Catalytic Asymmetric Mannich Reaction of α-Fluoronitriles with Ketimines: Enantioselective and Diastereodivergent Construction of Vicinal Tetrasubstituted Stereocenters

Abstract

Diastereodivergent and enantioselective conversion of isatin ketimines to α-fluoro-β-aminonitriles with vicinal tetrasubstituted stereocenters is achieved by a chiral copper complex/guanidine base catalyzed Mannich reaction with proper choice of the bisphosphine ligand. The reaction is broad in scope, scalable, and provides efficient access to a series of 3-aminoindolinones exhibiting a quaternary carbon-fluorine stereocenter with high yields and stereoselectivities. Selective transformations of the Mannich reaction products into multifunctional 3-aminooxindoles without erosion of enantiomeric and diastereomeric purity highlight the synthetic utility.

Graphical Abstract

Catalytic enantioselective reactions that produce multifunctional building blocks with carbon-fluorine quaternary stereocenters are of great interest due to the prevalence of this motif in biologically active compounds.¹ In many cases, the in situ generation of fluorinated nucleophiles requires the presence of a proximate carbonyl group which substantially limits the pool of substrates that can be applied in catalytic asymmetric synthesis of organofluorines displaying a quaternary chirality center.² The use of α-fluorinated nitriles devoid of an activating carbonyl moiety remains very challenging because of the inherent fluxionality of α-metalated nitriles and the low C-H acidity, which complicates catalytic formation of α-cyano carbanions under mild reaction conditions.³ To the best of our knowledge, stereodivergent catalytic asymmetric additions with α-fluoro-α-arylnitriles have not been reported to date despite the synthetic potential of these prenucleophiles for the construction of chemically versatile scaffolds around a tetrasubstituted carbon-fluorine stereocenter.

Mannich reactions with fluorinated nucleophiles are particularly attractive because they provide access to pharmaceutically important fluorinated amino compounds.⁴ Following Shibasaki’s pioneering work on aldol-type reactions with nitriles,⁵ silyl ketene imines that overcome some of the difficulties mentioned above have been used as reactive nitrile surrogates in asymmetric aldol and Mannich reactions.⁶ The direct use of nitrile compounds, however, appears more appealing because it obviates the necessity to prepare a silyl ketene imine derivative. To this end, the introduction of Shibasaki’s cooperative soft Lewis acid – hard Brønsted base catalysis strategy has significantly widened the substrate scope.⁷ In recent years, several groups have achieved enantioselective catalytic Mannich additions to aldimines with nitriles carrying an adjacent carbonyl, sulfonyl or another activating functionality.⁸ Decarboxylative methods and the catalytic addition of allenylnitriles, benzylnitriles or phenylthioacetonitrile to aldimines have also been reported by Shibasaki, Nakamura and others.⁹

Enantioselective Mannich reactions with ketimines have been accomplished with activated nitriles (Scheme 1a and b).^6j,10 To demonstrate the use of α-fluoro-α-substituted nitriles in asymmetric catalysis, we chose to investigate the possibility of a Mannich reaction with ketimines derived from isatin which affords an important scaffold encountered in many natural products and drugs.¹¹ Because this reaction establishes two chirality centers, we also recognized the importance of providing convenient access to all four stereoisomeric products, preferentially by easily adaptable diastereodivergent protocols.¹² We now wish to report a (bisphosphine)copper(I) catalyzed direct asymmetric addition of α-fluoro-α-arylnitriles to isatin ketimines that addresses these challenges (Scheme 1c). Our method provides efficient access to multifunctional α-fluoro β-aminonitriles bearing vicinal tetrasubstituted stereocenters in high yields and with excellent enantio- and diastereoselectivity. Moreover, all four stereoisomers are accessible by suitable selection of the chiral copper catalyst and the isatin protecting group. The practical diastereodivergence, amenability to upscaling and selective functional group manipulation of the fluorinated α,β-aminonitrile moiety toward multifunctional β-fluoro-α,γ-diamines, α-fluoro-β-amino amides and fluorinated α-amino acid derivatives underscore the synthetic utility of this reaction.

Scheme 1.

Synthesis of chiral β-aminonitriles bearing vicinal tetrasubstituted stereocenters.

At the beginning of our search for a stereodivergent catalytic asymmetric Mannich reaction, we chose α-fluorobenzylnitrile, 1a, and the isatin derived N-Boc ketimines 2a-c as test compounds and screened various Cu(I) salts, Segphos and Biphep ligands (L1-L4), solvents and base additives (Table 1 and SI). We found that the desired α-fluoro-β-aminonitrile 3aa can be obtained from the N-benzyl isatin derived ketimine 2a in 91% yield using catalytic amounts of copper(I) triflate, DTBM-Segphos (L1) and diisopropylethylamine as base in toluene, albeit with low stereoselectivities (entry 1). The enantio- and diastereoselectivity increased significantly to 80% ee and 5.2:1 dr when the N-trityl ketimine 2b was employed (entry 2). Extensive variation of bisphosphine and phosphinooxazoline ligands (L1-L8) and the introduction of amidine and guanidine bases further improved results (entries 3–13). We were pleased to observe almost quantitative formation of anti-3ab with 83% ee and 6.7:1 dr using 10 mol% of copper hexafluorophosphate, L1 and BTMG in toluene at room temperature (entry 5). A decrease in the reaction temperature finally allowed us to optimize the stereoselectivities and we isolated anti-3ab in 95% yield, 90% ee and 12.3:1 dr at −35 °C (SI and entry 14). Additional investigation of the reaction outcome revealed that the diastereoselectivity can be switched with C₁-symmetric bisphosphine ligands L9-L14. Using 5 mol% of CuPF₆ and BTMG, the opposite diastereomer was favored when 1,2-ferrocenyl bisphosphines were used as ligands (Table 1, entries 15–19). Poor stereoselectivities were initially observed until we resorted to the N-benzyl or N-phenyl ketimines and copper catalysts carrying either the Taniaphos ligands L9 and L14 or Walphos ligands L11-L13 under otherwise identical reaction conditions. We found that (Walphos)Cu(I) favors high diastereoselectivities while the use of Taniaphos as chiral ligand leads to superior ee’s. For example, the Mannich reaction between 1a and 2a gave syn-3aa in 99% yield with 13.4:1 dr and 70% ee which further increased to 80% when L13 was replaced with Taniaphos L14 (entries 20–22). The introduction of the N-phenyl isatin derived ketimine 2c resulted in excellent enantioselectivity and we obtained syn-3ac in 94% yield with 98% ee and 3.0:1 dr using 5 mol% of L14, CuPF₆ and BTMG at −35 °C (entry 23).

Table 1.

Optimization of the stereodivergent asymmetric Mannich reaction.

Entry	Cu(I) source	Ligand	2	Conditions	Yield (%)	dra (anti/syn)	eeb (%)
1	Cu(PhMe)0.5OTf	L1	2a	DIPEAc, 25 °C	91	1.7:1	41
2	Cu(PhMe)0.5OTf	L1	2b	DIPEAc, 25 °C	85	5.2:1	80
3	Cu(PhMe)0.5OTf	L2	2b	DIPEAc, 25 °C	74	4.6:1	75
4	Cu(PhMe)0.5OTf	L1	2b	BTMG, 25 °C	98	5.8:1	83
5	Cu(MeCN)4PF6	L1	2b	BTMG, 25 °C	98	6.7:1	83
6	Cu(MeCN)4PF6	L1	2b	DBU, 25 °C	99	6.6:1	73
7	Cu(MeCN)4PF6	L1	2b	MTBD, 25 °C	99	5.8:1	83
8	Cu(MeCN)4PF6	L3	2b	BTMG, 25 °C	99	2.0:1	26
9	Cu(MeCN)4PF6	L4	2b	BTMG, 25 °C	99	4.0:1	79
10	Cu(MeCN)4PF6	L5	2b	BTMG, 25 °C	99	1.5:1	50
11	Cu(MeCN)4PF6	L6	2b	BTMG, 25 °C	99	1.5:1	31
12	Cu(MeCN)4PF6	L7	2b	BTMG, 25 °C	99	1.3:1	40
13	Cu(MeCN)4PF6	L8	2b	BTMG, 25 °C	99	1.1:1	47
14	Cu(MeCN)4PF6	L1	2b	BTMG, −35 °C	95	12.3:1	90
15d	Cu(MeCN)4PF6	L9	2b	BTMG, 25 °C	97	1:1.6	3
16d	Cu(MeCN)4PF6	L9	2a	BTMG, 25 °C	99	1:5.7	31
17d	Cu(MeCN)4PF6	L10	2a	BTMG, −35 °C	75	1:2.5	4
18d	Cu(MeCN)4PF6	L11	2a	BTMG, −35 °C	99	1:7.3	19
19d	Cu(MeCN)4PF6	L12	2a	BTMG, −35 °C	99	1:5.6	60
20d	Cu(MeCN)4PF6	L13	2a	BTMG, −35 °C	99	1:13.4	70
21d	Cu(MeCN)4PF6	L13	2c	BTMG, −35 °C	98	1:8.7	75
22d	Cu(MeCN)4PF6	L14	2a	BTMG, −35 °C	94	1:5.7	80
23d	Cu(MeCN)4PF6	L14	2c	BTMG, −35 °C	94	1:3.0	98

Reaction condition: 1a (0.055 mmol), 2 (0.050 mmol), Cu(I) source (0.005 mmol), ligand (0.006 mmol) and base in 0.3 mL toluene.

^aDetermined by ¹⁹F NMR analysis.

^bDetermined by chiral HPLC analysis.

^cThe base loading was 80 mol%.

^dThe Cu complex and base loading were 5 mol%.

Having optimized the Mannich reaction conditions and with practical stereodivergent protocols in hand, we continued with the evaluation of the substrate scope using a variety of α-fluoro-α-arylacetonitriles (Scheme 2). The (DTBM-Segphos) Cu(I)/BTMG catalyzed reaction with the α-fluoro-arylacetonitriles 1a-1i and ketimine 2b gave quantitative yields and high stereoselectivities demonstrating excellent functional group tolerance of electron-withdrawing and electron-donating substituents in the ortho-, meta-, para-positions of the phenyl ring. It is noteworthy that the reaction with the chloro- and bromo-substituted α-fluorobenzylnitriles 1b and 1c furnished anti-3bb and anti-3cb in 97–98% yield, more than 35:1 dr and 97% ee. Addition of α-fluoro-3,5-dimethoxybenzylnitrile 1i to ketimine 2b produced 83% of anti-3ib with more than 50:1 diastereoselectivity and 91% ee. Excellent results were also obtained with fluoroacetonitriles 1j-l carrying 1,3-benzodioxole-5-yl, 2-naphthyl, or 2-fluorenyl rings. The corresponding α-fluoro-β-aminonitriles anti-3jb-lb were produced in high yield and with up to 45:1 dr and 93% ee.

Scheme 2.

Reaction scope with α-fluoro-α-arylnitriles. The absolute configuration of 3ab and 3lb were determined by crystallographic analysis. The configuration of the other compounds was assigned by analogy.

Slow evaporation of a solution of 3ab in ethanol and of 3lb in a hexane/diethyl ether/dichloromethane (2:2:1) solution led to the formation of single crystals.¹³ Crystallographic analysis revealed R configuration at the oxindole C3 position and S configuration at the fluorinated carbon atom, and NMR and chiral HPLC measurements proved that these single crystals relate to the major stereoisomer formed using ((R)-DTBM-Segphos)Cu(I) as catalyst. The reactivity substituted N-trityl isatin derived ketimines 2d-2h was also probed (Scheme 3). The presence of methyl, ethyl, and methoxy groups in the 5- or 6-position of the isatin moiety was well tolerated and we obtained high yields and stereoselectivities. All α-fluoro-β-aminonitriles were produced in high yields and with up to 34:1 dr and 96% ee.

Scheme 3.

Reaction scope with N-trityl isatin derived N-Boc ketimines.

We then evaluated the substrate scope for the diastereodivergent protocol using 5 mol% of ((S,Sp)-Taniaphos)Cu(I) as catalyst (Scheme 4). The reaction of five different α-fluoroarylacetonitriles to the N-phenyl isatin ketimine 2c gave syn-3ac-3kc in 84–99% yield and with good to high stereoselectivities ranging from 3:1 to 7:1 dr and 83–97% ee, respectively. We obtained a single crystal of 3ic by slow evaporation of a hexanes/ethanol/chloroform (3:1:1) solution. The crystallographic analysis is in agreement with NMR and chromatographic measurements which confirmed the favored formation of the syn-(S,S)-diastereomer.

Scheme 4.

Diastereodivergent synthesis syn-α-fluoro-β-aminonitriles from N-phenyl isatin N-Boc ketimines using ((S,Sp)-Taniaphos)Cu(I) as catalyst.

Based on NMR analysis and in analogy to previously reported mechanistic studies we propose the catalytic cycle and a plausible transition state shown in Scheme 5 (SI).^8d,g,9c Competition binding experiments revealed preferential binding of the α-fluorobenzylnitrile 1a to the (Segphos)Cu(I) complex in the presence of the ketimine 2. We then conducted H/D exchange and titration experiments and observed that the metal coordination of the nitrile significantly accelerates the reversible deprotonation of complex A to the cuprous keteniminate complex B. Irreversible C-C bond formation affords C which undergoes proton transfer and dissociation to 3, regenerating the free Cu(I) complex and BTMG. In the favored transition state, the N-cuprated ketenimine exposes the Si-face for nucleophilic attack by the isatin ketimine which is expected to occupy a tilted orientation to minimize steric repulsion as the large N-trityl group occupies the bottom left axial space and the N-carbamoyl resides in the top right axial space. This exposes the Si-face of the ketimine and gives the (R,S)-diastereomer as observed.

Scheme 5.

Proposed mechanism.

Finally, the possibility of upscaling and the synthetic utility of the synthesized α-fluoro-β-aminonitriles were investigated (Scheme 6). We were pleased to find that nearly one gram of anti-3ab was produced in quantitative amounts and without compromised stereoselectivities using 5 mol% of the (DTBM-Segphos)Cu(I) catalyst. Reduction of compound 3ab with NaBH₄ in the presence of NiCl₂ produced β-fluoro-α,γ-diamine 4 in 65% yield.¹⁴ Hydrolysis of the cyano group in 3ab using a catalytic amount of Pd(OAc)₂ and PPh₃ with acetaldoxime in aqueous EtOH gave the α-fluoro-β-amino amide 5, a fluorinated analogue of the cholecystokinin-2 (CCK2)/gastrin receptor antagonist AG-041R,¹⁵ in 97% yield.¹⁶ Methanolysis with sodium methoxide opened the oxindole lactam ring in 3ab without erosion of the original ee and dr, producing β-fluoro-α-amino acid methyl ester 6, a fluorinated unnatural amino acid derivative.¹⁷ Simultaneous deprotection of the trityl and Boc groups in 3ab gave 76% of 7 in 89% ee and 12:1 dr. Our protocol can also be applied to α-alkyl-α-arylnitriles. We obtained 9 from α-methylphenylacetonitrile, 8, in 96% yield and with 85% ee and more than 19:1 dr.

Scheme 6.

Gram scale synthesis, transformations of α-fluoro-β-aminonitrile 3ab and extension of the substrate scope to α-alkyl-α-arylnitriles.

In summary, we have developed an efficient diastereodivergent catalytic enantioselective Mannich reaction constructing α-fluoro-β-aminonitriles bearing vicinal tetrasubstituted stereocenters via (bisphosphine)copper(I) complex/guanidine catalyzed addition of α-fluoroarylacetonitriles to isatin derived N-Boc ketimines. The switching of diastereoselectivity is very practical and can be conveniently achieved by properly choosing the chiral bisphosphine ligand and the isatin N-protecting group. Using either Segphos or Taniaphos-derived copper(I) complexes and BTMG as base we have prepared a variety of syn- and anti-diastereomers of multifunctionalized 3-aminooxindoles with an adjacent quaternary C-F stereocenter in excellent yields and ee’s. The reaction can be conducted at the gram scale without compromising yield and stereoselectivity and the general utility of α-fluoro β-aminonitriles was demonstrated with selective transformations of the nitrile functionality and oxindole ring opening.