Direct Catalytic Asymmetric Mannich-Type Reaction of an α-CF₃ Amide to Isatin Imines

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Key words

asymmetric catalysis - copper catalysis - fluorine - Mannich reaction - heterocycle

Organofluorine compounds generally exhibit distinctive chemical properties compared to their corresponding nonfluorinated analogues owing to the strong C–F bond and high electronegativity of fluorine.[1] The altered attributes are often beneficial for medicinal and agrochemical applications.[2] Therefore, the incorporation of fluorine and perfluoroalkyl groups such as CF₃ into organic molecules has been a topic of the intensive research.[3] In addition to fluorinated aromatics, recent effort has also been dedicated to the preparation of fluorine-containing aliphatic compounds in enantioenriched form.[4] Two strategies exist for this purpose: fluorination/fluoroalkylation and building block approaches. Given the broad utility of enolate-based chemical transformations, α-CF₃ enolates would seem one of the most ideal building blocks for the construction of a trifluoromethylated stereogenic carbon. Nevertheless, only limited chemistry has been explored with this class of nucleo­philes due to their notorious instability associated with the high aptitude for β-fluoride elimination from the corresponding metal enolates (Scheme [1, a]).[5] [6]

Scheme 1 (a) Known decomposition pathway for α-CF₃ metal enolates. (b) Our chelated amide strategy.

As a part of our research program in direct enolization chemistry,[7] we have recently devised a chelated enolate strategy to tame otherwise unstable α-CF₃ metal enolates (Scheme [1, b]).[8] The designed pronucleophile[9] contains a 7-azaindoline amide as a bidentate chelating unit that prevents unfavorable metal–fluorine interactions. The thus generated α-CF₃ enolate has proven effective in the construction of CF₃-containing stereogenic carbons in a wide range of Cu(I)-catalyzed asymmetric transformations.[10] The applications have, however, been limited to the construction of trisubstituted stereocenters at the β-position of the amide carbonyl group.[11] [12] Facile Mannich addition of the α-CF₃ amide to Boc-aldimines[8] prompted us to examine activated ketimines as potential reaction partners. Herein, we report the successful implementation of this strategy for the preparation of tetrasubstituted carbons by means of a direct catalytic asymmetric Mannich-type reaction to isatin imines. [13]

Our experience with 7-azaindoline amides has established a combined soft Lewis acid/Brønsted base system comprising Cu(I)/chiral bisphosphine ligand/Barton’s base as a particularly effective catalyst for direct enolization chemistry.[8] [14] A recent systematic study has also found that the Ph-BPE ligand exhibits consistently high catalytic competency for a broad range of α-substituents of the amides including N₃, Cl, and alkyl groups, but not fluoroalkyl groups such as CF₃; biaryl-type phosphine ligands are preferred for the α-CF₃ amide.[15] With these factors in mind, our optimization studies for the Mannich-type reaction of amide 2 to isatin imine 1a commenced with screening various biaryl-type ligands (Table [1]). A quick examination revealed that the desired product was indeed formed in the presence of 5 mol% Cu(I)/chiral biaryl ligand complex, although the enantioselectivities were low to moderate (Table [1], entries 1–4). Hence, we turned our attention to different ligand backbones, and surprisingly, Ph-BPE (L8) was found to perform the best among the ligands evaluated (Table [1], entries 5–8). The catalyst loading was reduced to as little as 1 mol% without sacrificing the reactivity and selectivities (Table [1], entry 9).

Table 1 Optimization Studies^a

Entry	Ligand	x (mol%)	y (mol%)	Yield (%)b	drb	ee (%)c
1	L1	5	5	93	91:9	–69
2	L2	5	5	70	60:40	21
3	L3	5	5	90	92:8	–49
4	L4	5	5	80	90:10	–23
5	L5	5	5	59	89:11	–95
6	L6	5	5	95	94:6	–70
7d	L7	5	5	88	88:12	31
8d	L8	5	5	98	>95:5	99
9d	L8	1	2	98	>95:5	99

^a Reaction conditions: 1a (0.10 mmol), 2 (0.11 mmol), THF (0.1 M).

^b Yield and diastereomeric ratio were determined by ¹H NMR analysis of the unpurified reaction mixture using 3,4,5-trichloropyridine as an internal standard.

^c Enantiomeric excess of (S,S)-isomer was determined with normal-phase HPLC on a chiral support.

^d The reaction was performed on a 0.2 mmol scale in THF (0.2 M), and isolated yield was reported.

After the identification of a highly selective ligand for this transformation, a series of isatin imines 1 was evaluated with either 1 mol% or 3 mol% Cu catalyst (Table [2]). The Cbz-protected imine also proved suitable for this catalytic system, affording the corresponding product with almost the same level of selectivities (Table [2], entries 1, 2). Both electron-donating and electron-withdrawing substituents at the 5-position were tolerated (Table [2], entries 3–7). Positional isomers of 3d bearing a chlorine atom at different positions were obtained in comparable diastereo- and enantioselectivities (Table [2], entries 8, 9). Substituents on the oxindole nitrogen other than Me were also examined. While the PMB-protected substrate exhibited slightly lower reactivity and selectivities (Table [2], entry 10), the allyl-protected compound afforded results close to those of the Me-substituted one (Table [2], entry 11). The relative and absolute configurations of 3e were determined by X-ray diffraction, and those of the other compounds were assigned by analogy.[16]

Table 2 Substrate Scope of the Mannich-Type Reaction of α-CF₃ Amide 2 ^a

Entry	R1	R2	PG	Product	Yield (%)b	erc	ee (%)d
1	H	Me	Boc	3a	98	>95:5	99
2	H	Me	Cbz	3b	91	>95:5	99
3	5-F	Me	Boc	3c	86	94:6	99
4	5-Cl	Me	Boc	3d	89	92:8	99
5	5-Br	Me	Boc	3e	90	>95:5	99
6	5-Me	Me	Boc	3f	99	>95:5	98
7	5-MeO	Me	Boc	3g	81	>95:5	99
8	6-Cl	Me	Boc	3h	86	>95:5	99
9	7-Cl	Me	Boc	3i	90	>95:5	96
10	H	PMB	Boc	3j	66	86:14	92
11	H	Allyl	Boc	3k	97	>95:5	97

^a Reaction conditions: 1 (0.20 mmol), 2 (0.22 mmol), THF (0.2 M). For entries 1–4, [Cu(CH₃CN)]PF₆ (1.0 mol%), L8 (1.2 mol%), Barton’s base (2.0 mol%). For entries 5–11, [Cu(CH₃CN)]PF₆ (3.0 mol%), L8 (3.6 mol%), Barton’s base (3.0 mol%).

^b Yield values refer to isolated yield.

^c Diastereomer ratio was determined by ¹H NMR and ¹⁹F NMR analysis of the unpurified reaction mixture.

^d Enantiomeric excess of (S,S)-isomer was determined with normal-phase HPLC on a chiral support.

The reaction proceeded smoothly on a 3.0 mmol scale, producing 1.46 g of Mannich adduct 3a with almost perfect stereoselectivities, albeit a slightly higher catalyst loading was necessary for full consumption of the substrates (Scheme [2]).[17] [18] We have previously shown that 7-azaindoline amides can provide an in situ chelating group when treated with an organometallic reagent in a manner similar to Weinreb amides, and thus prevent further sequential addition of the reagent.[8b,9,11b,14b] Mannich adduct 3a was reduced by the action of DIBALH to form a masked aldehyde accompanied by the formation of an aluminum alkoxide derived from reduction of the oxindole moiety, which cyclized presumably during the workup. This triple-bond-forming process (two reductions and one cyclization) furnished highly decorated tricycle 4 in 46% yield with excellent diastereoselectivity.[19]

Scheme 2 A large scale reaction and the transformation of its product into a tricyclic skeleton.

In summary, we developed the direct catalytic Mannich-type reaction of an α-CF₃ amide to isatin imines. Enolization was promoted without decomposition by a proficient soft Lewis acidic Cu(I)/bisphosphine/Barton’s base catalytic system, and the generated enolate underwent a highly stereoselective addition, producing an α-tertiary amine with an adjacent trifluoromethylated stereogenic carbon. The Mannich adduct was smoothly transformed into a tricyclic framework by harnessing a unique property of the 7-azaindoline as a chelating unit in the reduction step.

• References and Notes

• 1a Mikami K, Itoh Y, Yamanaka M. Chem. Rev. 2004; 104: 1
• 1b O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 1c Hunter L. Beilstein J. Org. Chem. 2010; 6: 38
• 2a Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 2b Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 2c Fujiwara T, O’Hagan D. J. Fluorine Chem. 2014; 167: 16
• 2d Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA. J. Med. Chem. 2015; 58: 8315
• 2e Zhou Y, Wang J, Gu Z, Wang S, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 2f Meanwell NA. J. Med. Chem. 2018; 61: 5822
• 3a Kirk KL. Org. Process Res. Dev. 2008; 12: 305
• 3b Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
• 3c Furuya T, Kamlet AS, Ritter T. Nature 2012; 473: 470
• 3d Campbell MG, Ritter T. Chem. Rev. 2015; 115: 612
• 3e Champagne PA, Desroches J, Hamel J.-D, Vandamme M, Paquin J.-F. Chem. Rev. 2015; 115: 9073
• 4a Billard T, Langlois BR. Eur. J. Org. Chem. 2007; 891
• 4b Cahard D, Xu X, Couve-Bonnaire S, Pannecoucke X. Chem. Soc. Rev. 2010; 39: 558
• 4c Nie J, Guo H.-C, Cahard D, Ma J.-A. Chem. Rev. 2011; 111: 455
• 4d Yang X, Wu T, Phipps RJ, Toste FD. Chem. Rev. 2015; 115: 826
• 4e Noda H, Kumagai N, Shibasaki M. Asian J. Org. Chem. 2018; 7: 599
• 4f Zhu Y, Han J, Wang J, Shibata N, Sodeoka M, Soloshonok VA, Coelho JA. S, Toste FD. Chem. Rev. 2018; 118: 3887
• 5a Uneyama K, Katagiri T, Amii H. Acc. Chem. Res. 2008; 41: 817

For early contributions, see:
• 5b Yokozawa T, Nakai T, Ishikawa N. Tetrahedron Lett. 1984; 25: 3987
• 5c Yokozawa T, Nakai T, Ishikawa N. Tetrahedron Lett. 1984; 25: 3991
• 5d Yokozawa T, Ishikawa N, Nakai T. Chem. Lett. 1987; 16: 1971

Aldol reactions:
• 6a Itoh Y, Yamanaka M, Mikami K. Org. Lett. 2003; 5: 4807
• 6b Itoh Y, Yamanaka M, Mikami K. J. Am. Chem. Soc. 2004; 126: 13174
• 6c Franck X, Meniel BS, Figadère B. Angew. Chem. Int. Ed. 2006; 45: 5174
• 6d Shimada T, Yoshioka M, Konno T, Ishihara T. Org. Lett. 2006; 8: 1129
• 6e Ramachandran PV, Parthasarathy G, Gagare PD. Org. Lett. 2010; 12: 4474

Allylic alkylations:
• 6f Komatsu Y, Sakamoto T, Kitazume T. J. Org. Chem. 1999; 64: 8369
• 6g Shibata N, Suzuki S, Furukawa T, Kawai H, Tokunaga E, Yuan Z, Cahard D. Adv. Synth. Catal. 2011; 353: 2037

Conjugate additions:
• 6h Wang Q, Huan F, Shen H, Xiao J.-C, Gao M, Yang X, Murahashi S.-I, Chen Q.-Y, Guo Y. J. Org. Chem. 2013; 78: 12525
• 6i Foster RW, Lenz EN, Simpkins NS, Stead D. Chem. Eur. J. 2017; 23: 8810

α-Sulfenylation:
• 6j Yuan T, Yin L, Xu Y. Tetrahedron Lett. 2017; 58: 2521
• 7a Yamada YM. A, Yoshikawa N, Sasai H, Shibasaki M. Angew. Chem., Int. Ed. Engl. 1997; 36: 1871
• 7b Yoshikawa N, Yamada YM. A, Das J, Sasai H, Shibasaki M. J. Am. Chem. Soc. 1999; 121: 4168
• 8a Yin L, Brewitz L, Kumagai N, Shibasaki M. J. Am. Chem. Soc. 2014; 136: 17958
• 8b Brewitz L, Arteaga FA, Yin L, Alagiri K, Kumagai N, Shibasaki M. J. Am. Chem. Soc. 2015; 137: 15929
• 9 Weidner K, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2014; 53: 6150
• 10a Saito A, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2017; 56: 5551
• 10b Sun Z, Sun B, Kumagai N, Shibasaki M. Org. Lett. 2018; 20: 3070

In Cu(I)-catalyzed aldol reactions, the reactivity of the α-CF₃ enolate is somewhat lower than those with other substituents: While α-alkyl, vinyl, and N₃ 7-azaindoline amides smoothly undergo aldol additions to simple aldehydes, α-CF₃ amide 2 only reacts with activated arylglyoxal hydrates.
• 11a Weidner K, Sun Z, Kumagai N, Shibasaki M. Angew. Chem. Int. Ed. 2015; 54: 6236
• 11b Liu Z, Takeuchi T, Pluta R, Arteaga FA, Kumagai N, Shibasaki M. Org. Lett. 2017; 19: 710
• 11c Takeuchi T, Kumagai N, Shibasaki M. J. Org. Chem. 2018; 83: 5851
• 11d Matsuzawa A, Noda H, Kumagai N, Shibasaki M. J. Org. Chem. 2017; 82: 8304
• 12 For the construction of a tetrasubstituted carbon by aldol reaction of an α-N₃ amide to CF₃ ketones, see: Noda H, Amemiya F, Weidner K, Kumagai N, Shibasaki M. Chem. Sci. 2017; 8: 3260

For recent reviews on the use of isatin imines in asymmetric catalysis, see:
• 13a Pellissier H. Beilstein J. Org. Chem. 2018; 14: 1349
• 13b Kaur J, Chimni SS. Org. Biomol. Chem. 2018; 16: 3328
• 14a Sun Z, Weidner K, Kumagai N, Shibasaki M. Chem. Eur. J. 2015; 21: 17574
• 14b Arteaga FA, Liu Z, Brewitz L, Chen J, Sun B, Kumagai N, Shibasaki M. Org. Lett. 2016; 18: 2391
• 15 Li Z, Noda H, Kumagai N, Shibasaki M. Tetrahedron 2018; 74: 3301
• 16 See the Supporting Information for details. CCDC 1874483 contains the supplementary crystallographic data for 3e. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 17 With 1 mol% catalyst, 3a was obtained in 55% yield with the high selectivities retained (dr >95:5, 98% ee).
• 18 Compound 3a A flame-dried 30 mL flask equipped with a magnetic stirring bar and 3-way glass stopcock were charged with imine 1a (781 mg, 3.0 mmol, 1.0 equiv), and α-CF₃ amide 2 (760 mg, 3.3 mmol, 1.1 equiv), followed by the addition of anhydrous THF (9.6 mL, 0.2 M) via syringe with a stainless steel needle under an Ar atmosphere. After being stirred at 25 °C for 5 min, a solution of the catalyst in THF (4.5 mL) containing a chiral copper(I) complex (0.090 mmol, 3.0 mol%), which was prepared from [Cu(CH₃CN)₄]PF₆ (33.5 mg, 0.090 mmol) and (R,R)-Ph-BPE L8 (54.7 mg, 0.11 mmol, 3.6 mol%), and a solution of Barton’s base (0.1 M in THF, 0.90 mL, 0.09 mmol, 3.0 mol%) were sequentially added via a syringe with a stainless steel needle. After stirring at 25 °C for 12 h, the reaction mixture was filtered through a pad of silica gel and washed with EtOAc, then concentrated in vacuo to afford the crude residue. ¹H NMR analysis of the crude residue showed that the dr was >95:5. The combined crude residue was then purified by silica gel column chromatography (5% to 80% EtOAc in hexane) to afford product 3a (1.46 g, 99% yield). IR (thin film): ν = 3371, 2943, 1721, 1653, 1426, 1256, 1164, 754 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.93–7.92 (m, 1 H), 7.51–7.49 (m, 1 H), 7.44 (d, J = 7.2 Hz, 1 H), 7.35–7.31 (m, 1 H), 7.08–7.04 (m, 2 H), 6.91 (dd, J = 7.6 Hz, 5.2 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.31 (q, J = 8.8 Hz, 1 H), 4.31–4.10 (m, 2 H), 3.15–2.99 (m, 2 H), 2.96 (s, 3 H), 1.20 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.6, 163.4, 154.8, 153.8, 145.2, 143.2, 134.3, 129.3, 127.2, 126.8, 125.4 (d, J = 2.5 Hz), 124.3 (q, J = 281.1 Hz), 122.2, 119.0, 108.1, 80.0, 61.2, 48.9 (q, J = 26.1 Hz), 46.0, 27.9, 26.1, 23.7. ¹⁹F NMR (376 MHz, CDCl₃): δ = –57.98 (d, J = 8.5 Hz). HRMS (ESI): m/z calcd for C₂₄H₂₅O₄N₄F₃Na [M + Na]⁺: 513.1720; found: 513.1724. [α]_D ²⁴ –48.0 (c = 1.00, CHCl₃). Enantiomeric excess of the product was determined to be 98% by chiral stationary phase HPLC analysis (CHIRALPAK AD-H (φ 0.46 cm × 25 cm), 2-propanol/n-hexane = 1:4, flow rate 1.0 mL/min, detection at 254 nm, t _R = 5.9 min (major), 13.2 min (minor)).
• 19 The stereochemistry of 4 was assigned by NOE analysis. See the Supporting Information for details.