SO 2 F 2 -Promoted Dehydration of Aldoximes: A Rapid and Simple Access to Nitriles

Article abstract of DOI:10.1055/s-0037-1611840

A rapid, simple and mild process for the dehydration of aldoximes to give the corresponding nitriles, which utilizes SO ₂ F ₂ as an efficient reagent, has been developed. A variety of (hetero)arene, alkene, alkyne and aliphatic aldoximes proceeded with high efficiency to afford nitriles in excellent to quantitative yields with great functional group compatibilities in acetonitrile under ambient conditions. Furthermore, an eco-friendly synthetic protocol to access nitriles from aldehydes with ortho -, meta - and para -nitrile groups was also described in aqueous methanol by using inorganic base Na ₂ CO ₃, and a one-pot synthetic strategy to generate nitriles from aldehydes was proved to be feasible.

Full text of DOI:10.1055/s-0037-1611840

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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Y. Zhao et al.
Letter
Synlett
SO2F2-Promoted Dehydration of Aldoximes: A Rapid and Simple
Access to Nitriles
Yiyong Zhaoa
SO2F2 (balloon)
Guangyao Meib
Haibo Wangb
Guofu Zhang*a
Chengrong Ding*a
OH
N
Et3N or Na2CO3
CH3CN or CH3OH/H2O
r.t., 15–60 min
R
N
R
R = (hetero)aryl, alkenyl,
alkynyl, alkyl
32 examples
up to quantitative yields
Rapid and highly efficient process
a College of Chemical Engineering, Zhejiang University
of Technology, Hangzhou 310014, P. R. of China
gfzhang@zjut.edu.cn
Excellent functional group compatibility
One-pot strategy using inorganic reagents in green solvent
Up to gram scale
dingcr@zjut.edu.cn
b Zhejiang Hongyuan Pharmaceutical Co., Ltd., Linhai
317016, P. R. of China
Received: 20.03.2019
Accepted after revision: 04.05.2019
Published online: 25.06.2019
peratures, inert atmosphere protection, and participation
of capricious ligands were mostly inevitable. Considering
these issues, it is still highly desirable to develop a general,
high-efficiency and mild process for the dehydration of al-
doximes to nitriles.
DOI: 10.1055/s-0037-1611840; Art ID: st-2019-w0161-l
Abstract A rapid, simple and mild process for the dehydration of al-
doximes to give the corresponding nitriles, which utilizes SO2F2 as an ef-
ficient reagent, has been developed. A variety of (hetero)arene, alkene,
alkyne and aliphatic aldoximes proceeded with high efficiency to afford
nitriles in excellent to quantitative yields with great functional group
compatibilities in acetonitrile under ambient conditions. Furthermore,
an eco-friendly synthetic protocol to access nitriles from aldehydes with
ortho-, meta- and para-nitrile groups was also described in aqueous
methanol by using inorganic base Na2CO3, and a one-pot synthetic
strategy to generate nitriles from aldehydes was proved to be feasible.
Sulfuryl fluoride (SO2F2), as an inexpensive, abundant
and relatively inert gas,8 has recently attracted significant
attention for sulfonyl(VI) fluoride exchange (SuFEx)9 and
other transformations.10 Especially SuFEx click chemistry,
which was chiefly described by Sharpless’ team in 2014,
gave evidence that the proton can activate the exchange of
S–F bonds for S–O bonds to make functional products,9a and
the sulfuryl fluoride (-SO2F) functional group could be ap-
plied in a controllable and targeted manner for small mole-
cules, polymers, and biomolecules because the sulfate con-
nector is surprisingly stable toward hydrolysis.9b–h Subse-
quently, variant reactions were introduced by other
groups.10 Notably, Qin’s group demonstrated that the sys-
tem of SO2F2/base in DMSO can be directly utilized in versa-
tile manipulations of oxidative dehydrogenation and dehy-
dration.10e–l,11
Our research group has undertaken relevant work on
deoximation and cyanidation.12 Recently, we reported that
a Fe(NO3)3·9H2O-catalyzed aerobic oxidative deoximation
system can be used without any other additives.12a Soon af-
terwards, the use of aqueous ammonia (NH3·H2O), as the
simplest N-containing ligand, was reported to effectively
promote copper-catalyzed selective oxidation of alcohol to
nitriles under air in water.12b Inspired by the unique proper-
ties of SO2F2,9,10 we hypothesized that the proton of aldox-
imes 2 might activate the exchange of a S–F bond for a S–O
bond to generate the corresponding sulfonyl ester A with
the participation of SO2F2 and base. Given the attenuation
of the N–O bond by the -SO2F group with the assistance of
base, the formation of sulfonyl ester A was immediately fol-
lowed by -elimination to generate the desired carbon–ni-
Key words SO2F2, aldoxime, nitrile, dehydration, CH3CN, aqueous
methanol
As particularly useful compounds, nitriles are not only
versatile synthetic intermediates for pharmaceuticals, agri-
cultural chemicals, and dyes,1 but also key precursors for
conversion into amides, carboxylic acids, amines, ketones,
and esters.2 Compared with classic strategies for the con-
struction of nitriles,3a–d especially those using highly toxic
cyanides,3e–l dehydration of aldoximes is an advantageous
approach because of the easy availability of aldoximes, the
avoidance of very toxic cyanide ion, and production of wa-
ter as the side product.4–7 Although numerous methods for
the dehydration of aldoximes to give nitriles have been re-
ported, the limitations are still clear. For example, some
methodologies require inconvenient reaction conditions
and redundant work-up,4 the use of special reagents5 or a
plethora of dehydrants,6 suffering from drawbacks of low
functional group tolerance, and difficult product purifica-
tion. Besides, transition-metal-catalyzed routes using Pd,
Ru, Pt, Ni, Cu, and Fe catalysts have also received much at-
tention in recent years,7 but most of them are confronted
with obstacles of large catalyst loadings, high reaction tem-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
Y. Zhao et al.
Letter
Synlett
trogen triple bonds of nitrile 3 (Scheme 1). With our hy-
pothesis, we developed a rapid, simple, and versatile dehy-
dration of aldoximes to nitriles by using SO2F2 and organic
base Et3N in acetonitrile under ambient conditions. Fur-
thermore, an eco-friendly synthetic strategy to access ni-
triles from the corresponding aldehydes with ortho-, meta-
and para-nitrile functionalities could also be carried out in
aqueous methanol by using inorganic alkali Na2CO3.
respect to the aldoxime derivatives, which were quantita-
tively obtained from the corresponding aldehydes 1 with-
out further purification (Scheme 2). To our delight, benzal-
doxime and its derivatives bearing electron-donating
groups such as methyl, methoxyl, and benzyloxy, exhibited
excellent reactivity and gave almost quantitative conver-
sions to the corresponding products (3a–c, 3j, 3r, 3t, and
3u). Similar reactivities were also observed with substrates
bearing electron-withdrawing groups, including halogen,
nitro and trifluoromethyl substituents (3d–h, 3o–q, and
3s). What calls for special attention is that the isolated
yields of the temperature-sensitive arylnitriles (3a, 3b, 3d,
3h, 3w, and 3x) were lower than their GC yields on account
of their low boiling temperature and volatility. Notably,
compared with para- or meta-position substituted arylalde-
hydoximes (3c, 3g, 3o, 3z), the ortho-position functional-
ized substrates required longer reaction time to obtain ex-
cellent yields (3p, 3r, 3aa), because the ortho-position sub-
stituent groups introduces steric hindrance that decelerates
the deoximative transformation. To our delight, substrate
H
SO2F2
N
H
OH
base
– HF
base
OSO2F
R
R
N
– HOSO2F
R
N
2
A
3
Scheme 1 Plausible mechanism for dehydration of aldoximes to nitriles
To validate our hypothesis, we embarked on the dehy-
dration of aldoximes using SO2F2 and base as efficient re-
agents. Initially, 4-chlorobenzaldoxime (2e) was selected as
model substrate to optimize the reaction conditions (Table
1, for details see Supporting Information). To our surprise,
the initial result showed that the desired product 3e was
formed in almost quantitative yield when the reaction was
carried out with 2.0 equiv of 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU), SO2F2 was introduced by bubbling into 2.0 mL
acetonitrile (CH3CN) via a balloon at room temperature for
10 min (entry 1). Encouragingly, other bases such as diiso-
propylethylamine [(i-Pr)2NEt], triethylamine (Et3N), Na2CO3
and K2CO3 were also found to be suitable in following stud-
ies (entries 2–6). Notably, although the weaker alkalinity of
Et3N led to inferior reactivity, increasing reaction time
slightly could also result in nearly quantitative transforma-
tion (entries 3 and 4). It should be pointed out that, because
of their low solubility in CH3CN and alkalescence, very poor
results were obtained when using inorganic bases (entries
5 and 6). We also tried to perform the reaction with less
base, but the product yields decreased significantly with
the loadings of Et3N were reduced (entry 4 vs. entries 7 and
8). Several solvents, such as methanol (CH3OH), ethyl ace-
tate (EtOAc), dimethyl sulfoxide (DMSO) and dioxane were
also screened (entries 9–12). Compared with CH3CN, these
solvents were less effective for this transformation. Further-
more, there was no generation of desired 4-chlorobenzoni-
trile (3e) without the presence of base or SO2F2, respectively
(entries 13 and 14). Subsequently, considering the simpli-
fied purification of intermediates,13 and easy preparation of
aldoximes from the corresponding aldehydes without any
by-product14, a series of continuous conversions, including
oximation of aldehydes and cyanation of aldoximes in a sys-
tem of SO2F2/Et3N/CH3CN, was tested by using 4-chloro-
benzaldehyde (1e) as starting material. It was exciting to
find that the final product 3e was still generated in up to
nearly quantitative yield (entry 15).
Table 1 Optimization of Reaction Conditionsa
N
OH
SO2F2 (balloon)
N
base, solvent, r.t.
Cl
Cl
time
3e
2e
Entry Base (equiv)
Solvent
Time (min) Isolated yield (%)
1
2
DBU (2.0)
(i-Pr)2NEt (2.0)
Et3N (2.0)
Et3N (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
Et3N (1.5)
Et3N (1.0)
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
EtOAc
10
10
10
15
60
60
15
15
30
30
30
15
15
15
30
99
98
3
94
4
99
5
12
6
7
7
33 (34)b
9 (9)b
8
8
9
10
11
12
13
14c
15d
60
DMSO
dioxane
CH3CN
CH3CN
CH3CN
38
65
NRe
NRe
98
Et3N (2.0)
Et3N (2.0)
a Reaction conditions: A mixture of 4-chlorobenzaldoxime 2e (1.0 mmol,
1.0 equiv), base (2.0 mmol, 2.0 equiv), solvent (2.0 mL), and SO2F2 (intro-
duced by bubbling into the solution via a balloon) was stirred at r.t. in a 25
mL Schlenk flask.
b Isolated yield for 30 min in parentheses.
c Without SO2F2.
Having established the optimal reaction conditions, we
further explored the generality of this transformation with
d A series of reactions including oximation and cyanation, see Supporting
Information for details.
e NR = no reaction.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Y. Zhao et al.
Letter
Synlett
bearing a para-COOH group, which is sensitive to alkaline
systems, could also be smoothly transformed into 4-cyano-
benzoic acid as the only product when 3.0 equivalent of
Et3N was used (3m). Remarkably, derivatives bearing oxida-
tion-sensitive groups (methylthio and alkenyl groups) also
reacted efficiently, providing excellent yields of the desired
nitriles without the generation of other side products (3n,
3ab). Moreover, the SO2F2-promoted dehydration also
showed high compatibility with N/O/S-containing hetero-
cyclic functionalities, and the desired heteroaryl nitriles
3u–y were obtained in excellent yields. It is worth high-
lighting that the synthesis of 5-cyanindole 3y containing
SuFex-sensitive functionality was also achieved in 94%
yield. Respectively, cinnamyl nitrile 3ac and 3-phenylpropi-
olonitrile 3ad were also achieved in 95% and 87% yields
from corresponding aldoximes, indicating that the alkenyl
and alkynyl aldoximes were similarly appropriate for this
SO2F2-mediated dehydration process. Besides, the conver-
sion of aliphatic aldoximes into desired nitriles 3ae and 3af
were accomplished in excellent yields by simply extending
the reaction time.
SO2F2 (balloon)
Et3N (2.0 eq.)
N
OH
R
N
R
CH3CN, r.t., 15–30 min
3
2
CN
CN
CN
CN
Me
OMe
F
3a: 80% (99%)a
3b: 84% (99%)a
3c:98%
3d: 81% (99%)a
CN
CN
CN
CN
Cl
3e: 99%
CN
Br
3f:99%
CN
NO2
3g:99%
CN
CF3
3h: 75% (97%)a
CN
Ph
OBn
SO2Me
CO2Me
3i:99%
3j:98%
3k:97%
3l:99%
CN
CN
CN
CN
Subsequently, we were excited to find that the nitro-
benzaldoximes including para-, meta-, and ortho-positions,
could be used to accomplish the dehydration to afford the
corresponding nitrobenzonitriles in quantitative yields
when 1.5 equiv of Na2CO3 was used as the base in aqueous
methanol under SO2F2 atmosphere for 30 min (Scheme 3,
method a). Meanwhile, excitingly, a one-pot process of con-
verting nitrobenzaldehydes into the corresponding nitro-
NO2
NO2
COOH
3m: 78%b,c
CN
SMe
3p: 97%c
3n: 98%
3o: 99%
CN
CN
CN
CN
OMe
Cl
Me
Me
Cl
3q: 95%b
3r: 95%c
3s: 95%c
3t: 98%
N
SO2F2 (balloon)
Na2CO3 (1.5 eq.)
OH
CN
CN
CN
S
CN
O
N
O2N
O2N
method a
N
CH3OH (80% aq.), r.t.
30 min
MeO
OMe
3i, 3p, 3s
2i, 2p, 2s
3i, 4-NO2, 99%
3p, 3-NO2, 99%
3s, 2-NO2, 98%a
OMe
3w: 81% (99%)a
3x: 76% (99%)a
3u: 98%
3v: 96%
CN
CN
CN
CN
NH2OH.HCl (1.1 eq.)
Na2CO3 (2.0 eq.)
N
N
H
O
O2N
method bb
CH3OH (80% aq.), 80 °C, 30 min
O2N
O
3aa: 95%d
then SO2F2 (balloon)
r.t., 30 min
3y: 94%
3ac:95%
3z:95%
3ab:98%
1i, 1p, 1s
3i, 3p, 3s
3i, 4-NO2, 98% (96%)c
3p, 3-NO2, 97%
3s, 2-NO2, 95%b
CN
CN
CN
CN
3ae: 83%d
3af: 85%d
3ad: 87%
Scheme 3 SO2F2-mediated dehydration using Na2CO3 in aqueous
methanol. To a mixture of nitrobenzaldoximes 2 (1.0 mmol, 1.0 equiv),
Na2CO3 (1.5 mmol, 1.5 equiv), CH3OH (2.0 mL), and H2O (0.5 mL), SO2F2
was introduced by bubbling into the solution via a balloon, and the mix-
ture was stirred for 30 min at r.t. in a 25 mL Schlenk flask; isolated yields.
a Isolated yield for 60 min. b A mixture of nitrobenzaldehydes 1 (1.0
mmol, 1.0 equiv), NH2OH.HCl (1.1 mmol, 1.1 equiv), Na2CO3 (2.0 mmol,
2.0 equiv), CH3OH (2.0 mL) and H2O (0.5 mL) was heated at 80 °C for 30
min; after cooling to r.t., SO2F2 was introduced by bubbling into the
solution via a balloon and the mixture was reacted at r.t. for an addition-
al 30 min. c Isolated yield for 10 mmol scale given in parentheses.
Scheme 2 Substrate scope of dehydration of aldoximes. A mixture of
aldoximes 2 (1.0 mmol, 1.0 equiv), Et3N (2.0 mmol, 2.0 equiv), and
CH3CN (2.0 mL) was stirred at r.t. under a SO2F2 atmosphere (a SO2F2
balloon) in a 25 mL Schlenk flask; isolated yields. Aldoximes 2 were gen-
erated from the corresponding aldehydes 1 without further purification. a
GC yields in parentheses. b Using 3.0 mmol of Et3N. c 30 min. d 60 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
Y. Zhao et al.
Letter
Synlett
benzonitriles was also achieved in excellent yields (Scheme
3, method b); this was attributed to the optimized solvent
of aqueous methanol, which was suitable for both oxima-
tion of aldehydes and cyanation of aldoximes (see Support-
ing Information for screening details). Unfortunately, other
aldoximes, such as benzaldoxime (2a), 4-methylbenzalde-
hydoxime (2b), and 4-chlorobenzaldoxime (2e), were al-
most completely unresponsive under these adjusted condi-
tions (see Table S2). Nevertheless, a gram-scale reaction
was carried out with 4-nitrobenzaldehyde 1i as model sub-
strate, and product 3i was formed in excellent yield (96%),
which indicates the practicality of the application this one-
pot strategy in large batch production of nitriles.
In conclusion, we have developed a rapid, simple, mild
and practical process for conversion of aldoximes into ni-
triles promoted by the novel dehydration system of
SO2F2/Et3N/CH3CN.15,16 The reaction proceeded with a range
of aldoximes in excellent to near quantitative yields to af-
ford the corresponding nitriles, demonstrating the great
functional group compatibility and high efficiency of this
protocol. Moreover, the eco-friendly conditions of
SO2F2/Na2CO3/aqueous methanol were suitable for convert-
ing nitrobenzaldoximes into nitrobenzonitriles. In addition,
a one-pot synthetic strategy of obtaining nitrobenzonitriles
from nitrobenzaldehydes has been confirmed to be feasible.
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Funding Information
We acknowledge financial support from the National Natural Science
Foundation of China (no. 20702051), the Natural Science Foundation
of Zhejiang Province (LY13B020017).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611840.
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References and Notes
(1) (a) Smith, M. B.; March, J. Advanced Organic Chemistry: Reac-
tions, Mechanisms and Structure, 6th ed; Wiley Interscience:
Chichester, 2007. (b) Frizler, M.; Lohr, F.; Furtmann, N.; Kläs, J.;
Gütschow, M. J. Med. Chem. 2011, 54, 396. (c) Bagal, D. B.;
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Acc. Chem. Res. 2015, 48, 602. (e) Hu, P.; Chai, J. C.; Duan, Y. L.;
Liu, Z. H.; Cui, G. L.; Chen, L. Q. J. Mater. Chem. A 2016, 4, 10070.
(2) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd ed;
Wiley: New York, 1999. (b) Anbarasan, P.; Schareina, T.; Beller,
M. Chem. Soc. Rev. 2011, 40, 5049.
(3) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633.
(b) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. B. 1919,
52, 1749. (c) Nielsen, M. A.; Nielsen, M. K.; Pittelkow, A. Org.
Process Res. Dev. 2004, 8, 1059. (d) Pradal, A.; Evano, G. Chem.
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Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 10999.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
Y. Zhao et al.
Letter
Synlett
Chem. Commun. 2019, 55, 2845. (l) Zha G. F., Fang W. Y., Leng J.,
Qin H. L.; Adv. Synth. Catal.; 2019, preprint; DOI:
10.1002/adsc.201900104
room temperature for 15 min. After the reaction, the mixture
was diluted with water and extracted with ethyl acetate (3 × 10
mL). The combined organic layers were then washed with brine,
dried over anhydrous Na2SO4 and concentrated to dryness. The
residue was purified by column chromatography on silica gel
(300–400 mesh) with hexane and ethyl acetate to give 4-chloro-
benzonitrile 3e. 1H NMR (500 MHz, CDCl3):  = 7.62 (d, J =
8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
 = 139.6, 133.4, 129.7, 117.9, 110.9.
(11) Almost simultaneously Qin’s team published the results of a
study that demonstrated a one-pot method for converting alde-
hydes into nitriles using 0.55 equiv of NH2OH and 5.0 equiv of
Na2CO3, under SO2F2 atmosphere in DMSO for 12 h, which
exhibits differences from our dehydration conditions, see:
Fang, W.-Y.; Qin, H.-L. J. Org. Chem. 2019, 84, 5803.
(12) (a) Li, Y. S.; Xu, N. Z.; Mei, G. Y.; Zhao, Y.; Zhao, Y. Y.; Lyu, J. H.;
Zhang, G. F.; Ding, C. R. Can. J. Chem. 2018, 96, 810. (b) Zhang, G.
F.; Ma, D. T.; Zhao, Y. Y.; Zhang, G. H.; Mei, G. Y.; Lyu, J. H.; Ding,
C. R.; Shan, S. ChemistryOpen 2018, 7, 885.
(13) (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
Angew. Chem. Int. Ed. 2000, 39, 44. (b) Newhouse, T.; Baran, P. S.;
Hoffmann, R. W. Chem. Soc. Rev. 2009, 38, 3010.
(16) Converting Nitrobenzaldoximes into Nitrobenzonitriles in
Aqueous Methanol; Method a: 4-Nitrobenzaldoxime 2g (166
mg, 1.0 mmol), CH3OH (2.0 mL), H2O (0.5 mL) and Na2CO3 (159
mg, 1.5 mmol) were added into a 25 mL Schlenk flask equipped
with magnetic stirrer and rubber stopper. The SO2F2 gas was
introduced into the stirring reaction mixture by slow bubbling
from a SO2F2 balloon, and the reaction mixture was stirred at
room temperature for 30 min. After the reaction, the mixture
was diluted with water and extracted with ethyl acetate (3 × 10
mL). The combined organic layers were then washed with brine,
dried over anhydrous Na2SO4 and concentrated to dryness. The
residue was purified by column chromatography on silica gel
(300–400 mesh) with hexane and ethyl acetate to give the 4-
nitrobenzonitriles 3g. 1H NMR (500 MHz, CDCl3):  = 8.38 (d, J =
8.9 Hz, 2 H), 7.90 (d, J = 8.9 Hz, 2 H). 13C NMR (125 MHz, CDCl3):
 = 150.1, 133.5, 124.3, 118.4, 116.7.
(14) Li, S. S.; Wu, L.; Qin, L.; Zhu, Y. Q.; Su, F.; Xu, Y. J.; Dong, L. Org.
Lett. 2016, 18, 4214.
(15) Converting Aldoximes into the Corresponding Nitriles in
Acetonitrile; Typical Procedure: 4-Chlorobenzaldoxime 2e
(0.137 g, 1.0 mmol), CH3CN (2.0 mL) and Et3N (278 L, 2.0
mmol) were added into a 25 mL Schlenk flask equipped with
magnetic stirrer and rubber stopper. Then the SO2F2 gas was
introduced into the stirring reaction mixture by slow bubbling
from a SO2F2 balloon, and the reaction mixture was stirred at
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E