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

Article abstract of DOI:10.1016/j.tetlet.2013.05.149

While attempting to synthesize nitriles from aldoximes using O-sulfonate esters of oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate], an unexpected involvement of oxyma cleaved product in promoting the synthesis of nitriles was observed. Such involvement of the oxyma cleaved product in the reaction mechanism, together with the usual anticipated pathway improved drastically the applicability of the method by reducing the time needed for the reaction to be completed over that of the sulfonyl chlorides. Other advantages of the present protocol are excellent yields in ambient and milder conditions.

Full text of DOI:10.1016/j.tetlet.2013.05.149

Tetrahedron Letters 54 (2013) 4397–4400
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
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
⇑
Dharm Dev, Nani Babu Palakurthy, Nitesh Kumar, Bhubaneswar Mandal
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam 781039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
While attempting to synthesize nitriles from aldoximes using O-sulfonate esters of oxyma [ethyl
2-cyano-2-(hydroxyimino)acetate], an unexpected involvement of oxyma cleaved product in promoting
the synthesis of nitriles was observed. Such involvement of the oxyma cleaved product in the reaction
mechanism, together with the usual anticipated pathway improved drastically the applicability of the
method by reducing the time needed for the reaction to be completed over that of the sulfonyl chlorides.
Other advantages of the present protocol are excellent yields in ambient and milder conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 30 March 2013
Revised 28 May 2013
Accepted 31 May 2013
Available online 11 June 2013
Keywords:
Sulfonate esters
Oxyma
Aldoxime
Nitrile
Dehydration
Nitriles are important synthons in organic syntheses as they are
involved in many functional group transformations.1 There are two
essential general methods for their preparation. Firstly, the nucle-
ophilic substitution of alkyl halides/aryl halides with a stoichiom-
etric amount of inorganic cyanide resulting in alkyl/aryl nitriles,
respectively, which is frequently accompanied by the elimination
of hydrogen halides. Especially, alkyl and aromatic nitriles (benzo-
nitriles) can be synthesized by Sandmeyer reaction and ammoxida-
which are expensive and often associated with long heating condi-
tions. Recently, there was a report that describes the same trans-
formation using TsOBt/DBU.17 Though, it works well it is
noteworthy that N-hydroxybenzotriazole is explosive on heating.
In the present context, even though, the sulfonyl chlorides10 were
used for this transformation, longer reaction times were necessary.
We wish to report herein a new method for the said transformation
where aryl sulfonate esters of oxyma are used. A mechanistic
investigation is also performed. The increased reactivity of the oxy-
ma-O-sulfonates can be attributed to the unexpected involvement
of the oxyma-cleaved product and thereby enabling the reaction to
be completed much faster than its previous analogues. This is the
first report of such involvement of the oxyma-cleaved product in
the reaction mechanism.
In continuation of our work on the promotion of activated sul-
fonate esters as reagents for various organic transformations,18 we
want to enunciate the synthesis of nitriles from aldoximes using
sulfonate esters of oxyma which could be easily prepared from
the corresponding sulfonyl chloride and oxyma in the presence
of DIPEA (Scheme 1).19 In order to verify the applicability of the
sulfonate esters of oxyma in nitrile synthesis, we have prepared
2,6-dichlorobenzaldoxime from 2,6-dichlorobenzaldehyde and
hydroxyl amine hydrochloride and set our objective to synthesize
nitriles from respective aldoximes. We took 1 mmol of 2,6-dic-
hlorobenzaldoxime and 1 mmol of sulfonate ester of oxyma in
the presence of 3 equiv of triethyl amine in dichloromethane.
Interestingly, the reaction was completed within 1 h and furnished
tion. Although
a,b-unsaturated nitriles can be synthesized by
Wittig reaction of the corresponding aldehydes with cyanoalkyl
phosphate, the method often produces a mixture of E- and Z-iso-
meric nitriles.2 The second one involves the conversion of an alde-
hyde into oximes and dehydration of the latter into nitrile. The
dehydration of aldoximes, which are easily prepared from the cor-
responding aldehydes, is a candidate for clean nitrile synthesis.
Various procedures have been reported using reactive species like
N-chlorosuccinimide/PPh3,3 thionyl chloride-benzotriazole,4 N-(p-
toluenesulfonyl) imidazole (TsIm),5 Vilsmeier reagent,6 Burgess re-
agent,7 cyanuric chloride,8 S,S-dimethyl dithiocarbonate,9 sulfonyl
chlorides,10 and triflyl imidazole11. Apart from these, several tran-
sition metal catalysts such as [RuCl2(p-cymene)]2/molecular
sieves,12 rhenium(VII)oxo complexes,13 InCl3,14 TiCl3(OTf),15 and
Cu salts,16 have been used to carry out the same transformation
⇑
Corresponding author.
E-mail address: bmandal@iitg.ernet.in (B. Mandal).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.149

4398
D. Dev et al. / Tetrahedron Letters 54 (2013) 4397–4400
O
to the substrate should be 1:2.5 so that the reaction gets completed
within 10 min. Solvent screening experiments revealed that CH2Cl2
was the best solvent for this transformation (see Table S3 in
O
O
O
CN
O
O
S
CN
OH
DCM
O
Cl
O
S
O
+
DIPEA, N2
N
N
R1
R2
0°C-rt.
II
IIIa-d
Ia-d
Table 1
R2
R1
Synthesis of nitriles from aldoximes
(a) R1 = CH3 , R2 = H; b) R1 = NO2 , R2 = H,
(c) R1 = H , R2 = NO2; d) R1 = NO2 , R2 = NO2
IIIc
OH
R
N
Scheme 1. Synthesis of the sulfonate esters of oxyma.
N
R
DBU, DCM, rt, N2
R = aromatic, aliphatic
the product in very good yield. Inspired by this result, we went on
to standardize the reaction.
Entrya
1
Substrate
Productb
Yieldc
93
Having the proof of principle for the synthesis of nitriles from
aldoximes using the new reagents, we wanted to examine the po-
tential of the activated sulfonate esters. Out of all the sulfonate es-
ters that we have synthesized (IIIa–d), it was found that IIIa have
modest reactivity and took a little longer time. However the inser-
tion of the electron withdrawing group at the aromatic ring has
dramatically changed the reactivity and promoted the reaction
within 10 min (IIIb–d). The noteworthy point is that the reaction
with all these activated esters is so fast (10 min) that it was diffi-
cult to distinguish their reactivity for this transformation in pro-
moting the reaction and yielding the product. However, we
proceeded further to carry out this transformation using 2-NO2-
C6H4-SO3XY (IIIc, Fig. 1).
To determine the suitable base for this transformation, several
bases were tried over the same substrate as shown in Scheme 2.
It was observed that in the presence of a tertiary amine base the
reaction went to completion smoothly and furnished the product
in very good yield in all the cases except with 2,4,6-collidine and
2,3,5-collidine (see Table S1 in Supplementary data). DBU and
DABCO took very less time. Therefore, we decided to proceed fur-
ther with DBU. It is important to note that the formation of the
product in the absence of any base was not observed within
10 min. as it was found with DBU. Next, we envisaged the stoichi-
ometry of the base using different equivalents of DBU. We noted
that 2.5 equiv were compulsory for completion of the reaction.
The conversion was not complete with lesser amount of base and
resulted in the desired product in reduced yield (see Table S2 in
Supplementary data). However, the unreacted starting material
could be recovered. From this, it was clear that the ratio of the base
N
OH
CN
Cl
Cl
Cl
Cl
N
CN
Cl
2
94
OH
Cl
N
OH
CN
3
4
5
92
82
87
Br
Br
N
OH
CN
H3C
O
H3C
O
O
N
CN
O
OH
H3C
O
CH3
H3C
HO
CH3
O
N
CN
OH
6
7
79
89
HO
O
O
Et
Et
CN
N
OH
OH
OH
N
OH
CN
8
9
89
87
O2N
O2N
N
OH
CN
O2N
H3C
NO2
O2N
H3C
NO2
N
OH
CN
10
11
78
86
N
N
CH3
CH3
N
OH
OH
CN
12
13
85
83
N
N
OH
N
CN
N
O2N
O2N
CN
OH
S
S
CN
N
N
OH
OH
14
15
79
81
CN
OH
OH
OH
( )
CN
( )
N
N
16
17
6
82
76
7
CN
Figure 1. X-ray crystallographic structure of IIIc (ORTEP diagram with ellipsoid of
50% probability, CCDC No. 903881).
N
CN
OH
OH
18
19
74
78
CN
Cl
Cl
N
OH
C
N
N
IIIc
a
b
c
Cl
All the reactions were performed in 1 mmol scale.
Base, Solvent
Cl
All the products were characterized with 1H NMR, 13C NMR, IR, and GC–MS.
Yields were referred to the isolated yields after column chromatography.
Scheme 2. Synthesis of nitriles from aldoximes.

D. Dev et al. / Tetrahedron Letters 54 (2013) 4397–4400
4399
Supplementary data). In methanol there was a side product corre-
sponding to the competitive reaction for the formation of the sul-
fonate ester of methanol.
The current methodology is applicable to a wide veriety of sub-
strates (Table 1) and tolerates a wide variety of functional groups,
for example NO2, MeO–, EtO– etc. Under optimized conditions, all
the substrates went to completion within 10 min and yielded the
product in very good yield. There was no influence of electron
donating groups, for example MeO–, EtO–, Br, Cl etc. or electron
withdrawing groups, for example NO2 on the yield and dynamics
of the reaction.
The complicated substrates that included the conjugated aldox-
ime (entries 11, 13, and 14) underwent the reaction to furnish the
product in reasonably good yields. The important advantage of this
protocol is that (entry 11) the stereochemistry is retained, that is E
isomer of the aldehyde gave the E isomer of the corresponding ni-
trile unlike the Wittig reaction which gives a mixture of E and Z
isomers. This reaction works well for aliphatic systems as well (en-
tries 16–19). All the products have been characterized with 1H
NMR, 13C NMR, IR, and GC–MS.20 Out of all these, the product of en-
try 2 was characterized with single crystal XRD also (Fig. 2).
Figure 2. X-ray crystallographic structure of the product of entry 2 in Table 1
(ORTEP diagram with ellipsoid of 50% probability, CCDC No. 905250).
To investigate the mechanism of the reaction, we took 4-CH3–
C6H4–SO3XY (IIIa) as reagent and TEA as base to slow down the
reaction. Premature quenching (at 30 min) of the reaction, where
:DBU
O
O
S
Path A:
O
S
H
N
O
O
O
O
O
N
O
O
(A)
R
O-
O
R
H
N
S
R
C
N
N
O
O
C
N
O
CN
S
O
O
H
:DBU
O
R
N
R
H
N
Path B:
-CO2
O
O
R
O
-EtOH
O
O
O
O
S
O
O
N
S
O
N
:DBU
O
O
O
CN
O
CN
H
O
O
O
O
O
H
N
S
:DBU
R
N
R
N
N
C C N
O
O
(B)
Scheme 3. Two probable pathways for the formation of nitriles by dehydration of aldoximes.
Figure 3. X-ray crystallographic structure of (a) (E)-4-chlorobenzaldehyde-O-ethoxycarbonyloxime and (b) acetophenone-O-ethoxycarbonyloxime (ORTEP diagram with
ellipsoid of 50% probability, CCDC No. 918220 and 918221, respectively).

4400
D. Dev et al. / Tetrahedron Letters 54 (2013) 4397–4400
4-chlorobenzaldoxime was used as substrate, resulted in two new
spots in TLC, which were finally characterized as the intermediates
(E)-4-chlorobenzaldehyde-O-tosyloxime and (E)-4-chlorobenzal-
dehyde-O-ethoxycarbonyloxime (A and B in Scheme 3, respec-
tively). Existence of these two intermediates in the reaction
mixture indicates that the reaction may proceed following both
of the probable mechanisms as depicted in Scheme 3 as the path
A and the path B.
mechanism. This method has several advantages over the existing
methods as, (a) it precludes the usage of the expensive reagents
and toxic metals, (b) reaction times have been shortened, (c) the
reactions were carried out at lower temperatures (room tempera-
ture), etc. Therefore, the current methodology finds large applica-
tions in the synthesis of natural products where the tolerance of
a good number of other functional groups is in force.
In path A, base deprotonates the aldoxime to generate a nucle-
ophile which attacks the electrophilic centre over sulfur of the re-
agent IIIa and forms sulfonate ester of aldoxime as intermediate A.
Finally, second equiv of the base deprotonates the carbon of the
imine, thereby expels the –OSO2Ar group which is a good leaving
group and results in the generation of the nitrile along with oxyma
(by-product). We computed the charge distribution by Mulliken
analysis for compound IIIa at B3LYP/6-31G(D,P) level of theory21
and found that partial positive charge over the carbonyl carbon
(0.59) of compound IIIa is much less than that over the sulfur cen-
ter (1.29). Therefore, the path A is the logically anticipated route of
the reaction.
Acknowledgments
We thank the CIF-IITG for NMR, LC–MS; DST (FIST) for single
crystal XRD facility and the Department of Science & Technology,
India (FAST TRACK scheme, sanction no. SR/FT/CS-011/2008) for
financial support. D.D. and N.B.P. thank IIT-Guwahati for fellow-
ship. We also thank Mr. Harikrishna Sahu and Dr. Aditya Narayan
Panda for computational calculations. We also thank the reviewers
for their constructive suggestions.
Supplementary data
In path B, base deprotonates the aldoxime to generate a nucle-
ophile, which attacks the electrophilic centre over carbonyl carbon
of the reagent IIIa to produce O-ethoxycarbonyl aldoxime as inter-
mediate B along with the corresponding sulfonic acid. The second
equiv of the base deprotonates the carbon of the imine and gener-
ates nitrile. Such participation of the oxyma derived product in the
reaction mechanism has not been described before. The intermedi-
ates A and B were purified and characterized by 1H NMR, mass, and
FT-IR (see Supplementary data for experimental details, character-
ization data and copies of the spectra). The intermediate B was fur-
ther analyzed by single crystal XRD (Fig. 3a). However, the
possibility of generation of the product by intramolecular hydro-
gen abstraction from both of the intermediates (A and B) as shown
in Scheme 3 cannot be ruled out, but that should be predominant
in high dilution and high temperature condition such as in gas
phase reactions as it is reported for intermediate A.22
In order to precisely predict the ability of DBU whether it is
capable of deprotonating the ethylenic proton we have synthesized
the authentic intermediates A and B with complete characteriza-
tion and finally subjected to the reaction in the presence and in
the absence of 1 equiv of DBU. Interestingly, it was found that
the reaction completed in the presence of DBU in 10 min, whereas
it did not progress in the absence of DBU (checked until 12 h).
Therefore, it can be concluded that the intramolecular H-abstrac-
tion did not occur.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.149.
References and notes
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Furthermore, to support the mechanism, the reaction was re-
peated using a ketoxime as substrate and corresponding products
to the intermediates A and B were expected. However, O-eth-
oxycarbonylketoxime (Fig. 3b) was obtained as sole product with
very good yield. This indicates that in case of the ketoxime, either
the reaction follows only path B or the first step of path A is revers-
ible. No oxyma could be recovered when ketoxime was used,
which proves the complete involvement of oxyma cleaved product,
whereas, approximately 50% of oxyma could be recovered when
aldoxime was used as the substrate which proves that some of
the cleaved product of the oxyma is involved in the promotion of
the reaction in yielding the desired nitrile quickly and with better
yield than its counterpart, that is sulfonyl chlorides.10
In conclusion, we have demonstrated a newer method for the
synthesis of nitriles from aldoximes under milder conditions using
sulfonate esters of oxyma. The unusual involvement of oxyma in
promoting the reaction was established with single crystal X-ray
structure, which actually promotes the reaction in much shorter
times compared to that of the sulfonyl chlorides. This is the first re-
port of the involvement of an oxyma derived product in the
15. Iranpoor, N.; Zeynizadeh, B. Synth. Commun. 1999, 29, 2747–2752.
16. Attanasi, O.; Palma, P.; Serra-Zanetti, F. Synthesis 1983, 741–742.
17. Singh, M. K.; Lakshman, M. K. J. Org. Chem. 2009, 74, 3079–3084.
18. Palakurthy, N. B.; Mandal, B. Tetrahedron. Lett. 2011, 52, 7132–7134.
19. (a) Khattab, S. Chem. Pharm. Bull. 2010, 58, 501–506; (b) Palakurthy, N. B.; Dev,
D.; Rana, S.; Nadimpally, K. C.; Mandal, B. Eur. J. Org. Chem. 2013, 2627–2633.
20. Representative procedure for nitrile synthesis: In an oven-dried two-necked
50 mL round-bottomed flask, equipped with a stirring bar, a solution of the
oxime (1.0 mmol) and 2-NO2-C6H4-SO3XY (1.5 mmol) dissolved in anhydrous
CH2Cl2 (5.0 mL) was placed under the atmosphere of nitrogen. The reaction
mixture was stirred at room temperature for 5 min, then DBU (2.5 mmol) was
added drop wise over 2 min. The reaction mixture became
a clear
homogeneous solution after addition of DBU. The reaction was monitored by
TLC. The reaction mixture was diluted with EtOAc and washed with water
(2 Â 5 mL) followed by brine (2 Â 5 mL) upon complete consumption of the
starting material. Product was purified by column chromatography.
2,6-Dichlorobenzonitrile (Table 1, entry 2): Yield (160 mg, 94%), white powder;
Rf = 0.5 (EtOAc/hexane, 0.5:9.5); mp: 142–143 °C; 1H NMR (400 MHz, CDCl3) d
(ppm): 7.48–7.38 (m, 3H, 3Â ArH); 13C NMR (100 MHz, CDCl3): d (ppm) 138.51,
134.13, 128.32, 114.38, 113.46; IR (cmÀ1): 3092.23, 2928.14, 2232.43, 1572.11,
1558.54, 1432.13, 1199.25, 1098.12, 802.43, 784.12, 713.65; GC–MS (m/
z) = 171 [M+, calcd for C7H3Cl2N]; obs: 173, 172, 171, 136, 100, 99, 86, 75, 50.
21. Neese, F.; ORCA, version 2.9, An ab initio, DFT and semiempirical SCF-MO
package; Max-Planck Institute for Bioinorganic Chemistry, Mülheim a. d. Ruhr,
Germany, 2010.
22. Ying, X.; Kyung, A. L.; Chan, K. K. Bull. Korean Chem. Soc. 2003, 24, 853–858.