Direct allylation of aldimines catalyzed by C2-symmetric N,N′-dioxide-ScIII complexes: Highly enantioselective synthesis of homoallylic amines

Article abstract of DOI:10.1002/chem.200800534

A study was conducted for catalytic asymmetric direct allylation of aldimines accelerated by C₂-symmetric N,N'-dioxide-Sc^III complexes under mild conditions. The study observed that chiral N,N'-dioxidemetal complexes in catalytic asymmetric reactions showed good activation of allylstannane reagent and 2-aminophenol-derived aldimines. It was also observed that the modular and tuneable N,N'-dioxide ligands can be synthesized from readily accessible chiral amino acids and amines, that lead to the catalyst structure optimization. The chiral backbone and steric effects of the amide portion of ligands made a significant impact on the enantioselectivity for this reaction. It was also observed during study that homoallylic amines obtained with high enantioselectivities and good yields under mild conditions.

Full text of DOI:10.1002/chem.200800534

DOI: 10.1002/chem.200800534
Direct Allylation of Aldimines Catalyzed by C2-Symmetric N,N’-Dioxide–
ScIII Complexes: Highly Enantioselective Synthesis of Homoallylic Amines
Xing Li,[a] Xiaohua Liu,[a] Yingzi Fu,[a] Lijia Wang,[a] Lin Zhou,[a] and Xiaoming Feng*[a, b]
Optically active homoallylic amines are useful intermedi-
ates for the preparation of bioactive natural products and
relevant compounds.[1] The asymmetric allylation of imines
provides direct access to them and considerable efforts have
been devoted to devising enantioselective versions of this
transformation.[2–4] Among these methods,catalytic asym-
metric allylation of imines,as a more efficient method,has
made significant progress.[5–8] Despite these creative efforts,
the development of new methods,the design and synthesis
of new catalysts remain considerable challenge. Simplified
and environmentally friendly multicomponent strategy[9] has
been successfully adopted in the synthesis of racemic homo-
allylic amines.[10] Herein,we reported an efficient catalytic
asymmetric direct allylation of aldimines promoted by readi-
ly accessible and tuneable C2-symmetric N,N’-dioxide-ScIII
complexes under mild conditions.
of benzaldehyde,2-aminophenol and allyltributyltin as
benchmark,[14] catalytic ability of different metals complexed
with l-proline-derived N,N’-dioxide L1 was tested. The sig-
nificant effect of the central metal on both reactivity and
enantioselectivity was observed,as shown in Table 1. When
[6]
[5b–d]
Zr
G
(OAc)2
were adopted,the reaction
did not take place (Table 1,entries 1,2). Racemic products
were obtained with good yields in the presence of Cu-
[5h]
A
and InACHTREU(NG OTf)3 (Table 1,entries 3,4). Inspiringly,
AHCTRE(UNG OTf)3 complex catalyzed the reaction smoothly,
giving the desired allylic amine in 77% yield with 82% ee
(Table 1,entry 5).
Table 1. Asymmetric three-component allylation of aldimines under indi-
cated conditions.[a]
As a versatile catalyst,chiral N,N’-dioxide compounds[11–12]
and their complexes[13] with different metals have showed
superiority in the enantioselective reactions of carbonyl
compounds and imines. In our study of chiral N,N’-dioxide-
metal complexes in catalytic asymmetric reactions,they
have exhibited good ability for the activation of allylstan-
nane reagent and 2-aminophenol-derived aldimines.[13] We
sought to take advantage of the activation abilities of this
kind of catalysts for the asymmetric allylation of 2-amino-
phenol-derived aldimines,which has been extensively docu-
mented well in the allylation by Kobayashi,[6] Leighton[3c,d]
and Tsogoeva[4d,e] et al. With the three-component reaction
Entry
Metal
Zr(OiPr)4
Pd(OAc)2
Cu(OTf)2
In(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
(OTf)3
Ligand
Yield [%][b[
ee [%][c]
1
2
3
4
5
6
7
8
G
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L3
L3
L3
NR
NR
81
98
77
82
81
85
83
90
89
87
63
81
76
83
–
–
0
1
82
80
93
56
53
50
38
17
0
G
G
U
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
Sc
G
ACHTREUNG
ACHTREUNG
ACHTREUNG
9
ACHTREUNG
10
11
12
13[d]
14[e]
15[f]
16[g]
ACHTREUNG
AHCTREUNG
AHCTREUNG
[a] X. Li,Dr. X. Liu,Dr. Y. Fu,L. Wang,L. Zhou,Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
(Sichuan University)
AHCTREUNG
R
95
95
80
AHCTREUNG
Ministry of Education,College of Chemistry
Sichuan University,Chengdu 610064 (China)
Fax : (+86)28-8541-8249
AHCTREUNG
[a] Unless specific indication,all reactions were carried out with
10 mol% L/metal complex (1:1) catalyst,2-aminophenol (0.1 mmol),
benzaldehyde (0.105 mmol),4 Š molecular sieves (15 mg),allyltributyltin
(0.15 mmol) and CHCl3 (1.0 mL) under Ar atmosphere at 258C. [b] Iso-
lated yield. [c] Determined by HPLC analysis. [d] Reaction time was
40 h. [e] 1.5 mL CHCl3 was used. [f] Benzaldehyde was added after the
addition of allyltributyltin. [g] Pure aldimine prepared beforehand was
used as substrate.
E-mail: xmfeng@scu.edu.cn
[b] Prof. Dr. X. Feng
State Key Laboratory of Oral Diseases,Sichuan University
Chengdu 610041 (China)
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
4796
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2008, 14,4796 – 4798

COMMUNICATION
Modular and tuneable N,N’-dioxide ligands,easily synthe-
sized from readily accessible chiral amino acids and amines,
facilitated the catalyst structure optimization. Both the
chiral backbone and steric effects of the amide portion of li-
gands played important roles on enantioselectivity towards
this reaction. l-ramipril acid-oriented N,N’-dioxide L3 was
superior to l-proline-derived and (S)-pipecolic acid-based
N,N’-dioxides (Table 1,entry 7 vs 5,6). The enantioselectivi-
ty was also closely dependent on the steric effects of the ar-
omatic amide portion. Simple aniline derivative L4 provided
products with 90% and 96% ee,respectively (Table 2,en-
tries 21,22). It was noteworthy that excellent enantioselec-
tivities could be attained with 3- and 4-pyridinecarboxalde-
hyde (Table 2,entries 23,24,up to 96%
ee). Thiophene-2-
carbaldehyde also gave the desired product in 71% yield
with 87% ee (Table 2,entry 25). Cinnamaldehyde provided
71% ee (Table 2,entry 26). [15]
Table 2. Substrate scope for the catalytic asymmetric three-component
allylation of aldimines.[a]
Entry
R
Product
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
10
24
24
24
18
18
18
16
16
81
76
80
74
88
85
84
85
81
95
95
93
92
96
95
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
3,4-Cl2C6H3
2,4-Cl2C6H3
97 (S)[d]
96
97
10
4j
18
72
90
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3-MeOC6H4
3-PhOC6H4
4-PhC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-CNC6H4
4-FC6H4
1-naphthyl
2-naphthyl
3-pyridyl
4-pyridyl
2-thienyl
4k
4 L
4m
4n
4o
4p
4q
4r
18
20
20
18
18
18
18
18
18
18
18
18
30
30
20
20
80
89
76
85
79
73
81
81
78
75
82
75
81
79
71
67
95
93
95
97
95
97
90
97
96
96
90
96
96
96
87
71
56% ee (Table 1,entry 8). Ligands regardless of steric and
electronic substitution on para-position of aniline had not
too much effects on enantioselectivity (Table 1,entries 9,10
vs 8). Mono-ortho-substituted aniline derivatives greatly de-
creased the ee values (Table 1,entries 11,12 vs 8). While the
bulkier 2,6-diisopropyl aniline derived N,N’-dioxide L3 dra-
matically increased enantioselectivity to 93% ee (Table 1,
entry 7). With mother amide L9 as ligand,only racemic
product was obtained (Table 1,entry 13),which demonstrat-
ed that the existence of the N-oxide portion was essential
for the enantioselectivity.
4 s
4t
4u
4v
4w
4x
4y
4z
(E)-PhCH=CH
The direct allylation of aldimine with three-component
method exhibited clearly superiority also in the enantiose-
lectivity. The addition sequence of benzaldehyde and allyl-
tributyltin had no effect on ee (Table 1,entry 15 vs 14),
while with prepared pure aldimine as substrate,the enantio-
selectivity was decreased to 80% ee (Table 1,entry 16). Op-
timization of other conditions (see Supporting Information)
showed that 1.5 mL CHCl3,10 mol% catalyst with the ratio
of ligand to metal 1:1 in the presence of 4 Š molecular
sieves at 258C were optimal.
Under the optimal conditions,a variety of aldehydes were
investigated and the corresponding products were provided
in good yields with excellent enantioselectivities,as shown
in Table 2. Neither the electronic property of the substitu-
tion at the aromatic ring,nor the steric hindrance had obvi-
ous influence on the enantioselectivity and up to 97% ee
could be obtained (Table 2,entries 1–20). In addition,con-
densed-ring aromatic aldehydes (1- and 2-naphthaldehyde)
were also found to be suitable substrates,giving the desired
[a] All reactions were carried out with 10 mol% L3/metal complex (1:1)
catalyst,2–aminophenol (0.1 mmol),aldehyde (0.105 mmol),allyltributyl-
tin (0.15 mmol),4 Š molecular sieves (15 mg) and CHCl (1.5 mL) under
3
Ar at 258C. [b] Isolated yield. [c] Determined by HPLC analysis. [d] The
absolute configuration of the major product was determined by compari-
son with the reported value of optical rotation,see ref. [4d,e].
In summary,we have developed the catalytic asymmetric
three-component allylation of aldimines,in which readily ac-
cessible and tuneable C2-symmetric N,N’-dioxide–ScIII com-
plex catalysts were successfully utilized. A wide range of ho-
moallylic amines were obtained with high enantioselectivi-
ties (up to 97% ee) and good yields under mild conditions.
The operational simplicity,practicability,and mild reaction
conditions render it an attractive approach for the asymmet-
ric reactions. Further investigations to clarify the mechanism
of the reaction are currently underway.
Chem. Eur. J. 2008, 14,4796 – 4798
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
4797

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4798
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Chem. Eur. J. 2008, 14,4796 – 4798