N-methylmorpholine N-oxide: A rare nonmetallic catalyst for the most efficient silylcyanation of aldehydes

Article abstract of DOI:10.1081/SCC-200026652

An efficient method of addition of trimethylsilyl cyanide (TMSCN) to aldehydes by employing N-methylmorpholine N-oxide (NMO) alone as the catalyst has been described. Most of aromatic, aliphatic, cyclic, and heterocyclic aldehydes have been converted into

Full text of DOI:10.1081/SCC-200026652

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N‐Methylmorpholine N‐Oxide:
A Rare Nonmetallic Catalyst
for the Most Efficient
Silylcyanation of Aldehydes
Sung Soo Kim a , Gurusamy Rajagopal a , Dong Won
Kim a & Dae Ho Song a
a Department of Chemistry , Inha University ,
Incheon, 402‐751, South Korea
Published online: 06 Jan 2011.
To cite this article: Sung Soo Kim , Gurusamy Rajagopal , Dong Won Kim & Dae Ho
Song (2004) N‐Methylmorpholine N‐Oxide: A Rare Nonmetallic Catalyst for the Most
Efficient Silylcyanation of Aldehydes, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:16, 2973-2980,
DOI: 10.1081/SCC-200026652
To link to this article: http://dx.doi.org/10.1081/SCC-200026652
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 16, pp. 2973–2980, 2004
N-Methylmorpholine N-Oxide: A Rare
Nonmetallic Catalyst for the Most Efficient
Silylcyanation of Aldehydes
†
Sung Soo Kim, Gurusamy Rajagopal, Dong Won Kim,
and Dae Ho Song
*
Department of Chemistry, Inha University, Incheon, South Korea
ABSTRACT
An efficient method of addition of trimethylsilyl cyanide (TMSCN) to
aldehydes by employing N-methylmorpholine N-oxide (NMO) alone as
the catalyst has been described. Most of aromatic, aliphatic, cyclic, and
heterocyclic aldehydes have been converted into their corresponding
trimethylsilyl ethers in excellent yield within 10-min period. The mech-
anism of silylcyanation reaction has been also described.
Key Words: NMO; Aldehydes; TMSCN; Silylcyanation.
*
Correspondence: Sung Soo Kim, Department of Chemistry, Inha University, Incheon
402-751, South Korea; Fax: þ82-32-867-5604; E-mail: sungsoo@inha.ac.kr.
†Dr. G. Rajagopal is a Brain Pool Scientist from Dept of Chemistry, Crescent Engin-
eering College, Chennai 600 048, India and is assisted by a grant from the Korean
Federation of Science and Technology Societies and Korea Science and Engineering
Foundation.
2973
DOI: 10.1081/SCC-200026652
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Kim et al.
INTRODUCTION
Cyanohydrins[1] occupy very important role in organic synthesis due to
its synthetic versatility that can easily be converted into various polyfunc-
tionalized building blocks, including a-hydroxy compounds and b-amino
alcohols. Diorganotin dichloride[2] catalyzes the addition of trimethylsilyl
cyanide (TMSCN) to various ketones and aldehydes. A very similar addition
to the carbonyl compounds[3] was also found to be catalyzed by copper(II) tri-
flate. Silylcyanation of aromatic ketones[4] is strongly promoted in organic
solutions of lithium perchlorate and lithium tetrafluoroborate. Layered zirco-
nium hydrogen phosphate exchanged with potassium ion[5] was found to be an
efficient catalyst for silylcyanation of carbonyl compounds. Indium tribromide
(InBr3) is a very effective catalyst for the addition of TMSCN to function-
alized ketones. Silylcyanations of ketones[7] were also initiated by N-oxides/
Ti(iPro)4 as the catalysts. Chiral salen–titanium complex[8] proved to be an
effective catalyst for the enantioselective silylcyanation of aldehydes. A
new bifunctional asymmetric catalyst[9] was devised for the silylcyanation
of various aldehydes. It[9] is assumed that aluminum would work as a Lewis
acid to activate the carbonyl group and the oxygen atom of the phosphine
oxide would work as a Lewis base to activate the silylated nucleophiles.
The asymmetric addition of TMSCN to aldehydes[10] can be catalyzed by
chiral (salen)–titanium complexes. Chiral (salen) VO catalyst[11] is found to
be more enantioselective than the previous titanium-based systems[10] for
the silylcyanation.
N-Oxide was used in asymmetric synthesis such as allylation of alde-
hydes[12] and addition of ZnEt3 to aldehydes.[13] However, there is no report
about the utilization of N-oxide alone as the catalyst for silylcyanation of alde-
hyde. We wish to report herein the first example about silylcyanation reaction
of aldehydes by using a cheap, easy handling, and easily available chemical
N-methylmorpholine N-oxide (NMO) alone as catalyst to efficiently offer
racemic trimethylsilyl ethers.
RESULTS AND DISCUSSION
Representative and successful examples for the synthesis of various tri-
methylsilyl ethers from aromatic, aliphatic, and cyclic aldehydes are collected
in Table 1. Unsubstituted and substituted aromatic aldehydes (entries 1–6)
undergo very smooth silylcyanation with over 95% yield. The substituents
on the phenyl group have no significant effect on reaction time (entries 2–
6). Aliphatic allylic aldehydes (entries 7 and 8) were silylcyanated in excellent
yields for a little longer reaction time of 15–20 min. Especially, it should be

N-Methylmorpholine N-Oxide
Table 1. Addition of TMSCN to aldehydes catalyzed by NMO.
2975
Entry
1
Substrate
Time (min)
Yield (%)a
10
30
18
18
97
90[2]
81[3]
98[5]
2
10
18
95
75[3]
3
4
10
93
10
12
97
96[5]
5
10
95
98
6
7
10
20
97
(continued)

2976
Kim et al.
Table 1. Continued.
Substrate
Entry
8
Time (min)
15
Yield (%)a
95
9
10
330
93
71[2]
10
5
95
90
11
12
10
5
18
90
75[3]
aIsolated yield. The addition reactions to various ketones have been pressed in
Synthesis 2003.
noted that the sterically hindered pivalaldehyde (entry 9) which branched at the
a-position to the carbonyl group was transformed into the corresponding
silylether in 93% yield for 10min. The cyclic aliphatic aldehydes (entries 10
and 11) were converted into the corresponding cyanohydrin silylethers with
excellent yield. Furfural, a heterocyclic aldehyde (entry 12), gives correspond-
ing silylether in good yield (90%). This result indicates that NMO can selec-
tively activate the carbonyl function of furfural, keeping the furan ring intact.
To test the catalytic activity of NMO, a model reaction was carried out with ben-
zaldehyde without NMO and was found that there is no reaction taking place
within the typical reaction time. NMO is superior in activity to TMSCN
when compared with recently reported achiral catalytic system combination
of N,N-dimethyl-N-oxide/Ti(OiPr)4 used for the silylcyanation of carbonyl
compounds.[7] The present system indicates greater yield with quite short
reaction time. It is also worthwhile to note that the addition reaction of
TMSCN to aldehydes was done without any metal catalyst.
The possible mechanism for the reaction is as follows. The formation of
hypervalent silicate 1 is formed from the N-oxide and TMSCN 1 reacts with
the aldehyde to generate complex 2 which on fragmentation provides the
corresponding silylether 3 and N-oxide (Sch. 1).

N-Methylmorpholine N-Oxide
2977
Scheme 1.
CONCLUSION
An efficient catalytic system for silylcyanation of various kinds of alde-
hydes with greater yield has been developed. The mild experimental con-
ditions, extremely short reaction time, inexpensive catalyst, and the wide
range of substrate applicability represent the notable features of this pro-
cedure. Although variety of catalysts are known for this reaction, NMO has
greater potential for extension into asymmetric version of the reaction
which is also at progress in our laboratory.
EXPERIMENTAL SECTION
Typical Procedure for Silylcyanation of Benzaldehyde
To a stirred solution of benzaldehyde (1 mmol) and NMO (20 mol%) in
dry CH2Cl2 (1 mL) was added TMSCN (1.5 equiv.) dropwise. The resulting
solution was stirred continuously and progress of the reaction was followed
by TLC. The reaction mixture was purified by silica gel flash chromatography
by using EtOAc/hexanes (1 : 9) mixture as eluent. The desired 2-phenyl-2-
(trimethylsilyloxy)acetonitrile was obtained as colorless oil (yield: 97%).

2978
Kim et al.
2-Phenyl-2-(trimethylsilyloxy)acetonitrile (entry 1). 1H NMR
(CDCl3, 200 MHz): d ¼ 0.25 (s, 9H), 5.52 (s, 1H), 7.41–7.47 (m, 5H). 13C
NMR (CDCl3, 50 MHz): d ¼ 2 0.33, 63.59, 119.12, 126.29, 128.87,
129.27, 136.18.
2-(4-Cholorophenyl)-2-(trimethylsilyloxy)acetonitrile (entry 2). 1H
NMR (CDCl3, 200 MHz): d ¼ 0.25 (s, 9H), 5.48 (s, 1H), 7.37–7.38 (m, 5H).
13C NMR (CDCl3, 50 MHz): d ¼ 2 0.33, 62.93, 118.76, 127.64, 129.12,
134.80, 135.28.
2-(4-Methylphenyl)-2-(trimethylsilyloxy)acetonitrile (entry 3). 1H
NMR (CDCl3, 200 MHz): d ¼ 0.21 (s, 9H), 2.36 (s, 3H), 5.45 (s, 1H), 7.22
(d, 2H, J ¼ 7.8 Hz), 7.37 (d, 2H, J ¼ 7.8 Hz). 13C NMR (CDCl3, 50 MHz):
d ¼ 2 0.25, 55.78, 63.87, 114.66, 119.47, 127.88, 128.77, 160.23.
2-(4-Methoxyphenyl)-2-(trimethylsilyloxy)acetonitrile (entry 4). 1H
NMR (CDCl3, 200 MHz): d ¼ 0.24 (s, 9H), 3.84 (s, 3H), 5.45 (s, 1H), 6.96
(d, 2H, J ¼ 8.8 Hz), 7.38 (d, 2H, J ¼ 8.8 Hz). 13C NMR (CDCl3, 50 MHz):
d ¼ 2 0.23, 55.34, 63.34, 114.25, 119.32, 127.93, 128.46, 160.33.
2-(4-tert-Butylphenyl)-2-(trimethylsilyloxy)acetonitrile (entry 5). 1H
NMR (CDCl3, 200 MHz): d ¼ 0.25 (s, 9H), 1.34 (s, 9H), 5.49 (s, 1H),
7.43–7.44 (m, 5H). 13C NMR (CDCl3, 50 MHz): d ¼ 2 0.39, 31.10, 34.52,
63.32, 119.18, 125.73, 126.04, 133.19, 152.37.
2-(4-Phenoxyphenyl)-2-(trimethylsilyloxy)acetonitrile (entry 6). 1H
NMR (CDCl3, 200 MHz): d ¼ 0.22 (s, 9H), 5.46 (s, 1H), 6.99–7.13 (m, 5H),
7.31–7.44 (m, 4H). 13C NMR (CDCl3, 50 MHz): d ¼ 2 0.26, 63.18, 117.50,
118.75, 119.48, 120.42, 124.04, 124.94, 128.02, 128.41, 129.92, 130.73,
131.98, 156.38, 158.84.
4-Phenyl-2-trimethylsilyloxybutyronitrile (entry 7). 1H NMR
(CDCl3, 200 MHz): d ¼ 0.22 (s, 9H), 1.62 (s, 3H), 1.70–1.80 (m, 6H),
2.10–2.12 (m, 4H), 5.09–5.13 (m, 2H), 5.31–5.33 (m, 1H). 13C NMR
(CDCl3, 50 MHz): d ¼ 2 0.12, 16.76, 17.65, 23.18, 25.83, 39.13, 58.42,
119.50, 120.59, 123.14, 133.04, 142.82.
4,8-Dimethyl-2-trimethylsilyloxynona-3,7-dienenitrile (entry 8). 1H
NMR (CDCl3, 200 MHz): d ¼ 0.20 (s, 9H), 1.79 (dd, 3H, 2.4 Hz, 2.4 Hz),
4.90 (d, 1H, 8.4 Hz), 5.51–5.62 (m, 1H), 5.93–6.04 (m, 1H). 13C NMR
(CDCl3, 50 MHz): d ¼ 2 0.39, 17.16, 61.91, 118.55, 126.06, 130.98.
HRMS (EI): m/z calcd for C8H15NOSi (Mþ): 169.0922; found: 169.0917.
3,3-Dimethyl-2-trimethylsilyloxybutyronitrile (entry 9). 1H NMR
(CDCl3, 200 MHz): d ¼ 0.22 (s, 9H), 1.03 (s, 9H), 4.00 (s, 1H).
Cyclohexyl trimethylsilyloxyacetonitrile (entry 10). 1H NMR (CDCl3,
200 MHz): d ¼ 0.20 (s, 9H), 1.19–1.28 (m, 5H), 1.61–1.85 (m, 6H), 4.17
(d, 1H, 6.2 Hz). 13C NMR (CDCl3, 50 MHz): d ¼ 2 0.59, 25.40, 25.92,
27.99, 42.82, 66.37, 119.28. HRMS (EI): m/z calcd for C11H21NOSi (Mþ):
211.1392; found: 211.1387.

N-Methylmorpholine N-Oxide
2979
Cyclohex-3-enyl trimethylsilyloxyacetonitrile (entry 11). 1H NMR
(CDCl3, 200 MHz): d ¼ 0.23 (s, 9H), 1.60–2.12 (m, 7H), 4.27 (m, 1H),
5.70 (s, 2H). 13C NMR (CDCl3, 50 MHz): d ¼ 2 0.67, 23.72, 24.26, 26.48,
65.59, 119.07, 124.72, 126.75. HRMS (EI): m/z calcd for C11H19NOSi
(Mþ): 209.1235; found: 209.1239.
Furan-2-yl-trimethylsilanyloxy-acetonitrile (entry 12). 1H NMR
(CDCl3, 200 MHz): d ¼ 0.22 (s, 9H), 5.55 (s, 1H), 6.41–6.43 (m, 1H),
6.55–6.57 (m, 1H), 7.28–7.48 (m, 1H). 13C NMR (CDCl3, 50 MHz):
d ¼ 2 0.43, 57.41, 109.70, 110.78, 117.11, 143.84, 148.20. HRMS (EI): m/z
calcd for C9H13NO2Si (Mþ): 195.0715; found: 195.0712.
ACKNOWLEDGMENTS
The authors warmly thank Korea Science and Engineering Foundation for
the financial support (R01-2001-00057). One of us (G. R.) thanks the Manage-
ment, Correspondent, Principal, and HOD, Chemistry of Crescent Engineer-
ing College, Chennai, India for permitting him to do PDF research.
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Received in Japan January 15, 2004