Transformation of aldehydes into nitriles in an aqueous medium using O-phenylhydroxylamine as the nitrogen source

Article abstract of DOI:10.1016/j.carres.2021.108282

The conversion of an aldehyde into a nitrile can be efficiently performed using O-phenylhydroxylamine hydrochloride in buffered aqueous solutions. The reported method is specifically optimized for aqueous-soluble substrates including carbohydrates. Several reducing sugars including monosaccharides, disaccharides, and silyl-protected saccharides were transformed into cyanohydrins in high yields. The reaction conditions are also suitable for the formation of nitriles from various types of hydrophobic aldehyde substrates. Furthermore, cyanide can be eliminated from cyanohydrins, analogous to the Wohl degradation, by utilizing a readily-removed weakly basic resin as a promoter.

Full text of DOI:10.1016/j.carres.2021.108282

Carbohydrate Research 502 (2021) 108282
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Transformation of aldehydes into nitriles in an aqueous medium using
O-phenylhydroxylamine as the nitrogen source
Thamrongsak Cheewawisuttichai, Robert D. Hurst, Matthew Brichacek*
Department of Chemistry, University of Maine, Orono, ME, USA
A R T I C L E I N F O
A B S T R A C T
Keywords:
The conversion of an aldehyde into a nitrile can be efficiently performed using O-phenylhydroxylamine hy-
drochloride in buffered aqueous solutions. The reported method is specifically optimized for aqueous-soluble
substrates including carbohydrates. Several reducing sugars including monosaccharides, disaccharides, and
silyl-protected saccharides were transformed into cyanohydrins in high yields. The reaction conditions are also
suitable for the formation of nitriles from various types of hydrophobic aldehyde substrates. Furthermore, cy-
anide can be eliminated from cyanohydrins, analogous to the Wohl degradation, by utilizing a readily-removed
weakly basic resin as a promoter.
Nitriles
Cyanohydrin
Saccharide
Wohl degradation
A nitrile is an important functional group in organic synthesis
because it can be transformed into several functional groups such as an
amine [1,2], carboxylic acid [3,4], ester [5,6], ketone [7], and hetero-
cycles [8,9]. Furthermore, nitriles are utilized in many fields beyond
organic chemistry including pharmaceutical [10] and materials [11,12].
In the past decades, several methods have been reported for the for-
mation of nitriles from different functional groups such as amines, am-
ides, and alcohols. However, these methods require harsh conditions or
metal-complex catalysts [13].
ligands in catalysis or as intermediates in the synthesis of biologically
active compounds [23–25]. Herein, a method optimized for the forma-
tion and isolation of cyanohydrins from reducing sugars is described.
O-Phenylhydroxylamine hydrochloride (H2NOPh) was used as a nitro-
gen source, and the reaction proceeded under the aqueous condition at
room temperature.
In a preliminary study, the reaction of D-ribose and H2NOPh in an
aqueous solution yielded cyanohydrin (1). This observation led to an
evaluation of the reaction conditions under various aqueous environ-
ments at room temperature (Table 1). All aqueous solutions in the
optimization studies were prepared from deuterium oxide, which
allowed for monitoring the reaction by 1H NMR spectroscopy. The NMR
spectra demonstrated that the oxime was formed as an intermediate (I),
then phenol was subsequently eliminated [26], and the cyanohydrin (1)
was obtained as a product (Scheme 1). When the shelf-stable and
commercially available O-phenylhydroxylamine is used as the hydro-
chloride salt, a significant decrease in pH is observed. At low pH (entries
1 and 2), the aldehyde substrate was not fully consumed in the 7 h
timeframe of the reaction screen. However, the formation of cyanohy-
drin could proceed to the completion under phosphate buffered condi-
tions at pD 5.45 and pD 7.25 within 7 h (entries 3 and 4). The pD values
of the reaction mixtures in entries 3 and 4 were monitored, and the
changes of the pD values were not observed. It was reasoned that under
the buffered conditions, the hydrochloric acid produced from the
starting material was neutralized which allowed the oxime intermediate
to be fully formed. Based on these investigations, the reaction condition
The usage of aldehydes as precursors to nitriles is common due to the
mild reaction conditions and the readily available substrates. Formation
of nitriles through dehydration of oximes is one of the most simple
methods [14]. In general, an aldehyde is reacted with hydroxylamine to
form an aldoxime followed by dehydration with acetic anhydride, thi-
onyl chloride, or lead oxide to form the desired nitrile [14,15]. However,
these dehydration conditions often require an excess of dehydrating
agents or high temperatures resulting in low functional group tolerance
[16]. To avoid using harsh conditions and increase the compatibility of
the reaction with a variety of functional groups, several approaches have
been reported to convert aldehydes into nitriles in a one-pot manner
using various nitrogen sources [16–18] such as O-(diphenyl-phosphinyl)
hydroxylamine (DPPH) [19], hydroxylamine-O-sulfonic acid [20], and
N-hydroxyphthalimide [21].
Although many publications reported the formation of nitriles from
organic aldehydes, only a few examples studied cyanohydrin formations
from reducing sugars [22]. Cyanohydrins are versatile structures as
* Corresponding author.
E-mail address: mbrich@maine.edu (M. Brichacek).
https://doi.org/10.1016/j.carres.2021.108282
Received 19 October 2020; Received in revised form 3 March 2021; Accepted 3 March 2021
Available online 10 March 2021
0008-6215/© 2021 Elsevier Ltd. All rights reserved.

T. Cheewawisuttichai et al.
Carbohydrate Research 502 (2021) 108282
Table 1
Optimization study with D-ribose.
Entry
Condition
Yielda (%)
1
2
3
4
D2O
83
1% Acetic acid in D2O
83
0.2 M Sodium phosphate in D2O pDb 5.45
0.2 M Sodium phosphate in D2O pDb 7.25
100
100
a
Determined by 1H NMR.
b
pD = pH + 0.45 (Ref. 31).
of 0.2 M of sodium phosphate buffer at pD 7.25 was used as a general
procedure for further studies.
The scope of the aldehyde substrates was extended to aromatic,
aliphatic, and ,β-unsaturated aldehydes. However, the reaction condi-
α
Next, various types of hydroxylamines were evaluated for the for-
mation of a cyanohydrin from D-Ribose under the standard condition of
0.2 M sodium phosphate pD 7.25 (Table 2). The reactions were moni-
tions used for carbohydrate compounds needed to be modified for these
hydrophobic substrates because they are poorly soluble in water.
Furthermore, the deuterated conditions were replaced with the pro-
tonated solvents because the reactions could simply be monitored by
TLC. A 4:1 ratio of methanol to 0.5 M of sodium phosphate pH 6.5 was
found to be the best condition for dissolving most organic compounds.
The reactions were conducted at 60 ◦C with varying reaction times
depending on the type of aldehyde substrates resulting in acceptable to
good isolated yields (Table 4). The transformation of aromatic aldehydes
into nitriles appeared to be fast and provided exceptional yields. Entry 1
shows that 4-hydroxy-3-methoxybenzonitrile was obtained in 99% yield
after 8 h. The reaction of unsaturated aromatic and aliphatic aldehyde
(entries 2 and 3) required a longer reaction time (24–48 h) to obtain the
desired nitrile products in 63% and 58% yield, respectively. These re-
action conditions were also compatible with an acid-labile functional
group. Entry 4 shows that N-Boc-4-piperidine-acetaldehyde was trans-
formed into the corresponding nitrile in 60% yield after 72 h.
1
tored by H NMR spectroscopy for 24 h at room temperature. As ex-
pected, the cyanohydrin product was not obtained from the reaction of
D-ribose with O-benzylhydroxylamine hydrochloride (entry 2); howev-
er, only an oxime was observed. The cyanohydrin was obtained from the
reaction of D-ribose with hydroxylamine-O-sulfonic acid in 90% yield
after 24 h (entry 3). For the reaction of D-ribose with DPPH and O-
(mesitylsulfonyl)-hydroxylamine (entries 4 and 5, respectively), only a
trace of cyanohydrin product was observed. The poor solubility of both
substrates in water was believed to be a major reason. The quantitative
yield from entry 1 demonstrated that H2NOPh was a suitable nitrogen
source for the formation of cyanohydrins from a variety of carbohy-
drates under an aqueous condition.
The transformation of 13 reducing sugars to cyanohydrins is re-
ported in Table 3. All carbohydrate substrates were reacted with
H2NOPh in 0.2 M sodium phosphate at pD 7.25 and the reactions were
Wohl degradation was selected to demonstrate the utility of the cy-
anohydrins formed from reducing sugars. Wohl degradation is one of the
most common methods of shortening aldose sugars through the forma-
tion of an acetylated cyanohydrin and the elimination of cyanide using
ammonia or silver hydroxide [27,28]. To perform this cyanide elimi-
nation on the unprotected cyanohydrins formed above, it was necessary
to find a base that can be easily removed from the reaction mixture due
to the challenges of isolating unprotected carbohydrates.
1
monitored by H NMR spectroscopy. Phenol produced as a byproduct
could be easily removed from the reaction mixtures by extraction with
diethyl ether. In most cases, after evaporation of the aqueous solution to
dryness, the cyanohydrin products were obtained by dissolving the dried
mixture with ethanol. For hydrophobic substrates, such as silyl-
protected carbohydrates (entry 13), the products were purified by sil-
ica gel chromatography. The reactions of H2NOPh with pentoses (en-
tries 1 to 4) proceeded within 12 h to obtain cyanohydrins in 81–100%
yields. A longer reaction time was needed for the substrate 2-deoxy-D-
ribose (entry 5) to obtain the cyanohydrin in 96% yield. The reactions of
hexoses (entries 6 to 8) were slower and often required 48 h to provide
the cyanohydrin products in 63–97% yield. However, the stereochem-
istry of C-2 dramatically affects the rate of the reaction. As shown in
entry 9, the reaction of D-mannose required only 24 h for the full con-
version (96% yield). Maltose is a highly polar disaccharide that is poorly
soluble in ethanol. Although the 1H NMR of the crude reaction of
maltose after 48 h indicated that the reaction went to completion, the
isolated yield was lower than expected (53% yield, entry 10) because the
product maltonitrile could not be fully extracted using ethanol. L-Fucose,
GlcNAc, and silyl-protected ribose (entries 11, 12, and 13, respectively)
were rather sluggish (72 h), but still produced nitriles in good yields
(59–70% yield).
Weakly basic resins (WBS) can be conveniently removed by filtration
and are particularly well suited for the removal of ionic impurities from
aqueous solutions [29,30]. To our best knowledge, WBS have never been
used for shortening carbohydrates. It was hypothesized that the tertiary
amine-functionalized resin would promote the nucleophilic elimination
of cyanide from the cyanohydrin. Three cyanohydrins (compound 7, 9
and 10) were chosen to demonstrate a Wohl-type degradation using
Lewatit MP 62 (tertiary amine) resin as a base. The mixture was stirred
in ethanol at 70 ◦C for 7 h to obtain the desired products in moderate
isolated yields. As shown in Table 5, D-Galactonitrile (7) was shortened
to D-lyxose (18) in 79% yield (entry 1), and D-mannonitrile (9) was
shortened to D-arabinose (19) in 75% yield (entry 2). The same reaction
condition was applied to complex saccharides. Entry 3 shows that cya-
nide was eliminated from a D-maltonitrile (10) to form D-glucopyr-
anose-(1 → 3)-D-arabinopyranose (20) in 60% yield. The Wohl-type
Scheme 1. Proposed reaction mechanism.
2

T. Cheewawisuttichai et al.
Carbohydrate Research 502 (2021) 108282
Table 2
Evaluation of cyanohydrin formation with hydroxylamine sources.
Entry
1
Yielda (%)
100
2
3
0
90
4
5
trace
trace
a
Determined by 1H NMR.
degradation is one practical application of cyanohydrins produced from
reducing sugars.
FT-NMR (400 MHz, 101 MHz), and Bruker AVANCE NEO 500 (500 MHz,
126 MHz) respectively. Chemical shifts are reported in ppm and multi-
plicities are reported as s (singlet), d (doublet), t (triplet), q (quartet), p
(pentet), h (hextet), hep (heptet), m (multiplet), and br (broad). For 13C
NMR spectra of samples in the D2O solvent, a small amount of methanol
was added as the internal standard. Thin-layer chromatography (TLC)
analysis was performed on silica gel 60 with fluorescent indicator F254
(EMD Millipore) and visualized with UV light (254 nm) where appli-
cable. Silica gel column chromatography was performed on SiliaFlash®
Conclusion
A new method for transforming aldehydes into nitriles using
commercially available O-phenylhydroxylamine hydrochloride as a ni-
trogen source is described. The method works exceptionally well under
aqueous solution in the presence of sodium phosphate buffer. Several
reducing sugars were transformed to cyanohydrins in high yields. Poor
aqueous solubility of an aldehydes often results in longer reaction times
and diminished yields. This method was modified to be compatible with
hydrophobic compounds by using a mixture of an organic solvent and
sodium phosphate buffer. Several functionalized aliphatic and aromatic
aldehydes were transformed into nitriles in acceptable yields. The re-
action conditions were also suitable for compounds with a range of
functional groups including acid-labile functionalities. Furthermore, a
method for shortening reducing sugars by using weakly basic resins was
demonstrated. The cyanohydrin compounds (7, 9 and 10) were used as
reactants for the demonstration. The reducing sugars obtained from the
degradation of D-galactonitrile, D-mannonitrile, and D-maltonitrile were
F60 (Silicycle, 40–64 μm). Mass spectrometry analysis was performed by
the School of Chemical Sciences Mass Spectrometry Laboratory at the
University of Illinois.
1.1.2. Disposal
Cyanide is highly toxic and should be handled and disposed properly.
Since cyanide can eliminate from cyanohydrins, all products and waste
should be disposed in a separate waste container with clearly labelled.
The cyanide gas produced from the elimination of cyanohydrin was
stored as NaCN solution by trapping the gas with 5% NaOH solution.
1.1.3. General procedure for the formation of cyanohydrins
To a 7 mL vial was added reducing sugar (1 equiv), O-phenyl-
hydroxylamine hydrochloride (H2NOPh) (1.2 equiv), and 0.2 M sodium
phosphate pD 7.25 to the final concentration of 0.1 M. The reaction was
stirred at room temperature until the oxime intermediates were dis-
appeared (monitored by 1H NMR). Then, the reaction mixture was
transferred into a separatory funnel and washed with diethyl ether for
10 times. The remaining aqueous solution was evaporated to dryness.
Ethanol was added to the solid residue to extract the product from the
phosphate salt. The phosphate salt residues in the ethanol solution were
removed by centrifugation. The solvent was evaporated to obtain the
desired product.
D-lyxose (18), D-arabinose (19), and D-glucose-
(20), respectively.
α-(1 → 3)-D-arabinose
1.1. Experimental section
1.1.1. General procedures
All chemicals and reagents were purchased and used without further
purification. Deuterium oxide buffer solution was prepared by dissolv-
ing 0.227 g of Na2HPO4 and 0.221 g of NaH2PO4 in 16 mL of deuterium
oxide and measured the pD value of the buffer solution by pH meter. It is
worth noting here that the pH meter was calibrated with aqueous (H2O)
calibration buffer. Therefore, pD was calculated based on Krezel and Bal
[31] (pD = pH + 0.45). Concentrated phosphoric acid and 1 M NaOH in
deuterium oxide were used to adjust the pD values. Lewatit MP 62 resin
was purchased from Sigma and washed with ethanol using vacuum
filtration before use. Optical rotations were measured on a Jasaco
DIP-370 digital polarimeter. 1H and 13C NMR spectra were recorded on
an Varian INOVA 400 FT-NMR (400 MHz, 101 MHz), Varian Unity 400
1.1.4. D-Ribonitrile (1)
Prepared according to the general procedure using D-ribose (0.0226
g, 0.150 mmol) as reducing sugar. Yield = 0.0208 g (94%). [α D
]
20 + 8.1 (c
0.58, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.88 (d, J = 3.5 Hz, 1H, H-
2), 3.88–3.75 (m, 2H, H-3 and H-4), 3.72–3.60 (m, 2H, H-5a and H-5b).
13C NMR (101 MHz, D2O) δ (ppm): 119.2, 72.5, 72.1, 63.6, 63.0. HR-MS
3

T. Cheewawisuttichai et al.
Carbohydrate Research 502 (2021) 108282
Table 3
Transformation of reducing sugars to cyanohydrins.
Entry
1
Reducing sugar
D-Ribose
Time (h)
12
Yielda (%)
94
2
3
4
5
D-Arabinose
D-Xylose
12
12
12
16
83
98
L-Arabinose
2-Deoxy-D-ribose
100
96
6
7
D-Glucose
48
48
90
97
D-Galactose
8
D-Allose
48
24
48
63
96
53
9
D-Mannose
D-Maltose
10
11
12
L-Fucose
72
72
59
70
N-Acetyl-D-glucosamine (GlcNAc)
13
a
5-O-TBDPS-D-riboseb,c
72
69
Isolated yield.
b
c
MeOH was added (50% v/v) to increase solubility.
TBDPS = tert-butyldiphenylsilyl.
(ESI) m/z calcd. for C5H9NO4Na (M + Na)+ 170.0429, found 170.0431.
[
α 2D0
]
- 20.8 (c 0.34, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.90 (d, J =
2.3 Hz, 1H, H-2), 3.85–3.76 (m, 2H, H-3 and H-5a), 3.76–3.70 (m, 1H,
H-4), 3.66 (dd, J = 11.6, 5.4 Hz, 1H, H-5b). 13C NMR (126 MHz, D2O) δ
(ppm): 120.4, 72.0, 70.5, 63.2, 62.3. HR-MS (ESI) m/z calcd. for
C5H9NO4Na (M + Na)+ 170.0429, found 170.0434.
1.1.5. D-Arabinonitrile (2)
Prepared according to the general procedure using D-arabinose
(0.0086 g, 0.0577 mmol) as reducing sugar. Yield = 0.0071 g (83%).
4

T. Cheewawisuttichai et al.
Carbohydrate Research 502 (2021) 108282
Table 4
Transformation of aldehydes to nitriles.
Entry
1
Time (h)
8
Yielda(%)
99
2
72
63
3
4
24
72
58
60
a
Isolated yield.
1.1.8. 2-Deoxy-D-ribonitrile (5)
Table 5
Prepared according to the general procedure using 2-deoxy-D-ribose
Degradation of cyanohydrins.
(0.0114 g, 0.085 mmol) as reducing sugar. Yield = 0.0107 g (96%).
[
α 2D0
]
- 6.9 (c 0.27, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 3.99–3.91 (m,
1H, H-3), 3.84–3.71 (m, 1H, H-5a), 3.70–3.56 (m, 2H, H-4 and H-5b),
2.87 (ddd, J = 17.2, 4.1, 0.5 Hz, 1H, H-2a), 2.77 (ddd, J = 17.2, 6.8, 0.5
Hz, 1H, H-2b). 13C NMR (101 MHz, D2O) δ (ppm): 120.0, 74.0, 67.7,
62.9, 22.6. HR-MS (ESI) m/z calcd. for C5H9NO3Na (M + Na)+
154.0480, found 154.0484.
Entry
Product
Yielda (%)
1
2
79
75
1.1.9. D-Gluconitrile (6)
Prepared according to the general procedure using D-glucose
(0.0082 g, 0.045 mmol) as reducing sugar. Yield = 0.0072 g (90%).
[
α 2D0
]
+ 15.4 (c 0.38, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.72 (d, J =
7.3 Hz, 1H, H-2), 4.06 (dd, J = 7.4, 1.6 Hz, 1H, H-3), 3.82 (dd, J = 11.8,
2.4 Hz, 1H, H-6a), 3.79–3.70 (m, 2H, H-4 and H-5), 3.64 (dd, J = 11.5,
5.3 Hz, 1H, H-6b). 13C NMR (101 MHz, D2O) δ (ppm): 119.8, 71.2, 71.1,
70.1, 63.5, 63.2. HR-MS (ESI) m/z calcd. for C6H11NO5Na (M + Na)+
200.0535, found 200.0528.
3
60
1.1.10. D-galactonitrile (7)
a
Prepared according to the general procedure using D-galactose
(0.0162 g, 0.090 mmol) as reducing sugar. Yield = 0.0155 g (97%).
Isolated yield.
[
α 2D0
]
+ 11.3 (c 0.19, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.91 (d, J =
1.1.6. D-Xylonitrile (3)
1.9 Hz, 1H, H-2), 3.96–3.86 (m, 2H, H-3 and H-6a), 3.68–3.62 (m, 3H,
H-4, H-5, and H-6b). 13C NMR (101 MHz, D2O) δ (ppm): 120.6, 71.5,
70.4, 69.2, 63.6, 62.4. HR-MS (ESI) m/z calcd. for C6H11NO5Na (M +
Na)+ 200.0535, found 200.0540.
Prepared according to the general procedure using D-xylose (0.0489
g, 0.326 mmol) as reducing sugar. Yield = 0.0471 g (98%). [α D
]
20+ 7.5 (c
0.63, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.71 (dd, J = 5.8, 0.9 Hz,
1H, H-2), 3.91–3.80 (m, 2H, H-3 and H-4), 3.69–3.54 (m, 2H, H-5a and
H-5b). 13C NMR (101 MHz, D2O) δ (ppm): 119.8, 72.0, 71.2, 62.9, 62.7.
HR-MS (ESI) m/z calcd. for C5H9NO4Na (M + Na)+ 170.0429, found
170.0434.
1.1.11. D-Allonitrile (8)
Prepared according to the general procedure using D-allose (0.0139
g, 0.077 mmol) as reducing sugar. Yield = 0.0086 g (63%). [α D
]
20+ 2.9 (c
0.20, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.87 (dd, J = 3.9, 1.1 Hz,
1H, H-2), 3.96 (ddd, J = 7.6, 3.9, 1.1 Hz, 1H, H-3), 3.91–3.84 (m, 1H, H-
5), 3.78–3.70 (m, 2H, H-4, H-6a), 3.63 (ddd, J = 11.9, 7.3, 1.1 Hz, 1H, H-
6b). 13C NMR (101 MHz, D2O) δ (ppm): 119.5, 73.0, 72.7, 72.4, 63.7,
62.7. HR-MS (ESI) m/z calcd. for C6H11NO5Na (M + Na)+ 200.0535,
found 200.0540.
1.1.7. L-Arabinonitrile (4)
Prepared according to the general procedure using L-arabinose
(0.046 g, 0.307 mmol) as reducing sugar. Yield = 0.0455 g (100%).
[
α 2D0
]
+ 18.4 (c 0.59, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.89 (d, J
= 2.2 Hz, 1H, H-2), 3.84–3.75 (m, 2H, H-3 and H-4), 3.74–3.68 (m, 1H,
H-5a), 3.65 (dd, J = 11.6, 5.5 Hz, 1H, H-5b). 13C NMR (101 MHz, D2O) δ
(ppm): 120.4, 72.1, 70.5, 63.2, 62.3. HR-MS (ESI) m/z calcd. for
C5H9NO4Na (M + Na)+ 170.0429, found 170.0433.
5

T. Cheewawisuttichai et al.
Carbohydrate Research 502 (2021) 108282
1.1.12. D-Mannonitrile (9)
could not be observed (monitored by TLC). Then, the reaction mixture
was cooled to room temperature and extracted with 3 mL CH2Cl2 a total
of 5 times. The combined organic layer was dried over Na2SO4 and
concentrated by rotary evaporator. The crude product was purified by
silica column chromatography.
Prepared according to the general procedure using D-mannose
(0.0335 g, 0.186 mmol) as reducing sugar. Yield = 0.0317 g. (96%).
[
α 2D0
]
- 11.6 (c 0.57, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.62 (d, J =
8.4 Hz, 1H, H-2), 4.03 (dd, J = 8.3, 1.5 Hz, 1H, H-3), 3.81 (dd, J = 11.7,
2.6 Hz, 1H, H-6a), 3.75–3.69 (m, 1H, H-5), 3.68–3.58 (m, 2H, H-4 and
H-6b). 13C NMR (101 MHz, D2O) δ (ppm): 120.9, 71.0, 70.8, 69.1, 63.7,
62.7.
1.1.18. 4-Hydroxy-3-methoxybenzonitrile (14)
Prepared according to the general procedure using vanillin (0.0254
g, 0.167 mmol) as an aldehyde. The reaction time was 8 h. The crude
product was purified by silica column chromatography (EtOAc:Hexanes
HR-MS (ESI) m/z calcd. for C6H11NO5Na (M + Na)+ 200.0535, found
200.0537.
1
40:60). Yield = 0.0248 g (99%). H NMR (400 MHz, CDCl3) δ (ppm):
7.22 (dd, J = 8.2, 1.8 Hz, 1H, Ar–H), 7.08 (d, J = 1.7 Hz, 1H, Ar–H), 6.96
(d, J = 8.2 Hz, 1H, Ar–H), 3.92 (s, 3H, –OCH3). 13C NMR (101 MHz,
CDCl3) δ (ppm): 150.0, 146.7, 127.1, 119.4, 115.3, 113.8, 103.4, 56.4.
HR-MS (ESI) m/z calcd. for C8H8NO2 (M + H)+ 150.0555, found
150.0557.
1.1.13. D-Maltonitrile (10)
Prepared according to the general procedure using D-maltose
(0.0355 g, 0.098 mmol) as reducing sugar. Yield = 0.0186 g. (53%).
[
α 2D0
]
+ 80.3 (c 0.39, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 5.08 (d, J =
3.7 Hz, 1H, H–1B), 4.91 (d, J = 5.4 Hz, 1H, H-2A), 4.12 (ddd, J = 5.3,
3.9, 1.1 Hz, 1H, H-3A), 3.92 (m, 2H, H-4A and H-6A), 3.86–3.61 (m, 6H,
H-5A, H-6A′, H–3B, H–5B, H–6B and H–6B’), 3.55 (dd, J = 10.0, 3.9 Hz,
1H, H–2B), 3.40 (t, J = 9.6 Hz, 1H, H–4B). 13C NMR (101 MHz, D2O) δ
(ppm): 119.8, 101.5, 101.3, 80.4, 73.3, 72.9, 72.7, 72.3, 70.0, 63.0,
62.9, 61.0. HR-MS (ESI) m/z calcd. for C12H21NO10Na (M + Na)+
362.1063, found 362.1060.
1.1.19. Trans-Cinnamonitrile (15)
Prepared according to the general procedure using trans-cinna-
maldehyde (0.025 g, 0.189 mmol) as an aldehyde. The reaction time was
72 h. The crude product was purified by silica column chromatography
1
(EtOAc:Hexanes 10:90). Yield = 0.0155 g (63%). H NMR (400 MHz,
CDCl3) δ (ppm): 7.49–7.36 (m, 6H, Ar–H and = CH), 5.88 (d, J = 16.7
Hz, 1H, =CH). 13C NMR (101 MHz, CDCl3) δ (ppm): 150.7, 133.6, 131.4,
129.3, 127.5, 118.3, 96.4. HR-MS (ESI) m/z calcd. for C9H7N (M)+⋅
129.0578, found 129.0581.
1.1.14. L-Fuconitrile (11)
Prepared according to the general procedure using L-fucose (0.0133
g, 0.0812 mmol) as reducing sugar. CD3OD (20% v/v) was added to the
reaction to increase the solubility. Yield = 0.0078 g (59%). [α D
]
20- 16.9 (c
1.1.20. (3S)-Citronellylnitrile (16)
0.19, H2O). 1H NMR (400 MHz, D2O) δ (ppm): 4.92 (d, J = 2.0 Hz, 1H, H-
2), 4.11–4.03 (m, 1H, H-5), 3.85 (dd, J = 9.5, 2.1 Hz, 1H, H-3), 3.46 (dd,
J = 9.5, 1.6 Hz, 1H, H-4), 1.23 (d, J = 6.5 Hz, 3H, H-6). 13C NMR (101
MHz, D2O) δ (ppm): 120.6, 72.6, 71.9, 66.1, 62.6, 19.2. HR-MS (ESI) m/
z calcd. for C6H11NO4Na (M + Na)+ 184.0586, found 184.0591.
Prepared according to the general procedure using (ꢀ )-citronellal
(0.0244 g, 0.158 mmol) as an aldehyde. The reaction time was 24 h. The
crude product was purified by silica column chromatography (EtOAc:
Hexanes 5:95). Yield = 0.0139 g (58%). 1H NMR (400 MHz, CDCl3) δ
(ppm): 5.07 (tt, J = 7.1, 1.5 Hz, 1H, =CH), 2.42–2.16 (m, 2H, –CH2),
2.10–1.95 (m, 2H, –CH2), 1.86 (m, J = 13.1, 6.5 Hz, 1H, –CH), 1.68 (s,
3H, =CCH3), 1.61 (s, 3H, =CCH3), 1.46–1.22 (m, 2H, –CH2), 1.07 (d, J
= 6.7 Hz, 3H, –CH3).
1.1.15. N-Acetyl-D-glucosaminonitrile (12)
Prepared according to the general procedure using N-acetyl-D-
glucosamine (0.0250 g, 0.114 mmol) as reducing sugar. Yield = 0.0174
13C NMR (101 MHz, CDCl3) δ (ppm): 132.4, 123.6, 119.0, 36.0, 30.1,
25.8, 25.4, 24.6, 19.5, 19.5. HR-MS (ESI) m/z calcd. for C10H17N (M)+⋅
151.1361, found 151.1368. Optical rotation data reported previously
[32].
g (70%). [α 2D0
]
+ 36.8 (c 0.19, H2O). 1H NMR (400 MHz, D2O) δ (ppm):
4.93 (d, J = 8.2 Hz, 1H, H-2), 4.25 (dd, J = 8.2, 0.7 Hz, 1H, H-3),
3.89–3.82 (m, 1H, H-5), 3.77–3.73 (m, 2H, H-4 and H-6a), 3.70–3.59
(m, 1H, H-6b), 2.06 (s, 3H, COCH3). 13C NMR (101 MHz, D2O) δ (ppm):
174.9, 117.8, 71.2, 70.4, 69.4, 63.5, 57.2, 22.4. HR-MS (ESI) m/z calcd.
for C8H14N2O5Na (M + Na)+ 241.0800, found 241.0803.
1.1.21. N-Boc-4-(cyanomethyl)piperidine (17)
Prepared according to the general procedure using N-Boc-4-piperi-
dine-acetaldehyde (0.0308 g, 0.136 mmol) as an aldehyde. The reaction
time was 72 h. The crude product was purified by silica column chro-
matography (EtOAc:Hexanes 40:60). Yield = 0.0183 g (60%). 1H NMR
(101 MHz, CDCl3) δ (ppm): 4.14 (s, 2H, –CH2), 2.70 (t, J = 12.2 Hz, 2H,
–CH2), 2.30 (d, J = 6.4 Hz, 2H, –CH2), 1.93–1.73 (m, 3H, –CH2 and
–CH), 1.44 (s, 9H, -tBu), 1.32–1.17 (m, 2H, –CH2). 13C NMR (101 MHz,
CDCl3) δ (ppm): 154.7, 118.2, 79.8, 43.5, 33.5, 31.4, 28.6, 24.2. HR-MS
(ESI) m/z calcd. for C12H20N2O2Na (M + Na)+ 247.1422, found
247.1430.
1.1.16. Synthesis of 5-O-Tert-Butyl-Diphenylsilyl-D-Ribonitrile (13)
To a 7 mL vial was added 5-O-tert-butyl-diphenylsilyl-D-ribose
(0.131 g, 0.337 mmol, 1 equiv), O-phenylhydroxylamine hydrochloride
(H2NOPh) (0.059 g, 0.404 mmol, 1.2 equiv), 2 mL of 0.2 M sodium
phosphate pD 7.25 and 2 mL of methanol. The reaction was stirred at
room temperature until the change of starting materials could not be
observed (monitored by TLC). The reaction mixture was evaporated to
dryness. The crude mixture was purified by silica column (Rf = 0.3,
40:60 EtOAc:Hexanes) with a gradient of 20:80 to 40:60 (EtOAc:Hex-
anes). Yield = 0.0895 g (69%). [α D20
]
+ 11.4 (c 0.08, CH2Cl2). H NMR
1
1.1.22. General procedure for the elimination of cyanohydrins
To a 20 mL vial was added sugar cyanohydrin and ethanol to a final
concentration of 0.01 M. Lewatit MP 62 resins (approximately 10 times
by mass compared to the mass of cyanohydrin) were added to the
mixture then the vial was connected to a gas bubbler with a 5% NaOH
trap by way of a Tygon® tube and host adapter. The purpose of this
apparatus was to trap cyanide gas produced during the reaction. The
reaction was stirred (300 rpm) at 70 ◦C for 7 h. The resins were removed
by vacuum filtration, and the solution was evaporated to obtain the
desired product.
(400 MHz, CDCl3) δ (ppm): 7.76–7.56 (m, 4H, Ar–H), 7.55–7.34 (m, 6H,
Ar–H), 4.77 (d, J = 3.9 Hz, 1H, H-2), 3.93–3.81 (m, 3H, H-3, H-4, and H-
5a), 3.78 (dd, J = 8.0, 4.3 Hz, 1H, H-5b), 1.08 (s, 9H, -tBu). 13C NMR
(101 MHz, CDCl3) δ (ppm): 135.7, 132.5, 130.4, 128.2, 118.0, 72.8,
71.7, 64.6, 64.3, 27.0, 19.4. HR-MS (ESI) m/z calcd. for C21H28NO4Si
(M + H)+ 386.1788, found 386.1789.
1.1.17. General procedure for the formation of nitriles
To a 7 mL vial, aldehyde (1 equiv) and O-phenylhydroxylamine
hydrochloride (H2NOPh) (1.2 equiv) were dissolved in 4:1 of meth-
anol:0.5 M sodium phosphate pH 6.5 to the final concentration of 0.1 M.
The reaction was stirred at 60 ◦C until the changes of starting materials
1.1.23. Preparation of D-Lyxose (18)
Prepared according to the general procedure using D-galactonitrile
6

T. Cheewawisuttichai et al.
Carbohydrate Research 502 (2021) 108282
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(0.0058 g, 0.033 mmol) as sugar cyanohydrin. Yield = 0.0039 g (79%).
1.1.24. Preparation of D-Arabinose (19)
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pharmaceuticals: efficacious roles of the nitrile pharmacophore, J. Med. Chem. 53
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Prepared according to the general procedure using D-mannonitrile
(0.0065 g, 0.0365 mmol) as sugar cyanohydrin. Yield = 0.0041 g (75%).
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radical (co)polymerization of acrylonitrile and "click chemistry"-type
postpolymerization modification, Macromolecules 37 (2004) 9308–9313, https://
doi.org/10.1021/ma048207q.
1.1.25. Preparation of
(20)
α-D-Glucopyranosyl-(1 → 3)-D-Arabinopyranose
Prepared according to the general procedure using D-maltonitrile
(0.0037 g, 0.01 mmol) as sugar cyanohydrin. Yield = 0.0018 g (58%).
1H NMR (400 MHz, CDCl3) δ (ppm): 5.41 (d, J = 3.8 Hz, 1H, Glc-H-1),
5.22 (d, J = 3.3 Hz, 0.5H, Ara-H-1β), 4.65 (d, J = 7.9 Hz, 0.5H, Ara-H-
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1α), 4.05–3.58 (m, 9H), 3.47 (t, J = 9.5 Hz, 1.5H, Glc-H-4), 3.35–3.30
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(m, 0.5H, Ara-H-2
α
). 13C NMR (126 MHz, D2O) δ (ppm): 100.0, 96.2,
[15] A.F. Hegarty, P.J. Tuohey, Nitrile-forming eliminations from oxime ethers,
J. Chem. Soc. Perkin Trans. 2 (1980) 1313–1317, https://doi.org/10.1039/
p29800001313.
92.4, 77.3, 77.1, 76.7, 76.4, 75.1, 74.6, 74.5, 73.7, 73.3, 73.2, 72.2,
72.1, 70.4, 70.0, 69.8, 61.2, 61.0. HR-MS (ESI) m/z calcd. for C11H19O10
(M ꢀ H)- 311.0978, found 311.0977. Optical rotation data reported
previously [33].
[16] G. Yan, Y. Zhang, J. Wang, Recent advances in the synthesis of aryl nitrile
compounds, Adv. Synth. Catal. 359 (2017) 4068–4105, https://doi.org/10.1002/
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Declaration of competing interest
[18] K. Hyodo, K. Togashi, N. Oishi, G. Hasegawa, K. Uchida, Brønsted acid catalyzed
nitrile synthesis from aldehydes using oximes via transoximation at ambient
temperature, Org. Lett. 19 (2017) 3005–3008, https://doi.org/10.1021/acs.
orglett.7b01263.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
´
[19] S. Laulhe, S.S. Gori, M.H. Nantz, A chemoselective, one-pot transformation of
aldehydes to nitriles, J. Org. Chem. 77 (2012) 9334–9337, https://doi.org/
10.1021/jo301133y.
[20] D.J. Quinn, G.J. Haun, G. Moura-Letts, Direct synthesis of nitriles from aldehydes
with hydroxylamine-O-sulfonic acid in acidic water, Tetrahedron Lett. 57 (2016)
3844–3847, https://doi.org/10.1016/J.TETLET.2016.07.047.
Acknowledgements
This research was supported in part by funds provided by the Na-
tional Institutes of Health (U01-GM120410). Use of the Bruker Avance
NEO 500 MHz nuclear magnetic resonance (NMR) spectrometer was
supported by the National Science Foundation under grant CHE-
1828408.
[21] Y. Yan, X. Xu, X. Jie, J. Cheng, R. Bai, Q. Shuai, Y. Xie, Selective and facile
synthesis of α,β-unsaturated nitriles and amides with N-hydroxyphthalimide as the
nitrogen source, Tetrahedron Lett. 59 (2018) 2793–2796, https://doi.org/
10.1016/j.tetlet.2018.06.011.
[22] B.P. Bandgar, S.S. Makone, Organic reactions in water: transformation of aldehydes
to nitriles using NBS under mild conditions, Synth. Commun. 36 (2006)
1347–1352, https://doi.org/10.1080/00397910500522009.
[23] I.R. Cabrita, P.R. Florindo, A.C. Fernandes, Cyclopentadienyl-ruthenium(II)
complexes as efficient catalysts for the reduction of carbonyl compounds,
Tetrahedron 73 (2017) 1511–1516, https://doi.org/10.1016/j.tet.2017.01.067.
Appendix A. Supplementary data
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Supplementary data to this article can be found online at https://doi.
org/10.1016/j.carres.2021.108282.
heterocyclic derivatives containing isoxazole and tetrazole rings joined by a
carbohydrate tether, J. Heterocycl. Chem. 39 (2002) 221–224, https://doi.org/
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pivaloyloximes. Transition-state differences for the syn andAnti eliminations
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7