Improved schmidt conversion of aldehydes to nitriles using azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-Propanol

Article abstract of DOI:10.3390/molecules21010045

The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %) of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes with diverse functional groups and the corresponding nitriles were obtained in good to high yields without the need for aqueous work up.

Full text of DOI:10.3390/molecules21010045

Article
Improved Schmidt Conversion of Aldehydes
to Nitriles Using Azidotrimethylsilane
in 1,1,1,3,3,3-Hexafluoro-2-propanol
Hashim F. Motiwala, Qin Yin and Jeffrey Aubé *
Received: 5 November 2015 ; Accepted: 22 December 2015 ; Published: 29 December 2015
Academic Editor: Klaus Banert
Department of Medicinal Chemistry, Delbert M. Shankel Structural Biology Center, University of Kansas,
2034 Becker Drive, West Campus, Lawrence, KS 66047, USA; hashimmotiwala@ku.edu (H.F.M.);
qinyin@ku.edu (Q.Y.)
*
Correspondence: jaube@unc.edu; Tel.: +1-919-966-9650
Abstract: The Schmidt reaction of aromatic aldehydes using a substoichiometric amount (40 mol %)
of triflic acid is described. Low catalyst loading was enabled by a strong hydrogen-bond-donating
solvent hexafluoro-2-propanol (HFIP). This improved protocol tolerates a broad scope of aldehydes
with diverse functional groups and the corresponding nitriles were obtained in good to high yields
without the need for aqueous work up.
Keywords: Schmidt reaction; aldehydes; nitriles; HFIP
1. Introduction
Nitriles are versatile building blocks and precursors to other functionalities such as acids, amines,
amides, aldehydes, and tetrazoles. In addition, they are important structural motifs in many natural
products [
1
], pharmaceuticals [
2
], agrochemicals, and dyes [
3
–
6
]. Aromatic nitriles are particularly
]. Nitrile groups on
well-represented in pharmaceutical agents, such as those depicted in Figure 1 [
2
the aromatic ring have been viewed as ketone bioisosteres and may increase resistance of aromatic
system to the oxidative metabolism [2].
OH
N
N
N
N
N
CN
NC
CN
S
Letrozole
Pericyazine
(aromatase inhibitor)
(antipsychotic)
CN
Me
CN
NH
Me2N
O
Me
Me
HN
N
N
F
Escitalopram
(selective serotonin
reuptake inhibitor)
Dapivirine
(anti-HIV agent)
Figure 1. Drugs containing aromatic nitriles.
Molecules 2016, 21, 45; doi:10.3390/molecules21010045
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General strategies for the synthesis of aromatic nitriles include the Sandmeyer reaction of
aryldiazonium salts [ ], Rosenmund–von Braun reaction from aryl halides [ 11], transition
metal-catalyzed cyanation of aryl halides [12 15] or direct cyanation through C–H bond
functionalization of arenes [16 20], and ammoxidation of methyl arenes, which is a preferred industrial
process [21 23]. Major drawbacks for most of these processes are the use of stoichiometric to excess
amounts of toxic cyanide source, generation of heavy metal waste, requirement of relatively high
6–
9
9–
–
–
–
˝
temperatures (often >100 C), long reaction times, or the requirement of a reactive aryl halide
source (aryl iodides and bromides are generally preferred) [14 24]. Recently, other approaches,
such as the dehydration of primary amides [25 28] or aldoximes [29 32], and one pot synthesis
from aldehydes [33 43] have gained particular attention in lieu of directly attaching the nitrile group.
,
–
–
–
However, harsh reaction conditions, high temperatures, and functional groups intolerance are some of
the problems still associated with these recent methods.
An attractive alternative to the above methods is the Schmidt reaction of aromatic aldehydes with
hydrazoic acid as in principle it can deliver the nitriles in one straightforward step [44]. However,
historically this reaction has provided a mixture of nitriles and formylanilides (Scheme 1a), thus limiting
its utility [45]. Recently, Prabhu and co-workers demonstrated that the Schmidt reaction of aldehydes
with sodium azide (NaN3) in the presence of triflic acid (TfOH) as a catalyst and acetonitrile
(ACN, CH3CN) as solvent exclusively affords the corresponding nitriles (Scheme 1b) [46]. In order
to achieve complete conversions, 3 equiv of TfOH was minimally required for high yields of the
aromatic nitriles. For example, only 6% conversion was observed when 1.5 equiv of TfOH was used
during their optimization studies [46]. Similarly, good results can be obtained using a catalyst in an
ionic liquid medium [47]. A one-pot sequential Schmidt/Ritter reactions in the presence of 4 equiv of
HBF4 OEt2 (2 equiv for each reaction) was also reported for the synthesis of N-tert-butylbenzamides
¨
from benzaldehydes [48]. We recently reported an efficient substoichiometric catalytic version of
another type of Schmidt reaction, specifically the intramolecular Schmidt reaction of ketones with
alkyl azides. In that chemistry, using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, (CF3)2CHOH) was key
to high yields using low loadings of HCl generated in situ from dissolving acetyl chloride in the
solvent [49]. These results prompted us to investigate the strong hydrogen bond donor ability of HFIP
in the intermolecular Schmidt reaction of aromatic aldehydes.
(a)
(b)
Scheme 1. Schmidt Reactions of Aromatic Aldehydes. (a) Classical Schmidt reaction of aromatic
aldehydes (McEwen; [45]); (b) Chemoselective Schmidt reaction of aldehydes to nitriles (Prabhu; [46]).
2. Results and Discussion
2.1. Optimization of Reaction Conditions
As reported by Prabhu [46], we began our studies on the reaction of 4-nitrobenzaldehyde 1a with
NaN3 and TfOH, replacing ACN as reported by Prabhu with HFIP (Table 1, entry 1). Low conversions

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of 2a with 50 mol % TfOH (entry 1) and 80 mol % AcCl (entry 2) were obtained from these experiments,
likely resulting from the low solubility of NaN3 in HFIP. Changing to azidotrimethylsilane (TMSN3) as
a soluble azide source drastically improved the yield with 25 mol % of acid catalysts (entries 3 and 4).
However, incomplete reactions accompanied by polar byproducts were still observed (TLC) despite
long periods of stirring. Both AcCl and TiCl4 are converted to HCl when dissolved in HFIP, so the
comparable results seen in entries 2 and 3 make sense taking into account the fact that TiCl4 provides
fourfold more acid than AcCl. We therefore returned to using triflic acid with TMSN3 as the azide
source. Even though the reaction with 30 mol % TfOH offered complete conversion in 2 h, only a
modest yield of nitrile was obtained, again with unidentified byproducts (entry 5). Gratifyingly, a 1:1
solvent combination of HFIP and ACN significantly increased the yield but complete conversion was
not achieved even after 4 h (entry 6). Finally, the reaction of 1a with 40 mol % TfOH in HFIP/ACN
(1:1) mixture proved optimal, providing a slightly better yield of 2a along with a much shorter reaction
time (entry 7).
Table 1. Optimization of the Schmidt Reaction of 4-Nitrobenzaldehyde 1a a,b
.
Azide
Source (equiv)
Azide
Catalyst
(mol %)
Time
(h)
NMR Ratio
Yield
Entry
Catalyst
Solvent
(2a:1a) c
(%) d 2a
1
2
3
4
5
6
7
a
NaN3
NaN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
1.5
1.5
1.5
1.5
2.0
2.0
2.0
CF3SO3H
50
80
25
25
30
30
40
HFIP
HFIP
HFIP
HFIP
HFIP
16
8
24
8
2
4
30:70 e
19:81
ND
ND
ND
ND
ND
75
CH3COCl f
g
TiCl4
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
68
65 h
81
HFIP/ACN (1:1)
HFIP/ACN (1:1)
ND
ND
45 min
83
To a solution of 4-nitrobenzaldehyde 1a (0.25 or 0.50 mmol) and azide in solvent (0.50, 1.0, or 2.0 mL) was
b
added a catalyst and the reaction was allowed to stir at rt for a specified period. Concentration of 1a was ca.
0.25 or 0.50 M. c 1H-NMR ratio was determined on a crude reaction mixture. Corrected isolated yield of 2a
d
e
f
(
2a was contaminated with a small amount (ca. 3%–6%) of 1a). Other byproducts were also observed. Could
generate 80 mol % HCl in situ. A 1.0 M solution of TiCl4 in CH2Cl2 was used. h 1H-NMR only showed peaks
g
of 2a. ND = Not determined.
2.2. Substrate Scope
A series of aromatic aldehydes was examined under the optimized reaction conditions (Table 2).
A wide array of functional groups on the aldehydes was well tolerated and the corresponding nitriles
were obtained in good to excellent yields. Benzaldehydes containing electron-withdrawing substituents
at the para position gave the corresponding nitriles in good yields (entries 1–5). Benzaldehyde 1e
required a slightly higher catalyst loading (60 mol %) to achieve a good conversion of the nitrile 2e
(entry 5). Electron-rich substrates with a broad range of functional groups such as hydroxyl, O-allyl,
and O-propargyl at the para position underwent facile conversion (entries 6–14). Due to the presence
of a basic amine, the substrate with a morpholine substituent needed 1.4 equiv of triflic acid, where
1.0 equiv of acid probably ended up in the amine salt (entry 13). Biphenyl substrate 1o afforded
nitrile 2o in 80% yield (entry 15). The resulting nitriles were obtained in slightly lower yields for the
meta- and ortho-substituted benzaldehydes (entries 16–18). Disubstituted benzaldehydes were also
efficiently converted to the desired nitriles in good to high yields (entries 19–25). 2-Naphthonitrile 2z
was readily prepared in 77% yield from 2-naphthaldehyde 1z (entry 26). The scope could be extended
to heteroaromatic aldehydes affording the representative nitriles in good yields (entries 27 and 28).
Throughout, we found that the position of the substituents on the phenyl ring had a relatively minimal
influence on the reaction outcome.

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Table 2. Scope of Aromatic Aldehydes a,b
.
Entry
Aldehyde 1
Nitrile 2 (% yield) c
Entry
Aldehyde 1
Nitrile 2 (% yield) c
1
17
2
3
18
19
4
20
5
6
21
22
7
8
23
24
25
26
9
10

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Table 2. Cont.
Entry
Aldehyde 1
Nitrile 2 (% yield) c
Entry
Aldehyde 1
Nitrile 2 (% yield) c
CHO
11
27
O
1aa
CHO
12
13
28
29
S
1ab
CN
14
15
30
31
MeO
2ad (92%)
16
32
a
To a solution of aldehyde
1 (1.0 equiv) and TMSN3 (2.0 equiv) in a premixed HFIP/ACN solvent mixture
(2.0 mL, 1:1) was added TfOH (40 mol %) and the reaction was allowed to stir at rt for a period of 20–75 min.
b
d
Concentration of aldehyde
1
was ca. 0.25 M. c Isolated yields. Contains ca. 4% of unreacted 1a (see the
e
f
g
Experimental Section for details). TfOH (60 mol %) was used. TfOH (1.4 equiv) was used. Commercially
used 1af was ca. 77% pure. TfOH (25 mol %) and TMSN3 (3.0 equiv) was used; see the Experimental Section
for details. Yield of 2af was not corrected w.r.t. 77% purity of 1af.
h
i
Cinnamaldehydes 1ac and 1ad lacking double bond substitution reacted smoothly to afford
the resultant cinnamonitriles in excellent yields (entries 29–30) whereas -methyl substituted
α
cinnamaldehyde 1ae provided the nitrile 2ae in only 53% yield (entry 31). We would have been
pleased if this method were extendable to aliphatic ketones, which have proved problematic in
previous methods as well. Unfortunately, reaction of an aliphatic aldehyde, hydrocinnamaldehyde
1af, with 3 equiv of TMSN3 in the presence of 25 mol % TfOH resulted in a complex mixture from
which 3-phenylpropionitrile 2af was isolated in low yield (entry 32). Accordingly, additional aliphatic
aldehydes were not explored.
This seemingly simple transformation raises a number of interesting mechanistic questions
(Scheme 2). Most workers have adopted some variation of the mechanism originally suggested
by P. A. S. Smith [50], in which an initially formed azidohydrin adduct
A loses water to afford a
pair of equilibrating diazoiminium ions, which can undergo migration of the phenyl group leading
to phenylformamide after re-hydration and tautomerization (Scheme 2b). Alternatively, hydride
migration followed by deprotonation would similarly afford nitrile; a variation that involves the same
intermediate would entail an E2-style elimination of a proton and nitrogen gas, although this is rarely
proposed. Confining oneself to the Smith manifold in Scheme 2b, it is hard to justify why a change in
solvent would effect the essentially exclusive formation of nitrile since that would most likely be a

Molecules 2016, 21, 45
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matter of either intrinsic migration potential between a phenyl vs. hydride or differences in the ratio of
the acyliminium ion stereoisomers shown in brackets (in general, the barrier for the interconversion
between these is thought to be high) [51]. On the other hand, Ostrovskii et al. have suggested that
the Smith dehydration mechanism, leading to nitrile, is in competition with a direct rearrangement
pathway, leading to phenylformamide (Scheme 2c) [52,53]. Acidic HFIP is a strongly dehydrating
medium, which would be consistent with this observation. Finally, it is tempting to speculate that
“superelectrophilic” species [54] like the protonated (or hydrogen bonded) diazoiminium ion or
nitrilium ions shown in Scheme 2d might also be involved, although this must remain, for the moment,
an intriguing conjecture pending further mechanistic work.
Scheme 2. Mechanistic possibilities. In all cases, the SiMe3 group might be replaced by H under the
reaction conditions (leading to exactly analogous pathways).
3. Experimental Section
3.1. General Information
Reactions were performed in glass sample vial with rubber lined cap. All chemicals were
used as received from commercial source, without further purification. Acetonitrile was dried by
passage through neutral alumina columns using a commercial solvent purification system prior
to use. Thin-layer chromatography (TLC) was performed using commercial glass-backed silica
plates (250 microns) with an organic binder. Visualization was accomplished with UV light. Flash
chromatography was carried out on a CombiFlashr purification system using a 4 g normal phase
silica flash column. Infrared (IR) spectra were acquired as a solid (Shimadzu FTIR-8400S, Kyoto,
Japan). All nuclear magnetic resonance (NMR) spectra (1H, 13C, APT) were recorded on a 400 MHz
instrument (Bruker AV-400, Billerica, MA, USA). NMR spectra were recorded in deuterated chloroform.
Chemical shifts are reported in parts per million (ppm) and are referenced to the center line of the
solvent (δ δ
7.26 ppm for 1H-NMR and 77.23 for 13C-NMR, respectively). Coupling constants are given

Molecules 2016, 21, 45
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in Hertz (Hz). Melting points were determined on an automated melting point apparatus and are
uncorrected. A sample concentrator using N2 gas was used for the concentration of reaction mixtures.
Spectroscopic data for the aromatic nitriles prepared according to the methodology described in this
paper matched well with those reported in the literature.
3.2. General Procedure for the Optimization of Reaction Conditions for the Synthesis of 4-Nitrobenzonitrile 2a
To a solution of 4-nitrobenzaldehyde 1a (0.25 or 0.50 mmol, 1.0 equiv) and NaN3 or TMSN3
(1.5–2.0 equiv) in HFIP or HFIP/ACN mixture (0.50, 1.0, or 2.0 mL) was added a catalyst (effervescence
due to nitrogen gas evolution was immediately observed). The vial was capped and the reaction
mixture was allowed to stir at rt for a specified period (45 min to 24 h). The reaction mixture was
concentrated under nitrogen. The residue obtained was diluted with appropriate solvent (CH2Cl2
or EtOAc) and was either filtered through a Pasteur pipette containing a cotton plug to get a crude
1H-NMR ratio (for entries 1 and 2) or purified using a 4 or 12 g normal phase silica flash column on a
CombiFlash purification system with a gradient elution of 0%–10% EtOAc/hexanes (for entries 3–7).
Concentration of the appropriate fractions afforded 4-nitrobenzonitrile 2a contaminated with a small
amount (ca. 3%–6%) of 1a (except for entry 5, where pure 2a was obtained).
3.3. General Procedure A for the Synthesis of Aromatic Nitriles
To a solution of an aromatic aldehyde
2.0 equiv) in a premixed HFIP/ACN mixture (2.0 mL, 1:1) in a nitrogen-flushed two dram vial was
added triflic acid (TfOH; 17.7 L, 0.200 mmol, 0.40 equiv) (exotherm and brisk effervescence due to
1 (0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
µ
nitrogen gas evolution was immediately observed). The vial was capped and the reaction mixture was
allowed to stir at rt for 20–75 min. The reaction mixture was concentrated under nitrogen. The residue
obtained was suspended in CH2Cl2/hexanes mixture and loaded on a silica gel in a 5 g sample
cartridge. Purification using a normal phase silica flash column on a CombiFlash purification system
afforded a corresponding aromatic nitrile 2 upon concentration of appropriate fractions.
4-Nitrobenzonitrile (2a) [46]: Following the general procedure
(75.6 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was stirred
A, a solution of 4-nitrobenzaldehyde 1a
µ
at rt for 45 min. Purification using a 4 g flash column on a CombiFlash purification system (0%–10%
EtOAc/hexanes over 40 min) afforded 2a along with a small amount of unreacted 1a (eluted between
2.3%–4.0% EtOAc/hexanes) as a colorless crystalline solid (61.6 mg, 0.416 mmol, 83% corrected yield;
contains ca. 4% of 1a as determined by 1H-NMR).
Terephthalonitrile (2b) [55]: Following the general procedure
(65.6 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was stirred
A, a solution of 4-cyanobenzaldehyde 1b
µ
at rt for 60 min. Purification using a 4 g flash column on a CombiFlash purification system (0%–10%
EtOAc/hexanes over 40 min) afforded 2b (eluted between 5.0%–5.8% EtOAc/hexanes) as a colorless
solid (51.3 mg, 0.400 mmol, 80% yield).
4-Chlorobenzonitrile (2c) [46
1c (70.3 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
,56]: Following the general procedure A, a solution of 4-chlorobenzaldehyde
µ
stirred at rt for 45 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–5% EtOAc/hexanes over 50 min) afforded 2c (eluted between 0%–0.5% EtOAc/hexanes) as a
colorless solid (41.8 mg, 0.304 mmol, 61% yield).
Methyl 4-cyanobenzoate (2d) [46]: Following the general procedure
4-formylbenzoate 1d (82.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in
HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction
A, a solution of methyl
µ

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mixture was stirred at rt for 30 min. Purification using a 4 g silica flash column on a CombiFlash
purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2d (eluted between 2.5%–4.2%
EtOAc/hexanes) as a colorless crystalline solid (63.0 mg, 0.391 mmol, 78% yield).
4-Methylsulfonylbenzonitrile (2e) [57]: Following a slight modification of the general procedure
solution of 4-methylsulfonylbenzaldehyde 1e (92.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg,
1.00 mmol, 2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (26.6 L, 0.300 mmol,
A, a
µ
0.60 equiv). The reaction mixture was stirred at rt for 45 min. Purification using a 4 g silica flash
column on a CombiFlash purification system (0%–40% EtOAc/hexanes over 40 min) afforded 2e
(eluted between 25%–35% EtOAc/hexanes) as a colorless solid (72.9 mg, 0.402 mmol, 81% yield).
4-Hydroxybenzonitrile
4-hydroxybenzaldehyde 1f (61.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40
(
2f
)
[
46]:
Following the general procedure
A
,
a
solution of
µ
equiv). The reaction mixture was stirred at rt for 30 min. Purification using a 4 g silica flash column on
a CombiFlash purification system (0%–30% EtOAc/hexanes over 40 min) afforded 2f (eluted between
15%–20% EtOAc/hexanes) as a colorless crystalline solid (56.5 mg, 0.474 mmol, 95% yield).
4-Methoxybenzonitrile (2g) [46]: Following the general procedure
(68.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
A, a solution of p-anisaldehyde 1g
µ
stirred at rt for 30 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–10% EtOAc/hexanes over 40 min) afforded 2g (eluted between 2.3%–3.2% EtOAc/hexanes) as a
colorless crystalline solid (54.4 mg, 0.409 mmol, 82% yield).
4-Butoxybenzonitrile (2h) [15]: Following the general procedure
1h (89.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
A, a solution of 4-butoxybenzaldehyde
µ
stirred at rt for 30 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–5% EtOAc/hexanes over 40 min) afforded 2h (eluted between 1.1%–1.8% EtOAc/hexanes) as a
colorless oil (71.9 mg, 0.410 mmol, 82% yield).
4-(Benzyloxy)benzonitrile
4-(benzyloxy)benzaldehyde 1i (106 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
(
2i
)
[46]:
Following the general procedure A, a solution of
µ
The reaction mixture was stirred at rt for 20 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2i (eluted between
2.3%–3.2% EtOAc/hexanes) as a colorless crystalline solid (74.1 mg, 0.354 mmol, 71% yield).
4-(Allyloxy)benzonitrile
4-(allyloxy)benzaldehyde 1j (81.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
(
2j
)
[
46]:
Following the general procedure A, a solution of
µ
The reaction mixture was stirred at rt for 45 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–10% EtOAc/hexanes over 50 min) afforded 2j (eluted between
3.0%–4.0% EtOAc/hexanes) as a colorless solid (71.4mg, 0.448 mmol, 90% yield).
4-(Prop-2-yn-1-yloxy)benzonitrile (2k) [46]: Following the general procedure
4-(prop-2-yn-1-yloxy)benzaldehyde 1k (80.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg,
1.00 mmol, 2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol,
A, a solution of
µ
0.40 equiv). The reaction mixture was stirred at rt for 30 min. Purification using a 4 g silica flash
column on a CombiFlash purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2k
(eluted between 3.8%–5.0% EtOAc/hexanes) as a colorless solid (51.4mg, 0.327 mmol, 65% yield).

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4-(Methylthio)benonitrile
(
2l
)
[58]:
Following the general procedure
A
,
a
solution of
4-(methylthio)benzaldehyde 1l (76.2 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
µ
The reaction mixture was stirred at rt for 30 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2l (eluted between
4.0%–4.5% EtOAc/hexanes) as a colorless solid (67.2 mg, 0.450 mmol, 90% yield).
4-(4-Morpholinyl)benzonitrile (2m) [59]: Following the general procedure
4-(4-morpholinyl)benzaldehyde 1m (95.6 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (61.9 L, 0.700 mmol, 1.40 equiv).
A, a solution of
µ
The reaction mixture was stirred at rt for 60 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–1.5% MeOH/DCM over 40 min) afforded 2m (eluted between
0.4%–0.8% MeOH/DCM) as a light yellow solid (79.8 mg, 0.424 mmol, 85% yield).
4-tert-Butylbenzonitrile
4-tert-butylbenzaldehyde 1n (81.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
(
2n)
[56]:
Following the general procedure A, a solution of
µ
The reaction mixture was stirred at rt for 30 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2n (eluted between
0%–1% EtOAc/hexanes) as a yellow oil (56.9 mg, 0.357 mmol, 72% yield).
Biphenyl-4-carbonitrile
biphenyl-4-carboxaldehyde 1o (91.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP and ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol,
(
2o)
[46]:
Following the general procedure
A
,
a
solution of
µ
0.40 equiv). The reaction mixture was stirred at rt for 45 min. Purification using a 4 g silica flash
column on a CombiFlash purification system (0%–5% EtOAc/hexanes over 50 min) afforded 2o
(eluted between 0%–1.5% EtOAc/hexanes) as an off-white solid (71.4 mg, 0.398 mmol, 80% yield).
3-Ethoxybenzonitrile (2p) [55]: Following the general procedure
1p (75.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
A, a solution of 3-ethoxybenzaldehyde
µ
stirred at rt for 60 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–5% EtOAc/hexanes over 50 min) afforded 2p (eluted between 1.2%–1.5% EtOAc/hexanes) as a
colorless oil (44.0 mg, 0.299 mmol, 60% yield).
2-Methoxybenzonitrile (2q) [55]: Following the general procedure
(68.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
A, a solution of o-anisaldehyde 1q
µ
stirred at rt for 60 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–10% EtOAc/hexanes over 40 min) afforded 2q (eluted between 2.5%–5.0% EtOAc/hexanes) as a
colorless oil (46.4 mg, 0.348 mmol, 70% yield).
2-Bromobenzonitrile (2r) [46]: Following the general procedure
1r (92.5 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
A, a solution of 2-bromobenzaldehyde
µ
stirred at rt for 30 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–10% EtOAc/hexanes over 40 min) afforded 2r (eluted between 2.0%–2.5% EtOAc/hexanes) as a
colorless crystalline solid (61.7 mg, 0.339 mmol, 68% yield).
1,3-Benzodioxole-5-carbonitrile (2s) [46]: Following the general procedure
(75.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
stirred at rt for 60 min. Purification using a 4 g silica flash column on a CombiFlash purification system
A, a solution of piperonal 1s
µ

Molecules 2016, 21, 45
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(0%–25% EtOAc/hexanes over 40 min) afforded 2s (eluted between 3.8%–5.6% EtOAc/hexanes) as a
colorless solid (64.8 mg, 0.441 mmol, 88%).
3,4-Dimethoxybenzonitrile (2t) [46]:
3,4-dimethoxybenzaldehyde 1t (83.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
Following the general procedure A, a solution of
µ
The reaction mixture was stirred at rt for 20 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–30% EtOAc/hexanes over 40 min) afforded 2t (eluted between
11%–16% EtOAc/hexanes) as a colorless crystalline solid (70.0 mg, 0.429 mmol, 86% yield).
4-Hydroxy-3-methoxybenzonitrile (2u) [60
4-hydroxy-3-methoxybenzaldehyde (vanillin) 1u (76.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg,
1.00 mmol, 2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol,
,61]: Following the general procedure A, a solution of
µ
0.40 equiv). The reaction mixture was stirred at rt for 30 min. Purification using a 4 g silica flash
column on a CombiFlash purification system (0%–25% EtOAc/hexanes over 50 min) afforded 2u
(eluted between 12.5%–16% EtOAc/hexanes) as a colorless crystalline solid (66.5 mg, 0.446 mmol,
89% yield).
3-Ethoxy-4-hydroxybenzonitrile (2v) [62]: Following the general procedure
3-ethoxy-4-hydroxybenzaldehyde 1v (83.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
A, a solution of
µ
The reaction mixture was stirred at rt for 75 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–25% EtOAc/hexanes over 40 min) afforded 2v (eluted between
8.1%–12.5% EtOAc/hexanes) as a colorless solid (74.3 mg, 0.455 mmol, 91% yield).
4-Hydroxy-3-nitrobenzonitrile (2w) [46]: Following the general procedure
4-hydroxy-3-nitrobenzaldehyde 1w (83.6 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
A, a solution of
µ
The reaction mixture was stirred at rt for 45 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–20% EtOAc/hexanes over 40 min) afforded 2w (eluted between
6.5%–9% EtOAc/hexanes) as a yellow solid (67.7 mg, 0.413 mmol, 82% yield).
4-Hydroxy-(1,1-biphenyl)-3-carbonitrile (2x) [46]: Following the general procedure
4-hydroxy-(1,1-biphenyl)-3-carbaldehyde 1x (99.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg,
1.00 mmol, 2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol,
A, a solution of
µ
0.40 equiv). The reaction mixture was stirred at rt for 20 min. Purification using a 4 g silica flash
column on a CombiFlash purification system (0%–5% EtOAc/hexanes over 40 min) afforded 2x (eluted
between 1.0%–2.0% EtOAc/hexanes) as a yellow solid (52.5 mg, 0.269 mmol, 54% yield).
3,4-Dibromobenzonitrile
3,4-dibromobenzaldehyde 1y (132 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
(
2y)
[63]:
Following the general procedure A, a solution of
µ
The reaction mixture was stirred at rt for 45 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (100% hexanes over 5 min) afforded 2y as a colorless solid (108 mg,
0.414 mmol, 83% yield). Mp: 118–120 ˝C; TLC (10% EtOAc/hexanes): Rf = 0.55; IR (neat) 2227 cm´1
;
1H-NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.9 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.3, 1.9 Hz,
1H); 13C-NMR (101 MHz, CDCl3)
afford a good parent ion in MS.
δ 136.8, 134.7, 131.6, 131.0, 126.1, 116.8, 112.9. Compound 2y did not
2-Naphthonitrile (2z) [55]: Following the general procedure
mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture (2.0
mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was stirred
at rt for 60 min. Purification using a 4 g silica flash column on a CombiFlash purification system
A, a solution of 2-naphthaldehyde 1z (78.1
µ

Molecules 2016, 21, 45
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(0%–10% EtOAc/hexanes over 50 min) afforded 2z (eluted between 0.1%–0.4% EtOAc/hexanes) as a
light yellow solid (59.0 mg, 0.385 mmol, 77% yield).
Benzofuran-2-carbonitrile (2aa) [64]:
2-benzofurancarboxaldehyde 1aa (73.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
Following the general procedure A, a solution of
µ
The reaction mixture was stirred at rt for 20 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2aa (eluted between
0.5%–1.8% EtOAc/hexanes) as a yellow solid (55.2 mg, 0.386 mmol, 77% yield).
Benzo[b]thiophene-3-carbonitrile (2ab) [65]: Following the general procedure
thianaphthene-3-carboxaldehyde 1ab (81.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
A, a solution of
µ
The reaction mixture was stirred at rt for 20 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–5% EtOAc/hexanes over 50 min) afforded 2ab (eluted between
0.4%–0.9% EtOAc/hexanes) as a colorless crystalline solid (43.8 mg, 0.275 mmol, 55% yield).
Cinnamonitrile (2ac) [46]: Following the general procedure
(66.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol, 2.0 equiv) in HFIP/ACN mixture
(2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv). The reaction mixture was
A, a solution of trans-cinnamaldehyde 1ac
µ
stirred at rt for 45 min. Purification using a 4 g silica flash column on a CombiFlash purification system
(0%–10% EtOAc/hexanes over 40 min) afforded 2ac (eluted between 2.3%–2.8% EtOAc/hexanes) as a
colorless oil (58.0 mg, 0.449 mmol, 90% yield).
(E)-3-(4-Methoxyphenyl)acrylonitrile (2ad) [66]: Following the general procedure
4-methoxycinnamaldehyde 1ad (81.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7 L, 0.200 mmol, 0.40 equiv).
A, a solution of
µ
The reaction mixture was stirred at rt for 20 min. Purification using a 4 g silica flash column on a
CombiFlash purification system (0%–10% EtOAc/hexanes over 40 min) afforded 2ad (eluted between
4.3%–5.5% EtOAc/hexanes) as a colorless solid (73.1 mg, 0.459 mmol, 92% yield).
α
α
-Methyl-trans-cinnamonitrile (2ae) [67
-methyl-trans-cinnamaldehyde 1ae (73.1 mg, 0.500 mmol, 1.0 equiv) and TMSN3 (115 mg, 1.00 mmol,
L, 0.200 mmol, 0.40 equiv).
,68]: Following the general procedure A, a solution of
2.0 equiv) in HFIP/ACN mixture (2.0 mL, 1:1) was treated with TfOH (17.7
µ
The reaction mixture was stirred at rt for 45 min. Purification using a 12 g silica flash column on a
CombiFlash purification system (0%–5% EtOAc/hexanes over 50 min) afforded 2ae (eluted between
0.5%–1.5% EtOAc/hexanes) as a pale yellow oil (38.0 mg, 0.265 mmol, 53% yield).
3-Phenylpropionitrile (2af) [69,70]: Following a slight modification of the general procedure A, a solution
of ca. 77% pure hydrocinnamaldehyde 1af (26.8 mg, 0.200 mmol, 1.0 equiv; uncorrected for impurities)
and TMSN3 (69.1 mg, 0.600 mmol, 3.0 equiv) in HFIP/ACN mixture (1.0 mL, 1:1) was treated with
TfOH (4.43 µL, 0.0500 mmol, 0.25 equiv). The reaction mixture was stirred at rt for 60 min. Purification
using a 4 g silica flash column on a CombiFlash purification system (0%–5% EtOAc/hexanes over
40 min) afforded 2af (eluted between 2.8–3.4% EtOAc/hexanes) as a colorless oil (8.00 mg, 0.0610 mmol,
30% uncorrected yield and ca. 40% corrected yield w.r.t. 77% purity of 1af).
Acknowledgments: This work was supported by the University of Kansas.
Author Contributions: H.F.M. and J.A. conceived the study, H.F.M. and Q.Y. did the experiments and interpreted
the primary data, H.F.M. and J.A. wrote the paper, and all authors read, edited, and approved the manuscript
prior to submission.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Fleming, F.F. Nitrile-containing natural products. Nat. Prod. Rep. 1999, 16, 597–606. [CrossRef]

Molecules 2016, 21, 45
12 of 14
2.
3.
Fleming, F.F.; Yao, L.; Ravikumar, P.C.; Funk, L.; Shook, B.C. Nitrile-containing pharmaceuticals: Efficacious
roles of the nitrile pharmacophore. J. Med. Chem. 2010, 53, 7902–7917. [CrossRef] [PubMed]
Fatiadi, A.J. Preparation and synthetic applications of cyano compounds. In Triple-Bonded Functional Groups;
John Wiley & Sons, Ltd.: Chichester, UK, 1983; Volume 2, pp. 1057–1303.
4.
5.
Larock, R.C. Comprehensive Organic Transformations; Wiley-VCH: New York, NY, USA, 1989.
Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances: Syntheses, Patents, Applications,
4th ed.; Georg Thieme: Stuttgart, Germany, 2001.
6.
7.
8.
9.
Smith, M.B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed.;
Wiley: Hoboken, NJ, USA, 2007; p. 2374.
Sandmeyer, T. Substitution of the amido-group in aromatic derivatives by chlorine, bromine, and cyanogen.
Chem. Ber. 1884, 17, 2650–2653. [CrossRef]
Sandmeyer, T. Ueberführung der drei nitraniline in die nitrobenzoësäuren. Chem. Ber. 1885, 18, 1492–1496.
[CrossRef]
Mowry, D.T. The preparation of nitriles. Chem. Rev. 1948, 42, 189–283. [CrossRef] [PubMed]
10. Rosenmund, K.W.; Struck, E. Halogen attached to a ring carbon atom and its replacement by other
substituents. I. Replacement of the halogen by the carboxyl group. Chem. Ber. 1919, 52, 1749–1756. [CrossRef]
11. V. Braun, J.; Manz, G. Fluoranthen und seine derivate. III. Mitteilung. Justus Liebigs Ann. Chem. 1931, 488,
111–126. [CrossRef]
12. Takagi, K.; Okamoto, T.; Sakakibara, Y.; Oka, S. Palladium(II) catalyzed synthesis of aryl cyanides from aryl
halides. Chem. Lett. 1973, 2, 471–474. [CrossRef]
13. Ellis, G.P.; Romney-Alexander, T.M. Cyanation of aromatic halides. Chem. Rev. 1987, 87, 779–794. [CrossRef]
14. Anbarasan, P.; Schareina, T.; Beller, M. Recent developments and perspectives in palladium-catalyzed
cyanation of aryl halides: Synthesis of benzonitriles. Chem. Soc. Rev. 2011, 40, 5049–5067. [CrossRef] [PubMed]
15. Wen, Q.; Jin, J.; Mei, Y.; Lu, P.; Wang, Y. Copper-mediated cyanation of aryl halides by activation of benzyl
Cyanide as the cyanide source. Eur. J. Org. Chem. 2013, 2013, 4032–4036. [CrossRef]
16. Kim, J.; Chang, S. A new combined source of “CN” from N,N-dimethylformamide and ammonia in the
palladium-catalyzed cyanation of aryl C–H bonds. J. Am. Chem. Soc. 2010, 132, 10272–10274. [CrossRef]
[PubMed]
17. Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Palladium-catalyzed direct cyanation of indoles with K4[Fe(CN)6].
Org. Lett. 2010, 12, 1052–1055. [CrossRef] [PubMed]
18. Do, H.-Q.; Daugulis, O. Copper-catalyzed cyanation of heterocycle carbon-hydrogen bonds. Org. Lett. 2010
12, 2517–2519. [CrossRef] [PubMed]
,
19. Yang, Y.; Zhang, Y.; Wang, J. Lewis acid catalyzed direct cyanation of indoles and pyrroles with
N-cyano-N-phenyl-p-toluenesulfonamide (NCTS). Org. Lett. 2011, 13, 5608–5611. [CrossRef] [PubMed]
20. Ding, S.; Jiao, N. Direct transformation of N,N-dimethylformamide to –CN: Pd-catalyzed cyanation of
heteroarenes via C–H functionalization. J. Am. Chem. Soc. 2011, 133, 12374–12377. [CrossRef] [PubMed]
21. Pollak, P.; Romeder, G.; Hagedorn, F.; Gelbke, H.-P. Nitriles. In Ullmann's Encyclopedia of Industrial Chemistry;
Wiley-VCH: Weinheim, Germany, 2000.
22. Lücke, B.; Martin, A. Fine Chemicals through Heterogeneous Catalysis; VCH-Wiley: Weinheim, Germany, 2001.
23. Lücke, B.; Narayana, K.V.; Martin, A.; Jähnisch, K. Oxidation and ammoxidation of aromatics. Adv. Synth.
Catal. 2004, 346, 1407–1424. [CrossRef]
24. Hatsuda, M.; Seki, M. A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl
bromides employing heterogeneous Pd/C: In quest of an industrially viable process. Tetrahedron 2005, 61,
9908–9917. [CrossRef]
25. Nakajima, N.; Saito, M.; Ubukata, M. Activated dimethyl sulfoxide dehydration of amide and its application
to one-pot preparation of benzyl-type perfluoroimidates. Tetrahedron 2002, 58, 3561–3577. [CrossRef]
26. Kuo, C.-W.; Zhu, J.-L.; Wu, J.-D.; Chu, C.-M.; Yao, C.-F.; Shia, K.-S. A convenient new procedure for converting
primary amides into nitriles. Chem. Commun. 2007, 301–303. [CrossRef] [PubMed]
27. Olah, G.A.; Narang, S.C.; Fung, A.P.; Balaram Gupta, B.G. Synthetic Methods and Reactions; 82. Cyanuric
Chloride, a Mild Dehydrating Agent in the Preparation of Nitriles from Amides. Synthesis 1980, 1980,
657–658.
28. Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. A general and convenient catalytic synthesis of nitriles from
amides and silanes. Org. Lett. 2009, 11, 2461–2464. [CrossRef] [PubMed]

Molecules 2016, 21, 45
13 of 14
29. Yang, S.H.; Chang, S. Highly efficient and catalytic conversion of aldoximes to nitriles. Org. Lett. 2001, 3,
4209–4211. [CrossRef] [PubMed]
30. Denton, R.M.; An, J.; Lindovska, P.; Lewis, W. Phosphonium salt-catalysed synthesis of nitriles from in situ
activated oximes. Tetrahedron 2012, 68, 2899–2905. [CrossRef]
31. Choi, E.; Lee, C.; Na, Y.; Chang, S. [RuCl2(p-cymene)]2 on carbon: An efficient, selective, reusable,
and environmentally versatile heterogeneous catalyst. Org. Lett. 2002, 4, 2369–2371. [CrossRef] [PubMed]
32. De Luca, L.; Giacomelli, G.; Porcheddu, A. Beckmann rearrangement of oximes under very mild conditions.
J. Org. Chem. 2002, 67, 6272–6274. [CrossRef] [PubMed]
33. Baxendale, I.R.; Ley, S.V.; Sneddon, H.F. A clean conversion of aldehydes to nitriles using a solid-supported
hydrazine. Synlett 2002, 2002, 775–777. [CrossRef]
34. Chill, S.T.; Mebane, R.C. A facile one-pot conversion of aldehydes into nitriles. Synth. Commun. 2009, 39,
3601–3606. [CrossRef]
35. Srinivas, K.V.N.S.; Reddy, E.B.; Das, B. Highly convenient and efficient one-pot conversions of aldehydes
into nitriles and ketones into amides using HY-zeolite. Synlett. 2002, 2002, 0625–0627. [CrossRef]
36. Laulhé, S.; Gori, S.S.; Nantz, M.H. A chemoselective, one-pot transformation of aldehydes to nitriles.
J. Org. Chem. 2012, 77, 9334–9337. [CrossRef] [PubMed]
37. Augustine, J.K.; Bombrun, A.; Atta, R.N. A practical and cost-efficient, one-pot conversion of aldehydes into
nitriles mediated by “activated DMSO”. Synlett 2011, 2011, 2223–2227. [CrossRef]
38. Telvekar, V.N.; Patel, K.N.; Kundaikar, H.S.; Chaudhari, H.K. A novel system for the synthesis of nitriles
from aldehydes using aqueous ammonia and sodium dichloroiodate. Tetrahedron Lett. 2008, 49, 2213–2215.
[CrossRef]
39. Kelly, C.B.; Lambert, K.M.; Mercadante, M.A.; Ovian, J.M.; Bailey, W.F.; Leadbeater, N.E. Access to nitriles
from aldehydes mediated by an oxoammonium salt. Angew. Chem. Int. Ed. 2015, 54, 4241–4245. [CrossRef]
[PubMed]
40. Ghorbani-Choghamarani, A.; Zolfigol, M.A.; Hajjami, M.; Sardari, S. Direct synthesis of nitriles from alcohols
or aldehydes using H5IO6/KI in aqueous ammonia. Synth. Commun. 2012, 43, 52–58. [CrossRef]
41. Patil, U.B.; Shendage, S.S.; Nagarkar, J.M. One-pot synthesis of nitriles from aldehydes catalyzed by deep
eutectic solvent. Synthesis 2013, 45, 3295–3299.
42. Augustine, J.K.; Atta, R.N.; Ramappa, B.K.; Boodappa, C. Propylphosphonic anhydride (T3Pr): A
remarkably efficient reagent for the one-pot transformation of aromatic, heteroaromatic, and aliphatic
aldehydes to nitriles. Synlett 2009, 2009, 3378–3382. [CrossRef]
43. Zhu, J.-L.; Lee, F.-Y.; Wu, J.-D.; Kuo, C.-W.; Shia, K.-S. An efficient new procedure for the one-pot conversion
of aldehydes into the corresponding nitriles. Synlett. 2007, 2007, 1317–1319. [CrossRef]
44. Wrobleski, A.; Coombs, T.C.; Huh, C.W.; Li, S.-W.; Aubé, J. The Schmidt reaction. Org. React. 2012, 78, 1–320.
45. McEwen, W.E.; Conrad, W.E.; VanderWerf, C.A. The Schmidt reaction applied to aldehydes and epoxides.
J. Am. Chem. Soc. 1952, 74, 1168–1171. [CrossRef]
46. Rokade, B.V.; Prabhu, K.R. Chemoselective Schmidt reaction mediated by triflic acid: Selective synthesis of
nitriles from aldehydes. J. Org. Chem. 2012, 77, 5364–5370. [CrossRef] [PubMed]
47. Nandi, G.C.; Laali, K.K. 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. Tetrahedron Lett. 2013, 54, 2177–2179. [CrossRef]
48. Hazarika, N.; Baishya, G. One-pot sequential Schmidt and Ritter reactions for the synthesis of N-tert-butyl
amides. Eur. J. Org. Chem. 2014, 2014, 5686–5690. [CrossRef]
49. Motiwala, H.F.; Fehl, C.; Li, S.-W.; Hirt, E.; Porubsky, P.; Aubé, J. Overcoming Product Inhibition in Catalysis
of the Intramolecular Schmidt Reaction. J. Am. Chem. Soc. 2013, 135, 9000–9009. [CrossRef] [PubMed]
50. Smith, P.A.S. The Schmidt reaction: Experimental conditions and mechanism. J. Am. Chem. Soc. 1948, 70,
320–323. [CrossRef]
51. Bach, R.D.; Wolber, G.J. Theoretical study of the barrier to nitrogen inversion in N-cyano- and
N-diazoformimine. Mechanism of the Schmidt reaction. J. Org. Chem. 1982, 47, 239–245. [CrossRef]
52. Ostrovskii, V.A.; Koldobskii, G.I.; Shirokova, N.P.; Gidaspov, B.V. Mechanism of the Schmidt reaction. XVIII.
Kinetics of reaction of substituted benzaldehydes with hydrazoic acid in aqueous solutions of sulfuric acid.
Zh. Org. Khim. 1977, 13, 339–343.

Molecules 2016, 21, 45
14 of 14
53. Ostrovskii, V.A.; Kuznetsov, A.V.; Koldobskii, G.I.; Shirokova, N.P.; Gidaspov, B.V. Mechanism of the Schmidt
reaction. XIV. Determination of the ratio of reaction products of substituted benzaldehydes with hydrazoic
acid. Zh. Org. Khim. 1975, 11, 1027–1030.
54. Raja, E.K.; Klumpp, D.A. Superelectrophilic chemistry of amino-nitriles and related substrates. Tetrahedron
2011, 67, 4494–4497. [CrossRef] [PubMed]
55. Tsuchiya, D.; Kawagoe, Y.; Moriyama, K.; Togo, H. Direct oxidative conversion of methylarenes into aromatic
nitriles. Org. Lett. 2013, 15, 4194–4197. [CrossRef] [PubMed]
56. Yu, L.; Li, H.; Zhang, X.; Ye, J.; Liu, J.; Xu, Q.; Lautens, M. Organoselenium-catalyzed mild dehydration
of aldoximes: An unexpected practical method for organonitrile synthesis. Org. Lett. 2014, 16, 1346–1349.
[CrossRef] [PubMed]
57. Yu, B.; Guo, C.-X.; Zhong, C.-L.; Diao, Z.-F.; He, L.-N. Metal-free chemoselective oxidation of sulfides by
in situ generated Koser’s reagent in aqueous media. Tetrahedron Lett. 2014, 55, 1818–1821. [CrossRef]
58. Jang, Y.; Kim, K.T.; Jeon, H.B. Deoxygenation of sulfoxides to sulfides with thionyl chloride and
triphenylphosphine: Competition with the Pummerer reaction. J. Org. Chem. 2013, 78, 6328–6331. [CrossRef]
[PubMed]
59. Al-Amin, M.; Arai, S.; Hoshiya, N.; Honma, T.; Tamenori, Y.; Sato, T.; Yokoyama, M.; Ishii, A.; Takeuchi, M.;
Maruko, T.; et al. Development of second generation gold-supported palladium material with low-leaching
and recyclable characteristics in aromatic amination. J. Org. Chem. 2013, 78, 7575–7581. [CrossRef] [PubMed]
60. Yadav, A.K.; Srivastava, V.P.; Yadav, L.D.S. Visible-light-mediated efficient conversion of aldoximes and
primary amides into nitriles. RSC Adv. 2014, 4, 4181–4186. [CrossRef]
61. Saha, D.; Saha, A.; Ranu, B.C. Ionic liquid-promoted dehydration of aldoximes: A convenient access to
aromatic, heteroaromatic and aliphatic nitriles. Tetrahedron Lett. 2009, 50, 6088–6091. [CrossRef]
62. Dev, D.;
Palakurthy, N.B.;
Kumar, N.;
Mandal, B. An unexpected involvement of
ethyl-2-cyano-2-(hydroxyimino) acetate cleaved product in the promotion of the synthesis of nitriles from
aldoximes: A mechanistic perception. Tetrahedron Lett. 2013, 54, 4397–4400. [CrossRef]
63. Rudenko, A.P.; Salfetnikova, Y.N.; Vasil’ev, A.V. Oxidation of aromatic compounds. V. Oxidation of
substituted benzonitriles and 2,4,6-triaryl-1,3,5-triazines in the HSO3F-PbO2 system. Zh. Org. Khim.
1996, 32, 1499.
64. Luo, Y.; Wen, Q.; Wu, Z.; Jin, J.; Lu, P.; Wang, Y. Copper-mediated cyanation of aryl boronic acids using
benzyl cyanide. Tetrahedron 2013, 69, 8400–8404. [CrossRef]
65. Cohen, D.T.; Buchwald, S.L. Mild palladium-catalyzed cyanation of (hetero)aryl halides and triflates in
aqueous media. Org. Lett. 2015, 17, 202–205. [CrossRef] [PubMed]
66. Powell, K.J.; Han, L.-C.; Sharma, P.; Moses, J.E. Chemoselective palladium-catalyzed cyanation of alkenyl
halides. Org. Lett. 2014, 16, 2158–2161. [CrossRef] [PubMed]
67. Tomioka, T.; Sankranti, R.; Vaughan, T.G.; Maejima, T.; Yanase, T. An
α
-diaminoboryl carbanion assisted
stereoselective single-pot preparation of
[CrossRef] [PubMed]
α,β-disubstituted acrylonitriles. J. Org. Chem. 2011, 76, 8053–8058.
68. Zhou, W.; Xu, J.; Zhang, L.; Jiao, N. An efficient transformation from benzyl or allyl halides to aryl and
alkenyl nitriles. Org. Lett. 2010, 12, 2888–2891. [CrossRef] [PubMed]
69. Geoghegan, K.; Kelleher, S.; Evans, P. An investigation into the one-pot Heck olefination-hydrogenation
reaction. J. Org. Chem. 2011, 76, 2187–2194. [CrossRef] [PubMed]
70. Mirjafari, A.; Mohammadpoor-Baltork, I.; Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Khosropour, A.R.
Microwave-promoted, one-pot conversion of alkoxymethylated protected alcohols into their corresponding
nitriles, bromides, and iodides using [bmim][InCl4] as a green catalyst. Tetrahedron Lett. 2010, 51, 3274–3276.
[CrossRef]
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