Radical − Radical Cyclization Cascades of Barbiturates Triggered by Electron-Transfer Reduction of Amide-Type Carbonyls

: Radical − radical cyclization cascades, triggered by single-electron transfer to amide-type carbonyls by SmI 2 − H 2 O, convert simple achiral barbiturates in one step to hemiaminal- or enamine-containing tricyclic sca ﬀ olds containing up to ﬁ ve contiguous stereocenters (including quaternary stereocenters). Furthermore, we describe the surprising bene ﬁ cial e ﬀ ect of LiBr on the most challenging of the radical − radical cyclization cascades. An alternative fragmentation − radical cyclization sequence of related substrates allows access to bicyclic uracil derivatives. The radical − radical cyclization process constitutes the ﬁ rst example of a radical cascade involving ET reduction of the amide carbonyl. Products of the cascade can be readily manipulated to give highly unusual and medicinally relevant bi- and tricyclic barbiturates.


■ INTRODUCTION
Cascade cyclizations have the ability to convert simple starting materials to complex polycyclic molecular architectures in a single synthetic operation. 1 Such processes are particularly powerful when they operate on medicinally relevant feedstocks, use commercially available reagents, and efficiently deliver unprecedented scaffolds. We have recently developed cascade cyclizations, triggered by SmI 2 -mediated 2 electron transfer (ET) to the carbonyl groups of ester derivatives, 3 that deliver complex structures through the formation of two carbocyclic rings (Scheme 1A). 4 While such cascades convert esters to complex carbobicyclic products, they are ET intensive, in that they feature four ET events and deliver products at the alcohol oxidation level that are not amenable to further manipulation. 4 Here we describe SmI 2 -mediated radical−radical cyclization cascades of amide-type groups 5 in medicinally important barbiturates 6 that construct both a heterocyclic and a carbocyclic ring, generate up to five contiguous stereocenters including quaternary stereocenters, involve only two ET events, and deliver readily manipulated polycyclic hemiaminals or enamines similar in structure to motifs found in important targets 7 (Scheme 1B,C). Furthermore, we describe the surprising beneficial effect of LiBr on the most challenging of the radical−radical cyclization cascades, an alternative fragmentation radical-cyclization pathway that delivers important bicyclic uracil derivatives, and the synthesis of several unprecedented barbiturate scaffolds. The ubiquity and importance of amide groups, their resistance to ET reduction, and the limited precedent for radical C−C bond formation using the resultant radical anions 5 highlights the significance of the findings. The radical−radical cyclization cascade process constitutes the first example of a radical cascade involving ET reduction of the amide carbonyl.

■ RESULTS AND DISCUSSION
Optimization of the First Radical Cascade Cyclizations Involving ET Reduction of the Amide Carbonyl. We began by optimizing the cascade cyclization of readily accessible barbituric acid derivative 1a, synthesized in 3 steps from diethyl-2-methymalonate (Table 1). H 2 O facilitates the reduction of carboxylic acid derivatives using SmI 2 in THF, 2c,3 and the use of H 2 O as a cosolvent was essential for the reduction of 1a (entry 1). Upon treatment of 1a with SmI 2 −H 2 O in THF, hemiaminal and enamine cascade products, 2a and 3a, respectively, were obtained in good yield (entry 2) accompanied by heminal byproduct 4a. 5a Reducing the amount of H 2 O cosolvent improved conversion; however, 4a was still formed in significant amounts (entry 3). The use of LiBr as an additive with SmI 2 −H 2 O (vide inf ra) gave similar results (entry 4). 8 The use of an alternative proton donor, ethylene glycol, 9 resulted in no conversion (entry 5). Pleasingly, when SmI 2 was added over 1 h, 2a/3a were obtained in 85% NMR yield with little formation of 4a (entry 6). From this experiment, hemiaminal 2a could be isolated as the major product in 60% yield and 95:5 dr. Finally, quenching of the reaction with HCl triggered dehydration of hemiaminal 2a, and enamine 3a was obtained in 88% isolated yield and 75:25 dr (entry 7). (In some cases, the minor diastereoisomers from the cascade cyclization undergo more facile dehydration to the corresponding enamines; thus, diastereoisomeric ratios for hemiaminals 2 can be higher than for enamines 3).
Scope of the Radical−Radical Cyclization Cascade of Amides. The scope of the radical−radical, heterocyclization− carbocyclization cascade of amides 1 was assessed. In general, tricyclic hemiaminals 2 were the major products, whereas tricyclic enamines 3 could be isolated if a HCl quench was employed. Good diastereocontrol was observed in both cases. A range of alkyl substituents on the barbituric acid substrates (R = Me, iBu, iPr, and allyl) was tolerated in the cascade (e.g., formation of 3a, 3b, 3h, and 3i). Furthermore, bromo (2c, 3c, and 3j), fluoro (2e and 3e), trifluoromethyl (2d and 3d), methoxy (3n, 3o, and 3p), acetal (3m), and thienyl (2f and 3f) groups were compatible with the reaction conditions. Finally, employing an alkyne as the second radical trap in the cascade delivered alkene products 2g and 3g (Scheme 2). The cyclization of an alkyne substrate to give 2g essentially as a single diastereoisomer (2.3:1 mixture of alkene isomers) confirms that hemiaminals 2 are diastereoisomeric mixtures at the homobenzylic stereocenter generated in the last step of the cascade. The relative stereochemistry of the major products was confirmed by X-ray crystallographic analysis of 2c and 3a. 10 Beneficial Effect of LiBr on the Radical−Radical Cyclization Cascades of Amides. Barbituric acid derived substrates 1q−t possessing additional substituents on the second alkene radical trap were used to further explore the scope of the reaction and the feasibility of generating quaternary stereocenters in the cascade process. Treatment of 1q with SmI 2 − H 2 O gave hemiaminal 2q and/or enamine 3q bearing a new quaternary stereocenter in low yield (40%), the major product being that of monocyclization (30%) (i.e., reduction and protonation of radical intermediate analogous to 14 in Scheme 8).
Interestingly, the addition of LiBr to the SmI 2 −H 2 O reagent system resulted in more efficient cascade cyclization and improved isolated yields of 2q (57%) and 3q (76%), depending on the conditions employed (Scheme 3). 11 Additional substrates 1r−t with various alkyl substitution on the barbituric acid ring and on the alkene radical acceptor underwent cascade reactions to give hemiaminals 2r−t or enamines 3r−t in good isolated yield. Notably, the use of larger alkyl substituents on the barbituric acid ring resulted in the formation of cascade products with higher diastereoselectivity (e.g., compare the formation of 2q and the formation of 2r).
We next turned to the cascade cyclization of substrate 1u bearing an additional substituent at the terminus of the first alkene radical acceptor. Pleasingly, exposure of 1u to SmI 2 − H 2 O and LiBr gave 2u containing five new contiguous stereocenters in good yield and essentially as a single diastereoisomer: The secondary alkyl radical undergoes more selective 6-exocyclization than the corresponding primary radicals (cf. 14 in Scheme 8), possibly through boat transition structure 5 in which substituents adopt pseudoequatorial orientations and transannular interactions are minimized (Scheme 4).
Flowers has proposed that the combination of SmI 2 and LiBr generates SmBr 2 in situ. 8 Thus, the addition of LiBr may generate SmBr 2 −H 2 O. 12 Although SmBr 2 (approximately −1.55 V vs SCE) has a higher reduction potential than SmI 2 (−0.9 V vs SCE), 8,12 the radical intermediate in the cascade appears less susceptible to reduction to the anion under the SmI 2 −H 2 O/LiBr conditions, and radical cyclization is more efficient. A hindered approach of SmBr 2 −H 2 O to the radical may lie behind the slower outer-sphere process.

Journal of the American Chemical Society
Article Scalability of the Radical−Radical Cyclization Cascade and the Synthetic Utility of the Unusual Tricyclic Products. The scalability of the radical−radical cyclization cascade has been assessed: Conversion of 1g to tricyclic hemiaminal 2g was conveniently carried out on a gram scale and gave 2g in 80% isolated yield after 2 h (Scheme 5).
The synthetic potential of the products arising from the amide radical−radical cyclization cascade has been assessed (Scheme 6). The N-alkyl substituent in cascade products can be removed. For example, Wacker oxidation 13 of 3a and eliminative cleavage of the intermediate aryl ketone gave N−H product 6. Preliminary studies have also shown that the unusual tricyclic cascade products can be manipulated to give additional intriguing architectures. Treatment of 3a with mCPBA gave the unprecedented 9-membered heterocyclic system present in 7 Scheme 2. Scope of the Radical−Radical Cyclization Cascade of Amides 1 a 17% enamine 3a was also isolated (dr 25:75). b 14% enamine 3c was also isolated (dr 25:75). c 10% enamine 3d was also isolated (dr 25:75). d E/Z ratio of alkene isomers ≈ 2.3:1 . Diastereoisomeric ratios determined by 1 H NMR of crude mixtures.

Scheme 3. Amide Radical−Radical Cyclization Cascades
Forming Quaternary Stereocenters a a Reaction conditions A: To the substrate (0.1 mmol, in THF) under N 2 was added H 2 O (100 equiv), followed by slow addition of a premixed solution of SmI 2 in THF (3 equiv) and LiBr (20 equiv wrt SmI 2 ) over 1 h, and the reaction was quenched after a further 2 h. Reaction conditions B: To the substrate (0.1 mmol, in THF) under N 2 was added H 2 O (100 equiv), followed by slow addition of a premixed solution of SmI 2 in THF (3 equiv) and LiBr (20 equiv wrt SmI 2 ) over 1 h. After a further 2 h, HCl (2 M in Et 2 O) was added, and the reaction was stirred for a further 2 h.

Scheme 4. Amide Radical−Radical Cyclization Cascade
Forming Five Contiguous Stereocenters a a Reaction conditions: To the substrate (0.1 mmol, in THF) under N 2 was added H 2 O (100 equiv), followed by slow addition of a premixed solution of SmI 2 in THF (5 equiv) and LiBr (12 equiv wrt SmI 2 ) over 1 h, and the reaction was quenched after a further 1 h. by oxidative cleavage. 14 Analogous ring-opening of 3g gave 8, which upon Ru-catalyzed oxidation 15 resulted in diketone formation, alkyne oxidation, and cyclization to give reconfigured tricyclic barbiturate 9. Finally, catalytic oxidation of tricyclic hemiaminal 2g resulted in formation of cyclic ketone 10. Attractively, in the formation of 9 and 10, catalytic oxidative alkene cleavage was accompanied by conversion of the N-alkyl substituent to a removable 16 or functionalizable group.
Related Fragmentation−Radical Cyclization Sequence. The choice of tether lengths anchoring the radical acceptors to the barbituric acid core is key to the sequence integrity of the radical−radical cascade cyclizations of 1; 5-exotrig carbocyclization precedes heterocyclization. Adjusting the lengths of the tethers gave related substrates 11. Interestingly, upon treatment with SmI 2 −H 2 O, barbiturates 11 underwent a fragmentation-radical heterocyclization sequence to give bicyclic uracil derivatives 12 in good isolated yield (Scheme 7). Variation of the alkyl substituents on the barbituric acid ring (R 1 = Me and Et) and functionality [bromo (12b), TMS (12e), and methoxy (12h)] proved compatible with the process. The structure of 12b was confirmed by X-ray crystallographic analysis. The use of alkyne radical acceptors selectively delivered dienyl uracil derivatives 12d−h containing exocyclic E-alkenes as confirmed by X-ray crystallographic analysis of 12d. 10 Importantly, expulsion of the allyl unit allows the final dehydration to occur into conjugation with the amide carbonyl, thus delivering important 5-alkyl uracil derivatives. 17 Notably, these products cannot readily be prepared from the corresponding monoalkylated barbituric acid derivatives because of the synthetic inaccessibility of such substrates (vide inf ra).
Proposed Mechanisms for the Radical−Radical Cyclization Cascade and the Fragmentation−Radical Heterocyclization Sequence. Both the radical−radical cyclization cascade (substrates 1) and the fragmentation−radical heterocyclization sequence (substrates 11) are triggered by ET to the amide-type carbonyl group to give radical anions 13. 3 For substrates 1 (m = 1, n = 1; left-hand pathway), 5-exo-trig radical cyclization gives radical intermediate 14 that then undergoes 6-exo-trig/dig cyclization to give 15. Further reduction and protonation gives tricyclic hemiaminals 2 or the corresponding enamines 3 after dehydration (Scheme 8). For substrates 11 (m = 0, n = 2; right-hand pathway), radical anion 13 undergoes fragmentation 18 to give a Sm(III)-enolate 19 that is protonated to give 16. Further reduction and 5-exo-trig/dig cyclization gives radical 17 that undergoes further reduction and protonation to give bicyclic uracil derivatives 12 after dehydration. Notably, monoalkyl barbituric acids 16 are hard to prepare because of their acidity, and their in situ formation by fragmentation of 11 is an attractive synthetic solution.
In support of the proposed fragmentation−radical cyclization mechanism, we investigated the use of established radical leaving groups in the sequence. Pleasingly, barbituric acid derivatives 11i and 11j, bearing strained rings alpha to the amide Scheme 6. Manipulating the Novel Tricyclic Products of the Amide Radical−Radical Cyclization Cascade Scheme 7. Sequential Fragmentation−Radical Heterocyclization of Amides 11 a a Reaction conditions: To 11 (0.1 mmol, in THF) under N 2 was added H 2 O (100 equiv), followed by slow addition of SmI 2 (4.5 equiv) over 1 h, and the reaction was quenched after a further 1 h.

Scheme 8. Proposed Mechanism for the Formation of 2/3 and 12
Journal of the American Chemical Society Article carbonyl, 20 undergo efficient fragmentation followed by cyclization to give bicyclic uracils 12c and 12j, respectively (Scheme 9). The radical fragmentation of carbonyl compounds bearing cyclopropyl rings in the α-position is well-known. 20

■ CONCLUSIONS
Single-electron transfer to the amide-type carbonyl of simple achiral barbiturates using SmI 2 −H 2 O triggers a two electron, radical−radical cyclization cascade that allows the formation of quaternary stereocenters and provides direct access to structurally complex and synthetically versatile hemiaminal-or enamine-containing tricyclic scaffolds containing up to five contiguous stereocenters. In addition, related substrates undergo alternative fragmentation−radical cyclization cascades to give bicyclic uracil derivatives. The addition of LiBr was found to have a surprising beneficial effect on the most challenging of the radical−radical cyclization cascades. The process constitutes the first example of a radical cyclization cascade involving ET reduction of the amide carbonyl.