butyne, EtCCH, reacted under similar conditions to give the unsymmetrical and symmetrical product diphenylbutadiyne, PhCCCCPh, in comparable amounts. From the reaction (at 30 C) between 1-octyne, C6H13CCH, and 1-bromo-1-butyne, EtCCBr, the coupling product 3,5-dodecadiyne, C6H13CCCCEt, 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 RCCCCR1 in which both R and R1 contain long carbon chains. We succeeded in obtaining good (> 65%) yields of cross-coupling products from EtCCBr and the alcohols HCC(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, HCC(CH2)9OH, and bromobutyne gave yields of maximally 45% and 25% of 10,12-pentadecadiyn-1-ol, EtCCCC(CH2)9OH, when performed at 30 to 35 C and 15 to 20 C, respectively, homo-coupling of EtCCBr being the main reaction. An unfavourable factor in the case of HCC(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 favourable, whereas variations in the structure of the bromoacetylene, R1CCBr, 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 neutralise 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 RCCH.
14.1
INTRODUCTION
275
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, RCCH, and 30 C for enynes, RCH¼CHCCH, and diynes, RCCCCH. 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 RCCCCR1 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, PhCCCCEt, is to be prepared, route a is preferred (PhCCH þ BrCCEt), since couplings with more acidic acetylenes give better results.
276
14.
CROSS-COUPLING BETWEEN 1-ALKYNES . . .
For the preparation of, for example HOCMe2CCCCCH2NMe2, the combination of BrCCCMe2OH and HCCCH2NMe2 is better than HCCCMe2OH þ BrCCCH2NMe2, 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 bromoalkynes 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, R1CCH, 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
14.2
EXPERIMENTAL SECTION
277
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, CuCCCH2OH. 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 temperature 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, HCCCH2OH, and 2-methyl-3-butyn-2-ol, HCCC(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 combination; 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
278
14.
CROSS-COUPLING BETWEEN 1-ALKYNES . . . Table 14.1
Cadiot–Chodkiewicz cross-couplingsa Reactants C6H13CCH, BrCCEt PhCCH, BrCCEt EtCCH, BrCCPh HOCH2CCH, BrCCEt HOCH2CCH, BrCCEt HOC(Me)2CCH, BrCCEt HO(CH2)2CCH, BrCCEt HO(CH2)2CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)4CCH, BrCCEt HO(CH2)7CCH, BrCCEt HO(CH2)9CCH, BrCCEt HO(CH2)9CCH, BrCCEt HO(CH2)9CCH, BrCCEt ROCH2CCH, BrCCC5H11b EtSCH2CCH, BrCCEt EtSCH2CCH, BrCCEt Et2NCH2CCH, BrCCEt RO(CH2)2CCH, BrCCEtb 5% excess EtCCBr RO(CH2)4CCH, BrCCEt Et2N(CH2)2CCH, BrCCEt Et2N(CH2)2CCH, BrCCEt (EtO)2CHCCH, BrCCEt EtSCH¼CHCCH, BrCC–t-Bu H2NC(Me)2CCH, BrCCEt H2NC(Me)2CCH, BrCCEt
Temp. (in C) 30–35 or 15–20 44–48 25–30 45–50 25–45 20–25 25–28 9–11 15–17 28–32 42–47 25–30 45–50 35–40 15–20 30–35 15–18 40–45 30–35 17–20 17–20 25–30 10–13 24–27 30–35 37–40 11–13
Yield (in %)
Add. time (in hours)
% Excess RCCH
1
20
1 0.75
20 20 20 20 20 15 15
55 70 45 86 71 81 74 87 69 57 45 64 36 45 25 >80 80 70 >80 74 80 <10 55 77 >80c 43c 67c
15
1 1
15 15 20 1.2 1.2
a Reactions 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]. b R ¼ OCH(Me)OEt. c Undistilled products, purity 95%.
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.
REFERENCES
279 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 and W. 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.