Palladium-Catalyzed Cross-Coupling Reactions of Amines with Alkenyl Bromides: A New Method for the Synthesis of Enamines and Imines

Article abstract of DOI:10.1002/chem.200305406

The palladium-catalyzed cross-coupling reaction of alkenyl bromides with secondary and primary amines gives rise to enamines and imines, respectively. This new transformation expands the applicability of palladium-catalyzed C-N bond forming reactions (the Buchwald-Hartwig amination), which have mostly been applied to aryl halides. After screening of different ligands, bases, and solvents, the catalytic combination [Pd₂(dba)₃]/BINAP in the presence of NaOtBu in toluene gave the best results in the cross-coupling of secondary amines with 1-bromostyrene (dba=dibenzylideneacetone, BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl). The corresponding enamines are obtained cleanly and in nearly quantitative yields. However, steric hindrance seems to be a limitation of the reaction, as amines carrying large substituents are not well converted. The same methodology can be applied to the coupling of secondary amines with 2-bromostyrene. Moreover, the reaction with substituted 2-bromopropenes allows regioselective synthesis of isomerizable terminal enamines without isomerization of the double bond. The best catalytic conditions for the cross-coupling of 1-bromostyrene with primary amines include again the use of the Pd°/BINAP/NaOtBu system. The reaction gives rise to the expected imines in very short times and with low catalyst loadings. A set of structurally diverse imines can be prepared by this methodology through variations in the structure of both coupling partners. However, 2-bromostyrene failed to give good results in this coupling reaction, probably due to product inhibition of the catalytic cycle. Competition experiments of vinyl versus aryl amination reveal that the reaction occurs preferentially on vinyl bromides.

Full text of DOI:10.1002/chem.200305406

FULL PAPER
Palladium-Catalyzed Cross-Coupling Reactions of Amines with Alkenyl
Bromides: A New Method for the Synthesis of Enamines and Imines
Josÿ Barluenga,* M. Alejandro Fernµndez, Fernando Aznar, and Carlos Valdÿs[a]
Abstract: The palladium-catalyzed
cross-coupling reaction of alkenyl bro-
mides with secondary and primary
amines gives rise to enamines and
imines, respectively. This new transfor-
mation expands the applicability of pal-
ladium-catalyzed CÀN bond forming
reactions (the Buchwald Hartwig ami-
nation), which have mostly been ap-
plied to aryl halides. After screening of
different ligands, bases, and solvents,
the catalytic combination [Pd2(dba)3]/
BINAP in the presence of NaOtBu in
toluene gave the best results in the
cross-coupling of secondary amines
with 1-bromostyrene (dba=dibenzyli-
deneacetone, BINAP=2,2’-bis(diphe-
corresponding enamines are obtained
cleanly and in nearly quantitative
yields. However, steric hindrance
seems to be a limitation of the reac-
tion, as amines carrying large substitu-
ents are not well converted. The same
methodology can be applied to the
coupling of secondary amines with 2-
bromostyrene. Moreover, the reaction
coupling of 1-bromostyrene with pri-
mary amines include again the use of
the Pd0/BINAP/NaOtBu system. The
reaction gives rise to the expected
imines in very short times and with low
catalyst loadings. A set of structurally
diverse imines can be prepared by this
methodology through variations in the
structure of both coupling partners.
However, 2-bromostyrene failed to
give good results in this coupling reac-
tion, probably due to product inhibi-
tion of the catalytic cycle. Competition
experiments of vinyl versus aryl amina-
tion reveal that the reaction occurs
preferentially on vinyl bromides.
with
substituted
2-bromopropenes
allows regioselective synthesis of iso-
merizable terminal enamines without
isomerization of the double bond. The
best catalytic conditions for the cross-
Keywords: alkenes
¥ amination ¥
amines ¥ cross-coupling ¥ palladium
nylphosphino)-1,1’-binaphthyl).
The
Introduction
general, it presents several limitations, such as harsh reac-
tion conditions and low functional group tolerance. More-
over, no real control of the regiochemistry and stereochem-
istry can be expected in the synthesis of enamines from a
nonsymmetric ketone (Scheme 1).
Enamines have also been prepared by alternative ap-
proaches, for instance, by olefination strategies involving
amine-substituted Wadsworth Emmons reagents[3] or meth-
ylenation of amides.[4] Another appealing and atom-econom-
ical approach to enamines and imines is the metal-catalyzed
hydroamination of alkynes. This method, pioneered by our
group several years ago,[5] is currently an area of active re-
search.[6,7]
On the other hand, in the recent years, the palladium-cat-
alyzed cross-coupling reaction of aryl halides with amines,
known as the Buchwald Hartwig reaction,[8] has emerged as
a very powerful procedure for the creation of CÀN bonds
(Scheme 2A). Over the last few years, the work of the
Buchwald and Hartwig groups, and others, has led to the de-
velopment of very efficient catalytic systems for this trans-
formation. In fact, very active catalysts have been devised
for the amination not only of aryl bromides[9] but also for
the less reactive aryl chlorides[10] and sulfonates.[11] Further-
The CÀN bond can be found in a great number of organic
compounds of major importance, such as biologically active
natural products, pharmaceuticals, and dyes. Imines and en-
amines are among the most useful intermediates for intro-
ducing a nitrogen-containing fragment in a synthetic se-
quence due to their versatile reactivity.[1] For this reason, the
development of new methods to selectively prepare these
systems is of great interest.
The standard procedure to synthesize imines and enam-
ines is the condensation of an amine with the appropriate
carbonyl compound, usually in the presence of an acid cata-
lyst and a water scavenger.[2] While this approach is fairly
[a]Prof. Dr. J. Barluenga, M. A. Fernµndez, Prof. Dr. F. Aznar,
Dr. C. Valdÿs
Instituto Universitario de QuÌmica Organometµlica ™Enrique Moles∫
Universidad de Oviedo
33071 Oviedo (Spain)
Fax : (+34)985-103450
E-mail: barluenga@sauron.quimica.uniovi.es
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
494
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200305406
Chem. Eur. J. 2004, 10, 494 507

494 507
more, the reaction has been ap-
plied to many NÀH-containing
species other than amines.[12]
The application of the same
catalytic process to alkenyl ha-
lides should provide enamines
and imines (Scheme 2B). How-
ever, in spite of the great inter-
est that this reaction has at-
tracted in the recent years, its
Scheme 1. Synthesis of enamines and imines by condensation of an amine with a carbonyl compound: the clas-
sical approach.
application to vinyl halides instead of aryl halides has hardly
been studied.
To the best of our knowledge, only two contributions,
prior to our previous communication,[13] had described palla-
dium-catalyzed CÀN bond-forming reactions with vinyl ha-
lides: the synthesis of N-vinyl azoles from vinyl bromides[14]
and the palladium-catalyzed intramolecular cyclization of a
b-lactam and a vinyl bromide as the key step in the synthesis
of carbapenem derivatives.[15] More recently, the palladium-
catalyzed amination of vinyl sulfonates has also been report-
ed.[16]
Scheme 2. a) Buchwald Hartwig amination. b) Amination of vinyl hal-
ides.
A major research theme in our group over the years has
been the synthesis and applications of simple and cross-con-
jugated enamines (2-amino-1,3-dienes). We uncovered sev-
eral years ago a very efficient method for the synthesis of
enamines by hydroamination of terminal acetylenes cata-
lyzed by thalium or mercury salts.[5] The enamines resulting
from this approach are very versatile intermediates, for in-
stance, as dienes in cycloaddition reactions,[17] substrates for
Claisen rearrangements,[18] and chameleon linkers in solid-
phase organic synthesis.[19] However, the use of highly toxic
salts and the sometimes sluggish purification methods re-
quired prompted us to search for alternative synthetic
routes to these types of enamines.
In a previous communication we disclosed the cross-cou-
pling reaction of vinyl bromides with secondary amines,
which can be regarded as a new alternative for the synthesis
of enamines.[13] In this paper we wish to report a detailed
study of the scope and limitations of this particular transfor-
mation oriented toward the preparation of imines and en-
amines by coupling of vinyl bromides with primary or secon-
dary amines, respectively.
Abstract in Spanish: La reacciÛn de acoplamiento cruzado
de bromuros de alquenilo con aminas secundarias y prima-
rias da lugar a enaminas e iminas respectivamente. Esta
nueva transformaciÛn expande las aplicaciones de la reacciÛn
de formaciÛn de enlaces CÀN catalizada por paladio (amina-
ciÛn Buchwald Hartwig), que se habÌa limitado fundamen-
talmente a haluros de arilo. Despuÿs de un estudio de diferen-
tes ligandos. bases y disolventes, los mejores resultados en la
reacciÛn de acoplamiento cruzado de aminas secundarias
con 1-bromoestireno, se obtuvieron para el catalizador cons-
tituido por la combinaciÛn Pd/BINAP en presencia de
NaOtBu en tolueno. Las correspondientes enaminas se obtie-
nen limpiamente y con rendimientos prµcticamente cuantitati-
vos. Sin embargo, los impedimentos estÿricos en la amina pa-
recen ser una limitaciÛn de la reacciÛn, puesto que aminas
con sustituyentes voluminosos proporcionan conversiones
bajas. La misma metodologÌa puede aplicarse al acoplamien-
to de aminas secundarias con 2-bromoestireno. Ademµs, la
reacciÛn con 2-bromopropenos sustituidos permite obtener
de forma regioselectiva enaminas terminales isomerizables,
sin que la isomerizaciÛn del doble enlace tenga lugar. Las
mejores condiciones catalÌticas para el acoplamiento de
aminas primarias con 1-bromoestireno incluyen de nuevo la
utilizaciÛn del sistema Pd(0)/BINAP/NaOtBu. La reacciÛn
proporciona las iminas esperadas en tiempos de reacciÛn
muy cortos y con baja carga del catalizador. Mediante esta
metodologÌa pueden prepararse un conjunto de iminas de
gran diversidad estructural, permitiendo variaciones en
ambos reactivos de acoplamiento. Sin embargo, la reacciÛn
con 2-bromoestireno no produce buenos resultados en este
acoplamiento, probablemente debido a inhibiciÛn del ciclo
catalÌtico por parte del producto de reacciÛn. Finalmente, ex-
perimentos de competencia de aminaciÛn vinÌlica frente a
aminaciÛn arÌlica, ponen de manifiesto que esta reacciÛn se
produce de forma preferente sobre los bromuros de vinilo.
Results and Discussion
Coupling of vinyl halides with secondary amines: Synthesis
of enamines from vinyl bromides: In our initial experiments
we chose the reaction of 1-bromostyrene (1a) with morpho-
line (2a) as a model to develop suitable reaction conditions
(Table 1). The reaction was studied in the presence of differ-
ent palladium sources and ligands,[20] with NaOtBu, the stan-
dard base for amination of aryl halides, being used as an ad-
ditive. The reactions were carried out in toluene at 908C for
6 h. The coupling took place under several of the reaction
conditions to furnish enamine 3a. As presented in Table 1,
complete conversion (based on 1-bromostyrene) was ach-
ieved with several different catalytic combinations. Howev-
er, the best yields of 3a were obtained in the reactions that
495
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J. Barluenga et al.
FULL PAPER
Table 1. Influence of the ligand and the temperature in the synthesis of enamine 3a by the cross-coupling re-
action of 1-bromostyrene (1a) with morpholine (2a) in toluene.[a]
methylbenzylamine (2b), and
an aromatic amine such as N-
methylaniline (2c). However,
the reaction is very sensitive to
the bulkiness of the substitu-
ents, and a slight increase in
their size, from methyl to ethyl
Entry
Pd source (mol%)
Ligand
t [h]
T [8C]Conversion
[b] [%]
[d]
[Pd2(dba)3][c] (1)
[Pd2(dba)3](1)
Pd(OAc)2 (1)
[Pd2(dba)3](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
6
6
6
6
6
6
6
90
90
90
90
90
90
90
100 (78)
(compare entries 3 and
6 in
1
2
3
4
5
6
7
8
[e]
100 (96)
100 (91)
100 (85)
100 (69)
100 (95)
100 (85)
100 (69)
<1
Table 3) or benzyl (compare en-
tries 2 and 7 in Table 3), gives
rise to a dramatic decrease in
the conversion of the reaction.
For instance, under the condi-
tions described complete con-
version is achieved with N-
methylaniline (2c) and only 50
% is converted with N-ethylani-
line (2e). Unfortunately, con-
versions and yields could not be
improved by raising the temper-
ature or increasing the catalyst
loading. However, an increase
in the catalyst loading remarka-
bly accelerates the cross-cou-
pling reaction with unhindered
amines. As shown in entry 4 in
Table 3, complete conversion is
achieved for the coupling of N-
methylaniline (2c) in only
1 hour when the reaction is con-
BINAP
PPh 3
[f]
DPPF
4[g]
[h]
P tBu3
BINAP
BINAP
BINAP
BINAP
4
6
90
9
6
6
6
16
6
90
40
20
20
20
10
11
12
13
100 (89)
22
19[i]
[h]
P tBu3
2
[a]Reaction conditions: 1 equivalent of 1a, 1.1 equivalents of 2a, 1:3 Pd:Ligand molar ratio, 1.4 equivalents of
NaOtBu, 4 mL of toluene per mmol of 1a, 908C. [b]Determined by GC. Yields are indicated in parentheses.
[c]dba =dibenzylideneacetone. [d] o-Tol=ortho-Tolyl. [e]BINAP =2,2’-bis(diphenylphosphino)-1,1’-binaphth-
yl. [f]DPPF =1,1’-bis(diphenylphosphino)ferrocene. [g] 4=2-dicyclohexylphosphino-2’-dimethylaminobiphen-
yl. [h]A 1:0.8 Pd:ligand molar ratio was used.
employed either BINAP or 4 as the ligand. Further experi-
ments with lower catalyst loadings and temperatures
(Table 1, entries 8 13) revealed [Pd2(dba)3]/BINAP[21] as the
more active catalytic combination. Interestingly, bulky and
electron-rich ligands such as 4 and PtBu3, which are able to
catalyze the amination of aryl bromides at room tempera-
ture, did not perform better than BINAP in this reaction at
RT or at higher temperatures. Presumably, the kinetics in
this process are different from the amination of aryl halides
and the oxidative addition is not the rate-determining step.
For these reasons, we carried out the following studies by
using the Pd/BINAP combination.
ducted with 3 mol% of Pd. In fact, faster reaction rates are
important when potentially sensitive functional groups are
present. For example, functionalized piperidines 2g and 2h
Table 2. Influence of the solvent and base in the synthesis of enamine 3a
by the cross-coupling reaction of 1-bromostyrene (1a) with morpholine
(2a) in the presence of the Pd/BINAP catalytic system.[a]
Entry
Base
Solvent
t [h]Conversion
[b] [%]
First, we examined different reaction conditions, solvents,
and bases (Table 2). No particular improvement was found
by changing to more polar solvent such as dioxane, while
the reaction in DMF and the presence of water led to very
low conversion. The reactions in the presence of milder
bases were also assayed. However, the most common bases
used in aminations of aryl halides (Cs2CO3, K3PO4, and
NaOH) did not provide complete conversion under the re-
action conditions studied. These preliminary results estab-
lished the Pd/BINAP/NaOtBu catalytic combination in tolu-
ene as the most appropriate. Therefore, we set out to inves-
tigate the scope of this transformation regarding both cou-
pling partners, the amine and the alkenyl bromide.
1
2
3
4
5
6
7
8
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
Cs2CO3
Cs2CO3
K3PO4
toluene
toluene
dioxane
DMF[c]
1
6
6
65
100 (96)
100 (94)
>5
16
20
45
>5
10
>5
65
87
40
24
24
6
24
6
24
24
6
24
6
toluene/H2O (1:1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
dioxane
dioxane
dioxane
9
K3PO4
Na2CO3
NaOH
10
11
12
13
14
15
16
NaOH
Cs2CO3
Cs2CO3
K3PO4
24
6
24
60
10
18
K3PO4
The results of the reaction of 1-bromostyrene (1a) with a
set of structurally diverse secondary amines 2 are presented
in Table 3. Excellent yields are obtained for a cyclic amine
such as morpholine (2a), an aliphatic acyclic amine such N-
[a]Reaction conditions: 1 equivalent of 1a, 1.1 equivalents of 2a, 1 mol
% of [Pd2(dba)3], 3 mol% of BINAP, 1.4 equiv of base, 4 mL of solvent
per mmol of 1a, 908C. [b]Determined by GC. Yields indicated in paren-
theses in specific cases.[c]DMF =N,N-Dimethylformamide.
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Chem. Eur. J. 2004, 10, 494 507

Palladium-Catalyzed Cross-Coupling Reactions
494 507
Table 3. Reaction of 1-bromostyrene (1a) with secondary amines 2 catalyzed by the Pd/BINAP system in tolu-
ene at 908C.[a]
tries 3 5 in Table 4 against en-
tries 6 and 7 in Table 3). An ac-
ceptable yield was obtained
even for branched amine 2j
(Table 4, entry 6). Clearly, the
diminished steric hindrance
around the vinyl bromide in 1b
in comparison to that in 1a
allows for easier participation
of amines bearing large sub-
stituents in the reaction.
Entry
1
Amine 2
Pd source (mol%)
[Pd2(dba)3](1)
t [h]Enamine
3
Yield [%]
96
6
The reactions described in
Table 4, carried out with trans-
2-bromostyrene, furnished ex-
clusively the trans isomer of the
enamine. However, when the
same reactions were conducted
with cis-2-bromostyrene a mix-
ture of both isomers was ob-
tained under all the reaction
2
[Pd2(dba)3](1)
6
6
95
3
[Pd2(dba)3](1)
Pd(OAc)2 (3)
Pd(OAc)2 (1)
97
98
75
4[b]
1
5
12
conditions
examined,
even
when the catalyst loading was
increased substantially in order
to reduce the reaction times
(Scheme 3). This lack of stereo-
specificity differs from the ob-
servations of Voskoboynikov
and co-workers,[14] who report-
ed the palladium-catalyzed ster-
eospecific vinylation of azoles.
Nevertheless, this different be-
havior is not surprising, as the
isomerization of the enamines
can take place easily by a tauto-
merism, which is not likely to
happen in the case of the vinyl
azoles.
6[c]
[Pd2(dba)3](1)
Pd(OAc)2 (1)
20
50[d]
35[d]
7[c]
20
1
8[b]
Pd(OAc)2 (3)
Pd(OAc)2 (3)
90
90
9[b]
1
[a]Reaction conditions: 1 equivalent of 1a, 1.1 equivalents of amine, 1 3 mol% Pd, 3 mol% BINAP,
1.4 equivalents of base, 4 mL of toluene per mmol of 1a, 908C. [b]Carried out at 80 8C with 6 mol% BINAP
and 1 equiv of amine. [c]Carried out at 100 8C. [d]Conversion (%) determined by GC and 1H NMR spectro-
scopy of the crude reaction mixture.
Alkenyl bromides with the
general structure 5 (3-substitut-
(Table 3, entries 8 and 9) were successfully coupled with 1a
in 1 hour in the presence of 3 mol% of Pd without forma-
tion of any of the side products that may have been pro-
duced with longer reaction times.
ed-2-bromopropenes) are particularly challenging substrates
(Scheme 4). The amination reaction of 5 gives rise to termi-
nal enamines 6, which may undergo a very easy isomeriza-
tion to the more substituted internal enamine 7. In fact,
when the coupling reactions are conducted under the stan-
dard reaction conditions described above, a mixture of both
enamines is obtained. For instance, the reaction of 2-bromo-
4-phenyl-1-butene (5a) with N-methylaniline (2c) under
those conditions (1 mol% Pd(OAc)2, BINAP, 808C, 6 h)
produces a 1:2 mixture of the terminal and the internal en-
In all cases the enamines were isolated as pure com-
1
pounds (as judged by H and 13C NMR spectroscopy) after
dilution with dry hexanes, filtration through celite, evapora-
tion of the solvents, and removal of the slight excess of
amine under high vacuum. This is an important feature, as
aqueous work-up and chromatographic techniques are not
suitable for the purification of enamines because of their
water sensitivity whereas high-vacuum distillation is only
possible for systems with reasonably low boiling points.
The same reaction was then studied with trans-2-bromo-
styrene (1b), a typical b-substituted vinyl bromide. The re-
sults are summarized in Table 4. Again, very high yields are
obtained for the coupling with morpholine (2a) and N-
methylaniline (2c). Contrary to the case of 1-bromostyrene
(1a), high conversions were also achieved for reactions of 1
b with bulkier amines such as 2e, 2f, and 2i (compare en-
Scheme 3. Stereoselectivity in the amination of cis- and trans-2-bromos-
tyrene.
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J. Barluenga et al.
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Table 4. Synthesis of enamines 4 by reaction of trans-2-bromostyrene (1b) with secondary amines 2 catalyzed
amines, 6a and 7a, respectively
(Scheme 2). Nevertheless, it is
possible to obtain exclusively
the terminal enamine 6a by in-
creasing the catalyst loading
and, therefore, reducing the re-
action time. Thus, when the
same reaction is carried out
with 3 mol% of Pd, complete
conversion is achieved in
1.5 hours and the terminal en-
amine 6a is isolated without
formation of the internal
isomer 7a, as determined from
1H and 13C NMR spectra.
by the Pd/BINAP system.[a]
Entry
1[c]
Amine
Pd source (mol%)
[Pd2(dba)3](1)
t [h][b]
Product
Yield [%]
95
6
2[c]
[Pd2(dba)3](1)
6
96
The regioselective formation
of terminal enamines 6 was ex-
tended to several different sub-
strates, including functionalized
bromoolefins (Table 5). In all
cases, the terminal regioisomers
were cleanly obtained after pu-
rification by dilution of the re-
action mixture with dry hex-
anes, filtration through celite,
and removal of the solvents.
However, most of the terminal
enamines undergo spontaneous
isomerization upon standing.
It is worth noting that, with
the exception of some particu-
lar examples,[22] to the best of
our knowledge no general
method for the preparation of
these terminal isomerizable en-
amines has been described pre-
viously. Moreover, the bro-
mides required for the amina-
tion reaction are very easily ac-
cessible from commercial 2,3-
3
[Pd2(dba)3](1)
[Pd2(dba)3](2)
20
20
80
90
4[d]
5
[Pd2(dba)3](1)
20
70
6[d]
7[e]
8[e]
Pd(OAc)2 (2)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
20
64
97
95
1
1
9[e]
Pd(OAc)2 (3)
1
97
[a]Reaction conditions: 1 equivalent of 1b, 1.1 equivalents of amine, 1.4 equivalents of NaOtBu, 1 3 mol%
Pd, 2 6 mol% BINAP, 4 mL of toluene per mmol of 1b, 1008C. [b]Reaction times have not been optimized.
[c]Reaction carried out at 90 8C. [d]Ligand =P(o-tol)3. [e]Reaction carried out at 80 8C with 6 mol% of
BINAP and 1 equiv of amine.
dibromopropene.
Therefore,
the present method constitutes
a unique and very convenient
procedure for accessing this
type of system.
Coupling of vinyl bromides
with primary amines: Synthesis
of imines: We next turned our
attention to the coupling reac-
tion of vinyl bromides with pri-
mary amines, which gives rise
to imines after tautomerization
of the initially formed enamine.
The synthesis of imine 9a from
1-bromostyrene (1a) and p-ani-
sidine (8a) was selected as a
representative example to de-
velop suitable reaction condi-
Scheme 4. Regioselectivity in the synthesis of terminal isomerizable enamines 6.
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Palladium-Catalyzed Cross-Coupling Reactions
494 507
Table 5. Regioselective synthesis of terminal isomerizable enamines 6.[a]
ene at 908C as the typical ex-
perimental conditions. Repre-
sentative examples of the cou-
pling with different amines are
presented in Table 8. The cou-
pling proceeds with excellent
yields with all types of aromatic
amines carrying electron-donat-
ing substituents, such as OMe
and Me (Table 8, entries 1,6
and 2,5, respectively), or elec-
tron-withdrawing substituents,
such as CN and NO2 (Table 8,
entries 3 and 4), although the
latter required longer reaction
times. Moreover, steric hin-
drance is not a serious limita-
tion for this reaction, as ortho-
substituted aromatic amines
react readily (Table 8, entries 5
7) and even the very hindered
2,4,6-trimethylaniline (Table 8,
entry 10) was coupled quantita-
tively in 90 min. Only for 2,6-di-
bromoaniline (Table 8, entry 11)
was a lower yield (50%) ob-
tained. It is interesting to note
the chemoselectivity of the re-
action (vinyl amination versus
aromatic amination), as no ho-
mocoupling by aromatic amina-
tion was observed when bro-
moanilines were employed
(Table 8, entries 7 9). Aliphatic,
allylic, and benzylic amines
were also coupled equally effec-
tively (Table 8, entries 12 15).
Linear and also branched
(Table 8, entry 15) amines were
Entry
1[c]
Bromide
Amine
Pd source (mol%)
Pd(OAc)2 (3)
t [h][b]
Product
Yield[%]
86
0.5
2
3
Pd(OAc)2 (3)
Pd(OAc)2 (3)
1.5
1
90
96
4
5
6
Pd(OAc)2 (3)
Pd(OAc)2 (3)
Pd(OAc)2 (3)
1.5
1
95
96
95
1.5
7
8
Pd(OAc)2 (3)
Pd(OAc)2 (3)
1
96
95
1.5
[a]Reaction conditions: 1 equivalent of vinyl bromide 5, 1 equivalents of amine 2, 1.4 equivalents of NaOtBu,
3 mol% Pd, 6 mol% BINAP, 4 mL of toluene per mmol of 5, 808C. [b]Reaction times have not been opti-
mized. [c]Reaction carried out at 65 8C.
tions. The activities of different ligands in toluene with
NaOtBu as the base are represented in Table 6. BINAP and
phosphine 4 were the best ligands for this transformation.
The reaction proceeds much faster and requires lower cata-
lyst loading than the coupling with secondary amines. For in-
stance, complete conversions are achieved with 1 mol% of
Pd and 3 mol% of BINAP, 4, or DPPF in only 15 min at
908C, to provide quantitative yields of imine 9a (Table 6, en-
tries 1,3, and 8, respectively). Moreover, the reaction can be
carried out also with almost quantitative yields in 45 min by
using as little as 0.1 mol% of Pd at 908C (Table 6, entry 12).
The influence of the solvent and the base was also studied
(Table 7). As in the reaction with secondary amines, toluene
performed better than more polar solvents such as dioxane
or DMF. Moreover, NaOtBu was the most effective base,
and again, in our hands, milder bases such as Cs2CO3 and
K3PO4 were not able to provide complete conversion at
1 mol% Pd loading (Table 7).
employed, with nearly quantitative yields, which shows that
the steric effects are not as important as in the synthesis of
enamines by coupling of secondary amines as discussed
before.
Excellent results were also obtained with a set of structur-
ally diverse 3-substituted-2-bromopropenes 5. The expected
imines 10 were obtained in very high yields under the same
reaction conditions (Table 9). Again, both aromatic (Table 9,
entries 1 4) and benzylic (Table 9, entries 5 and 6) amines
were successfully coupled.
Following the same sequence as for the secondary amines,
we next examined the coupling with 2-bromostyrene (1b).
Unexpectedly, the reactions of p-anisidine (8a) or 4-methoxy-
benzylamine (8n) with 2-bromostyrene (1b) failed to pro-
ceed with high conversion (Scheme 5). Several reaction con-
ditions and catalytic systems were tested in this particular
coupling, and in the best cases the crude reaction mixture
consisted of starting reagents and the enamine coming from
the amination reaction, with conversions of around 50%.
Therefore, the scope of the reaction was studied with the
Pd/BINAP/NaOtBu catalytic system (1 mol% of Pd) in tolu-
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J. Barluenga et al.
FULL PAPER
Table 6. Optimization of the catalyst for the synthesis of imine 9a by the cross-coupling reaction of 1-bromo-
styrene (1a) with p-anisidine (8a) in toluene with NaOtBu as the base.[a]
No improvement in conver-
sion was achieved by increasing
the catalyst loading. Moreover,
addition of more Pd species or
more Pd and ligand once the
50% conversion had been
reached did not increase the
conversion of the reaction.
These observations point to an
interruption of the catalytic
cycle by product inhibition.[23]
Entry
Pd source (mol%)
Ligand
t [min]
15
15
15
15
24 h
15
24 h
15
15
180
15
45
T [8C]Conversion
90 100 (98)
[b] [%]
1
2
3
4
5
6
7
8
[Pd2(dba)3](1)
Pd(OAc)2 (1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](0.5)
[Pd2(dba)3](0.1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
[Pd2(dba)3](1)
none
BINAP
BINAP
4
90
90
90
100 (98)
100 (98)
70
[c]
DTPB
DTPB
90
85
Alkenyl amination versus aryl
amination: The cross-coupling
reaction of amines with alkenyl
bromides discussed herein is an
extension of the well-known
Buchwald Hartwig amination
of aryl halides. The convention-
al mechanism accepted for this
reaction catalyzed by the Pd/
BINAP system is shown in
Scheme 6. The catalytic cycle
involves three main steps:[9b,24]
1) the oxidative addition of the
aryl halide to generate aryl pal-
ladium bromide complex I;[25]
2) coordination of the amine to
give rise to amido complex II
P( o-Tol)3
P( o-Tol)3
DPPF
90
90
26
63
90
90
90
100 (97)
94
60
[d]
9
XANTPHOS
[e]
10
11
12
13
14
15
16
P tBu3
BINAP
BINAP
BINAP
BINAP
none
90
100 (95)
100 (94)
100 (95)
15
90
45
20
90
150
180
180
180
[f]
none
90
[a]Reaction conditions: 1 equivalent of 1a, 1.1 equivalents of 8a, 1.4 equivalents of NaOtBu, 1 mol% Pd
(unless stated otherwise), 3 mol% ligand, 4 mL of toluene per mmol of 1a. [b]Determined by GC and
1H NMR spectroscopy of the crude reaction mixture. Yields are indicated in parentheses. [c]DTPB =2-Di-tert-
butylphosphinobiphenyl. [d]XANTPHOS =9,9-Dimethyl-4,5-bis-(diphenylphosphino)xanthene. [e]1 mol% of
ligand was used.
Table 7. Optimization of the reaction conditions for the reaction of 1a
and 8a with 1 mol% [Pd2(dba)3]and 3 mol% BINAP at 90 8C.
after abstraction of a proton by the base present;[26] 3) re-
ductive elimination to release the aryl amine and regenerate
the Pd(0) catalyst.[27]
Entry
Base
Solvent
t [h]Conversion
[a] [%]
1
2
3
4
5
6
7
8
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
Cs2CO3
Cs2CO3
K3PO4
toluene
dioxane
DMF
15 min
15 min
15 min
15 min
3
1
24
1
1
1
1
24
1
24
1
24
1
24
1
100
75
8
The same catalytic cycle can be proposed for the amina-
tion of alkenyl bromides discussed in this paper, simply by
replacing the aryl with a vinyl bromide. As both types of
bromides share a common mechanism, we found it interest-
ing to compare their relative reactivities. From a synthetic
point of view, it is interesting to study the relative rates, in
order to carry out chemoselective aminations of alkenyl bro-
mides in the presence of aryl bromides, or vice versa. In
fact, we had already observed very high chemoselectivity in
DME
6
toluene/H2O (1:1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DME
DME
DME
DME
dioxane
dioxane
dioxane
dioxane
25
9
Na2CO3
KOH
10
11
12
13
14
15
16
17
18
19
20
NaOH
NaOH
Cs2CO3
Cs2CO3
K3PO4
20
40
11
47
7
57
4
K3PO4
Cs2CO3
Cs2CO3
K3PO4
K3PO4
24
27
[a]Determined by GC and 1H NMR spectroscopy of the crude reaction
mixture.
Scheme 6. Proposed mechanism for palladium-catalyzed aryl and vinyl
aminations.
Scheme 5. Amination of 2-bromostyrene (1b) with primary amines.
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Palladium-Catalyzed Cross-Coupling Reactions
494 507
Table 8. Synthesis of imines 9 by coupling of primary amines 8 with 1-bromostyrene (1a).[a]
Entry
1
Amine
t [min]Product
Yield [%]Entry
98
Amine
9
t [min]Product
Yield [%]
15
45
98
2
15
98
86
86
10
90
90
3
20 h
4 h
11[c]
6h
3h
50[d]
4[b]
12
Bu-NH2
88
8l
5
6
15
15
98
98
13
14
15
15
98
96
7
8
15
25
98
98
15
15
94
[a]Reaction conditions: 1 equivalent of 1a, 1.1 equivalents of amine 8, 1.4 equivalents of NaOtBu, 1 mol% of [Pd2(dba)3], 3 mol% of BINAP, 4 mL of
toluene per mmol of 1a, 908C. [b]Reaction carried out with 2 mol% of [Pd 2(dba)3]and 6 mol% of BINAP in dioxane. [c]Reaction carried out with
2 mol% of [Pd2(dba)3]and 6 mol% of BINAP. [d]Determined by GC.
the coupling of primary amines (Table 8, entries 7,8,9, and
11). For these reasons, we decided to undertake a more de-
tailed study to confirm the preference of vinyl versus aryl
amination. With this purpose, competition experiments were
conducted in which equimolar amounts of 4-bromobiphenyl
(12) and 1-bromostyrene (1a) were reacted with 1 equiv of
morpholine (2a), N-methylaniline (2b), and 4-methoxyben-
zylamine (8n), respectively (Scheme 7). The reactions were
monitored by GC and by NMR spectroscopic analysis of the
crude reaction mixture. As represented in Scheme 7, in the
three examples examined, the compound coming from the
vinyl amination was the only product formed and in no case
were the aromatic amines 13 detected. It is apparent from
these results that in the absence of additional steric effects
the vinyl amination occurs preferentially to the aryl amina-
tion. The oxidative addition probably occurs faster for the
vinyl bromide 1a and, as an irreversible step, drives the re-
action exclusively to the vinyl amination. This is an interest-
ing observation that may allow sequential catalytic events in
cascade or step-by-step synthetic processes to be programed.
We are currently investigating different applications of this
selective reactivity.
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J. Barluenga et al.
FULL PAPER
Table 9. Synthesis of imines 10 by the cross-coupling reaction of vinyl bromides 5 with primary amines 8.[a]
and secondary amines. The re-
action with secondary amines
provides a new method for the
preparation of enamines, and in
particular, the present method-
ology constitutes the first gener-
al method for the preparation
of terminal isomerizable enam-
ines. Moreover, the reaction
with primary amines gives rise
to imines in very reduced times
and with lower catalyst loadings
than other methods. Among the
main limitations of the reaction
at this point of development
are the sensitivity to steric hin-
drance in both coupling part-
ners in the synthesis of enam-
ines and the low conversions
achieved in the reactions of pri-
mary amines with 2-bromosty-
renes. Nevertheless, taking into
account the wide scope of the
reaction and the synthetic ver-
satility of enamines and imines,
we believe this reaction will
become a very useful transfor-
mation in synthetic organic
chemistry.
Entry
Bromide
Amine
t [min]Imine
Yield [%]
1
15
90
2
3
4
15
15
20
94
95
92
5
6
25
45
94
93
[a]Reaction conditions: 1 equivalent of 5, 1 equivalent of amine, 1.4 equivalents of NaOtBu, 1 mol% of
[Pd2(dba)3], 3 mol% of BINAP, 4 mL of toluene per mmol of 5, 908C.
Experimental Section
General: All reactions were carried
out under a nitrogen atmosphere. Tol-
uene and hexane solvents were contin-
uously refluxed and freshly distilled
over sodium/benzophenone under ni-
trogen. NMR spectra were recorded at
300 or 200 MHz for 1H and 75 or
50.3 MHz for 13C spectra, with tetra-
methylsilane as the internal standard
for 1H and the residual solvent signals
as the standard for 13C spectra. Chemi-
cal shifts are given in ppm. Mass spec-
tra were obtained by EI (70 eV).
Pd(OAc)2 and Pd2(dba)3 were pur-
chased from Strem Chemical Co. and
used without further purification. All
phosphine ligands used are commer-
cially available from Strem or Aldrich
Scheme 7. Competition experiments of amination of alkenyl versus aryl bromides. [a]Obtained as the imine
tautomer
and were used without further purifi-
cation. NaOtBu was purchased from
Aldrich, stored in a flask purged with
Conclusion
nitrogen, and weighed in air. (2-Bromobut-3-enyl)benzene (5a),[28] (2-
bromoallyloxymethyl)benzene (5b),[29] (2-bromoallyl)methylphenylamine
(5c),[30] 2-bromodec-1-ene (5d),[31] and 1-(2-bromoallyloxy)-but-2-yne (5
e)[29] were all prepared according to literature procedures. All other
chemicals were used as received from commercial suppliers.
In summary, we have demonstrated that the palladium-cata-
lyzed amination of alkenyl bromides constitutes a very effi-
cient method for the preparation of imines and enamines
and that it expands the applicability of the palladium-cata-
lyzed CÀN bond forming cross-coupling reaction. The cata-
lytic system Pd/BINAP/NaOtBu has been found to be a
very suitable combination for the reaction with both primary
General procedure for palladium-catalyzed amination of vinyl bromides
with [Pd2(dba)3] (Method A): A Schlenk flask under a nitrogen atmos-
phere was charged with (Æ)-BINAP (0.03 mmol, 3 mol%), tris(dibenzyli-
deneacetone)dipalladium(0) (0.005 mmol, 1 mol%), sodium tert-butoxide
(1.4 mmol), and toluene (4 mL). After 1 min the vinyl bromide (1 mmol)
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Palladium-Catalyzed Cross-Coupling Reactions
494 507
and the amine (1.1 mmol) were added under nitrogen and the flask was
immersed in an oil bath and heated to 908C with stirring until the start-
ing vinyl bromide had been completely consumed as judged by GC anal-
ysis. The mixture was allowed to cool to room temperature, taken up in
hexanes (15 mL), and filtered through celite. The solvents were evaporat-
ed under reduced pressure. The residue was redissolved in hexanes
(15 mL), filtered again through celite, concentrated under reduced pres-
sure, and dried under high vacuum to remove the excess of amine. This
afforded a residue which consisted of the essentially pure enamine. The
enamines can be purified by Kugelrohr distillation under high vacuum
(dependent on the boiling point).
ture of 1008C gave 3e in 50% yield as a yellow oil after distillation in a
Kugelrohr apparatus (1908C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz):
d=1.30 1.25 (t, 3J=7.1 Hz, 3H), 3.75 3.69 (q, 3J=7.1 Hz, 2H), 4.91 (s, 1
H), 5.06 (s, 1H), 7.14 6.80 (m, 3H), 7.49 7.20 (m, 7H) ppm; 13C NMR
(CDCl3, 75 MHz): d=12.6 (CH3), 46.2 (CH2), 102.3 (CH2), 119.5 (2CH),
127.2 (2CH), 127.8 (CH), 128.1 (2CH), 128.3 (CH), 128.6 (2CH), 139.4
(C), 147.6 (C), 151.8 (C) ppm; HRMS: m/z calcd for C16H17N: 233.13555;
found: 233.13580.
Dibenzyl(1-phenylvinyl)amine (3f): The general procedure A with 1 mol
% of Pd(OAc)2, 3 mol% of (Æ)-BINAP, and a reaction temperature of
1008C gave 3f in 35% yield as a yellow oil after distillation in a Kugel-
rohr apparatus (2408C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz): d=
4.11 (s, 4H), 4.16 (s, 1H), 4.39 (s, 1H), 7.40 7.32 (m, 15H) ppm;
13C NMR (CDCl3, 75 MHz): d=53.22 (2CH2), 93.3 (CH2), 126.8 (2CH),
128.0 (3CH), 128.1 (3CH), 128.2 (3CH), 128.3 (2CH), 128.5 (2CH),
138.2 (2C), 139.5 (C), 154.8 (C) ppm; HRMS: m/z calcd for C22H21N:
299.16685; found: 299.16666.
General procedure for palladium-catalyzed amination of vinyl bromides
with Pd(OAc)2 (Method B): A Schlenk flask was charged with (Æ)-
BINAP (0.06 mmol, 6 mol%) under a nitrogen atmosphere and toluene
(2 mL) was added. The mixture was heated to 808C with stirring until
the BINAP was dissolved (ꢀ1 min). The solution was cooled to room
temperature and Pd(OAc)2 (0.03 mmol, 3 mol%) was added. Toluene
(1 mL) was added to rinse the Pd from the sides of the flask. The mixture
was stirred at room temperature for approximately 2 min, and the vinyl
bromide (1 mmol) and the amine (1.1 mmol) were added. After 2 min,
the sodium tert-butoxide (1.4 mmol) was added under nitrogen and addi-
tional toluene (1 mL) was added. The flask was immersed in an oil bath
and heated to 808C with stirring until the starting vinyl bromide had
been completely consumed as judged by GC analysis. The mixture was
allowed to cool to room temperature, taken up in hexanes (15 mL), and
filtered through celite. The solvents were evaporated under reduced pres-
sure. The residue was redissolved in hexanes (15 mL), filtered again
through celite, concentrated under reduced pressure, and dried under
high vacuum to remove the excess of amine. This afforded a residue
which consisted of the essentially pure enamine. The enamines can be pu-
rified by Kugelrohr distillation under high vacuum (dependent on the
boiling point).
1-(1-Phenylvinyl)piperidine 4-carboxylic acid ethyl ester (3g): The gener-
al procedure B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a
reaction temperature of 808C gave 3g in 90% yield as a yellow syrup
1
after distillation in a Kugelrohr apparatus (1908C) at 10À2 Torr. H NMR
(CDCl3, 300 MHz): d=1.30 1.26 (t, 3J=7.2 Hz, 3H), 1.95 1.83 (m, 4H),
2.53 2.41 (m, 3H), 3.30 3.26 (m, 2H), 4.19 4.15 (m, 3H), 4.31 (s, 1H),
7.34 7.30 (m, 3H), 7.48 7.45 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz):
d=14.1 (CH3), 28.2 (2CH2), 41.2 (CH), 48.9 (2CH2), 60.3 (CH2), 90.8
(CH2), 127.5 (2CH), 127.9 (CH), 128.1 (2CH), 139.8 (C), 157.3 (C), 175.0
(C) ppm; HRMS: m/z calcd for C16H21NO2: 259.15668; found: 259.15642.
8-(1-Phenylvinyl)-1,4-dioxa-8-aza-spiro[4,5]decane (3h): The general pro-
cedure B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reac-
tion temperature of 808C gave 3h in 90% yield as a yellow syrup after
distillation in a Kugelrohr apparatus (2008C) at 10À2 Torr. 1H NMR
(CDCl3, 200 MHz): d=1.82 1.76 (t, 3J=5.9, 4H), 3.02 2.96 (t, 3J=5.9, 4
H), 3.98 (s, 4H), 4.22 (s, 1H), 4.32 (s, 1H), 7.35 7.31 (m, 3H), 7.57 7.47
(m, 2H) ppm; 13C NMR (CDCl3, 50.3 MHz): d=34.6 (2CH2), 47.2 (2
CH2), 64.1 (2CH2), 91.1 (CH2), 107.2 (C), 127.4 (2CH), 127.8 (CH), 128.0
(2CH), 139.8 (C), 156.6 (C) ppm; HRMS: m/z calcd for C15H19NO2:
245.14103; found: 245.14142.
4-(1-Phenylvinyl)morpholine (3a): The general procedure A with 1 mol
% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of
908C gave 3a in 96% yield as a light yellow oil after distillation in a Ku-
1
gelrohr apparatus (1508C) at 10À2 Torr. H NMR (CDCl3, 300 MHz): d=
2.85 2.82 (t, 3J=4.8 Hz, 4H), 3.78 3.75 (t, 3J=4.8 Hz, 4H), 4.21 (s, 1H),
4.35 (s, 1H), 7.34 7.30 (m, 3H), 7.48 7.46 (m, 2H) ppm; 13C NMR
(CDCl3, 75 MHz): d=49.6 (2CH2), 66.7 (2CH2), 90.9 (CH2), 127.6 (2
CH), 127.9 (CH), 128.0 (2CH), 138.9 (C), 156.9 (C) ppm; HRMS: m/z
calcd for C12H15NO: 189.11481; found: 189.11456.
4-Styrylmorpholine (4a): The general procedure A with 1 mol% of
[Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of 908C
gave 4a in 95% yield as a yellow solid after distillation in a Kugelrohr
apparatus (1608C) at 10À2 Torr. M.p.: 78 808C; 1H NMR (CDCl3,
200 MHz): d=3.07 3.03 (t, 3J=4.8 Hz, 4H), 3.82 3.77 (t, 3J=4.8 Hz, 4
H), 5.52 5.45 (d, 3J=14.1 Hz, 1H), 6.69 6.62 (d, 3J=14.1 Hz, 1H), 7.29
7.26 (m, 5H) ppm; 13C NMR (CDCl3, 50.3 MHz): d=48.7 (2CH2), 66.2
(2CH2), 101.1 (CH), 124.0 (2CH), 124.2 (CH), 128.3 (2CH), 138.5 (C),
139.4 (CH) ppm; HRMS: m/z calcd for C12H15NO: 189.11481; found:
189.11468.
Benzylmethyl(1-phenylvinyl)amine (3b): The general procedure A with
1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 908C gave 3b in 95% yield as a yellow oil after distillation in a
Kugelrohr apparatus (1808C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz):
d=2.67 (s, 3H), 4.08 (s, 2H), 4.19 (s, 1H), 4.31 (s, 1H), 7.43 7.32 (m, 8
H), 7.65 7.62 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=38.4 (CH3),
57.3 (CH2), 90.6 (CH2), 127.4 (CH), 128.4 (2CH), 128.5 (2CH), 128.6 (2
CH), 128.7 (3CH), 139.2 (C), 140.5 (C), 157.2 (C) ppm; HRMS: m/z
calcd for C16H17N: 223.13555; found: 223.13586.
Methylphenylstyrylamine (4b): The general procedure A with 1 mol% of
[Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of 908C
gave 4b in 96% yield as a yellow oil after distillation in a Kugelrohr ap-
paratus (1808C) at 10À2 Torr . 1H NMR (CDCl3, 300 MHz): d=3.39 (s, 3
H), 5.86 5.81 (d, 3J=15 Hz, 1H), 7.27 7.12 (m, 4H), 7.56 7.41 (m, 7
H) ppm; 13C NMR (CDCl3, 75 MHz): d=35.2 (CH3), 103.4 (CH), 117.6
(2CH), 121.2 (CH), 124.1 (2CH), 124.2 (CH), 128.4 (2CH), 129.1 (2CH),
133.8 (CH), 138.7 (C), 147.4 (C) ppm; HRMS: m/z calcd for C15H15N:
209.11990; found: 209.12039.
Methylphenyl(1-phenylvinyl)amine (3c): The general procedure A with
1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 908C gave 3c in 97% yield as a yellow oil after distillation in a
Kugelrohr apparatus (1608C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz):
d=3.36 (s, 3H), 4.94 (s, 1H), 5.13 (s, 1H), 6.97 6.92 (m, 1H), 7.08 7.04
(m, 1H), 7.37 7.25 (m, 6H), 7.61 7.58 (m, 2H) ppm; 13C NMR (CDCl3,
75 MHz): d=40.8 (CH3), 100.5 (CH2), 120.1 (2CH), 120.2 (CH), 127.1 (2
CH), 127.7 (CH), 128.0 (2CH), 128.5 (2CH), 139.0 (C), 148.7 (C), 153.4
(C) ppm; HRMS: m/z calcd for C15H15N: 209.11990; found: 209.12035.
Ethylphenylstyrylamine (4c): The general procedure A with 1 mol% of
[Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of 100
8C gave 4c in 80% yield as a yellow oil after distillation in a Kugelrohr
apparatus (2008C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz): d=1.55
1.49 (t, 3J=7.2 Hz, 3H), 4.06 3.95 (q, 3J=7.2 Hz, 2H), 6.01 5.93 (d, 3J=
14.2 Hz, 1H), 7.55 7.27 (m, 10H) ppm; 13C NMR (CDCl3, 75 MHz): d=
11.6 (CH3), 42.5 (CH2), 103.2 (CH), 117.5 (2CH), 121.1 (CH), 124.1
(CH), 124.2 (CH), 128.4 (3CH), 129.2 (2CH), 131.9 (CH), 138.8 (C),
146.2 (C) ppm; HRMS: m/z calcd for C16H17N: 233.13555; found:
233.13775.
Diallyl(1-phenylvinyl)amine (3d): The general procedure A with 1 mol%
of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of 90
8C gave 3d in 75% yield as a yellow oil after distillation in a Kugelrohr
apparatus (1708C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz): d=3.62
3.60 (d, 3J=5.9 Hz, 4H), 4.16 (s, 1H), 4.23 (s, 1H), 5.22 5.16 (m, 4H),
5.89 5.78 (m, 2H), 7.37 7.34 (m, 3H), 7.51 7.46 (m, 2H) ppm; 13C NMR
(CDCl3, 75 MHz): d=51.9 (2CH2), 90.6 (CH2), 116.8 (2CH2), 127.8 (2
CH), 127.9 (2CH), 134.4 (CH), 140.2 (C), 154.8 (C) ppm; HRMS: m/z
calcd for C14H17N: 199.13555; found: 199.13567.
Dibenzylstyrylamine (4d): The general procedure A with 1 mol% of
[Pd2(dba)3], 3 mol% of P(o-tol)3, and a reaction temperature of 1008C
gave 4d in 90% yield as a yellow solid after distillation in a Kugelrohr
apparatus (2108C) at 10À2 Torr. M.p.: 120 1228C; 1H NMR (CDCl3,
Ethylphenyl(1-phenylvinyl)amine (3e): The general procedure A with
1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tempera-
503
Chem. Eur. J. 2004, 10, 494 507
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Barluenga et al.
FULL PAPER
300 MHz): d=4.37 (s, 4H), 5.43 5.39 (d, 3J=13.9 Hz, 1H), 7.18 7.13 (d,
3J=13.9 Hz, 1H), 7.42 7.26 (m, 15H) ppm; 13C NMR (CDCl3, 75 MHz):
d=54.6 (2CH2), 98.2 (CH), 123.3 (CH), 123.4 (2CH), 127.1 (2CH), 127.4
(3CH), 128.4 (4CH), 128.5 (3CH), 137.8 (2C), 138.9 (CH), 139.4
(C) ppm; HRMS: m/z calcd for C22H21N: 299.16685; found: 299.16733.
35.1 (CH2), 47.9 (2CH2), 66.5 (2CH2), 86.9 (CH2), 125.7 (CH), 128.0
(CH), 128.1 (CH), 128.2 (CH), 128.4 (CH), 141.5 (C), 154.4 (C) ppm.
4-(1-Benzyloxymethylvinyl)morpholine (6c): The general procedure B
with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction tem-
perature of 808C gave 6c in 96% yield as an orange oil. 1H NMR
(CDCl3, 300 MHz): d=3.00 2.97 (t, 3J=4.8 Hz, 4H), 3.78 3.75 (t, 3J=
4.8 Hz, 4H), 4.00 (s, 1H), 4.09 (s, 2H), 4.11 (s, 1H), 4.54 (s, 2H), 7.40
7.37 (m, 5H) ppm; 13C NMR (CDCl3, 75 MHz): d=47.4 (2CH2), 66.4 (2
CH2), 70.3 (CH2), 71.2 (CH2), 88.4 (CH2), 127.4 (2CH), 127.8 (2CH),
128.1 (CH), 137.9 (C), 150.4 (C) ppm; HRMS: m/z calcd for C14H19NO2:
233.14103; found: 233.13994.
Benzyl(3-bromobenzyl)styrylamine (4e): The general procedure A with
1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 1008C gave 4e in 70% yield as a yellow solid. 1H NMR (CDCl3,
3
200 MHz): d=4.48 (s, 4H), 5.39 5.34 (d, J=13.9 Hz, 1H), 7.5 7.2 (m, 15
H) ppm; 13C NMR (CDCl3, 50.3 MHz): d=54.7 (CH2), 55.5 (CH2), 98.6
(CH), 122.9 (C), 123.4 (CH), 123.5 (CH), 127.2 (2CH), 127.3 (CH), 127.4
(CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.5 (2CH), 128.6 (2CH),
132.7 (CH), 136.4 (C), 137.7 (C), 138.3 (CH), 139.2 (C) ppm.
(1-Benzyloxymethylvinyl)methylphenylamine (6d): The general proce-
dure B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reac-
tion temperature of 808C gave 6d in 95% yield as an orange oil.
1H NMR (CDCl3, 200 MHz): d=3.23 (s, 3H), 4.11 (s, 2H), 4.50 (s, 1H),
4.55 (s, 2H), 4.66 (s, 1H), 7.24 7.19 (m, 2H), 7.44 7.36 (m, 8H) ppm;
13C NMR (CDCl3, 50.3 MHz): d=40.9 (CH3), 69.9 (CH2), 71.7 (CH2),
93.4 (CH2), 112.1 (CH), 123.1 (CH), 123.6 (2CH), 127.5 (2CH), 128.1 (2
CH), 128.8 (2CH), 138.1 (C), 148.1 (C), 149.4 (C) ppm; HRMS: m/z
calcd for C17H19NO: 253.14734; found: 253.14611.
Benzyl(1-phenylethyl)styrylamine (4f): The general procedure A with
1 mol% of Pd(OAc)2, 3 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 1008C gave 4f in 64% yield as a yellow solid after distillation in a
Kugelrohr apparatus (2208C) at 10À2 Torr. M.p.: 122 1258C; 1H NMR
(CDCl3, 200 MHz): d=1.86 1.83 (d, 3J=6.9 Hz, 3H), 4.59 4.35 (q, 3J=
14.2 Hz, 2H), 4.86 4.76 (q, 3J=6.9 Hz, 1H), 5.59 5.53 (d, 3J=13.8 Hz, 1
H), 7.58 7.22 (m, 16H) ppm; 13C NMR (CDCl3, 50.3 MHz): d=19.0
(CH3), 51.1 (CH2), 60.6 (CH), 98.8 (CH), 123.1 (CH), 123.4 (2CH), 126.6
(2CH), 126.7 (3CH), 126.8 (2CH), 127.1 (CH), 128.3 (4CH), 136.1 (CH),
138.4 (C), 139.7 (C), 142.4 (C) ppm; HRMS: m/z calcd for C23H23N:
313.18250; found: 313.18301.
Methyl(2-morpholin-4-ylallyl)phenylamine (6e): The general procedure
B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction
temperature of 808C gave 6e in 96% yield as an orange oil. 1H NMR
(CDCl3, 300 MHz): d=2.97 2.94 (t, 3J=4.8 Hz, 4H), 3.00 (s, 3H), 3.78
3
Diallylstyrylamine (4g): The general procedure
B
with 3 mol% of
3.75 (t, J=4.8 Hz, 4H), 3.98 (s, 2H), 4.05 (s, 1H), 4.14 (s, 1H), 6.80 6.78
Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction temperature of 808C
gave 4g in 97% yield as a yellow oil after distillation in a Kugelrohr ap-
paratus (1608C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz): d=3.77 3.75
(d, 3J=5.7 Hz, 4H), 5.33 5.22 (m, 5H), 5.94 5.82 (m, 2H), 6.88 6.83 (d,
3J=14.2 Hz, 1H), 7.05 7.00 (m, 1H), 7.25 7.22 (m, 4H) ppm; 13C NMR
(CDCl3, 75 MHz): d=53.5 (2CH2), 97.8 (CH), 116.8 (2CH2), 123.1 (CH),
123.3 (2CH), 128.4 (2CH), 133.8 (CH), 137.8 (2CH), 139.6 (C) ppm;
HRMS: m/z calcd for C14H17N: 199.13555; found: 199.13574.
(m, 2H), 7.30 7.26 (m, 3H) ppm; 13C NMR (CDCl3, 75 MHz): d=37.4
(CH3), 48.1 (2CH2), 54.6 (CH2), 66.6 (2CH2), 87.4 (CH2), 112.2 (2CH),
116.4 (CH), 128.8 (2CH), 149.4 (C), 150.3 (C) ppm; HRMS: m/z calcd
for C14H20N2O: 232.15701; found: 232.15743.
N,N’-dimethyl-1-methylene-N,N’-diphenyl-1,2-ethanediamine (6f): The
general procedure B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP,
and a reaction temperature of 808C gave 6f in 95% yield as an orange
oil. 1H NMR (CDCl3, 300 MHz): d=3.01 (s, 3H), 3.21 (s, 3H), 4.00 (s, 2
H), 4.56 (s, 1H), 4.61 (s, 1H), 6.86 6.77 (m, 2H), 7.20 7.14 (m, 2H),
7.46 7.32 (m, 5H) ppm; 13C NMR (CDCl3, 75 MHz): d=37.9 (CH3), 41.5
(CH3), 55.2 (CH2), 93.5 (CH2), 111.8 (2CH), 115.9 (CH), 122.9 (CH),
123.0 (CH), 128.7 (2CH), 128.8 (CH), 128.9 (2CH), 148.2 (C), 148.9 (C),
149.2 (C) ppm; HRMS: m/z calcd for C17H20N2: 252.16210; found:
252.16314.
1-Styrylpiperidine 4-carboxylic acid ethyl ester (4h): The general proce-
dure B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reac-
tion temperature of 808C gave 4h in 95% yield as a yellow solid after
distillation in a Kugelrohr apparatus (1908C) at 10À2 Torr. M.p.: 62 65
8C; 1H NMR (CDCl3, 300 MHz): d=1.30 1.25 (t, 3J=7.1 Hz, 3H), 1.84
1.71 (m, 3J=4.2, 11.1 Hz, 2H), 1.99 1.93 (m, 2H), 2.46 2.36 (tt, 3J=3.7,
11.1 Hz, 1H), 2.79 2.70 (td, 3J=12.8, 11.6, 3.1 Hz, 2H), 3.44 3.38 (dt,
3J=3.7, 12.8 Hz, 2H), 4.20 4.13 (q, 3J=7.1 Hz, 2H), 5.42 5.38 (d, 3J=
14.2 Hz, 1H), 6.67 6.63 (d, 3J=14.2 Hz, 1H), 7.05 7.00 (m, 1H), 7.21
7.18 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz): d=14.1 (CH3), 27.4 (2
CH2), 40.9 (CH), 48.1 (2CH2), 60.3 (CH2), 100.3 (CH), 123.8 (2CH),
128.3 (2CH), 138.9 (C), 139.4 (CH), 174.5 (C) ppm; HRMS: m/z calcd
for C16H21NO2: 259.15668; found: 259.15677.
4-(1-methylenenonyl)morpholine (6g): The general procedure B with
3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 808C gave 6g in 96% yield as an orange oil. 1H NMR (CDCl3,
300 MHz): d=0.89 0.85 (t, 3J=6.7 Hz, 3H), 1.29 1.21 (m, 12H), 2.13
2.08 (t, 3J=7.6 Hz, 2H), 2.85 2.82 (t, 3J=4.8 Hz, 4H), 3.73 3.69 (t, 3J=
4.8 Hz, 4H), 3.79 (s, 1H), 3.89 (s, 1H) ppm; 13C NMR (CDCl3, 75 MHz):
d=13.9 (CH3), 22.5 (CH2), 24.3 (CH2), 29.1 (CH2), 29.2 (CH2), 29.3
(CH2), 31.7 (CH2), 33.4 (CH2), 48.1 (2CH2), 66.7 (2CH2), 85.9 (CH2),
155.4 (C) ppm; HRMS: m/z calcd for C14H27NO: 210.18793; found:
210.18741.
8-Styryl-1,4-dioxa-8-aza-spiro[4,5]decane (4i): The general procedure B
with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction tem-
perature of 808C gave 4i in 97% yield as a yellow solid after distillation
in a Kugelrohr apparatus (1908C) at 10À2 Torr. M.p.: 65 688C; 1H NMR
(CDCl3, 300 MHz): d=3.01 2.97 (t, 3J=5.8 Hz, 4H), 4.42 4.38 (t, 3J=
5.8 Hz, 4H), 5.18 (s, 4H), 6.64 6.59 (d, 3J=14.1 Hz, 1H), 7.90 7.86 (d,
3J=14.1 Hz, 1H), 8.27 8.24 (m, 1H), 8.44 8.42 (m, 4H) ppm; 13C NMR
(CDCl3, 75 MHz): d=33.9 (2CH2), 46.6 (2CH2), 64.1 (2CH2), 100.4
(CH), 106.9 (C), 123.7 (2CH), 128.3 (2CH), 128.4 (CH), 138.8 (C), 139.0
(C) ppm; HRMS: m/z calcd for C15H19NO2: 245.14103; found: 245.14170.
Methyl(1-methylenenonyl)phenylamine (6h): The general procedure B
with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction tem-
perature of 808C gave 6h in 95% yield as an orange oil. 1H NMR
3
(CDCl3, 300 MHz): d=0.97 0.91 (t, J=6.7 Hz, 3H), 1.43 1.26 (m, 12H),
2.19 2.14 (t, 3J=7.5 Hz, 2H), 3.11 (s, 3H), 4.28 (s, 1H), 4.35 (s, 1H),
7.08 7.05 (m, 3H), 7.37 7.29 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz):
d=14.0 (CH3), 22.6 (CH2), 28.3 (CH2), 29.0 (CH2), 29.1 (CH2), 29.3
(CH2), 31.5 (CH2), 34.1 (CH2), 41.4 (CH2), 92.4 (CH2), 122.4 (CH), 123.3
(2CH), 128.7 (2CH), 148.8 (C), 153.8 (C) ppm; HRMS: m/z calcd for
C17H27N: 245.21380; found: 245.21334.
Methyl(1-methylene-3-phenylpropyl)phenylamine (6a): The general pro-
cedure B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reac-
tion temperature of 808C gave 6b in 90% yield as an orange oil.
1H NMR (CDCl3, 300 MHz): d=2.76 2.71 (m, 2H), 3.00 2.90 (m, 2H),
3.34 (s, 3H), 4.54 (s, 1H), 4.61 (s,1H), 7.55 7.30 (m, 10H) ppm; 13C NMR
(CDCl3, 75 MHz): d=34.7 (CH2), 36.1 (CH2), 41.4 (C), 92.4 (CH2), 122.1
(CH), 123.6 (CH), 125.4(CH), 127.9 (CH), 128.1 (2CH), 128.1 (2CH),
128.7 (2CH), 141.6 (C), 148.4 (C), 152.4 (C) ppm.
General procedure for palladium-catalyzed amination of vinyl bromides
with primary amines by using [Pd2(dba)3]: A Schlenk flask was charged
with (Æ)-BINAP (0.03 mmol, 3 mol%), tris(dibenzylideneacetone)dipal-
ladium(0) (0.005 mmol, 1 mol%), sodium tert-butoxide (1.4 mmol), and
toluene (2 mL) under a nitrogen atmosphere. After 1 min, the vinyl bro-
mide (1 mmol) and the amine (1.1 mmol) were added under nitrogen and
the flask was immersed in an oil bath and heated to 908C with stirring
until the starting vinyl bromide had been completely consumed as judged
by GC analysis. The mixture was allowed to cool to room temperature,
taken up in hexanes (15 mL), and filtered through celite. The solvents
were evaporated under reduced pressure. The residue was redissolved in
4-(1-Methylene-3-phenylpropyl)morpholine (6b): The general procedure
B with 3 mol% of Pd(OAc)2, 6 mol% of (Æ)-BINAP, and a reaction
temperature of 658C gave 6a in 90% yield as an orange oil . 1H NMR
(CDCl3, 300 MHz): d=2.53 2.59 (m, 2H), 2.86 2.81 (m, 2H), 2.93 2.90
(t, 3J=4.8 Hz, 4H), 3.85 3.82 (t, 3J=4.8 Hz, 4H), 4.01 (s, 1H), 4.09 (s, 1
H), 7.30 7.40 (m, 5H) ppm; 13C NMR (CDCl3, 75 MHz): d=34.6 (CH2),
504
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 494 507

Palladium-Catalyzed Cross-Coupling Reactions
494 507
hexanes (15 mL), filtered again through celite, concentrated under re-
duced pressure, and dried under high vacuum to remove the excess of
amine. This afforded a residue which consisted of the essentially pure
imine. The imines can be purified by Kugelrohr distillation under high
vacuum (dependent on the boiling point).
8.04 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=17.9 (CH3), 113.6 (C),
120.2 (CH), 124.3 (CH), 127.3 (2CH), 127.8 (CH), 128.2 (CH), 128.3
(CH), 130.7 (CH), 132.7 (CH), 138.7 (C), 149.8 (C), 167.3 (C) ppm;
HRMS: m/z calcd for C14H12BrN: 273.01476; found: 273.01371.
(3-Bromophenyl)(1-phenylethylidene)amine (9h): The general procedure
with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9h in 98% yield as a yellow oil after distillation in
(4-Methoxyphenyl)(1-phenylethylidene)amine (9a): The general proce-
dure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction
temperature of 908C gave 9a in 98% yield as a light yellow oil after dis-
1
a Kugelrohr apparatus (1908C) at 10À2 Torr. H NMR (CDCl3, 200 MHz):
1
tillation in a Kugelrohr apparatus (1808C) at 10À2 Torr. H NMR (CDCl3,
d=2.28 (s, 3H), 6.79 6.76 (m, 1H), 7.03 7.02 (m, 1H), 7.26 7.24 (m, 2
H), 7.51 7.48 (m, 3H), 8.02 7.99 (m, 2H) ppm; 13C NMR (CDCl3,
50.3 MHz): d=17.4 (CH3), 118.0 (CH), 122.2 (CH), 122.3 (C), 125.9
(CH), 127.1 (2CH), 128.3 (2CH), 130.2 (CH), 130.7 (CH), 138.8 (C),
152.9 (C), 166.2 (C) ppm; HRMS: m/z calcd for C14H12BrN: 273.01476;
found: 273.01454.
300 MHz): d=2.27 (s, 3H), 3.62 (s, 3H), 6.80 6.78 (d, 3J=8.6 Hz, 2H),
3
6.95 6.92 (d, J=8.6 Hz, 2H), 7.47 7.43 (m, 3H), 8.01 7.98 (m, 2H) ppm;
13C NMR (CDCl3, 75 MHz): d=17.1 (CH3), 55.2 (CH3), 114.1 (2CH),
120.6 (2CH), 126.9 (2CH), 128.2 (2CH), 130.1 (CH), 139.6 (C), 144.6
(C), 155.8 (C), 165.5 (C) ppm; HRMS: m/z calcd for C15H15NO:
225.11481; found: 225.11505.
(4-Bromophenyl)(1-phenylethylidene)amine (9i): The general procedure
with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9i in 98% yield as a yellow oil after distillation in
(1-Phenylethylidene)p-tolylamine (9b): The general procedure with
1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 908C gave 9b in 98% yield as a light yellow oil after distillation
1
a Kugelrohr apparatus (1908C) at 10À2 Torr. H NMR (CDCl3, 300 MHz):
Kugelrohr apparatus (1708C) at 10À2 Torr. 1H NMR (CDCl3,
d=2.24 (s, 3H), 6.72 6.69 (d, 3J=8.5 Hz, 2H), 7.49 7.46 (m, 5H), 8.01
7.97 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=17.2 (CH3), 115.9 (C),
121.1 (2CH), 127.0 (2CH), 128.2 (2CH), 130.5 (2CH), 131.8 (CH), 138.9
(C), 150.5 (C), 165.9 (C) ppm; HRMS: m/z calcd for C14H12BrN:
273.01476; found: 273.01444.
in
a
3
200 MHz): d=2.32 (s, 3H), 2.45 (s, 3H), 6.84 (d, J=8 Hz, 2H), 7.28 7.24
(d, 3J=8 Hz, 2H), 7.55 7.52 (m, 3H), 8.10 8.05 (m, 2H) ppm; 13C NMR
(CDCl3, 50.3 MHz): d=17.0 (CH3), 20.6 (CH3), 119.2 (2CH), 126.9 (2
CH), 128.1 (2CH), 129.3 (2CH), 130.1 (CH), 132.3 (C), 139.4 (C), 148.9
(C), 165.1 (C) ppm; HRMS: m/z calcd for C15H15N: 209.11990; found:
209.11962.
(1-Phenylethylidene)(2,4,6-trimethylphenyl)amine (9j): The general pro-
cedure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reac-
tion temperature of 908C gave 9j in 92% yield as a yellow oil after distil-
lation in a Kugelrohr apparatus (1908C) at 10À2 Torr. 1H NMR (CDCl3,
300 MHz): d=2.06 (s, 6H), 2.12 (s, 3H), 2.35 (s, 3H), 6.94 (s, 2H), 7.53
7.51 (m, 3H), 8.09 8.07 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=
17.3 (CH3), 17.8 (CH3), 20.6 (CH3), 125.4 (C), 126.9 (2CH), 128.3 (2CH),
128.4 (2CH), 130.2 (CH), 131.7 (C), 139.1 (C), 146.3 (C), 165.3 (C) ppm;
HRMS: m/z calcd for C17H19N: 237.15120; found: 237.15218.
4-(1-Phenylethylideneamino)benzonitrile (9c): The general procedure
with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9c in 86% yield as a yellow solid. 1H NMR
(CDCl3, 300 MHz): d=0.22 (s, 3H), 6.86 6.83 (d, 3J=8.5 Hz, 2H), 7.48
7.45 (m, 3H), 7.61 7.58 (d, 3J=8.3 Hz, 2H), 7.98 7.95 (m, 2H) ppm;
13C NMR (CDCl3, 75 MHz): d=17.6 (CH3), 106.2 (C), 119.2 (C), 119.8 (2
CH), 127.1 (2CH), 128.4 (2CH), 131.0 (CH), 133.1 (2CH), 138.2 (C),
155.6 (C), 166.1 (C) ppm; HRMS: m/z calcd for C15H12N2: 220.0995;
found: 220.10012.
(2,6-Dibromophenyl)(1-phenylethylidene)amine (9k): The general proce-
dure with 2 mol% of [Pd2(dba)3], 6 mol% of (Æ)-BINAP, and a reaction
temperature of 908C gave 9k in 50% conversion as an orange solid.
1H NMR (CDCl3, 300 MHz): d=0.19 (s, 3H), 6.85 6.80 (t, 3J=7.9 Hz, 1
H), 7.58 7.49 (m, 5H), 8.01 8.06 (m, 2H) ppm; 13C NMR (CDCl3,
75 MHz): d=18.7 (CH3), 113.8 (C), 124.8 (CH), 127.5 (2CH), 128.4 (2
CH), 131.1 (CH), 131.6 (2CH), 131.7 (CH), 138.2 (C), 148.2 (C), 164.4
(C) ppm; HRMS: m/z calcd for C14H11Br2N: 350.92527; found: 350.92542.
(4-Nitrophenyl)(1-phenylethylidene)amine (9d): The general procedure
with 2 mol% of [Pd2(dba)3], 6 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9d in 86% yield as a yellow solid after distillation
in
a
Kugelrohr apparatus (1908C) at 10À2 Torr. M.p.: 125 1288C;
1H NMR (CDCl3, 300 MHz): d=2.26 (s, 3H), 6.89 6.86 (d, 3J=8.5 Hz, 2
H), 7.49 7.46 (m, 3H), 7.98 7.96 (d, 3J=7.4 Hz, 2H), 8.24 8.21 (d, 3J=
8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=17.7 (CH3), 119.4 (2
CH), 124.9 (2CH), 127.2 (2CH), 128.4 (2CH), 131.1 (CH), 138.1 (C),
143.5 (C), 157.6 (C), 166.1 (C) ppm; HRMS: m/z calcd for C14H12N2O2:
240.08932; found: 240.09015.
Butyl(1-phenylethylidene)amine (9l): The general procedure with 1 mol
% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of
908C gave 9l in 88% yield as a yellow oil after distillation in a Kugelrohr
apparatus (1508C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz): d=1.09
(1-Phenylethylidene)-o-tolylamine (9e): The general procedure with
1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tempera-
ture of 908C gave 9e in 98% yield as a yellow oil after distillation in a
Kugelrohr apparatus (1708C) at 10À2 Torr. 1H NMR (CDCl3, 200 MHz):
d=2.16 (s, 3H), 2.23 (s, 3H), 6.72 6.69 (d, 3J=7.9 Hz, 1H), 7.08 7.03 (t,
3J=7.7 Hz, 1H), 7.29 7.21 (m, 2H), 7.52 7.50 (m, 3H), 8.08 8.05 (m, 2
H) ppm; 13C NMR (CDCl3, 50.3 MHz): d=17.3 (CH3), 17.6 (CH3), 118.3
(CH), 123.1 (CH), 126.3 (CH), 127.0 (2CH), 128.3 (2CH), 130.2 (CH),
130.3 (CH), 139.3 (2C), 150.2 (C), 164.8 (C) ppm; HRMS: m/z calcd for
C15H15N: 209.11990; found: 209.11950.
3
1.04 (t, J=7.3 Hz, 3H), 1.64 1.49 (m, 3J=7.3 Hz, 2H), 1.87 1.77 (q, 3J=
7.3 Hz, 2H), 2.26 (s, 3H), 3.57 3.52 (t, 3J=7.3 Hz, 2H), 7.43 7.40 (m, 3
H), 7.88 7.83 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=13.8 (CH3),
15.1 (CH3), 20.6 (CH2), 32.9 (CH2), 51.7 (CH2), 126.3 (2CH), 127.9 (2
CH), 128.9 (CH), 141.2 (C), 164.4 (C) ppm; HRMS: m/z calcd for
C12H17N: 175.12772; found: 175.12773.
Allyl(1-phenylethylidene)amine (9m): The general procedure with 1 mol
% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction temperature of
908C gave 9m in 98% yield as a yellow oil after distillation in a Kugel-
rohr apparatus (1408C) at 10À2 Torr. 1H NMR (CDCl3, 300 MHz): d=
2.24 (s, 3H), 4.19 4.18 (d, 3J=4.4 Hz, 2H), 5.18 5.14 (dd, 3J=1.7,
10.5 Hz, 1H), 5.30 5.24 (dd, 3J=1.7, 17.1 Hz, 1H), 6.20 6.07 (m, 1H),
7.39 7.37 (m, 3H), 7.83 7.80 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz):
d=15.4 (CH3), 54.4 (CH2), 114.9 (CH2), 126.5 (2CH), 128.1 (2CH), 129.4
(CH), 135.8 (CH), 140.9 (C), 166.1 (C) ppm.
(2-Methoxyphenyl)(1-phenylethylidene)amine (9f): The general proce-
dure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction
temperature of 908C gave 9f in 98% yield as a yellow oil after distilla-
tion in a Kugelrohr apparatus (1808C) at 10À2 Torr. 1H NMR (CDCl3,
200 MHz): d=2.25 (s, 3H), 3.82 (s, 3H), 6.87 6.82 (m, 1H), 7.1 6.98 (m,
3H), 7.51 7.48 (m, 3H), 8.09 8.0 (m, 2H); 13C NMR (CDCl3, 50.3 MHz):
d=17.6 (CH3), 55.4 (CH3), 111.4 (CH), 120.4 (CH), 120.7 (CH), 123.9
(CH), 127.1 (2CH), 128.1 (2CH), 130.2 (CH), 139.2 (C), 140.4 (C), 148.7
(C), 16.8 (C) ppm; HRMS: m/z calcd for C15H15NO: 225.11481; found:
225.11464.
4-Methoxybenzyl(1-phenylethylidene)amine (9n): The general procedure
with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9n in 96% yield as a yellow oil after distillation in
1
a Kugelrohr apparatus (2008C) at 10À2 Torr. H NMR (CDCl3, 200 MHz):
d=2.36 (s, 3H), 3.84 (s, 3H), 4.73 (s, 2H), 6.97 6.93 (d, 3J=8.7 Hz, 2H),
7.45 7.38 (m, 5H), 7.91 7.88 (m, 2H) ppm; 13C NMR (CDCl3,
50.3 MHz): d=15.6 (CH3), 54.9 (CH2), 55.4 (CH3), 113.6 (2CH), 126.6 (2
CH), 128.1 (2CH), 128.6 (2CH), 129.4 (CH), 132.5 (C), 140.9 (C), 158.2
(C), 165.5 (C) ppm; HRMS: m/z calcd for C16H17NO: 239.13046; found:
239.13018.
(2-Bromophenyl)(1-phenylethylidene)amine (9g): The general procedure
with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9g in 98% yield as a yellow oil after distillation in
1
a Kugelrohr apparatus (1908C) at 10À2 Torr. H NMR (CDCl3, 300 MHz):
d=2.23 (s, 3H), 6.88 6.83 (dd, 3J=1.4, 7.7 Hz, 1H), 7.35 7.30 (t, 3J=
3
7.7 Hz, 1H), 7.52 7.49 (m, 3H), 7.66 7.63 (dd, J=1.1, 7.9 Hz, 1H), 8.06
505
Chem. Eur. J. 2004, 10, 494 507
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Barluenga et al.
FULL PAPER
(1-Phenylethyl)(1-phenylethylidene)amine (9o): The general procedure
with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction tem-
perature of 908C gave 9o in 94% yield as a yellow oil after distillation in
Acknowledgement
Financial support for this work by was provided by the DirecciÛn Gener-
al de InvestigaciÛn (DGI) of Spain (BQU-2001 3853) and and the
FYCYT of Spain (PR-01-GE-09).
1
a Kugelrohr apparatus (2008C) at 10À2 Torr. H NMR (CDCl3, 300 MHz):
3
3
d=1.65 1.63 (d, J=6.5 Hz, 3H), 2.33 (s, 3H), 4.95 4.81 (q, J=6.5 Hz, 1
H), 7.55 7.30 (m, 8H), 7.57 7.55 (m, 2H) ppm; 13C NMR (CDCl3,
75 MHz): d=15.4 (CH3), 24.9 (CH3), 59.7 (CH), 126.4 (CH), 126.5 (2
CH), 126.6 (2CH), 128.1 (2CH), 128.2 (2CH), 129.2 (CH), 141.3 (C),
146.1 (C), 163.3 (C) ppm; HRMS: m/z calcd for C16H17N: 223.13555;
found: 223.15517.
[1]a) The Chemistry ofEnamines (Ed.: Z. Rappaport), Wiley, New
York, 1994. b) Enamines: Synthesis, Structure and Reactions, 2nd ed.
(Ed.: A. G. Cook), Marcel Dekker, New York, 1998.
(2-Benzyloxy-1-methylethylidene)(4-methoxyphenyl)amine (10a): The
general procedure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP,
and a reaction temperature of 908C gave 10a in 90% yield as an orange
oil. 1H NMR (CDCl3, 300 MHz): d=1.89 (s, 3H), 3.80 (s, 3H), 4.23 (s, 2
H), 4.67 (s, 2H), 6.75 6.70 (m, 2H), 6.91 6.88 (m, 2H), 7.43 7.40 (m, 5
H) ppm; 13C NMR (CDCl3, 75 MHz): d=16.5 (CH3), 55.1 (CH3), 72.8
(CH2), 75.4 (CH2), 113.9 (2CH), 120.5 (2CH), 127.6 (CH), 127.7 (2CH),
128.2 (2CH), 137.5 (C), 143.4 (C), 155.8 (C), 169.3 (C) ppm; HRMS: m/z
calcd for C17H19NO2: 269.14103; found: 269.14074.
[2]P. W. Hickmott, Tetrahedron 1982, 38, 1975 2050.
[3]S. F. Martin, R. Gompper, J. Org. Chem. 1974, 39, 2814.
[4]N. A. Petasis, S. P. Lu, Tetrahedron Lett. 1995, 36, 2393 2396.
[5]a) J. Barluenga, F. Aznar, Synthesis 1975, 704 705; b) J. Barluenga,
F. Aznar, Synthesis 1977, 195 196; c) J. Barluenga, F. Aznar, R. Liz,
R. Rodes, J. Chem. Soc. Perkin Trans. 1 1980, 2732 2737.
[6]For recent reviews in metal-catalyzed alkyne hydroaminations, see:
a) M. Beller, C. Breindl, M. Eichberger, C. G. Hartung, J. Seayad,
O. R. Thiel, A. Tillack, H. Trauthwein, Synlett 2002, 10, 1579 1594;
b) I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2003, 935 946.
[7]For some very recent examples of intermolecular hydroaminations,
see: a) T. Shimada, Y. Yamamoto, J. Am. Chem. Soc. 2002, 124, 12
670 12671; b) A. Tillack, I. GarcÌa Castro, C. G. Hartung, M.
Beller, Angew. Chem. 2002, 114, 2646 2648; Angew. Chem. Int. Ed.
2002, 41, 2541 2543.
[8]For recent reviews in the palladium-catalyzed aryl amination, see:
a) J. P. Wolfe, S. Wagaw, J. F. Marcoux, S. L. Buchwald, Acc. Chem.
Res. 1998, 31, 805 818; b) J. F. Hartwig, Acc. Chem. Res. 1998, 31,
852 860; c) J. F. Hartwig, in Modern Amination Methods (Ed.: A.
Ricci), Wiley-VCH, Weinheim, Germany, 2000; d) A. R. Muci, S. L.
Buchwald, Top. Curr. Chem. 2002, 219, 133 209.
[9]For some leading references on the amination of aryl bromides, see:
a) J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy,
L. M. Alcazar-Roman, J. Org. Chem. 1999, 64, 5575 5580; b) J. P.
Wolfe, S. L. Buchwald, J. Org. Chem. 2000, 65, 1144 1157, and ref-
erences therein.
[10]For some leading references on the amination of aryl chlorides, see:
a) D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998,
120, 9722 9723; b) J. P. Stambuli, R. Kuwano, J. F. Hartwig, Angew.
Chem. 2002, 114, 4940 4942; Angew. Chem. Int. Ed. 2002, 41,
4746 4748; c) A. Schnyder, A. F. Indolese, M. Studer, H.-U. Blaser,
Angew. Chem. 2002, 114, 3820 3823; Angew. Chem. Int. Ed. 2002,
41, 3668 3671; d) S. M. Viciu, R. A. Kelly III, E. D. Stevens, F.
Naud, M. Studer, S. P. Nolan, Org. Lett. 2003, 5, 1479 1482.
[11]X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L.
Buchwald, J. Am. Chem. Soc. 2003, 125, 6653 6655, and references
therein.
[12]a) J. P. Wolfe, R. A. Rennels, S. L. Buchwald, Tetrahedron 1996, 52,
7525 7546; b) B. H. Yang, S. L. Buchwald, Org. Lett. 1999, 1, 35
37; c) J. Yin, S. L. Buchwald, Org. Lett. 2000, 2, 1101 1104; d) J.
Yin, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 6043 6048;
e) M. C. Harris, X. Huang, S. L. Buchwald, Org. Lett. 2002, 4, 2885;
f) J. F. Hartwig, M. Kawatsura, S. L. Hauck, K. H. Shaughnessy,
L. M. Alcazar-Roman, J. Org. Chem. 1999, 64, 5575 5580.
[13]Preliminary report of this article: J. Barluenga, F. Aznar, M. A.
Fernµndez, C. Valdÿs, Chem. Commun. 2002, 2362 2363.
[14]A. Y. Lebedev, V. V. Izmer, D. N. Kazyul ’kin, I. P. Beletskaya, A. Z.
Voskoboynikov, Org. Lett. 2002, 4, 623 626.
[15]a) Y. Kozawa, M. Mori, Tetrahedron Lett. 2002, 43, 111; b) Y.
Kozawa, M. Mori, J. Org. Chem. 2003, 68, 3064 3067.
[16]M. C. Willis, G. N. Brace, Tetrahedron Lett. 2002, 43, 9085 9088.
[17]J. Barluenga, C. Mateos, F. Aznar, C. Valdÿs, Org. Lett. 2002, 4,
1971 1974, and references therein.
(2-But-2-ynyloxy-1-methylethylidene)(4-methoxyphenyl)amine
(10b):
The general procedure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-
BINAP, and a reaction temperature of 908C gave 10b in 94% yield as an
orange oil. 1H NMR (CDCl3, 300 MHz): d=1.72 (s, 6H), 3.62 (s, 3H),
4.10 (s, 4H), 6.58 6.54 (m, 2H), 6.74 6.71 (m, 2H) ppm; 13C NMR
(CDCl3, 75 MHz): d=3.0 (CH3), 16.2 (CH3), 54.7 (CH3), 58.2 (CH2), 74.1
(CH2), 74.3 (C), 82.6 (C), 113.6 (2CH), 120.6 (2CH), 143.1 (C), 155.5
(C), 169.4 (C) ppm; HRMS: m/z calcd for C14H17NO2: 231.12538; found:
231.12493.
(4-Methoxyphenyl)(1-methylnonylidene)amine (10c): The general proce-
dure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a reaction
temperature of 908C gave 10c in 95% yield as an orange oil. 1H NMR
3
(CDCl3, 300 MHz): d=0.91 0.87 (t, J=6.1 Hz, 3H), 1.35 1.20 (m, 10H),
1.73 1.69 (m, 2H), 1.78 (s, 3H), 2.42 2.36 (t, 3J=7.9 Hz, 2H), 3.78 (s, 3
H), 6.66 6.62 (m, 2H), 6.89 6.82 (m, 2H) ppm; 13C NMR (CDCl3,
75 MHz): d=13.9 (CH3), 19.1 (CH3), 22.5 (CH2), 26.3 (CH2), 29.1 (CH2),
29.2 (CH2), 29.3 (CH2), 31.7 (CH2), 41.7 (CH2), 55.2 (CH3), 113.9 (2CH),
120.5 (2CH), 144.7 (C), 155.5 (C), 172.4 (C) ppm; HRMS: m/z calcd for
C17H27NO: 261.20871; found: 261.20993.
(4-Methoxyphenyl)[1-methyl-2-(methylphenylamino)ethylidene]amine
(10d): The general procedure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-
BINAP, and a reaction temperature of 908C gave 10d in 92% yield as an
orange oil. 1H NMR (CDCl3, 300 MHz): d=1.81 (s, 3H), 3.13 (s, 3H),
3.81 (s, 3H), 4.19 (s, 2H), 6.81 6.71 (m, 3H), 6.92 6.86 (m, 4H), 7.34
7.29 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz): d=16.7 (CH3), 39.2
(CH3), 55.1 (CH3), 62.0 (CH2), 112.1 (2CH), 113.9 (2CH), 116.6 (CH),
120.4 (2CH), 128.9 (2CH), 143.6 (C), 149.1 (C), 155.7 (C), 170.9
(C) ppm; HRMS: m/z calcd for C17H20N2O: 268.15701; found: 268.15743.
(2-Benzyloxy-1-methylethylidene)(4-methoxybenzyl)amine (10e): The
general procedure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP,
and a reaction temperature of 908C gave 10e in 94% yield as an orange
oil. 1H NMR (CDCl3, 200 MHz): d=2.02 (s, 3H), 3.82 (s, 3H), 4.16 (s, 2
H), 4.52 (s, 2H), 4.59 (s, 2H), 6.95 6.91 (m, 2H), 7.40 7.28 (m, 7H) ppm;
13C NMR (CDCl3, 50.3 MHz): d=14.8 (CH3), 54.3 (CH2), 54.9 (CH3),
72.5 (CH2), 76.4 (CH2), 113.6 (2CH), 127.5 (CH), 127.6 (2CH), 128.1 (2
CH), 128.7 (2CH), 131.8 (C), 137.7 (C), 158.2 (C), 168.1 (C) ppm;
HRMS: m/z calcd for C18H21NO2: 283.15668; found: 283.15680.
[2-(4-Methoxybenzylimino)propyl]methylphenylamine (10f): The general
procedure with 1 mol% of [Pd2(dba)3], 3 mol% of (Æ)-BINAP, and a re-
action temperature of 908C gave 10f in 93% yield as an orange oil.
1H NMR (CDCl3, 200 MHz): d=1.92 (s, 3H), 3.09 (s, 3H), 3.85 (s, 3H),
4.12 (s, 2H), 4.56 (s, 2H), 6.88 6.82 (d, 3J=8.7 Hz, 2H), 6.97 6.94 (d,
3J=8.7 Hz, 2H), 7.32 7.30 (m, 5H) ppm; 13C NMR (CDCl3, 50.3 MHz):
d=14.8 (CH3), 38.9 (CH3), 54.3 (CH2), 54.9 (CH3), 62.4 (CH2), 112.2 (2
CH), 113.6 (2CH), 116.4 (CH), 128.6 (2CH), 128.8 (2CH), 131.9 (C),
149.3 (C), 158.1 (C), 169.3 (C) ppm; HRMS: m/z calcd for C18H22N2O:
282.17266; found: 282.17303.
[18]J. Barluenga, F. Aznar, R. Liz, M. Bayod, J. Org. Chem. 1987, 52,
5190 5194.
[19]F. Aznar, C. Valdÿs, M.-P. Cabal, Tetrahedron Lett. 2000, 41, 5683.
[20]The ligand screening was restricted to commercially available and
mostly air-stable ligands.
[21]The preformed Pd(OAc) 2/BINAP system, as described by Wolfe and
Buchwald in ref. [9b], gives similar results to [Pd2(dba)3]/BINAP.
506
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 494 507

Palladium-Catalyzed Cross-Coupling Reactions
494 507
[22]J. Barluenga, F. Aznar, R. Liz, C. Postigo, J. Chem. Soc. Chem.Com-
mun. 1986, 1465 1467.
[23]Product inhibition has been previously observed in palladium-cata-
lyzed aryl aminations: L. M. Alcazar-Roman, J. F. Hartwig, A. L.
Rheingold, L. M. Liable-Sands, I. A. Guzei, J. Am. Chem. Soc. 2000,
122, 4618 4630.
[24]L. M. Alcazar-Roman, J. F. Hartwig, A. L. Rheingold, L. M. Liable-
Sands, I. A. Guzei, J. Am. Chem. Soc. 2000, 122, 4618 4630.
[25]L. M. Alcazar-Roman, J. F. Hartwig, Organometallics, 2002, 21, 491
502.
[26]Recently Buchwald and co-workers have proposed an alternative
mechanism in which amine coordination to the metal center would
take place first, followed by the oxidative addition: U. K. Singh,
E. R. Strieter, D. G. Blackmond, S. L. Buchwald, J. Am. Chem. Soc.
2002, 124, 14104 14114.
[27]G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118, 13109 13110.
[28] Org. Syn. Coll. Vol. 1, John Wiley & Sons, New York, 1948, p. 186.
[29]S. Weigand, R. Br¸ckner, Synlett, 1997, 225 228.
[30]J. Barluenga, R. M. Canteli, J. FlÛrez, S. GarcÌa-Granda, A. Gutier-
rez-Rodriguez, E. MartÌn, J. Am. Chem. Soc. 1998, 120, 2514 2522.
[31]S. Hara, H. Dojo, S. Takinami, A. Suzuki, Tetrahedron Lett. 1983,
24, 731 734.
Received: July 29, 2003 [F5406]
507
Chem. Eur. J. 2004, 10, 494 507
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim