Development of chiral dinitrones as modular Lewis base catalysts: Asymmetric allylation of aldehydes with allyltrichlorosilanes

Article abstract of DOI:10.1016/j.tetasy.2010.05.048

Chiral dinitrones were synthesized by the condensation of a C ₂-symmetrical chiral dihydroxylamine with various aldehydes. The electronic and steric properties of the dinitrones can be modified by changing the aldehyde component. The activity o

Full text of DOI:10.1016/j.tetasy.2010.05.048

Tetrahedron: Asymmetry 21 (2010) 1833–1835
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Development of chiral dinitrones as modular Lewis base catalysts: asymmetric
allylation of aldehydes with allyltrichlorosilanes
a,
Young Seon Oh a, Shunsuke Kotani b, Masaharu Sugiura a, , Makoto Nakajima
*
*
a Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
b Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2010
Accepted 26 May 2010
Chiral dinitrones were synthesized by the condensation of a C2-symmetrical chiral dihydroxylamine with
various aldehydes. The electronic and steric properties of the dinitrones can be modified by changing the
aldehyde component. The activity of dinitrones as Lewis base catalysts was examined for the asymmetric
allylation of aldehydes with allyltrichlorosilanes. Using DMPU as an additive in chloroform, the reaction
proceeded at room temperature to afford allylated products in good yields and good enantioselectivities.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
sodium bicarbonate in dichloromethane at reflux for 6 h (Table 1).8
After purification by silica gel column chromatography, dinitrones
The effectiveness of a given catalyst generally depends on the
reaction, the substrates, and the conditions. Therefore, modifica-
tion of the catalyst structure is an important factor for catalyst de-
sign.1 We have previously reported that chiral bisquinoline or
bisisoquinoline N,N0-dioxides or diphosphine dioxides serve as
effective Lewis base catalysts for reactions including the allylation
of aldehydes with allyltrichlorosilanes or aldol reaction with tri-
chlorosilyl enol ethers.2 The polar N–O or P–O bond enables these
catalysts to nucleophilically activate chlorosilane reagents to pro-
mote these enantioselective transformations.3 However, a low
ability to modify the catalyst structure has been a drawback. In or-
der to address this issue, we herein propose the use of chiral dinit-
rones as new and readily modifiable Lewis base catalysts.
Nitrones are imine N-oxides possessing a negatively charged
oxygen similar to that of pyridine N-oxides. Although nitrones
have been successfully utilized as electrophiles or 1,3-dipoles in
organic synthesis,4 their use as Lewis base catalysts has not yet
been exploited.5 We envisaged that chiral dinitrones 1 derived
readily from C2-symmetrical dihydroxylamine and various alde-
hydes would be effective asymmetric Lewis base catalysts (Fig. 1).6
1a–1g were obtained in high yield as stable and crystalline com-
pounds having high specific rotations.
To examine the activity of dinitrone 1a as a Lewis base catalyst,
the asymmetric allylation of benzaldehyde (2a) with allytrichlo-
rosilane was investigated under various conditions (Table 2).9
When 1a and the reactants were mixed in dichloromethane at rt,
both the yield and enantioselectivity were low (entry 1). To im-
prove the reactivity, several additives were next examined (entries
O
+
2
N+
–O O–
Dinitrones 1
N+
HN
HO OH
NH
H
R
R
R
Figure 1. Design of chiral dinitrones 1.
Table 1
Preparation and properties of chiral dinitrones 1a
Entry
R in dinitrone 1
Yield (%)
Mp (°C)
[a]
D
2. Results and discussion
1
2
3
4
5
6
7
Ph 1a
98
83
93
95
Quant
91
99
207–208
249–250
203–204
179–180
213–214
215–216
240–241
+279.8
ꢀ56.6
1-Naphthyl 1b
2-Naphthyl 1c
p-ClC6H4 1d
p-NO2C6H4 1e
p-MeOC6H4 1f
3,4,5-(MeO)3C6H2 1g
Dihydroxylamine dihydrochloride was prepared from (S,S)-
1,2-cyclohaxanediamine according to the procedure reported by
Yamamoto et al.7 Condensation of the dihydrochloride salt with
various aromatic aldehydes was conducted in the presence of
+578.6
+223.6
+418.4
+185.8
+111.9
a
All reactions were performed using the dihydroxylamine dihydrochloride
* Corresponding authors. Tel.: +81 96 371 4680; fax: +81 96 362 7692.
E-mail addresses: msugiura@kumamoto-u.ac.jp (M. Sugiura), nakajima@gpo.ku-
mamoto-u.ac.jp (M. Nakajima).
(0.5 mmol), an aldehyde (3 equiv), and sodium bicarbonate (6 equiv) in dichloro-
methane at reflux for 6 h.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.048

1834
Y. S. Oh et al. / Tetrahedron: Asymmetry 21 (2010) 1833–1835
Table 2
rich p-MeOC6H4 group (dinitrone 1f) significantly improved the
Allylation of benzaldehyde using 1aa
catalyst performance (entry 6). However, increasing steric hin-
drance as well as the electron-donating ability (dinitrone 1g) pro-
vided inferior results (entry 7). Varying the reaction temperature
(35 or 0 °C) did not affect the yield and selectivity of the reaction
using dinitrone 1f (entries 8 and 9). Finally, the use of 20 mol %
of 1f provided an improved result (entry 10). It should be noted
that dinitrones 1a–g were stable under the reaction and work-up
conditions and could be recovered by silica gel column chromatog-
raphy after isolation of the product.12
Using catalyst 1f (20 mol %), the allylation of various aldehydes
was investigated (Table 4).13 The reaction of hydrocinnamalde-
hyde, a non-conjugated aldehyde, afforded the desired product
3b in moderate yield with diminished selectivity (entry 2) com-
pared with benzaldehyde (entry 1).14 In contrast, conjugated aro-
matic aldehydes showed good reactivities (entries 3–11). The
reaction tolerated relatively bulky aromatic aldehydes to provide
good yields and selectivities (entries 3–5). Benzaldehyde deriva-
tives having electron-withdrawing groups increased the yield,
but tended to decrease the selectivity (entries 6 and 7). p-Anisalde-
hyde bearing an electron-donating methoxy substituent decreased
both the yield and selectivity (entry 8), whereas m-anisaldehyde
gave a comparable result with benzaldehyde (entry 9). Further
substitution at the 3,5- or 3,4,5-positions of benzaldehyde with
methoxy groups was found to improve the selectivity (entries 10
and 11), and the latter aldehyde 2k provided the highest enanti-
oselectivity among the aldehydes tested (entry 11).
1a (10 mol %)
OH
O
additive (1.5 equiv)
SiCl3
+
Ph
Ph
H
solvent, rt, 24 h
(R)-3a
2a
Entry
Additiveb
Solvent
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
None
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
6
13
27
7
36
13
19
41
46
17
26
11
31
19
35
10
18
44
45
—
iPr2NEt
NMP
DMI
DMPU
DMPU
DMPU
DMPU
DMPU
DMPU
EtCN
CHCl3
CHCl3
CH2Cl2
9c
10d
a
Unless otherwise noted, reactions were performed using 1a (10 mol %), an
additive (1.5 equiv), benzaldehyde (0.4 mmol), and allyltrichlorosilane (1.2 equiv)
in a solvent at rt for 24 h.
b
NMP, N-methyl-2-piperidone; DMI, 1,3-dimethyl-2-imidazolidinone; DMPU,
N,N0 -dimethylpropyleneurea.
c
With allyltrichlorosilane (1.5 equiv).
Without 1a.
d
2–5), and N,N0-dimethylpropyleneurea (DMPU) emerged as the
most effective additive (entry 5).10,11 Interestingly, the combined
use of 1a and DMPU gave higher enantioselectivity than did 1a
alone (entries 1 vs 5), although DMPU itself was found to promote
the reaction (entry 10). Screening of solvents identified chloroform
as the optimal solvent (entries 6–8). The use of 1.5 equiv of allyltri-
chlorosilane resulted in the further improvement of the yield (en-
try 9).
The combination of catalyst 1f and DMPU was also applied to
the crotylation of benzaldehyde with (E)- and (Z)-trichlorocrotyl-
silanes 4a and 4b (Scheme 1). Branched anti- and syn-crotylated
Table 4
Allylation of various aldehydesa
Under the conditions optimized for catalyst 1a (see Table 2, en-
try 9), the activity of the other nitrones 1b–g was investigated (Ta-
ble 3). Dinitrone 1b having a 1-naphthyl group lowered the
selectivity, whereas dinitrone 1c bearing a 2-naphthyl group pro-
vided good selectivity (entries 2 and 3). Electron-deficient benzene
rings significantly decreased both the yield and selectivity (entries
4 and 5). Presumably because of the low Lewis basicity of the cat-
alyst, the reaction with 1e was promoted by only DMPU to give the
racemic product (see Table 2, entry 10). In contrast, the electron-
OH
O
1f (20 mol %)
SiCl3
+
R'
R'
H
DMPU (1.5 equiv)
CHCl3, rt, 24 h
(R)-3
2
Entry
R0 in aldehyde 2
3
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Ph 2a
Ph(CH2)2 2b
3a
3b
3c
3d
3e
3f
3g
3h
3i
78
42
75
69
81
84
93
68
76
71
82
74
8
3,5-Me2C6H3 2c
1-Naphthyl 2d
2-Naphthyl 2e
p-BrC6H4 2f
p-NO2C6H4 2g
p-MeOC6H4 2h
m-MeOC6H4 2i
3,5-(MeO)2C6H3 2j
3,4,5-(MeO)3C6H2 2k
75
71
77
74
64
63
74
77
87
Table 3
Catalyst screening for allylation of 2aa
2a
+
1 (10 mol %)
(R)-3a
N+
N+
DMPU (1.5 equiv)
CHCl3, rt, 24 h
SiCl3
10
11
3j
3k
R
–O O–
R
1
a
All reactions were performed using 1f (20 mol %), DMPU (1.5 equiv), an alde-
hyde (0.4 mmol), and allyltrichlorosilane (1.5 equiv) in CHCl3 at rt for 24 h.
Entry
R in dinitrone 1
Yield (%)
ee (%)
1
2
3
4
5
Ph 1a
46
62
57
28
27
66
39
61
59
78
45
35
60
32
0
71
37
71
70
74
1-Naphthyl 1b
2-Naphthyl 1c
p-ClC6H4 1d
p-NO2C6H4 1e
p-MeOC6H4 1f
3,4,5-(MeO)3C6H2 1g
1f
Me
SiCl3
4a (80% E)
OH
OH
5a, 61% yield
anti/syn = 5/1
71% ee (anti)
Ph
Ph
6
7
1f (20 mol %)
DMPU (1.5 equiv)
CHCl3, rt, 24 h
O
8b
9c
10d
1f
1f
Ph
H
5b, 51% yield
anti/syn = 1/99
63% ee (syn)
2a
a
All reactions were performed using 1 (10 mol %), DMPU (1.5 equiv), benzalde-
SiCl3
hyde (0.4 mmol), and allyltrichlorosilane (1.5 equiv) in CHCl3 at rt for 24 h.
b
4b (99% Z)
At 35 °C.
At 0 °C.
With 20 mol % of catalyst.
Me
c
d
Scheme 1. Crotylation of 2a.

Y. S. Oh et al. / Tetrahedron: Asymmetry 21 (2010) 1833–1835
1835
5. For recent examples of nitrone ligands for metal-catalysts, see: (a) Yao, Q.;
Zabawa, M.; Woo, J.; Zheng, C. J. Am. Chem. Soc. 2007, 129, 3088–3089; (b)
Zhang, Y.; Song, G.; Ma, G.; Zhao, J.; Pan, C.-L.; Li, X. Organometllics 2009, 28,
3233–3238.
products 5a and 5b were obtained from 4a and 4b with moderate
yields and enantioselectivities, respectively. The observed high ste-
reospecificity suggests a mechanism involving a chair-like cyclic
transition state with the aryl group of the aldehyde in the equato-
rial orientation. Further studies are needed to elucidate the de-
tailed mechanism involving the role of the DMPU additive.
6. C2-Symmetrical
bisimidazole
N,N0-dioxides
derived
from
1,2-
cyclohaxanediamine have recently been reported as Lewis base catalysts for
´
enantioselective allylation, see: Kwiatkowski, P.; Mucha, P.; Mloston, G.;
Jurczak, J. Synlett 2009, 1757–1760.
7. Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int.
Ed. 2005, 44, 4389–4391.
8. General procedure for preparation of dinitrones: To (S,S)-N,N’-dihydroxyl1-1,2-
cyclohexanediamine dihydrochloride7 (0.5 mmol), dichloromethane (10 mL),
NaHCO3 (252 mg, 6 equiv), and an aldehyde (1.5 mmol) were added at room
3. Conclusion
In summary, we have proposed the use of chiral dinitrones as
new and modular Lewis base catalysts. With DMPU as an additive
in chloroform, chiral dinitrones effectively catalyzed the asymmet-
ric allylation of aldehydes with allyltrichlorosilanes to give good
yields and good enantioselectivities. Further improvement of the
catalytic activity and selectivity as well as application to other
reactions utilizing the concept of modularity of dinitrone catalysts
are currently in progress.
temperature. The reaction mixture was refluxed for
6 h, filtered, and
evaporated. The residue was purified by silica gel column chromatography
(hexane/acetone or dichloromethane/EtOH) to give a dinitrone.
9. Leading references on enantioselective allylation of aldehydes with
allyltrichlorosilanes catalyzed by various types of chiral Lewis bases. For
chiral phosphoramides, see: (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel,
B. D. J. Org. Chem. 1994, 59, 6161–6163; (b) Denmark, S. E.; Fu, J.; Lawler, M. J. J.
Org. Chem. 2006, 71, 1523–1536; (c) For chiral pyridine N-oxides, see: Ref. 2a.;
(d) Malkov, A. V.; Orsini, M.; Pernazza, D.; Muir, K. W.; Langer, V.; Meghani, P.;
ˇ
´
Kocovsky, P. Org. Lett. 2002, 4, 1047–1049; (e) Shimada, T.; Kina, A.; Ikeda, S.;
Hayashi, T. Org. Lett. 2002, 4, 2799–2801; (f) Malkov, A. V.; Bell, M.; Castelluzzo,
F.; Kocˇovsky´, P. Org. Lett. 2005, 7, 3219–3222; (g) Chai, Q.; Song, C.; Sun, Z.; Ma,
Y.; Ma, C.; Dai, Y.; Andrus, M. B. Tetrahedron Lett. 2006, 47, 8611–8615; (h)
Acknowledgment
ˇ
Kadlcíková, A.; Hrdina, R.; Valterová, I.; Kotora, M. Adv. Synth. Catal. 2009, 351,
This work was partially supported by a Grant-in-Aid of Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
1279–1283; For chiral formamides, see: (i) Iseki, K.; Mizuno, S.; Kuroki, Y.;
Kobayashi, Y. Tetrahedron Lett. 1998, 39, 2767–2770; For chiral sulfoxides, see:
ˇ
´
(j) Massa, A.; Malkov, A. V.; Kocovsky, P.; Scettri, A. Tetrahedron Lett. 2003, 44,
7179–7181; (k) Rowlands, G. J.; Barnes, W. K. Chem. Commun. 2003, 9, 2712–
2713; (l) For chiral phosphine oxides, see: Ref. 2c.; (m) Simonini, V.; Benaglia,
M.; Benincori, T. Adv. Synth. Catal. 2008, 350, 561–564; For chiral pyrrolidine N-
oxides, see: (n) Traverse, J. F.; Zhao, Y.; Hoveyda, A. H.; Snapper, M. L. Org. Lett.
2005, 7, 3151–3154; (o) Simonini, V.; Benaglia, M.; Pignataro, L.; Guizzetti, S.;
Celentano, G. Synlett 2008, 1061–1065.
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a
solution of dinitrone 1f (20 mol %), an aldehyde 2 (0.4 mmol), and DMPU (1.5
equiv) in chloroform (1 mL) was added allyltrichlorosilane (1.5 equiv) under
argon at room temperature. After being stirred at that temperature for 24 h, the
reaction was quenched with satd aqueous NaHCO3 (10 mL), and the slurry was
stirred for 1 h. The mixture was filtered through cotton wool and extracted
with ethyl acetate (3 ꢁ 15 mL). The combined organic layers were washed with
brine (1 ꢁ 30 mL), dried over MgSO4, filtered, and concentrated under vacuum.
The crude product was purified by silica gel column chromatography (hexane/
ethyl acetate) to give the product 3. The enantiomeric excess was determined
by HPLC analysis.
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