Novel method for the synthesis of enamines by palladium catalyzed amination of alkenyl bromides

Article abstract of DOI:10.1039/b207524e

The intermolecular palladium catalyzed cross-coupling reaction between secondary amines and alkenyl bromides is described for the first time, giving rise to enamines with very high yields and regioselectivity.

Full text of DOI:10.1039/b207524e

Novel method for the synthesis of enamines by palladium catalyzed
amination of alkenyl bromides
José Barluenga,* M. Alejandro Fernández, Fernando Aznar and Carlos Valdés
Instituto Universitario de Química Organometálica ‘Enrique Moles’, Universidad de Oviedo, Oviedo, 33071
Asturias, Spain. E-mail: barluenga@sauron.quimica.uniovi.es; Fax: 34 985 103450; Tel: 34 985 103450
Received (in Cambridge, UK) 1st August 2002, Accepted 3rd September 2002
First published as an Advance Article on the web 18th September 2002
The intermolecular palladium catalyzed cross-coupling
reaction between secondary amines and alkenyl bromides is
described for the first time, giving rise to enamines with very
high yields and regioselectivity.
examined different ligands which have been shown to generate
active catalysts in the amination of aryl halides: P(o-Tol)3,9
(±)-BINAP,10 DPPF,11 DCPDAB ( = 2-dicyclohexylphos-
phino-2A-dimethylaminobiphenyl)12 and P(t-Bu)3.13 All the
reactions were carried out in toluene and using 1.5 equivalents
of NaOt-Bu as base (Scheme 1).
Enamines are valuable intermediates in organic synthesis. They
have been extensively employed as nucleophiles in Michael
type additions, and also as intermediates in the synthesis of
heterocycles, dienes and dienophiles in cycloaddition reactions,
precursors of chiral amines upon asymmetric transformations
and intermediates in natural product synthesis.1
The classical approach for the synthesis of enamines is the
condensation of a secondary amine with a carbonyl compound,
usually under mineral or Lewis acid catalysis.2 However, this
method presents several limitations, such as harsh reaction
conditions, lack of regio- and chemoselectivity, and low
functional group tolerance. Alternative methods for the synthe-
sis of enamines are hydroaminations of alkynes3 and methylen-
ation of amides.4
On the other hand, in recent years, great interest has been
devoted to the development of metal catalyzed cross-coupling
reactions of aryl halides with amines. In particular, the parallel
and concurrent efforts of the groups of Hartwig and Buchwald
have led to the development of a very efficient palladium
catalyzed reaction for the creation of C–N bonds from amines
and aryl halides and pseudohalides (Fig. 1).5 Over the last years,
these two research groups and others have fine-tuned the
catalytic system, allowing this type of transformation to be
performed under very mild conditions and with a variety of
coupling patterns.
Good results were obtained for most ligands, since the
reaction proceeded with complete conversion and the enamine
3 was isolated as a pure material from the reaction crud (Table
1). The Pd(0)/BINAP system was also successful with different
palladium sources† and with lower catalyst loading (0.5%) but
failed to react at very low concentrations of catalyst (0.05%).
Moreover, the reaction proceeded to completion even at 40 °C
(entry 9), but furnished very little conversion at room
temperature. Interestingly, no particular improvement was
obtained in the rt reaction when the biphenyl derived ligand
DCPDAB or the bulky electron rich P(t-Bu)3 were used,
although these systems promote the room temperature amina-
tion of aryl bromides. Therefore, given the good performance of
the Pd(0)/BINAP system we decided to study the scope of the
reaction of this catalytic system with other amines and alkenyl
bromides (Scheme 2, Table 2).
The reactions were conducted at 90 °C in toluene and with
1% Pd unless otherwise indicated, and the results are summa-
rized in Table 2 (Scheme 2). Excellent results were obtained for
cyclic and acyclic aliphatic amines, and also for the aromatic
substituted N-methylaniline with different substituted alkenyl
bromides. In all cases the enamines 6 were isolated as pure
compounds (as judged by 1H and 13C NMR) after dilution with
Fig. 1 Palladium catalyzed cross-coupling of amines with aryl halides.
The application of the same cross-coupling reaction to
alkenyl halides would furnish imines or enamines. However,
this reaction has been scarcely studied. To the best of our
knowledge, the palladium catalyzed intramolecular cyclization
of a b-lactam and a vinyl bromide reported by Mori recently in
a synthesis of carbapenems remains as the unique example of
the Buchwald–Hartwig reaction involving a vinyl halide.6
For many years, we have been engaged in the study of the
synthesis and applications of simple and cross-conjugated
enamines (2-amino-1,3-butadienes). Several years ago, we
disclosed the amination of terminal acetylenes catalyzed by
thallium or mercury salts.3 However, this method requires the
use of toxic metal salts, and sometimes the purification of the
resulting enamines is difficult. Nevertheless, the enamines
resulting from the aminomercuration reaction are very versatile
synthetic intermediates, for instance as dienes in cycloaddition
reactions7 and as chameleon linkers in solid-phase organic
synthesis.8 For these reasons, in an attempt to devise new
strategies for the synthesis of enamines, we decided to explore
the application of the Buchwald–Hartwig amination reaction to
alkenyl halides.
Scheme 1 Palladium catalyzed cross-coupling of morpholine 2 with a-
bromostyrene 1.
Table 1 Formation of enamine 3 under different catalytic conditions
Entry
Pd source, %
Ligandb
t/h
T/°C Conv.a (%)
1
2
3
4
5
6
7
8
9
Pd2(dba)3, 1%
Pd2(dba)3, 1%
Pd(OAc)2, 1%
Pd2(dba)3, 1%
Pd2(dba)3, 1%
Pd2(dba)3, 1%
Pd2(dba)3, 0.5%
Pd2(dba)3, 0.05%
Pd2(dba)3, 1%
Pd2(dba)3, 1%
Pd2(dba)3, 1%
Pd2(dba)3, 1%
P(o-Tol)3
BINAP
BINAP
DPPF
DCPDAB
P(t-Bu)d
BINAP
BINAP
BINAP
BINAP
DCPDAB
P(t-Bu)d
6
6
6
6
6
6
6
6
6
90
90
90
90
90
90
90
90
40
20
20
20
100 (78)
100 (96)
100 (91)
100 (69)
100 (95)
100 (85)
100 (69)
< 1
100 (89)
22
19c
10
11
12
6
16
6
2
a Determined by analysis of the 1H NMR spectra of the reaction crud.
Isolated yields are indicated in parentheses. b A 1+2 molar relationship of
Pd+ligand was employed. c Reaction run in DME as solvent. d A 1+0.8
molar relationship of Pd+ligand was employed.
We chose as a model system the reaction of a-bromostyrene
1 with morpholine 2 in the presence of a palladium species and
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This journal is © The Royal Society of Chemistry 2002

achieved by selecting carefully the reaction conditions. For
instance, the reaction of 2-bromo-4-phenyl-1-butene with N-
methylaniline under the standard reaction conditions (1%
Pd(OAc)2, BINAP, 80 °C, 6 h) gives rise to a 1+2 mixture of the
terminal and the internal enamines. However, by reducing the
reaction time to 1 h (which required the increase in the amount
of catalyst to 3% in order to achieve complete conversion)§
(entry 10) the desired terminal enamine was isolated without
formation of the internal isomer 7. For the morpholine case
(entry 9) the isomerization was avoided by running the reaction
at lower temperature (65 °C) for 30 min and again with higher
(3% Pd) catalyst loading.
In summary, we have reported the first palladium catalyzed
cross-coupling reaction of amines with vinyl halides, which
represents a novel method for the regioselective preparation of
enamines. Studies regarding the scope and applications of this
reaction, as well as a more comprehensive coverage of ligands
and potential substrates, are currently being carried out in our
laboratory and will be reported in due course.
Scheme 2 Synthesis of enamines 6 by amination of alkenyl bromides 4.
Table 2 Enamines 6 synthesized with the Pd(0)/BINAP system‡
Yielda
Entry Bromide Amine
1
Pd source, % t/h Product
(%)
Pd2(dba)3,
1%
6
96 (74)
2
3
4
5
Pd2(dba)3,
1%
6
6
97 (65)
95
We thank Dirección General de Investigación DGI and
Principado de Asturias (PR-01-GE-9) for financial support.
Pd2(dba)3,
1%
Notes and references
Pd(OAc)2, 12
1%
75 (45)
95 (73)
† The reactions with the Pd(OAc)2/BINAP system were carried out by
preforming the catalyst as described by Buchwald et al. in ref. 10.
‡ Typical experimental procedure for the amination reaction: A Schlenk
flask under nitrogen atmosphere was charged with Pd2(dba)3 (0.005 mM,
1% Pd), (±)-BINAP (0.015 mmol), NaOt-Bu (1.5 mmol), 5 mL of dry
toluene, 1 mmol of alkenyl bromide and 1 to 1.1 mmol of amine. The
reaction was stirred at 90 °C for 6 h and then allowed to cool to room
temperature. The mixture was diluted with 30 mL of dry hexanes and
filtered through celite. The solvents were evaporated under reduced
pressure and dried under high vacuum to remove the excess of amine, to
afford a residue which consisted of the essentially pure enamine. Depending
on the boiling point, the enamines can be purified by Kugelrohr distillation
under high vacuum (1023 Torr).
§ Longer reaction times resulted in a mixture of both enamines, for instance
when the reaction was carried out with 2% Pd for 2.5 h at 80 °C a 3+1
mixture of terminal+internal enamines was obtained. Moreover, the
terminal enamines undergo isomerization upon standing at room tem-
perature, therefore, if they were going to be employed in a subsequent
reaction, they should be used immediately after their synthesis.
Pd2(dba)3,
1%
6
6
6
Pd2(dba)3,
1%
96 (79)
7
8
Pd(OAc)2,
1%
6
6
94 (81)
91 (79)
Pd(OAc)2,
1%
1 (a) The Chemistry of Enamines, ed. Z. Rappaport, Wiley, New York,
1994; (b) Enamines: Synthesis, Structure and Reactions, 2nd edn., ed.
A. G. Cook, Marcel Dekker, New York, 1998.
2 P. W. Hickmott, Tetrahedron, 1982, 38, 1975–2050.
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5 For reviews of the palladium catalyzed cross-coupling reaction of
amines with aryl halides see: (a) J. F. Hartwig, in Modern Amination
Methods, ed. A. Ricci, Wiley-VCH, Weinheim, 2000; (b) A. R. Muci
and S. L. Buchwald, Top. Curr. Chem., 2002, 219, 133–209.
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1971–1974 and references cited therein.
9b
Pd(OAc)2, 0.5
3%
86
90
10c
Pd(OAc)2,
3%
1
a Based on the amount of pure material (by 1H and 13C NMR) isolated form
the reaction crud. Isolated yields after high vacuum Kugelrohr distillation
are indicated in parentheses. b Reaction run at 65 °C. c Reaction run at 80
°C.
8 F. Aznar, C. Valdés and M-P. Cabal, Tetrahedron Lett., 2000, 41,
5683.
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5575–5580.
hexanes and filtration through celite. This is an important
feature, because due to the acid and water sensitivity of the
enamine functionality, aqueous workup and conventional
chromatographic techniques are not suitable for their purifica-
tion.
Particularly challenging substrates are those derived from
2-bromopropene such as 2-bromo-4-phenyl-1-butene (entries 9
and 10). The product of the amination reaction of 2-bromo-
4-phenyl-1-butene affords a terminal enamine 6, which under-
goes very easy isomerization to the more substituted internal
enamine 7. In fact, with the exception of some particular
examples,14 to the best of our knowledge, no general method for
the preparation of these terminal enamines has been described.
The regioselective synthesis of these enamines could be
14 J. Barluenga, F. Aznar, R. Liz and C. Postigo, J. Chem. Soc., Chem.
Commun., 1986, 1465–1467.
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