Volume 54, Issue 33, 14 August 2013, Pages 4397–4400

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


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.


  • 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 nucleophilic substitution of alkyl halides/aryl halides with a stoichiometric 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 (benzonitriles) can be synthesized by Sandmeyer reaction and ammoxidation. Although α,β-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-isomeric nitriles. 2 The second one involves the conversion of an aldehyde into oximes and dehydration of the latter into nitrile. The dehydration of aldoximes, which are easily prepared from the corresponding aldehydes, is a candidate for clean nitrile synthesis. Various procedures have been reported using reactive species like N-chlorosuccinimide/PPh3, 3 thionyl chloride-benzotriazole, 4N-(p-toluenesulfonyl) imidazole (TsIm), 5 Vilsmeier reagent, 6 Burgess reagent, 7 cyanuric chloride, 8S,S-dimethyl dithiocarbonate, 9 sulfonyl chlorides, 10 and triflyl imidazole 11. Apart from these, several transition 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 which are expensive and often associated with long heating conditions. Recently, there was a report that describes the same transformation 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 chlorides 10 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 oxyma-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 sulfonate 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-dichlorobenzaldoxime 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 the product in very good yield. Inspired by this result, we went on to standardize the reaction.

Full-size image (10 K)
Scheme 1. 

Synthesis of the sulfonate esters of oxyma.

Having the proof of principle for the synthesis of nitriles from aldoximes using the new reagents, we wanted to examine the potential of the activated sulfonate esters. Out of all the sulfonate esters that we have synthesized (IIIad), it was found that IIIa have modest reactivity and took a little longer time. However the insertion of the electron withdrawing group at the aromatic ring has dramatically changed the reactivity and promoted the reaction within 10 min (IIIbd). The noteworthy point is that the reaction with all these activated esters is so fast (10 min) that it was difficult to distinguish their reactivity for this transformation in promoting the reaction and yielding the product. However, we proceeded further to carry out this transformation using 2-NO2-C6H4-SO3XY (IIIc, Fig. 1).

Full-size image (32 K)
Figure 1. 

X-ray crystallographic structure of IIIc (ORTEP diagram with ellipsoid of 50% probability, CCDC No. 903881).

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 further 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 stoichiometry 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 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 Supplementary data). In methanol there was a side product corresponding to the competitive reaction for the formation of the sulfonate ester of methanol.

Full-size image (3 K)
Scheme 2. 

Synthesis of nitriles from aldoximes.

The current methodology is applicable to a wide veriety of substrates (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.

Table 1.

Synthesis of nitriles from aldoximes

Full-size image (28 K)
Scheme 3. 

Two probable pathways for the formation of nitriles by dehydration of aldoximes.

In path A, base deprotonates the aldoxime to generate a nucleophile which attacks the electrophilic centre over sulfur of the reagent 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 center (1.29). Therefore, the path A is the logically anticipated route of the reaction.

In path B, base deprotonates the aldoxime to generate a nucleophile, which attacks the electrophilic centre over carbonyl carbon of the reagent IIIa to produce O-ethoxycarbonyl aldoxime as intermediate B along with the corresponding sulfonic acid. The second equiv of the base deprotonates the carbon of the imine and generates nitrile. Such participation of the oxyma derived product in the reaction mechanism has not been described before. The intermediates A and B were purified and characterized by 1H NMR, mass, and FT-IR (see Supplementary data for experimental details, characterization data and copies of the spectra). The intermediate B was further analyzed by single crystal XRD ( Fig. 3a). However, the possibility of generation of the product by intramolecular hydrogen 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

Full-size image (34 K)
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).

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 characterization 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-abstraction did not occur.

Furthermore, to support the mechanism, the reaction was repeated using a ketoxime as substrate and corresponding products to the intermediates A and B were expected. However, O-ethoxycarbonylketoxime ( 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 reversible. 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 report of the involvement of an oxyma derived product in the 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 temperature), etc. Therefore, the current methodology finds large applications in the synthesis of natural products where the tolerance of a good number of other functional groups is in force.


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 fellowship. 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

References and notes

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    • 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 × 5 mL) followed by brine (2 × 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) δ (ppm): 7.48–7.38 (m, 3H, 3× ArH); 13C NMR (100 MHz, CDCl3): δ (ppm) 138.51, 134.13, 128.32, 114.38, 113.46; IR (cm−1): 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.

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Corresponding author.

All the reactions were performed in 1 mmol scale.


All the products were characterized with 1H NMR, 13C NMR, IR, and GC–MS.


Yields were referred to the isolated yields after column chromatography.

Full-size table

The complicated substrates that included the conjugated aldoxime (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 nitrile unlike the Wittig reaction which gives a mixture of E and Z isomers. This reaction works well for aliphatic systems as well (entries 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 entry 2 was characterized with single crystal XRD also (Fig. 2).

Full-size image (14 K)
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 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-chlorobenzaldehyde-O-ethoxycarbonyloxime (A and B in Scheme 3, respectively). 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.