Palladium-catalyzed vinylation of aminals with simple alkenes: A new strategy to construct allylamines

Article abstract of DOI:10.1021/ja310848x

A novel, highly selective palladium-catalyzed vinylation reaction for the direct synthesis of allylic amines from styrenes and aminals has been established. The utility of this method was also demonstrated by the rapid synthesis of cinnarizine from aldehydes, amines, and simple alkenes in one-pot manner. Mechanistic studies suggested that the reaction proceeds through a valuable cyclometalated Pd(II) complex generated by the oxidative addition of aminal to a Pd(0) species.

Full text of DOI:10.1021/ja310848x

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Vinylation of Aminals with Simple Alkenes: A
New Strategy To Construct Allylamines
Yinjun Xie, Jianhua Hu, Yanyu Wang, Chungu Xia, and Hanmin Huang*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
S
* Supporting Information
intermediate, would be an attractive alternative to the
ABSTRACT: A novel, highly selective palladium-cata-
lyzed vinylation reaction for the direct synthesis of allylic
amines from styrenes and aminals has been established.
The utility of this method was also demonstrated by the
rapid synthesis of cinnarizine from aldehydes, amines, and
simple alkenes in one-pot manner. Mechanistic studies
suggested that the reaction proceeds through a valuable
cyclometalated Pd(II) complex generated by the oxidative
addition of aminal to a Pd(0) species.
aforementioned traditional methods. However, such a reaction
is a synthetic challenge exacerbated by the intrinsic poor
nucleophilicity of simple alkenes.4 One way to circumvent this
problem would be to develop an umpolung process, in which
the electrophilic imine or its surrogate is converted into a
nucleophilic species and the nucleophilic alkene is switched to
an electrophilic one. In this respect, we envisioned that the
palladium-catalyzed Heck-type reaction could be desirable for
realizing such a transformation, since simple alkenes exhibit
umpolung reactivity in Heck-type reactions.5
To this end, the main challenge is to identify an imine
surrogate that can act as an electrophile to undergo the Heck-
type reaction. Aminals are recognized as surrogates of imines
and are widely used as electrophiles in metal-catalyzed
nucleophilic addition reactions.6 The C−N bond in these
molecules is easily cleaved under mild conditions to generate an
iminium ion because of the better leaving ability of the amino
group, and therefore, aminals have good electrophilicity toward
organometallic reagents. Intrigued by this unique feature and
the fact that oxidative addition of anilines,7 ammonium salts,8
arylhydrazines,9 and allylamines10 to low-valent transition
metals can be realized via cleavage of unactivated C−N
bonds, we envisaged that oxidative addition of aminals to low-
valent metals via C−N bond cleavage might also be possible.
Herein we report a novel palladium-catalyzed vinylation of
aminals with simple alkenes that provides access to allylic
amines in stereodefined fashion. The proposed process is
initiated by the formation of a Pd(II) complex, A, via oxidative
addition of the aminal to a Pd(0) complex. A then undergoes a
Heck-type reaction, affording the desired allylamine (eq 2 in
Scheme 1).
llylic amines represent an important structural motif
A
frequently found in natural products, pharmaceuticals, and
other synthetics (Figure 1).1b Among the myriad methods
Figure 1. Examples of Significant Allylamine-Containing Pharmaceut-
icals.
available for constructing the allylamine scaffold,1 metal-
catalyzed vinylation of imines is one of the most commonly
used approaches, but the incorporation of reactive functionality
into the alkene moiety prior to nucleophilic addition (such as
halogenation and subsequent metalation) is required for such
elegant methods (eq 1 in Scheme 1).2 In this context, direct
vinylation of imines or their surrogates via C−H functionaliza-
tion of alkenes,3 which would avoid the use of a vinylmetallic
To test our initial proposal, the model reaction of styrene
(1a) and N,N,N′,N′-tetrabenzylmethanediamine (2a) was used
to optimize the reaction conditions (Table 1). Our initial
attempts demonstrated that no desired reaction occurred when
commonly used PdCl2, Pd(CH3CN)2Cl2, or Pd(OAc)2 was
utilized as the catalyst (entries 1−3). Furthermore, other typical
Lewis acids such as Zn(OTf)2, Cu(OTf)2, Fe(OTs)3, and AlCl3
were ineffective catalysts for this reaction [see the Supporting
Information (SI)], which indicated that the reaction is most
likely not Lewis acid-catalyzed. Next, we investigated the effect
of the ligand. When Pd(dppf)Cl2 [dppf = 1,1'-bis-
(diphenylphosphino)ferrocene] was used as the catalyst, the
Scheme 1. Strategies for the Formation of Allylamines via
Vinylation
Received: November 4, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja310848x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
With the optimized conditions in hand, a wide variety of
substituted styrenes 1 were submitted to the Pd-catalyzed
vinylation reaction to investigate its substrate scope and
generality. As shown in Table 2, the reaction proceeded in
Table 1. Screening of Reaction Conditions
a
entry
[Pd]
solvent
T (°C)
yield (%)
Table 2. Substrate Scope of Pd-Catalyzed Vinylation
1
2
PdCl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
110
100
80
<5
<5
<5
17
30
85
89
82
79
75
64
92
74
74
75
93
88
75
54
Pd(CH3CN)2Cl2
Pd(OAc)2
Pd(dppf)Cl2
Pd(BINAP)Cl2
Pd(Xantphos)Cl2
Cat A
3
4
5
6
7
8
Cat B
9
Cat C
10
11
12
13
14
15
16
17
18
19
Cat A
Cat A
n-PrOH
2-PrOH
n-BuOH
CH3CN
THF
Cat A
Cat A
Cat A
Cat A
Cat A
2-PrOH
2-PrOH
2-PrOH
2-PrOH
Cat A
Cat A
Cat A
60
a
Reaction conditions: 1a (0.8 mmol), 2a (0.4 mmol), [Pd] (0.02
mmol), solvent (1.5 mL), 12 h. only the (E)-allylamine was obtained
in all cases. Cat A, Pd(Xantphos)(CH3CN)2(OTf)2; Cat B, Pd-
(Xantphos)(CH3 CN)2 (SbF6 )2 ; Cat C, Pd(Xantphos)-
(CH3CN)2(BF4)2.
desired product 3aa was isolated in 17% yield (entry 4).
Moreover, with BINAP as the ligand, the yield was improved to
30% (entry 5). Encouraged by these results, we investigated a
series of phosphine ligands with different bite angles and
electronic natures and found that the reactivity was significantly
affected by the nature of phosphine ligand (see the SI).
Xantphos turned out to be far superior, affording 3aa in 85%
yield (entry 6). Further investigation of the palladium catalyst
demonstrated that the reactivity was affected by the nature of
the counterion (entries 6−9). For example, with Pd-
(Xantphos)(CH3CN)2(SbF6)2 as the catalyst, 3aa was obtained
in 82% yield (entry 8), while Pd(Xantphos)(CH3CN)2(BF4)2
delivered the desired product in 79% yield (entry 9). Among
those tested, Pd(Xantphos)(CH3CN)2(OTf)2 led to the best
result (89% yield; entry 7). Finally, control reactions
demonstrated that the vinylation product 3aa was not formed
in the absence of a palladium catalyst.
After Pd(Xantphos)(CH3CN)2(OTf)2 was identified as the
best catalyst, the other reaction parameters were optimized
using it. The effects of solvent and temperature in this reaction
were also investigated. The reaction could be conducted
perfectly in alcohol solvents, and the green solvent 2-PrOH was
the best for this reaction (Table 1, entry 12). Other nonprotic
polar solvents, such as CH3CN and THF (entries 14 and 15),
were also suitable for the vinylation reaction but gave only
moderate yields. The best yield of 3aa (93%; entry 16) was
obtained at 110 °C, whereas at higher temperatures no
appreciable increase in yield was obtained (see the SI). On
the contrary, the use of temperatures below 110 °C reduced the
reactivity and conversion (entries 17−19). It is worth
mentioning that the reaction is highly selective: only the linear
E isomer 3aa was observed in all cases.
a
Reaction conditions: 1 (0.8 mmol), 2 (0.4 mmol), Pd(Xantphos)-
(CH3CN)2(OTf)2 (0.02 mmol), 2-PrOH (1.5 mL), 110 °C, 12 h,
unless otherwise noted. Isolated yields are shown. Only the E isomer
was observed in all cases. 24 h. Pd(Xantphos)(CH3CN)2(OTf)2
(0.04 mmol), CH3CN (1.5 mL). Pd(Xantphos)Cl2 (0.02 mmol),
MeOH (1.5 mL). 1a (2.0 mmol), Pd(Xantphos)Cl2 (0.02 mmol),
MeOH (1.5 mL), 120 °C, 12 h. Pd(Xantphos)Cl2 (0.04 mmol),
MeOH (1.5 mL), 110 °C, 12 h.
b
c
d
e
f
good to excellent yields in the presence of both electron-
deficient and electron-rich aromatic systems. In general,
styrenes bearing electron-donating groups provided higher
yields than those containing electron-withdrawing groups. For
instance, the reactions of substrates with electron-donating
substituents, such as Me and MeO at the 4-position of the
benzene ring, proceeded smoothly to provide the coupling
products in >90% yield (3ba and 3ga). Typical functional
groups such as alkyl, alkyoxyl, fluoro, chloro, trifluoromethyl,
ester, and nitro were also tolerated under the reaction
conditions. Importantly, the successful preparation of 3ja with
an intact chlorine provides a good opportunity for further
formation of C−C or C−heteroatom bonds by transition-
metal-catalyzed coupling and other reactions. In addition to
substituted styrenes, naphthyl-substituted alkenes and hetero-
aryl-substituted alkenes such as 2-vinylpyridine and 2-vinyl-
pyrazine were also compatible with this new reaction,
generating the corresponding allylic amines (3na, 3oa, and
3pa) in good to excellent yields under slightly modified
B
dx.doi.org/10.1021/ja310848x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
conditions. The structure of the allylic amines was confirmed by
X-ray crystallographic analysis of derivative 3na (see the SI).11
In addition, the scope of the aminal was also explored. Aminals
derived from alkylamines afforded the desired products in
moderate to good yields (3ab−ad). Moreover, aminals derived
from cyclic amines could also be used as coupling partners,
giving the corresponding products (3ae−ah) in good yields.
However, under the present reaction conditions, only an 11%
yield of 3ai was observed when a benzaldehyde-derived aminal
was employed as the coupling partner. The observed lower
reactivity for this type of substrate may stem from difficulty in
the oxidative addition step.
To gain some preliminary understanding of the mechanism,
several experiments were carried out under the optimized
conditions (Scheme 2).12 A stoichiometric reaction of 2a with
Figure 2. Proposed reaction mechanism.
by the acid, generating the key intermediate A, an analogue of
the fully characterized complex 4. Alternatively, A might be
formed via direct oxidative addition of an iminium species
(generated in situ from aminal 2) to Pd(0). This key active
species A would then react with styrene 1 via carbopalladation
to give intermediate B, which would undergo syn-β-hydride
elimination to deliver the cross-coupling product 3 as well as
intermediate C. Reductive elimination of C to regenerate the
active catalyst species would complete the catalytic cycle.
The usefulness of this new protocol was demonstrated via a
one-pot, three-component cascade cross-coupling starting from
aldehyde, styrene, and amine without separation of the aminal.
As shown in Scheme 3, we successfully applied our present
Scheme 2. Preliminary Mechanistic Studies
Scheme 3. Synthesis of Cinnarizine via a One-Pot Procedure
method in a one-pot manner with simple starting materials to
achieve the rapid synthesis of cinnarizine, a commercially
available antihistamine pharmaceutical used to treat cerebral
apoplexy, post-traumatic cerebral symptoms, cerebral arterio-
sclerosis, and seasickness.15 This approach represents a highly
atom-economical protocol for the synthesis of allylamines, since
only water is formed as a coproduct.
In summary, we have developed a novel palladium-catalyzed
vinylation reaction that enables the catalytic functionalization of
alkenes with aminals. The reaction proceeds with complete
regioselectivity and stereoselectivity, delivering exclusively the
linear E isomer of the allylic amine product. Importantly, this
reaction can also be employed in a one-pot, three-component
cascade with high efficiency. Evidence suggests that the reaction
proceeds through a cyclometalated Pd(II) complex generated
by oxidative addition of the aminal to a Pd(0) species, which
has promise as a valuable catalytic intermediate in a variety of
C−C bond-forming manifolds. Further investigations to gain a
detailed mechanistic understanding of this reaction and apply
this strategy in other C−C bond-forming reactions are
currently in progress.
Pd(Xantphos)(CH3CN)2(OTf)2 was conducted under the
standard conditions. After 2 h, cyclometalated Pd(II) complex
4 containing a three-membered-ring was obtained in 94% yield,
and its structure was unambiguously characterized by X-ray
crystallography and high-resolution mass spectrometry (see the
SI). The corresponding Pd−C σ bond was undoubtedly formed
[Pd−C bond, 2.031(2) Å; Pd−N bond, 2.185(3) Å],13
suggesting that the oxidative addition process indeed occurred.
This result represents the first observation of oxidative addition
of aminals to a Pd(0) species. Here the Pd(0) species was
generated by the reduction of Pd(II) with 2-propanol.14 The
stoichiometric reaction of complex 4 with styrene at 110 °C
successfully provided the desired Heck coupling product 3aa in
43% yield. Moreover, complex 4 catalyzed the vinylation of 2a
with styrene to give 3aa in high yield, suggesting the plausible
intermediacy of 4 in the catalytic cycle.
On the basis of the results described above, a tentative
reaction mechanism for the palladium-catalyzed vinylation
reaction is presented in Figure 2. Initial reduction of the Pd(II)
precatalyst by 2-PrOH should furnish a catalytically active
Pd(0) species together with a catalytic amount of acid.14
Subsequent oxidative addition of aminal 2 to the Pd(0) species
would then take place via cleavage of the C−N bond facilitated
ASSOCIATED CONTENT
* Supporting Information
Experimental details and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
C
dx.doi.org/10.1021/ja310848x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
metallics 1986, 5, 1559. (c) Murahashi, S.-I.; Makabe, Y.; Kunita, K. J.
AUTHOR INFORMATION
Corresponding Author
hmhuang@licp.cas.cn
■
Org. Chem. 1988, 53, 4489. (d) Garro-Helion, F.; Merzouk, A.; Guibe,
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reaction, affording the homoallylamines in good yields with migration
of the double bond. Simple aliphatic alkenes and acrylates did not react
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Professor Huilin Chen on the
occasion of his 75th birthday. This research was supported by
the Chinese Academy of Sciences and the National Natural
Science Foundation of China (21222203, 21172226, and
21133011).
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