Addition-elimination reactions of 2,2-disubstituted malononitriles and  -aryl nitriles . Subsequent transformations

This review focuses on addition-eliminations on the cyano group of 2,2-disubstituted malononitriles and  -aryl nitriles. Mechanistic insights and applications are provided. This mechanism operates in cyanations of organometallics and in various decyanations. Further reactions of the expelled anion offer new perspectives in organic synthesis.


Introduction
Nitriles are important intermediates in organic synthesis, precursors of a large variety of other functional groups such as ketones, amides, carbamidines and different carbocyclic or heterocyclic compounds. [1][2][3][4] Many reviews illustrate the versatility of these building blocks. [5][6][7][8][9][10][11] On the other hand, the preparation of nitriles remains an attractive challenge. In recent years, efforts have been focused on safe cyanide sources and cyanating agents. 12 One of the strategies consists of electrophilic cyanation with reagents acting as formal "CN + " cation donors ( Figure 1). [12][13][14][15][16]  A plausible mechanism for such cyanation involves a nucleophilic addition to the nitrile group followed by an elimination (fragmentation) involving a carbon-heteroatom bond breaking. [17][18][19][20][21] If the expelled carbanion is stabilized, such a pathway can be applied to nitriles (Scheme 1). The nucleophile R 2 M adds to the cyano group to give a metal imine adduct A, precursor of a carbonyl product in the classical way (path a). Alternatively, A can fragment into the cyanation product B and the stabilized leaving group C. While the strong C-CN bond usually needs activation to be cleaved, 9 this reaction proceeds under transition metal-free conditions. When C is protonated, the decyanation product is obtained (path b). Under aprotic conditions, the nucleophile The addition-elimination pathway proposed is outlined in Scheme 4 in the case of PhMgBr (6). After the addition step, part of the imine adduct 7 was transformed into ketone 8 by quenching the reaction mixture after 30 minutes. The elimination step (retro-Thorpe fragmentation) 38 furnishes benzonitrile 9 (transnitrilation from 1a to 6) and isobutyronitrile anion 10a (decyanation-metalation of 1a). Infrared monitoring of the Page 5 of 23 © AUTHOR(S) reaction confirmed the formation of 7, 9 and 10a. The structure of 10a was proposed according to the IR assignments and comparison with an authentic sample prepared from i-PrMgBr and isobutyronitrile. [39][40] Interestingly, "small amounts" of 8 were detected "even after extended reaction times" in agreement with a reversible step. However, the fragmentation is favored due to stabilization of the expelled anion, relief of steric strain and increased entropy. DFT calculations supported an energetically favorable fragmentation.

Scheme 4.
Addition-elimination mechanism for the reaction of phenylmagnesium bromide 6 with 1a.

Transnitrilation-SNAr reaction
Starting from 4-fluorophenylmagnesium bromide 11 and disubstituted malononitriles 1, a tandem transnitrilation-SNAr reaction takes place to give the 1,4-dicarbofunctionalized product 13. 41 The scope of the reaction was first examined by varying the structure of disubstituted malononitriles 1 and, therefore, the nature of the anionic leaving group 10 acting as nucleophile in the SNAr reaction (Scheme 5). The reaction can be achieved with cyclic malononitriles (13b), and malononitriles substituted with benzyl (13c) or allyl (13d) groups.
The scope of the 4-fluoroaryl organometallic reagents was then investigated (Scheme 6). Reagents were prepared in situ from halogen/magnesium (conditions A, 13e-13g) or lithium (conditions B for electron-rich aryl bromides, 13h) exchange reactions. 37 Fair to very good yields are obtained. The presence of a methyl group ortho to the fluorine was tolerated (13e) but two neighboring methyl groups preclude the SNAr reaction, and the sequence failed for o-fluoro and m-fluoro Grignard reagents. Rousseaux and co-workers used a similar strategy for the preparation of -(hetero)aryl nitriles 15. 42 The novelty of this work is that the expelled anion 10 reacts with an activated (hetero)aryl halide electrophile. After evaluation of reaction conditions, the decyanation-metalation of 1 was induced with MeMgBr in THF with LiCl to increase the solubility of the resulting anionic intermediate 10 (transnitrilation of MeMgBr). The latter was then reacted in a mixture of DMSO and THF with various electrophiles (Scheme 7). This one-pot method seems to be efficient with a large number of electrophiles and malononitriles 1. Many heterocycles (15a, 15b, 15e-15h) and functional groups (15c, 15e-15g) are compatible. This sequence is applicable to alkyl iodides as electrophiles (15d) and dialkyl malononitriles (15g, 15h).

The transnitrilation-deprotonation strategy: synthesis of disubstituted malononitriles
The strategy outlined in this section corresponds to path (d) in Scheme 1 and has been investigated by Rousseaux and Mills. 43 A primary nitrile 16 is deprotonated with a base and led to an addition-elimination process with DMMN or DBMN (dibenzylmalononitrile). Fragmentation of the metal imine intermediate 17 generates the -anion 19. The latter deprotonates the dinitrile 18 to produce the more stable carbanion 20, which can be trapped with an electrophile (Scheme 8). Primary benzylic nitriles 16 were used including electron-rich (21f), electron-deficient (21e) and heterocyclic (21g) derivatives. If the mixture was quenched after reaction with 1a, the monosubstituted malononitrile 21a was isolated. The reaction with electrophiles was successful for various primary alkyl halides (21b-21g). The SNAr reaction was possible using the activated pentafluorobenzonitrile (21h). This method was applicable from primary alkyl nitriles using LDA as a base instead of MeMgBr (2 examples: 85% and 98%). The conversion of benzyl bromide into disubstituted malononitriles was also feasible via formation of the Grignard reagent, double transnitrilation with DBMN and electrophile trapping (3 examples 60% -81%).

Scheme 9.
One-pot transnitrilation, deprotonation and electrophile trapping: scope of the reaction. a With DBMN 1b instead of DMMN 1a. E + is shown in brackets.

The Ni-catalyzed cross coupling reaction
Rousseaux and co-workers developed a Ni-catalyst for cross coupling of the generated nucleophile with aryl iodides. 44 A screening of benzonitrile-containing ligands led them to design the optimal bidentate ligand L. The -anion 19 resulting from the addition-elimination process was previously prepared in THF and added to a mixture of L, NiCl2(dme) and aryl iodide (Ar 2 I) in PhMe/THF (Scheme 10). The reaction was successfully performed with electron-rich aryl iodides (22a-22c, 22g, 22h) and (hetero)aryl iodides (22d, 22e). Electronneutral (22f) and especially electron-deficient aryl iodides (<5% yield) gave lower yields due to formation of a larger amount of the reduced product Ar 2 H. Regarding the malononitrile, the method is convenient with electron-deficient (22b, 22e, 22g, 22h) and electron-neutral (22c) aryl substituents. The substitution of 1 with some other alkyl substituents R instead of a methyl group is also described (22g, 22h). However, -anions resulting from electron-rich malononitriles gave only poor conversions in the coupling step. A set of experiments including a kinetic study and a Hammett analysis allowed to suggest a catalytic cycle and clarify the role of L.

Preparation of -cyano carboxamides by reductive cyanation
Dong and co-workers developed a route to -cyano carbonyls bearing a quaternary carbon center by using an organozinc reagent as nucleophile in the addition-elimination process. 45 An -bromo compound was reacted with zinc dust and NCTs or MPMN (1c, methylphenylmalononitrile) as cyanating reagents. Starting from bromo ketones and esters, NCTs was the more reactive reagent, while for the reductive cyanation of -bromo carboxamides 23, both reagents displayed a similar reactivity. Scheme 11 shows the reaction scope of synthesis of carboxamides 24 using MPMN 1c as cyanating reagent. -Cyano N-aryl and N-alkyl isobutyramides (24a-24g) are prepared usually in high yields as well as cyclobutanecarboxamide 24h. Many functional groups are tolerated (24b-24f, 24i) and the method can be applied to the cyanation of -bromo-lactams (24i). DFT calculations supported the addition-elimination pathway and were in agreement with reactivity of cyanating reagents.
In an additional work, the authors introduced, after the transnitrilation step, electrophiles for the reaction with the expelled anionic leaving group. Thus, they formed, in a one pot manner, another type of nitriles bearing a quaternary center (Scheme 12). 46 The benzoyl group was successfully introduced from benzoyl chloride or benzoic anhydride (25a) and substitution reactions with various alkyl halides gave the expected nitriles 25b-25d. The reaction with phenyl disulfide led to the hindered sulfide 25e in a very good yield, while the fluorination can be performed with Selectfluor (25f). This sequence was also applied to other disubstituted malononitriles (8 examples, 60% -90%) and allyl bromides were used as both precursors of the organozinc reagent and electrophiles, usually in fair yields (4 examples, 41% -63%). Scheme 12. One-pot reductive cyanation of -bromo carboxamide 23a and electrophile trapping. E + is shown in brackets.

Decyanation of disubstituted malononitriles promoted by NaHMDS
Tanino et al. have developed a procedure for the decyanation of disubstituted malononitriles without reducing agents (Scheme 13). 47 When they attempted to induce the decyanation of 26a in an additionelimination process using n-BuLi, they observed side reactions involving the anionic leaving group. They solved this drawback by using NaHMDS (sodium bis(trimethylsilyl)amide) as a nucleophile. In this case, the trimethylsilyl nitrile 27a is formed and treated with methanol to yield the decyanation product 28a. After the addition-elimination process, the leaving group 30a is rapidly silylated with bis(trimethylsilyl)cyanamide 31 to give 27a and the less reactive anion 32 thus avoiding side reactions. This method appears convenient for cyclic (28a, 28b) and acyclic (28c, 28d) malononitriles.

Scheme 13.
Mechanism and examples of decyanation of disubstituted malononitiles with NaHMDS. The reaction time before treatment with MeOH is shown in brackets. a Reaction in a mixture Et2O/toluene, -78 °Crt, 3 h.

Reaction with organolithiums: the transnitrilation-deprotonation strategy from -aryl nitriles
The reductive decyanation of -diaryl substituted nitriles induced by Grignard reagents was particularly described in the 1950s. [48][49][50][51] Later, Kulp and Romanelli observed similar decyanation reactions with organolithium nucleophiles. 52 Rousseaux and co-workers investigated a strategy comparable to section 2.3 to obtain nitriles containing quaternary centers (Scheme 14). After the addition-elimination process involving 33 and 34a, the tertiary organolithium leaving group 37 acts as a base for deprotonation of 36 in an "equilibrium driven transnitrilation and anion-relay strategy". 53 The basicity of 37 appears essential to drive the equilibrium towards the transnitrilated organolithium intermediate 38, which can react with various electrophiles E + .
Before the evaluation of the scope of the reaction, the authors examined the transnitrilation of s-BuLi 33a with several electrophilic "CN + " sources (namely structure of the leaving group 37) and trapping with benzyl bromide. They found that 2-methyl-2-phenylpropanenitrile 34a was the reagent of choice. Then, they optimized the reaction conditions for the imine fragmentation by deprotonation of imine 40, prepared by the reaction between s-BuLi 33a and 34a. Key results are given in Table 1. When the nitrogen atom is bound to Li, the fragmentation is favored in THF compared to Et2O (Entries 1-2). The dissociative power and Lewis base strenght of THF compared to Et2O could favor the fragmentation by complexation with the lithium cation. A similar solvent effect was observed for the decyanation reaction induced by LiAlH4 (see . When the nitrogen atom is bonded to MgBr, the metal imine intermediate does not undergo fragmentation (Entry 3). 22 This trend could be related to the higher electronegativity of the MgBr group compared to Li. 54  The authors explored the reaction of s-BuLi 33a with 34a in THF. Alkyl halides (39a), carbonyl-based compounds (39b, 39c), aromatic halides (39d) and phenyl disulfide (39e) appeared as efficient electrophiles for trapping (Scheme 15).

Scheme 15.
Reaction scope of the one-pot transnitrilation and anion-relay functionalization of s-BuLi 33a. E + is shown in brackets.
The authors examined the reaction scope by varying the alkyllithium reagents 33 prepared by a lithiumhalogen exchange from alkyl iodides 41. This procedure needs a solvent switch to THF to trigger the fragmentation, and therefore, the anion-relay process (Scheme 16). This method was convenient starting from secondary and primary alkyl lithium reagents to respectively yield nitriles bearing quaternary (39f, 39g) and tertiary centers (39h).

Scheme 16. Reaction scope of one-pot transnitrilation and anion-relay functionalization of alkyllithiums. E + is shown in brackets.
-Aryl nitriles 39 can be prepared using the carbolithiation of styrene with alkyllithiums to get the starting -aryllithium reagent 33 (3 examples, 69% -83%). Another protocol involves the deprotonation of toluene derivatives with the superbase t-BuOK/t-BuLi in THF; switch to THF was not necessary in this case (5 examples, 46% -77%).

Tandem addition-rearrangement under aryne forming conditions
The addition of -lithiated arylacetonitriles to arynes, followed by a tandem addition-rearrangement pathway provides an access to ortho-cyanated diarylmethanes. [56][57][58][59][60] Cao and co-workers have investigated the reaction of haloarenes with arylacetonitriles in the presence of LDA. 61 Scheme 17 focuses on the reaction between fluorobenzene 42 and arylacetonitriles 43 under the optimized conditions. The reaction was successful both with electron-donating (44b) and withdrawing (44c) groups in the aromatic ring of arylacetonitriles as well as with a more hindered substrate (44d). The reaction was extended to chloro and bromoarenes. When the initial halobenzene was substituted, regioisomers were usually obtained.

Addition-elimination on a bis(allyl)nitrile
Although not related to -aryl nitriles, this section describes the comparable bis(allyl)nitrile framework. Tanino et al. have investigated the total synthesis of the 6,11-epoxyisodaucane natural sesquiterpene 57, an essential oil extracted from the Tritomaria polita liverwort (Scheme 19). 62 This synthesis starts from methyl geranate 50 and pent-4-enenitrile 51 and uses an anionic 8 electrocyclic reaction for the construction of the sevenmembered ring. After the three first steps, the oxidation of cyclic nitrile 52 with m-CPBA leads to the epoxynitrile 53. Treatment of crude 53 with n-BuLi triggers the addition-elimination process with formation of the stabilized bis-allylic carbanion 54 and release of n-BuCN. Interestingly, n-BuCN was isolated among other reaction products. The epoxide group then is opened by an intramolecular attack to give alkoxide 55. A onepot desilylation with tetrabutylammonium fluoride (TBAF) in acetic acid gives the keto alcohol 56 in 36% yield (from 52, 2 steps). The desired 6,11-epoxyisodaucane 57 was obtained in 5 steps from 56. This study allows the correction of the initial stereochemistry assigned to the natural product 57.

Decyanations with metal hydrides
In 1978, Black and Doyle found that the LiAlH4 reduction in Et2O of 9-allylfluorene-9-carbonitrile (34b) and 2,2,4-triphenylpent-3-enenitrile (34c) yielded predominantly the decyanation product together with the expected primary amine. 63 In contrast, no decyanation was observed starting from 2,2-diphenylpent-4enenitrile 34d and related compounds. [64][65][66] They concluded that decyanation was observed with nitriles leading to the more stabilized carbanions in an addition-elimination process. They proposed that the initial hydride addition was "followed by elimination of a hydrogen cyanide complex and formation of a highly stabilized carbanion". Later, Chanon's group investigated the LiAlH4 reduction of 2,2-diphenylpropionitrile 34e, they observed decyanation in THF but not in Et2O. 67 The use of LiAlD4 led to quantitative deuterium incorporation while a basic and polar solvent such as HMPA favors the decyanation pathway. The authors proposed an addition-elimination pathway followed by a fast protonation of the leaving group (carbanion) with HCN in a solvent cage. Scheme 20 summarizes the reactivity observed. Scheme 20. LiAlH4 slurry reduction of various -diaryl nitriles: the decyanation/primary amine ratio (59b-59e/58b-58e) and the solvent used are given. The addition-elimination mechanism was discussed again from the unusual nucleophilic properties of the NaH-NaI or LiI composite. [68][69] Indeed, Chiba and co-workers found an unexpected reactivity during the methylation of 2,2-diphenylethanenitrile 34f: they obtained the alkylated nitrile 34e (74% yield) and 1,1diphenylethane (59e) in 25% yield (Scheme 21). 70 Scheme 21. Unexpected decyanation upon alkylation of 2,2-diphenylethanenitrile 34f.
They assumed that 59e was produced from the decyanation of 2,2-diphenylpropanenitrile 34e and investigated the optimization of reaction conditions. They observed that NaH alone was ineffective. Since NaI was formed upon the methylation reaction, they explored the use of several additives and found that NaI and LiI gave the best results. After a set of experiments on stoichiometry and reaction time, the authors examined the scope of this new decyanation with conditions described in Scheme 22. The protocol was extended to 27 nitriles giving monoaryl-(59g-59i), diaryl-(59f, 59j, 59k) or triarylmethane (59l) derivatives from the corresponding nitriles. 71 Scheme 22. Scope of the decyanation by sodium hydride-iodide composite. The reaction time is shown in brackets. a From the endo nitrile substrate 34h.
The reaction of nitrile 34i proceeded in a high yield (92%) after 24 h but when the reaction mixture was quenched after 2.5 h, aldehyde 60 was isolated in 42% yield together with the decyanated product 59i (37%). This experiment suggests that the first step could be a hydride addition to the cyano group giving an Nmetalated imine intermediate. The reduction of nitrile 34h shows that this reaction proceeds with the retention of configuration (59h). No radical intermediates were trapped using radical probe substrates 34g Page 17 of 23 © AUTHOR(S) and 34j (5-hexenyl cyclization) or 34f (cyclopropylcarbinyl ring-opening). The absence of deuterium incorporation using THF-d8 as solvent also fits with the absence of radical intermediates. DFT calculations performed on 2-methyl-2-phenylpropanenitrile 34a support a mechanism involving nucleophilic attack of the hydride ion to give the intermediate 61 where a sodium cation- interaction occurs. Then, a fast fragmentation involving an intramolecular proton transfer with retention of configuration gives the decyanation product 59a (Scheme 23). The NaH-Na(Li)I composite in THF is composed of NaI interspersed with activated NaH. Synergistic cooperation between NaH and NaI at the surface could be crucial for the observed hydride reactivity. 68 Scheme 23. Addition-elimination mechanism proposed for the decyanation by sodium hydride-iodide composite.

Decyanations with the hydroxide anion
Tertiary and secondary nitriles activated with phenyl groups are decyanated in the presence of molten 85% potassium hydroxide. 72 This transformation is described from -mono and diaryl-substituted nitriles (Scheme 24). The decyanation reaction in an acid or basic medium is a well-known transformation. The nitrile group is first hydrolyzed into a carboxylic acid, which is removed by decarboxylation. [73][74] However, in alkali fusion, the addition-elimination pathway proposed in Scheme 25 fits better with experimental data. Treatment of primary and unactivated secondary and tertiary nitriles does not afford the decyanation product but leads to the expected hydrolysis products (carboxylic acids and/or amides). Moreover, potassium cyanate (KOCN) was trapped with semicarbazide hydrochloride. A similar decyanation can be performed under milder conditions. Khadilkar and co-workers have reduced alkyldiphenylacetonitriles with NaOH by microwave irradiation in PEG-400 (Scheme 26). 75 Under the reaction conditions, they were able to trap cyanic acid (HOCN) evolved by discoloration of an NH4OH-CuSO4 indicator.

Conclusions
The addition-elimination mechanism on -aryl nitriles and disubstituted malononitriles is well-established. This reaction leads to a cyanation product and an anionic leaving group. Disubstituted malononitriles appear as fruitful reagents for transnitrilation of organometallics. Subsequent reactions of the leaving group such as electrophilic trapping were successfully explored in one-pot reactions. The addition-elimination mechanism also was proposed using hydride donors and the hydroxide anion. Particularly, NaH-iodide composite and NaOH (or KOH) appear as efficient reagents for the decyanation of -aryl nitriles. The extension of this process to a bis(allyl)nitrile offers an original perspective in organic synthesis. Recently, AIBN was described as a new electrophilic reagent for cyanation of aryllithiums. This new application illustrates the versitality of the addition-elimination pathway. 76