synthesis of acetylenes, allenes and cumulenes || cross-coupling between 1-alkynes and...
Post on 23-Dec-2016
214 Views
Preview:
TRANSCRIPT
[13.1.2004–9:57pm] [273–280] [Page No. 273]
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.
273
[13.1.2004–9:57pm] [273–280] [Page No. 274]
E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d
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 . . .
[13.1.2004–9:57pm] [273–280] [Page No. 275]
E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d
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.
14.1 INTRODUCTION 275
[13.1.2004–9:57pm] [273–280] [Page No. 276]
E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d
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
276 14. CROSS-COUPLING BETWEEN 1-ALKYNES . . .
[13.1.2004–9:57pm] [273–280] [Page No. 277]
E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d
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
14.2 EXPERIMENTAL SECTION 277
[13.1.2004–9:57pm] [273–280] [Page No. 278]
E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d
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)7C�CH, BrC�CEt 25–30 64
HO(CH2)9C�CH, BrC�CEt 45–50 36 15
HO(CH2)9C�CH, BrC�CEt 35–40 45
HO(CH2)9C�CH, BrC�CEt 15–20 25
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%.
278 14. CROSS-COUPLING BETWEEN 1-ALKYNES . . .
[13.1.2004–9:57pm] [273–280] [Page No. 279]
E:/Archive files/4188-Brandsma/Printer-Files/4188-Chapter-14.3d
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
top related