C- and N-Metalated Nitriles: The Relationship between Structure and

Article Cite This: Acc. Chem. Res. 2017, 50, 2556-2568

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C- and N‑Metalated Nitriles: The Relationship between Structure and Selectivity Xun Yang and Fraser F. Fleming* Department of Chemistry, Drexel University, Philadelphia, Pennsylvania 19104, United States

CONSPECTUS: Metalated nitriles are exceptional nucleophiles capable of forging highly hindered stereocenters in cases where enolates are unreactive. The excellent nucleophilicity emanates from the powerful inductive stabilization of adjacent negative charge by the nitrile, which has a miniscule steric demand. Inductive stabilization is the key to understanding the reactivity of metalated nitriles because this permits a continuum of structures that range from N-metalated ketenimines to nitrile anions. Solution and solid-state analyses reveal two different metal coordination sites, the formally anionic carbon and the nitrile nitrogen, with the site of metalation depending intimately on the solvent, counterion, temperature, and ligands. The most commonly encountered structures, C- and N-metalated nitriles, have either sp3 or sp2 hybridization at the nucleophilic carbon, which essentially translates into two distinct organometallic species with similar but nonidentical stereoselectivity, regioselectivity, and reactivity preferences. The hybridization differences are particularly important in SNi displacements of cyclic nitriles because the orbital orientations create very precise trajectories that control the cyclization selectivity. Harnessing the orbital differences between C- and Nmetalated nitriles allows selective cyclization to afford nitrile-containing cis- or trans-hydrindanes, decalins, or bicyclo[5.4.0]undecanes. Similar orbital constraints favor preferential SNi displacements with allylic electrophiles on sp3 centers over sp2 centers. The strategy permits stereoselective displacements on secondary centers to set contiguous tertiary and quaternary stereocenters or even contiguous vicinal quaternary centers. Stereoselective alkylations of acyclic nitriles are inherently more challenging because of the difficulty in creating steric differentiation in a dynamic system with rotatable bonds. However, judicious substituent placement of vicinal dimethyl groups and a trisubstituted alkene sufficiently constrains C- and N-metalated nitriles to install quaternary stereocenters with excellent 1,2-induction. The structural differences between C- and N-metalated nitriles permit a rare series of chemoselective alkylations with bifunctional electrophiles. C-Magnesiated nitriles preferentially react with carbonyl electrophiles, whereas N-lithiated nitriles favor SN2 displacement of alkyl halides. The chemoselective alkylations potentially provide a strategy for late-stage alkylations of polyfunctional electrophiles en route to bioactive targets. In this Account, the bonding of metalated nitriles is summarized as a prelude to the different strategies for selectively preparing C- and N-metalated nitriles. With this background, the Account then transitions to applications in which C- or N-metalated nitriles allow complementary diastereoselectivity in alkylations and arylations, and regioselective alkylations and arylations, with acyclic and cyclic nitriles. In the latter sections, a series of regiodivergent cyclizations are described that provide access to cis- and trans-hydrindanes and decalins, structural motifs embedded within a plethora of natural products. The last section describes chemoselective alkylations and acylations of C- and N-metalated nitriles that offer the tantalizing possibility of selectively manipulating functional groups in bioactive medicinal leads without recourse to protecting groups. Collectively, the unusual reactivity profiles of C- and N-metalated nitriles provide new strategies for rapidly and selectively accessing valuable synthetic precursors.

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prostate cancer,3 the nitrile most likely removes electron density from the aromatic ring to limit clearance by the liver. Saxagliptin (3), an antidiabetic,4 is an exception in that the nitrile is the key pharmacophore, undergoing reversible attack by a cysteine in the active site.

INTRODUCTION

The nitrile functionality exhibits unique chemical reactivity and biological activity. Found in a small but important number of pharmaceuticals1 and natural products,2 the nitrile usually accentuates the biological activity rather than functioning as the key pharmacophore (Figure 1). For example, in the nitrilecontaining anticancer drug Arimidex (1) the nitriles engage in two key hydrogen bonds, whereas in Xtandi (2), a drug for © 2017 American Chemical Society

Received: June 30, 2017 Published: September 20, 2017 2556

DOI: 10.1021/acs.accounts.7b00329 Acc. Chem. Res. 2017, 50, 2556−2568

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Accounts of Chemical Research

Figure 1. Nitrile-containing pharmaceuticals.

investigated only in solution.8 In general, lithium cations13 and high-valent transition metals14 prefer N-metalation in the solid state and in solution, whereas metals capable of covalent bonding prefer C-metalation. Low-valent transition metal counterions and less electropositive metals,14 such as boron,15 magnesium,16 and zinc,17 favor C-coordination. In contrast to N-lithiated nitriles, where deprotonation with lithium amide is kinetically favored,18 Cmetalated nitriles appear to be thermodynamically favored, though this depends on the metal and the ligands; some N- and C-metalated nitriles with ruthenium19 or palladium20 counterions can be thermally equilibrated. C-Metalated nitriles, such as 12,17 exhibit short bond lengths consistent with charge stabilization primarily through induction. Crystallographically determined CN bond lengths display minimal elongation (1.15−1.19 Å vs 1.14 Å for neutral nitriles)21 with CCN bond lengths (1.36−1.40 Å) close to the bond length in benzene (1.38 Å).22 The CCN bond contraction stems from the electrostatic attraction between the negative electron density on the nucleophilic carbon and the powerful inductive electron withdrawal of the nitrile group.8 Structure 7 succinctly captures the bonding in N-lithiated nitriles, where the bond order of the nucleophilic carbon, based on crystallographically determined bond lengths, is greater than 4. Solvation dramatically influences the metal coordination site. NMR analyses of lithiated acetonitrile with a chelating chiral amino ether ligand identified only the N-lithiated nitrile 14 in THF at −87 °C (Figure 4).23 However, in ether at −100 °C an equilibrium exists between 14 and the C- and N-lithiated nitrile 15. The rapid equilibration underscores the difficulty in accessing a configurationally stable metalated nitrile. The two different metal coordination sites vary between planar and tetrahedral extremes at the formally anionic carbon (Figure 3). The geometric variability is a consequence of the inductive stabilization, which does not require planarity for

Syntheses with nitrile intermediates en route to natural products and pharmaceuticals often feature metalated nitrile alkylations because of an exceptional nucleophilicity and a high reagent tolerance.5 The excellent nucleophilicity stems from the high charge density on the nucleophilic carbon and the minuscule size of the nitrile functionality, which is roughly 8 times smaller than comparable electron-withdrawing groups.6 As a point of comparison, the A value of the nitrile is 0.2 kcal mol−1, whereas the A values of carbonyl functionalities range from 0.6 to 2.0 kcal mol−1.7 Deprotonating alkylnitriles generates a metalated nitrile that is largely stabilized by inductive electron withdrawal rather than through resonance.8 The confluence of small size and inductive stabilization positions most of the charge density on carbon, which facilitates displacements at hindered centers in cases where enolates are unreactive.9 For example, installing the hindered quaternary center in diisopropylacetonitrile (4) proceeds in 70% yield, whereas the corresponding acid and ester fail to react (Figure 2).10

Figure 2. Sterically demanding metalated nitrile alkylation.

Inductive stabilization of metalated nitriles creates two potential metal coordination sites: N-metalation at the nitrile nitrogen and C-metalation at the formally anionic carbon (Figure 3). Metalated nitriles occupy a continuum that varies from the ketenimine 6 on one extreme through the Nmetalated nitrile 7 and the C-metalated nitrile 8 (depicted with the short CCN bond based on crystallographically determined bond lengths)11 to the solvent-separated nitrile anion 9. These structures have been closely analyzed in the solid state,12 though solvent-separated nitrile anions have been

Figure 3. Continuum of metalated nitrile structures. 2557


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A versatile route to C- or N-metalated nitriles is through organometallic-induced halogen−metal exchange.30 Organolithium, Grignard, and organocopper reagents16 engage in facile halogen−metal exchange with bromo-, iodo-, and even chloronitriles.31 The value of selectively accessing metalated nitriles with different metal counterions is captured in the regiodivergent SN2 and SN2′ displacements of propargyl bromide (Scheme 2). Conventional LDA deprotonation of Figure 4. Lithiated nitrile equilibration.

Scheme 2. Regiodivergent Alkylations of N- and C-Metalated Nitriles

orbital overlap, a structural feature reproduced in numerous molecular modeling calculations.24 C-Metalated nitriles such as 12 have geometries that approximate the tetrahedral ideal, though the long carbon−metal bond usually leads to a pyramidal geometry because the bond angles relax from the ideal value of 109.5°.14 The structural features of metalated nitriles vary considerably, but most exist as N- or C-metalated nitriles (7 and 8; Figure 3). These two structures capture the distinctive reactivity of metalated nitriles, which are best considered as two different organometallics with complementary reactivity profiles. The structural and reactivity differences necessitate selective access to C- and N-metalated nitriles.

22a affords lithiated cyclohexanecarbonitrile (23), which reacts with propargyl bromide to afford alkyne 24. Bromine−copper exchange of 22b generates cuprated nitrile 25, which displaces propargyl bromide to afford allene 26.16 Cuprated nitrile 25 can also be generated by addition of MeCu to lithiated nitrile 23. The regiodivergent alkylations of propargyl bromide illustrate the necessity of understanding N- and C-metalated nitriles as distinct organometallics rather than as generic nitrile anions. Sulfoxide−metal exchange of sulfinyl nitriles provides a valuable alternative synthesis of metalated nitriles (Scheme 3).32 Sulfinyl nitriles are easily synthesized by reactions that are

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GENERATION OF METALATED NITRILES Metalated nitriles are routinely generated by deprotonation of alkyl nitriles with lithium amide bases.5 Lithium diisopropylamide (LDA) is by far the most commonly employed lithium amide,5 though lithium diethylamide is preferred for deprotonation of hindered tertiary nitriles.25 Sodium amide and sodium hydride are generally ineffective for deprotonation of alkyl nitriles,5 whereas organolithiums and organomagnesiums competitively attack the nitrile group.26 Acetonitrile is anomalous because its small size and high polarity lead to complete deprotonation with butyllithium27 or methyllithium− lithium bromide.28 Nitriles bearing proximal chelating groups can be selectively deprotonated by organolithiums or Grignards. For example, addition of 2 equiv of i-PrMgBr to hydroxynitrile 16 generates isopropylmagnesium alkoxide 17, which is ideally oriented for internal deprotonation while geometrically prevented from attacking the nitrile (Scheme 1).29 Subsequent alkylation of 18

Scheme 3. Comparative Deprotonation and Sulfoxide−Metal Exchange Alkylations

Scheme 1. Chelation Control in Deprotonation and Conjugate Addition significantly more functional-group-tolerant than those for the halogenation of nitriles. Additionally, the parent phenylsulfinylacetonitrile (27) is readily deprotonated with Cs2CO3 (Scheme 3). Performing two sequential alkylations with Cs2CO3 is significant because the alkylation−exchange− alkylation sequence requires only 1 equiv of an organometallic rather than the usual 3 equiv of a lithium amide base (cf. 27 → 34 with 31 → 34). Sulfoxide−metal exchange−alkylation overcomes a longstanding problem in nitrile alkylations. While the alkylations of acetonitrile (31) and disubstituted nitriles 33 are highyielding, the alkylation of primary alkyl nitriles 32 are often compromised by overalkylation to give the quaternary nitrile 34 (R3 = R2).33 Sulfinyl nitriles 28 engage in a facile sulfinyl− magnesium exchange−alkylation to afford tertiary nitriles 33 without deprotonation of the acidic methine proton of 28 (pKa

to 19a occurs from the axial direction with retention of the absolute configuration of the carbon−magnesium bond. The same C-magnesiated nitrile 18 is generated by addition of excess MeMgCl to oxonitrile 20 through sequenced 1,2−1,4addition (20 → 21 → 18). 2558


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Accounts of Chemical Research ∼ 12).34 The sulfoxide−metal exchange of sulfinyl nitriles is extremely fast; butyllithium initiates the exchange at roughly the same rate as deuteration by CD3OD.32a The rapid sulfoxide−metal exchange translates into a remarkable functional group tolerance.32 For example, performing the exchange−acylation of 29a by adding a solution of iPrMgCl to a −78 °C THF solution of the sulfinyl nitrile and methyl cyanoformate is not accompanied by addition of the Grignard reagent to either functionality (Scheme 4). The

Scheme 6. Arylthio−Metal Exchange−Alkylations

Scheme 4. Functional Group Tolerance of Sulfoxide−Metal Exchange triles, but not phenylthioalkanenitriles, engage in exchange reactions with Et2ZnBuLi and Bu2CuLi (40b → 42; Scheme 6). A remarkable sulfone−metal exchange−alkylation of 44 demonstrates that all three oxidation states of sulfur-substituted acetonitriles are precursors of metalated nitriles (Scheme 7).37 Scheme 7. Sulfone−Metal Exchange−Alkylation

sulfoxide−metal exchange is equally efficacious with BuLi, iPrMgBr, or Et2ZnBuLi, providing efficient access to diverse metalated nitriles suited for construction of an array of substituted nitriles. Sulfoxide−metal exchange provides an excellent method for accessing metalated alkenenitriles. The exchange−alkylation affords trisubstituted alkenes with reasonable stereochemical fidelity, though the intermediate magnesiated nitriles 38 slowly equilibrate to afford mixtures of E and Z geometric isomers 39 (Scheme 5).35 Scheme 5. Sulfoxide−Magnesium Exchange of Sulfinylalkenenitriles Commercially available 2-pyridylsulfonylacetonitrile (43) readily alkylates diverse electrophiles in the presence of K2CO3 or DBU to provide substituted sulfonyl nitriles such as 44. The 2pyridyl moiety is critical in anchoring the organometallic proximal to the sulfone moiety (45) to override competitive directed ortho-metalation. Sulfone−metal exchange requires either BuLi or Bu3MgLi, affording metalated nitriles (46) for the installation of quaternary centers. For example, the arylation of sulfonyl nitrile 44 with 2-chloropyridine efficiently achieves a challenging bond construction (44 → 42c, R = 2-pyridyl, 85%). The sulfone−metal exchange strategy complements the sulfide and sulfoxide exchanges because 2-pyridinesulfonylacetonitrile is commercially available and readily deprotonated with K2CO3 or DBU and most sulfonylnitriles are stable crystalline solids. Stereoselective alkylation of chiral metalated nitriles is a daunting challenge. The challenge arises because N-metalated nitriles with chiral ligands locate the chirality remote from the nucleophilic center whereas C-metalated nitriles rapidly epimerize.38 Pioneering deprotonations of cyclopropanecarbonitrile 47a39 demonstrate that the free carbanion 48a has a short, discrete existence (Scheme 8). Performing the deprotonation in deuterated methanol provides an internal trap that minimizes equilibration (48a → 48b → 50), allowing

Arylthio−metal exchange of arylthioalkanenitriles provides an alternative route to metalated nitriles36 with the added benefit that arylthioalkanenitriles are not prone to elimination like highly substituted sulfinyl nitriles and are readily prepared through displacement and alkylation sequences. Arylthio−metal exchange with BuLi or Bu3MgLi affords nucleophilic intermediates that alkylate an array of electrophiles (Scheme 6). NMR spectroscopic analysis of the organometallic obtained by the addition of BuLi to phenylthionitrile 40a identified a threecoordinate sulfuranylide 41 as the predominant solution species. Mechanistic experiments identified an equilibrium between 41 and 23 consistent with the loss of stereochemistry in alkylations of stereochemically defined arylthio nitriles. Compared with sulfoxide−metal exchange, sulfide−metal exchange requires a more reactive organometallic: i-PrMgBr does not trigger an exchange unless the aromatic sulfide substituent is a 2-pyridyl substituent. 2-Pyridylthioalkaneni2559


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Accounts of Chemical Research Scheme 8. Stereochemical Integrity of Metalated Nitriles

Scheme 10. Diastereoselective Trapping of Metalated Nitriles

isolation of 49 with greater than 99.7% retention of stereochemistry. An analogous deprotonation of 47a with LDA leads to rapid racemization. Metal−halogen exchange established an 11 kcal mol−1 inversion barrier for epimerization of C-magnesiated nitrile 51, which translates into a half-life for racemization of 11.4 h at −100 °C for the magnesiated nitrile compared with less than 12 s for the corresponding lithiated nitrile.40 Intricate mechanistic experiments suggested that enantiomerization occurs through a solvent-dependent41 ion pair separation and inversion mechanism (51 → 48)42 rather than through a conducted-tour equilibration.18 Armed with the knowledge that magnesiated nitriles epimerize more slowly,43 research has focused on trapping chiral magnesiated nitriles44 with adjacent coordinating groups.45 For example, magnesiated nitrile 53 derived by deprotonation of 52 has half-lives for epimerization of 3 min in ether at −104 °C and 2 min in THF. Selective trapping of the acyclic nitrile 55 requires in situ alkylation with reactive electrophiles to achieve >90:10 enantiomeric ratios of 56 (Scheme 9).46 The chiral alkylations demonstrate the challenge in overcoming the facile epimerization of metalated nitriles.

arises because deprotonation of nitrile 57 preferentially affords planar N-lithiated nitrile 58 in conformation 58″ rather than 58′ because positioning the small nitrile group on the same side as the vicinal methyl group avoids a severe methyl−methyl gauche interaction. Acylation from conformer 58″ occurs opposite the phenyl ring to afford ester nitrile 59 as a single diastereomer. The same diastereoselectivity preference is maintained with the C-cuprated and C-magnesiated nitriles because the preferred conformation 61″ avoids a similar methyl−methyl gauche interaction (61′). The phenethyl group is a critical design component: the proclivity to minimize allylic strain favors projection of the phenyl ring over the plane of the N-lithiated nitrile. Truncating the phenyl ring to a trisubstituted olefin maintains the requisite control elements while extending the strategy to highly substituted acyclic nitriles (64; Scheme 11). For example, Scheme 11. Diastereoselective Alkylation of a γ-Alkenenitrile

Scheme 9. Deprotonation−Alkylation of Chiral Nitriles

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DIASTEREOSELECTIVE ALKYLATIONS OF ACYCLIC METALATED NITRILES The inherent configurational lability of metalated nitriles can be harnessed by prior equilibration to generate a configurationally defined metalated nitrile for electrophilic trapping. The strategy has proven to be particularly effective because the tunable geometry of the nucleophilic carbon sometimes provides access to two diastereoisomers from the same precursor. In addition, judicious choice of the metal allows complementary chemoselective alkylations while installing highly hindered quaternary stereocenters. Alkylations of acyclic nitriles containing vicinal methyl and phenyl groups, or a trisubstituted alkene, are exceptionally diastereoselective (Scheme 10).14,47 The chiral environment

alkylation of 62 with i-PrI via 63″ installs contiguous tertiary and quaternary stereocenters, demonstrating the ability of the strategy for hindered, diastereoselective bond constructions (dr >19:1). Diastereoselective alkylations of acyclic metalated nitriles in which the resident chirality is separated by two carbons are particularly challenging.48 Access to a single reactive conformation requires overcoming the inherent flexibility of the single bonds between the asymmetric center and the nucleophilic carbon. A strategy predicated on the preference of the carbon backbone to adopt a low-energy zigzag conformation demonstrates the challenge: deprotonation of phenyl-substituted nitrile 65 affords two reactive conformers, 66′ and 66″, with the phenyl ring screening approach to one 2560


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is not the final product because a highly selective internal hydride delivery occurs from the proximal isopropylmagnesium alkoxide to afford dihydroxy nitrile 75 as the sole diastereomer.

face of the lithiated nitrile. Selective acylation affording 67a (4.5−2.0:1) is consistent with preferential attack on conformer 66′ (Scheme 12).

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α-ARYLATION OF METALATED NITRILES The α-arylacetonitrile motif is an important structural core in several pharmaceuticals1 (Figure 5). α-Arylation of nitriles has

Scheme 12. 1,3-Asymmetric Induction in Nitrile Alkylations

Figure 5. Cyclohexylcarbonitrile-based pharmaceuticals.

emerged much more slowly than the comparable reactions of carbonyl compounds because of the low acidity of alkyl nitriles.50 The challenge with α-arylation is that α-aryl alkyl nitriles are more acidic than the starting alkyl nitriles, which predisposes products to diarylation. Judicious choice of the ligand and metal, particularly zinc,51 affords a less basic metalated nitrile that minimizes diarylation. Control over the nitrile configuration during α-arylation of cyclohexanecarbonitriles led to an efficient palladium-catalyzed coupling with an unusual diastereoselectivity preference.52 Various conformationally constrained cyclohexanecarbonitriles 78 preferentially afford α-arylcyclohexanecarbonitriles 81 with the small nitrile in an axial orientation but with diastereomeric ratios that do not directly correlate with the steric demand of the anchoring substituent. Deprotonation of cyclohexanecarbonitriles 78 with the versatile tetramethylpiperidide base TMPZnCl·LiCl53 affords, through equilibration, zincated nitrile 79 that engages the palladium(II) complex 84 to afford the axial and equatorial C-palladated nitriles 80a and 80b. Reductive elimination involves a delicate interplay between the electronic influence of the aromatic group and the ring substituents R that depends upon the s character at the metalated carbon (Scheme 14).

Higher levels of 1,3-asymmetric induction are achieved with acyclic hydroxy nitriles 68, in which internal chelation imparts greater conformational bias in the electrophilic attack (Scheme 13).49 Chelation-controlled deprotonation through 69 is Scheme 13. Diastereoselective Hydroxynitrile Alkylations

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REGIOSELECTIVE ALKYLATIONS AND ARYLATIONS OF ALKENENITRILES Relatively few alkylations or arylations have been performed on alkenenitriles,5 probably because alkenenitriles are good Michael acceptors that are prone to self-condense (Scheme 15). 54 TMPZnCl·LiCl is particularly effective for the deprotonation−arylation of unsaturated nitriles because the greater covalency of the zincated nitriles minimizes deleterious Michael addition.55 The coupling primarily affords the conjugated alkenenitriles resulting from γ-arylation (85 → 86 → 88/89), implying that the preferred palladium intermediate is 87, in which the nitrile is conjugated with the adjacent olefin. The reaction has considerable scope for cyclic and acyclic nitriles, tolerates modest functionalization, and retains the configuration in couplings with (E)- and (Z)-vinyl iodides. A complementary copper-catalyzed coupling accomplishes αalkylation or α-arylation of cyclic five- to seven-membered α,βunsaturated nitriles (90; Scheme 16). Use of an amidocuprate, generated from LDA and CuCN, is critical to the success of the deprotonation. The amidocuprate is thought to complex the

thought to afford complex 70 in which the small nitrile group occupies the sterically demanding axial-like orientation. Alkyl halides are preferentially displaced by the carbon−magnesium σ bond with retention of configuration (71 → 72, dr 16.0−4.7:1). Ester electrophiles, with larger, more diffuse π* orbitals, preferentially attack the back side of the carbon−magnesium bond with inversion of configuration through a collinear twocenter, two-electron transition structure (73 → 74). Ketone 74 2561


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illustrate how the nucleophile geometries translate into different diastereomeric ratios (Scheme 17).57 Approach of

Scheme 14. Palladium-Catalyzed Arylation of Metalated Nitriles

Scheme 17. Diastereoselective N- and C-Metalated Nitrile Alkylations

methyl iodide to planar lithiated nitrile 94 occurs with a modest 2.8:1 preference for equatorial alkylation because of the steric compression encountered in an axial trajectory. Methylation of the corresponding C-magnesiated nitrile 95 generated by bromine−magnesium exchange occurs only from the equatorial direction. The apparent retention of configuration at the magnesiated carbon reflects equilibration to the most favored configuration. In situ bromine−magnesium exchange−acylation of a 1:1 diastereomeric mixture of 81b that exclusively generated the equatorial diastereomer (96, but with CO2Me in place of Me).43 The structural integrity of magnesiated nitriles is enhanced by internal chelation.58 Alkylations of 97a with alkyl iodides and sulfonates install the substituents in an axial orientation through retentive overlap of the nucleophilic C−Mg bond with the electrophilic σ* orbital (97a″).59 Although the alignment is far from optimal, the alternative approach to the small lobe of the C−Mg σ bond (97a′) is sterically prohibited (Scheme 18; cf. 16 → 19a in Scheme 1). The axial alkylations (R = MeI, PrI, Me2SO4) are efficient (57−86%) despite the three-center, twoelectron transition structure emanating from 97a″. Alkylations of 97a with allylic and benzylic halides afford mixtures of quaternary nitriles 19 and 99 (Scheme 18). Mechanistic experiments reveal that single electron transfer from the formal dianion 97a is at least partially responsible for the erosion of stereochemistry. Partial alkylation through

Scheme 15. Pd-Catalyzed Coupling of Alkenenitriles

Scheme 16. Deconjugative α-Alkylation of Cyclic Alkenenitriles

Scheme 18. Diastereoselective Alkylations of a Magnesiated Nitrile

nitrile π bond (91), positioning the basic amide nitrogen adjacent to the γ-proton for deprotonation. Trapping lithiated delocalized nitrile 92 with electrophiles regioselectively affords α-alkylated quaternary nitriles 93.56 Arylations with 2chloropyridine or 4-iodobenzonitrile afford the corresponding α-arylated nitriles.

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DIASTEREOSELECTIVE ALKYLATIONS OF CYCLIC METALATED NITRILES The two different metal coordination sites in N- and Cmetalated nitriles, particularly those in conformationally constrained cyclohexanecarbonitriles, create distinctly different geometries at the nucleophilic carbon. Alkylations of N- and Cmetalated nitriles 94 and 95, respectively, derived from 81 2562


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Accounts of Chemical Research radical rebound of nitrile-stabilized radical 98 likely favors the formation of 99 in which the less sterically demanding nitrile is in the axial orientation. The preference of 97a for axial alkylation can be reversed (Scheme 19). Disrupting the internal complexation of the

tunable control over the configuration of the nitrile-bearing carbon. Cyclic C-magnesiated nitrile 97 is remarkable in exhibiting an unusual preference for acylation on nitrogen with acid chlorides (Scheme 21).61 Sequential addition of two Grignard reagents

Scheme 19. Interconverting Magnesiated and Lithiated Nitriles for Stereodivergent Alkylations

Scheme 21. N-Acylation of a Magnesiated Nitrile

magnesium−carbon bond by addion of lithium alkoxide 100 favors the formation of oxygen-bound magnesiate 101. Alkylation of the planar lithiated nitrile preferentially occurs from the equatorial direction, providing predominantly 19b accompanied by 99a, which presumably arises through alkylation via 97a.60 The conversion of the C-magnesiated nitrile to the corresponding N-lithiated nitrile provides a route to diastereomeric nitriles from the same precursor (Scheme 19). Acylations of C-magnesiated nitrile 97a with carbonylcontaining electrophiles exhibit stereoselectivity preferences that depend on the steric and electronic nature of the carbonyl (Scheme 20). Reactive carbonyl electrophiles with large, diffuse

affords C-magnesiated nitrile 97, which pivaloyl chloride is unable to attack at the nucleophilic carbon and therefore acylates on nitrogen to afford acyl ketenimine 104. Ketenimines are notoriously reactive,62 and 104 rapidly reacts with a Grignard reagent to afford enamide 105 and ultimately 106. The conversion of cyclic nitrile 20 to densely functionalized enamide 106 installs four new bonds in a process that highlights the diverse reactivity of metalated nitriles.

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DIASTEREOSELECTIVE METALATED NITRILE CYCLIZATIONS Cyclic nitriles, particularly cyclohexanecarbonitriles, have a relatively rigid core that allows the variable geometry of metalated nitriles to direct the cyclization trajectory to cis or trans ring-junction configurations.63 The strategy is succinctly captured in the metal-dependent cyclizations of nitrile 107 to cis- and trans-decalins (Scheme 22).64 Cyclization of planar potassiated nitrile 108, favored in toluene, preferentially proceeds through 108c to give cis-decalin 110 (110:111 ratio = 4.5:1) because the torsional strain imposed in the electrophilic tether prevents cyclization from 108a. Although

Scheme 20. Orbital Control in Diastereoselective Nitrile Alkylations

Scheme 22. Stereodivergent Metalated Nitrile Cyclizations

π* orbitals, such as methyl cyanoformate and benzoyl cyanide, acylate with inversion of configuration (97a‴ → 102). The preferred overlap is between the π* orbital and the small σ lobe of the C−Mg bond, an overlap that benefits by proceeding through a collinear two-center, two-electron transition structure. Less reactive carbonyl electrophiles with smaller π* orbitals or sterically demanding carbonyl electrophiles, such as cyclohexanone, are unable to access the small C−Mg σ orbital and therefore alkylate from the axial direction with retention of configuration (97a⁗ → 103). Collectively, 1,2−1,4-addition alkylations or acylations install three new stereocenters with 2563


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Accounts of Chemical Research 108b would cyclize to afford cis-decalin 110, the conformation is disfavored by significant syn-axial steric compression. Performing the same cyclization in refluxing THF preferentially affords trans-decalin 111 (110:111 ratio = 1:6.3). In refluxing THF the cation is only loosely associated, which favors pyramidal nitrile anion 109. Access to the tetrahedral geometry allows the small nitrile group to adopt an axial orientation in the developing trans-decalin 109c, which avoids placing either the side chain (109a) or the developing carbon− carbon bond (109b) in an axial orientation. Greater stereoselectivity in the cyclization to give transdecalin 111 is achieved with a cuprated nitrile (Scheme 23).

Scheme 25. Chelation-Controlled Cyclization To Give a trans-Hydrindane

The chelation-controlled cyclization of 119 to give transhydrindane 121 proceeds through 120 with an axial nitrile and an equatorial nucleophilic orbital. Stereodivergent metalated nitrile cyclizations can be controlled with a single hydroxyl stereochemistry by exploiting the different N- and C-coordination modes of monovalent and divalent lithium and magnesium cations, respectively (Scheme 26). The requisite magnesiated nitrile 124 is generated by

Scheme 23. Cyclization of a C-Cuprated Nitrile

Scheme 26. Stereodivergent Metal-Dependent Nitrile Cyclizations

Deprotonation of 107 at −78 °C generates a lithiated nitrile that, because cyclization is slow, can be transmetalated with methylcopper to afford C-cuprated nitrile 112. C-Cuprated nitrile 112 orients the nitrile in the sterically demanding axial position with copper in an equatorial orientation, and subsequent reductive elimination affords only trans-decalin 111 (Scheme 23).65 Cuprated nitriles such as 112 are only weakly nucleophilic; cyclizing the corresponding hydrindane requires silver tetrafluoroborate to facilitate the ring closure. An alternative strategy for highly stereoselective decalin cyclizations is to control the nitrile anion geometry by internal chelation (Scheme 24). Deprotonation of hydroxy nitriles 113 Scheme 24. Chelation-Controlled Decalin Cyclizations

chelation-controlled deprotonation (123) of hydroxy nitrile 122. Nucleophilic attack on the carbon−chlorine bond by magnesiated nitrile 124 occurs through a side-on SE2Ret orbital overlap to afford cis-decalin 125 because the alternative SE2Inv collinear approach to the small lobe of the carbon−magnesium bond is too sterically demanding (Scheme 26).66 Stereodivergent cyclization of 122 to give trans-decalin 127 is readily achieved through the corresponding dilithiated nitrile 126. Preferential coordination of the alkoxy lithium to the nitrile π electrons favors bond formation from 126, which directs cyclization to form trans-decalin 127. Collectively, these two cyclizations show how the complementary coordination modes of N-lithiated and C-magnesiated nitriles can be translated into stereodivergent cyclizations. The exceptional nucleophilicity of metalated nitriles is ideally suited to the construction of hindered stereocenters (Scheme 27).67 Deprotonation of 128 with excess butyllithium generates a dilithiated nitrile that displaces a secondary electrophile, in preference to an SN2′ displacement, to afford 130 with vicinal quaternary and tertiary stereocenters. The regioselectivity likely reflects the smaller than expected steric demand of the tiedback nitrile anion 129 and the high electron density that allows for a strong interaction with the polarized σ* orbital. The cyclization of 131 pits an SNi′ 6-exo-trig displacement of the lithiated nitrile against an SNi closure to form an eightmembered ring; the cyclization of 132 to give trans-decalin 133 is favored despite the installation of vicinal quaternary centers. Related SNi′ displacements of a tethered propargylic chloride generate allene-substituted hydrindanes.68

and 116 with excess LiNEt2 permits selective cyclization to form either the trans- or cis-decalin through temporary chelation with the adjacent axial or equatorial alkoxide, respectively. Complexation between the lithium cation of the alkoxide and the nitrile π electrons25 effectively locks the lithiated nitrile in a pyramidal geometry as shown for 114, relaying the chirality from the carbinol to the nucleophilic orbital. Cyclization of 113 occurs preferentially to afford transdecalin 115, consistent with cyclization through internally complexed dianion 114. An analogous cyclization of the axial diastereomer 116 through complex 117 affords cis-decalin 118. The efficacy of chelation as a stereocontrol element is illustrated in the cyclization of nitrile 119 to give transhydrindane 121 (Scheme 25). trans-Hydrindanes are challenging to synthesize because the inherent distortion imposed by the trans ring junction favors the more stable cis-hydrindanes. 2564


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organometallics with the electrophiles (Scheme 30). Complexation of carbonyl electrophiles with the Lewis acidic lithium of

Scheme 27. Cyclizations Forming Hindered Quaternary Centers

Scheme 30. Chemoselective Metalated Nitrile Alkylation/ Acylation

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CHEMOSELECTIVE ALKYLATIONS OF METALATED NITRILES Chemoselectivity is a pressing challenge in organic synthesis.69 Chemoselective reactions of metalated nitriles exploit the different reactivities of C- and N-metalated nitriles, essentially two distinct organometallics.43 Scouting experiments with a mixture of electrophiles revealed a distinct preference of Cmetalated nitriles for the acylation of carbonyl-containing electrophiles, whereas N-metalated nitriles prefer to attack alkyl halides (Scheme 28).70

N-lithiated nitrile 141 effectively sequesters the electrophile from approaching the nucleophilic carbon while allowing the alkyl halide an unimpeded approach (141 → 142; Scheme 30). Coordination of magnesiated nitrile 143 with the carbonyl electrophile places the nucleophilic carbon and the activated electrophile in close proximity. Fission of the carbon− magnesium bond followed by rapid attack on the activated electrophile leads to acylated nitrile 144.

Scheme 28. Chemoselective Metalated Nitrile Alkylations and Acylations

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SUMMARY AND PERSPECTIVES Historically metalated nitriles were viewed as nitrile anions, the nitrogen equivalent of enolates. Crystallographic and NMR analyses have revealed that metalated nitriles exist as discrete organometallics whose precise structural integrity varies across a continuum of structures stabilized by the powerful inductive electron-withdrawing effect of the nitrile. Localization of high electron density on the nucleophilic carbon creates an exceptional nucleophile capable of forging vicinal quaternary centers. Planar N-lithiated nitriles traditionally prepared by deprotonation with LDA exhibit significant differences compared with C-metalated nitriles generated by exchange-based strategies. Sulfoxide−metal and sulfone−metal exchange are particularly advantageous because the alkylations employ very mild bases, avoiding the use of 2 equiv of a reactive organometallic. Metal exchange with halides, sulfoxides, sulfones, and sulfides generates metalated nitriles under extremely mild conditions in the presence of functionalities that would not be compatible with traditional deprotonations and overcomes the longstanding challenge of selectively generating metalated nitriles in the presence of reactive or acidic functionality. Metalated nitriles are extremely versatile chemical chameleons because solvent, temperature, chelation, and judicious choice of the metal ion allow access to two different organometallics with complementary stereo-, chemo-, and regioselectivity preferences. The versatility is captured in the stereodivergent alkylations of cyclic nitriles that predictably provide cis- and trans-hydrindanes and decalins simply through judicious choice of the metal cation. Similarly, chemoselective alkylation of lithiated nitriles and acylation of magnesiated nitriles allow selective attack at one of two different sites in

Establishing the chemoselectivity preferences with pairs of electrophiles provided the fundamental profiles for selective reactions with bifunctional electrophiles (Scheme 29).70 Scheme 29. Chemoselective Alkylations with a Bifunctional Electrophile

Intercepting bromoamide 137 with C- or N- metalated cyclopentanecarbonitriles selectively affords two different quaternary nitriles: acylation of magnesiated nitrile 8b affords ketonitrile 138, whereas lithiated nitrile 7a displaces the bromide to afford amide ester 139. Mechanistically, the chemoselective alkylations are thought to arise from the different chelation preferences of the two 2565


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carbanions: structure and substituent effects. Adv. Carbanion Chem. 1996, 2, 189−263. (9) (a) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Conjugate hydrocyanation of 17-acetyl-11-carbomethoxygona-1,3,5(10),13(17)tetraenes. Steroids 2007, 72, 297−304. (b) Matteson, D. S.; Lu, J. Asymmetric synthesis of 1-acyl-3,4-disubstituted pyrrolidine-2-boronic acid derivatives. Tetrahedron: Asymmetry 1998, 9, 2423−2436. (c) Barton, D. H. R.; Bringmann, G.; Motherwell, W. B. RadicalInduced Reductive Deamination of Amino Acid Esters. Synthesis 1980, 1980, 68−70. (10) MacPhee, J.-A.; DuBois, J.-E. Steric effects in synthesissteric limits to the alkylation of nitriles and carboxylic acids. Tetrahedron 1980, 36, 775−777. (11) (a) Boche, G.; Marsch, M.; Harms, K. [(α-cyanobenzyllithium•Tetramethyl-ethylenediamine)2•Benzene]: X-ray Structure Analysis of an α-Nitrile ″Carbanion″. Angew. Chem., Int. Ed. Engl. 1986, 25, 373−374. (b) Boche, G.; Harms, K.; Marsch, M. X-ray Structure Determination of [1-Cyano-2,2-dimethylcyclopropyllithiumTetrahydrofuran]∞. J. Am. Chem. Soc. 1988, 110, 6925−6926. (c) Carlier, P. R.; Lucht, B. L.; Collum, D. B. 6Li/15N NMR-Based Solution Structural Determination of Et2O- and TMEDA-Solvated Lithiophenylacetonitrile and a LiHMDS Mixed Aggregate. J. Am. Chem. Soc. 1994, 116, 11602−3. (12) Boche, G. The Structure of Lithium Compounds of Sulfones, Sulfoximides, Sulfoxides, Thioethers and 1,3-Dithianes, Nitriles, Nitro Compounds and Hydrazones. Angew. Chem., Int. Ed. Engl. 1989, 28, 277−297. (13) Carlier, P. R.; Lo, C. W.-S. 7Li/31P NMR Studies of Lithiated Arylacetonitriles in THF−HMPA Solution: Characterization of HMPA-Solvated Monomers, Dimers, and Separated Ion Pairs. J. Am. Chem. Soc. 2000, 122, 12819−12823. (14) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward, O. W. Metalated Nitriles: Internal 1,2-Asymmetric Induction. J. Org. Chem. 2008, 73, 2803−2810 particularly references14 and 15. (15) (a) Tomioka, T.; Takahashi, Y.; Vaughan, T. G.; Yanase, T. A Facile, One-Pot Synthesis of β-Substituted (Z)-Acrylonitriles Utilizing an α-Diaminoboryl Carbanion. Org. Lett. 2010, 12, 2171−2173. (b) Man, H.-W.; Hiscox, W. C.; Matteson, D. S. A Facile, One-Pot Synthesis of β-Substituted (Z)-Acrylonitriles Utilizing an α-Diaminoboryl Carbanion. Org. Lett. 1999, 1, 379−381. (16) Fleming, F. F.; Zhang, Z.; Liu, W.; Knochel, P. Metalated Nitriles: Organolithium, -magnesium, and -copper Exchange of αHalonitriles. J. Org. Chem. 2005, 70, 2200−2205. (17) Brombacher, H.; Vahrenkamp, H. Pyrazolylborate−Zinc Alkoxide Complexes. 3. Acid−Base Reactions. Inorg. Chem. 2004, 43, 6054−6060. (18) Carlier, P. R. Configurational Stability of Chiral Lithiated Cyclopropylnitriles: A Density Functional Study. Chirality 2003, 15, 340−347. (19) Naota, T.; Tannna, A.; Murahashi, S.-I. Synthesis and Characterization of C- and N-Bound Isomers of Transition Metal αCyanocarbanions. J. Am. Chem. Soc. 2000, 122, 2960−2961. (20) Kujime, M.; Hikichi, S.; Akita, M. N/O- and C-Bound (Enolato)palladium Complexes with Hydrotris(pyrazolyl)borato Ligands (TpR: R = iPr2, Me2) Obtained via Dehydrative Condensation between the Hydroxo Complexes TpRPd(Py)OH and Active Methylene Compounds: Factors Determining the Isomer Distribution and Dimerization of Cyano Compounds. Organometallics 2001, 20, 4049−4060. (21) Le Questel, J.-Y.; Berthelot, M.; Laurence, C. Hydrogen-bond acceptor properties of nitriles: a combined crystallographic and ab initio theoretical investigation. J. Phys. Org. Chem. 2000, 13, 347−358. (22) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. Tables of bond lengths determined by X-ray and neutron diffraction. Part 1. Bond lengths in organic compounds. J. Chem. Soc., Perkin Trans. 2 1987, S1−S19. (23) Sott, R.; Granander, J.; Hilmersson, G. Mixed Complexes Formed by Lithioacetonitrile and Chiral Lithium Amides: Observation

bifunctional electrophiles. Harnessing these differences provides an array of functionalized carbon scaffolds contained within diverse natural products and bioactive targets that should see nitrile-based methodology rival that of enolate chemistry.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: fl[email protected]. ORCID

Fraser F. Fleming: 0000-0002-9637-0246 Notes

Disclosure: This Account was adapted from the Ph.D. thesis of Xun Yang, Drexel University, 2017. The authors declare no competing financial interest. Biographies Xun Yang obtained a B.E. at Dalian University of Technology, China, in 2010 and a Ph.D. from Drexel University in Philadelphia under the guidance of Professor Fraser. F. Fleming. His graduate research mainly focused on metalated nitrile alkylations. In 2017 he moved to Emory University in Atlanta for postdoctoral research with Professor Huw Davies. Fraser F. Fleming completed his B.Sc. (Hons.) at Massey University, New Zealand, developing selective ion exchange resins for separating heparin. He obtained a Ph.D. focused on the synthesis of clerodane diterpenoids under the direction of Edward Piers at the University of British Columbia and then developed an approach to indolizidine alkaloids in postdoctoral research with James D. White at Oregon State University. He joined the faculty at Duquesne University in 1992, and then in 2013 he became a rotating Program Director at NSF and after two years transitioned to Drexel University in Philadelphia. His research interests lie in unmasking new reactivity with metalated nitriles and isocyanides.

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ACKNOWLEDGMENTS Support from NSF, particularly 1464494, is gratefully acknowledged because it allowed the development of new reactivities with metalated nitriles. Caleb Holyoke is thanked for valuable discussions and advice on refining a draft of this Account.

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REFERENCES

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