Acetic Anhydride-Acetic Acid as a New Dehydrating Agent of Aldoximes for the Preparation of Nitriles: Preparation of 2-Cyanoglycals

Article abstract of DOI:10.1055/s-0040-1708007

Glycals, 1,2-unsatrated carbohydrates, are versatile building blocks for the synthesis of various scaffolds. Despite their potential to serve as suitable precursors in diversity-oriented synthesis, 2-cyanoglycals are less explored in terms of their synthesis and derivatization. Herein, we report a combination of Ac ₂ O and AcOH as new and efficient dehydrating agent of aldoximes for the synthesis of 2-cyanoglycals. In comparison to the conventional dehydrating system of Ac ₂ O-base (such as NaOH, NaOAc and K ₂ CO ₃), the current protocol provides superior yields and faster reaction rates. The scope and limitations of the dehydrating system are investigated.

Full text of DOI:10.1055/s-0040-1708007

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
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T. F. Mabasa et al.
Letter
Synlett
Acetic Anhydride–Acetic Acid as a New Dehydrating Agent of
Aldoximes for the Preparation of Nitriles: Preparation of
2-Cyanoglycals
Tommy F. Mabasaa
Jackie Mabasaa
Mthokozisi Simelaneb
Banele Vatshaa
Banothile C.E. Makhubelaa
Henok H. Kinfe*a
O
N
RO
RO
R1
or
reasonable time
N
O
OR
RO
a Centre of Synthesis and Catalysis, University of Johannesburg,
Auckland Park Campus, Auckland Park 2006, Johannesburg,
South Africa
b Department of Biochemistry, University of Johannesburg,
Auckland Park Campus, Auckland Park 2006, Johannesburg,
South Africa
NOH
N
9 examples, yields 50–98%
diverse aldoximines and glycals
R = Bn, Me (both glucal and galactal)
or
OH
R1
R
1 = Me, OH, Br, Cl, NO2, OMe
hhkinfe@uj.ac.za
110 °C
Received: 01.02.2020
Accepted after revision: 04.03.2020
Published online: 27.03.2020
nation of aryl halides and triflates1,12 as well as the dehydra-
tion of aldoximes. In terms of simplicity and reduced toxici-
ty, the dehydration of aldoximes is the preferred protocol
for its synthesis. Accordingly, alternative dehydrating con-
ditions have been developed that include [RuCl2(p-cy-
mene)]2/MeCN,13 chlorosulfonic acid,14 bromodimethylsul-
foniumbromide (BDMS)/MeCN,15 Pd(OAc)2/PPh3/MeCN,16
Zn(acac)2/H2O/toluene,17 Cu(OAc)2/MeCN,18 FeCl3/DMF,19
Fe3O4 nanoparticles/DMF,20 and TiCl4/pyridine.21 Notably,
the use of acetic anhydride as a readily available dehydrat-
ing agent in the absence or presence of bases such as NaOH,
NaOAc, and K2CO3 are also reported as favorable alterna-
tives.22
DOI: 10.1055/s-0040-1708007; Art ID: st-2020-u0065-l
Abstract Glycals, 1,2-unsatrated carbohydrates, are versatile building
blocks for the synthesis of various scaffolds. Despite their potential to
serve as suitable precursors in diversity-oriented synthesis, 2-cyanogly-
cals are less explored in terms of their synthesis and derivatization.
Herein, we report a combination of Ac2O and AcOH as new and effi-
cient dehydrating agent of aldoximes for the synthesis of 2-cyanogly-
cals. In comparison to the conventional dehydrating system of Ac2O-
base (such as NaOH, NaOAc and K2CO3), the current protocol provides
superior yields and faster reaction rates. The scope and limitations of
the dehydrating system are investigated.
Key words aldoximes, 2-cyanoglycals, nitriles
In a continuation of our efforts to develop methodolo-
gies for the transformation of glycals into precursors suit-
able for diversity oriented synthesis (DOS),23,24 we required
access to 2-cyanoglycals 2a (Table 1) in order to use them as
precursors for the synthesis of various scaffolds. The nitrile
functional group can be transformed into various 2-C
branched sugar derivatives and glycomimetics.25 Further-
more, with the advance of C–H activation and transition-
metal-catalyzed coupling reactions, the ready availability of
novel ,-unsaturated systems such as the 2-cyanoglycals
2a are crucial to expand the scope and diversity of these re-
actions. Despite their potential, there is only one low-yield-
ing (<42%) method reported for the synthesis of 2-cyano-
glycals that involves the reaction of glycals with chlorosul-
fonyl isocyanate.26 In this communication, we describe a
new approach to the preparation of 2-cyanoglycals, and
their potential in DOS is demonstrated by their transforma-
tion into an interrupted-Ferrier product.
Nitriles are versatile precursors that can be easily trans-
formed into a variety of functional groups such as amidines,
amides, imidoesters, benzamidines, amines, heterocycles,
and aldehydes.1 Besides its ease of derivatization, the nitrile
functional group is a key structural unit found in a number
of drugs (e.g., Escitalopram, Etravirine, Bicalutamide,
Febuxostat,
Letrozole,
Cyamemazine,
Gallopamil,
Alogliptin, and Nilvadipine) and biologically active com-
pounds.1 Moreover, the lone pair of electrons of the nitro-
gen from a nitrile functional group chelates with metals in
the preparation of complexes and also serves as a directing
group in C–H activation reactions.2–10 Owing to its plethora
of applications, preparation strategies are continuously be-
ing developed. Approaches include the nucleophilic substi-
tution of alkyl halides or aryl diazonium salts (Sandmeyer
reaction) with a cyanide,11 transition-metal-catalyzed cya-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. F. Mabasa et al.
Letter
Synlett
Table 1 Optimization of the Dehydration of Aldoxime 2a
group (entry 7). The only difference between K2CO3 and
acetic acid as additives is the yield and the reaction time as
mentioned above; however, both methods can be utilized in
nitrile formation. The positive advantage for both will only
be shown when base- or acid-sensitive substrates are used
for nitrile formation.
O
O
BnO
BnO
BnO
BnO
Reaction conditions
N
OBn
N
OBn
OH
1a
2a
The structure of the 2-cyano glucal 2a was elucidated
based on HRMS, NMR and IR spectroscopy. Among others,
the disappearance of the signal of the aldoxime proton that
appeared at H = 7.67 ppm in the starting material con-
firmed the successful dehydration of the aldoxime func-
tional group. The C≡N stretch at 2214.3 cm–1 in the IR spec-
trum of the product, further supported a successful dehy-
dration reaction. The identity of the 2-cyano glucal 2a was
further confirmed by single-crystal X-ray diffraction (SCD)
analysis (Figure 1) of the methyl protected analogue 2d (see
below).27 Needle-like crystals of diffraction quality for 2d
were grown by the slow evaporation method. The crystal
data collected at 298 K revealed that 2d crystallizes in the
monoclinic space group P21. In the molecule, there are
weak interactions between the neighboring molecules: hy-
drogen bonding [N···H (2.823 Å), O···H (3.527 Å)] originating
from terminal methyl groups, nitrile propagating along the
a-axis. Also, along c-axis, there is C–H··· (3.793 Å) stacking
involving two independent glycal rings that links the mole-
cules into a supramolecular structure (see the Supporting
Information, Figure S1).
Entry
Ac2O (mL) Additive (1 equiv) Temp (°C) Time (h) Yield (%)a
1
2
3
4
5
6
7
1
1
1
1
1
1
–
–
85–145
110
24
16
24
24
24
8
NP
50
NP
NP
NP
72
NP
K2CO3
AcOH
AcOH
AcOH
AcOH
AcOH
25
65
85
110
110
8
a NP = no product formed.
In our current investigation, we prepared a solution of
1a in Ac2O, which was stirred for 8 h at room temperature
on the basis of a report that Ac2O alone can dehydrate al-
doximes.22 When TLC analysis indicated no formation of a
new product, the reaction mixture was heated at 85, 110,
and 145 °C successively, each for 24 h (Table 1, entry 1). The
reaction, however, did not lead to product formation, there-
by justifying the need for an additive. As is commonly em-
ployed, the use of a base additive (e.g., K2CO3)22d provided
the desired 2-cyano glucal 2a with a lower yield of 50% after
stirring at 110 °C (after trying different temperatures from
room temperature) for 16 h under alkaline conditions (en-
try 2). In the search for a variant that can work under acidic
conditions, a combination of AcOH–Ac2O under various re-
action conditions was investigated. After screening of the
conditions (entries 3–5), the use of AcOH/Ac2O (1:1.75, 2
mL) at 110 °C yielded the 2-cyano glucal 2a with a superior
yield of 72% and a shorter reaction time of 8 h (entry 6).
Carrying out the reaction in AcOH but in the absence of
Ac2O, no desired product was formed, suggesting the im-
portance of the anhydride in dehydrating the aldoxime
Figure 1 ORTEP molecular structure of 2d drawn at the 50% probability
H
H+
O
OH
O
R
O
OH
R
O
OH
R
H
O
O
N
N
N
O
O
H
O
II
O
O
O
I
O
Path A
O
H
N
H
O
O
O
R
O
H
O
R
H
R
N
N
O
O
N
R
O
O
H
O
III
V
IV
O
O
Path B
Scheme 1 Proposed mechanism of the dehydration reaction
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
T. F. Mabasa et al.
Letter
Synlett
Under the optimal conditions,28 aldoximes 1b–d were
stirred in a mixture of AcOH/Ac2O according to Table 2 at
110 °C to give the corresponding 2-cyanoglycals in high to
excellent yields and in short reaction time without the for-
mation of the possible Beckman rearrangement product
(entries 1–4). Furthermore, the substrate scope of the reac-
tion was examined with various aryl aldoximes possessing
either electron-withdrawing or electron-donating groups
(entries 5–9). The results are summarized in Table 2; the
scope and yields compare favorably with the reported
K2CO3–Ac2O protocol for the aldoximes bearing electron-
withdrawing groups.22d However, lower yields were ob-
tained when aryl aldoximes possessing electron-donating
groups were employed as substrates (entry 8).
Table 2 (continued)
Entry
Substrate
Product
Yield (%)
98c
HO
N
N
7
OAc
OH
2g
1g
1h
HO
N
N
8
9
50a
OMe
OMe
HO
2h
N
N
70c
Table 2 Dehydration of Aldoximes Using the Ac2O/AcOH Reaction
System at 110 °C
Cl
2i
Cl
1i
N
AcOH/Ac2O (1:1.75)
OH
a Reaction run for 8 h.
b Reaction run for 6 h.
c Reaction run for 4 h.
R
N
R
110 °C, 4–8 h
50–98%
2a–i
1a–i
Entry
1
Substrate
Product
Yield (%)
72a
A proposed mechanism for the dehydration reaction is
outlined in Scheme 1. The reaction may commence with
the activation of the acetic anhydride by the acetic acid to
form complex I, considering the acidic conditions of the re-
action. This complex then delivers an acyl group to the hy-
droxyl group of the aldoxime II to yield the oxonium inter-
mediate III along with equimolar amounts of acetic acid
and acetate (Path A). Abstraction of the imine proton in the
oxonium intermediate III by the acetate promotes deacetyl-
ation with the subsequent formation of the nitrile function-
al group in the final product IV.
Alternatively, the hydroxy group might attack the car-
bonyl group of the acetic anhydride without the involve-
ment of the acetic acid to provide oxonium intermediate V,
which, upon abstraction of the imine proton, leads to for-
mation of the desired product (Path B). However, it is un-
likely that the formation of the nitriles is through Path B
since the use of acetic anhydride alone was not favored (Ta-
ble 1, entry 7).
The strategy provided access to a series of these valu-
able 2-cyanoglycals 2a–d and a simple derivatization by
treating a solution of 2-cyano galactal 2b in MeCN with 4-
methylthiophenol and catalytic amount of Al(OTf)3 pro-
duced the interrupted-Ferrier product, 2-cyano galactal 3
demonstrating their potential use in diversity oriented syn-
thesis as shown in Scheme 2. The absence of the formation
of a Ferrier product (2,3-unsaturated galactoside) or a
Michael addition product suggests that the cyano group at
position C-2 influences the reactivity of glycals in a similar
fashion to formyl groups.29 The molecular structure of 3
was further confirmed by SCD analysis (Figure 2). The
structure crystallizes in the monoclinic space group P21.
O
BnO
BnO
O
BnO
BnO
OBn
N
N
N
OBn
OH
2a
1a
O
O
BnO
BnO
BnO
BnO
2
3
4
5
6
77a
74b
90b
97c
92a
OBn
N
N
N
OBn
OH
2b
1b
O
O
MeO
MeO
MeO
MeO
N
OMe
OMe
O
OH
2c
1c
O
MeO
MeO
MeO
MeO
N
OMe
OMe
OH
2d
1d
HO
N
N
O2N
O2N
2e
1e
HO
N
N
NO2
NO2
2f
1f
Thieme. All rights reserved. Synlett 2020, 31, A–E

D
T. F. Mabasa et al.
Letter
Synlett
OBn
O
O
BnO
BnO
SH
BnO
BnO
O
S
NC
N
Al(OTf)3, MeCN, rt, 10 h, 68%
N
OBn
OBn
S
3
2b
3
O
BnO
BnO
N
SH
I
Scheme 2 Interrupted-Ferrier rearrangement of 2-cyano galactal 2b
The half-chair conformation of the galactal ring propagates
along <001> plane. The crystal packing of the molecule is
dominated by hydrogen bonding in a similar fashion to that
in structure 2d. The disordered phenyl ring was modeled to
refine the occupancy ratio of 0.55:0.45 with about two po-
sition atoms: C8-C15 and C8A-C15A. All non-hydrogen at-
oms were refined anisotropically (see the Supporting Infor-
mation, Figure S2).
Funding Information
We acknowledge the South African Agency for Science and Technolo-
gy Advancement (NRF 118552) for funding.
S
o
uthAfri
c
a
n
A
g
e
n
c
y
for
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
A
d
v
a
n
c
e
m
e
nt(N
R
F
1
1
8
5
5
2)
Acknowledgment
We thank the Centre for Synthesis and Catalysis of the University of
Johannesburg (UJ). We are indebted to the UJ-Spectrum NMR facility
at University of Johannesburg.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1708007.
S
u
p
p
orit
n
gInformati
o
n
S
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p
p
orit
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gInformati
o
n
References and Notes
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Figure 2 ORTEP molecular structure of 3 drawn at the 50% probability
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In conclusion, we have demonstrated that a combina-
tion of AcOH and Ac2O can be employed as a new dehydrat-
ing system for the preparation of nitriles from the corre-
sponding aldoximes. Furthermore, the strategy was used in
the synthesis of 2-cyanoglycals, which are potential precur-
sors for the transformation of glycals in diversity oriented
synthesis. To our knowledge, this is the first report in which
a combination of Ac2O with an acid (in this case AcOH) is
used to facilitate dehydration of aldoximes. The short reac-
tion time, high chemoselectivity, and high yields make the
method an attractive alternative in organic synthesis.
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T. F. Mabasa et al.
Letter
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tary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
(28) Typical procedure: A solution of pre-prepared aldoxime 1a
(100 mg, 0.218 mmol) in AcOH/Ac2O (1:1.75, 2 mL) in a 10 mL
round-bottom flask fitted with a condenser was heated at
110 °C for 4 h under a nitrogen atmosphere. The reaction
mixture was then allowed to cool to room temperature and 15%
aq. NaOH was added until the solution became slightly basic.
The resultant mixture was extracted with ethyl acetate and the
combined organic phases were washed successively with satu-
rated bicarbonate, brine and water, dried over MgSO4 and con-
centrated to dryness. The residue product was purified by
column chromatography on silica gel using a mixture of ethyl
acetate/hexane (9:1) as eluent to provide 2-cyanoglucal 2a in
72% yield.
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Compound 2a: Yield: 72%; colorless oil. IR (neat): 2214.3 cm–1
(C≡N). HRMS: m/z [M + Na]+ calcd: 441.1940; found: 441.1835.
1H NMR (CDCl3, 400 MHz):  = 7.40–7.23 (m, 15 H, Ar), 7.15 (s,
1 H, H1), 4.78 (d, J = 11.5 Hz, 1 H, -CH1aPh), 4.70–4.55 (m, 3 H,
-CH2Ph and -CH1bPh), 4.50 (s, 2 H, -CH2Ph), 4.39 (q, J = 14.8 Hz,
1 H, H5), 4.14 (d, J = 4.8 Hz, 1 H, H3), 3.86 (t, J = 10.4 Hz, 1 H,
H4), 3.77 (dd, J = 6.0, 11.0 Hz, 1 H, H6a), 3.68 (dd, J = 3.5, 14.5 Hz,
1 H, H6b). 13C NMR (100 MHz, CDCl3):  = 157.0 (C1), 137.5,
137.2, 137.1, 128.6, 128.5, 128.4, 128.2, 128.1, 128.06, 128.0,
127.9, 127.8, 127.7 (Ar), 117.9 (C2), 89.1 (CCN), 77.9 (C5), 73.5,
73.1, 72.6 (CH2Ph×3), 71.9 (C3 and C4), 67.5 (C6).
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E