One-Pot Reductive Allylation of Amides by Using a Combination of Titanium Hydride and an Allylzinc Reagent: Application to a Total Synthesis of (–)-Castoramine

Abstract

A one-pot direct reductive allylation protocol has been developed for the synthesis of secondary amines by using titanium ­hydride and an allylzinc reagent. This protocol is applicable to a broad range of substrates, including acyclic amides, benzamides, α,β-unsaturated amides, and lactams. The stereochemical outcome obtained from the reaction with crotylzinc reagent suggested that the allylation reaction proceeds through a six-membered cyclic transition state. A total synthesis of (–)-castoramine was accomplished by following this protocol for the highly stereoselective construction of contiguous stereo­centers.

Key words

amides - reduction - allylation - amines - total synthesis - alkaloids

• References and Notes


For selected recent reviews on amide formation, see:
• 1a Humphrey JM. Chamberlin AR. Chem. Rev. 1997; 97: 2243
• 1b Han S.-Y. Kim Y.-A. Tetrahedron 2004; 60: 2447
• 1c Montalbetti CA. G. N. Falque V. Tetrahedron 2005; 61: 10827
• 1d Valeur E. Bradley M. Chem. Soc. Rev. 2009; 38: 606
• 1e El-Faham A. Albericio F. Chem. Rev. 2011; 111: 6557
• 1f Pattabiraman VR. Bode JW. Nature 2011; 480: 471
• 1g Lanigan RM. Sheppard TD. Eur. J. Org. Chem. 2013; 7453
• 1h Lundberg H. Tinnis F. Selander N. Adolfsson H. Chem. Soc. Rev. 2014; 43: 2714
• 2 For a review on nucleophilic addition to amides, see: Pace V. Holzer W. Olofsson B. Adv. Synth. Catal. 2014; 356: 3697

For a review and a recent example through a thioamide, see:
• 3a Murai T. Mutoh Y. Chem. Lett. 2012; 41: 2
• 3b Murai T. Mutoh N. J. Org. Chem. 2016; 81: 8131

For recent examples through iminium triflates, see:
• 4a Huang P.-Q. Huang Y.-H. Xiao K.-J. Wang Y. Xia X.-E. J. Org. Chem. 2015; 80: 2861
• 4b Wang A.-E. Yu C.-C. Chen T.-T. Liu Y.-P. Huang P.-Q. Org. Lett. 2018; 20: 999
• 4c Chen H. Ye J.-L. Huang P.-Q. Org. Chem. Front. 2018; 5: 943
• 5a Oda Y. Sato T. Chida N. Org. Lett. 2012; 14: 950
• 5b Nakajima M. Oda Y. Wada T. Minamikawa R. Shirokane K. Sato T. Chida N. Chem. Eur. J. 2014; 20: 17565

For examples of direct reductive nucleophilic additions to amides by using Vaska’s complex, see:
• 6a Xie L.-G. Dixon DJ. Chem. Sci. 2017; 8: 7492
• 6b Fuentes de Arriba ÁL. Lenci E. Sonawane M. Formery O. Dixon DJ. Angew. Chem. Int. Ed. 2017; 56: 3655

For direct reductive nucleophilic additions to N-alkoxy amides, see:
• 7a Shirokane K. Kurosaki Y. Sato T. Chida N. Angew. Chem. Int. Ed. 2010; 49: 6369
• 7b Yanagita Y. Nakamura H. Shirokane K. Kurosaki Y. Sato T. Chida N. Chem. Eur. J. 2013; 19: 678
• 7c Shirokane K. Wada T. Yoritate M. Minamikawa R. Takayama N. Sato T. Chida N. Angew. Chem. Int. Ed. 2014; 53: 512
• 7d Sato T. Chida N. Org. Biomol. Chem. 2014; 12: 3147
• 7e Nakajima M. Sato T. Chida N. Org. Lett. 2015; 17: 1696
• 7f Fukami Y. Wada T. Meguro T. Chida N. Sato T. Org. Biomol. Chem. 2016; 14: 5486
• 8 When spirocyclic lactam 4 was treated with the Schwartz reagent, a fully reduced amine was detected as the major product.
• 9 Sato M. Azuma H. Daigaku A. Sato S. Takasu K. Okano K. Tokuyama H. Angew. Chem. Int. Ed. 2017; 56: 1087
• 10 Bower S. Kreutzer KA. Buchwald SL. Angew. Chem. Int. Ed. Engl. 1996; 35: 1515
• 11 Hatano M. Suzuki S. Ishihara K. J. Am. Chem. Soc. 2006; 128: 9998
• 12 For an example of a titanium hydride-mediated one-pot partial reduction/intramolecular Henry reaction of a tertiary amide, see: Jakubec P. Hawkins A. Felzmann W. Dixon DJ. J. Am. Chem. Soc. 2012; 134: 17482
• 13 For details of the preparation of lactam 8, see the Supporting Information.
• 14 The relative stereochemistry (trans) of compound 10 was determined after conversion to the known compound; see the Supporting Information.
• 15 The conditions of Table 2, entry 2 gave the allylated compounds in higher yields than those of Table 2, entry 1. For instance, the latter conditions gave 13a (62%), 13b (54%), 13ie (0%), 13ka (31%), and 13kc (53%).
• 16 N-Benzyl-1-phenylbut-3-en-1-amine (13d): Gram-Scale Synthesis A 1.0 M solution of allylmagnesium chloride in THF (14.2 mL, 14.2 mmol) was added to a suspension of ZnCl₂ (1.00 g, 7.35 mmol) in THF (7.7 mL) at r.t., and the mixture was stirred for 1 h at r.t., before being used in the next reaction. Ti(O-i-Pr)₄ (2.1 mL, 7.1 mmol) was added to a solution of amide 12d (1.00 g, 4.74 mmol) and Ph₂SiH₂(4.4 mL, 24 mmol) in THF (47 mL) at r.t., and the mixture was stirred at r.t. for 7.5 h. The mixture was then cooled to –78 °C, and the freshly prepared allylzinc reagent was added at –78 °C. The resulting mixture was warmed to 0 ℃ and stirred at 0 ℃ for 1 h before the reaction was quenched with sat. aq NH₄Cl (100 mL). The mixture was then filtered through a pad of Celite, which was washed with EtOAc (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL), and the combined organic extracts were washed with brine, dried (Na₂SO₄), and filtered. The organic solvents were removed under reduced pressure to give a crude material that was purified by column chromatography [silica gel, hexanes–EtOAc (1:1)] to give a colorless oil; yield: 1.02 g (4.31 mmol, 91%); R_f = 0.75 (hexanes–EtOAc, 1:1). IR (neat): 3068, 3028, 2916, 2835, 1455, 1119, 916, 749, 703 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.21 (m, 10 H), 5.76–5.65 (m, 1 H), 5.07 (d, J = 17.2 Hz, 1 H), 5.03 (d, J = 10.0 Hz, 1 H), 3.71-3.66 (m, 2 H), 3.52 (d, J = 13.2 Hz, 1 H), 2.45-2.35 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.7, 140.6, 135.4, 128.34, 128.28, 128.1, 127.3, 127.0, 126.8, 117.5, 61.6, 51.4, 43.0. HRMS (ESI): m/z [M + H]⁺ calcd. for C₁₇H₂₀N: 238.1590; found: 238.1580. Spectroscopic data were identical with those reported for this compound (see Ref. 5a).
• 17 Four- and five-membered lactams were not suitable substrates for this protocol. Initial reduction of a four-membered lactam did not proceed at all, and in the case of a five-membered lactam, the reduction step was sluggish.
• 18 The relative stereochemistry (trans) of compound 13f was determined after conversion into the known compound; see the Supporting Information.
• 19 The structure of compound 14 was determined by NOE experiments after several transformations; see the Supporting Information.

For the isolation, see:
• 20a Valenta Z. Khaleque A. Tetrahedron Lett. 1959; 1: 1(12): 1

For total syntheses, see:
• 20b Bohlmann F. Winterfeldt E. Laurent H. Ude W. Tetrahedron 1963; 19: 195
• 20c Goodenough KM. Moran WJ. Raubo P. Harrity JP. A. J. Org. Chem. 2005; 70: 207
• 21 For the preparation of amide 18, see the Supporting Information.
• 22 Under the optimal conditions, we obtained compound 19 (19%) together with a considerable amount of the over-reduced amine (18%).
• 23 Jansen DJ. Shenvi RA. J. Am. Chem. Soc. 2013; 135: 1209