Schmidt reaction in ionic liquids: Highly efficient and selective conversion of aromatic and heteroaromatic aldehydes to nitriles with [BMIM(SO3H)][OTf] as catalyst and [BMIM][PF6] as solvent

Article abstract of DOI:10.1016/j.tetlet.2013.02.051

A mild and selective method is presented for the conversion of aromatic and heteroaromatic aldehydes to nitriles via the Schmidt reaction with TMSN ₃ by using [BMIM(SO₃H)][OTf] as catalyst and [BMIM][PF₆] as solvent. The method offers high yields and simple product isolation, and avoids the use of liquid superacids or corrosive Lewis acids commonly employed for this transformation. It also offers some potential for recycling/reuse of the IL solvent.

Full text of DOI:10.1016/j.tetlet.2013.02.051

Tetrahedron Letters 54 (2013) 2177–2179
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Schmidt reaction in ionic liquids: highly efficient and selective conversion of
aromatic and heteroaromatic aldehydes to nitriles with [BMIM(SO H)][OTf] as
3
catalyst and [BMIM][PF ] as solvent
6
⇑
Ganesh C. Nandi, Kenneth K. Laali
Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and selective method is presented for the conversion of aromatic and heteroaromatic aldehydes to
Received 18 January 2013
Revised 12 February 2013
Accepted 15 February 2013
Available online 24 February 2013
3 3 6
nitriles via the Schmidt reaction with TMSN by using [BMIM(SO H)][OTf] as catalyst and [BMIM][PF ] as
solvent. The method offers high yields and simple product isolation, and avoids the use of liquid super-
acids or corrosive Lewis acids commonly employed for this transformation. It also offers some potential
for recycling/reuse of the IL solvent.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Schmidt reaction
Aromatic aldehydes
Nitriles
[
BMIM(SO
3
H)][OTf]
[
BMIM][PF
6
]
As a highly versatile functional group that is abundantly present
convert electron rich aromatic aldehydes into nitriles with NaN
3
/
in natural products, pharmaceuticals, and functional materials, and
can be easily transformed into other functionalities, the nitrile
moiety occupies a pivotal place in organic chemistry. Synthesis of
nitriles via the aldoximes is extensively studied over the years and
a plethora of reagents have been employed.1 The efficacy of the
Schmidt reaction as a method to convert carbonyl compounds into
AlCl in boiling THF. Under these conditions gem-diazides were
formed as side products with electron deficient or hindered
3
aldehydes.
9
A recent study by Rokade and Prabhu showed that NaN
3
/TfOH
provides a superior medium for selective conversion of aromatic
aldehydes to nitriles, when MeCN is used as solvent.
2
amides, lactams, and oxazolines is well documented, and the
intramolecular Schmidt reaction of alkyl azides and allyl azides
has been successfully implemented as a key step in a number of
synthetic schemes. The related Brønsted acid-promoted addition
IL1
δ
OH2
O
H
3
H
TMSN3
IL2
N
H
δ
of azides to activated olefins as a method to synthesize the corre-
N
4
N
N
sponding aziridines has also been studied. By comparison, direct
synthesis of nitriles from aldehydes via the classical Schmidt reac-
5
H
tion has not received wide acceptance by the synthetic commu-
nity likely due to the drawbacks associated with the use of toxic
N
N
N
N
HN
3
which is generated in situ via NaN
3
and HX (typically sulfuric
N
acid). In addition, this method requires the use of large quantities
of liquid acid and presents handling, acid-neutralization, and dis-
posal issues. Another drawback of the classical method is the for-
mation of variable amounts of formanilide byproduct depending
-
N2
NH
6
on the amount of sulfuric acid. Formation of gem-diazides was
7
reported by Nishiyama et al. by using TMSN
3
, with SnCl
2
as cata-
H+
-
8
lyst and chloroform as solvent. Suzuki and Nakaya were able to
CN
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: Kenneth.laali@UNF.edu (K.K. Laali).
Figure 1. Mechanism of the Schmidt reaction.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.051

2
178
G. C. Nandi, K. K. Laali / Tetrahedron Letters 54 (2013) 2177–2179
Table 1
Influence of IL and catalyst in the Schmidt reaction with benzaldehyde and TMSN
0 °C
Table 2
3
at
6
Recycling and reuse of [BMIM][PF ] using benzaldehyde as substrate
5
Run #
Time (h)
Yield (%)
Entry
Ionic liquid
EAN
Catalyst
Time (h)/yield (%)
1
2
3
4
6
10
24
24
98
95
88
57
1
2
—
—
24/—
24/—
[BMIM][BF
4
]
NO2
n-Butyl
N
3
—
24/—
N
NTf2
Ethylammonium nitrate (EAN), [BMIM][BF
nitro-BMIM][NTf
additional protic activation is required. We therefore turned our
attention to [BMIM][SO H][OTf] as a Brønsted acid-IL in combina-
tion with EAN or [BMIM][PF ] as solvent. Surprisingly, where
EAN/[BMIM][SO H][OTf] did not work, the [BMIM][PF ]/[BMIM]
SO H][OTf] system proved quite effective. The conversion achieved
4
], [BMIM][PF
6
], and
Et
[
2
] proved ineffective (entries 1–5), showing that
4
5
6
[BMIM][PF
EAN
6
]
]
—
IL2
IL2
24/—
24/—
2/100
3
[BMIM][PF
6
6
IL2 = [BMIM][SO
3
H][OTf].
3
6
[
3
in entry 6 after 24 h at 25 °C was typically around 50%. Raising the
temperature to 50 °C led to quantitative conversion after 2 h,
whereas no reaction occurred at 50 °C for other entries in Table 1.
CHO
+
CN
[
[
5
BMIM][SO H][OTf]
3
TMSN3
BMIM][PF6]
0 °C
R
Based on this study, [BMIM][PF
selected for the investigation of the scope of this transformation
Fig. 2). Reactions were conveniently carried out at 50 °C and were
completed between 30 min and 2.5 h depending on the substrate
6 3
]/[BMIM][SO H][OTf] was
R
(
Figure 2. Schmidt reaction in IL.
1
1,12
The Schmidt reaction requires carbonyl activation by proton-
ation or Lewis acid complexation to generate a carboxonium ion
which undergoes nucleophilic attack by azide to form the meso-
meric iminodiazonium/azidocarbenium ion as a key intermediate
that can form the nitrile either directly upon dediazoniation/
deprotonation or via the iminocarbenium ion (Fig. 1).
(Chart 1).
A variety of aromatic aldehydes bearing activating and deacti-
vating substituents were conveniently transformed to the corre-
sponding nitriles in high yields (close to quantitative in most
cases). The method is equally applicable to heterocyclic aldehydes
and to cinnamaldehyde (see Chart 1).
In continuation of our work on electrophilic chemistry in ionic
Having demonstrated the efficacy of the IL version of the
Schmidt reaction, the prospects of recycling/re-use of the IL solvent
10
liquids (ILs) as solvents and catalysts and in line with our ongo-
ing interest in the development of environmentally more accept-
able synthetic/preparative methods for carbocation and onium
ion chemistry, we turned our attention to the Schmidt reaction
of aldehydes with the goal to develop a high yielding selective
method that avoids the use of liquid superacids. At the onset, sev-
eral control experiments were performed by using benzaldehyde
1
3
were examined. Using benzaldehyde to benzonitrile reaction as
model, the reaction was repeated by adding a fresh catalyst to
6
the recycled [BMIM][PF ]. The outcomes are shown in Table 2.
The data indicate that under these conditions the used IL can be
re-employed for at least 3 cycles but longer reaction times are
needed to achieve acceptable yields. There is a significant drop in
yield in the 4th cycle even after 24 h, likely due to gradual buildup
3
as substrate and TMSN as a convenient azide source (Table 1).
CN
CN
CN
CN
F
CN
CN
OMe
NO2
Br
Me
a
a
b
a
b
98%b
CN
a
b
100% ; 100%b
a
9
8% ; 100%b
100% ; 100% 84% ; 100%
100% ; 100%
CN
CN
CN
F
CN
MeO
Br
O N
Cl
2
F
8% ; 93%b
a
100% ; 100%b
a
100%b
a
100% ; 100%b
a
9
100% ; 100%
CN
CN
OMe
OMe
CN
CN
CN
N
CH
CN
N
H
O
MeO
OMe
100% ; 100%
3
1
00%b
CN
a
b
76% ; 98%b
a
90% ; 100%
a
b
100% ;100%
a
b
92% ; 97%b
a
Br
CN
CN
N
CN
S
CN
S
CN
S
N
S
100%b
100% ; 98%b
a
CH3 b
a
b
a
100% ; 96%b
a
00% ; 100%b
100% ; 97%
1
a
8
8% ; 100%
aGC-MS Yield; bNMR Yield
Chart 1. Scope of the Schmidt reaction of aldehydes.

G. C. Nandi, K. K. Laali / Tetrahedron Letters 54 (2013) 2177–2179
2179
of impurities and tar in the IL which requires additional steps for
cleanup.
In summary, we have developed a mild and selective method to
convert aromatic and heteroaromatic aldehydes into nitriles in
high yields with high selectivity via the Schmidt reaction with
4. Moheney, J. M.; Smith, C. R.; Johnston, J. R. J. Am. Chem. Soc. 2005, 127, 1354–
1
4
1355.
5.
(a) Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511; (b) Schmidt, K. F. Chem. Ber.
924, 57, 704–706; (c) Koldobskii, G. I.; Ostrovskii, V. A.; Gidaspov, B. V. Russ.
1
Chem. Rev. 1978, 47, 1084–1094.
6
.
.
McEwan, W. E.; Conrad, W. E.; Vanderwerf, C. A. J. Am. Chem. Soc. 1952, 74,
1168–1171.
TMSN
3
3
by using the Brønsted acid IL [BMIM(SO H)][OTf] as cata-
7
Nishiyama, K.; Oba, M.; Watanabe, A. Tetrahedron 1987, 43, 693–700.
lysts and [BMIM][PF
6
] as solvent. The method offers simple prod-
8. Suzuki, H.; Nakaya, C. Synthesis 1992, 641–643.
Rokade, B. V.; Prabhu, K. R. J. Org. Chem. 2012, 77, 5364–5370.
0. See for example (a) Kumar, G. G. K. S. N.; Laali, K. K. Tetrahedron Lett. 2013, 54,
65–969; (b) Kumar, G. G. K. S. N.; Laali, K. K. Tetrahedron Lett. 2012, 53, 3066–
3069; (c) Kumar, G. G. K. S. N.; Laali, K. K. Org. Biomol. Chem. 2012, 10, 7347–
355; (d) Aridoss, G.; Laali, K. K. Tetrahedron Lett. 2011, 52, 6859–6864; (e)
Aridoss, G.; Laali, K. K. J. Org. Chem. 2011, 76, 8088–8094.
1. General procedure: [BMIM][PF ] ionic liquid (2 ml) was charged into an oven-
dried 5 ml round bottom flask. The corresponding aldehyde (1 mmol) and
trimethylsilyl azide (TMSN ) (1.5 mmol) were introduced, and finally the
catalyst [BMIM][SO H][OTf] (20 mol %) was added under stirring at rt. The
9
1
.
uct isolation, avoids the use of liquid superacids or corrosive
Lewis acids for carbonyl activation, and offers the possibility of
recycling/reuse of the IL solvent. The combined attributes promise
a new life for the classical Schmidt reaction as a selective and high
yielding approach for the synthesis of a wide range of nitriles.
9
7
1
6
Acknowledgment
3
3
reaction mixture was sonicated to achieve homogeneity and subsequently
heated at 50 °C between 30 min and 2.5 h depending on the substrate. After
completion (monitored by GC–MS) the reaction mixture was extracted several
times with 30% ethyl acetate in hexane and the combined organic extract was
We thank the University of North Florida for research support.
References and notes
3 4
washed with aq. saturated NaHCO followed by water, dried (MgSO ), and
evaporated under reduced pressure to obtain the pure product. The ArCN
compounds synthesized in this study are all known compounds. They were
characterized by GC–MS and NMR ( H and C) and by comparison of the data
with the literature.
1
.
.
Kalkhambkar, R. G.; Bunge, S. D.; Laali, K. K. Tetrahedron Lett. 2011, 52, 5184–
187. and references cited therein.
Hassner, A.; Namboothiri, I. Organic Syntheses Based on Name Reactions, 3rd ed.;
Elsevier: Oxford, UK, 2012. p 420.
1
13
5
2
3
12. Under the reaction conditions employed and working on small scale we have
not experienced any problems with the use of TMSN in the Schmidt reaction.
.
(a) Liu, R.; Gutierrez, O.; Tantillo, D. J.; Aubé, J. J. Am. Chem. Soc. 2012, 134,
3
6
528–6531; (b) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aubé, J. J. Am.
However, necessary precautions should be taken on scaling up this chemistry.
13. Recycling and re-use of IL: After extraction, the ionic liquid was dried under high
vacuum at 70 °C for about 5 h and re-used in successive runs (see Table 2).
14. This can be accomplished by dissolving the used IL in MeCN, filtration, removal
of solvent, and vacuum drying.
Chem. Soc. 2008, 130, 6018–6024; (c) Chaudhry, P.; Schoenen, F.;
Neuenswander, B.; Lushington, G. H.; Aubé, J. J. Comb. Chem. 2007, 9, 473–
4
1
76; (d) Iyengar, R.; Schildknegt, K.; Morton, M.; Aubé, J. J. Org. Chem. 2005, 70,
0645–10652; (e) Forsee, J. E.; Aubé, J. J. Org. Chem. 1999, 64, 4381–4385; (f)
Gutierrez, O.; Aubé, J.; Tantillo, D. J. J. Org. Chem. 2012, 77, 640–647.