COMMUNICATION
Nickel-catalyzed four-component connection of oraganoaluminium
(organozinc), isoprene, aldehydes and amines: stereo- and regioselective
synthesis of trisubstituted (E)-homoallylamines{
Keisuke Kojima,a Masanari Kimuraa and Yoshinao Tamaru*b
Received (in Cambridge, UK) 24th May 2005, Accepted 1st August 2005
First published as an Advance Article on the web 25th August 2005
DOI: 10.1039/b507229h
Ni(acac)2 catalyzes the four-component connection reaction of
trimethylaluminium (or diphenylzinc), isoprene, aromatic
aldehydes and p-anisidine in this order and provides (E)-1-
aryl-1-(p-methoxyphenyl)amino-3-methyl-3-hexenes (or (E)-1-
aryl-1-(p-methoxyphenyl)amino-3-methyl-5-phenyl-3-pentenes)
(1)
selectively in good yield.
Multi-component connection reactions of simple molecules
provide very versatile and efficient methods to construct desired
molecules, which have been achieved mostly by making the best
use of transition-metal catalysis.1 Isoprene is among the most
important constituents of the frameworks of natural products, and
the regio- and stereoselective incorporation of an isoprene unit into
desired molecules has long been a subject of strong concern for
synthetic organic chemists.
In order to improve the stereoselectivity and the chemical yield
of 1a, we thoroughly examined the reaction conditions and found
that trimethylaluminium was the best choice of methylation
reagents. With this reagent, not only the yield of 1a, but also the
stereoselectivity could be improved greatly (runs 3–5, Table 1). The
stereoselectivity was temperature dependent; curiously, the higher
the temperature, the better the (E)-selectivity. At the moment, it
may be premature to give a rationale behind this unusual
reactivity; however, we postulate that the monomer content,
which increases with temperature in the monomer–dimer equili-
brium of trimethylaluminium, is one of the important factors
affecting the stereoselectivity in favor of the (E)-isomer.{
We recently demonstrated that a nickel salt, without applying
any phosphane or nitrogen ligands, nicely catalyzed the three-
component connection reaction of organozincs, dienes and
aldehydes.2 For the regio- and stereoselective incorporation of
isoprene, organoboranes have proved to work much better than
organozincs; the former gives rise to (E)-isomers almost exclu-
sively.3 Here, we would like to disclose that the same method, with
slight modification, is successfully applicable to the reaction with
aldimines. This might be a great achievement, since aldimines are
generally by far less reactive electrophiles than aldehydes,4 and
through this method a variety of structurally defined homoally-
lamines of synthetic importance can be prepared (eqn (1)).
For the reaction with aldimine, generated in situ from
benzaldehyde and p-anisidine, in addition to the expected product
1a (R 5 H) (E : Z 5 2 : 1), 2a (R 5 H) was formed in a
considerable amount, a type of product having never been
observed for the reactions with aldehydes (run 1, Table 1).2,3
The 1H NMR spectrum indicates that 2a is a mixture of 4
stereoisomers arising from C3 and C8 stereocenters. The tail-to-tail
connection of two molecules of isoprene was verified by ozonolysis
experiments.5
The reaction could be performed very easily as follows (run 4,
Table 1). A mixture of benzaldehyde (1 mmol) and p-anisidine
(2 mmol) in dry THF (2 mL) was stirred overnight at 30 uC. The
temperature was allowed to rise to 50 uC, and into this mixture,
Table 1 Optimization of reaction conditions for the reaction of
organomethyls, isoprene and benzaldehyde-p-anisidine iminea
Yield (%)
Run
MenM
Temp./uC
Time/h
1a (E : Z)b
2a
1
2
3
4
5
a
Me2Zn
Me2Zn
Me3Al
Me3Al
Me3Al
30
50
30
50
60
3
3
1
1
1
28 (2 : 1)
36 (2 : 1)
81 (2 : 1)
80 (9 : 1)
74 (10 : 1)
14
10
10
18
21
aGraduate School of Science and Technology, Nagasaki University, 1-14
Bunkyo, Nagasaki 852-8521, Japan.
E-mail: masanari@net.nagasaki-u.ac.jp
Reaction conditions: benzaldehyde (1 mmol) and p-anisidine
(2 mmol) in THF (2 mL) at 30 uC overnight, and then Ni(acac)2
(0.1 mmol in 3 mL of THF), isoprene (4 mmol), MenM (3.6 mmol,
bDepartment of Applied Chemistry, Faculty of Engineering, Nagasaki
University, 1-14 Bunkyo, Nagasaki 852-8521, Japan.
E-mail: tamaru@net.nagasaki-u.ac.jp; Fax: +95-819-2677;
Tel: +95-819-2677
b
1 M in hexane) at the temperature indicated. Isolated yield of
spectroscopically homogeneous materials. In parentheses are
shown the ratio of stereoisomers determined by 1H NMR spectra
(400 MHz).
{ Electronic supplementary information (ESI) available: A typical reaction
procedure and spectral and analytical data of products (1a–j and 3a–e).
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 4717–4719 | 4717