Selective Reduction of Barbituric Acids Using SmI2/H2O: Synthesis, Reactivity, and Structural Analysis of Tetrahedral Adducts

Since the 1864 landmark discovery by Adolf von Baeyer,1 barbituric acids have played a prominent role in medicine and organic synthesis. The barbituric acid scaffold occurs in more than 5000 pharmacologically active compounds, including commonly used anticonvulsant, hypnotic, and anticancer agents (Figure 1 a).2 Moreover, as an easily accessible feedstock material, it is an extremely useful building block for organic synthesis.3 However, despite the fact that barbiturates have been extensively studied for over a century, the general monoreduction of barbituric acids remains unknown,4 even though it would have considerable potential for the production and discovery of pharmaceuticals, materials, and polymers. Interestingly, the barbiturate monoreduction products would formally constitute a new class of tetrahedral intermediates of amide bond addition reactions, only few of which have been successfully isolated to date because of their transient nature.5


General Methods
All experiments involving SmI 2 were performed using standard Schlenk or glovebox techniques under argon or nitrogen atmosphere unless stated otherwise. All solvents were purchased at the highest commercial grade and used as received or after purification by passing through activated alumina columns or distillation from sodium/benzophenone under nitrogen. All solvents were deoxygenated prior to use. All other chemicals were purchased at the highest commercial grade and used as received. Reaction glassware was oven-dried at 140 °C for at least 24 h or flame-dried prior to use, allowed to cool under vacuum and purged with argon (three cycles). Samarium(II) iodide was prepared by standard methods and titrated prior to use. 1-5 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 on Bruker spectrometers at 300, 400 and 500 MHz ( 1 H NMR) and 75, 100 and 125 MHz ( 13 C NMR).
All shifts are reported in parts per million (ppm) relative to residual CHCl 3 peak (7.27 and 77.2 ppm, 1 H NMR and 13 C NMR, respectively). All coupling constants (J) are reported in hertz (Hz). Abbreviations are: s, singlet; d, doublet; t, triplet; q, quartet; br s, broad singlet.
All flash chromatography was performed using silica gel, 60 Å, 230−400 mesh. TLC analysis was carried out on aluminium sheets coated with silica gel 60 F254, 0.2 mm thickness. The plates were visualized using a 254 nm ultraviolet lamp or aqueous potassium permanganate solutions.

C(O)CD 3 ) and/or GC-MS (neat) to
determine the product distribution and diastereoselectivity from the crude reaction mixture.
The crude product was purified by chromatography on silica gel, concentrated under reduced pressure and stored neat or as a solution in acetone. All compounds have been prepared as racemates.
After stirring for 5 min at -78 °C, the reaction mixture was warmed up to room temperature over 3 h, quenched with NH 4 Cl (aq, sat., 1 mL) and extracted with CH 2 Cl 2 (3 × 2 mL).   and GC-MS to obtain conversion and yield using internal standard.  which is in agreement with the stabilization of ketyl-type radicals in these systems. It is worthwhile to note that the SmI 2 -H 2 O system is fully chemoselective over acyclic carboxylic acid derivatives (esters, carboxylic acids, amides) in that no reduction of these functional groups is observed even if excess of the reagent is used.

SI-40
2) The reduction of cyclic 1,3-diimides using SmI 2 -H 2 O is facilitated by electron withdrawing groups and slowed down by steric substitution at the alpha carbon (Table SI-6, entries [4][5]. This is consistent with stabilization of the ketyl radical intermediate by electron withdrawing groups and reflects the importance of coordination of Sm(III) to the ketyl-type radical in the transition state of the reaction. Note that this trend allows high levels of chemoselectivity to be achieved in the reduction by careful fine-tuning of both the Sm(II) reagent system and steric/electronic substitution of the substrate.
3) The selectivity studies on reductive cyclizations of cyclic 1,3-diimides using SmI 2 -H 2 O show that the cyclization rate is governed by electronic and steric properties of the -acceptor (   1-3). Application of the above findings to the cascade processes employing C-centered radicals is currently underway in our laboratory and these results will be reported shortly.

F) Additional Selectivity Studies
Scheme SI-2. Additional Selectivity Studies in the Reduction of Cyclic 1,3-Diimides.
Eq. 1. According to the general procedure for reduction of cyclic 1,3-diimides with SmI 2 -H 2 O, 1,3-dimethyltetrahydropyrimidin-2(1H)-one (0.10 mmol) was reacted with SmI 2 (0.40 mmol, 4 equiv) and H 2 O (200 equiv) for 2 h at room temperature, which resulted in the formation of a characteristic burgundy-red color of the SmI 2 (H 2 O) n complex (n > 5 with respect to SmI 2 ). After the standard work-up as described above, the sample was analyzed by 1 H NMR to obtain conversion and yield using internal standard: conversion <5%; yield of recovered starting material: >80%.
Eq. 2. According to the general procedure for reduction of cyclic 1,3-diimides with SmI 2 -H 2 O, 5-isobutyl-1,3-dimethyldihydropyrimidine-4,6(1H,5H)-dione (0.10 mmol) was reacted with SmI 2 (0.60 mmol, 6 equiv) and H 2 O (1000 equiv) for 1 h at room temperature, which resulted in the formation of a characteristic burgundy-red color of the SmI 2 (H 2 O) n complex (n > 5 with respect to SmI 2 ). After the standard work-up as described above, the sample was analyzed by 1 H NMR to obtain conversion and yield using internal standard: conversion <5%; yield of recovered starting material: >95%. In another optimization run, a reaction SI-45 using SmI 2 (6 equiv) and H 2 O (200 equiv) for 1 h at room temperature resulted in <5% conversion.

SI-47
Additional discussion. The alpha-amino alcohol moiety is stabilized by a nonplanar arrangement of atoms. The X-ray crystal structure of 4a reveals that the C1-O1 bond (1.407 Å) is shorter than the average Cs p3 -O bond (1.432 Å), while the N1-C1 bond is 1.466 Å, which corresponds to a typical C sp3 -N bond (1.469 Å). The C1-C4 bond length of 1.552 Å is slightly longer than the average C sp3 -C sp3 bond (1.530 Å). The torsion angle between N lp and C1-O1 of 57.3° is consistent with the absence of N lp →* C-O interactions in this system.