Indium-mediated catalytic enantioselective allylation of N -benzoylhydrazones using a protonated chiral amine

Article abstract of DOI:10.1021/ja1035336

A catalytic enantioselective indium-mediated allylation of N-benzoylhydrazones in conjunction with a protonated chiral amine affording enantioenriched homoallylic amines with an extremely high level of enantioselectivity and chemical yield was developed.

Full text of DOI:10.1021/ja1035336

Published on Web 08/16/2010
Indium-Mediated Catalytic Enantioselective Allylation of N-Benzoylhydrazones
Using a Protonated Chiral Amine
Sung Jun Kim and Doo Ok Jang*
Department of Chemistry, Yonsei UniVersity, Wonju, Gangwon 220-710, Korea
Received April 26, 2010; E-mail: dojang@yonsei.ac.kr
In an initial experiment, the benzaldehyde-derived N-benzoyl-
hydrazone 2a was reacted with allylindium generated in situ in
Abstract: A catalytic enantioselective indium-mediated allylation
of N-benzoylhydrazones in conjunction with a protonated chiral
amine affording enantioenriched homoallylic amines with an
extremely high level of enantioselectivity and chemical yield was
MeOH in the presence of 0.1 equiv of the protonated chiral amine
[1aH]+. The reaction proceeded smoothly at room temperature,
affording the addition adduct 3a in an 89% chemical yield.
developed.
Scheme 1
Allylation of imine derivatives is an important tool for
carbon-carbon bond formation and the introduction of amino
groups into carbon skeletons. The resulting homoallylic amine
products are highly versatile intermediates, are useful synthetic
building blocks, and are biologically active compounds.1 As such,
a great deal of effort has been devoted to developing synthetic
methods for their synthesis.2 Addition of allylic metal nucleophiles
However, the enantioselectivity of the reaction was very poor (Table
1, entry 1). With an increase in the amount of [1aH]+ under
to CdN bonds is a straightforward strategy for the synthesis of
otherwise identical conditions, the enantioselectivity of the reaction
improved dramatically up to 99% ee (entries 2-3). The nonlinear
increase in ee values are attributed to deprotonation of some [1aH]+
by allyl indium species in competition with catalytic turnover by
[1aH]+. Further investigation into catalyst loading revealed that
the use of as little as 0.3 equiv of [1aH]+ was sufficient to attain
high levels of enantioselectivity and chemical yield (entry 4).
Decreasing amounts of allyl bromide and indium afforded the
product in lower yield while attaining high enantioselectivity,
suggesting a catalytic turnover (entries 5-6). A control experiment
was carried out with the chiral amine 1a, providing a racemic
homoallylic amines. Strong organometallic reagents are required
for the nucleophilic addition of imine derivatives due to their low
reactivity. The strong basic property of organometallic reagents
limits their utility as nucleophilic allylation reagents for base-
sensitive imine derivatives. Among the various allylic metal
reagents, allylindium reagents are promising for this purpose as
they display low basicity, high chemoselectivity, and low toxicity.3
Asymmetric variants of indium-mediated allylation of imine
derivatives are problematic since the low heterophilicities of
allylindium reagents with a chiral ligand are not able to provide a
chiral environment suitable for chiral induction. Asymmetric
allylation of imine derivatives with allylindium reagents has mainly
relied on chiral auxiliaries in the imine derivatives.4,5 On the other
hand, examples of catalytic asymmetric indium-mediated allylation
of imine derivatives are very rare. Cook and Lloyd-Jones6a,b as
well as Jacobsen6c reported indium-mediated enantioselective
allylation of N-acylhydrazones using binol derivatives and chiral
ureas, respectively, with low catalyst loading at low temperature.
These reagents gave high enantioselectivity with aryl aldehyde-
derived hydrazones bearing an ortho substituent, while aryl alde-
hyde-derived hydrazones possessing a para substituent afforded
lower ee values.
Table 1. Enantioselective Allylation of 2a under Various Conditions
Allyl
bromide
(equiv)
[1aH]+
(equiv)
In
(equiv)
Yield
(%)a
ee
(%)b
Entry
Solvent
1
2
3
4
0.1
0.2
0.3
0.5
0.3
0.3
1.0
0.3
0.3
0.3
0.3
0.3
0.3
3
3
3
3
2
1.5
3
3
3
3
3
3
3
3
3
3
3
2
1.5
3
3
3
3
3
3
3
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
THF
Toluene
CH3CN
CH2Cl2
C2H4Cl2
89
90
94
93
84
77
83
81
38
88
71
55
57
8
30
99
99
99
98
0
Here, we report a catalytic enantioselective indium-mediated
allylation of N-benzoylhydrazones in conjunction with a protonated
chiral amine that gives rise to enantioenriched homoallylic amines
with extremely high levels of enantioselectivity and chemical yield
at ambient temperature. To the best of our knowledge, the levels
of enantioselectivity and substrate generality reported herein are
the highest among those previously reported.
5
6
7c
8d
9
0
95
38
47
69
67
10
11
12
13
Protonated chiral reagents have proved to be extremely useful
as chiral promoters for enantioselective reactions.7 We assumed
that low-basicity indium reagents might permit the use of protonated
chiral amines as chiral promoters in indium-mediated allylation of
imine derivatives.
a Isolated yield. b Enantiomeric excess was determined by HPLC
analysis using
a
chiral column (Daicel Chiralpak IA) with
hexane-isopropanol as solvent. c 1a was used instead of [1aH]+. d 1a
and Et3N+HPF6 were used instead of [1aH]+.
-
9
12168 J. AM. CHEM. SOC. 2010, 132, 12168–12169
10.1021/ja1035336  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Allylation of N-Benzoylhydrazones with
lower ee values and yields (entries 12-13). Functional groups such
as chloro, bromo, nitro, ketone, amide, and methoxy were intact
under conditions. Interestingly, the labile phenolic functionality did
not require protection.
[1aH]+
Enantioselective allylation of N-benzoylhydrazones with the
chiral promoter [1bH]+, the pseudoenantiomer of [1aH]+, also
underwent the reactions efficiently and provided allylated products
with reversed chiralities (Table 3). The allylation of N-benzoylhy-
drazones with [1bH]+ was comparable to that of [1aH]+ in terms
of chemical yield and enantioselectivity. The two promoters [1aH]+
and [1bH]+, which are salts, were readily recovered after a simple
aqueous workup in more than 95% yield. The absolute configuration
of 3c was determined to be S by comparing the optical rotation
with that reported in the literature.8 The absolute configurations of
all other allylated products were determined in reference to 3c.
In conclusion, we developed an enantioselective allylation of
N-benzoylhydrazones in the presence of a protonated chiral amine
affording enantioenriched homoallylic amines in high yields, with
extremely high enantioselectivities. To the best of our knowledge,
this is the first example of employing a protonated chiral amine
with organometallic reagents. The method presented here has several
features including operational simplicity, generality of substrates,
low cost, and reuse of chiral promoters. Further work to expand
the scope of the reaction is underway.
Yield
(%)a
ee
(%)b
Entry
Substrate
R
Product
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
4-F-Ph-
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
94
92
92
90
90
88
90
86
90
90
92
95
80
99 (S)
98 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
99 (S)
86 (R)
80 (R)
4-Cl-Ph-
4-NO2-Ph-
4-MeC(O)-Ph-
4-MeC(O)NH-Ph-
4-Et-Ph-
4-OMe-Ph-
4-OH-Ph-
3-Cl-Ph-
2-Br-Ph-
2-OMe-Ph-
PhCH2CH2-
CH3(CH2)6-
9
10
11
12
13
a Isolated yield. b Enantiomeric excess was determined by HPLC
analysis using chiral column (Daicel Chiralpak IA) with
a
hexane-isopropanol as the solvent.
mixture in 83% yield (entry 7). A reaction performed in the presence
of Et3N+HPF6- and 1a afforded a racemic mixture (entry 8). These
results and NMR evidence indicate that the promoter [1aH]+ might
interact with N-benzoylhydrazone via hydrogen bonding and π-π
interaction, providing a chiral environment, while the allylindium
nucleophile generated in situ attacks at the Si-face of the CdN
bond, resulting in an allylated adduct with high enantioselectivity
(see Supporting Information). The addition of allylindium to the
N-benzoylhydrazone 2a in THF afforded the product 3a with a high
selectivity of 95% ee, but only in 38% yield (entry 9). Other organic
solvents such as toluene, acetonitrile, dichloromethane, and 1,2-
dichloroethane compared to methanol were less effective in terms
of chemical yield and enantioselectivity (entries 10-13).
We evaluated the scope of the reaction with a wide range of
N-benzoylhydrazones derived from aldehydes under optimal condi-
tions, and the results are summarized in Table 2. Reactions with
aryl aldehyde-derived N-benzoylhydrazones with either an ortho
substituent or a para/meta substituent proceeded smoothly at ambient
temperature in the presence of the protonated chiral amine [1aH]+,
affording allylated products in high yields with extremely high
enantioselectivities, demonstrating the generality of the reaction
(entries 1-11). N-Benzoylhydrazones derived from aliphatic alde-
hydes underwent allylation at room temperature with relatively
Acknowledgment. This research was funded by the National
Research Foundation of Korea (2009-0074839). CBMH is also
acknowledged.
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC traces. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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Table 3. Enantioselective Allylation of N-Benzoylhydrazones with
[1bH]+
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Entry
Substrate
R
Product
Yield (%)a
ee (%)b
(7) Protonated chiral catalysts: (a) Singh, A.; Johnston, J. N. J. Am. Chem. Soc.
2008, 130, 5866. (b) Wilt, J. C.; Pink, R. M.; Johnston, J. N. Chem. Commun.
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1
2
3
4
5
6
7
2a
2b
2d
2e
2g
2h
2n
Ph
4-F-Ph-
ent-3a
ent-3b
ent-3d
ent-3e
ent-3g
ent-3h
ent-3n
92
90
89
90
90
88
81
99 (R)
99 (R)
99 (R)
99 (R)
96 (R)
99 (R)
78 (S)
4-NO2-Ph-
4-MeC(O)-Ph-
4-Et-Ph-
4-OMe-Ph-
CH3(CH2)6-
(8) Kobayashi, S.; Orgawa, C.; Konish, H.; Sugiura, M. J. Am. Chem. Soc. 2003,
125, 6610.
a Isolated yield. b Enantiomeric excess was determined by HPLC
analysis using chiral column (Daicel Chiralpak IA) with
hexane-isopropanol as the solvent.
a
JA1035336
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J. AM. CHEM. SOC. VOL. 132, NO. 35, 2010 12169