1,3-Addition of silyl enol ethers to nitrones catalyzed by mesoporous aluminosilicate

Article abstract of DOI:10.1016/j.tetlet.2014.07.020

Mesoporous aluminosilicate (Al-MCM-41) was found to be an effective and reusable catalyst for 1,3-addition of silyl enol ethers to nitrones. The reaction proceeded under mild reaction conditions to afford the corresponding β-(siloxyamino)ketones in high y

Full text of DOI:10.1016/j.tetlet.2014.07.020

Accepted Manuscript
1,3-Addition of silyl enol ethers to nitrones catalyzed by mesoporous alumino-
silicate
Suguru Ito, Yoshihiro Kubota, Masatoshi Asami
PII:
S0040-4039(14)01161-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.07.020
TETL 44863
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 May 2014
26 June 2014
4 July 2014
Please cite this article as: Ito, S., Kubota, Y., Asami, M., 1,3-Addition of silyl enol ethers to nitrones catalyzed by
mesoporous aluminosilicate, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.07.020
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
1,3-Addition of silyl enol ethers to nitrones catalyzed by
mesoporous aluminosilicate
Suguru Ito, Yoshihiro Kubota, Masatoshi Asami*
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
Tokiwadai 79-5, Hodogaya-ku, Yokohama 240-8501, Japan
Abstract— Mesoporous aluminosilicate (Al-MCM-41) was found to be an effective and reusable catalyst for 1,3-addition of silyl enol
ethers to nitrones. The reaction proceeded under mild reaction conditions to afford the corresponding β-(siloxyamino)ketones in high yields.
Furthermore, a unique chemoselectivity of a nitrone over an aldehyde and an acetal, which are more reactive toward silyl enol ether in the
presence of Al-MCM-41 than a nitrone, was observed.
© 2014 Elsevier Science. All rights reserved
Keywords: Al-MCM-41; Solid acid catalyst; 1,3-Addition of nitrones; Chemoselective reaction
(a)
−O
Nitrones are generally used for 1,3-dipolar cycloaddition
R2
R2
H
+
with dipolarophiles to afford the corresponding
heterocyclic compounds because of the synthetic utility of
the cycloadducts.1,2 The reactions of nitrones with silyl enol
ethers derived from ketones are known to give the
corresponding cycloadducts under heating conditions2a or
in the presence of trimethylsilyl trifluoromethanesulfonate
(TMSOTf) (Scheme 1a).2b In contrast, the reactions of
nitrones with silyl enol ethers derived from esters can
afford the corresponding 1,3-adducts in the presence or
absence of Lewis acids (Scheme 1b).3 1,3-Adducts of
nitrones, hydroxylamine derivatives, are the precursors of
amines and imines, which are synthetically useful
intermediates.3,4
OSi
R3
∆ or TMSOTf
N
O
N
+
OSi
R3
cycloadduct
R1
R1
(b)
−O
R2
H
SiO
R2
+
N
OSi
OR4
rt or Lewis acid
N
O
+
R1
R1
OR4
1,3-adduct
Scheme 1. (a) 1,3-Dipolar cycloaddition of nitrone with
silyl enol ether, (b) 1,3-Addition of silyl enol ether to
nitrone.
In the first place, the reaction of C,N-diphenylnitrone (1a)
and 1-phenyl-1-trimethylsiloxyethene (2a) was examined
using Al-MCM-41 (Si/Al = 26) synthesized according to a
known procedure with slight modification.6,7 After drying
Al-MCM-41 (25 mg) at 120 °C for 1 h under vacuum, 1a
(0.5 mmol) and 2a (0.6 mmol) in dichloromethane was
added to the catalyst, and the mixture was stirred at 0 °C
for 1 h. The catalyst was filtered off and washed with
dichloromethane. The filtrate was then concentrated under
reduced pressure to give the crude product containing the
corresponding 1,3-adduct 3a in quantitative yield (Table 1,
entry 1).8 The result was in sharp contrast to the reaction of
1a with 2a in refluxing xylene,2a where the corresponding
cycloadduct was obtained. The reaction was then carried
out in the presence of stoichiometric amount of Lewis acids
We have recently reported that the ordered mesoporous
aluminosilicate (Al-MCM-41) could catalyze aldol
reactions of silyl enol ethers with aldehydes5a and acetals5b
in a heterogeneous manner. The high catalytic activity of
Al-MCM-41 was attributed to their uniform pore diameter
(2.7 nm) and high surface area (1120 m2/g). The catalyst
was easily recovered by filtration and reusable without a
significant loss of catalytic activity. Herein, we report that
the Al-MCM-41 could catalyze 1,3-addition of nitrones
with silyl enol ethers derived from a ketone.
———
* Corresponding author. Tel./fax: +81 45 339 3968; e-mail:m-asami@ynu.ac.jp.

2
Tetrahedron Letters
(TMSOTf, TiCl4, SnCl4, BF3·OEt2, or AlCl3) under the
same reaction conditions as entry 1. The reaction of 1a with
2a using TMSOTf gave a complex mixture and neither 1,3-
adduct 3a nor cycloadduct was obtained (entry 2), though
the reaction of C,N-dialkylnitrone with 2a in
electron-rich nitrones 1d and 1e, having methyl or methoxy
group on the aromatic ring, with 2a were slower than that
of electron-poor nitrones, 1,3-adducts were obtained in
high yields (entries 3 and 4). 1,3-Addition of 2a to C-2-
naphthyl-N-phenylnitrone (1f) or N-phenyl-C-trans-
styrylnitrone (1g) afforded the product in 86% and 83%
dichloromethane
using
TMSOTf
afforded
the
corresponding cycloadduct in good yields.2b The reactions
using TiCl4, SnCl4, or BF3·OEt2 also afforded complex
mixtures without the formation of 3a or cycloadduct
(entries 3–5). Although the 1,3-adduct 3a was obtained by
using AlCl3, the catalytic activity of AlCl3 for the 1,3-
addition was much lower (35% yield, entry 6) than that of
Al-MCM-41. When amorphous silica–alumina (SiO2–
Al2O3, Si/Al = 31)9 or aluminum-free MCM-4110 was used
in place of Al-MCM-41, the reaction did not proceed and
1a was recovered quantitatively (entries 7 and 8). These
results indicate that the presence of both mesoporous
structure and aluminum moiety in the catalyst is
indispensable to the high catalytic activity of Al-MCM-41
as was observed in the case of the Al-MCM-41-catalyzed
aldol reaction.5 When the Al-MCM-41-catalyzed reaction
was carried out at 30 °C, the reaction was completed in 15
min to give 3a in 96% isolated yield (entry 9). The
recovered catalyst could be reused four times without a
significant loss of catalytic activity (entry 10).
yields, respectively (entries 5 and 6). N-Benzyl-C-
phenylnitrone (1h) was less reactive than 1a and the
reaction was completed in 2.5 h to give the 1,3-adduct in
83% yield (entry 7), whereas the reaction of N-benzyl-C-4-
nitrophenylnitrone (1i) was completed in 0.5 h (86% yield,
entry 8). As bulkier silyl ethers are often useful than
trimethylsilyl ethers from a synthetic point of view,12 1-
phenyl-1-triethylsiloxyethene (2b) was applied to the
reaction with 1a. The corresponding triethylsilyl (TES)
ether of the 1,3-adduct was obtained in 96% yield (entry 9).
However,
the
yield
decreased
when
1-tert-
butyldimethylsiloxy-1-phenylethene (2c) was employed
(41% yield, entry 10).
Table 2. 1,3-Addition of silyl enol ethers to various
nitrones catalyzed by Al-MCM-41.8
Al-MCM-41
(50 mg/mmol, Si/Al = 26)
−O
R2
H
SiO
R2
+
N
OSi
Ph
N
O
+
CH2Cl2 (0.5 M), 30 °C
R1
R1
Ph
1
2
(1.2 equiv)
3
Table 1. 1,3-Addition of silyl enol ether 2a to nitrone 1a.11
Lewis acid
(1.0 equiv)
Time Yield
Silica catalyst
(50 mg/mmol)
−O
Ph
Me3SiO
Ph
Entry
1
R1
R2 2a
+
or
(%)b
96
87
91
95
94
86
83
86
96
41
OSiMe3
Ph
(h)
0.25
0.25
1
2
0.25
2
2.5
0.5
0.25
5
N
N
O
+
1c
2d
3
4e
5
b
c
d
e
f
g
h
i
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
a
a
a
a
a
a
a
a
b
c
CH2Cl2 (0.5 M)
0 °C, 1 h
Ph
H
Ph
Ph
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
2-Naphtyl
1a
2a
(1.2 equiv)
3a
Silica catalyst (Si/Al)
or Lewis acid
Al-MCM-41 (26)
TMSOTf
Conv. of
Yield of
3a (%)a
>95
Entry
1a (%)a
>95
>95
49
6c,e
7e
8e
9
(E)-PhCH=CH Ph
1
2
3
4
5
6
7
8
N.D.b
N.D.b
N.D.b
N.D.b
35
Ph
4-NO2C6H4
Ph
Bn
Bn
Ph
Ph
TiCl4
SnCl4
BF3·OEt2
AlCl3
a
a
53
43
37
0
0
>95
>95
10
Ph
a 2a, Si = SiMe3; 2b, Si = TES; 2c, Si = TBDMS. b Isolated yield
after column chromatography. CH2Cl2 (0.25 M). d CH2Cl2 (0.1
c
SiO2-Al2O3 (31)
MCM-41 (∞)
Al-MCM-41 (26)
Al-MCM-41 (26)
N.D.b
N.D.b
96d
M). e 2a (2.0 equiv) was used.
9c
10c,e
In the case of Al-MCM-41-catalyzed aldol reaction, Al-
MCM-41 promoted the reaction with complete
chemoselectivity. That is, only benzaldehyde dimethyl
acetal (5) reacted with 2a in the presence of both
benzaldehyde (4) and 5.5b Therefore, the Al-MCM-41-
catalyzed reaction of 1a (0.5 mmol) and 2a (0.6 mmol) was
95d
Determined by 1H NMR analysis of the crude product using
a
nitromethane as an internal standard unless otherwise noted. b Not
detected. c Reaction was performed at 30 °C for 15 min. d Isolated
yield after column chromatography. e Recovered catalyst was used.
The result of fifth run is shown.
examined in the presence of
4
(0.5 mmol) in
As Al-MCM-41 showed a charasteristic feature in the
reaction of nitrone 1a and silyl enol ether 2a, the reaction
was applied to various nitrones 1 and silyl enol ethers 2 in
dichloromethane at 30 °C (Table 2). Among N-
phenylnitrones, the reactions of electron-poor nitrones 1b
and 1c, having chloro or nitro group on the aromatic ring,
with 2a were completed in 15 min to afford the
corresponding 1,3-adducts in 96% and 87% yields,
respectively (entries 1 and 2). Although the reaction of
dichloromethane at 30 °C for 15 min. Interestingly, only 1a
reacted with 2a to give 3a in quantitative yield,14 though
the aldol reaction of 2a with 4 was much faster than the
1,3-addition of 2a to 1a.5a,13 Moreover, 1a was selectively
reacted with 2a also in the presence of 5 to afford 3a in
88% yield under the same reaction conditions (Table 3).
The origin of the reversed reactivity was considered to be
in the high adsorption ability of the nitrone for the acid
sites of Al-MCM-41. The hypothesis was further supported

Tetrahedron Letters
3
by the result that electron-rich nitrone 1d, which should
have higher adsorption ability than electron-poor nitrone 1b,
was preferentially reacted with 2a in the presence of 1b
(Scheme 2). Namely, the reaction of 2a with 1b and 1d in
dichloromethane at 30 °C for 1 h gave 3d in 71% yield and
3b was obtained in 19% yield although the reactivity of 1b
in the absence of 1d was higher than that of 1d in the
absence of 1b (Table 2, entries 1 and 3).
Supplementary data associated with this article can be
found, in the online version, at
doi:10.1016/j.tetlet.201X.XX.XXX.
References and notes
1. For reviews, see: (a) Confalone, P. N.; Huie, E. M. Org.
React. 1988, 36, 1–173; (b) Koumbis, A. E.; Gallos, J. K.
Curr. Org. Chem. 2003, 7, 585–628; (c) Borschberg, H.-J.
Curr. Org. Chem. 2005, 9, 1465–1491.
2. (a) Hosomi, A.; Shoji, H.; Sakurai, H. Chem. Lett. 1985,
1049–1052; (b) Camiletti, C.; Dhavale, D. D.; Gentilucci, L.;
Trombini, C. J. Chem. Soc., Chem. Commun. 1992, 1268–
1270.
3. (a) Tomoda, S.; Takeuchi, Y.; Nomura, Y. Chem. Lett. 1982,
1787–1790; (b) Camiletti, C.; Dhavale, D. D.; Donati, F.;
Trombini, C. Tetrahedron Lett. 1995, 36, 7293–7296; (c)
Qian, C.; Wang, L. Tetrahedron 2000, 56, 7193–7197; (d)
Merino, P.; Francoa, S.; Jimeneza, P.; Tejeroa, T.; Chiacchiob,
M. A. Lett. Org. Chem. 2005, 2, 302–305.
4. (a) Tsuge, O.; Urano, S.; Iwasaki, T. Bull. Chem. Soc. Jpn.
1980, 53, 485–489; (b) Gianotti, M.; Lombardo, M.;
Trombini, C. Tetrahedron Lett. 1998, 39, 1643–1646; (c)
Nelson, D. W.; Easley, R. A.; Pintea, B. N. V. Tetrahedron
Lett. 1999, 40, 25–28; (d) Kawakami, T.; Ohtake, H.;
Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Bull.
Chem. Soc. Jpn. 2000, 73, 2423–2444; (e) Merino, P.; Franco,
S.; Merchan, F. L.; Tejero, T. Synlett 2000, 442–454; (f)
Lombardo, M.; Trombini, C. Synthesis 2000, 759–774; (g)
Lombardo, M.; Trombini, C. Curr. Org. Chem. 2002, 6, 695–
713.
Table 3. Chemoselective 1,3-addition of nitrone 1a over
aldehyde 4 and acetal 5.
PhCHO
4 (0.5 mmol)
or
Al-MCM-41
(25 mg, Si/Al = 26)
−O
Ph
+
N
OSiMe3
+
+
CH2Cl2 (0.5 M)
30 °C, 15 min
Ph
Ph
1a
(0.5 mmol)
H
PhCH(OMe)2
5 (0.5 mmol)
2a
(0.6 mmol)
Me3SiO
N
Ph
RO
O
O
+
Ph
Ph
Ph
Ph
3a
6 R = SiMe3
7 R = Me
Product (Yield/%)a
PhCHO (4)
PhCH(OMe)2 (5)
3a (>95)
3a (88)
6 (N.D.)b
7 (Trace)
Determined by 1H NMR analysis of the crude product using
a
nitromethane as an internal standard. Yields are based on the
corresponding substrates. b Not detected.
Al-MCM-41
(25 mg, Si/Al = 26)
−O
Ph
H
−O
Ph
H
+
+
5. (a) Ito, S.; Yamaguchi, H.; Kubota, Y.; Asami, M. Chem. Lett.
2009, 38, 700–701; (b) Ito, S.; Hayashi, A.; Komai, H.;
Kubota, Y.; Asami, M. Tetrahedron Lett. 2010, 51, 4243–
4245.
6. (a) Chen, C.-Y.; Li, H.-X.; Davis, M. E. Micropor. Mater.
1993, 2, 17–26; (b) Ito, S.; Hayashi, A.; Komai, H.;
Yamaguchi, H.; Kubota, Y.; Asami, M. Tetrahedron 2011, 67,
2081–2089.
OSiMe3
Ph
N
N
+
+
CH2Cl2 (0.2 M)
30 °C, 1 h
4-ClC6H4
1b
4-MeC6H4
1d
2a
(0.6 mmol)
(0.5 mmol)
(0.5 mmol)
Me3SiO
Ph
O
Me3SiO
Ph
O
N
N
+
4-ClC6H4
Ph
4-MeC6H4
Ph
7. The specific surface area (BET) and the average pore
diameter (BJH) were 1120 m2/g and 2.7 nm, respectively.
8. The structure of the 1,3-adducts was fully characterized by IR
and 1H, 13C NMR spectroscopy.
9. Amorphous silica–alumina (SiO2–Al2O3, Si/Al = 31) was
synthesized according to the same procedure as the one used
in the synthesis of Al-MCM-41 without the addition of
surfactant, cethyltrimethylammonium bromide. The specific
surface area (BET) was 385 m2/g.
10. Aluminum-free MCM-41 was synthesized according to the
same procedure as the one used in the synthesis of Al-MCM-
41 without the addition of aluminum source, Al(OiPr)3. The
specific surface area (BET) and the average pore diameter
(BJH) were 1080 m2/g and 2.6 nm, respectively.
11. Typical experimental procedure for Al-MCM-41-catalyzed
1,3-addition of silyl enol ethers to nitrones (Table 1, entry 8):
Under an atmosphere of argon, to a mixture of C,N-
diphenylnitrone (1a) (98.6 mg, 0.50 mmol) and Al-MCM-41
(25 mg, Si/Al = 26, dried prior to use at 120 °C for 1 h under
vacuum) in dichloromethane (0.5 mL), 1-phenyl-1-
trimethylsiloxyethene (2a) (115 mg, 0.60 mmol) in
dichloromethane (0.5 mL) was added through a syringe at
30 °C. The reaction mixture was stirred at 30 °C for 15 min.
The catalyst was removed by filtration and washed with
dichloromethane (40 mL). The filtrate was concentrated under
reduced pressure, and nitromethane (30.5 mg, 0.50 mmol) in
3b 19%
(based on 1b)
3d 71%
(based on 1d)
Scheme 2. Chemoselective 1,3-addition of nitrone 1d over
nitrone 1b.
In summary, 1,3-addition reaction of silyl enol ethers to
various nitrones was achieved by using Al-MCM-41 as a
reusable solid acid catalyst. The corresponding β-
(siloxyamino)ketones were obtained in high yields under
mild reaction conditions. Moreover, Al-MCM-41 was
found to effect interesting chemoselectivive activations
because of the selective adsorption of the substrates on the
catalyst.
Acknowledgments
Y.K. thanks New Energy and Industrial Technology
Development Organization (NEDO) for financial support.
Supplementary data

4
Tetrahedron Letters
CDCl3 (1.0 mL) was then added to the crude product as an
internal standard. After the crude product was analyzed by 1H
NMR spectroscopy, nitromethane and CDCl3 were removed
under reduced pressure. The residue was purified by silica-gel
column chromatography (hexane/Et2O=15:1) to give 3-
[phenyl(trimethylsiloxy)amino]-1,3-diphenylpropan-1-one
(3a) as a colorless oil (187 mg, 96%); IR (neat): ν max 2958,
1
1686, 1597, 1487, 1449, 1251, 878, 844, 751, 697 cm–1; H
NMR (270 MHz, CDCl3): δ (ppm) 7.88 (d, J = 7.6 Hz, 2H),
6.96–7.56 (m, 13H), 5.11 (dd, J = 8.4, 5.0 Hz, 1H), 3.75 (dd,
J = 17.3, 8.4 Hz, 1H), 3.58 (dd, J = 17.3, 5.0 Hz, 1H), –0.14
(s, 9H); 13C NMR (67.8 MHz, CDCl3): δ (ppm) 197.6, 152.1,
138.6, 136.9, 132.7, 129.3, 128.3, 128.0, 127.8, 127.7, 127.4,
123.3, 120.1, 69.4, 37.5, –0.6.
12. Wuts, P. G. M.; Green, T. W. Green’s Protective Groups in
Organic Synthesis, 4th Ed.; Wiley: New Jersey, 2007, and
references therein.
13. The reaction of 4 with 2a (1.2 equiv) in acetonitrile at 0 °C
was completed in 15 min to give the corresponding aldol
adduct in 99% yield.5a On the other hand, the reaction of 1a
with 2a (1.2 equiv) in dichloromethane at 0 °C required 1 h to
give 3a in quantitative yield (Table 1, entry 1).
14. Excess 2a was recovered as acetophenone.

Tetrahedron Letters
5
Graphical Abstract
To create your abstract, type over the instructions in the
template box below.
Leave this area blank for abstract info.
1,3-Addition of silyl enol ethers to nitrones
catalyzed by mesoporous aluminosilicate
Suguru Ito, Yoshihiro Kubota, Masatoshi Asami*
Al-MCM-41
(50 mg/mmol, Si/Al = 26)
−O
R2
SiO
R2
+
N
OSi
Ph
(1.2-2.0 equiv)
N
O
+
CH2Cl2, 30 °C
R1
H
R1
Ph
41-96% yield
11 examples
Click here to remove instruction text...