Ru-catalyzed β-selective and enantioselective addition of amines to styrenes initiated by direct arene-exchange

Article abstract of DOI:10.1039/c2ob25457c

A catalytic β-selective addition of amines to styrenes proceeded in the presence of cationic Ru complexes combined with diphosphine ligands. In the reaction of α-methylstyrene, an enantioselective addition was achieved by using xylylBINAP.

Full text of DOI:10.1039/c2ob25457c

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COMMUNICATION
Ru-catalyzed β-selective and enantioselective addition of amines to styrenes
initiated by direct arene-exchange†
Maiko Otsuka,a Hiroya Yokoyama,a Kohei Endob and Takanori Shibata*a
Received 1st March 2012, Accepted 23rd March 2012
DOI: 10.1039/c2ob25457c
stability of η6-arene metal complexes. Actually, as far as we
A catalytic β-selective addition of amines to styrenes pro-
know, there is only an example, which realized catalytic β-selec-
tive nucleophilic addition to styrenes via η6-arene metal com-
plexes, however the reaction required thermally sensitive
ruthenium complex (Ru(cod)(2-methylallyl)2) and strong acid
(trifluoromethanesulfonic acid) for the preparation of η6-arene
Ru complexes.4
On the other hand, we have previously developed the catalytic
SNAr reaction of nonactivated arenes with amines using [Ru-
(benzene)Cl2]2, AgOTf, and P(p-FC6H4)3.5 This reaction pro-
ceeded via η6-fluoroarene ruthenium complexes, which were
generated in situ by direct arene-exchange of the benzene coordi-
nated to ruthenium with fluoroarenes. We then hypothesized that
the desired catalytic β-selective nucleophilic addition to styrenes
could proceed using our catalysis. Moreover, in the reaction of
α-substituted styrenes, the use of chiral ligands could achieve
enantioselective and β-selective nucleophilic addition via η6-
arene ruthenium complexes (Scheme 2).
ceeded in the presence of cationic Ru complexes combined
with diphosphine ligands. In the reaction of α-methylstyrene,
an enantioselective addition was achieved by using
xylylBINAP.
η6-Arene metal complexes have a number of distinguishing fea-
tures, which free arenes do not show and the stabilization of the
negative charge on the benzylic position is one of them.1 Actu-
ally, η6-arene chromium tricarbonyl ((arene)Cr(CO)3) complexes
are widely used in organic synthesis. For example, (styrene)Cr-
(CO)3 complexes undergo nucleophilic attack at exclusively the
β-position of the complexed styrenes. The generated anion reacts
with electrophiles (El+) in a highly stereoselective manner,
because the metal moiety of the complexes effectively shields
one of the π-faces of benzene (Scheme 1).2 The synthesis of
(styrene)Cr(CO)3 complexes and the demetallation of (trans-
formed-styrene)Cr(CO)3 complexes are so facile that this method
can be used for the synthesis of various substituted arenes.
Recently we developed an exclusively β-selective nucleophilic
addition of various heteronucleophiles to (styrene)Cr(CO)3 com-
plexes. Alcohols, amines, and thiols could be used as nucleo-
phile, and the functionalized substituted arenes could be readily
obtained by exposure to sunlight in air.3 This transformation is
useful, but the major drawback is the use of a stoichiometric
amount of transition metal, and the development of a catalytic
version of this reaction is a challenging topic, because of the
In this report, we demonstrate the ruthenium-catalyzed
β-selective nucleophilic addition of amines to styrenes via
Scheme 1 Regioselective addition of nucleophiles and electrophiles to
(styrene)Cr(CO)3 complexes.
aDepartment of Chemistry and Biochemistry, School of Advanced
Science and Engineering, Waseda University, Shinjuku, Tokyo169-8555,
Japan. E-mail: tshibata@waseda.jp; Fax: +81-3-5286-8098;
Tel: +81-3-5286-8098
bWaseda Institute for Advanced Study, Shinjuku, Tokyo169-8050, Japan
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25457c
Scheme 2 Proposed mechanism of catalytic (enantioselective) nucleo-
philic addition to α-substituted styrenes via η6-arene ruthenium
complexes.
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Table 1 Optimization of reaction conditions
Table 2 β-Selective nucleophilic addition of amines to styrenes
Entry
1
Product
Yield (%)
73
Entry Ligand
Time (h) Yield of 1 (%) Yield of 1′ (%)
2
3
4
5
6
7
8
43
1
2
3
4
5
6
2P(p-FC6H4)3
2PPh3
2P(p-OMeC6H4)3 24
DPPF
DPPPent
DPPPent
24
24
24
22
50
48
40
78
5
10
20
27
0
24
24
72
75
0
DPPF:
1,1′-bis(diphenylphosphino)ferrocene,
DPPPent:
1,5-bis
(diphenylphosphino)pentane.
67
η6-arene metal complexes. We further describe the first catalytic
enantioselective nucleophilic addition of amines to styrenes, in
which η6-arene metal complexes are used as chiral templates.
First we screened phosphine ligands for the β-selective
nucleophilic addition using styrene and piperidine as model sub-
strates in dioxane at 100 °C for 24 h (Table 1). When P(p-
FC6H4)3 was examined, which was the most efficient ligand for
the catalytic SNAr reaction,5 the desired catalytic reaction pro-
ceeded and β-adduct 1 was obtained in 24% yield, while
α-adduct 1′ was also obtained as a by-product (entry 1). Then
other monodentate phosphine ligands were examined. Using
PPh3, undesired α-adduct 1′ was also obtained along with
β-adduct 1 (entry 2). In the case of the electron-donating ligand
P(p-OMeC6H4)3, the conversion ratio increased, and the yield of
desired product 1 was significantly improved to 50%, but
α-adduct 1′ was also obtained in 20% yield (entry 3). Next, we
explored the bidentate phosphine ligands: ferrocenyl ligand
DPPF gave almost the same result as P(p-OMeC6H4)3 (entry 4).
When DPPPent was used, only β-adduct 1 was obtained in 40%
yield without the formation of α-adduct 1′ (entry 5). As a result
of the prolonged reaction time from 24 h to 72 h, the conversion
ratio was improved significantly, and the corresponding product
1 was obtained in 78% yield as a sole product (entry 6).
Under the optimal reaction conditions (entry 6 in Table 1), the
substrate scope was examined (Table 2). When the reaction of
morpholine with styrene was tested, the corresponding product 2
was obtained in comparable yield as with piperidine (entry 1).
The reaction of N-phenylpiperazine also proceeded to give the
desired product 3 in moderate yield (entry 2). On the other hand,
tetrahydroisoquinoline gave the corresponding product 4 in good
yield (entry 3). p-Methylstyrene, bearing electron-donating
group, also underwent the addition to give the corresponding
product 5 in 67% yield (entry 4), however the reaction of a
styrene possessing more the electron-donating methoxy group
did not proceed at all, probably because the methoxy substituted-
styrene is too electron-rich to undergo the nucleophilic addition
N.D.
15
50
52
(entry 5). When a styrene with an electron-deficient CF3 group
was examined, the reaction proceeded, albeit in low yield
(entry 6). It is probably difficult for p-trifluoromethylstyrene to
undergo arene-exchange with benzene of the Ru complex. Then,
we examined α-substituted styrene and found that α-methylstyr-
ene was a suitable substrate, which reacted with piperidine and
morpholine giving the corresponding products 8 and 9, contain-
ing an asymmetric carbon atom, in moderate yields (entries 7
and 8).
To develop an enantioselective reaction, we further screened
chiral phosphine ligands in the nucleophilic addition of piper-
idine to α-methylstyrene (Table 3). When (S,S)-CHIRAPHOS
was tested, the desired reaction did not efficiently proceed
(entry 1). On the other hand, the desired catalytic reaction pro-
ceeded when (S)-Et-FerroTANE was used, and the yield was
increased significantly (entry 2). Besides, (S)-BINAP gave a
3816 | Org. Biomol. Chem., 2012, 10, 3815–3818
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Table 3 Screening of chiral ligands
Entry
Ligand
Time (h)
Yield (%)
Ee (%)
1
2
3
4
5
6
(S,S)-CHIRAPHOS
(S,S)-Et-FerroTANE
(S)-BINAP
(S)-tolBINAP
(S)-xylylBINAP
(S)-xylylBINAP
24
24
24
24
24
72
4
6
39
42
45
76
76
26
27
25
27
52
(S,S)-CHIRAPHOS: (−)-(2S,3S)-bis(diphenylphosphino)butane, (S,S)-
Et-FerroTANE: (−)-1,1′-bis((2S,4S)-2,4-diethylphosphotano)ferrocene.
Table 4 Enantioselective β-selective nucleophilic addition of amines
to α-methylstyrene
Scheme 3 Proposed reaction mechanism.
Entry
1
Product
Yield (%)
44
Ee (%)
61
2
3
25
20
64
75
Scheme 4 Characterization of η6-arene Ru complexes B and E.
arene-exchange from benzene to α-methylstyrene. Second,
complex B undergoes nucleophilic attack. At the step of the for-
mation of D via transition state C, the enantioselection is
induced. The protonation to D proceeds from the other side of
the ruthenium, and complex E is obtained. Finally, complex E
dissociates the product along with association with the starting
material (Scheme 3).
We tried to ascertain the formation of the proposed intermedi-
ates by ESI-MS analysis (Scheme 4). To a mixture of [Ru-
(benzene)Cl2]2, AgOTf, and (S)-xylylBINAP in dioxane, an
excess amount of α-methylstyrene was added, and the mixture
was heated at 100 °C for 1 h. Then the excess amount of
α-methylstyrene was removed in vacuo, and the resulting crude
products were analyzed. As a result, the desired complex B was
successfully detected ([M]+) (see ESI†). Next, to the crude pro-
ducts including complex B, 10 equiv. of piperidine was added in
THF at 50 °C for 2 h, and the resulting mixture was analyzed
and the desired complex E was also detected ([M − TfOH]+)
(see ESI†).
similar result to (S)-Et-FerroTANE (entry 3). Then, we screened
BINAP derivatives: (S)-tolBINAP did not improve the yield
nor enantioselectivity of the β-adduct, while (S)-xylylBINAP
achieved good enantioselectivity (76% ee) (entries 4 and 5).
When the reaction time was prolonged, the yield was improved
to 52% without loss of enantioselectivity (entry 6).6,7
Under the optimal conditions (Table 3, entry 6), the nucleo-
philic addition of a few amines was examined (Table 4). When
morpholine was examined, the desired nucleophilic addition pro-
ceeded to give the corresponding product ent-9 in 44% yield
with 61% ee (entry 1). In the case of tetrahydroisoquinoline, the
yield of ent-10 was low, but the enantioselectivity was good
(entry 2). 4-Piperidone ethylene ketal also gave the correspond-
ing product ent-11 with high enantioselectivity, albeit in low
yield (entry 3).
In conclusion, we demonstrated the β-selective catalytic
Next, we considered the proposed mechanism of the present
reaction; first, complex A is transformed into complex B by
nucleophilic addition of amines to styrenes via η6-arene
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6 Only two examples of enantioselective β-selective addition of amines to
styrenes have been reported by using chiral Pd catalysts, but the amines
were limited to aniline derivatives: (a) M. Kawatsura and J. F. Hartwig,
J. Am. Chem. Soc., 2000, 122, 9546; (b) A. Hu, M. Ogasawara,
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ruthenium complexes. Furthermore, an asymmetric version of
the reaction was also realized using an α-substituted styrene in
the presence of a chiral ruthenium catalyst. The enantioselective
nucleophilic addition is the first example of η6-arene ruthenium
complexes as chiral templates.
This research was supported by Global COE program “Practi-
cal Chemical Wisdom,” Waseda University, Japan.
Notes and references
1 (a) M. F. Semmelhack and A. Chlenov, in Transition Metal Arene
π-Complexes in Organic Synthesis and Catalysis, ed. E. P. Kündig,
Springer-Verlag, Berlin, Germany, 2004, p. 157; (b) M. F. Semmelhack, in
Comprehensive Organometallic Chemistry II, ed. E. W. Abel,
F. G. A. Stone and G. Wilkinson, Pergamon, New York, 1995, vol. 12,
p. 979; (c) K. E. Polunin and H.-G. Schmalz, Russ. J. Coord. Chem.,
2004, 30, 252.
7 The absolute configuration of compound 8 was determined to be R from
by the comparison of the sign of optical rotation (R)-8, which was prepared
from (R)-2-phenylpropan-1-amine.
2 (a) M. F. Semmelhack, W. Seufert and L. Keller, J. Am. Chem. Soc., 1980,
102, 6584; (b) M. Uemura, T. Minami and Y. Hayashi, J. Chem. Soc.,
3818 | Org. Biomol. Chem., 2012, 10, 3815–3818
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