Palladium-catalyzed aminoallylation of activated olefins with allylic halides and phthalimide

Article abstract of DOI:10.1021/jo025747h

The three-component aminoallylation reaction of the activated olefins 2 with the phthalimide 1a and allyl chloride proceeded very smoothly in the presence of Pd₂dba₃·CHCl₃ (5 mol %)/P(4-FC₆H₄)₃ (40 mol %) and Cs₂CO₃ (3 equiv against 2) in dichloromethane at room temperature to give the corresponding aminoallylated products, N-pent-4-enylphthalimides 3, in 58-99% yields. The reaction of oxazolidinone 1b also proceeded very smoothly to give N-(2,2-dicyano-1-phenylpent-4-enyl)-oxazolidinone in a quantitative yield; however, the Tsuji-Trost-type allylation products 4 were obtained in the case of dibenzylamine, N-tosylaniline, and pyrrolidin-2-one. Further, 2 underwent cycloaddition with N-tosylvinylaziridine 9a in the presence of Pd₂dba₃·CHCl₃ (5 mol %)/P(4-FC₆H₄)₃ (40 mol %) in THF at room temperature, giving the corresponding pyrrolidines 11 in 69-99% yields.

Full text of DOI:10.1021/jo025747h

P a lla d iu m -Ca ta lyzed Am in oa llyla tion of Activa ted Olefin s w ith
Allylic Ha lid es a n d P h th a lim id e
Kouichi Aoyagi, Hiroyuki Nakamura, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, J apan
yoshi@yamamoto1.chem.tohoku.ac.jp
Received March 22, 2002
The three-component aminoallylation reaction of the activated olefins 2 with the phthalimide 1a
and allyl chloride proceeded very smoothly in the presence of Pd2dba3‚CHCl3 (5 mol %)/P(4-FC6H4)3
(40 mol %) and Cs2CO3 (3 equiv against 2) in dichloromethane at room temperature to give the
corresponding aminoallylated products, N-pent-4-enylphthalimides 3, in 58-99% yields. The reaction
of oxazolidinone 1b also proceeded very smoothly to give N-(2,2-dicyano-1-phenylpent-4-enyl)-
oxazolidinone in a quantitative yield; however, the Tsuji-Trost-type allylation products 4 were
obtained in the case of dibenzylamine, N-tosylaniline, and pyrrolidin-2-one. Further, 2 underwent
cycloaddition with N-tosylvinylaziridine 9a in the presence of Pd2dba3‚CHCl3 (5 mol %)/P(4-FC6H4)3
(40 mol %) in THF at room temperature, giving the corresponding pyrrolidines 11 in 69-99% yields.
In tr od u ction
is a competitive process, and in general, this reaction
takes place more readily than the three-component
coupling reaction (eq 2). We recently found that the three-
component coupling reactions between certain nucleo-
philes, allylic halides, and activated alkenes occurs
unexpectedly easily in the presence of Pd catalysts (eq
3). As nucleophiles, allylic stannanes,7 allyl acetoacetate,8
alcohols,9,10 and trimethyl cyanide11 could be utilized.
Interestingly, in these previous cases, the direct reaction
between Nu- and allylic halides was not observed, and
the three-component coupling reaction proceeded well.
Our next interest was focused on a nitrogen nucleophile.
Can similar three component coupling reactions be
The transition-metal-catalyzed addition of amines
across C-C multiple bonds is an efficient process for the
introduction of a nitrogen functionality into unsaturated
organic molecules and also in the synthesis of physiologi-
cally active substances.1 Hydroamination of alkenes,
alkynes, allenes, dienes, and enynes has been developed
using transition-metal,2,3 lanthanide,4 and/or actinide5
catalysts for this purpose (eq 1). A three-component
coupling reaction of amines (>N-H), C-C multiple
bonds, and organic halides (R-X) must be a more
powerful strategy for the multifunctionalization of un-
saturated organic molecules;6 however, it is not an easy
task since the production of ammonium salts (>NH+RX-)
(4) Lanthanide-catalyzed intermolecular hydroamination: (a) Li, Y.;
Marks, T. J . Organometallics 1996, 15, 3770. intramolecular hy-
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10.1021/jo025747h CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/03/2002
J . Org. Chem. 2002, 67, 5977-5980
5977

Aoyagi et al.
TABLE 1. P a lla d iu m (0)-Ca ta lyzed Th r ee-Com p on en t
Am in oa llyla tion of th e Activa ted Olefin s 2 w ith
P h th a lim id e 1a a n d Allyl Ch lor id e
carried out with amines? As mentioned in eq 2, amines
are stronger nucleophiles, in general, than the oxygen
and carbon nucleophiles shown in eq 3, and therefore,
there was a possibility for the formation of ammonium
salts. Herein we report the aminoallylation of the acti-
vated olefins 2 with the amines 1, bearing an EWG group,
and allyl chloride takes place efficiently in the presence
of palladium(0) catalyst (eq 4). The present transition-
metal-catalyzed three-component coupling reaction en-
ables us to perform the traditional two-step organic
transformation, Michael addition of Nu- to activated
alkenes followed by trapping the resulting carbanion with
allylic halides, in one pot without producing the allyl-
amine 4, which is an expected product via the ordinary
Tsuji-Trost type nucleophilic allylation.12
a
Isolated yields based on 2.
amine source for further investigation of the three
component coupling reactions. The results are sum-
marized in Table 1. The various activated olefins 2a -f
having aromatic substituents underwent the aminoally-
lation with 1a and allyl chloride to give the corresponding
â-amino-R-allylated adducts 3a -f in 85-99% yields
(entries 1-6). The reaction of tert-butyl-substituted olefin
2g also proceeded very smoothly to give 3g in 89% yield
(entry 7). Not only the activated olefins derived from
malononitrile (2a -g) but also those from Meldrum’s acid
(2h -k ) underwent the three-component aminoallylation,
giving the corresponding adducts 3h -k in good to high
yields (entries 8-11), and di-tert-butyl ethylidenemalo-
nate 2l afforded 3l in 58% yield under the same condition
(entry 12).
Resu lts a n d Discu ssion
In ter m olecu la r Am p h ip h ilic Am in oa llyla tion Re-
a ction . Benzylidenemalononitrile 2a underwent the
facile aminoallylation with phthalimide 1a and allyl
chloride in the presence of Pd2dba3‚CHCl3 (5 mol %)/P(4-
FC6H4)3 (40 mol %), and Cs2CO3 (3 equiv against 2a ) in
dichloromethane at room temperature to give the corre-
sponding three-component coupling product 3a in a
quantitative yield (eq 4). The reaction of oxazolidinone
1b also proceeded very smoothly to give N-(2,2-dicyano-
1-phenylpent-4-enyl)oxazolidinone in a quantitative yield,
however, the Tsuji-Trost-type allylation products 4 were
obtained in the case of dibenzylamine, N-tosylaniline, and
pyrrolidin-2-one. Accordingly, it is essential to use the
amines 1a and 1b, having an EWG, to avoid the direct
reaction between the nucleophiles 1 and allyl chloride.
Since N-substituted phthalimides can be easily converted
to the corresponding primary amines, 1a was used as an
Various allylic halides were also examined in the
palladium-catalyzed three-component aminoallylation
reaction, and the results are summarized in eq 5 and
Table 2. As shown in Table 1, in the case of simple
allylation, the use of allyl chloride gave very high yields
of the desired products. However, in the case of substi-
(12) Intramolecular aminoallylations: (a) Iritani, K.; Matsubara, S.;
Utimoto, K. Tetrahedron Lett. 1988, 29, 1799. (b) Kimura, M.; Tanaka,
S.; Tamaru, Y. J . Org. Chem. 1995, 60, 3764.
5978 J . Org. Chem., Vol. 67, No. 17, 2002

Pd-Catalyzed Aminoallylation of Activated Olefins
TABLE 2. P a lla d iu m -Ca ta lyzed Am in oa llyla tion of th e
Activa ted Olefin s 2a w ith P h th a lim id e 1a a n d Va r iou s
Allyl Ha lid esa
7, although the direct allylation were observed in the case
of other nitrogen nucleophiles, such as dibenzylamine,
N-tosylaniline, and pyrrolidin-2-one. The nucleophilic
carbon of 8 attacks the π-allylpalladium complex result-
ing in the formation of the aminoallylation adducts 3.
We examined the simple Michael addition between 1a
and 2a , but no reaction took place even at elevated
temperatures and the starting materials were recovered.
Next, the reaction of potassium phthalimide with 2a was
examined, but again no reaction occurred. It is considered
that there would be equilibrium between 7 and 8, and
the reductive elimination from 8 would promote the
catalytic cycle. The key for the palladium-catalyzed three-
component aminoallylation is a choice of the nitrogen
nucleophiles. The less electron density on the nitrogen
atom may avoid the direct attack of the nitrogen nucleo-
philes to π-allyl group on the palladium(II) complex 7.
The palladium(II) of 7 would act as a Lewis acid to
activate the Michael acceptor at this step. This thought
is supported by the need for a poor donor ligand, such as
P(4-FC6H4)3, which makes the metal more electrophilic.13
In tr a m olecu la r Ver sion of th e Am in oa llyla tion .
F or m a tion of P yr r olid in e Der iva tives. It was envi-
sioned from the mechanism that the nitrogen-containing
heterocycles would be readily prepared if the π-allyl
group in 6 is connected to the amide through a carbon
chain. Since it is known that vinylaziridines 9 react with
palladium(0) to form π-allylpalladium amides 10 as
shown in eq 6,14we examined the cycloaddition of N-
tosylvinylaziridine 9a 15 with activated olefins in the
presence of the palladium catalyst (eq 7). The results are
a
The reactions were carried out in the presence of Pd2dba3‚CH3Cl
catalyst (5 mol %), P(4-FC6H4)3 ligand (40 mol %), and Cs2CO3
(3.0 equiv) in CH2Cl2 at room temperature. Isolated yields based
b
on 2.
SCHEME 1
shown in Table 3. The reaction of 2a proceeded very
TABLE 3. Cycloa d d ition of th e Activa ted Olefin s 2 w ith
N-Tosylvin yla zir id in e 9a
tuted allylic derivatives, the use of allylic bromides gave
higher yields in comparison to the corresponding allylic
chlorides. The reaction of 1a , 2a , and methallyl bromide
produced the corresponding aminoallylation product 3m
in 76% yield (entry 1). The three-component coupling
reaction also proceeded with prenyl and cinnamyl bro-
mide and methyl 4-bromo-2-butenoate to give 3n -p in
71-99% yields (entries 2-4). It should be noted that the
allylation with the substituted allylic bromides took place
exclusively at the R-position, and no C-C bond forming
products at the γ-position were obtained.
entry
olefin, 2
product, 3
yielda (%)
ratio (cis/trans)
1
2
3
4
5
6
7
2a
2c
11a
11b
11c
11d
11e
11f
11g
>99
84
88
92
69
55/45
54/46
52/48
52/48
35/65
23/77
2d
2e
2g
2h
2m b
84
78
a
b
Isolated yields based on 2. CH2dC(SO2Ph)2.
Mech a n ism . A plausible mechanism for the three-
component aminoallylation is shown in Scheme 1. The
π-allylpalladium complex 5 generated from Pd(0) and
allyl chloride would react with 1a to afford the π-allylpal-
ladium amide 6. The Michael addition of the nitrogen
nucleophile of 6 to the activated olefin 2 would give the
C-N bond-forming product 8 through the intermediate
7. It is interesting that no direct coupling between the
nitrogen nucleophile, such as phthalimide and oxazoli-
dinone, and π-allyl group takes place in the intermediate
smoothly in the presence of Pd2dba3‚CHCl3 (5 mol %)/
P(4-FC6H4)3 (40 mol %) catalyst in THF at room temper-
(13) We thank a reviewer who pointed out the possibility that the
Lewis acidity of the palladium(II) catalyst may activate the reactivity
of the Michael acceptor in 7.
(14) (a) Fugami, K.; Morizawa, K.; Oshima, K.; Nozaki, H. Tetra-
hedron Lett. 1985, 26, 857. (b) Spears, G. W.; Nakanishi, K.; Ohfune,
Y. Synlett 1991, 91.
(15) Ali, I. S.; Nikalje, D. M.; Sudalai, A. Org. Lett. 1999, 1, 705.
J . Org. Chem, Vol. 67, No. 17, 2002 5979

Aoyagi et al.
ature to give 3,3-dicyano-2-phenyl-N-tosyl-4-vinylpyrro-
lidine 11a in a quantitative yield as a 55/45 mixture of
cis and trans isomers (entry 1). The various activated
olefins (2c-e and 2g-h ) underwent the cycloaddition
reaction similarly, giving the corresponding pyrrolidines
(11b-f) in 69-92% yields (entries 2-6). Unfortunately,
the diastereoselectivities of the cycloaddition reactions
were low. The reaction of 1,1-bis(phenylsulfonyl)ethylene
2m also afforded 3,3-bis-phenylsulfonyl-N-tosyl-4-vi-
nylpyrrolidine 11g in 78% yield (entry 7).
Exp er im en ta l Section
Gen er a l P r oced u r e for th e In ter m olecu la r Am in oa l-
lyla tion . To a solution of Pd2dba3‚CHCl3 (0.025 mmol), (4-
FC6H4)3P (0.20 mmol), 2 (0.50 mmol), phthalimide 1a (0.60
mmol), and Cs2CO3 (1.50 mmol) in CH2Cl2 (4 mL) was added
allyl chloride (0.60 mmol) under Ar atmosphere. The reaction
mixture was stirred at room temperature, and the reaction
progress was monitored by TLC. When 2 was consumed
completely (6-24 h), the reaction mixture was filtered through
a short florisil column chromatography to remove the catalysts.
Purification by a silica gel column chromatography (hexane/
ethyl acetate ) 10:1) gave 3.
Gen er a l P r oced u r e for th e Cycloa d d ition of N-To-
sylvin yla zir id in e 9a w ith th e Activa ted Olefin s 2. To a
solution of Pd2dba3‚CHCl3 (0.025 mmol), (4-C6H4F)3P (0.20
mmol), and 2 (0.50 mmol) in THF (5 mL) was added N-
tosylvinylaziridine 9a (0.60 mmol) under Ar atmosphere. The
reaction mixture was stirred at room temperature and the
reaction progress was monitored by TLC. When 2 was con-
sumed completely (∼1 d), the reaction mixture was filtered
through a short florisil column chromatography to remove the
catalysts. Purification by a silica gel column chromatography
(hexane/ethyl acetate ) 6:1) gave 11.
Con clu sion
The current palladium-catalyzed three-component
aminoallylation reaction proceeded smoothly by using
phthalimide 1a and oxazolidinone 1b as an amine source.
The use of cyclic amines having an electron-withdrawing
group is essential for the reaction, since higher electron
density on a nitrogen atom induces the direct allylation
to the π-allylpalldium complex 5, and the palladium(II)
complex promotes the Michael addition of the nitrogen
nucleophiles to the activated olefins 2 at the stage of 7
in the catalytic cycle. The present finding enables us to
conduct the one-pot multifunctionalization of carbon-
carbon unsaturated compounds.
Su p p or tin g In for m a tion Ava ila ble: Characterization
date for new compounds 3a -p and 11a -g (PDF). This
material is available free charge via the Internet at http://
pubs.acs.org.
J O025747H
5980 J . Org. Chem., Vol. 67, No. 17, 2002