Effect of varying the anionic component of a copper(I) catalyst on homologation of arylacetylenes to allenes by the Mannich reaction

Article abstract of DOI:10.1002/ejoc.200700859

The effect of varying the anionic component of a copper(I) catalyst in the homologation of terminal arylacetylenes to allenes by the Mannich reaction was investigated. Varying amounts of allenes, Mannich bases and dimers were obtained depending on the nature of the anionic component of the copper catalyst. On the other hand, Eglinton-Glaser dimerizations were achieved in high yields with 0.5 equiv. of triethylamine. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700859

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700859
Effect of Varying the Anionic Component of a Copper(I) Catalyst on
Homologation of Arylacetylenes to Allenes by the Mannich Reaction
Vipan Kumar,[a] Alex Chipeleme,[a] and Kelly Chibale*[a,b]
Keywords: Allene / Homologation / Mannich reaction / Copper(I) catalyst / Alkyne dimerization
The effect of varying the anionic component of a copper(I)
catalyst in the homologation of terminal arylacetylenes to all-
enes by the Mannich reaction was investigated. Varying
of the copper catalyst. On the other hand, Eglinton–Glaser
dimerizations were achieved in high yields with 0.5 equiv. of
triethylamine.
amounts of allenes, Mannich bases and dimers were ob- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tained depending on the nature of the anionic component
Germany, 2008)
Introduction
Results and Discussion
Our interest in the synthesis of biologically active aryl
acetylenic Mannich bases led us to explore the homologa-
tion of aryl acetylenes to allenes. In this letter, we report
the effect of varying the anionic component of the copper(I)
catalyst and the nature of the aryl substituent on the prod-
uct and yield distribution.
The synthesis of allenes from terminal alkynes was at-
tempted by employing various sources of copper(I) catalyst
with different anionic components. Initially, the arylacetyl-
enes 1a, 1b, 1c, and 1d were treated with diisopropylamine
and paraformaldehyde in the presence of CuIBr under
modified reaction conditions described by Crabbe and co-
workers to afford the allenes 2a–d, the Mannich bases 3a–
d and homocoupling products 4b and 4d (Scheme 1). The
results are presented in Table 1.
The two cumulated double bonds of allenes represent a
versatile functional group that can be utilized in a variety
of synthetic transformations, leading to complex structures
that are useful for constructing natural and nonnatural
products.[1] The versatility and synthetic utility of the allene
moiety in organic chemistry have been extensively docu-
mented in the recent literature. For instance, allenes partici-
pate in a variety of cycloaddition and electrocyclic reactions
affording products such as sterpurenes that are not easily
accessible by other synthetic methods.[2,3] In addition, the
allene moiety can be transformed into a variety of other
functional groups such as olefins, α,β-unsaturated carbonyl
compounds and alkynes.[4] Moreover, allene axial chirality
has been used to transfer asymmetry in cycloaddition reac-
tions.[5]
Allenes have also received considerable attention due to
the discovery of interesting biological properties[6,7] as well
as to the development of improved synthetic methods.
Homologation of acetylenes to allenes by the Mannich
reaction has been previously reported.[8–13] However, these
reports have only addressed a limited range of acetylene
systems. In addition, effects of the nature of aryl substitu-
ents as well as variation of the catalyst component on the
pattern of product and yield distribution have to date not
been investigated.
[a] Department of Chemistry, University of Cape Town,
Rondebosh, 7701, South Africa
Scheme 1. CuI-catalyst-mediated reaction of arylacetylene 1a–1d
with paraformaldehyde, N,N-diisopropylamine in dry dioxane.
[b] Institute of Infectious Disease and Molecular Medicine, Uni-
versity of Cape Town,
Rondebosh, 7701, South Africa
The reactions were repeated in the presence of CuIICl as
a source of CuI. A similar product and yield distribution as
those with CuIBr were obtained. When the source of CuI
Fax: +27-21-689-7499
E-mail: Kelly.Chibale@uct.ac.za
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 43–46
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
43

V. Kumar, A. Chipeleme, K. Chibale
SHORT COMMUNICATION
Table 1. CuIBr/CuIICl/CuIIOAc-catalyzed reaction of 1a–d with di- nent is attached to the β-carbon of the α,β-unsaturated car-
isopropylamine and paraformaldehyde.
bonyl system may be explained on electronic grounds. In
studies carried out by Bohlmann et al.[15] on the rate of
dimerization as influenced by the electronic nature of con-
jugated acetylenes, they found that more acidic acetylenes
underwent more rapid dimerization under alkaline condi-
tions, which was consistent with results obtained by Kleb-
ansky et al.[16] However, under acidic conditions, an inverse
relationship was observed, and addition of a copper(I) salt
became necessary. This is also in a agreement with the re-
cent results obtained by Balcioglu et al.[17]
was substituted by CuIIOAc, only the Mannich bases 3a–d
and homocoupling products 4b and 4d were obtained as
products. From the results in Table 1, it is clear that the
product and yield distribution are influenced by both the
anionic component of the catalyst and the nature of the aryl
substituent. Comparable yields are obtained for catalysts
[(CuBr and CuIICl)] which gave same product composition. Scheme 2. Mechanism of allene formation in CuBr-catalyzed reac-
tions.
The different behaviour of aldehyde 1a and ketone 1b was
somewhat surprising with the former not giving any dimer-
In order to investigate the generality of our initial obser-
ization product. The stronger electron-withdrawing effect of
vations, the reactions were investigated with a diverse range
the aldehyde carbonyl in 1a may lead to weaker complex-
of simple substituted aryl acetylenes. The reaction of the
ation with the CuI ion and hence a slower rate of dimeriza-
acetylenes 9 with paraformaldehyde and diisopropylamine
tion due to a decrease in nucleophilicity of the intermediate
in the presence of CuIBr as catalyst in refluxing dry dioxane
acetylide ion. This is contrast to 1b in which the possible
led to the exclusive formation of the corresponding Man-
existence of the ketone in enolic form under the reaction
nich adducts with no traces of the homologated product or
conditions may lead to stronger complexation with the CuI
allenes as evidenced by their crude 1H and 13C spectro-
ion. The absence of allenes from copper(II)-acetate-cata-
scopic data (Scheme 3). Similar trends in yields as well as
lyzed reactions may be explained by considering the mecha-
the product distribution were observed using CuIICl as cat-
nism for the formation of allenes from Mannich bases. The
alyst (Table 2).
mechanism involves an intramolecular transfer of an α-hy-
drogen atom in an N-alkyl group of the intermediate Man-
nich base, to the carbon terminus of the allene. First, the
copper(I) forms a 1:1 π complex 5 with the Mannich base
in which the hydrogen is well positioned to be lost from the
α-position of an isopropyl group (Scheme 2). Hydride ion
shift occurs to give a hydridocopper(I) complex 6 which is
similar to the cuprate complex as postulated by Pasto and
co-workers for the reaction of a lithium cuprate with prop-
2-ynylic halides.[14] Then, rotation of the copper atom takes
place making the hydrogen available for transfer to the R-
substituted terminus of the alkyne and electronic shifts to
the allene 8, thus releasing the diisopropylimine and the
Scheme 3. CuI-catalyst-mediated reaction of arylacetylene 9a–9g
with paraformaldehyde, N,N-diisopropylamine in dry dioxane.
catalyst. Formation of 7 (Scheme 2) may not have occurred
However, when the above reactions were carried out
due to structural reasons (steric effects) when the acetate using Cu(OAc)2, formation of Mannich adducts was ac-
ion is the anionic component of the copper(I) catalyst gen- companied by concomitant homologation (Scheme 3). The
erated in situ. The bulky carboxylate ion may have pre- product distribution depended upon the nature of the sub-
vented rotation of the copper atom from delivering the hy- stituent on the aromatic ring of aryl acetylenes with the
drogen in a favorable position for transfer to the R-substi- better yields of the homologated adducts being obtained
tuted terminus of the alkyne. On the other hand the absence with the introduction of electron-donating substituents
of homocoupling products when the aryl acetylenic compo- (Table 3).
44
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Eur. J. Org. Chem. 2008, 43–46

Homologation of Arylacetylenes to Allenes
Table 2. CuIBr- and CuIICl-catalyzed reaction of 9a–g with diiso- aryl acetylenic component attached to β-carbon of the α,β-
propylamine and paraformaldehyde.
unsaturated carbonyl system) gave low yields compared to
their counterparts 1b and 1d.
R
Products (% yield)
CuIBr
CuIICl
9a
9b
9c
9d
9e
9f
H
p-CH3
Br
p-OCH3
o-OCH3
o-NO2
p-CN
10a (82)
10b (86)
10c (73)
10d (78)
10e (75)
10f (68)
10g (69)
10a (80)
10b (78)
10c (74)
10d (71)
10e (69)
10f (71)
10g (65)
Scheme 4. Homodimerization reaction of 1a–1d.
9g
Table 4. Cu(OAc)2-catalyzed dimerization of 1a–d.
Table 3. Cu(OAc)2-catalyzed reaction of 9a–g with diisopropyl-
amine and paraformaldehyde.
Product (% yield)
1a
1b
1c
1d
4a (32)
4b (72)
4c (62)
4d (99)
Compd.
R
Products (% yield)
9a
9b
9c
9d
9e
9f
H
p-CH3
p-Br
o-OCH3
p-OCH3
o-NO2
p-CN
10a (57)
10b (61)
10c (60)
10d (54)
10e (51)
10f (64)
10g (62)
11a (21)
11b (19)
11c (16)
11d (26)
11e (23)
11f (12)
11g (13)
9g
Conclusions
In conclusion, the product composition depends on both
the nature of the aryl substituent and the anionic compo-
nent of the catalyst. Low yields of homocoupling products
were obtained from substrates with electron-withdrawing
groups due to weaker complexation with CuI ion which
leads to slow formation of the homodimers compared to
the Mannich bases. The yields of homocoupling products
also decrease as the strength of the electron-withdrawing
group increases due to the decrease in the nucleophilicity of
the intermediate acetylide ion. On the other hand, the cata-
lyst, Cu(OAc)2, with a bulky nonlinear anionic component
does not give allene products presumably because the car-
boxylate ion prevents rotation of the copper atom from de-
livering the hydrogen in a favorable position for transfer to
the R-substituted terminus of the alkyne. Cu(OAc)2 in the
presence of 0.5 equiv. of triethylamine mediated the forma-
tion of homodimers in a superior manner to the typical
Eglinton–Glaser coupling conditions.
Because the mechanism (Scheme 2) involves the forma-
tion of a π complex between CuI ion and the triple bond,
thus activating the alkyne toward deprotonation by the
amine to generate a copper acetylide, the low yields in the
experiments involving electron-withdrawing groups may be
due to the low nucleophilicity of the generated acetylides.
The rate of reaction of substrates with electron-withdrawing
groups attached to the aryl acetylenic component was
slower than those with electron-donating groups. Because
dimerization reactions were competing with Mannich base
formation, the yields of homocoupling adducts were usually
lower than for the corresponding Mannich base adducts.
The absence of allene formation in these reactions is sup-
ported by earlier observations reported by Crabbé and co-
workers in the homologation reactions of alk-1-ynes to all-
enes.[18] A remarkable decrease in the reactivity of alkynes
with the introduction of phenyl substituent was reported.
The reaction time had to be increased to 30 h in the conver-
sion of phenyl acetylene to phenyl allene.
The trend in yield distribution was further addressed by
embarking on a study of the dimerization reactions. First,
the reaction conditions were optimized using 1b as a model
substrate in the presence of Cu(OAc)2 as the catalyst and
triethylamine as a base (Scheme 4). It was found that the
use of 0.5 equiv. of Cu(OAc)2 and 1.0 equiv. of triethyl-
amine in dioxane effectively mediated formation of dimers
even though prolonged reaction times were necessary
(Table 4). Attempts to reduce the amount of Cu(OAc)2 re-
sulted in incomplete reactions. This result is worth noting
because typical Eglinton–Glaser Cu-mediated reactions re-
quire an excess amount (10 equiv.) of Cu(OAc)2 in the ab-
sence of dioxygen. The results are summarized in Table 4.
As can be seen from Table 4, a similar trend in the yield
distribution of homocoupling products was observed as
Experimental Section
General Method for the Preparation of Compounds 2a–d, 3a–d, 4b
and 4d: A mixture of acetylenic chalcone (1.0 mmol), paraformal-
dehyde (2.5 mmol), amine (2.0 mmol) and anhydrous cuprous bro-
mide or cupric chloride (0.5 mmol) in dry 1,4-dioxane (5.0 mL) was
heated under reflux at 100 °C for 3 h. The reaction mixture was
cooled to room temperature and then filtered. The filtrate was
poured into water and extracted with diethyl ether (3ϫ10 mL). The
combined ether extracts were concentrated to give a light brown
solid residue, which was subjected to column chromatography on
silica gel (10% EtOAc/hexane and MeOH/CHCl3/17% NH4OH,
2:2:1) to afford the title compounds 2a–d, 3a–d, 4b and 4d.
General Method for the Preparation of Compounds 10a–g and 11a–
g: A mixture of aryl acetylene (1.0 mmol), paraformaldehyde
(2.5 mmol), amine (2.0 mmol) and anhydrous cuprous bromide or
those in Tables 1 and 3. Compounds 1a and 1c (with the cupric chloride or Cu(OAc)2 (0.5 mmol) in dry 1,4-dioxane
Eur. J. Org. Chem. 2008, 43–46
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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45

V. Kumar, A. Chipeleme, K. Chibale
SHORT COMMUNICATION
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a light brown solid residue, which was subjected to column
chromatography on silica gel (5% EtOAc/hexane and 10% EtOAc/
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Acknowledgments
We thank the South African National Research Foundation for
financial support
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