Organocatalytic activation of TMSCN by basic ammonium salts for efficient cyanation of aldehydes and imines

Article abstract of DOI:10.1016/j.tetlet.2007.07.188

Basic ammonium salts act as highly effective catalysts for the cyanosilylation of aldehydes and in Strecker-type aminonitrile synthesis using TMSCN as cyanide source at 25 °C under extremely mild conditions, affording very good to excellent yields of silylated cyanohydrins and α-aminonitriles.

Full text of DOI:10.1016/j.tetlet.2007.07.188

Tetrahedron Letters 48 (2007) 7211–7214
Organocatalytic activation of TMSCN by basic ammonium
salts for efficient cyanation of aldehydes and imines
I. Victor Paul Raj, Gurunath Suryavanshi and A. Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road,
Pune 411 008, India
Received 19 June 2007; revised 17 July 2007; accepted 27 July 2007
Available online 2 August 2007
Abstract—Basic ammonium salts act as highly effective catalysts for the cyanosilylation of aldehydes and in Strecker-type amino-
nitrile synthesis using TMSCN as cyanide source at 25 °C under extremely mild conditions, affording very good to excellent yields of
silylated cyanohydrins and a-aminonitriles.
Ó 2007 Published by Elsevier Ltd.
Hydrocyanation and cyanosilylation of aldehydes are
important C–C bond-forming reactions1 in organic syn-
thesis, as they provide versatile intermediates such as
cyanohydrins and cyanohydrin silyl ethers, respectively.
In particular, cyanohydrin silyl ethers 2 are industrially
valuable and important intermediates for the synthesis
of a-hydroxy acids and esters, acyloins, vicinal diols,
b-amino alcohols and other biologically active com-
pounds.2 They are generally prepared by the addition
of trimethylsilyl cyanide (TMSCN), a safe and easily
handled reagent compared to HCN or KCN,3 to car-
bonyl compounds in the presence of Lewis acids,4 Lewis
bases,5 metal alkoxides,6 bifunctional catalysts7 and
inorganic salts.8 However, many of these methods suffer
from several disadvantages such as prolonged reaction
times, use of heavy metal catalysts and poor yields of
the corresponding cyanotrimethylsilyl ethers. Our
particular interest in this transformation stems from
the fact that metal-free organocatalysis for the cyana-
tion of aldehydes and imines with TMSCN should lead
to efficient syntheses of cyanotrimethyl silyl ethers
without any metal contamination. In this regard, we
screened several Lewis bases such as DBU (1,8-diazabi-
new products, that is, their respective methyl esters 1 in-
stead of the cyanohydrins, when the reaction was carried
out in methanol (Scheme 1). This observation led us to
modify the Lewis basicity in DBU by quaternizing one
of the nitrogen atoms with benzyl bromide. Thus, qua-
ternary basic ammonium salt 4 was prepared and, when
employed for this transformation, gave exclusively cya-
nohydrin silyl ether 2. Similarly, ammonium salts 3
and 5 were prepared from the corresponding diamines
by quaternizing with benzyl bromide and methyl iodide,
respectively, in toluene as solvent. Organocatalysts 3
(mp: 259 °C), 4 (mp: 169 °C) and 5 (mp: 201 °C) were
1
characterized by H, 13C NMR and IR spectroscopy
and by single crystal XRD and elemental analysis.
Figure 2 shows the ORTEP diagram of catalyst 4 where
quaternization with benzyl bromide occurred at the
imine nitrogen atom.9
CO2Me
O2N
DBU (0.5 mol%)
1, 93%
CHO
cyclo[5.4.0]undec-7-ene),
DABCO
(1,4-diazabi-
TMSCN
MeOH, 25 oC
cyclo[2.2.2]octane), or (À)-sparteine, in catalytic
amounts, for the cyanation of 4-nitro- and 4-cyanobenz-
aldehydes and unexpectedly observed the formation of
OTMS
CN
O2N
3 h
4 (0.5 mol%)
O2N
Keywords: Aldehydes; Aminonitriles; Cyanosilylation; Cyanohydrin;
Multicomponent reactions; TMSCN.
2, 67%
*
Scheme 1. Base catalyzed reaction of 4-nitrobenzaldehyde with
Corresponding author. Tel.: +91 020 25902174; fax: +91 020
TMSCN.
25893359; e-mail: a.sudalai@ncl.res.in
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.07.188

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I. V. P. Raj et al. / Tetrahedron Letters 48 (2007) 7211–7214
In this Letter, we report a new high-yielding proce-
dure for the synthesis of trimethylsilyl cyanides 2 and
a-aminonitriles 6 catalyzed by monoquaternized bases
3, 4 and 5 (Fig. 1) under ambient conditions. A system-
atic study on the hydrocyanation of 4-nitrobenzalde-
hyde as a test substrate in various solvents was carried
out using catalytic amount of either diamines or their
ammonium salts 3, 4 and 5 and the results are summa-
rized in Table 1. Ammonium salt 4 was found to be
the best catalyst for the hydrocyanation of 4-nitrobenz-
aldehyde with TMSCN as cyanide source. Encouraged
by this result, a wide range of aldehydes were subjected
to cyanosilylation using a catalytic quantity of 4
(0.5 mol %) under optimized reaction conditions
(1 equiv of TMSCN, 25 °C, CH2Cl2). Table 2 shows
the scope of the reaction wherein moderate to high
yields of 2 were obtained in all the cases studied. For
aromatic substrates with electron-donating substituents,
the reaction time was longer giving moderate yields of 2.
Notably, the cyanosilylation of (E)-cinnamaldehyde
afforded the corresponding 1,2-addition product exclu-
sively (entry i). However, the reaction failed in the case
of ketones, probably due to steric reasons.
multi-component reaction.10 a-Aminonitriles 6 are the
precursors for several amino acids and also for popular
bifunctional synthons that have found numerous syn-
thetic applications.11 We have extended the present
catalytic system to Strecker-type a-aminonitrile synthe-
sis, the results of which are presented in Table 3. After
initial experimentation, again catalyst 414 was found to
be the most effective for the three-component reaction.
Many aldehydes possessing both electron-donating as
well as electron-withdrawing groups underwent this con-
densation to afford the corresponding a-aminonitriles 6
in good yields. However, both the cyanosilylation and
Strecker reaction failed to give optical induction when
chiral catalyst 5 was employed, only racemic products
2 and 6 were produced.
Scheme 2 shows a possible mechanistic pathway in
which activation of the silyl group in TMSCN by cata-
lyst 4 leads to the formation of ion-pair 7. Reaction of
Table 1. Organocatalytic reaction of 4-nitrobenzaldehyde with
TMSCN: screening of basesa
Entry
Base
Solvent
Product (% yield)b
1
2
The Strecker reaction between an aldehyde, an amine
and hydrogen cyanide is widely regarded as the first
1
2
3
4
5
6
7
DBU
DABCO
Et3N
3
4
4
5
MeOH
MeOH
MeOH
MeOH
CH2Cl2
MeOH
MeOH
93, 87c
92, 78c
81
—
—
—
—
—
57
92
64
61
Bn
Bn
N+
H
Me
+
H
N
N+
Br-
I-
N
Br-
—
—
N
N
H
a Reagents and conditions: 4-nitrobenzaldehyde (5.0 mmol), TMSCN
(6.0 mmol), base (0.5 mol %), solvent, 25 °C, 3 h.
b Isolated yield after column chromatographic purification.
c Yield corresponds to 4-cyanomethylbenzoate when 4-cyanobenz-
aldehyde was used.
H
3
4
5
Figure 1. Quaternized organocatalysts for TMSCN addition to
aldehydes and imines.
Figure 2. ORTEP diagram of catalyst 4.

I. V. P. Raj et al. / Tetrahedron Letters 48 (2007) 7211–7214
7213
Table 2. Cyanosilylation of various aldehydes using organocatalyst 4a
Bn
N+
OTMS
Br-
TMSCN
OTMS
R
CN
TMSCN, 4 (0.5 mol%)
CH2Cl2, 25 °C
RCHO
2
N
R
CN
2a-l
4
Bn
N+
Yieldb (%)
Bn
Br-
Entry
R
T (h)
Br-
N+
a
b
c
d
e
f
g
h
i
C6H5
24
24
24
24
10
3
51
52
62
57
4-MeOC6H4
4-MeC6H4
4-HOC6H4
4-FC6H4
4-NCC6H4
4-O2NC6H4
Ph(CH2)2
Ph–CH@CH
BnO(CH2)4
BnO(CH2)5
(CH3)2CH
N+
Si
N+
CN-
-
Si
R
H
73
O
7
72, 53c, 58d
RCHO
8
CN
3
92
80
60
83
81
90
10
10
10
10
10
Scheme 2. Possible pathway for the cyanosilylation of aldehydes.
j
k
l
Acknowledgements
VPRI thanks CSIR, New Delhi, for the award of
research fellowships. The authors are thankful to Dr.
B. D. Kulkarni, Head, CE-PD Division, for his constant
encouragement and support.
a Reagents and conditions: aldehyde (5.0 mmol), TMSCN (6.0 mmol),
organocatalyst 4 (0.5 mol %), CH2Cl2, 25 °C.
b Isolated yield after column chromatographic purification.
c % Yield when catalyst 3 was used.
d % Yield when catalyst 5 was used.
References and notes
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4 (0.5 mol%), TMSCN
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NHPMP
RCHO
R
CN
6
Entry
R
Yield (%)b
1
2
3
4
5
6
7
8
9
C6H5
77
79
67
81
81
69
72
68
73
83c
90d
4-MeOC6H4
3,4-(MeO)2C6H3
Ph(CH2)2
4-O2NC6H4
4-ClC6H4
3-O2NC6H4
3,4-Methylenedioxyphenyl
CH3–(CH2)3
10
11
CH3–(CH2)3
CH3–(CH2)3
a Reagents and conditions: aldehyde (5.0 mmol), TMSCN (6.0 mmol),
p-anisidine (5.0 mmol),
(25 mL), 25 °C, 12 h.
4 (0.5 mol %), anhyd MgSO4, CH2Cl2
b Isolated yield after column chromatographic purification.
c Yield when morpholine was used as the amine source.
d Yield when n-butylamine was used as the amine source.
7 with aldehydes gives intermediate 8, which subse-
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In conclusion, we have shown, for the first time, the use
of ammonium salts as new Lewis base catalysts for
cyanosilylation of aldehydes and the three-component
Strecker- type a-aminonitrile synthesis under ambient
conditions.12,13 Both the methods are effective and uti-
lize the readily available cyanide source TMSCN. These
catalysts have also shown advantages in terms of chemi-
cal stability and high solubility in organic solvents.
9. The crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as deposition
No. CCDC 651284. Copies of the data can be obtained,

7214
I. V. P. Raj et al. / Tetrahedron Letters 48 (2007) 7211–7214
free of charge on application to CCDC, 12 Union Road,
12. General experimental procedure for cyanosilylation: To a
solution of catalyst 3, 4 or 5 (0.5 mol %) in dichlorometh-
ane (25 mL) under an argon atmosphere at 25 °C was
added aldehyde (5.0 mmol) followed by TMSCN
(6.0 mmol). The resulting mixture was stirred at 25 °C
and the reaction was monitored by TLC. After comple-
tion, the reaction mixture was concentrated in vacuum.
The crude product was purified by column chromatogra-
phy on silica gel using 5% ethyl acetate in petroleum ether
as eluent to afford the pure product.
Cambridge CB2 1EZ, UK [Fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk].
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´
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NMR, FT-IR and elemental analysis.
14. Spectral data for catalyst 4: Colourless solid; mp: 169 °C
(crystallized from CH2Cl2); IR (CHCl3, cmÀ1): 3417, 2936,
2176, 1621, 1525, 1453, 1327, 1200, 924, 733; 1H
NMR(200 MHz, CDCl3): d 1.68–1.71 (m, 6H), 2.18–2.29
(m, 2H), 2.94–3.0 (m, 2H), 3.71–3.84 (m, 6H), 4.91 (s, 2H),
7.23–7.43 (m, 5H); 13C NMR (50 MHz, CDCl3): d 19.95,
22.24, 25.71, 28.06, 29.09, 47.52, 49.32, 55.45, 56.72,
126.11, 127.90, 128.91, 134.11, 167.04. Anal. Calcd for
C16H23BrN2: C, 59.45; H, 7.17; N, 8.67; Br, 24.72. Found:
C, 59.41; H, 7.19; N, 8.69; Br, 24.70.
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