Palladium-Catalyzed Three-Component Synthesis of Functionalized Allylamines by Intermolecular Tandem Carbopalladation-Amination

Article abstract of DOI:10.1002/1615-4169(20010330)343:3<255::aid-adsc255>3.0.co;2-t

Highly regio- and stereoselective formation of allylamines has been achieved through a three-component reaction between iodobenzene, an allene, and an amine in acetonitrile, catalyzed by in situ formed and by isolated palladium-diphosphine catalysts.

Full text of DOI:10.1002/1615-4169(20010330)343:3<255::aid-adsc255>3.0.co;2-t

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Palladium-Catalyzed Three-Component Synthesis
of Functionalized Allylamines by Intermolecular
Tandem Carbopalladation±Amination
Martijn W. van Laren, Jeroen J. H. Diederen, Cornelis J. Elsevier*
Institute of Molecular Chemistry, Coordination and Organometallic Chemistry, Universiteit van Amsterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands
Fax: (+31) 20-525-6456, E-mail: else4@anorg.chem.uva.nl
Received December 20, 2000; Accepted January 31, 2001
Abstract: Highly regio- and stereoselective forma- an allene, and an amine in acetonitrile, catalyzed by
tion of allylamines has been achieved through a in situ formed and by isolated palladium-diphos-
three-component reaction between iodobenzene, phine catalysts.
Catalytic carbon-nitrogen
coupling is a highly de-
sired chemical reaction
and the development of
suitable synthetic proto-
cols for such reactions is
and 3). These can be cho-
sen relatively freely, but
few methods allow intro-
duction of substituents at
position 2 (see Scheme 1
for numbering). In one
Keywords: allylamines; allylic amination; carbo-
palladation; homogeneous catalysis; palladium; P
ligands
currently receiving ample attention. Examples are instance, a zirconocene-imine complex was reacted
the catalytic amination of aryl halides (Scheme 1)[1] with an alkyne to provide stereochemically pure
and the amination of allylic substrates.[2]
products. This procedure allows the choice of substi-
tuents at all three positions of the allylic moiety, but a
severe drawback is the stoichiometric use of the
zirconium compound involved.[5] Direct hydro-
amination of dienes and allenes would be a very at-
tractive route to allylamines, but the selectivity is of-
ten very difficult to control and dimers or telomers
are often obtained.[6]
Scheme 1. Selected transition metal-catalyzed C±N coup-
ling reactions.
Allylamines are important synthetic targets which are
found in many natural products; they often find appli-
cation in products after subsequent transformations,
e. g., amino acids, alkaloids.[3] Several stoichiometric
and catalytic methods for the synthesis of a wide
range of allylamines are known.[3,4,5] In these cases
two components are employed and, usually, substitu-
ents are introduced at the allylic termini (positions 1
Scheme 2. Anticipated reactions for a three-component in-
termolecular carbopalladation-amination of allenes to give
allylamines.
Adv. Synth. Catal. 2001, 343, No. 3
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Insertion of allenes into palladium-carbon bonds of
aryl-Pd and acyl-Pd compounds proceeds readily and
protocols based on this reaction involving intramole-
cular attack by N-nucleophiles on the incipient p-al-
lylpalladium complex to give valuable heterocyclic
compounds are known.[7] An elegant example is the
trapping of an allylpalladium(II) complex by internal
N-nucleophiles in reactions of w-2,3-dienyllactams
with iodobenzene to give tetrahydropyrrolizin-3-ones
and tetrahydro-2H-indolizin-3-ones.[7b] Intermolecu-
lar variants involving two components have also been
established;[8] these proceed by intramolecular ring
closure as the final step.
Figure 1.
We reasoned that, if the direct nucleophilic attack
of the amine on the organic halide is slow (which is
known to be the case for aryl halides) as compared to
the allene insertion, one could envisage a three-com-
ponent tandem-type reaction as indicated in
Table 1. Palladium-catalyzed three component synthesis of allylamines from 1,2-diene, iodobenzene and amine.
256
Adv. Synth. Catal. 2001, 343, 255±259

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Scheme 2, leading to allylamines A and B (see Fig- lectivity of the reaction. Thus, as shown in entries 3±5
ure 1).[9] Shimizu and Tsuji have reported such a of Table 1, reacting 4,4-dimethylpenta-1,2-diene ac-
three-component reaction,[10] but it is limited to the cording to the same protocol with iodobenzene and
use of non-volatile allenes and only the very nucleo- amines as in entries 1 and 2, led to good yields of the
philic pyrrolidine has been employed as the amine. corresponding regiopure allylamines 3±5 with high
When low-boiling allenes or diethylamine were used, stereoselectivity for the (E)-isomer. No reaction was
this method led to a disappointing (< 10%) yield. observed with diisopropylamine or potassium diiso-
Hence, we chose to use a closed vessel (Ace tube) to propylamide. However, diethylamine was a suitable
carry out the allylic aminations, which resulted in nucleophile and gave (E)-5 regio- and stereospecif-
good yields for a broader range of substrates. Further- icly. Stereospecificity depends on the nucleophile;
more, the catalyst precursor was varied (see below).
secondary, more basic amines give only the (E)-iso-
Indeed, reaction of iodobenzene with 3-methylbu- mer, whereas isopropylamine gives an 80 : 20 E/Z
ta-1,2-diene and pyrrolidine or isopropylamine in mixture. This may be due to lower nucleophilicity
acetonitrile in the presence of a palladium-diphos- and less steric hindrance (as compared to pyrrolidine
phine catalyst, obtained in situ from palladium ace- and diethylamine), hence less stereodifferentiation in
tate and 1,2-bis(dihenylphosphino)ethane (dppe), at the nucleophilic attack on the intermediate syn- and
100 °C in an Ace pressure tube for 3 hours cleanly pro- anti-(p-allyl)palladium compounds.
vided the respective allylamines 1 and 2 (Table 1,
Phenylpropadiene as the substrate gave similar re-
sults regarding the regiochemistry but generally
compare [10]) in good yield.
Regiospecificity was obtained in both the arylation much lower and opposite stereocontrol was obtained,
at C2 and for the amination at C1, i. e., the expected with a slight preference for the Z-isomer. This may be
nucleophilic substitution by the amine at the unsub- explained by invoking the position of equilibrium be-
stituted terminal allene carbon atom. Next, substrates tween syn- and anti-isomers of the intermediate p-al-
with one substituent at the allenic terminus were se- lyl-palladium complex (as compared to the situation
lected to assess the regioselectivity for a more de- for the products arising from 4,4-dimethylpenta-1,2-
manding substrate and in order to probe the stereose- diene) and the relative rate of attack of the N-nucleo-
Table 2. Formation of allylamines as a function of the bidentate ligand in the catalyst.
Adv. Synth. Catal. 2001, 343, 255±259
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asc.wiley-vch.de
phile on these species. Further studies must shed
light on this conjecture.
Experimental Section
Varying the organic halide to alkyl halides led to
disappointing results. Reaction of methyl iodide (en-
try 7) with 4,4-dimethylpenta-1,2-diene and pyrroli-
dine gave only very low yields of 6, whereas other al-
kyl iodides like n-butyl iodide gave irreproducible
results and very low or no yield of the desired product
at all. In these and other attempted cases we only ob-
tained the alkylated amine (presumably via quaterni-
zation of the amine) and the hydroamination product
arising from direct addition of the amine to the allene.
The composition of the catalyst, notably the type of
donor atoms and their spacing in the ligand on palla-
dium turned out to be an important parameter for the
rate and stereoselectivity of the reaction. Whereas bi-
dentate phosphine ligands provide reactive catalysts
for the reaction discussed, employing a monodentate
ligand such as triphenylphosphine, or the bidentate
N-ligand Ar-bian[11] did not yield a reactive catalyst
at all. In agreement with earlier observations,[10] the
use of diphosphines is superior to monophosphines
in these reactions, bidentate phosphine ligands ap-
peared to be the ligands of choice. The in situ pre-
pared palladium compounds combine excellent
regio- and stereoselectivity to allylamines, as has
been shown above for bisdiphenylphosphinoethane
(dppe). From Table 2 it is seen that a catalyst derived
from a bidentate mixed P,N-ligand is more active (in
terms of turnover frequency) but gives lower stereo-
selectivity and more of the branched allylamine (9).
However, higher activity and stereoselectivity (com-
pared to dppe) were obtained for the catalysts derived
from the bidentate diphosphines dppf, (rac)-Binap
and Xanthphos.[12] Although these give also small
amounts of 9 as the byproduct (entries 2±4), no con-
tamination with the direct hydroamination product
(10) was observed. Finally, the application of isolated,
well-defined catalyst precursors Pd(Ph)I(diphos) ob-
tained from oxidative addition of iodobenzene to a
zero-valent Pd-precursor in the presence of dppf or
Binap gave similar or slightly better results in terms
of selectivity and yield, but catalysis was faster. This
aspect will be elucidated in a forthcoming paper.
In conclusion, a highly regio- and stereoselective
three-component palladium-catalyzed synthesis of
allylamines has been achieved. Bidentate phosphines
are the preferred ligands, the composition and struc-
ture of which greatly influence the stereoselectivity
and rate of the reaction. Mechanistic aspects and al-
ternative bidentate ligands as well as the application
of defined precatalystst are currently subject of our
continuing investigations.
General Procedure
To 10 mL of acetonitrile (distilled from CaH2) in an Ace pres-
sure tube (35 mL) was added, under stirring, 14 mg (62
mmol, 2.5 mol %) of Pd(OAc)2, 37 mg (93 mmol) of dppe (or
similar amounts for other ligands), 0.28 mL (0.51 g,
2.5 mmol) of iodobenzene, 2.75 mmol (1.1 equivalent) of
the appropriate 1,2-diene and 1 mL of the appropriate amine
(ca. 4±5 equivalents) under a nitrogen atmosphere. The
pressure tube was closed and heated to 100 °C in an oil bath.
Samples were taken at regular intervals, by cooling the tube
to 20 °C before opening it. Samples were passed over a short
silica column and the composition was determined by use of
GC±MS. The composition of the reaction mixture was deter-
mined by the use of GC±MS, 1H and 13C NMR. The crude
product could be purified by use of flash chromatography,
using silica gel as column material and mixtures of hex-
anes/ether as eluent. Yields of the pure products were about
25% lower than the GC-yields indicated in Table 1.
References and Notes
[1] (a) M. Kosugi, M. Kameyama, T. Migita, Chem. Lett.
1983, 927; (b) A. S. Guram, R. A. Rennels, S. L. Buch-
wald, Angew. Chem., Int. Ed. Engl. 1995, 34, 1348;
(c) J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36,
3609; (d) J. F. Hartwig, Angew. Chem., Int. Ed. 1998,
37, 2046.
[2] (a) T. Hayashi, A. Yamomoto, Y. Ito, J. Am. Chem. Soc.
1989, 111, 6301; (b) T. Hayashi, in Catalytic Asym-
metric Synthesis, (Ed.: I. Ojima), VCH, New York, 1993;
p. 325; (c) B. M Trost, D. L. Van Vranken, Chem. Rev.
1996, 96, 395; (d) P. E. BloÈchl, A. Togni, Organometal-
lics 1996, 15, 4125.
[3] M. Johanssen, K. A. Jùrgensen, Chem. Rev. 1998, 98,
1689.
[4] From allylic alcohols: (a) O. Mitsonobu, Synthesis
1981, 1; (b) L. E. Overman, J. Am. Chem. Soc. 1976, 98,
2901; (c) R. A. T. M. van Benthem, J. J. Michels, H.
Hiemstra, W. N. Speckamp, Synlett 1994, 368.
[5] (a) J. B. Baruah, A. G. Samuelson, Tetrahedron 1991,
47, 9449; (b) D. Enders, M. Finkam, Synlett 1993, 401;
(c) S. L. Buchwald, B. T. Watson, M. W. Wannamaker,
J. C. Dewan, J. Am. Chem. Soc. 1989, 111, 4486.
[6] (a) Y. Yamomoto, U. Radhakrishnan, Chem. Soc. Rev.
1999, 28, 199; (b) R. Zimmer, C. U. Dinesh, E. Nanda-
nan, F. A. Khan, Chem. Rev. 2000, 100, 3067.
[7] (a) J. S. Prasad, L. S. Liebeskind, Tetrahedron Lett.
1988, 29, 4257; (b) W. F. J. Karstens, F. P. J. T. Rutjes,
H. Hiemstra, Tetrahedron Lett. 1997, 38, 6275; (c) R. C.
Larock, C. Tu, P. Pace, J. Org. Chem. 1998, 63, 6859;
(d) I. W. Davies, D. I. C. Scopes, T. Gallagher, Synlett
1993, 85.
[8] (a) J. Kiji, E. Sasakawa, K. Yamomoto, J. Furukawa J.
Organometal. Chem. 1974, 77, 125; (b) L. Besson,
J. GoreÂ, B. Cazes Tetrahedron Lett. 1995, 36, 3857;
(c) R. C. Larock, N. G. Barrios-Pena, C. A. Fried, J.
Org. Chem. 1991, 56, 2615; (d) R. C. Larock, Y. Wang,
258
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Y. Lu, C. E. Russell, J. Org. Chem. 1994, 59, 8107;
(e) J. J. H. Diederen, R. W. Sinkeldam, H.-W. FruÈ hauf,
H. Hiemstra, K. Vrieze, Tetrahedron Lett. 1999, 40,
4255; (f) R. C. Larock, E. K. Yum, M. D. Refvik, J. Org.
Chem. 1998, 63, 7652.
[10] I. Shimizu, J. Tsuji, Chem. Lett. 1984, 233.
[11] (a) R. van Asselt, C. J. Elsevier, W. J. J. Smeets, A. L.
Spek, R. Benedix, Recl. Trav. Chim. Pays-Bas 1994,
113, 88; (b) M. W. van Laren, C. J. Elsevier, Angew.
Chem., Int. Ed. 1999, 38, 3715.
[9] Surprisingly little is known about three-component
approaches in general; for the synthesis of allylamines
an example employing amines, alkenes, and vinyl ha-
lides has been published: R. C. Larock, C. Tu, Tetrahe-
dron 1995, 51, 6635±6650.
[12] M. Kranenburg, Y. E. M. van der Burgt, P. C. J. Kamer,
P. W. N. M. van Leeuwen, Organometallics 1995, 14,
3081.
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