Strategies for the Catalytic Enantioselective Synthesis of α-Trifluoromethyl Amines

Abstract

The exploitation of the α-trifluoromethylamino group as an amide surrogate in peptidomimetics and drug candidates has been on the rise. In a large number of these cases, this moiety bears stereochemistry with the stereochemical identity having important consequences on numerous molecular properties, such as the potency of the compound. Yet, the majority of stereoselective syntheses of α-CF₃ amines rely on diastereoselective couplings with chiral reagents. Concurrent with the rapid expansion of fluorine into pharmaceuticals has been the development of catalytic enantioselective means of preparing α-trifluoromethyl amines. In this work, we outline the strategies that have been employed for accessing these enantioenriched amines, including normal polarity approaches and several recent developments in imine umpolung transformations.

Graphical Abstract

1. INTRODUCTION

The introduction of fluorine into organic molecules has changed the landscape of drug design and discovery, bringing about an avalanche of exploration in the last two decades.¹ Unlike other atoms commonly found in small-molecule drugs, fluorine does not appear in biological molecules, and Nature’s lack of employing fluorine is likely one reason for its success. Its small size (ionic radius of 0.42 Å, C—F bond length of ca. 1.35 Å) allows it to stand in for hydrogen (ionic radius of 0.53 Å, C—H bond length of ca. 1.1 Å) and block metabolism at that site.² Additionally, fluorine may offer hydrogen bond opportunities, alter the conformational bias of molecules,³ modify the pK_a of neighboring functional groups,⁴ and increase the lipophilicity of a compound.¹ These factors can affect the potency, selectivity, toxicity, and pharmacokinetic (PK) parameters of a drug, including absorption, distribution, metabolism, and excretion (ADME).⁵ Furthermore, the use of the ¹⁸F radioisotope for positron emission tomography (PET) imaging is prevalent due to its long half-life (t_1/2 = 109.8 min).⁶

1.1. Importance of α-Trifluoromethyl Amines in Bioactive Small Molecules.

Replacement of a methyl group with a trifluoromethyl group has been one significant structural manipulation in biologically active molecules.^1b,2,4 This substitution occurs in a variety of settings, from aliphatic chains to aryl rings and at N-methylamines and methyl ethers and thioethers.

One medicinally important functionality is the α-trifluoromethylamino group, which has been incorporated in several biologically active compounds with various therapeutic indications (Figure 1).¹ These molecules illustrate the wide scope of chemical space within this α-CF₃ amine framework, which encompasses both tri- and tetrasubstituted stereogenic centers and a range of flanking chemical functionalities. For example, Merck advanced odanacatib,⁷ a benzylic α-trifluoromethyl amine, to phase III clinical trials for the treatment of osteoporosis. A CF₃ analogue of taxol (α-hydroxy- β-amino acid) has been explored as a second-generation anticancer agent that shows greater activity against drug-resistant tumors as well as fewer side effects.⁸ Additionally, triazolopyrimidines (trifluoroisopropylamine) have been shown to cross the blood—brain barrier and thus have exciting potential as candidates for microtubule stabilization in treatments for cancer of the central nervous system.⁹ Structure—activity relationship studies demonstrated that a trifluoromethylamino group at the 5-position is required for potency.¹⁰

Figure 1.

α-Trifluoromethyl amine motif in biologically active molecules.

Several properties of the α-trifluoromethyl amine motif enable it to act as a bioisostere for an amide (Figure 2).¹¹ There is a linear correlation between increasing fluoride substitution at the α-position and the basicity of the amine, as exemplified for ethylamine through its trifluoroethylamine analogue (Figure 2A). The basicity can be further modulated by the presence of neighboring functional groups.^1b This effect renders the hydrogen-bonding nature of the α-CF₃ amine more like that of an amide. Other aspects of this unique functionality also enable it to mimic an amide (Figure 2B). The F₃C—C—N bond angle is approximately 120°, thus presenting an orientation of the trifluoromethyl group with respect to the nitrogen atom similar to that of a carbonyl in an amide.¹¹ The C—F dipole is also believed to be comparable to the dipole of the oxygen lone pairs of electrons within the amide’s carbonyl group.¹² One important difference, however, that helps make the α-CF₃ amine attractive for medicinal chemistry is that, unlike the amide, the sp³-hybridized nature of the trifluoromethyl amine α-carbon renders it resistant to proteolytic cleavage.¹¹ This may not only slow drug metabolism but also reduce toxicity that might arise from one or both halves of the hydrolyzed amide.¹³ Additionally, the substitution of amides by CF₃ amines may prove complementary due to the rotational freedom imparted by the sp³-hybridized center in comparison to the constraints of an amide bond.

Figure 2.

Properties and applications of α-trifluoromethyl amines.

These properties of α-CF₃ amines make this moiety attractive for integration into a peptide backbone as a means to prepare protease-resistant peptidomimetics (Figure 2C).^11,14 Within a vicinal diamine linker, the α-trifluoromethyl amine maintains the normal direction of a peptide linkage; however, the CF₃ amine might instead be incorporated to invert the direction of the peptide chain.

However, as attractive as the α-trifluoromethyl amine is as an amide surrogate in medicinal chemistry, effective use of this functionality comes with an added synthesis challenge. This idea was recently captured well by Meanwell, who wrote, “While deployment of the CF₃CH₂NH or CHF₂CH₂NH moieties eliminates metabolic sensitivity to amidases, esterases, and proteases, these motifs do introduce a new asymmetric center.”^1b As has been well established, among other effects, the stereochemical identity of the chiral amine can alter the potency of a molecule, as illustrated in Figure 2D, where the S enantiomer of a lead inhibitor for a hepatitis C viral target is >30-fold more effective than its R isomer.¹⁵ Therefore, the development of methods that furnish highly enantioenriched α-CF₃ amines is an important synthesis goal.

1.2. Strategies for Enantioselective Synthesis of α-CF₃ Amines.

With a growing need for single-enantiomer α-CF₃ amines, a number of stereoselective methods for their construction have emerged.¹⁶ The majority of these approaches have relied on diastereoselective transformations with chiral reagents, often taking one of two forms: (1) conjugate addition of chiral amines to β-CF₃-substituted Michael acceptors¹⁷ or (2) nucleophilic additions to imines bearing a chiral auxiliary attached at the nitrogen atom.¹⁸

The past two decades, however, have witnessed a growing collection of catalytic enantioselective protocols for assembling the α-trifluoromethyl amine moiety. Several of these methods mirror established diastereoselective disconnections, but a plethora of catalytic transformations are unique, enabling the construction of new chemical space for α-CF₃ amines. Many of these reactions generate primary amines with the amino group protected in some fashion or they furnish secondary aniline based products. A handful deliver secondary or tertiary aliphatic amines. Most transformations afford the α-CF₃ amines in an acyclic framework, and a nearly equal number of methods generate trisubstituted stereogenic centers (α-secondary amines) as well as tetrasubstituted centers (α-tertiary amines).

As shown in Scheme 1, these catalytic enantioselective methods can be divided into five major categories. (1) Reduction of CF₃-substituted ketimines by hydrogenation, transfer hydrogenation, and other methods is a well-trodden area. (2) Several nucleophiles have undergone catalytic addition to CF₃-substituted imines, including classic transformations such as the Strecker and Mannich reactions. (3) With only one report to date, one underdeveloped disconnection is the addition of a trifluoromethyl nucleophile to imines. (4) A burgeoning field involves umpolung reactions with CF₃-substituted imines that enable couplings with several classes of electrophiles. (5) Finally, numerous amination reactions, including amine—olefin couplings, have been examined, including both nucleophilic and electrophilic amination.

Scheme 1.

Strategies for Accessing α-CF₃ Amines

In this review, we highlight several of the catalytic enantioselective methods that afford α-trifluoromethyl amines, especially examples from the last five years. In some instances, older examples are included that epitomize a particular type of disconnection and/or illustrate important details regarding the practicality of the method toward downstream synthesis (e.g., the removal of myriad groups on nitrogen within the products to access primary amines). This collection reveals multiple approaches, which require a range of catalysts that operate under different mechanisms, but at the same time highlights a number of common catalytic strategies that are applied across several reaction categories.

2. KETIMINE REDUCTION

The catalytic enantioselective reduction of trifluoromethyl-substituted imines is a common strategy for preparing α-trifluoromethyl amines.¹⁹ As with any reaction involving ketimines, beginning with a single imine stereoisomer can be critical to achieving high enantioselectivity (E and Z isomers may lead to opposite enantiomers). The identity of the major imine stereoisomer is dependent on the relative size of the CF₃ group and the other carbon substituent in comparison to the group at the nitrogen atom in combination with their electronic nature. Moreover, imines bearing a CF₃ group pose a greater challenge: the inductive effect of the trifluoromethyl group can impede coordination of the catalyst and, after the reaction, can facilitate racemization. Even so, several groups have established various means of accessing α-CF₃ amines by reduction with boranes or silanes, transition-metal-catalyzed hydrogenation, or transfer hydrogenation protocols. Additionally, related hydrogenations of enamines,²⁰ enamides,²¹ or hydrazones²² have also yielded these chiral amines.

2.1. Hydrogenation and Transfer Hydrogenation.

Following pioneering work by Uneyama on enantioselective hydrogenation of fluoroalkyl-substituted α-iminoesters,²³ in 2010, the Zhou group was able to extend the transformation to other classes of fluoroalkyl ketimines (Scheme 2).^24,25 A Pd-based catalyst proved to be essential, and chloromethoxy-BIPHEP (1) as the supporting ligand led to the highest levels of enantioselectivity and reaction efficiency for aryl ketimines. As noted by Uneyama,²³ solvents such as ethanol undergo addition to the electrophilic imines; thus, both a high pressure of hydrogen gas and trifluoroethanol as a non-nucleophilic alcohol solvent were critical. Lower catalyst loadings (2 mol %) were permissible with the addition of molecular sieves to suppress imine hydrolysis. Product yields and enantiomer ratios are unaffected by the electronics of aryl imines; however, an o-tolyl substituent leads to slightly lower enantioselectivity. Alkyl imines smoothly undergo hydrogenation with high enantioselectivity utilizing SynPhos as the ligand (2).

Scheme 2.

Hydrogenation of Aryl- and Alkyl-Substituted CF₃ Imines

Like many transformations with trifluoromethyl-substituted imines, the reaction employs an N-aryl activating group, which may provide effective steric differentiation with the nitrogen lone pair of electrons but which gives rise to secondary aniline products. When a desired synthesis target falls within the scope of the N-aryl group, these methods provide a step-economical route; however, oftentimes the goal is to attain a primary amine. For that purpose, a commonly employed aryl group is p-methoxyphenyl (PMP), which can be cleaved via oxidative hydrolysis, a transformation that requires harsh oxidants such as ceric ammonium nitrate (CAN), as shown in Scheme 2.

Transfer hydrogenations with the same class of imines utilizing Noyori’s catalyst (3) have also recently been disclosed by Liu and co-workers (Scheme 3).²⁶ The use of sodium formate as the reducing agent is important to achieving both high yield and enantioselectivity, as other reducing agents lead to poor yield (i-PrOH) or poor yield and modest enantioselectivity (formic acid or formic acid/Et₃N). The reaction scope is limited to aryl imines, but yields and enantioselectivities are high for substrates with a range of steric and electronic characteristics and for a number of N-aryl groups as well. Strongly acidic and oxidizing conditions again have to be employed for unmasking the primary amine.

Scheme 3.

Noyori Transfer Hydrogenation with N-Aryl Ketimines

The Cahard laboratory has described a related transfer hydrogenation with a Ru—amino alcohol catalyst and i-PrOH as the reducing agent.²⁷ Under these conditions, aryl ketimines again lead to high enantioselectivity but alkyl ketimines are ineffective, leading to low reactivity and/or poor enantioselectivity. The poorer behavior of alkyl ketimines might be attributed to imine—enamine tautomerism and/or to a mixture of imine stereoisomers.

The Akiyama group has reported enantioselective transfer hydrogenations of the same class of aryl ketimines with benzothiazoline 4 as the reducing agent (Scheme 4, top).²⁸ Although the transformation is less atom economical in comparison to those that employ i-PrOH or sodium formate, the use of chiral phosphoric acid catalyst 5 might have cost advantages over Ru-based complexes. In comparison to the commonly used Hantzsch ester, benzothiazoline 4 leads to superior reactivity and enantioselectivity in the reactions. A handful of para- and meta-substituted aryl ketimines were explored, although notably no ortho-substituted substrates. Reduction of a thiophenyl imine proceeds uneventfully with high enantioselectivity. The imine could be generated in situ; however, the transformations required a considerably longer 3 day reaction time.

Scheme 4.

Transfer Hydrogenation Promoted by a Chiral Phosphoric Acid

More recently, Peng and co-workers have described another reaction with chiral phosphoric acid 5 and benzothiazoline 4 for the reduction of fluorinated alkynyl ketimines (Scheme 4, bottom). This method enables chiral fluorinated propargylamines to be obtained in spite of the chemoselectivity challenges, such as partial or complete reduction of the alkyne triple bond. An additional enantioselective reduction of alkynylimines has also been reported.³⁰

2.2. Borane Reductions.

An early strategy for the enantioselective reduction of N-aryl trifluoromethyl imines, explored by the Uneyama group, employed oxazaborolidine catalysts with catecholborane as the reducing agent.³¹ Although yields were excellent, the enantioselectivity was modest at room temperature and further deteriorated upon cooling, despite the positive effect low-temperature reductions had for the related α-trihalomethyl ketones.³²

Similar oxazaborolidine-promoted reductions were explored by Gosselin, O’shea, and co-workers³³ for N-trimethylsilyl imines, which could be formed in situ by trifluoromethyl ketone condensation with lithium hexamethyldisilazide (LiHMDS); however, these reactions also resulted in low enantioselectivity. Recognizing that an N—H imine would more closely resemble the steric properties of trifluoromethyl ketones, these researchers carried out a one-pot condensation and protodesilylation to yield the N—H imine as a mixture of stereoisomers along with its accompanying methanol adduct (Scheme 5). Although these N,O-acetals are often inert to formation of the imine, the resulting mixture of compounds was efficiently converted with oxazaborolidine 6 and catecholborane to the chiral α-CF₃ amines, which could be directly isolated in excellent yields and enantioselectivities as their ammonium salts.³⁴

Scheme 5.

Oxazaborolidine-Catalyzed Borane Reductions of N—H Imines

3. ADDITION OF CARBON- AND HETEROATOM-BASED NUCLEOPHILES TO TRIFLUOROMETHYL IMINES

The addition of several classes of carbon-based nucleophiles to trifluoromethyl imines has been extensively explored for the stereoselective synthesis of α-trifluoromethyl amines. Many of these nucleophiles have been utilized in conjunction with chiral auxiliary strategies in addition to catalytic enantioselective technologies, including a number of organometallic reagents, alkynes, allyl nucleophiles, enolate-type nucleophiles, and cyanide.^16,18 Both aldimine and ketimine electrophiles have been employed, giving rise to α-secondary and α-tertiary amines. Therefore, a broad range of chemical space has been covered by this inclusive category of transformations.

3.1. Aryl, Indole/Pyrrole, and Phenol Addition.

Benzylic amines are important pharmacophores, and their enantioselective synthesis is therefore a compelling goal. The addition of aryl nucleophiles to CF₃ imines is an attractive approach to this class of α-trifluoromethyl amines. In 2013, the Lautens group showed that arylboroxines could undergo addition to aniline-derived N,O-acetals of trifluoroacetaldehyde utilizing a neutral Pd(II) catalyst supported by PyOX ligand 7 (Scheme 6, top).³⁵ Several N-aryl groups were tolerated; however, with an o-methoxy group low enantioselectivity was observed and with a p-nitro group no reaction occurred. The arylboroxine scope was explored with the removable PMP N-aryl group. Enantioselectivity was modest with more electron-rich nucleophiles and the PMP activating group (92:8 er for p-methoxyphenyl); however, the selectivity was noticeably higher for electron-rich aryl boroxines with other N-aryl groups (96:4 er for m-bromoaniline). Slightly electron-rich or neutral nucleophiles add with high enantioselectivity within 8 h. The lack of reactivity with electron-poor arylboroxines was a significant limitation; notably even the p-fluorophenyl nucleophile requires a 48 h reaction time. The slower transmetalation rate of electron-deficient nucleophiles and the propensity of the Pd(II) catalyst to undergo reduction to inactive Pd(0) species likely contribute to these problems.

Scheme 6.

Pd—PyOX-Catalyzed Addition of Arylboroxines

Lautens and co-workers later reported a modified catalytic system to address some of the synthetic challenges they had encountered (Scheme 6, bottom).³⁶ Switching to Cl₂Pd-(PyOX) complex 8 with a silver additive that renders the Pd(II) species cationic facilitates transmetalation of the arylboroxine. Similar cationic Pd(II) catalysts have been utilized by the Stoltz group³⁷ for conjugate addition with arylboron nucleophiles and by Hayashi and co-workers³⁸ for addition to cyclic sulfonyl imines. The researchers also switched the electrophile to the preformed imine, enabling both electron-poor and electron-rich boroxines to add with high enantioselectivity within 20 h. However, ortho-substituted nucleophiles remain a challenge: o-tolyl addition occurs in 58% yield and 87:13 er.

The Xu group has disclosed an interesting chiral sulfur—olefin ligand (9) for arylboronic acid additions to imines, among them cyclic sulfonyl imines (Scheme 7).^39,40 Utilizing conditions similar to those for other Rh—diene-catalyzed imine arylation reactions,⁴¹ these researchers illustrated the excellent reactivity and enantioselectivity with ligand 9 for several cyclic sulfonyl imine classes, including the cyclic trifluoromethyl imine in Scheme 7. The scope of the aryl nucleophile was modestly explored with this imine. A variety of substitution patterns and electronics are tolerated and lead to good product yields; however, an o-tolyl nucleophile afforded only a 26% yield of the product.

Scheme 7.

Rh-Catalyzed Arylboronic Acid Addition to Cyclic Sulfonyl Imines with a Chiral Sulfur—Olefin Ligand

The Tang group has developed a Rh—bis(phosphine)-catalyzed method for the coupling of arylboroxines with acyclic trifluoromethyl ketimines (Scheme 8).⁴² Notably, the use of the unprotected N—H imine enables direct access to the primary amine of the products and likely facilitates formation of the sterically congested stereogenic center. Of the chiral phosphines explored, WingPhos (10) provided the greatest conversion to the diaryl trifluoroethylamine products, and CsF proved to be the optimal base. Electron-poor imines led to higher product yields, and the transformation is also tolerant of a furyl imine. A handful of boroxines were explored, with most being electron-rich or neutral. The most electron-deficient p-chlorophenyl nucleophile furnishes the chiral amine in 73% yield. A single enantiomer of the product was obtained in every case.

Scheme 8.

Arylboroxine Addition to N—H Imines with a Rh—Bis(phosphine) Catalyst

Several research groups have investigated the addition of indoles and pyrroles to trifluoromethyl aldimines and ketimines catalyzed by BINOL-derived chiral phosphoric acids. In 2008, Ma and co-workers showed that aldimines generated in situ from trifluoroacetaldehyde hemiacetal and 3,4,5-trimethoxyaniline undergo coupling with variously substituted indoles in the presence of chiral phosphoric acid 11 (Scheme 9).⁴³ The aniline identity is critical, as the PMP aniline leads to racemic product. The use of unprotected indoles is also important: N-benzyl and N-acetylindoles are unreactive, which the authors attribute to a weak hydrogen-bonding interaction of the indole N—H and phosphoric acid 11. Several 5-, 6-, and 7-substituted indoles react with high enantioselectivity, furnishing the products in good yields, although several reactions are sluggish. The more hindered 2-methylindole requires a 4 day reaction time and adds with modest enantioselectivity (89.5:10.5 er).

Scheme 9.

Chiral Phosphoric Acid Catalyzed Additions of Indole and Pyrrole

Subsequently, several other groups investigated similar reactions with various ketimines. Bolm and co-workers studied indole additions to an N-Boc trifluoromethylpyruvate-derived imine with phosphoric acid 11.⁴⁴ Later, the Ohshima group utilized unsymmetrical chiral phosphoric acid 12 for indole and pyrrole additions to the unprotected imine of the same ketimino ester.⁴⁵ The Akiyama laboratory has explored indole and pyrrole additions to unprotected aryl CF₃ imines with catalyst 11.⁴⁶

The Lin group has reported several examples of indole couplings with CF₃ imines (Scheme 10). Their earliest method concerned a Pictet—Spengler reaction between an indolo aniline and trifluoromethyl ketones, whereby C—C bond formation occurs at the indole C3 position (Scheme 10, left).⁴⁷ The transformations are promoted by the spirocyclic chiral phosphoric acid 13. Aryl ketones lead to high levels of enantioselectivity and good yields; however, the reactions of alkyl ketones are poorly enantioselective (e.g., 77.5:22.5 er for the benzyl ketone). Although the main substrate variation was in the ketone, a handful of indoles were explored, albeit with identical R¹ and R² groups in each case.

Scheme 10.

Spirocyclic Chiral Phosphoric Acid Catalyzed Indole and Pyrrole Additions to Cyclic CF₃ Imines

Lin and co-workers have also investigated a number of intermolecular couplings of indoles and pyrroles with cyclic CF₃ imines, all utilizing a chiral spirocyclic phosphoric acid catalyst. As shown on the right-hand side of Scheme 10 for example, reactions of the tetracyclic substrates, bearing a seven-membered-ring imine, take place within 24 h with phosphoric acid catalyst 14.^48,49 A handful of reaction partners were explored, and although the yields were good, the enantioselectivities were modest in most cases.

Trifluoromethyl-substituted quinazolinones are favorite targets for reaction development, as allylic or propargylic amines derived from their alkenylation or alkynylation, analogues of efavirenz, have shown activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment.⁵⁰ Aryl additions to this substrate class have also been explored in preparing related benzylic amines.

In 2013, the Ma laboratory disclosed indole additions to these quinazolinones promoted by chiral phosphoric acid 11 (Scheme 11, left).⁵¹ Like many other transformations of this electrophile class, a PMB protecting group at the amide nitrogen was employed, which was crucial for obtaining high enantioselectivity. Most reactions take place within 24 h at −35 °C; however, more electron-poor indoles require extended reaction times, with the 5-cyano derivative delivering only a 56% yield after 5 days. Still, a good range of reaction partners undergo coupling with excellent enantioselectivity levels. Additionally, one example of pyrrole addition (92% yield, 90:10 er) and phenol addition (94% yield, 81.5:18.5 er) were demonstrated (not illustrated).

Scheme 11.

Indole and Phenol Additions to CF₃ Quinazolinones

Wang, Xie, and co-workers have also shown that phenols and naphthols competently add to CF₃ quinazolinones.⁵² The team utilized the cinchona alkaloid derived squaramide 15 as the catalyst rather than a chiral phosphoric acid (Scheme 11, right), which is unusual for these types of couplings of electron-rich arenes to CF₃ imines. Equally rare, they also demonstrated that unprotected quinazolinones undergo highly efficient and enantioselective couplings. Several electron-rich nucleophiles add to a handful of substituted quinazolinones. The most electron-poor nucleophile reported was 4-chloro-1-naphthol.

3.2. Alkylation.

The synthesis of α-trifluoromethylamines that bear an alkyl group at the stereogenic center is an important subset of this valuable class of compounds. Even so, there are limited catalytic enantioselective approaches to these chiral amines. One direct strategy is the alkylation approaches of CF₃-substituted imines with organometallic reagents. Two methods for the addition of diorganozinc reagents to aryl CF₃ imines have been reported (Scheme 12).

Scheme 12.

Additions of Diorganozinc Reagents to Aryl CF₃ Ketimines

In 2006, the Charette group disclosed a Cu-catalyzed enantioselective addition of dimethyl- and diethylzinc to N-phosphinoyl ketimines generated in situ from N,O-acetals (Scheme 12, top).⁵³ The Charette laboratory discovered that the use of Me-DuPhos monoxide (BozPhos, 16), which they notably employ in lower concentration in comparison to Cu, is essential for higher reactivity with the less reactive dimethylzinc. Still, reactions require 48 h at 0 °C, but yields and enantioselectivities are excellent. The transformations with diethylzinc are significantly faster but deliver products in lower yields and enantiomer ratios. The diphenylphosphinoyl group can be cleaved under strongly acidic conditions to yield the corresponding ammonium salt.

Shortly thereafter, the Hoveyda and Snapper laboratories illustrated dimethylzinc additions to CF₃ ketimines bearing an o-methoxyphenyl activating group on nitrogen (Scheme 12, bottom).⁵⁴ This aryl group is critical for providing a chelation site for the zirconium Lewis acid. The phenylalanine—valine-derived dipeptide 17 plays a dual role in the catalysis. The aminophenol and valine carbonyl afford tridentate chelation for zirconium, delivering a chiral Lewis acid to activate the imine, while the C-terminal amide carbonyl provides Lewis base activation for dimethylzinc. Several imines, including an indole derivative, undergo highly enantioselective additions with a noteworthy electronic effect upon yield: more electron-deficient imines react readily and in good yields at room temperature, whereas the more electron-rich substrates (e.g., p-methoxyphenyl) require elevated temperature and are obtained in more modest yields (66%). An o-methoxy substrate was unreactive. The aniline can be cleaved through oxidation with PhI(OAc)₂ followed by hydrolysis.

3.3. Allylation.

The Hoveyda group has recently detailed a boron(aminophenol)-catalyzed addition of (Z)-crotyl and other Z-disubstituted allylboron reagents to N—H ketimines (Scheme 13).⁵⁵ The sensitivity of the unprotected imine makes it unsuitable as the starting material for the reaction. Instead, Hoveyda and co-workers realized that the desired imines might be formed in situ from N-trimethylsilyl precursors; however, unlike previous reports (cf., Scheme 5), methanol alone proved insufficient for the task, leading to <2% conversion to product. A substoichiometric quantity of (n-Bu)₄N(Ph₃SiF₂) as a fluoride source in conjunction with methanol enables the controlled generation of the N—H imine and avoids the formation of the unreactive N,O-acetal.

Scheme 13.

Boron—Aminophenol-Catalyzed Addition of (Z)-Allylboron Reagents to In Situ Generated N—H Ketimines

Threonine-based 18 proved to be crucial for achieving high enantioselectivity in these sterically driven reactions in comparison to valine-derived catalysts utilized in the group’s trifluoromethylketone—allyl coupling work, where electrostatic attraction of the CF₃ group to the catalyst’s ammonium functionality was the dominating factor.⁵⁶ Hyperconjugation of the σ_C–N bond within 18 with the neighboring methyl ether’s σ*_C–O bond achieves the optimal catalyst conformation for maximizing the imine’s facial discrimination.

Transformations are highly α-selective and stereoretentive with respect to the allylboron, furnishing the α-tertiary-α-CF₃ homoallylic amine products. A boron atom from the allylboron reagent becomes chelated by the aminophenol and neighboring carbonyl of 18, affording the active catalyst. The observed net α-selectivity arises from a double γ-transfer of the allylboron reagent, first to the boron atom of the active catalyst and from there to the imine, a process which also preserves the initial stereochemistry of the nucleophile. The (E)-crotyl boron reagent is considerably less reactive. The Zn(OMe)₂ Lewis acid cocatalyst facilitates the reaction by binding to Lewis basic sites within the boron—18 catalyst.⁵⁷

Several aryl imines participate effectively in the reactions. Notably, the more electron-rich substrates are slightly slower to react (e.g., p-NMe₂). In general, α-selectivity is high; however, sterically hindered imines, such as o-tolyl, lead to an approximately equal mixture of α- and γ-isomers. As C—C bond formation becomes more difficult, a 1,3-borotropic shift of the allyl group occurs at the catalyst, eroding regioselectivity. Certain heterocyclic imines are tolerated (e.g., 2-thiophenyl), as are alkenyl and alkynyl imines, but alkyl-substituted imines result in a variety of decomposition pathways under the reaction conditions, preventing their coupling. Beyond crotylation, other allyl fragments may be added to the imine, including (Z)-alkenylhalides that may facilitate further synthesis applications.⁵⁸

3.4. Alkynylation.

Enantioenriched propargylamines are important building blocks for natural product and drug synthesis, and one method for preparing them involves terminal alkyne additions to imines. A significant number of methods utilizing several different catalytic systems have been established to this end. Among these, a handful of approaches to α-CF₃ propargylic amines have been investigated.

One of these valuable alkynylation reactions involves additions to CF₃-substituted quinazolinones for the construction of NNRTI analogues that have been directly explored as HIV therapeutics.⁵⁰ Early work in preparing these compounds includes diastereoselective 1,4-addition of a magnesium acetylide to quinazolinones containing a chiral auxiliary substituent⁵⁹ or 1,2-enantioselective addition of a lithium acetylide, coordinated by cinchona alkaloids, to cyclic ketimines.⁶⁰ These methods require the use of 3—5 equiv of organometallics and low temperature (−60 to −75 °C); under strongly basic conditions, decomposition of the product was observed. In 2004, Jiang and a co-worker reported a direct alkynylation reaction at room temperature utilizing a stoichiometric chiral zinc—amino alcohol complex.⁶¹

1,3-Enyne additions to these cyclic trifluoromethyl ketimines have been reported more recently by Zhang, Ma, and co-workers (Scheme 14).⁶² Although stoichiometric in dimethylzinc, a substoichiometric quantity of chiral BINOL 19 efficiently promotes the coupling of several monosubstituted enynes. When the nucleophile’s substituent is aryl, enantioselectivities are good to excellent; however, alkyl-containing enynes add with lower levels of selectivity. Notably, in most cases, the products can be crystallized to higher levels of enantiomeric purity.

Scheme 14.

Zinc—BINOL-Catalyzed Alkynylation of CF₃ Quinazolinones

Building on efforts with trifluoropyruvate-derived ketimines,⁶³ the Zhang group developed a zinc-catalyzed alkynylation of acyclic trifluoromethyl ketimines by employing stoichiometric dimethylzinc and a substoichiometric quantity of the BINOL derivative 20 (Scheme 15).⁶⁴ The steric and electronic parameters of the 3/3′-substituents of 20 were critical for reaction efficiency. The N-aryl activating group on the imine contains the familiar o-methoxy substituent but additionally a p-nitro group to increase electrophilicity. The products’ aniline therefore requires reduction of this nitro group prior to oxidative cleavage to reveal the primary amine (Scheme 15, bottom). Several aryl ketimines undergo addition of phenylacetylene, but whereas electron-rich and neutral substrates proceed with high enantioselectivity, more electron-poor imines react with modest selectivity levels (e.g., 77.5:22.5 er for a p-CF₃ substrate). A thiophenyl-substituted imine (not shown) and an α,β-unsaturated imine (97% yield, 93:7 er) are also effective partners. The acetylene scope encompasses a variety of substituents, including cyclopropyl and trimethylsilyl.

Scheme 15.

Zinc—BINOL-Catalyzed Alkynylation of Acyclic Imines

The Ohshima laboratory has explored alkynylation reactions of the N-Cbz imine of trifluoromethylpyruvate ethyl ester (Scheme 16).^65,66 After initially disclosing reactions with a Rh(OAc)₂(OH₂)—PheBox catalyst, the researchers discovered that the related alkynyl—Rh(κ²-OAc)—PheBox complex 21 allows for lower catalyst loadings (0.5 mol %) with aryl acetylenes.⁶⁷ The identification of this optimal precatalyst also enabled an expanded substrate scope to α-ketiminophosphonates with complex 22. Intriguingly, complexes 21 and 22 lead to alkyne addition to the same face of their respective imine substrates despite their having an opposite sense of absolute stereochemistry and the imine geometry being the same in both cases.

Scheme 16.

Rh—PheBox-Catalyzed Alkynylation of CF₃ Ketimino Esters and Diethylphosphonate Analogues

For the carboxylic esters, aryl acetylene additions occur readily with 0.5 mol % of complex 21 at room temperature within 12 h. In contrast, aliphatic alkynes require 3.0 equiv of the acetylene, the addition of molecular sieves, 48 h reaction times or longer in some cases, and 0 °C reaction temperature; transformations are less enantioselective in comparison to their aryl counterparts. The functional group tolerance of the reaction, however, is excellent, including acetal and free hydroxyl groups. Even a formyl group goes unscathed, with acetylene addition occurring only at the imine (86% yield, 97.5:2.5 er). The reaction efficiency and enantioselectivity are also excellent for aryl acetylene additions to the α-iminophosphonate esters but are somewhat lower for the cyclopropylacetylene (86% yield, 90:10 er).

3.5. Strecker Reaction.

The Strecker reaction is a hallmark method for constructing α-amino acids, and the enantioselective version has received considerable attention.⁶⁸ Cyanide additions to ketimines provide an invaluable route to α,α-disubstituted amino acids, useful moieties for introducing secondary structure to peptides among other applications. With the additional benefits of a trifluoromethyl group, the catalytic enantioselective Strecker reaction with CF₃ ketimines is a compelling goal.

Initial forays into the stereoselective synthesis of this building block utilized chiral auxiliaries bound to the imino nitrogen atom,^18a,69 but in 2010, the Enders laboratory reported the catalytic enantioselective addition of trimethylsilyl cyanide to N-aryl trifluoromethyl ketimines catalyzed by Takemoto’s thiourea 23 in the presence of isopropyl alcohol (Scheme 17, top).^70–72 The transformations are highly enantioselective for aryl ketimines regardless of electronics; however, ortho-substituted arenes show poor reactivity. Heteroaromatic, α,β-unsaturated, and aliphatic substrates are viable reaction partners, although these imines all require double the catalyst loading (10 mol %). A serious drawback to an otherwise attractive method is the long reaction times needed, the shortest of which is 5 days and some that require 27 days. Additionally, beyond the strong oxidant needed to remove the PMP group at nitrogen, hydrolysis of the nitrile, directly adjacent to the fully substituted stereogenic center, also requires harsh conditions (refluxing 12.0 M aqueous HCl for 36 h).

Scheme 17.

Thiourea- and Urea-Catalyzed Strecker Reactions with CF₃ Ketimines

In contrast, the research team of Wang and Zhou discovered that a quinidine-derived urea catalyst (24), in conjunction with 1 equiv of hexafluoroisopropyl alcohol as an additive, leads to a large rate acceleration in comparison to thiourea 23, with reactions taking place within 1–2 days (Scheme 17, bottom).^73,74 The authors suggest that the role of the alcohol is to form HCN from trimethylsilyl cyanide;⁷⁵ the alcohol identity was vital to obtaining high enantioselectivity, as it was suggested that other alcohols lead to a high rate of uncatalyzed reaction. On the basis of a survey of H-bond donor catalysts, the authors propose that 24 is bifunctional: its tertiary amine deprotonates HCN while its urea engages in hydrogen bonding with the imine nitrogen and fluorine of the CF₃ group. Such a mode of H-bond donation requires isomerization of the (Z)-imine starting material to the E isomer.⁷⁶ Yields and enantioselectivities are impressive and comparable to those obtained by the Enders group with the Takemoto catalyst (23) for both aryl and alkyl imines but at significantly reduced reaction times.

A research team led by Zheng, Cao, and Zhao recently reported Strecker reactions of aryl CF₃ imines (Scheme 18).⁷⁷ A bifunctional phosphine—thiourea catalyst (25) was employed with methyl acrylate acting as a cocatalyst. The authors propose that the thiourea moiety engages in H-bond activation of the imine electrophile while the phosphine portion of 25 undergoes conjugate addition to methyl acrylate, with the resulting enolate oxygen activating the trimethylsilyl cyanide for nucleophilic attack. This unusual quaternary complex, orchestrated by 25, elicits highly efficient and enantioselective transformations. The research group first explored N-PMP imines (Scheme 18, top), which the authors propose engage in H-bonding with 25 through the imine nitrogen and a fluoride of the CF₃ group. Note that the paper’s authors suggest that the (E)-imine is utilized in the transformation in order to conform to their stereochemical model; however, given that other laboratories report this substrate as the Z isomer and taking into account the fluxional stereochemical nature of ketimines in the presence of H-bond donors,⁷⁶ it is perhaps more likely that the (Z)-imine is added to the reaction medium but isomerizes to the E isomer under the reaction conditions. A range of aryl groups was explored, with most transformations taking place within 24 h at −20 °C. ortho-Substituted arenes, however, are sluggish, as exemplified by the o-chlorophenyl substrate, which leads to only a 45% yield of the product after 3 days.

Scheme 18.

Phosphine—Thiourea and Methyl Acrylate Cocatalyzed Strecker Reaction with Aryl CF₃ Ketimines

This research group has also explored reactions of the synthetically more useful N-Boc imines (Scheme 18, bottom). Remarkably, the same catalyst system leads to the opposite major enantiomer of the product. The researchers attribute this switch to a different mode of hydrogen bonding between the catalyst and the imine, again with the imine nitrogen but this time through the Boc carbonyl oxygen. This leads to a different face of the imine being presented to the incoming cyanide. The reactions are considerably more efficient (1 — 10 h at −72 °C) but less enantioselective.

In 2012, the Ma laboratory disclosed a thiourea-catalyzed enantioselective cyanide addition to CF₃ quinazolinones (Scheme 19).^78,79 The efficient transformations utilize just 1 mol % of cinchona alkaloid derived catalyst 26 with a handful of quinazolinones bearing different substituents about the aromatic ring. All of the reactions deliver products in excess of 95:5 er. The familiar PMB-protected quinazolinone was utilized in most cases, but the Ma group also illustrated one example of cyanide addition to the free quinazolinone, which proceeded uneventfully with high enantioselectivity (not shown).

Scheme 19.

Thiourea-Catalyzed Strecker Reaction with Quinazolinones

3.6. Mannich, Vinylogous Mannich, and Aza-Henry Reactions.

The Mannich reaction is a venerable C—C bond-forming approach involving imines, and there has been great investment in developing enantioselective versions throughout the years.⁸⁰ Several groups have explored Mannich reactions with trifluoromethyl imines, promoted either by H-bond donor or chiral amine catalysts.

A number of laboratories have investigated proline-catalyzed addition of acetone to fluoroalkyl imines.⁸¹ For example, in 2005, the Fustero group disclosed the proline-catalyzed direct Mannich reaction of aldehydes and an N-PMP trifluoromethyl imine (Scheme 20).⁸² The transformations afford the syn-addition product exclusively as a single enantiomer. A handful of aldehydes were shown to participate. However, there are several drawbacks to the method. The reactions require 3 days and give low yields (ca. 40%). Furthermore, the reaction procedure is laborious, requiring the temperature to be raised by 10 °C each day (from −20 to 0 °C).

Scheme 20.

Proline-Catalyzed Mannich Reaction between Aldehydes and CF₃ Aldimines

In contrast to Mannich reactions with proline as the catalyst, the Wang group has shown that amino acid based catalysts 27 and 28 can promote the addition of acetone and acetophenones to cyclic sulfonyl imines bearing a CF₃ group (Scheme 21, left).⁸³ With the imine hydrate as the starting material, reactions proceed under fairly mild conditions with the catalytic 2,6-difluorobenzoic acid additive 29 assisting in imine formation. The transformations with acetone largely employ amine 27 as the catalyst (5 mol %), delivering products in excellent yields and enantiomer ratios. Reactions with aryl ketones require 20 mol % of amino alcohol 28, prolonged reaction times (60 h vs 36 h), and higher temperature (35 °C).

Scheme 21.

Mannich Reaction of Cyclic Sulfonyl N,O-Acetals with Amino Acid Derived Catalysts

The same group has explored a cascade Mannich reaction—conjugate amination with α,β-unsaturated methyl ketones (Scheme 21, right).⁸⁴ Benzoic acid 29 is completely ineffective in delivering the tricyclic product; however, the stronger Brønsted acid p-nitrobenzoic acid (30) is able to facilitate the annulation process. A number of enone β-aryl groups are tolerated, generally affording ≥10:1 dr and >95:5 er. Notably, an o-tolyl group at the β-position leads to a modest 6:1 dr. Two related β-alkyl-substituted enones were also investigated and deliver the α-CF₃ amine products in moderate diastereoselectivity and good to excellent er. A number of aryl substituents on the electrophile were also studied and lead to products with exquisitely high stereoselectivity.

The authors propose that amine catalyst 28 replaces the hydroxyl group on the N,O-acetal substrate, forming an aminal that they observe spectroscopically. They then conjecture that this intermediate lies on the catalytic pathway, with the catalyst directly displaced by the enol of the enone before cyclization by sulfamide conjugate addition. Perhaps a more likely scenario involves initial enone condensation with 28 to form a chiral enamine, which then undergoes a Mannich reaction with the imine of the dehydrated N,O-acetal.

In 2020, Zhang, Wang, and co-workers related an amine-catalyzed Mannich reaction of methyl ketones with a different class of cyclic sulfonyl imines (Scheme 22).⁸⁵ Diphenylethy-lenediamine 31, in conjunction with a substoichiometric quantity of trifluoroacetic acid, promotes the addition of a number of dialkyl ketones, including acetone. Several substitutions of the imine’s arene were explored as well. Enantioselectivities are broadly excellent for the ketone substrates that lack α-branching. However, cyclopropyl methyl ketone delivers the product in only 86.5:13.5 er, which the authors attribute to steric hindrance from the cyclopropyl group in this context. A large excess (10 equiv) of the ketone is required for the transformation.

Scheme 22.

Amine-Catalyzed Mannich Reaction of Cyclic Sulfonyl Imines with Aliphatic Ketones

The Ohshima group has disclosed Mannich reactions between two different classes of nucleophiles and the N—H α-imino ester derived from trifluoromethylpyruvate (Scheme 23)⁸⁶ Transformations are promoted by the cinchona alkaloid-derived thiourea 26. First, symmetrical acyclic 1,3-diketones add to the highly electrophilic imine with good to excellent levels of enantiocontrol (Scheme 23, top). Both aryl and heteroaryl diketones may serve as partners, and alkyl diketones are also effective nucleophiles. Additionally, Morimoto, Ohshima, and co-workers demonstrated that α-substituted 2-oxindoles also participate in Mannich reactions (Scheme 23, bottom), delivering products with two contiguous fully substituted stereogenic centers. Impressively, the nucleophilic partner is not limited to substrates bearing an α-electron-withdrawing group but as shown may include simple α-alkyl groups (e.g., methyl or benzyl). Both the diastereo- and enantioselectivity are high.⁸⁷

Scheme 23.

Thiourea-Catalyzed Mannich Reaction of Trifluoromethylpyruvate-Derived N—H Imine

More recently, in 2018 You and Luo reported the addition of malonyl-type nucleophiles to N-Cbz trifluoromethyl aldimines formed from N,O-acetals, leading to α-secondary amines (Scheme 24).⁸⁸ A simple diamine (32), utilized as its monoammonium salt, acts as the catalyst, although a 20 mol % loading is required (60 °C, 48 h). Still, a single enantiomer of the product is obtained in every case. The diastereoselectivity in the reaction of unsymmetrical pronucleophiles varies considerably. For example, diketones lead to a 1:1 mixture of diastereomers, whereas secondary amide-derived ketoamides give much higher selectivity (≥10:1 dr). In contrast, tertiary amide-derived ketoamides are poorly stereoselective ((2—3):1 dr). α-Substituted ketoesters were investigated, delivering products bearing quaternary stereogenic centers; although a single diastereomer is obtained, yields are much more modest.

Scheme 24.

Amine-Catalyzed Mannich Reaction of 1,3-Dicarbonyl Nucleophiles

A handful of Mannich reactions have also been developed with CF₃ quinazolinone substrates. The Ma laboratory has studied a decarboxylative Mannich reaction with β-ketoacids (Scheme 25, left).⁸⁹ This group employed a β-glucose-derived bifunctional thiourea catalyst (33), the thiourea unit of which activates the imine through H-bonding and the tertiary amine of which acts as a general base in engaging with the carboxylic acid of the nucleophile. A wide range of aryl and aliphatic ketones take part, with products obtained in excellent yields and enantioselectivities (>95:5 er in every case) within 2—3 days at −20 °C. A trifluoro- or difluoromethyl group on the quinazolinone ring is required for the reaction to take place.

Scheme 25.

H-Bonding Catalysis for β-Keto Acid Decarboxylative Mannich Reaction and Pyrazoleamide Mannich Reaction with CF₃-Substituted Quinazolinones

In 2018, Xu, Yuan, and co-workers demonstrated that pyrazole amide-based enolates may add with high degrees of diastereo- and enantioselectivity to quinazolinones (Scheme 25, right).⁹⁰ A bifunctional cinchona alkaloid derived squaramide catalyst (34) was utilized. Similar to other related catalysts, the tertiary amine acts as a base and engages in H bonding with the nucleophile while the squaramide activates the quinazolinone. The stereoselectivity is exceptional, but yields are highly variable.

A team led by Zhao and Shi has reported an interesting Mannich reaction and annulation cascade with CF₃ quinazolinones utilizing α-isonitrile acetates (Scheme 26).⁹¹ The transformations are cocatalyzed by the quinine-based squaramide 35 and AgOAc. The proposed role of the silver catalyst is to coordinate the isonitrile, presumably activating the pronucleophile toward deprotonation by the tertiary amine of 35. The researchers also propose additional structural organization by the secondary alcohol of 35 within the quaternary complex of the two catalysts and two substrates. The authors suggest bidentate hydrogen bonding of the quinazolinone carbonyl with the hydroxyl and proximal squaramide N—H of 35, while at the same time the remaining squaramide N—H is bifurcated between the quinazolinone imine and the deprotonated nucleophile. The tertiary amine of 35 provides an additional H-bonding interaction with the nucleophile. The reactions are exceptionally fast (10 min at 0 °C), and the yields and stereoselectivities are universally high.⁹²

Scheme 26.

CF₃-Quinazolinone Annulation with α-Isonitrile Acetates through H-Bonding Catalysis

The Trost group has developed a highly enantio- and diastereoselective vinylogous Mannich reaction with unsaturated γ-butyrolactone derivatives (one of two tautomers depending on the R² group identity) and alkynyl CF₃ imines (Scheme 27).⁹³ The transformations are chemoselective for 1,2-addition to the unsaturated imines and show excellent γ-selectivity with respect to the nucleophile. The small size of the alkyne allows for a single imine stereoisomer to be prepared, and its electron-withdrawing nature facilitates the formation of the γ-product, which bears two contiguous tetrasubstituted stereogenic centers.

Scheme 27.

Zinc—ProPhenol-Catalyzed Vinylogous Mannich Reaction with Alkynyl Trifluoromethyl Imines

Key to these outcomes was the use of a dinuclear zinc catalyst formed from ProPhenol ligand 36 or 37, developed in the Trost laboratory.⁹⁴ Interestingly, when the nucleophile’s R² group is methyl, the unsymmetrical ligand 36 offers higher diastereoselectivity in comparison to the more widely used C₂-symmetric 37. It was discovered that a substoichiometric quantity of an alcohol additive (38) suppresses decomposition of the starting materials.

The reaction scope is excellent. A number of internal alkyne classes are tolerated, including aryl, alkenyl, silyl, and alkyl, but alkenyl- and alkyl-substituted acetylenes require double the catalyst loading (20 mol % of 36, 40 mol % of Et₂Zn). A variety of synthetically useful groups within the nucleophile also work for the coupling, such as a protected hydroxymethyl group and an allyl group, utilizing the catalyst derived from 37. Use of an N-Boc activating group for the imine allows for its easy subsequent conversion to the free amine.^95,96

In 2017, the Enders group disclosed an N-heterocyclic carbene (NHC)-catalyzed oxidative vinylogous Mannich reaction of β,β-disubstituted enals with CF₃ quinazolinones, wherein subsequent cyclization of the imine nitrogen enables catalyst release and furnishes the tricyclic product (Scheme 28).⁹⁷ Triazolium 39 serves as the NHC precursor and bis(quinone) 40 as the stoichiometric oxidant. NHC condensation with the enal affords the Breslow intermediate, which is then oxidized by 40 to deliver an acyl azolium species. Deprotonation then affords a dienolate bound to 39, poised for vinylogous Mannich and cyclization to deliver the product. A mixture of enal stereoisomers could be utilized. When R² is an aryl group, the yields and enantioselectivities are good, and several quinazolinones could be combined with a variety of these enals. Geranyl aldehyde was also explored but leads to more modest levels of enantioselectivity and reaction efficiency.

Scheme 28.

NHC-Catalyzed Oxidative Vinylogous Mannich Reaction/Annulation with CF₃-Substituted Quinazolinones

Wang and co-workers have investigated an aza-Henry reaction (nitro-Mannich) with CF₃-substituted quinazolinones (Scheme 29).⁹⁸ The reactions are catalyzed by just 1 mol % of the cinchona alkaloid derived 6′-thiourea 41. Nitromethane adds to variously substituted quinazolinones with good efficiency and high enantioselectivity. Longer chain nitroalkanes react with similarly good metrics; however, the diastereoselectivity is low (up to 3:1 dr). For simple substrates, such as nitroethane, the two diastereomers have approximately equal enantiomeric ratios. In contrast, a cyclopropyl-containing nitroalkane, which the researchers utilized in preparing the anti-HIV drug DCP 083, affords a 1.5:1 mixture of diastereomers where the two isomers have significantly different er values (95:5 for the major isomer but 85:15 for the minor isomer).

Scheme 29.

Thiourea-Catalyzed Aza-Henry Reaction with CF₃-Substituted Quinazolinones

More recently, Lin, Duan, and co-workers have reported a phase transfer/H-bonding catalyst (42), based on a catalyst originally designed by the Dixon group, for the addition of nitroalkanes to N-Boc trifluoromethyl ketimines (Scheme 30).^99,100 The phenylglycinol side arm of the urea within 42 offers superior enantioselectivity in comparison to the original catalyst, which bears a 3,5-bis(trifluoromethyl)phenyl moiety. The transformations are sluggish, with most requiring 5—7 days at −20 °C with 5 mol % of 42, but the yields and enantioselectivities are high. The authors mainly explore nitromethane additions, although the one example of a nitroethane reaction leads to excellent diastereoselectivity (major isomer not identified). However, the nitroalkane partner is used in gross excess (25 equiv), essentially as the cosolvent, thus limiting the scope of the method.

Scheme 30.

Urea-Catalyzed Aza-Henry Reaction with N-Boc Trifluoromethyl Ketimines

3.7. Aza-Benzoin.

The enantioselective aza-benzoin reaction enables a complexity-building C—C bond-forming route to α-amino ketones, yet few examples of this carbonyl umpolung process have been reported.¹⁰¹ One method, developed in the Ye laboratory, combines α,β-unsaturated aldehydes with N-Boc trifluoromethyl ketimines, catalyzed by the NHC formed from triazolium salt 43 (Scheme 31).¹⁰² The chemoselectivity in this reaction is impressive, as the catalyst directs the aza-benzoin over the homobenzoin and Stetter reactions between aldehyde reaction partners. Additionally, regioselectivity with respect to the Breslow intermediate is perfect, with only carbonyl carbon addition observed, giving rise to the α-amino ketone (versus homoenolate addition to form a γ-lactam). The researchers attribute the regioselectivity to the small steric properties and flexibility of the N-benzyl group within 43. They also ascribe the enhanced reactivity with 43, in comparison to related catalyst candidates, to result from the free hydroxyl group, which they propose engages in H-bonding with the imine, a phenomenon enhanced by the adjacent electron-withdrawing aryl groups.

Scheme 31.

NHC-Catalyzed Aza-Benzoin Reaction between Unsaturated Aldehydes and Trifluoromethyl Ketimines

Each α-amino ketone product is formed with excellent enantioselectivity. Yields are good to excellent with cinnamyl aldehydes but appear to be tied to electronics, with electron-rich arenes generally affording greater product yields. A β-furyl aldehyde leads to the amino ketone in 68% yield and 95:5 er. With β-alkyl-substituted aldehydes, yields are more modest and alkynyl aldehydes deliver the ketone products in low yield (<40% yield). Substitution of the arene within the imine was only somewhat explored but nevertheless furnished the corresponding α-amino ketones in good yields.

The highly functionalized aza-benzoin products derived from the couplings can be further transformed into other useful scaffolds. Removal of the Boc protecting group under acidic conditions affords the free amine in 83% yield. A Pd/C hydrogenation of the alkene delivers the saturated ketone in 78% yield, whereas LiBH₄ reduction of the carbonyl furnishes a 1,2-amino alcohol chemoselectively as the exclusive anti diastereomer (73% yield).

3.8. Hydrophosphonylation.

The development of methods for additions of heteroatom nucleophiles to CF₃ imines are uncommon, although the geminal heteroatom-substituted carbon might be useful in certain contexts. One such reaction was developed in 2013 by Sheng, Wang, and co-workers and involves the catalytic hydrophosphonylation of CF₃ quinazolinones (Scheme 32). Thiourea catalyst 26 promotes the addition of a handful of phosphites to PMB-protected quinazolinones with good levels of enantioselectivity, and the resulting α-amino phosphinate esters are interesting α-amino acid analogues.¹⁰⁴

Scheme 32.

Thiourea-Catalyzed Hydrophosphonylation of CF₃-Substituted Quinazolinones

4. NUCLEOPHILIC TRIFLUOROMETHYLATION

Introducing the trifluoromethyl group in a reaction to generate α-trifluoromethyl amines can circumvent the challenges associated with preparing CF₃ imines.¹⁰⁵ However, such an approach has its own difficulties, foremost the low nucleophilicity of the trifluoromethyl anion. Building on their earlier work in trifluoromethylation of ketones,¹⁰⁶ in 2009, the Shibata group demonstrated that trimethylsilyltrifluoromethane undergoes addition to azomethine imines under phase transfer catalysis (Scheme 33).¹⁰⁷ Three structural aspects of the substrate’s activating group, an azomethine imine commonly employed in [3 + 2]-cycloadditions, were identified as critical. The increased electrophilicity of the azomethine imine in comparison even to an N-tosyl imine was needed to offset the low nucleophilicity of the CF₃ anion. The constrained nature of the cyclic activating group and the gem-dimethyl moiety within it greatly improve reactivity and enantioselectivity. A large quantity of KOH and Me₃SiCF₃ is necessary because of low KOH solubility; however, the carbonyl oxygen of the imine activating group was proposed to assist in turning over the reaction.

Scheme 33.

Trifluoromethylation of Azomethine Imines with a Chiral Phase Transfer Catalyst

The cinchona alkaloid derived ammonium catalyst 44 was optimal in a handful of cases, whereas the related 45 was employed in the majority. A number of aryl imines were explored, furnishing the acyl hydrazine products in good yields and enantiomeric ratios regardless of substitution pattern. Notably, halogen-containing substrates (e.g., chloro) were the most electron-poor reaction partners reported. Cinnamyl and cyclohexyl imines are also good substrates, but their products are formed in more modest enantioselectivities (<90:10 er). On the basis of X-ray crystallographic studies of the catalyst 44 and a substrate molecule, Shibata and co-workers propose that H-bonding between the hydroxyl group of 44 and the substrate’s carbonyl oxygen orients their complexation, with the bulky N-benzyl group of 44 then blocking the Re face of the imine.

In order to liberate the free amine, the researchers had to develop a two-step protocol particular to their residual activating group. First, Raney nickel-catalyzed reduction of the N—N bond occurs at 180 °C in methanol. Then, β-elimination of the β-aminoamide requires 2 days in boiling concentrated hydrochloric acid.

In 2012, the Shibata group also reported another example of a nucleophilic trifluoromethylation but with an environmentally benign SOLKANE 365 mfc solvent rather than the mixture of toluene and dichloromethane from their 2009 work.¹⁰⁸ Modification of the phase transfer catalyst was needed under these conditions. Enantioselective nucleophilic trifluoromethylation remains a significant area for development.

5. IMINE UMPOLUNG

Umpolung technologies¹⁰⁹ are powerful and enabling strategies that can streamline the synthesis of myriad highly functionalized chemical building blocks. The ability of chiral catalysts to promote these transformations enantioselectively further adds to their value. In section 3.7, an N-heterocyclic carbene catalyst brought about a cross-electrophile coupling by aldehyde umpolung, allowing for pairings with CF₃ imines that yield α-amino ketones (Scheme 31). Although this moiety might be garnered in other ways, one might argue that the swiftness of pairing two widely available and easily accessible reaction partners facilitates the rapid construction of a library of related compounds in a convergent manner. Reversing the polarity of an imine¹¹⁰ is also a highly effective portal to several classes of chiral amines through C—C bond formation that would be challenging via normal polarity disconnections. A growing number of imine umpolung reactions are being utilized for the enantioselective construction of α-trifluoromethyl imines.

5.1. Prototropic Shift.

The tautomerization of N-benzyl CF₃ ketimines to α-trifluoromethyl amines, or a [1,3]-prototropic shift,¹¹¹ is an elegant approach to constructing this motif that is rooted in the action of PLP-dependent transaminases.¹¹² Early work on the enantioselective synthetic reaction from Soloshonok,¹¹³ however, illustrated the difficulty in mimicking Nature: reactions with cinchonidine-based catalysts were inefficient, requiring 52 days reaction time, and were poorly enantioselective (up to 67.5:32.5 er).

However, in 2012, the Deng group discovered that cinchona alkaloid 46, acting as a chiral base in conjunction with a substrate whose N-benzyl group bears a highly electron-withdrawing p-nitro substituent, allows for high conversions in the isomerization within short times (0.5 h at 22 °C), proceeding at lower temperature with higher enantioselectivity (Scheme 34, top).¹¹⁴ Key structural features of the catalyst include a free 9-hydroxy group and an electron-withdrawing chloride on the quinoline ring that enable higher conversions. Reactions at room temperature were fast but modestly enantioselective (84:16 er when R = Ph); however, cooling the reaction mixture to −30 °C greatly improved the selectivity (95:5 er) but at the expense of longer reaction times (24—72 h).

Scheme 34.

Prototropic Shift of N-Benzyl CF₃ Imines

Several ketimines undergo prototropic shifts to their aldimine tautomers. For aryl ketimines, electron-donating groups (e.g., p-methoxy) slow the reaction and require higher temperature to proceed but still lead to excellent enantioselectivity (95:5 er). Electron-poor substrates react more quickly but with lower enantioselectivity. Although the researchers showed that product enantiomerization does not occur over the course of the reaction when R = Ph, reaction reversibility could be responsible for the lower enantiomer ratios observed with electron-deficient imines. Aliphatic imines are also competent reaction partners but require a higher temperature (10 °C). The selectivity is still excellent in most cases (≥95:5 er), but the α-benzyl amine product is generated in 93.5:6.5 er. These findings by Deng and co-workers foreshadowed a slew of enantioselective C—C bond-forming conjugate addition reactions, seminal work in the area of imine umpolung (see section 5.2).

The imine functionality within the products serves as a double protecting group for an amine, but an important aspect of the transformation, just as in biological transamination, is the ability to hydrolyze the imine under mild conditions. As shown in Scheme 34, the amine hydrochloride salt can be formed efficiently from the imine in just 2 h with 1.0 M hydrochloric acid.

Shortly after this work, the Shi group reported a different cinchona alkaloid catalyst (47) for accomplishing the enantioselective prototropic shift (Scheme 34, bottom).¹¹⁵ On comparison of the performance of the two catalysts, two features stand out. (1) Amine 47 promotes the proton shift more efficiently for alkyl imines, delivering products in higher yields (ca. 99% in comparison to 58—69% with catalyst 46) but with similar levels of enantioselectivity. (2) The tautomerization of aryl imines is more highly enantioselective with amine 46 (90:10 to 95:5 er versus 83.5:16.5 er with 47); potentially enantiomerization by equilibration with catalyst 47 is the culprit of the lower selectivity.

5.2. Conjugate Addition.

The Deng group has pioneered catalytic enantioselective CF₃ imine umpolung additions. Following their 2012 prototropic shift work, in 2015 they published a seminal paper on ketimine-derived azaallyl anion conjugate addition to enals (Scheme 35, top).¹¹⁶ Their weakly basic prototropic shift catalyst 46 (Scheme 34) and related compounds proved ineffectual for C—C bond formation; thus, they turned to phase transfer catalysis to mitigate reprotonation of the azaallyl anion. In the optimal catalyst (48), both the electronic and steric nature of the N-benzyl group (R³) were vital to chemoselectivity (conjugate addition versus prototropic shift), proposed to be at least partially due to π—π interactions between 48 and the ketimine. In most cases, only a small quantity of prototropic shift product was formed (<5%); 1,2-addition to the aldehyde and fluoride elimination from the azaallyl anion were not observed.

Scheme 35.

Imine Umpolung for Enantio-, Regio-, and Chemoselective Conjugate Additions under Phase Transfer Catalysis

Regioselectivity with respect to the azaallyl anion is also high (>95% α′ in most cases), favoring addition from the CF₃-substituted carbon. While this may be augmented by the inductive effect of the trifluoromethyl group, the p-nitrobenzyl group and the catalyst structure greatly influence this result, as other classes of imines also react to form α-tertiary amine products.

Several alkyl imines, including those with a sensitive functionality (e.g., primary bromide), undergo reaction with crotonaldehyde or acrolein in excellent yields and enantioselectivities. The diastereoselectivity is also good in additions to crotonaldehyde and cinnamaldehyde, although in the latter, the regioselectivity is poor. Aryl imines and an α,β-unsaturated imine were also explored with acrolein. The latter are particularly challenging, as the resulting azaallyl anions are expected to be less stable in comparison to those formed from aryl imines. The products may be easily converted to other complex structures: hydrolysis of the imine and reductive amination furnish an α-CF₃ pyrrolidine (Scheme 35, bottom left).

Deng and co-workers have successfully extended this concept to several other classes of unsaturated carbonyls (Scheme 35, bottom right). Enones,¹¹⁷ N-acyl pyrroles,¹¹⁸ and acrylates¹¹⁹ are all competent partners, each delivering products in excellent yields and enantiomer ratios. α-Substituted enals¹²⁰ and unsaturated lactones¹¹⁹ afford products with nonadjacent or vicinal stereogenic centers, respectively, with superb diastereoselectivities. In each case, optimization of the catalyst with respect to the N-benzyl group and the quinoline ring was required.¹²¹ Additionally, for α-substituted enals, N-acyl pyrroles, and esters, a catalytic quantity of a phenol additive was needed. This Brønsted acid additive in conjugate addition or aldol reactions with phase transfer catalysts serves to accelerate protonation of the enolate/alkoxide to minimize β-elimination/retro-aldol. The phenol identity was optimized for each substrate class.

5.3. Allylation.

Several groups have explored allylation through allylic substitution, thereby accessing homoallylic amines with a number of substitution patterns. Both organic molecule-based catalysts and transition-metal catalysts have been investigated.

Reactions promoted by chiral phosphine- or amine-based catalysts have relied upon highly electrophilic allylic carbonates that bear an ester moiety (Scheme 36). These Morita—Baylis—Hillman (MBH) carbonates may couple with CF₃ imines that lead to either α-secondary or α-tertiary amine-substituted stereogenic centers. In 2016, Zhang and co-workers discovered that chiral phosphine 49 (Scheme 36, top) promotes the addition of CF₃ ketimines bearing a p-nitrobenzyl activating group to an allylic carbonate derived from a primary alcohol.¹²² Phosphine addition to the electrophile forms the activated chiral allylic phosphonium salt, which is then captured by the in situ-generated azaallyl anion. The authors speculate that phosphine 49 is bifunctional, inducing H-bonding between its amide N—H and the imine nitrogen (azomethine ylide-like reactive species). The electron-withdrawing nature of the catalyst’s benzamide group greatly enhances H-bond donation.

Scheme 36.

Nucleophilic Catalysis for the Coupling of Imines with Morita—Baylis—Hillman Allylic Carbonates

The scope of the reaction is restricted to imine variation but includes aryl, alkyl, and alkenyl imines. The transformations are fairly efficient, taking place within 8 h at room temperature, although the catalyst loading (10 mol %) is somewhat high. Enantioselectivities all exceed 95:5 er. Attempts to employ secondary alcohol derived carbonates lead to exclusive azaallyl anion addition from the activating group side of this ambidentate nucleophile (α-addition).

Related work from the Wang group (Scheme 36, bottom) utilizes β-isocupreidine (50) as the catalyst (10 mol %).¹²³ Here, MBH carbonates derived from secondary benzylic alcohols were engaged in reactions with azaallyl anions. In this instance, the authors utilized a chloro-substituted isatin-based activating group to generate the azaallyl anion. The isatin renders a significantly more stabilized anion due to carbonyl conjugation, forming an azadienolate. Despite the possibility for α-addition from this azadienolate only the γ-alkylation product (addition from the CF₃-substituted carbon) is observed. Likewise, the electrophile is ambidentate but coupling takes place exclusively at the site of the leaving group through a double S_N²′ displacement mechanism: first the carbonate undergoes addition by 50, which is in turn substituted by the azadienolate. Consistent with this mechanism, electron-poor arenes undergo faster coupling but lead to lower diastereo- and enantioselectivity.

The process furnishes homoallylic amines comprised of vicinal trisubstituted stereogenic centers with the syn isomer as the major product. Several aryl groups can be incorporated at the allylic position; however, the transformation is limited to MBH substrates that bear a methyl ester. An ethyl ketone electrophile furnishes the α-CF₃ amine in poor yield and enantioselectivity. Although the electrophile scope is broader than that of the phosphine-catalyzed procedure (Scheme 36, top), only a single nucleophile is employed. It is likely that α-branched imines are unreactive due to a combination of steric congestion in the product and difficulty in deprotonating the methine proton to form the azadienolate.¹²⁴

Recently, transition-metal-catalyzed reactions have garnered considerable interest for assembling homoallylic α-trifluoromethyl amines. Related to a program in their laboratory, Wang and co-workers have disclosed allylations of isatin-derived azadienolates with allylic carbonates, promoted by an iridium complex and phosphoramidite 51 (Scheme 37, top).^125,126 In this case, the azadienolate undergoes a-selective allylation, attacking the Ir—π-allyl with customary branch selectivity. The initial product, however, is unstable and spontaneously undergoes a stereoselective aza-Cope rearrangement to yield a net γ-allylation product, a process attributed to relief of steric congestion imposed by the vicinal tetra- and trisubstituted stereogenic centers and likely also due to the resulting olefin conjugation with the arene. The products thus have a single stereogenic center and a 1,2-disubstituted alkene. Products bearing several (hetero)aryl groups can be prepared, most formed in ≥95:5 er. The transformation was largely restricted to a single nucleophile, as γ,γ-disubstituted substrates are slow to react. For example, as part of a mechanistic probe, the authors examined a γ -methyl-γ-trifluoromethyl isatin, which required 7 days to proceed to completion.

Scheme 37.

Ir—Phosphoramidite-Catalyzed Allylation/Aza-Cope Rearrangement

However two different research teams have further investigated this concept for generating α-tertiary α-trifluoromethyl amines. The Wang group¹²⁷ and the team of Zhang and Niu¹²⁸ utilized a fluorenyl activating group to accomplish the process, with Wang and co-workers employing a preformed Ir/51 organometallic complex and Zhang and Niu forming such a complex in situ with phosphoramidite 52 (Scheme 37, bottom). The reactions again proceed with branch selectivity for the electrophile and initial α-allylation before undergoing stereoselective aza-Cope rearrangement at the 50 °C reaction temperature. The net α′-allylation products contain one stereogenic center and an (E)-1,2-disubstituted alkene, complementary in structure to the related (Z)-homoallylic amines generated by the Hoveyda group’s nucleophilic allylation (cf., Scheme 13, section 3.3). The scope of the transformations is excellent as are the product yields and enantiomer ratios. Several (hetero)aryl groups can be incorporated at the stereogenic center (R¹) and as the alkene substituent (R²). Both research teams also illustrate that alkyl-substituted allylic carbonates work well but require refluxing toluene to complete the sigmatropic rearrangement.

Recently the Wang group added another contribution to this area in which they developed a method for the synthesis of α,α-disubstituted amino acids wherein one of the α groups is CF₃.¹²⁹ The reaction proceeds through allylation of α-trifluoromethyl α-imino esters followed by a kinetic resolution of the products.

The team of Zhang et al. has disclosed an imine umpolung allylation utilizing Pd catalysis. A fluorenyl imine pronucleophile and allylic acetates that afford symmetrical 1,3-diaryl-substituted Pd—π-allyl intermediates were employed (Scheme 38, top).¹³⁰ With PHOX ligand 53, the reactions occur with high levels of enantioselectivity and modest to good diastereoselectivity. Despite the similarity to the work with Ir-based catalysts (Scheme 37), the authors illustrate that the transformations proceed by direct allylation at the α′-position rather than by an α-allylation/aza-Cope mechanism.

Scheme 38.

Pd—PHOX-Catalyzed Enantioselective or Enantiospecific Tsuji—Trost Allylation of Azaallyl Anions

The research team also demonstrated the enantiospecific and regiodivergent allylation with enantiopure allylic acetates, further suggesting that their mechanistic hypothesis is correct (Scheme 38, bottom). With the S enantiomer of the electrophile, regardless of substrate electronics or sterics, the catalyst derived from (R)-53 always leads to bond formation at the site of the leaving group as the major pathway, and (S)-53 leads to exclusive addition at the other electrophilic π-allyl position.

5.4. Diene Hydrofunctionalization.

In 2020, our group demonstrated that an isatin-derived N-trifluoroethyl imine may undergo regioselective addition to terminal dienes promoted by a Pd-based catalyst via a π-allyl intermediate (Scheme 39).¹³¹ Unlike the majority of enantioselective Tsuji—Trost reactions that proceed through acyclic π-allyl intermediates, diene hydrofunctionalization gives rise to unsymmetrical 1,3-disubstituted π-allyls that go on to afford products with both allylic stereogenic centers and internal alkenes (for example, compare the products in Scheme 37 with those in Scheme 39).¹³² As a result, the diene hydrofunctionalizations deliver homoallylic amines with anti-vicinal stereogenic centers and 1,2-disubstituted olefins.

Scheme 39.

Enantio- and Regioselective Couplings of Terminal Dienes with Isatin-Derived Azadienolates

We discovered that most bis(phosphine) ligands for palladium, although controlling the regioselectivity with respect to the diene perfectly, give a mixture of α- and γ-allylation of the azadienolate (formed from the isatin with triethylamine). However, ligands bearing DTBM aryl groups at phosphorus afford perfect γ-selectivity for aryl dienes and for most alkyl dienes (Scheme 39). DTBM-SegPhos led to the best reactivity, and the use of preformed complex 54 was needed to avoid a large induction period in the reaction. Employing NaBAr^F₄ as a substoichiometric additive gave slightly improved enantioselectivities for several of the aryl diene substrates but greatly retarded the reaction rate. Aryl and heteroaryl dienes readily react at room temperature to deliver the homoallylic α-CF₃ amines in good yields and diastereo- and enantioselectivities. Alkyl dienes are poorly reactive at room temperature and lead to lower stereoselectivities at 50 °C. Still, a number of useful functional groups are tolerated, including a tertiary amine and an ester. These transformations represent the first examples of catalytic enantioselective couplings of dienes and umpolung reagents.

5.5. Annulations with Azomethine Ylides.

Several groups have investigated [3 + 2]-annulations of CF₃-substituted azomethine ylides with electron-deficient alkenes.¹¹⁰ Processes likely proceed stepwise with conjugate addition of the dipolar component’s anion preceding an (aza)-Mannich reaction. The majority of reactions utilize a bifunctional cinchona alkaloid derived H-bonding catalyst to form the azomethine ylide and template this reactant with a Michael acceptor. Transformations result in a number of highly substituted pyrrolidines with multiple contiguous stereogenic centers, often with a spirocyclic center as well.

One of the most useful transformations in this collection of dipolar cycloadditions was reported by the Enders group in 2017 (Scheme 40).^133–135 The squaramide catalyst 34 promotes the annulation of 2-oxomalonyl-derived imines, which generate an azomethine ylide upon deprotonation by the catalyst, with β-substituted nitroalkenes. The resulting 3-nitropyrrolidines bear three contiguous stereogenic centers and are formed as the all-anti isomer exclusively. Notably it is the CF₃-substituted carbon of the azomethine ylide that adds to the nitroalkene’s β-position. Although the only point of variation is the nitroalkene substituent, this group can be either aryl or alkyl, and although each pyrrolidine necessarily contains a geminal diester, the transformations are highly enantioselective (≥97:3 er in all cases). Reduction of the products’ nitro group could give way to medicinally valuable 3-aminopyrrolidines.

Scheme 40.

H-Bonding Catalysis for Annulations of 2-Oxomalonyl-Derived Azomethine Ylides with Nitroalkenes

The research team of Yan, Wang, and Wang has investigated a related dipolar cycloaddition (Scheme 41).¹³⁶ The same dipolar component and catalyst were explored as in the Enders study but with an unsaturated 2-oxindole partner, resulting in a spiro-fused pyrrolidine/2-oxindole. Transformations are generally fast for this type of coupling, in most cases requiring only 1.5—12 h at room temperature with 1 mol % of 34. More electron-rich oxindoles and those with larger R³ groups require longer reaction times. The reactions afford a single diastereomer in all cases except for the N-phenyl oxindole; a single enantiomer of the product is obtained in nearly every case as well. In comparison to the reaction reported by Enders (Scheme 40), with the unsaturated oxindoles it is the gem-diester carbon that adds in the conjugate addition, putting the CF₃ group vicinal to the spirocyclic center. Perhaps this difference in comparison to the nitroalkene is partially due to the steric hindrance of the other regioisomer, which would afford contiguous tetrasubstituted and quaternary centers.

Scheme 41.

H-Bonding Catalysis for Annulations of 2-Oxomalonyl-Derived Azomethine Ylides with 2-Oxindole Exocyclic Alkylidenes

Several research groups have studied similar dipolar cycloadditions with isatin-derived azomethine ylides. In one case, a team led by Chen and Yuan coupled these dipolar reagents with β-CF₃ enones catalyzed by bifunctional squaramide 34 (Scheme 42, top).¹³⁷ A number of isatin-derived imines and aryl enones were coupled, delivering spirocyclic pyrrolidines with four contiguous stereogenic centers, including vicinal trifluoromethyl-substituted carbons. The stereoselectivities and yields were outstanding.

Scheme 42.

H-Bonding Catalysis for Annulations of Isatin-Derived Azomethine Ylides with Various Unsaturated Carbonyls

The same research team also investigated β-CF₃ unsaturated 2-oxindoles with catalyst 34 (Scheme 42, bottom),¹³⁷ which were also studied by the research groups of Lin, Weng, and Lu (squaramide—tertiary amine catalyst)¹³⁸ and Enders (thiourea-tertiary amine catalyst),¹³⁹ delivering bis(spirocycles).¹⁴⁰ The Du laboratory has examined annulations with rhodanine derivatives to form bis(spirocycles) (squaramide—tertiary amine catalyst).¹⁴¹ Additionally, Zhang, Ye, and co-workers found that α,β,γ,δ-unsaturated dienones undergo [3 + 2]-cycloaddition with the same 1,3-dipolar reaction partner (chiral amine catalyst).¹⁴²

An additional dipolar cycloaddition with unsaturated 2-oxindoles and isatin-based azomethine ylides was developed by the team of Hua, Wang, and co-workers (Scheme 43).¹⁴³ The bis(spirocyclic) products are obtained with excellent yields and diastereo- and enantioselectivities utilizing the Zn—ProPhenol catalyst derived from 37. The use of a bifunctional metal-based catalyst is notable in an arena dominated by organic molecule catalysts.

Scheme 43.

Zn—ProPhenol-Catalyzed Annulations of Isatin-Derived Azomethine Ylides with Unsaturated 2-Oxindoles

6. AMINATION

Although the forging of carbon—carbon bonds offers the greatest potential for quickly building molecular complexity and broadly covers the most diverse chemical space and largest area of investigation in forming α-CF₃ amines, several amination protocols have also been developed that allow for fundamentally different bond disconnections and thus provide additional options for chemical synthesis. Principally, these C—N bond-forming reactions lead to secondary or tertiary amine products and are in that way also complementary to C—C bond assembly, which customarily delivers primary amines after deprotection. A handful of nucleophilic and electrophilic amination methods have been developed.

6.1. Nucleophilic Amination.

Kawatsura, Itoh, and co-workers have illustrated that racemic CF₃-containing allylic acetates and carbonates may undergo enantioconvergent allylic amination utilizing a Pd—BINAP-based catalyst (Scheme 44).¹⁴⁴ Prior work from this team demonstrated enantiospecific allylic amination with the same substrates.¹⁴⁵ In those reports, they found that cationic Pd catalysts with wide natural bite angle ligands selectively afford isomer 55 (R¹ = aryl), whereas a neutral Pd complex with a small bite angle ligand leads to 56 (R¹ = aryl). Stereospecific isomerization of 56 to 55 could be achieved when the matched enantiomer of Pd—BINAP was employed.

Scheme 44.

Enantio- and Regioselective Allylic Amination

In comparison to these more established stereospecific Tsuji—Trost reactions, enantioconvergent transformations that proceed through acyclic unsymmetrically 1,3-disubstituted Pd—π-allyl intermediates are rare.¹³² The Kawatsura—Itoh team provides convincing evidence that the reaction may generate a 55/56 mixture before ultimately converting to regioisomer 55 (R¹ = aryl): racemic 56 can be converted to highly enantioenriched amine 55 in high yields. Given the double-inversion nature of Pd-catalyzed allylic substitutions, the results are best explained by a rapid exchange of the π-allyl ligand between two Pd—BINAP complexes,¹⁴⁶ thereby making either of the two enantiotopic faces of the electrophile available for nucleophilic attack.

Several aryl-substituted electrophiles are viable substrates, including those that are sterically hindered: an o-tolyl cinnamyl acetate favors regioisomer 55. Cyclic and acyclic secondary amines are excellent reaction partners, delivering α-trifluoromethyl amines in high yields in 12—36 h. In contrast, primary amines need longer reaction times (36—96 h) due to their lower nucleophilicity and require an allylic carbonate substrate to avoid acyl transfer to the amine. Alkyl electrophiles primarily afford isomer 56 due to sterics.

In 2015, the Huang group demonstrated an uncommon catalytic enantioselective conjugate addition of alkyl amines (Scheme 45).¹⁴⁷ The transformations utilize β-CF₃-trisubstituted nitroalkenes and are promoted by 20 mol % of an NHC derived from triazolium 57, delivering α-tertiary amines in excellent yields and enantioselectivities. In comparison to other enantioselective conjugate addition strategies with organic molecule catalysts, which usually rely upon LUMO lowering of the Michael acceptor, here H-bonding between the NHC and the amine increases amine nucleophilicity, thereby promoting its addition to the nitroolefin. The addition of hexafluoroisopropyl alcohol is necessary for reactivity, and the authors propose that this Brønsted acid acts as a proton shuttle.

Scheme 45.

NHC-Catalyzed Conjugate Addition of Primary Aliphatic Amines to β-CF₃-Substituted Nitroalkenes

A number of synthetically useful primary amines undergo addition to β-aryl-β-CF₃ nitroalkenes; the amine structure has little effect upon efficiency or selectivity. The more sterically hindered secondary amines are unreactive. Variation of the nitroalkene’s aryl group was also explored. Most arenes lead to products in >80% yield and 95:5 er, but a handful are poorer partners (e.g., p-CF₃). The authors suggest that the trends imply a weak π—π stacking interaction between the catalyst and substrate arenes. The presence of an aryl group at the β-position is therefore critical for achieving high enantioselectivity, as illustrated with the β-benzyl substrate, which leads to amine adduct in only 65:35 er. A disubstituted nitroalkene (R¹ = H) affords the racemic product.

Such a disubstituted β-trifluoromethyl nitroalkene has been utilized by the Wang group, however, in an annulation reaction with 2-nosylamino chalcones (Scheme 46).¹⁴⁸ The reactions are catalyzed by cinchona alkaloid derived thiourea 58, which likely engages in hydrogen bonding with the nitro group, first prompting conjugate addition of the sulfonamide. The nitronate then engages in a diastereoselective Michael addition with the enone to form the tetrahydroquinoline ring. A number of chalcones are competent reaction partners. A thiophene and a methyl ketone also deliver highly functionalized products in good yields and er values. A single diastereomer is obtained in each case.¹⁴⁹

Scheme 46.

Thiourea-Catalyzed Annulation of Chalcones and a β-CF₃-Substituted Nitroalkene

6.2. Electrophilic Amination.

In 2019, Hirano, Miura, and a co-worker disclosed a reverse-polarity hydroamination of trifluoromethylalkenes with a CuH catalyst bearing DTBM-BINAP (59) as the chiral ligand (Scheme 47).^150,151 This electrophilic amination with N-benzoyloxyamines permits a number of tertiary amine products to be accessed in high enantioselectivity. Although several classes of alkenes had been explored for hydrocupration/amination sequences, reactions of trifluoromethylalkenes had been limited by competing β-fluoro elimination of the alkyl—copper species. In this regard, the cesium acetate base and ligand 59 proved to be crucial in promoting hydroamination. The researchers investigated a handful of alkene substituents. Yields are moderate in most cases; however, the presence of a benzyl ether substrate led to an inefficient reaction (23% yield). The authors demonstrate that by incorporating dibenzylamine, primary amines can be obtained after a subsequent hydrogenolysis step.

Scheme 47.

Cu—Bis(phosphine)-Catalyzed N-Benzoyloxyamine Reductive Coupling with CF₃-Substituted Alkenes

7. CONCLUSIONS AND OUTLOOK

Enantioenriched α-trifluoromethylamines are important targets for medicinal chemistry applications, and recent years have witnessed a wealth of catalytic enantioselective pathways toward this functionality. Reduction, carbon—carbon bond-forming, and amination strategies have been developed, many based upon related chiral auxiliary methods that had appeared previously. However, several transformations are unique to new catalyst-controlled approaches, notably including myriad imine umpolung reactions and carbonyl and amine polarity reversal as well. As a result, a great swath of chemical space surrounding the α-CF₃ amine can be obtained including benzylic, propargylic, homoallylic, α-, β-, and γ-amino-carbonyls, and vicinal diamines to name a few. Such a broad range of synthetic strategies for preparing these chiral amines has required many different catalysts, yet a handful of reaction types have been utilized several times over, such as hydrogen bond catalysis, phase transfer catalysis, and transition-metal-catalyzed electrophilic allylation.

Despite these advances, the catalytic enantioselective synthesis of α-trifluoromethyl amines remains a fertile area for reaction discovery. Only a few transformations have generated α-amino acids bearing a CF₃ group,^16b–f such as indole and alkyne addition to α-imino esters or Strecker reactions with trifluoromethyl imines. There is a dearth of transformations that deliver allylic amines or β-amino alcohols. Within the reaction subtypes, the ability to access α-tertiary but not α-secondary amines or vice versa is a limitation, requiring new catalyst development or new reaction concepts for solutions. Such innovations, and the invention of new reactions that do not fit into the major categories covered in this review,¹⁵² will likely spur this research area forward in the coming years.