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Radical-radical cyclization cascades of barbiturates triggered by electron-transfer reduction of amide-type carbonyls Huanming Huang, and David J. Procter J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04086 • Publication Date (Web): 31 May 2016 Downloaded from http://pubs.acs.org on May 31, 2016
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Journal of the American Chemical Society
Radical-radical cyclization cascades of barbiturates triggered by electron-transfer reduction of amide-type carbonyls Huanming Huang, David J. Procter* School of Chemistry, Oxford Road, University of Manchester, Manchester, M13 9PL, UK ABSTRACT: Radical-radical cyclization cascades, triggered by single electron transfer to amide-type carbonyls by SmI2-H2O, convert simple achiral barbiturates in one step to hemiaminal or enamine-containing tricyclic scaffolds containing up to five contiguous stereocenters (including quaternary stereocenters). Furthermore, we describe the surprising beneficial effect 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 first 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 biand 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 SmI2-mediated2 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 SmI2-mediated radicalradical cyclization cascades of amide-type groups5 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 targets7 (Scheme 1B and 1C). 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. Scheme 1. A Cascade cyclizations of esters forming tertiary alcohols and two new carbocyclic rings. B Radical-radical cascade cyclizations of amides that form hemiami-
nals/enamines possessing a new heterocyclic ring and a new carbocyclic ring. C The importance of related scaffolds. A. Previously: Four-electron, carbo-carbocyclization cascades of esters R1
O
OH OR
R1
R2
OR
2e
R2
O
O OR
R
OH
R1
R
R2
2e
3°ary alcohols
R
esters complexity generation ET intensive carbo-carbocyclization B. This work: Two-electron, carbo-heterocyclization cascades of amides R2 R2 R1
R2
R1 O
N
O
R1 HO
1e
O
N
NR'
NR'
O O
OH N
1e
O NR'
6-exo-trig/dig
polycyclic O hemiaminals & enamines NR R amides complexity generation 2e process carbo-heterocyclization up to 5 new stereocentres quaternary stereocentres novel scaffolds
O
C. The importance of related scaffolds H
H H N Me
N
O
N
N
R=H isoschizogaline R = OMe isoschizogamine
H
H
O
Et vallesamidine
N H N
N
N
O Me NH
MeO strempeliopine
R antihypertensive EtO 2C agent
N
O
N 17-azaeburnamonine
O
N
N
N
N CN
O NH
Me
NH 5-HT3 receptor antagonist
HO
N
N
O fluorescent material OH
RESULTS AND DISCUSSION Optimization of the first radical cascade cyclizations involving ET reduction of the amide carbonyl. We began by
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optimizing the cascade cyclization of readily accessible barbituric acid derivative 1a, synthesized in 3 steps from diethyl-2methymalonate (Table 1). H2O facilitates the reduction of carboxylic acid derivatives using SmI2 in THF2c,3 and the use of H2O as a cosolvent was essential for the reduction of 1a (entry 1). Upon treatment of 1a with SmI2-H2O 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 H2O cosolvent improved conversion, however, 4a was still formed in significant amounts (entry 3). The use of LiBr as an additive with SmI2H2O (vide infra) gave similar results (entry 4).8 The use of an alternative proton donor, ethylene glycol,9 resulted in no conversion (entry 5). Pleasingly, when SmI2 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). Table 1. Optimization of the radical-radical cyclization cascade of amide 1aa
ployed. Good diastereocontrol was observed in both cases. A range of alkyl substituents on the barbituric acid substrates (R = Me, iBu, iPr, allyl) was tolerated in the cascade (e.g. formation of 3a, 3b, 3h and 3i). Furthermore, bromo (2c, 3c, 3j), fluoro (2e, 3e), trifluoromethyl (2d, 3d), methoxy (3n, 3o, 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 Scheme 2. Scope of the radical-radical cyclization cascade of amides 1
O Ar
R
N O R' 1
Conditions A
Ph
Ph Me
O
HO
SmI 2–H 2O
N N R'
O
1a R' = CH2CH 2=CHPh
THF see Table
OH N O 2a
Ph
Me O O
N R'
3a
N
Me O
N R'
Me
O
N R'
O
N
Br
R O
Yield [%]b
(equiv)
1a
2a
3a
4a
1
3
–
100
0
0
0
2
3
200
10
40
20
22
3
100
–
40
20
40
3
100
–
51
15
10
3
–d
100
–
–
–
20
5
92h
-
3
S
5 e
3
100
-
65
7e,f
3
100
-
-
6
g
a
Reaction conditions: to 1a (0.1 mmol, in THF) under N2, was added H2O, followed by SmI2 and the reaction quenched after for 1 h. b Yield was determined by 1H NMR spectroscopy using 2,3,5,6tetrachloronitrobenzene as internal standard. c LiBr (20 equiv. wrt SmI2) was used. d Ethylene glycol (36 equiv. or 100 equiv.) was used in place of H2O. e 3 equiv. SmI2 (0.1 M, 3 mL) was added by syringe pump over 1 h and the reaction quenched after 1 h. f after 1 h, HCl (1 M, 2 mL) was added and stirred for 2 h. g 60% isolated yield; >95:5 dr. h 88% isolated yield; 75:25 dr.
OH N
Me O
Me O N R' 2g 81% >95:5 drd [R' = CH 2CCPh] O
2f 66% 66:34 dr [R' = CH 2CH=CHTh-3]
Conditions B
R O
N R' 3a R = Me, 88% 75:25 dr X-ray 3b R = iBu, 71% 86:14 dr 3h R = iPr, 64% 92:8 dr 3i R = allyl, 40% 85:15 dr [R' = CH 2CH=CHPh] O
N
Br
N R'
O
R O
N
F 3C
N
R Me O O N N O R' R' 3k R = Me, X = Me, 92% 75:25 dr 3f 78% 66:34 dr 3l R = iPr, X = Me, 81% 85:15 dr [R' = CH 2CH=CHTh-3] [R' = CH 2CH=CH(4-MeC 6H 4)]
O
N
MeO
N
R O
N N O R' R' 3e X = F, 79% 66:34 dr 3o R = Me, 87% 66:34 dr [R' = CH 2CH=CH(2-FC 6H 4)] 3p R = iPr, 51% 89:11 dr 3n X = OMe, 64% 75:25 dr [R' = CH 2CH=CH(4-MeOC6H 4)] [R' = CH 2CH=CH(2-MeOC 6H 4)] O
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Me
O N R' 3m 62% 75:25 dr [R' = CH 2CH=CHAr]
O
Me O
Me O
O
S
N
N R'
O
3d 60% 75:25 dr 3c R = Me, 76% 75:25 dr 3j R = iPr, 58% 87:13 dr [R' = CH 2CH=CH(4-CF3C6H 4)] [R' = CH 2CH=CH(4-BrC 6H 4)]
N
Me
X
Scope of the radical-radical cyclization cascade of amides. The scope of the radical-radical, heterocyclizationcarbocyclization cascade of amides 1 was assessed. In general, tricyclic hemiaminals 2 were the major products, while tricyclic enamines 3 could be isolated if a HCl quench was em-
2d 50% >95:5 drc [R' = CH 2CH=CH(4-CF3C 6H 4)]
H
N R'
O
N R' 2e 57% 66:34 dr [R' = CH 2CH=CH(2-FC 6H 4)] O
Me O
N R'
O
OH N
Me O
N
4
c
N
F 3C
H
N
F
(equiv)
Entry
OH
Me O
N R'
O
OH
H2O
H OH
H
SmI2
R O N R' 3 major Conditions B
O
H
2c 50% >95:5 drb 2a R = Me, 60% >95:5 dra 2b R = iBu, 69% 88:12 dr [R' = CH 2CH=CH(4-BrC 6H 4)] [R' = CH 2CH=CHPh] X-ray
4a
N
R
O N R' 2 major Conditions A O
H
N R'
O
N
OH
OH
Ph
H
Ar
H
N
Conditions B SmI 2 –H2O, THF rt, 2 h then 2 M HCl, 2 h
N O
Ar
Conditions A SmI 2–H2O, THF rt, 2 h
N
O
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O
N O
Me O N R' 3g 76%d [R' = CH 2CCPh]
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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 ~2.3:1 E:Z ratio of alkene isomers. Diastereoisomeric ratios determined by 1H NMR of crude mixtures.
The beneficial effect of LiBr on the radical-radical cyclization cascades of amides. Returning to the radical-radical cyclization cascades of substrates 1, barbituric acid derived substrates 1q-t possessing additional substituents on the second alkene radical trap were used to further explore the scope of the process and the feasibility of generating quaternary stereocenters in the cascade process. Treatment of 1q with SmI2H2O 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 the radical intermediate analogous to 8 in Scheme 4). Interestingly, the addition of LiBr to the SmI2-H2O reagent system resulted in more efficient cascade cyclization and improved isolated yields of 2q (57%) and 3q (76%), respectively, depending on the conditions employed (Scheme 3).15 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). Scheme 3. Amide radical-radical cyclization cascades forming quaternary stereocenters.a O Ph
Conditions A SmI2 –H2O–LiBr THF, rt, 3 h
R1
N R2
O
N R'
O
1q-t R' = CH 2C(R 2)=CHPh
R2
R2
H
Ph
Ph
OH N
N
R1 O N R' 2q-t major Conditions A
Conditions B SmI2-H2O-LiBr THF, rt, 3 h then 2 M HCl, 2 h
R1 O N R' 3q-t major Conditions B
Me
Me
H OH
N
Ph
OH N
Me
Ph
N R'
O
H
Me Ph
OH N
iPr O
N R' 2r 52%, >95:5 dr O
O N R' 2q 57%, 85:15 dr O
H
Et
H
iPr O
2s 56%, >95:5 dr
OH N N R'
O
iBu O
2t 64%, >95:5 dr
Conditions B Et
Me
Me
N
Me O
N R' 3q 76%, 85:15 dr O
Me
Ph
Ph
Ph
N
iPr O
N R' 3r 66%, >95:5 dr O
Scheme 4. An amide radical-radical cyclization cascade forming five contiguous stereocenters.a Me O
Me Me
SmI 2–H2O–LiBr
N Br
O
N R'
O
THF, rt, 2 h
O
N R'
iPr O
3s 64%, >95:5 dr
OH N
Br
Me O N R' 2u 64% >95:5 dr O
1u R' = CH2CH=CH(4-BrC 6H 4) H
SmIII O H
Ar
N
Me 5
O
Me O N R'
a
Reaction conditions: to the substrate (0.1 mmol, in THF) under N2, was added H2O (100 equiv.), followed by slow addition of a premixed solution of SmI2 in THF (5 equiv.) and LiBr (12 equiv. wrt SmI2) over 1 h and the reaction quenched after a further 1 h.
Flowers has proposed that the combination of SmI2 and LiBr generates SmBr2 in situ.8 Thus, the addition of LiBr may generate SmBr2-H2O.16 Although, SmBr2 (approx. –1.55 V vs SCE) has a higher reduction potential than SmI2 (–0.9 V vs SCE),8,16 the radical intermediate in the cascade appears less susceptible to reduction to the anion under the SmI2-H2O/LiBr conditions and radical cyclization is more efficient. A hindered approach of SmBr2-H2O to the radical may lie behind the slower outer-sphere process. The 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). Scheme 5. Gram scale amide radical-radical cyclization cascade.
Ph N
H
O
O
Conditions A
Ph
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).
Ph
N
N R' 3t 68%, >95:5 dr O
a
Reaction conditions A: to the substrate (0.1 mmol, in THF) under N2, was added H2O (100 equiv.), followed by slow addition of a premixed solution of SmI2 in THF (3 equiv.) and LiBr (20 equiv. wrt SmI2) over 1 h and the reaction quenched after a further 2 h. Reaction conditions B: to the substrate (0.1 mmol, in THF) under N2, was added H2O (100 equiv.), followed by slow addition of a premixed solution of SmI2 in THF (3 equiv.) and LiBr (20 equiv. wrt SmI2) over 1 h. After a further 2 h, HCl (2 M in Et2O) was added and the reaction stirred for a further 2 h.
H
O
iBu O
N Ph 1.06 g
O
OH Me O
N R' 1g (R' = CH2CCPh)
SmI 2–H2O
N
Me O N R' 2g 80% >95:5 dr (R' = CH 2CCPh) O
THF, rt, 2 h
0.857 g
Scheme 6. Manipulating the novel tricyclic products of the amide radical-radical cyclization cascade.
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 SmI2-H2O and
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cannot readily be prepared from the corresponding monoalkylated barbituric acid derivatives due to the synthetic inaccessibility of such substrates (vide infra).
Ph
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
1. PdCl 2, CuCl DMF:H 2O Ph N
3a
Me O
N
O
N
2. NaH, DMF 61% (2 steps)
6
Me O
N H O
O
Scheme 7. Sequential fragmentation-radical heterocyclization of amides 11a.
O
Ph mCPBA Ph
N CH 2Cl 2, 63%
7
Me O
N
O
O
Ph Ph
O
Ph
O
mCPBA N
3g
Me CH 2Cl 2 O 72%
N
O
N
O
Me CH 2Cl 2:CH 3CN :H 2O, 85% O O
Ph
9 Ph
H 1 mol% RuCl 3•XH 2O, NaIO 4
OH N O
N
Me O
O
Me O O Ph
OH N
CH 2Cl 2:CH 3CN:H 2O 68% Ph
O
H
O
N O R' 11
O
N
O
Ph
A 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-exo-trig carbocyclization precedes heterocyclization. Adjusting the lengths of the tethers gave related substrates 11. Interestingly, upon treatment with SmI2-H2O, 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 (R1 = Me, Et) and functionality [bromo (12b), TMS (12e), 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.11 Notably, these products
R1
N
THF, rt 2h
O
N R'
R1
N
O
O
N R'
O 12
Br Me
N
Me
N
O N R' 12a 85% [R' = CH 2CH 2CH=CHPh] O
N
Et
O N N O O R' R' 12b 65% X-ray 12c 72% [R' = CH 2CH 2CH=CH(4-BrC6H 4)] [R' = CH 2CH2CH=CHPh] O
X
R
Me
N O
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 oxidation17 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 by oxidative cleavage.18 Analogous ring-opening of 3p gave 8 which upon Ru-catalyzed oxidation19 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 removable20 or functionalizable group.
R2
O SmI 2–H2O R 2
Me
Me O O
10 2g E/Z = 69:31
N
R1
N
RuCl 3•XH 2O (1 mol%), NaIO 4
8 Ph
R2
O
O
N
N
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N N R'
O
Me
Me
N
O N R' 12d R = Ph, 81% X-ray 12g X = Me, 76% [R' = CH2CH 2CCPh] [R' = CH2CH 2CC(3-MeC6H 4] 12f 79% 12e R = TMS, 24% 12h X = OMe, 63% [R' = CH2CH 2CCTMS] [R' = CH2CH 2CC(4-MeC6H 4)] [R' = CH 2CH2CC(3-MeOC6H 4)] O
O
N R'
O
a Reaction conditions: to 11 (0.1 mmol, in THF) under N2, was added H2O (100 equiv), followed by slow addition of SmI2 (4.5 equiv.) over 1 h and the reaction quenched after a further 1 h.
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-exotrig/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 fragmentation12 to give a Sm(III)-enolate13 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 due to their acidity and their in situ formation by fragmentation of 11 is an attractive synthetic solution. Scheme 8. Proposed mechanism for the formation of 2/3 and 12.
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Journal of the American Chemical Society III Sm
R2
SmIII O N O
m=1 n = 1 R2
O
m
N R' 13
m=0 2 n=2 R
R2
O
O
R2 OSmIII R1
OX N
N
R1 O
O
N R' 15 X = SmIII
O
N R' 17
1e 2H
2H
2/3
Corresponding Author O
[email protected] R1
N
deallylation & quenching of Sm(III)-enolate
6-exo-trig/dig
1e
III Sm
R1
nN
R1 O 5-exo -trig
N R' 14
O
N R'
O
We thank the EPSRC (EPSRC Established Career Fellowship to D. J. P.), the Leverhulme Trust (Research Fellowship to D. J. P.), and the University of Manchester (President’s Scholarship to H. H.) for funding.
H
O 1e
R2
R1
N
5-exo -trig/dig
O
O
N R'
O
16 –H2O
12
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 carbonyl,14 undergo efficient fragmentation followed by cyclization to give bicyclic uracils 12c and 12i, respectively (Scheme 9). The radical fragmentation of carbonyl compounds bearing cyclopropyl rings in the α-position is well-known.14 Scheme 9. Alternative fragmentation-radical cyclization sequences.
Ph
N O
n
N R'
SmIII O
Ph
O
O
SmI2-H2O THF, rt 1h
11i n = 0 11j n = 1 [R' = CH 2CH 2CH=CHC 6H 5]
Me
N O
N
n
N R'
O
O –via
n
N R'
O
12c n = 0, 72% 12i n = 1, 70% [R' = CH2CH 2CH=CHC6H 5]
CONCLUSIONS Single electron transfer to the amide-type carbonyl of simple achiral barbiturates using SmI2-H2O 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.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental details, characterization data and spectra, X-ray structures, nOe studies are in the Supplementary Information (PDF).
AUTHOR INFORMATION
ACKNOWLEDGMENT
REFERENCES 1. For selected reviews on cascade reactions, see: (a) Anderson, E. A. Org. Biomol. Chem. 2011, 9, 3997. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993. (d) Tietze, L. F. Chem. Rev. 1996, 96, 115. 2. For recent reviews of SmI2, see: (a) Szostak, M.; Fazakerley, N. J.; Parmar, D.; Procter, D. J. Chem. Rev. 2014, 114, 5959. (b) Szostak, M.; Spain, M.; Procter, D. J. Chem. Soc. Rev. 2013, 42, 9155. (c) Szostak, M.; Spain, M.; Parmar, D.; Procter, D. J. Chem Commun. 2012, 48, 330. (d) Szostak, M.; Procter, D. J. Angew. Chem., Int. Ed. 2012, 51, 9238. (e) Beemelmanns, C.; Reissig, H.-U. Chem. Soc. Rev. 2011, 40, 2199. (f) Beemelmanns, C.; Reissig, H.-U. Pure Appl. Chem. 2011, 83, 507. (g) Nicolaou, K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48, 7140. (h) Organic Synthesis using Samarium Diiodide: A Practical Guide, Procter, D. J.; Flowers, II, R. A.; Skrydstrup, T. RSC Publishing, Cambridge, 2009; (i) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104, 3371. (j) Kagan, H. Tetrahedron 2003, 59, 10351. (k) Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745. (l) Molander, G. A.; Harris, C. R.; Chem. Rev. 1996, 96, 307. (m) Flowers, II, R. A. Synlett 2008, 2008, 1427. 3. Just-Baringo, X.; Procter, D. J. Acc. Chem. Res. 2015, 48, 1263. 4. (a) Parmar, D.; Matsubara, H.; Price, K.; Spain, M.; Procter, D. J. J. Am. Chem. Soc. 2012, 134, 12751. (b) Parmar, D.; Price, K.; Spain, M.; Matsubara, H.; Bradley, P. A.; Procter, D. J. J. Am. Chem. Soc. 2011, 133, 2418. (c) Yalavac, I.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Chem. Commun. 2014, 50, 12863. (d) Sautier, B.; Lyons, S. E.; Webb, M. R.; Procter, D. J. Org. Lett. 2012, 14, 146. 5. (a) For the reduction of barbiturates and mono-carbocyclization of barbiturates, see: Szostak, M.; Sautier, B.; Spain, M.; Behlendorf, M.; Procter, D. J. Angew. Chem., Int. Ed. 2013, 52, 12559. (b) For an excellent study on the cyclization of imides, see: Shi, S.; Szostak, M. Org. Lett. 2015, 17, 5144. 6. For the landmark discovery of barbituric acids, see: (a) Baeyer, A. Justus Liebigs Ann. Chem. 1864, 130, 129. For a review of the chemistry and pharmacology of barbiturates, see: (b) Bojarski, J. T.; Mokrosz, J. L.; Bartoń, H. J.; Paluchowska, M. H. Adv. Heterocycl. Chem. 1985, 38, 229. As useful building blocks for organic synthesis, see: (c) Takenaka, K. Itoh, N. Sasai, H. Org. Lett. 2009, 11, 1483. (d) Holzwarth, M. Dieskau, A. Tabassam, M. Plietker, B. Angew. Chem., Int. Ed. 2009, 48, 7251. (e) Fujimori, S. Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4964. (f) Schmidt, M. U.; Brüning, J.; Glinnemann, J.; Hützler, M. W.; Mörschel, P.; Ivashevskaya, S. N.; van de Streek, J.; Braga, D.; Maini, L.; Chierotti, M. R.; Gobetto, R. Angew. Chem., Int. Ed. 2011, 50, 7924. (g) Mori, K. Sueoka, S. Akiyama, T. J. Am. Chem. Soc. 2011, 133, 2424. (h) Chidipudi, S. R.; Khan, I.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 12115. (i) Daniewski, A. R. Liu, W. Okabe, M. Org. Process Res. Dev. 2004, 8, 411. (j) Ruble, J. C. Hurd, A. R. Johnson, T. A. Sherry, D. A. Barbachyn, M. R. Toogood, P. L. Bundy, G. L. Graber, D. R. Kamilar, G. M. J. Am. Chem. Soc. 2009, 131, 3991. (k) Huang, X. Li, C. Jiang, S. Wang, X. Zhang, B. Liu, M. J. Am. Chem. Soc. 2004, 126, 1322. (l) Best, D.; Burns, D. J.; Lam, H. W. Angew. Chem., Int. Ed. 2015, 54, 7410. (m) Burns, D. J.; Best, D.; Wieczysty, M. D.; Lam, H. W. Angew. Chem., Int. Ed. 2015, 54, 9958. (n) Qiu, J.-K.; Jiang, B.; Zhu, Y.-L.; Hao, W.J.; Wang, D.-C.; Sun, J.; Wei, P.; Tu, S.-J.; Li, G. J. Am. Chem. Soc. 2015, 137, 8928. 7. Vallesamidine: (a) Dickman, D. A.; Heathcock, C. H. J. Am. Chem. Soc. 1989, 111, 1528. (b) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K. Tetrahedron 2004, 60, 3273. Strempeliopine: (c) Stephens,
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P. J.; Pan, J.-J.; Devlin, F. J.; Urbanová, M.; Hájíček, J. J. Org. Chem. 2007, 72, 2508. (d) Bobeck, D. R.; Lee, H. I.; Flick, A. C.; Padwa, A. J. Org. Chem. 2009, 74, 7389. Isoschizogaline and isoschizogamine: (e) Kariba, R. M.; Houghton, P. J.; Yenesew, A. J. Nat. Prod. 2002, 65, 566. (f) Hubbs, J. L.; Heathcock, C. H. Org. Lett. 1999, 1, 1315. (g) Padwa, A.; Flick, A. C.; Lee, H. I. Org. Lett. 2005, 7, 2925. (h) Miura, Y.; Hayashi, N.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2012, 134, 11995. (i) Takada, A.; Fujiwara, H.; Sugimoto, K.; Ueda, H.; Tokuyama, H. Chem. -Eur. J. 2015, 21, 16400. (j) Wang, X.; Xia, D.; Tan, L.; Chen, H.; Huang, H.; Song, H.; Qin, Y. Chem. Eur. J. 2015, 21, 14602. (k) Xu, Z.; Bao, X.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2015, 54, 14937. Bioactive compounds and materials: (l) López, I.; Diez, A.; Rubiralta, M. Tetrahedron 1996, 52, 8581. (m) Zhang, Y.; Zheng, J.; Cui, S. J. Org. Chem. 2014, 79, 6490. (n) Mizuta, M.; Seio, K.; Miyata, K.; Sekine, M. J. Org. Chem. 2007, 72, 5046. (o) Bandurco, V. T.; Wong, E. M.; Levine, S. D.; Hajos, Z. G. J. Med. Chem. 1981, 24, 1455.
K.; Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 3811. (e) Batey, R. A.; Harling, J. D.; Motherwell, W. B. Tetrahedron 1996, 52, 11421. (f) Breitler, S.; Carreira, E. M. Angew. Chem. Int. Ed. 2013, 52, 11168. See also ref. 3. For the fragmentation of a carbonyl compound bearing a cyclobutyl ring in the α-position, see: (g) Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc. 2006, 128, 7025.
15. For the beneficial effect of LiBr (and LiCl) on SmI2-mediated carbon-carbon bond-forming processes, see: (a) Peltier, H. M.; McMahon, J. P.; Patterson, A. W.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 16018. (b) Asano, Y.; Suzuki, S.; Aoyama, T.; Shimizu, K.; Kajitani, M.; Yokoyama, Y. Synthesis 2007, 1309. (c) Iwasaki, H.; Eguchi, T.; Tsutsui, N.; Ohno, H.; Tanaka, T. J. Org. Chem. 2008, 73, 7145. (d) Zörb, A.; Brückner, R. Eur. J. Org. Chem. 2010, 4785. (e) J. Y. Cha, J. T. S. Yeoman, S. E. Reisman, J. Am. Chem. Soc. 2011, 133, 14964. (f) Gilles, P.; Py, S. Org. Lett. 2012, 14, 1042. (g) Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764. For examples using SmI2-H2O-LiBr, see: (h) Rao, C. N.; Lentz, D.; Reissig, H.-U. Angew. Chem., Int. Ed. 2015, 54, 2750. (i) Rao, C. N.; Bentz, C.; Reissig, H.-U. Chem. -Eur. J. 2015, 21, 15951. 16. For the effective redox potential of SmBr2-H2O, see: Szostak, M.; Spain, M.; Procter, D. J. J. Org. Chem. 2014, 79, 2522. 17. (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Rüttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176. (b) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. 1962, 74, 93. (c) Tsuji, J. Synthesis. 1984, 369. (d) Sigman, M. S.; Werner, E. W. Acc. Chem. Res. 2012, 45, 874. (e) Cornell, C. N.; Sigman, M. S. Inorg. Chem. 2007, 46, 1903. 18. (a) Back, T. G.; Edwards, O. E.; MacAlpine, G. A. Tetrahedron Lett. 1977, 18, 2651. (b) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T. Tetrahedron 2000, 56, 8855.
8. (a) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, II, R. A. Tetrahedron Lett. 1997, 38, 8157. (b) Miller, R. S.; Sealy, J. M.; Shabangi, M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, II, R. A. J. Am. Chem. Soc. 2000, 122, 7718. (c) Knettle, B. W.; Flowers, II, R. A. Org. Lett. 2001, 3, 2321. 9. For a recent study on alternative proton donors, see: Chciuk, T. V.; Anderson Jr, W. R.; Flowers II, R. A. Angew. Chem. Int. Ed. 2016, 55, 6033.
10. See Supporting Information for X-ray structures and CCDC numbers (CCDC 1448372 for 2c, CCDC 1448373 for 3a, CCDC 1474811 for 12b, and CCDC 1474810 for 12d). 11. For selected recent examples of medicinal studies involving 5alkyl uracils, see: (a) Pizzirani, D.; Pagliuca, C.; Realini, N.; Branduardi, D.; Bottegoni, G.; Mor, M.; Bertozzi, F.; Scarpelli, R.; Piomelli, D.; Bandiera, T. J. Med. Chem. 2013, 56, 3518. (b) Butini, S.; Pickering, D. S.; Morelli, E.; Sanna Coccone, S.; Trotta, F.; De Angelis, M.; Guarino, E.; Fiorini, I.; Campiani, G.; Novellino, E.; Schousboe, A.; Christensen, J. K.; Gemma, S. J. Med. Chem. 2008, 51, 6614. (c) Dolman, N. P.; More, J. C. A.; Alt, A.; Knauss, J. L.; Pentikäinen, O. T.; Glasser, C. R.; Bleakman, D.; Mayer, M. L.; Collingridge, G. L.; Jane, D. E. J. Med. Chem. 2007, 50, 1558. 12. For selected examples of related fragmentations, see: (a) Haque, A.; Ghosh, S. Chem. Commun. 1997, 2039; (b) Hutton, T. K.; Muir, K.; Procter, D. J. Org. Lett. 2002, 4, 2345; (c) Xu, Q.; Cheng, B.; Ye, X.; Zhai, H. Org. Lett. 2009, 11, 4136.
19. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936. (b) Zibuck, R.; Seebach, D. Helv. Chim. Acta 1988, 71, 237.
20. Ishikawa, K.; Tomatsu, M.; Nagase, H.; Fujii, H. Heterocycles 2014, 88, 1051.
13. For a review on the chemistry of samarium enolates, see: Rudkin, I. M.; Miller, L. C.; Procter, D. J. Organomet. Chem. 2008, 34, 19. 14. For selected examples, see: (a) Molander, G. A.; McKie, J. A. J. Org. Chem. 1991, 56, 4112. (b) McKerlie, F.; Rudkin, I. M.; Wynne, G.; Procter, D. J. Org. Biomol. Chem. 2005, 3, 2805. (c) Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira,
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SmI2–H 2O–LiBr
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H
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Page 6 of 6
N O
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radical anions from amides 2 electrons carbo-heterocyclization up to 5 new stereocenters quaternary stereocenters novel scaffolds
>95:5 dr
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