Sodium bis(trimethylsilyl)amide in the oxidative conversion of aldehydes to nitriles

Article abstract of DOI:10.1002/ejoc.200600134

The feasibility of the Me₃Si species acting as a nucleofuge was investigated in compounds containing the NSiMe₃ moiety. Treatment of various aromatic aldehydes with 2.2 equiv. of NaN(SiMe₃)₂ at 185°C in a sealed tube produced the corresponding nitriles in high yields (81-98%). In these reactions, NaN(SiMe₃)₂ acted as an oxidizing agent. Results from control experiments indicate that the Me ₃Si unit can depart efficiently from the NSiMe₃ moiety of N-silylimine intermediates. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600134

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600134
Sodium Bis(trimethylsilyl)amide in the Oxidative Conversion of
Aldehydes to Nitriles
Jih Ru Hwu*[a] and Fung Fuh Wong[a]
Keywords: Aldehydes / Nitriles / Nucleofuge / Oxidation / Sodium bis(trimethylsilyl)amide
The feasibility of the Me3Si species acting as a nucleofuge
was investigated in compounds containing the NSiMe3 moi-
ety. Treatment of various aromatic aldehydes with 2.2 equiv.
of NaN(SiMe3)2 at 185 °C in a sealed tube produced the cor-
responding nitriles in high yields (81–98%). In these reac-
tions, NaN(SiMe3)2 acted as an oxidizing agent. Results from
control experiments indicate that the Me3Si unit can depart
efficiently from the NSiMe3 moiety of N-silylimine intermedi-
ates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
Results and Discussion
The trimethylsilyl cation (Me3Si+) has been referred to
as a “bulky proton”[1,2] and this concept has been applied
in the control of organic reactions.[1,3,4] The trimethylsilyl
radical (Me3Si·) is also involved in many organosilicon reac-
tions,[5] whilst the trimethylsilyl anion (Me3Si–) can donate
one electron to a substrate[6–8] or act as a nucleophile.[9–12]
The silicon analogues of the species H+, H·, H–, and H2
would be Me3Si+, Me3Si·, Me3Si–, and Me3SiSiMe3, respec-
tively, so the trimethylsilyl group can be regarded as a bulky
analogue of a hydrogen atom.
The trimethylsilyl group usually leaves organosilanes as
an electrofuge.[13] To broaden the scope of silicon com-
pounds in organic synthesis, we have been seeking for po-
tential for the trimethylsilyl group to function as a nucleo-
fuge.[14–19] Here we report a new method for the conversion
of aromatic aldehydes into the corresponding nitriles by
treatment with NaN(SiMe3)2 as an oxidizing agent
(Scheme 1). Results from our mechanistic studies indicate
that the trimethylsilyl group departed from the NSiMe3
moiety of N-silyl imine intermediates in the form of Me3Si–
in the key step.
To establish a new method for the oxidative conversion
of aldehydes to nitriles, we added 2.2 equiv. of NaN(SiMe3)2
to a solution containing an aromatic aldehyde (e.g., 1, 3, or
5) in 1,3-dimethylimidazolidin-2-one. The aldehyde pos-
sessed a hydroxy group at an ortho, meta, or para position
(see Scheme 1). After the solution had been heated at
185 °C in a sealed tube for 12 h, the corresponding nitrile
(i.e., 2, 4, or 6) was obtained in good to excellent yield (88–
98%). Although the same reactions also proceeded at a
lower temperature (e.g., 120 °C), they required longer reac-
tion times and produced the desired nitriles in lower yields.
We also allowed an aromatic aldehyde with a methoxy –
instead of a hydroxy – group at the para position (i.e., 7) to
react with 2.2 equiv. of NaN(SiMe3)2. The corresponding
demethylated aromatic nitrile 6 was generated in 86% yield.
The formyl group in a more complicated compound,
benzoquinolizine 8, can also be converted to a cyano group
efficiently; we obtained an 86% yield for the transformation
8 Ǟ 9. Similarly, conversions of naphthaldehydes, such as
10 and 12, to the corresponding naphthalenecarbonitriles
11 and 13 were accomplished in 81% and 89% yields,
respectively. Note that the demethylation also took place in
situ during the conversion of 12 to 13 (cf. 7 Ǟ 6).
In addition to demethylation, we found that the methyl-
ene units in benzaldehyde derivatives 14 and 16 fell off dur-
ing the conversion of their formyl groups into cyano groups
by treatment with 2.2 equiv. of NaN(SiMe3)2. The yields for
the transformations 14 Ǟ 15 and 16 Ǟ 17 were 84% and
91%, respectively.
Furthermore, we treated pyrrole-2-carboxaldehyde (18)
with 2.2 equiv. of NaN(SiMe3)2 in DMEU at 185 °C and
the corresponding nitrile 19 was generated in 85% yield af-
ter 12 h. By the same method we converted indole-3-car-
boxaldehyde (20) and its derivatives 22 and 24, with an
Scheme 1.
[a] Department of Chemistry, National Tsing Hua University,
Hsinchu, Taiwan 30013, R.O.C.
Fax: +886-3-572-1594
E-mail: jrhwu@mx.nthu.edu.tw
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J. R. Hwu, F. F. Wong
SHORT COMMUNICATION
Scheme 2.
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Oxidative Conversion of Aldehydes with Sodium Bis(trimethylsilyl)amide
SHORT COMMUNICATION
0.930–2.60 mmol) was injected into the tube, which was then sealed
by torch and heated in an oven at 185 °C for 12 h. The reaction
mixture was diluted with water at room temperature, neutralized
with HCl (10%), and extracted with Et2O (4×25 mL). The com-
bined ethereal solutions were washed with water and saturated
aqueous NaCl. The combined organic extracts were dried with
MgSO4 (s), filtered, and concentrated under reduced pressure. The
residue was chromatographed through a column packed with silica
gel (2.2 cm×16 cm column) to provide the desired product with
purity Ͼ99.5%, as checked by GC.
OMe or OCH2Ph substituent at their 5-positions, into the
indole-3-carbonitriles 21, 23, and 25, respectively, in 87–
94% yields.
We illustrate a plausible, but not exclusive, mechanism
for the oxidative conversion of aromatic aldehydes to ni-
triles by NaN(SiMe3)2 in Scheme 2. In addition to acting
as a base for the removal of the proton from the hydroxy
group in 5, NaN(SiMe3)2 also reacts with aldehydes or
ketones to give the corresponding imines.[20] The resultant
N-silyl imine 26a and 26b are resonance hybrids, in which
silicon can exert a stabilizing effect on the α-amide center
in 26b.[21,22]
A Representative Example. Formation of 8-Hydroxy-2,3,6,7-tetra-
hydro-1H,5H-benzo[i,j]quinolizine-9-carbonitrile (9): The standard
procedure was followed, with use of 8-hydroxy-2,3,6,7-tetrahydro-
A catalytic amount of NaN(SiMe3)2 can initiate depro-
tonation along with desilylation in N-silyl imines 26a/26b
to give 27a/27b and Me3SiH. When the trimethylsilyl group
departs from 26a/26b, its silicon atom bears a negative
charge. So the oxidation state of this silicon atom decreases
by two during the conversions of 26a/26b Ǟ 27a/
27b + Me3Si–. Moore et al.[23] proposed a similar nitrile-
stabilized anion intermediate (27a/27b) in the thermolysis
of vinyl azides. Finally, protonation of 27a/27b gives the
target aromatic nitriles.
According to the mechanism shown in Scheme 2, oxi-
dation of aromatic aldehydes to the corresponding nitriles
by NaN(SiMe3)2 should generate Me3SiH as the by-prod-
uct. We did not isolate Me3SiH because of its low boiling
point (6.7 °C).[17] Nevertheless, in a control experiment, we
treated the N-methyldiphenylsilyl imine of 5 with 1.2 equiv.
of NaN(SiMe3)2 in DMEU at 185 °C. The by-product HSi-
MePh2 was obtained as a colorless, irritant liquid in 87%
yield along with nitrile 6 in 91% yield. These results indi-
cate that Ph2MeSi– can also act as a nucleofuge.
1H,5H-benzo[i,j]quinolizine-9-carboxaldehyde
(8,
152 mg,
0.700 mmol, 1.0 equiv.), sodium bis(trimethylsilyl)amide (1.0  in
THF, 1.5 mL, 1.5 mmol, 2.2 equiv.), and DMEU (0.50 mL). The
reaction mixture was worked up after 12 h and the residue was
purified by column chromatography on silica gel (40% EtOAc in
hexanes as eluent) to give pure 9 (129 mg, 0.602 mmol) as a white
solid in 86% yield: m.p. 172.0–174.0 °C. GC tR = 20.16 min; TLC
1
Rf 0.30 (40% EtOAc in hexanes). H NMR (CDCl3, 400 MHz): δ
= 1.91 (m, 4 H, 2×CH2), 2.64 (m, 4 H, 2×CCH2), 3.06 (br.s, 1 H,
OH), 3.21 (m, 4 H, 2×NCH2), 6.84 (s, 1 H, ArH) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 20.46, 20.65, 21.26, 26.84, 49.00, 49.61,
84.85, 107.20, 113.96, 119.29, 129.05, 146.81, 155.04 ppm. IR
(neat): ν = 3317 cm–1 (br.s, OH), 2899 (s, C–H), 2499 (s, CϵN),
˜
1608 (s, C=C), 1508 (m, C=C), 1455 (m), 1308 (m), 1152 (m), 458
(m) cm–1. MS m/z (%) = 214 (100) [M]+, 197 (3), 185 (49), 171 (4),
158 (3), 142 (3), 130 (3), 116 (2), 106 (4), 102 (3), 92 (3), 77 (5),
63 (3), 51 (3). HRMS for C13H14N2O 214.1106, found 214.1104.
C13H14N2O (214.27): calcd. C 72.87, H 6.59, N 13.07; found C
72.63, H 6.60, N 12.97.
Acknowledgments
Moreover, the Me3Si– moiety that departs from a mole-
cule of 26b could also act as a base to trap the acidic proton
in another molecule of 26b, so only a catalytic amount of
NaN(SiMe3)2 would be required for the conversion 26b Ǟ
27b. This design allows us to use 2.2 equiv. of NaN-
(SiMe3)2 to complete the transformation 5 Ǟ 6: the first
equivalent was used for deprotonation, the second equiva-
lent was consumed during the imine formation, and the re- [4] J. R. Hwu, K. P. Khoudary, S.-C. Tsay, J. Organomet. Chem.
maining 0.2 equivalent was used for initiation of the process
26a/26b Ǟ 27a/27b + Me3SiH.
We thank the National Science Council and Ministry of Education
of the R.O.C. for financial support.
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Standard Procedure for the Conversion of Aromatic Aldehydes into
Nitriles: A solution containing an aldehyde (0.424–1.19 mmol) in
DMEU (0.50 mL) was transferred into a Pyrex combustion tube
under argon. Sodium bis(trimethylsilyl)amide (1.0  in THF,
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Received: February 15, 2006
Published Online: April 18, 2006
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Eur. J. Org. Chem. 2006, 2513–2516