DOI: 10.1002/chem.201500424
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Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions Martin Holan,[a] Radek Pohl,[a] Ivana Csarˇov,[b] Blanka Klepetrˇov,[a] Peter G. Jones,[c] and Ullrich Jahn*[a] Abstract: Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with a-benzylidene and a-alkylidene b-dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the
Introduction Domino, cascade, tandem, and multicomponent reactions are today indispensable tools to improve the effectiveness of synthetic organic chemistry.[1] Their application allows time- and resource-efficient approaches to complex structures from simple precursors. Such reaction sequences are based either on pericyclic processes or on the careful choice of reactive intermediates. The majority of domino processes are based on a single intermediate type (either main-group or transitionmetal organometallic, radical, or carbocationic intermediates). Such reaction sequences can be planned reliably, because the general reactivity patterns of the chosen intermediate type are well established. This sets the scope of an envisaged domino reaction but also defines the limitations of applicability, because the kinetics of the individual reaction steps of intermediates or pericyclic [a] Ing. M. Holan, Dr. R. Pohl, Dr. B. Klepetrˇov, Dr. U. Jahn Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo nmeˇst 2, 16610 Prague (Czech Republic) E-mail: [email protected] [b] Dr. I. Csarˇov Department of Inorganic Chemistry, Faculty of Science Charles University in Prague Hlavova 2030/8, 12843 Prague (Czech Republic) [c] Prof. Dr. P. G. Jones Institut fìr Anorganische und Allgemeine Chemie Technische Universitt Braunschweig Hagenring 30, 38106 Braunschweig (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500424. Chem. Eur. J. 2015, 21, 9877 – 9888
cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C¢C bonds and one C¢O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.
processes vary widely and are often not complementary to each other. For efficient domino or tandem processes, the individual steps in the sequence must have reasonable reaction rates to achieve good chemo-, regio-, and stereoselectivity. This fact has to be considered particularly for sequences involving inter- and intramolecular reaction steps, in which cyclization steps are often considerably faster than intermolecular addition steps. In addition, the lifetime of the involved intermediate has to be taken into account. Whereas organometallic reaction steps often generate relatively stable and long-lived intermediates, carbocations and especially radicals are transient intermediates that require a strict kinetic regime in the domino process to avoid competing reaction steps, such as deprotonations for the former or abstraction reactions for the latter, which would lead to the disappearence of these intermediates and, therefore, the undesired termination of the sequences. This is especially important if the desired reaction steps are at the slower end of the kinetic scale of the envisaged intermediate type.[2, 3] An attractive strategy to significantly broaden the scope of domino processes is to couple the chemistry of intermediate types of different redox states, because the reactivity limitations of one type will be overcome by switching the redox level oxidatively or reductively to result in constitutionally identical but more or less reactive intermediate types, as desired for the envisaged process. In the past, domino processes employing multiple intermediates with different oxidation states were used in connection with radical processes for the initiation and termination steps. Oxidative radical reactions of neutral carbonyl compounds with Mn(OAc)3[4] or ceric ammonium nitrate[5] are well
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Full Paper established, and reductive radical sequences employing samarium diiodide,[6] the titanocene chloride dimer,[7] tetrathiafulvalene,[8] organic electron donors,[9] or photoredox catalysis[10] are also known. In contrast, our interest centers on oxidative tandem reactions, which rely on the sequential application of intermediates of different oxidation states, such as enolate anions, radicals, and carbocations. We found that such sequences are efficiently mediated by ferrocenium hexafluorophosphate, which allows the oxidative interconversion of these intermediate types by single-electron transfer (SET) without undergoing other reactions with the involved intermediates, either in its oxidized or reduced forms. These sequences found applications in the total synthesis of natural products[11a–d] and the preparation of antiviral compounds.[11e] In this context, we hypothesized that Michael addition reactions,[12] in which different enolate intermediates are sequentially generated, might be coupled with radical cyclization steps for efficient tandem reactions (Scheme 1). Anionic Michael additions proceed with enolates A¢ of carbonyl compounds A and a,b-unsaturated carbonyl compounds B. The latter can be mono- and disubstituted at the b position and work with nearly stoichiometric amounts of reactants. The Giese reaction is a radical variant of the Michael addition; it typically starts with halides F (X: I, Br), from which radicals G are generated by halogen abstraction. In contrast to anionic Michael additions, the Giese reaction follows complex kinetics and requires a large excess of the radical acceptors B,
which must be unsubstituted in the b position (R3 : H) or must carry an additional acceptor substituent in this position to permit reasonable reaction rates. With regard to the cyclization steps, the situation is the opposite. Cyclization reactions of radicals H to electron-rich and electron-poor alkene units proceed reliably to give I, which may stabilize by abstraction or radical coupling to form functionalized cyclic compounds J. Michael cyclizations of C to D are, in contrast, strictly limited to those bearing strong electron-accepting groups (R2 : Acc). Thus, a controlled switch between the two intermediate classes should provide the most efficient access to cyclic compounds J, whereas both a purely anionic and a purely radical pathway are limited because of their kinetic features. Herein, we report that oxidative tandem Michael addition/ radical 5-exo cyclization sequences employing lithium ester enolates A¢ and diverse a-alkylidene or arylidene b-dicarbonyl compounds are a convenient strategy to obtain highly functionalized cyclopentane derivatives.[13] The reaction sequences are terminated by 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO), which allows effective oxygenation of a remote position and, thus, a further useful increase of functionality in the process. The substrate scope is probed, and the means to control the stereoselectivity of the overall process based on the unique properties of the various intermediate types are revealed. It is demonstrated that the products can be further functionalized in a selective manner.
Results Based on optimized Michael addition conditions,[14] the tandem reactions were initiated by selective generation of the (E)- or (Z)-enolates by using esters 1 and lithium diisopropylamide (LDA), followed by addition of Michael acceptors 2. After completion of this step, TEMPO (5) and ferrocenium hexafluorophosphate (4) were introduced to mediate the SET oxidation, cyclization, and oxygenation (see Tables 1–4). It proved to be optimal to add 12.5 mol % of 5 first and a thoroughly homogenized mixture of 4 and 5 subsequently in small portions. This guarantees low radical concentrations and a modest excess of 5 to avoid premature trapping of the initial acyclic radical. In cases in which double-bond-containing compounds are present as impurities in the cyclic products 6–9, Upjohn dihydroxylation is the most convenient catalytic way to remove them.[15] Tandem Michael addition/radical 5-exo cyclization reactions of (Z)-enolates with monosubstituted Michael acceptors 2 A–C
Scheme 1. Michael versus Giese addition/cyclization sequences. Acc = electron-accepting group. Chem. Eur. J. 2015, 21, 9877 – 9888
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The reactions of the (Z)-enolates of esters 1 a,b bearing a terminal alkene unit with Michael acceptors 2 A–C provided cyclic products 6 a,b,g,h in moderate to good yields and good diastereoselectivity (Table 1, entries 1–3, 8, and 9). Potassium hexamethyldisilazide could also be used as a base (Table 1, entry 2).[16] 2,3-cis-Cyclopentane derivatives 8 and 9 were detected only in some cases (Table 1, entries 1, 2, 4, and 9). If 4pentenoates 1 are substituted at the 5-position, as in 1 c–f, diastereomers 6 and 7 were formed as the predominant products, 9878
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Full Paper Table 1. Tandem Michael addition/radical cyclization reactions of (Z)-enolates of 1 a–f with acceptors 2 A–C (only the major diastereomers of 6 and 7 at the exocyclic stereocenter are shown).[a]
Entry
1
2
6–9
Yield [%]
d.r. 6(aR1/bR1)/7(bR1/aR1)/8/9
Other products (yield [%])
1 2[b] 3 4 5 6 7 8 9[g]
a a b c d e f a a
A A A A A A A B C
a a b c d e f g h
79 77 71 79 82 86 87 58[d] 48[d]
30:1:1:1 33:1:1:1 1:0:0:0 15:6:1:2 1.8:1:0:0 2.3(22:1):1(> 20:1):0:0 1.6(6:1):1(> 20:1):0:0 10:1:0:0[e] 10:1.7:1:1
– – – 10 c (6) 10 d[c] – – 11 (18)[f] 12 (7)
[a] Standard conditions: LDA (1.6 mmol), THF/HMPA, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 4 and 5 at ¢40 8C. [b] Potassium hexamethyldisilazide (1.5 mmol) used. [c] Forms slowly on standing after isolation of 6 d. [d] Yield after Upjohn dihydroxylation. [e] The stereochemistry of the minor diastereomer was not assigned; traces of a third diastereomer were present. [f] d.r. 1:1. [g] LDA (1.2 mmol), 1 a (1.4 mmol).
both with 2,3-trans orientation of the substituents but with different configurations at the 5position (Table 1, entries 4–7). If the alkene unit in 1 is prochiral, as in 1 e or 1 f, the oxygenation by TEMPO to form products 6 e,f and 7 e,f proceeded with good to excellent diastereoselectivity (Table 1, entries 6 and 7). Products 6 c,d bearing a tertiary alkoxyamine unit are sensitive to light and acid, which led to alkene derivatives 10 by elimination of N-hydroxytetramethylpiperidine, whereas diastereomers 7 c,d were much more Chem. Eur. J. 2015, 21, 9877 – 9888
stable (Table 1, entries 4 and 5). To obtain good yields of 6 c,d, the products must be handled in the absence of strong light sources. Column chromatography should be performed in the shortest possible times, samples should be stored in the freezer, and NMR spectra should be run in [D6]benzene rather than in CDCl3. For benzylidenedibenzoylmethane 2 B, 1,2-addition competed to a small extent with the Michael addition, which resulted in the formation of 11 as a side product in 18 % yield (Table 1, entry 8).[14] With Michael acceptor 2 C, g-oxygenated ethylidenemalonate 12 was isolated as a byproduct in 7–26 % yield (Table 1, entry 9; see the Supporting Information for additional results). When ethylidenemalonate 2 C was subjected to the same reaction conditions in the absence of 1 a, product 12 was isolated in 50 % yield as a single regioisomer (Scheme 2). The relative configuration of compounds 6 b and 6 g was de-
Scheme 2. g-Deprotonation/SET oxidation/oxygenation of 2 C. HMPA: hexamethyl phosphoramide; TMP = 2,2,6,6-tetramethylpiperidinyl.
termined by X-ray crystallography (Figure 1).[17] In both structures, the cyclopentane ring adopts a half-chair conformation, and the substituents in the 2-, 3-, and 5-positions occupy pseudoequatorial positions. The configuration of 6 c,d,f and 7 c,f was assigned by NOE investigations. The relative configuration of 6 a,e and 7 d,e was assigned by analogy with their NMR data (see the Supporting Information).
Figure 1. ORTEP drawings of 6 b (left) and 6 g (right). Thermal ellipsoids are drawn at 30 % probability level for 6 b and at 50 % for 6 g.
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Full Paper Tandem Michael addition/radical 5-exo cyclization reactions of (E)-enolates with Michael acceptors 2 A, 2 C, and 2 D The reactions of (E)-enolates of esters 1 a–c with malonates 2 A,C afforded predominately cyclic products 8 and 9 in reasonable yields with good 2,3-cis but low 3,5 diastereoselectivity (Table 2, entries 1, 3, and 4). The enolate of tert-butyl ester 1 a
The relative configuration of 9 i was determined by X-ray crystallography (Figure 2). The cyclopentane ring of 9 i adopts an envelope conformation. The substituents in the 3- and 5positions occupy pseudoequatorial positions. The assignment of the relative configuration of 8 a,b and 9 h was based on NOE experiments.
Table 2. Tandem Michael addition/radical cyclization/oxygenation reactions of enolates (E)-1 a–c with Michael acceptors 2 A, 2 C, and 2 D.[a]
Figure 2. ORTEP drawing of 9 i. Thermal ellipsoids are drawn at 30 % probability level.
Tandem Michael addition/radical cyclization reactions of esters 1 a,b with Michael acceptors 2 E–I
Entry
1
2
6–9
Yield [%]
d.r. 6/7/8/9
Other products (yield [%])
1 2[c] 3 4[e] 5[e]
a b c a a
A A A C D
a b c h i
60[b] 36[b] 65 60[b] 82
1:0:2.5:2.5 1:0:1:1.5 1:0:5:8 1:0:1.8:2.5[f] 0:0:1:2.5
syn-3 a (8) syn-3 b (35) 10/13/14 c (15)[d] syn-3 h (15) 15, 8; 3 i (4)
[a] Standard conditions: LDA (1.6 mmol), THF, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 4 and 5 at ¢40 8C. [b] Yield after Upjohn dihydroxylation. [c] Anhydrous LiCl (7.2 mmol) was added for better syn selectivity of the Michael addition; cyclization at 0 8C. [d] d.r. 1:2.5:5. [e] LDA (1.2 mmol), 1 a (1.4 mmol). [f] Traces of 7 h were present.
provided the cyclized products in significantly better yield than that of methyl ester 1 b (Table 2, entry 1 versus 2). In contrast to the reactions with (Z)-enolates of 1, uncyclized Michael adducts syn-3 were also found here (Table 2, entries 1, 2, and 4). The formation of isopropenylcyclopentanes 10 c, 13 c, and 14 c was also observed in small amounts if 1 c was used in the cyclization sequence (Table 2, entry 3; see above). In contrast to the reactions of the (Z)-enolates, the formation of product 12 was not observed in the tandem reaction of enolate (E)-1 a with 2 C (Table 2, entry 4). Disubstituted malonate 2 D underwent the addition/cyclization sequence with (E)1 a, which provided two separable diastereomers with vicinal quaternary centers, 8 i and 9 i, in a high yield of 82 % (Table 2, entry 5). Additionally, 8 % of g-TEMPO-trapped isopropylidenemalonate 15 and 4 % of Michael adduct 3 i were detected. Chem. Eur. J. 2015, 21, 9877 – 9888
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It was known that all of the Michael acceptors 2 E–I underwent the Michael addition with low diastereoselectivity.[14] It was nonetheless of interest to learn the factors influencing the radical cyclization selectivity. Meldrum’s acid derivative 2 E provided a 1:1 mixture of anti/syn Michael adducts 3 k, as determined by an individual Michael addition,[14] but only the anti Michael adduct enolate underwent the radical cyclization step to give a 6:1 diastereomeric mixture of 6 k and 7 k together with the 6-endo cyclized product 16 k as a single diastereomer (Table 3, entry 1). Michael adduct syn-3 k was not isolated because of its acidity; it may have been retained or decomposed during column chromatography, as indicated by the formation of unidentified byproducts. The use of triethylamine as a coeluent did not improve the outcome. Benzylidene malononitrile 2 F gave a similar result (Table 3, entries 2–4). The yield and diastereomeric ratio of 6 l,m and 7 l,m based on the anti-Michael adduct enolates 3 l,m is good, whereas the syn-enolates 3 l,m cyclized to a small extent (Table 3, entries 2 and 3) or not at all (Table 3, entry 4). The reaction in 1,2-dimethoxyethane gave a similar result (see the Supporting Information). However, almost no Michael adducts syn-3 l,m were recovered, probably because of decomposition during the oxidation step. Cyclohexylidene malononitrile 2 G gave diastereomers 6 n and 7 n in a good 83 % yield but with a low 1.6:1 diastereomeric ratio at 0 8C (Table 3, entry 5). In this case, the Michael adduct dimer 17 and exo-methylenecyclopentane derivative 18 were also detected in 8 and 2 % yields, respectively. The unsymmetrical cyanoacetates 2 H and 2 I reacted with 1 a in moderate to good overall yields (Table 3, entries 6 and 7; see also the Supporting Information). Only three out of the eight possible cyclic diastereomers were isolated in all cases,
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Full Paper smaller ethyl group providing significant selectivity for 9 p over 8 p relative to the larger phenyl ring in 8 o/9 o (Table 3, entries 6 versus 7). The relative configuration of compounds 6 m and 6 n was unambiguously proved by X-ray crystallography (Figure 3). The cyclopentane ring of 6 m adopts a distorted envelope conformation. The substituents in the 2-, 3-, and 5-positions occupy pseudoequatorial positions. The cyclohexane ring of spiro compound 6 n has a chair conformation, whereas the cyclopentane ring adopts a half-chair conformation with the substituents in the 3- and 5-positions oriented cis to each other. The relative configuration of the diastereomers of 6–9 l and 6/ 8/9 o could not be assigned by NMR spectroscopy or X-ray crystallography. However, individual oxidative radical cyclizations of Michael adducts 3 l and 3 o allowed their assignment (see the Supporting Information).
Table 3. Tandem Michael addition/radical cyclization/oxygenation reactions of enolates of 1 a and 1 b with 2 E–I.[a]
Reactions of 2-, 3-, and 4-substituted ester enolates 1 g–j with benzylidene malonate 2 A Entry
1
2
Solvent
6–9 Yield d.r. [%] 6/7/8/9
Other products (yield [%])
1 2 3 4 5[d] 6 7[d,f]
a a a b a a a
E F F F G H I
THF/HMPA THF/HMPA THF THF/HMPA THF THF/HMPA THF
k l l m n o p
16 k[b] 16 l (3) syn-3 l (12), 16 l (3) syn-3 m (9), 16 m (4) 17 (8), 18 (2) 16 o (1) –
24 35[c] 39[c] 42 83 71[c] 78
6:1:0:0 8:1.3:1.4:1 19:3:1:1 6:1:0:0 1.6:1:0:0 3.5:0:1:1[e] 10:1:3:12
Differently substituted esters were briefly investigated to outline the reactivity and selectivity patterns of the tandem reactions. The enolate of 2-methyl-4-pentenoate 1 g gave cyclopentanes 6 q–9 q with malonate 2 A in very good yields (Scheme 3). The limiting factor in these tandem reactions is the diastereoselectivity of the Michael addition step, because
[a] Standard conditions: LDA (1.6 mmol), solvent, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 4 and 5 at 0 8C. [b] Approximately 10 % 16 k formed together with other unidentified byproducts. [c] Yield after Upjohn dihydroxylation. [d] LDA (1.2 mmol), 1 a (1.4 mmol). [e] Traces of another diastereomer present. [f] Cyclization at ¢40 8C.
with the R2 substituent always being cis oriented with respect to the smaller nitrile group (Acc1). The Michael adduct enolates anti-3 o¢ and anti-3 p¢ provided diastereomers 6 o or 6 p with excellent diastereoselectivity. The syn-enolates furnished two diastereomers 8 o,p and 9 o,p. The diastereomeric ratio seemed to be dependent on the size of the R2 substituent, with the
Scheme 3. Tandem Michael addition/radical cyclization reaction of ester 1 g with 2 A. [a] Yield after Upjohn dihydroxylation.
Figure 3. ORTEP drawing of 6 m (left) and 6 n (right). Displacement ellipsoids are drawn at 30 % probability level. Chem. Eur. J. 2015, 21, 9877 – 9888
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the (E)- or (Z)-enolates of 1 g cannot be selectively generated (see the Supporting Information).[18] The cyclization step proceeded similarly to that of unbranched 1 a; thus, Michael adduct enolate anti-3 q¢ cyclized with high diastereoselectivity, whereas syn-3 q¢ cyclized less selectively. The relative configuration of 6 q was determined by X-ray crystallography (Figure 4). The
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Full Paper relative configuration of 4a-6 r was confirmed by NOE measurements. 4-Alkenoates 1 i and 1 j, with a methyl substituent at the 4position, cleanly underwent the sequence with malonate 2 A but, in contrast to esters 1 a–h, gave selectively the 6-endo cyclization products 19 a–22 a and 19 b, respectively, in reasonable yield, high 2,3-trans diastereoselectivity, and moderate to excellent oxygenation diastereoselectivity (Scheme 5). Only very small amounts of syn-Michael adduct derived 21 a and 22 a were detected, together with trace amounts of the Michael adduct syn-3 (not shown).
Figure 4. ORTEP drawing of 6 q. Displacement ellipsoids are drawn at 30 % probability level.
cyclopentane ring in 6 q adopts an envelope conformation with the more bulky groups in pseudoequatorial positions. The methyl group in the 3-position is pseudoaxially oriented. For the assignment of 7 q–9 q, see the Supporting Information. The tandem reaction of the (Z)-enolate of 3-methylpentenoate 1 h with malonate 2 A provided two diastereomeric cyclopentanes 4a-6 r and 4b-6 r (Scheme 4). Both cyclic products
Scheme 5. Tandem Michael addition/radical 6-endo cyclization reaction of 1 i and 1 j with 2 A. [a] Yield after Upjohn dihydroxylation.
Extension to a ketone and a nitrile 4-Pentenone 1 k and benzylidene malonate 2 A afforded cyclopentane 6 s with very high diastereoselectivity (Table 4, entry 1). Pent-4-enenitrile 1 l similarly reacted with 2 A to provide tetrasubstituted cyclopentane derivative 6 t with orthogonal carbonyl functionalities in good yield and diastereoselectivity (Table 4, entry 2). From both reactions, some Michael adduct 3 was also isolated. Michael acceptors with aliphatic b substituents, such as ethylidene malonate 2 C or cyanoacetate 2 I, afforded the products 6–9 in good yield but with lower diastereoselectivities (Table 4, entries 3–6). For the tandem reaction of 1 k with 2 I, the diastereoselectivity improved in favor of isomer 6 v if the reaction was performed in pure THF (Table 4, entry 6 versus 5). Scheme 4. Tandem Michael addition/radical cyclization reaction of ester 1 h with 2 A.
Reductive cleavage of the alkoxyamine units in compounds 6–9 and 19
display the 2,3-trans configuration and vary only in the relative 3,4-orientation of the substituents. Although the Michael addition proceeded with moderate 3:1 2,3-anti/syn diastereoselectivity, as indicated by an individual experiment (see the Supporting Information), only enolates 2,3-anti-3 r¢ underwent the oxidative cyclization step. However, each diastereomer with the 3,4-syn and 3,4-anti orientation of the methyl substituents reacted with very high cyclization diastereoselectivity to form cyclopentanes 4a-6 r and 4b-6 r, respectively. The relative configurations of 4a-6 r and 4b-6 r were established after reductive alkoxyamine cleavage/lactonization (see below). Moreover the Chem. Eur. J. 2015, 21, 9877 – 9888
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The alkoxyamine unit in compounds 6–9 and 19 represents a protected hydroxy group. Therefore, a chemoselective N¢O bond cleavage must be guaranteed for these compounds to be synthetically useful. Treatment of various diastereomers of compounds 6/7 a,h with zinc in acetic acid at 80 8C gave mixtures of lactones 23/24 a,h in satisfactory yields and with practically unchanged diastereomeric ratios (Table 5, entries 1 and 2). The dinitrile 6/7 l also cyclized after reductive cleavage of the alkoxyamine to give cyano-substituted lactones 23 l and 24 l (Table 5, entry 3). However, the enriched diastereomers of 8 a and 9 a behaved in a strikingly different manner in the de-
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Full Paper amounts of acetate 27 were even detected (Table 5, entry 5). It may be assumed that hydrolysis of the tert-butyl ester and other side reactions compromises the results during the significantly longer reaction times. Lactonization of cyclic cyano diesters 6–9 o,p also proceeded well (Scheme 6). A mixture of 6/8/9 o gave partly separable lac-
Table 4. Tandem Michael addition/radical cyclization/oxygenation reactions of 1 k and 1 l with acceptors 2 A, 2 C, and 2 I.[a]
Entry
1
2
Solvent
6–9
Yield [%]
d.r. 6/7/8/9
3 (yield [%], anti/syn)
1 2 3[c] 4[c] 5[e] 6[e]
k l k k k k
A A C C I I
THF/HMPA THF/HMPA THF/HMPA THF THF/HMPA THF
s t u u v v
66 62 75[d] 68[d] 68[d] 87
17:1:0:0[b] 6:1:0:1 1:0:2:2 3:1:2.5:2.5 2:0:1:1[f] 5:0:1:1[f]
s (5, 1:0) t (19, 1.4:1) – – – –
[a] Standard conditions: LDA (1.6 mmol), solvent, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 5 and 4 at ¢40 8C. [b] The stereochemistry of the minor diastereomer was not assigned. [c] Reagents: LDA (1.2 mmol), 1 k (1.25 mmol), 2 C (1.0 mmol). [d] Yield after Upjohn dihydroxylation. [e] Reagents: LDA (1.2 mmol), 1 k (1.4 mmol), 2 I (1.0 mmol). [f] Traces of another diastereomer present.
Scheme 6. Chemoselective deprotection of cyano diesters 6–9 o,p and ORTEP drawing of 26 p. Displacement ellipsoids are drawn at 30 % probability level. [a] Traces of 23 p were detected.
tones 23 l, 25 a, and 26 l in a practically unchanged ratio and 79 % yield. The products resulted from completely cis-selective lactonization to either the ester function to give 23 l and 26 l or to the nitrile function to result in ester 25 a, which is identical to the lactone obtained from 8 a. This supports the configuration assignment of the cyclization products. The lactonization of the ethyl derivatives 6/7 p and 6/8/9 p proceeded similarly in good yield. The structure of lactone 26 p was solved by Xray crystallography. The cyclopentane ring adopts a half-chair conformation in the crystal, and all substituents are oriented cis to each other. Cleavage of the alkoxyamine unit in 4a/4b-6 r gave the two lactones a-23 r and b-23 r in an essentially unchanged ratio (Scheme 7). Both lactones gave crystals suitable for X-ray analysis. They have a cis-fused bicyclic core; the cyclopentane ring in a-23 r adopts a half-chair conformation, whereas b-23 r has an envelope conformation. The structures confirm that their relative configurations only differ in the orientation of the methyl substituent. The reductive N¢O bond cleavage of the tertiary alkoxyamine function in cyclohexane derivative 19 a also succeeded in high yield and provided bridged lactone 28 (Scheme 8).
Table 5. Reductive N-O Bond cleavage/lactonization of 6–9.
Entry
6–9
d.r. 6/7/8/9
23–26
Yield [%]
d.r. 23/24/25/26
27 (yield [%])
1 2 3 4 5[b]
a h l a a
30:1:1:1 6:1:0:0[a] 6:1:0:0 1:0:0:2 0:0:4:1
a h l a a
70 54 60 69 27
1:0:0:0 8:1:0:0 8:1:0:0 1:0:0:2 0:0:2.4:1
– – – – 27 (5)
Elimination of tertiary alkoxyamines 6–9 c
[a] Traces of two other diastereomers present. [b] Reaction time of 5 days.
protection. Whereas diastereomer 9 a lactonized cleanly (Table 5, entry 4), the all-cis isomer 8 a reacted sluggishly, the mass recovery was low after the long reaction time, and small Chem. Eur. J. 2015, 21, 9877 – 9888
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Cyclopentane derivatives with tertiary alkoxyamine units in the side chain, such as 6–9 c, slowly eliminated N-hydroxytetramethylpiperidine in solution under ambient daylight to give olefins 10 c, 13 c, and 14 c (Scheme 9). The ease of elimination depends, however, on the relative configuration in 6–9 c. Isomer 6 c underwent this transformation quickly, whereas the elimina-
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Scheme 10. Hydrolysis of 6 a.
fluoroacetic acid in dichloromethane (Scheme 10). The ethyl ester and alkoxyamine functionalities remained unaffected.
Discussion Reactivity patterns
Scheme 7. Alcohol deprotection/lactonization of the alkoxyamine unit of 6 r and ORTEP drawing of a-23 r (left) and b-23 r (right). Displacement ellipsoids are drawn at 30 % probability level.
Scheme 8. Chemoselective deprotection/lactonization of 19 a.
Scheme 9. Deoxygenation of 6/8/9 c and ORTEP drawing of 14 c. Displacement ellipsoids are drawn at 30 % probability level. a) Ambient light, CHCl3, heating to reflux for 72 h; b) microwave, tBuOH, 130 8C, 15 min.
tion from isomers 8 c and 9 c proceeded only slowly and heating at reflux for 72 h was required to form compounds 13 c and 14 c. The elimination of N-hydroxytetramethylpiperidine was much faster with microwave irradiation without loss in the yields. The structure of isopropenylcyclopentane 14 c was proved by X-ray crystallography. These reactions can mechanistically proceed either by intermolecular hydrogen atom transfer after C¢O bond cleavage or by an intramolecular concerted Cope-type elimination, but a distinction cannot be made at present.[19] Hydrolysis of the tert-butyl ester group Acidic hydrolysis of the tert-butyl ester unit of 6 a to form acid 29 was achieved in high yield in the presence of excess triChem. Eur. J. 2015, 21, 9877 – 9888
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The deprotonation of esters 1 a–f,h–j provides (E)- or (Z)-enolates with good diastereoselectivity, whereas ketone 1 k leads always to the corresponding (Z)-enolate, which is consistent with literature precedents (Scheme 11).[20] The Michael addition to b-aryl- or b-alkyl-substituted acceptors 2 leads reliably to Michael adduct enolates 3¢ in high yields and often good diastereoselectivity (see below). However, methyl-substituted acceptors 2 C and 2 D are an exception, because g deprotonation by enolate 1¢ or LDA (leading to dienolates 2¢) competes to a certain extent, especially in the presence of HMPA. All resulting enolates 3¢ (and 2¢) undergo facile SET oxidation by ferrocenium hexafluorophosphate 4, to generate efficiently the corresponding radicals 30. All substrates can now also be envisaged to be oxidized by catalytic amounts of 4, based on very recent results.[21] The major path of stabilization is cyclization, which proceeds under very mild conditions. Only if the rate becomes slower is some Michael adduct 3 often recovered, the formation of which is attributed to hydrogen transfer from the solvent to radical 30 rather than to protonation of unreacted enolate 3¢ . This is based on the fact that, on the one hand, the consumption of 4 was always more than stoichiometric, which indicates complete oxidation of 3¢ to the radical, and, on the other hand, deuterated products were not detected upon quenching the reaction mixtures with D2O. Dimerization competed only in the case of 3 n, which gave 17 as a minor product. Although coupling products similar to 31 were observed before by coupling of malonyl radicals with an excess of 5,[22] coupling products 31 were never detected in the tandem processes. This can be rationalized, on one hand, by the operation of the Thorpe–Ingold effect to accelerate the cyclization and, on the other hand, by the concentration of 5 being kept low through portionwise addition of a mixture of 4 and 5. The cyclization regioselectivity was strongly dependent on the substitution pattern of the double bond in radical 30. The 5-exo cyclization mode furnishing radicals 32 was predominant or exclusive with all unsubstituted or terminally substituted alkene units. Only for radicals derived from malononitrile, Meldrum’s acid, or cyanoacetate precursors anti-3 k–m,o¢ were small amounts of 6-endo cyclization products 16 k–m,o detected. However, radicals 30 with methyl substituents at the internal position of the double bond, such as those derived from
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Scheme 11. Observed reaction pathways for tandem Michael addition/radical cyclization/oxygenation reactions.
1 i,j and 2 A, cyclize exclusively in the 6-endo mode to radicals 33 because of a more hindered 5-exo cyclization trajectory. All cyclized radicals 32 and 33 were oxygenated efficiently by TEMPO (5) to give the products 6–9 a–v, 19 a,b, and 20 a. It must be noted that, in contrast to potential purely radical tandem reactions, b,b-disubstituted Michael acceptors, such as 2 D and 2 G, can be conveniently applied in the anionic/radical sequence in high yields. Diastereoselectivity The diastereoselectivity of the overall tandem sequence is strongly dependent on the diastereoselectivity of the Michael addition step and the substitution pattern of the alkene cyclization acceptor. (Z)-Enolates of esters and ketones give Michael adduct enolates anti-3¢ , often with good diastereoselectivity.[14] The subsequent radical 5-exo cyclization proceeds after oxidation via Beckwith–Houk transition state 34 to radicals 35 with high diastereoselectivity, to give ultimately cyclopentanes 6, if the alkene acceptor is unsubstituted (Scheme 12).[23] However, those anti-3¢ enolates with an internally substituted alkene acceptor (R3 : CH3) cyclize exclusively in the 6-endo mode via chair transition state 36 to provide radicals 37. The radicals derived from 3 k–m,o¢ can also reach the terminus of the alkene and cyclize via the same transition state, 36, which is higher in energy in these cases than that of the 5-exo cyclization. With 1,2-di- and trisubstituted alkene units, the cyclization diastereoselectivity was lower and cyclization via boat transition state 38 becomes competitive, which results in the formation of significant amounts of compounds 7 after oxygenation of radical 39 with 5. Remarkably, the oxygenation of the cyclized radicals 35, 37, and 39 by TEMPO (5) proceeds with good diastereoselectivity if the radical is prochiral. In the case of 35 and 39, the radical conformation is constrained based on Chem. Eur. J. 2015, 21, 9877 – 9888
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Scheme 12. Rationalization of the diastereoselectivity of the oxidative radical cyclizations of enolates anti-3¢ . EWG = electron-withdrawing group.
A-strain and the approach of 5 can only proceed from the front face, because the back face is blocked by the acceptor groups. In the six-membered radical 37, the approach of the bulky TEMPO molecule is more facile from the less hindered a face, which gives access to compounds 19 a,b with a reasonable level of diastereoselectivity. The Michael addition step involving (E)-ester enolates generated predominately Michael adduct enolates syn-3¢ (Scheme 13). SET oxidation and cyclization usually provided two diastereomers. After SET oxidation of syn-3¢ , the cyclization can, in principle, proceed via two energetically similar
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Full Paper and one C¢O bond are formed in the sequence. The methodology is applicable to a wide range of acidic carbonyl compounds and a,b-unsaturated acceptors and, thus, gives the opportunity to construct scaffolds with orthogonal functional groups. The radical cyclization and oxygenation steps proceed with high diastereoselectivity for substrates with an anti arrangement of the substituents in the chain and often result in a single diastereomer. Substrates with a syn configuration usually give two diastereomers. The oxygen functionality can be liberated under reductive conditions. Further advantages compared to traditional cyclization processes are the tin-free, mild conditions and the use of the stable, recyclable, and much less toxic oxidant ferrocenium hexafluorophosphate. Based on the substrate scope, applications of this methodology in the total synthesis of terpenoid natural products are envisaged. Investigations along these lines are in progress.
Experimental Section Tandem Michael addition/radical cyclization/oxygenation of 1 and 2 induced by 4 in the presence of TEMPO (5) and HMPA: General procedure Scheme 13. The diastereoselectivity of the oxidative radical cyclizations of enolates syn-3¢ .
chair transition state arrangements, 40 and 42, in which one of the substituents has to be located pseudoaxially. The cyclization proceeds to form radicals 41 and 43, respectively, which furnish cyclopentanes 8 and 9 in almost equal amounts after coupling with TEMPO (5). However, moderate cyclization diastereoselectivity was observed for enolates syn-3 p,q¢ , which provided predominately 9 p and 9 q, respectively. This suggests a preference for transition state 42, in which the alkoxycarbonyl group is located in the pseudoaxial position. Boat transition states 44 or 45 are less likely to be populated, because they display even more unfavorable interactions. With b,b-disubstituted Michael acceptors 2 D and 2 G, the diastereoselectivity of the radical cyclization remained moderate, which suggests that the difference in the energy of the transition states is similar for an equatorially or axially located alkoxycarbonyl group (not shown).
Conclusion Densely functionalized cyclopentane or cyclohexane derivatives with up to four stereogenic centers can be assembled in a single operation by the sequence of enolate Michael addition/SET oxidation/radical 5-exo (6-endo) cyclization/oxygenation. The sequences proceed with stoichiometric amounts of substrates, in contrast to classical Giese radical addition/cyclization reactions that require a large excess of the radical acceptor. Furthermore, in contrast to Giese additions, b- and even b,b-disubstituted a,b-unsaturated acceptors can be applied with high yields. Moreover, the present strategy allows the efficient incorporation of an oxygen functionality by employing the fast radical coupling agent TEMPO; thus, two C¢C bonds Chem. Eur. J. 2015, 21, 9877 – 9888
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nBuLi (1.0 mL, 1.6 mmol, 1.6 m in hexanes) was added to a solution of iPr2NH (210 mL, 1.6 mmol) in dry THF (10 mL) at ¢78 8C under a nitrogen atmosphere. After the mixture had been stirred for 30 min, dry HMPA (2.5 mL) was added by using a syringe. A solution of 1 (1.2 mmol) in dry THF (0.5 mL) was added by using a syringe. The reaction mixture was stirred at ¢78 8C for 30 min, and 2 (1 mmol) was added, either neat (2 A, 2 C, 2 I) or as a solution in THF (0.5 mL; 2 B, 2 E, 2 F, 2 H). The mixture was slowly warmed from ¢78 8C to a maximum temperature of 0 8C, until the reaction was complete as indicated by TLC (approximately 2 h). TEMPO (5; 20 mg, 0.125 mmol) was added in one portion, followed by small portions of a thoroughly homogenized solid mixture of TEMPO (5; 180 mg, 1.152 mmol) and ferrocenium hexafluorophosphate (4; 400 mg, 1.2 mmol) at ¢40 8C (2 A, 2 B, 2 C, 2 I) or 0 8C (2 E, 2 F, 2 H). Salt 4 was consumed quickly, and the orange solution was subsequently treated with further portions of 4 until the mixture remained blue-green. Stirring at the appropriate temperature was continued for 10 min. The reaction mixture was quenched with four drops of water for 2 A, 2 C, 2 E, 2 H, and 2 I or with HCO2H (130 mL) for 2 B and 2 F, stirred for 5 min, diluted with diethyl ether to double the volume, and filtered through a plug of silica gel. The solvent was evaporated, and the inhomogeneous residue was preadsorbed on silica gel and purified by column chromatography (silica gel, hexanes/EtOAc, 50:1 gradient to 1:1).
Tandem Michael addition/radical cyclization/oxygenation of 1 and 2 induced by 4 in the presence of TEMPO (5): General procedure nBuLi (1.0 mL, 1.6 mmol, 1.6 m in hexanes) was added to a solution of iPr2NH (210 mL, 1.6 mmol) in dry THF (13 mL) at ¢78 8C under a nitrogen atmosphere. After the mixture had been stirred for 30 min, a solution of 1 (1.2 mmol) in dry THF (0.5 mL) was added by using a syringe. The reaction mixture was stirred at ¢78 8C for 30 min, and 2 (1 mmol) was added, either neat (2 A, 2 C, 2 D, 2 G, 2 I) or as a solution in THF (0.5 mL; 2 H). The mixture was slowly warmed from ¢78 8C to a maximum temperature of 0 8C, until the reaction was complete as indicated by TLC (approximately 2 h).
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Full Paper TEMPO (5; 20 mg, 0.125 mmol) was added in one portion, followed by small portions of a thoroughly homogenized solid mixture of TEMPO (5; 180 mg, 1.152 mmol) and ferrocenium hexafluorophosphate (4; 400 mg, 1.2 mmol) at ¢40 8C (2 A, 2 C, 2 D, 2 H, 2 I) or 0 8C (2 F, 2 G). Salt 4 was consumed quickly, and the orange solution was subsequently treated with further portions of 4 until the mixture remained blue-green. Stirring at the appropriate temperature was continued for 10 min. The reaction mixture was quenched with four drops of water for 2 A, 2 C, 2 D, 2 H, and 2 I or with HCO2H (130 mL) for 2 F and 2 G, stirred for 5 min, diluted with diethyl ether to double the volume, and filtered through a plug of silica gel. The solvent was evaporated, and the inhomogeneous residue was preadsorbed on silica gel and purified by column chromatography (silica gel, hexanes/EtOAc, 50:1 gradient to 1:1).
[3]
[4]
Reductive cleavage of the alkoxyamine unit: Typical procedure A mixture of three diastereomers of cyclic cyanoacetates 6 o, 8 o, and 9 o (340 mg, 0.6 mmol, 3:1:1) with AcOH (6 mL), water (2 mL), THF (2 mL), and zinc dust (1.7 g, 26 mmol) was heated to 80 8C for 4 h and subsequently stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and filtered through a plug of silica gel. The solvent was evaporated, and the crude product was dissolved in diethyl ether, washed with brine, and dried with anhydrous Na2SO4. The crude mixture was preadsorbed on silica gel and purified by column chromatography (silica gel, hexanes/EtOAc, 5:1 gradient to 2:1) to give a partly separable mixture (158 mg, 79 %) of three lactonized compounds 23 l, 25 a, and 26 l in a 3:1:1 ratio.
[5]
[6]
Acknowledgements Generous financial support by the Grant Agency of the Czech Republic (13-40188S), the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (RVO: 61388963), the COST action CM1201 “Biomimetic Radical Chemistry”, and the Gilead Sciences & IOCB Research Center is gratefully acknowledged. I.C. thanks the Ministry of Education, Youth and Sports of the Czech Republic (MSM0021620857) for financial support. Keywords: cyclization · domino reactions · electron transfer · Michael addition · radical reactions [1] Selected books and reviews: a) Domino Reactions: Concepts for Efficient Organic Synthesis (Ed.: L. F. Tietze), Wiley-VCH, Weinheim, 2014; b) Multicomponent Reactions in Organic Synthesis (Eds.: J. Zhu, Q. Wang, M. Wang), Wiley-VCH, Weinheim, 2014; c) H. Pellissier, Asymmetric Domino Reactions, RSC, Cambridge, 2013; d) H. Pellissier, Chem. Rev. 2013, 113, 442 – 524; e) H. Clavier, H. Pellissier, Adv. Synth. Catal. 2012, 354, 3347 – 3403; f) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237 – 294; g) A. Grossmann, D. Enders, Angew. Chem. Int. Ed. 2012, 51, 314 – 325; Angew. Chem. 2012, 124, 320 – 332; h) E. A. Anderson, Org. Biomol. Chem. 2011, 9, 3997 – 4006; i) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. Int. Ed. 2011, 50, 6234 – 6246; Angew. Chem. 2011, 123, 6358 – 6371; j) B. B. Tour¦, D. G. Hall, Chem. Rev. 2009, 109, 4439 – 4486; k) S. K. Bur, A. Padwa, Adv. Heterocycl. Chem. 2007, 94, 1 – 105. [2] For nucleophilicity and electrophilicity scales, see: a) H. Mayr, S. Lakhdar, B. Maji, A. R. Ofial, Beilstein J. Org. Chem. 2012, 8, 1458 – 1478; b) N. Streidl, B. Denegri, O. Kronja, H. Mayr, Acc. Chem. Res. 2010, 43, 1537 – 1549; c) H. Mayr, A. R. Ofial, J. Phys. Org. Chem. 2008, 21, 584 – 595; d) H. Mayr, A. R. Ofial, Nachr. Chem. 2008, 56, 871 – 877; e) H. Mayr, A. R. Ofial Chem. Eur. J. 2015, 21, 9877 – 9888
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Received: February 2, 2015 Published online on May 26, 2015
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Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions Martin Holan,[a] Radek Pohl,[a] Ivana Csarˇov,[b] Blanka Klepetrˇov,[a] Peter G. Jones,[c] and Ullrich Jahn*[a] Abstract: Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single-electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single-electron transfer oxidant. Ester enolates were coupled with a-benzylidene and a-alkylidene b-dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the
Introduction Domino, cascade, tandem, and multicomponent reactions are today indispensable tools to improve the effectiveness of synthetic organic chemistry.[1] Their application allows time- and resource-efficient approaches to complex structures from simple precursors. Such reaction sequences are based either on pericyclic processes or on the careful choice of reactive intermediates. The majority of domino processes are based on a single intermediate type (either main-group or transitionmetal organometallic, radical, or carbocationic intermediates). Such reaction sequences can be planned reliably, because the general reactivity patterns of the chosen intermediate type are well established. This sets the scope of an envisaged domino reaction but also defines the limitations of applicability, because the kinetics of the individual reaction steps of intermediates or pericyclic [a] Ing. M. Holan, Dr. R. Pohl, Dr. B. Klepetrˇov, Dr. U. Jahn Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Flemingovo nmeˇst 2, 16610 Prague (Czech Republic) E-mail: [email protected] [b] Dr. I. Csarˇov Department of Inorganic Chemistry, Faculty of Science Charles University in Prague Hlavova 2030/8, 12843 Prague (Czech Republic) [c] Prof. Dr. P. G. Jones Institut fìr Anorganische und Allgemeine Chemie Technische Universitt Braunschweig Hagenring 30, 38106 Braunschweig (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500424. Chem. Eur. J. 2015, 21, 9877 – 9888
cyclization mode from a 5-exo pattern for terminally substituted olefin units to a 6-endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6-tetramethyl-1-piperidinoxyl, and two C¢C bonds and one C¢O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.
processes vary widely and are often not complementary to each other. For efficient domino or tandem processes, the individual steps in the sequence must have reasonable reaction rates to achieve good chemo-, regio-, and stereoselectivity. This fact has to be considered particularly for sequences involving inter- and intramolecular reaction steps, in which cyclization steps are often considerably faster than intermolecular addition steps. In addition, the lifetime of the involved intermediate has to be taken into account. Whereas organometallic reaction steps often generate relatively stable and long-lived intermediates, carbocations and especially radicals are transient intermediates that require a strict kinetic regime in the domino process to avoid competing reaction steps, such as deprotonations for the former or abstraction reactions for the latter, which would lead to the disappearence of these intermediates and, therefore, the undesired termination of the sequences. This is especially important if the desired reaction steps are at the slower end of the kinetic scale of the envisaged intermediate type.[2, 3] An attractive strategy to significantly broaden the scope of domino processes is to couple the chemistry of intermediate types of different redox states, because the reactivity limitations of one type will be overcome by switching the redox level oxidatively or reductively to result in constitutionally identical but more or less reactive intermediate types, as desired for the envisaged process. In the past, domino processes employing multiple intermediates with different oxidation states were used in connection with radical processes for the initiation and termination steps. Oxidative radical reactions of neutral carbonyl compounds with Mn(OAc)3[4] or ceric ammonium nitrate[5] are well
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Full Paper established, and reductive radical sequences employing samarium diiodide,[6] the titanocene chloride dimer,[7] tetrathiafulvalene,[8] organic electron donors,[9] or photoredox catalysis[10] are also known. In contrast, our interest centers on oxidative tandem reactions, which rely on the sequential application of intermediates of different oxidation states, such as enolate anions, radicals, and carbocations. We found that such sequences are efficiently mediated by ferrocenium hexafluorophosphate, which allows the oxidative interconversion of these intermediate types by single-electron transfer (SET) without undergoing other reactions with the involved intermediates, either in its oxidized or reduced forms. These sequences found applications in the total synthesis of natural products[11a–d] and the preparation of antiviral compounds.[11e] In this context, we hypothesized that Michael addition reactions,[12] in which different enolate intermediates are sequentially generated, might be coupled with radical cyclization steps for efficient tandem reactions (Scheme 1). Anionic Michael additions proceed with enolates A¢ of carbonyl compounds A and a,b-unsaturated carbonyl compounds B. The latter can be mono- and disubstituted at the b position and work with nearly stoichiometric amounts of reactants. The Giese reaction is a radical variant of the Michael addition; it typically starts with halides F (X: I, Br), from which radicals G are generated by halogen abstraction. In contrast to anionic Michael additions, the Giese reaction follows complex kinetics and requires a large excess of the radical acceptors B,
which must be unsubstituted in the b position (R3 : H) or must carry an additional acceptor substituent in this position to permit reasonable reaction rates. With regard to the cyclization steps, the situation is the opposite. Cyclization reactions of radicals H to electron-rich and electron-poor alkene units proceed reliably to give I, which may stabilize by abstraction or radical coupling to form functionalized cyclic compounds J. Michael cyclizations of C to D are, in contrast, strictly limited to those bearing strong electron-accepting groups (R2 : Acc). Thus, a controlled switch between the two intermediate classes should provide the most efficient access to cyclic compounds J, whereas both a purely anionic and a purely radical pathway are limited because of their kinetic features. Herein, we report that oxidative tandem Michael addition/ radical 5-exo cyclization sequences employing lithium ester enolates A¢ and diverse a-alkylidene or arylidene b-dicarbonyl compounds are a convenient strategy to obtain highly functionalized cyclopentane derivatives.[13] The reaction sequences are terminated by 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO), which allows effective oxygenation of a remote position and, thus, a further useful increase of functionality in the process. The substrate scope is probed, and the means to control the stereoselectivity of the overall process based on the unique properties of the various intermediate types are revealed. It is demonstrated that the products can be further functionalized in a selective manner.
Results Based on optimized Michael addition conditions,[14] the tandem reactions were initiated by selective generation of the (E)- or (Z)-enolates by using esters 1 and lithium diisopropylamide (LDA), followed by addition of Michael acceptors 2. After completion of this step, TEMPO (5) and ferrocenium hexafluorophosphate (4) were introduced to mediate the SET oxidation, cyclization, and oxygenation (see Tables 1–4). It proved to be optimal to add 12.5 mol % of 5 first and a thoroughly homogenized mixture of 4 and 5 subsequently in small portions. This guarantees low radical concentrations and a modest excess of 5 to avoid premature trapping of the initial acyclic radical. In cases in which double-bond-containing compounds are present as impurities in the cyclic products 6–9, Upjohn dihydroxylation is the most convenient catalytic way to remove them.[15] Tandem Michael addition/radical 5-exo cyclization reactions of (Z)-enolates with monosubstituted Michael acceptors 2 A–C
Scheme 1. Michael versus Giese addition/cyclization sequences. Acc = electron-accepting group. Chem. Eur. J. 2015, 21, 9877 – 9888
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The reactions of the (Z)-enolates of esters 1 a,b bearing a terminal alkene unit with Michael acceptors 2 A–C provided cyclic products 6 a,b,g,h in moderate to good yields and good diastereoselectivity (Table 1, entries 1–3, 8, and 9). Potassium hexamethyldisilazide could also be used as a base (Table 1, entry 2).[16] 2,3-cis-Cyclopentane derivatives 8 and 9 were detected only in some cases (Table 1, entries 1, 2, 4, and 9). If 4pentenoates 1 are substituted at the 5-position, as in 1 c–f, diastereomers 6 and 7 were formed as the predominant products, 9878
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Full Paper Table 1. Tandem Michael addition/radical cyclization reactions of (Z)-enolates of 1 a–f with acceptors 2 A–C (only the major diastereomers of 6 and 7 at the exocyclic stereocenter are shown).[a]
Entry
1
2
6–9
Yield [%]
d.r. 6(aR1/bR1)/7(bR1/aR1)/8/9
Other products (yield [%])
1 2[b] 3 4 5 6 7 8 9[g]
a a b c d e f a a
A A A A A A A B C
a a b c d e f g h
79 77 71 79 82 86 87 58[d] 48[d]
30:1:1:1 33:1:1:1 1:0:0:0 15:6:1:2 1.8:1:0:0 2.3(22:1):1(> 20:1):0:0 1.6(6:1):1(> 20:1):0:0 10:1:0:0[e] 10:1.7:1:1
– – – 10 c (6) 10 d[c] – – 11 (18)[f] 12 (7)
[a] Standard conditions: LDA (1.6 mmol), THF/HMPA, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 4 and 5 at ¢40 8C. [b] Potassium hexamethyldisilazide (1.5 mmol) used. [c] Forms slowly on standing after isolation of 6 d. [d] Yield after Upjohn dihydroxylation. [e] The stereochemistry of the minor diastereomer was not assigned; traces of a third diastereomer were present. [f] d.r. 1:1. [g] LDA (1.2 mmol), 1 a (1.4 mmol).
both with 2,3-trans orientation of the substituents but with different configurations at the 5position (Table 1, entries 4–7). If the alkene unit in 1 is prochiral, as in 1 e or 1 f, the oxygenation by TEMPO to form products 6 e,f and 7 e,f proceeded with good to excellent diastereoselectivity (Table 1, entries 6 and 7). Products 6 c,d bearing a tertiary alkoxyamine unit are sensitive to light and acid, which led to alkene derivatives 10 by elimination of N-hydroxytetramethylpiperidine, whereas diastereomers 7 c,d were much more Chem. Eur. J. 2015, 21, 9877 – 9888
stable (Table 1, entries 4 and 5). To obtain good yields of 6 c,d, the products must be handled in the absence of strong light sources. Column chromatography should be performed in the shortest possible times, samples should be stored in the freezer, and NMR spectra should be run in [D6]benzene rather than in CDCl3. For benzylidenedibenzoylmethane 2 B, 1,2-addition competed to a small extent with the Michael addition, which resulted in the formation of 11 as a side product in 18 % yield (Table 1, entry 8).[14] With Michael acceptor 2 C, g-oxygenated ethylidenemalonate 12 was isolated as a byproduct in 7–26 % yield (Table 1, entry 9; see the Supporting Information for additional results). When ethylidenemalonate 2 C was subjected to the same reaction conditions in the absence of 1 a, product 12 was isolated in 50 % yield as a single regioisomer (Scheme 2). The relative configuration of compounds 6 b and 6 g was de-
Scheme 2. g-Deprotonation/SET oxidation/oxygenation of 2 C. HMPA: hexamethyl phosphoramide; TMP = 2,2,6,6-tetramethylpiperidinyl.
termined by X-ray crystallography (Figure 1).[17] In both structures, the cyclopentane ring adopts a half-chair conformation, and the substituents in the 2-, 3-, and 5-positions occupy pseudoequatorial positions. The configuration of 6 c,d,f and 7 c,f was assigned by NOE investigations. The relative configuration of 6 a,e and 7 d,e was assigned by analogy with their NMR data (see the Supporting Information).
Figure 1. ORTEP drawings of 6 b (left) and 6 g (right). Thermal ellipsoids are drawn at 30 % probability level for 6 b and at 50 % for 6 g.
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Full Paper Tandem Michael addition/radical 5-exo cyclization reactions of (E)-enolates with Michael acceptors 2 A, 2 C, and 2 D The reactions of (E)-enolates of esters 1 a–c with malonates 2 A,C afforded predominately cyclic products 8 and 9 in reasonable yields with good 2,3-cis but low 3,5 diastereoselectivity (Table 2, entries 1, 3, and 4). The enolate of tert-butyl ester 1 a
The relative configuration of 9 i was determined by X-ray crystallography (Figure 2). The cyclopentane ring of 9 i adopts an envelope conformation. The substituents in the 3- and 5positions occupy pseudoequatorial positions. The assignment of the relative configuration of 8 a,b and 9 h was based on NOE experiments.
Table 2. Tandem Michael addition/radical cyclization/oxygenation reactions of enolates (E)-1 a–c with Michael acceptors 2 A, 2 C, and 2 D.[a]
Figure 2. ORTEP drawing of 9 i. Thermal ellipsoids are drawn at 30 % probability level.
Tandem Michael addition/radical cyclization reactions of esters 1 a,b with Michael acceptors 2 E–I
Entry
1
2
6–9
Yield [%]
d.r. 6/7/8/9
Other products (yield [%])
1 2[c] 3 4[e] 5[e]
a b c a a
A A A C D
a b c h i
60[b] 36[b] 65 60[b] 82
1:0:2.5:2.5 1:0:1:1.5 1:0:5:8 1:0:1.8:2.5[f] 0:0:1:2.5
syn-3 a (8) syn-3 b (35) 10/13/14 c (15)[d] syn-3 h (15) 15, 8; 3 i (4)
[a] Standard conditions: LDA (1.6 mmol), THF, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 4 and 5 at ¢40 8C. [b] Yield after Upjohn dihydroxylation. [c] Anhydrous LiCl (7.2 mmol) was added for better syn selectivity of the Michael addition; cyclization at 0 8C. [d] d.r. 1:2.5:5. [e] LDA (1.2 mmol), 1 a (1.4 mmol). [f] Traces of 7 h were present.
provided the cyclized products in significantly better yield than that of methyl ester 1 b (Table 2, entry 1 versus 2). In contrast to the reactions with (Z)-enolates of 1, uncyclized Michael adducts syn-3 were also found here (Table 2, entries 1, 2, and 4). The formation of isopropenylcyclopentanes 10 c, 13 c, and 14 c was also observed in small amounts if 1 c was used in the cyclization sequence (Table 2, entry 3; see above). In contrast to the reactions of the (Z)-enolates, the formation of product 12 was not observed in the tandem reaction of enolate (E)-1 a with 2 C (Table 2, entry 4). Disubstituted malonate 2 D underwent the addition/cyclization sequence with (E)1 a, which provided two separable diastereomers with vicinal quaternary centers, 8 i and 9 i, in a high yield of 82 % (Table 2, entry 5). Additionally, 8 % of g-TEMPO-trapped isopropylidenemalonate 15 and 4 % of Michael adduct 3 i were detected. Chem. Eur. J. 2015, 21, 9877 – 9888
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It was known that all of the Michael acceptors 2 E–I underwent the Michael addition with low diastereoselectivity.[14] It was nonetheless of interest to learn the factors influencing the radical cyclization selectivity. Meldrum’s acid derivative 2 E provided a 1:1 mixture of anti/syn Michael adducts 3 k, as determined by an individual Michael addition,[14] but only the anti Michael adduct enolate underwent the radical cyclization step to give a 6:1 diastereomeric mixture of 6 k and 7 k together with the 6-endo cyclized product 16 k as a single diastereomer (Table 3, entry 1). Michael adduct syn-3 k was not isolated because of its acidity; it may have been retained or decomposed during column chromatography, as indicated by the formation of unidentified byproducts. The use of triethylamine as a coeluent did not improve the outcome. Benzylidene malononitrile 2 F gave a similar result (Table 3, entries 2–4). The yield and diastereomeric ratio of 6 l,m and 7 l,m based on the anti-Michael adduct enolates 3 l,m is good, whereas the syn-enolates 3 l,m cyclized to a small extent (Table 3, entries 2 and 3) or not at all (Table 3, entry 4). The reaction in 1,2-dimethoxyethane gave a similar result (see the Supporting Information). However, almost no Michael adducts syn-3 l,m were recovered, probably because of decomposition during the oxidation step. Cyclohexylidene malononitrile 2 G gave diastereomers 6 n and 7 n in a good 83 % yield but with a low 1.6:1 diastereomeric ratio at 0 8C (Table 3, entry 5). In this case, the Michael adduct dimer 17 and exo-methylenecyclopentane derivative 18 were also detected in 8 and 2 % yields, respectively. The unsymmetrical cyanoacetates 2 H and 2 I reacted with 1 a in moderate to good overall yields (Table 3, entries 6 and 7; see also the Supporting Information). Only three out of the eight possible cyclic diastereomers were isolated in all cases,
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Full Paper smaller ethyl group providing significant selectivity for 9 p over 8 p relative to the larger phenyl ring in 8 o/9 o (Table 3, entries 6 versus 7). The relative configuration of compounds 6 m and 6 n was unambiguously proved by X-ray crystallography (Figure 3). The cyclopentane ring of 6 m adopts a distorted envelope conformation. The substituents in the 2-, 3-, and 5-positions occupy pseudoequatorial positions. The cyclohexane ring of spiro compound 6 n has a chair conformation, whereas the cyclopentane ring adopts a half-chair conformation with the substituents in the 3- and 5-positions oriented cis to each other. The relative configuration of the diastereomers of 6–9 l and 6/ 8/9 o could not be assigned by NMR spectroscopy or X-ray crystallography. However, individual oxidative radical cyclizations of Michael adducts 3 l and 3 o allowed their assignment (see the Supporting Information).
Table 3. Tandem Michael addition/radical cyclization/oxygenation reactions of enolates of 1 a and 1 b with 2 E–I.[a]
Reactions of 2-, 3-, and 4-substituted ester enolates 1 g–j with benzylidene malonate 2 A Entry
1
2
Solvent
6–9 Yield d.r. [%] 6/7/8/9
Other products (yield [%])
1 2 3 4 5[d] 6 7[d,f]
a a a b a a a
E F F F G H I
THF/HMPA THF/HMPA THF THF/HMPA THF THF/HMPA THF
k l l m n o p
16 k[b] 16 l (3) syn-3 l (12), 16 l (3) syn-3 m (9), 16 m (4) 17 (8), 18 (2) 16 o (1) –
24 35[c] 39[c] 42 83 71[c] 78
6:1:0:0 8:1.3:1.4:1 19:3:1:1 6:1:0:0 1.6:1:0:0 3.5:0:1:1[e] 10:1:3:12
Differently substituted esters were briefly investigated to outline the reactivity and selectivity patterns of the tandem reactions. The enolate of 2-methyl-4-pentenoate 1 g gave cyclopentanes 6 q–9 q with malonate 2 A in very good yields (Scheme 3). The limiting factor in these tandem reactions is the diastereoselectivity of the Michael addition step, because
[a] Standard conditions: LDA (1.6 mmol), solvent, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 4 and 5 at 0 8C. [b] Approximately 10 % 16 k formed together with other unidentified byproducts. [c] Yield after Upjohn dihydroxylation. [d] LDA (1.2 mmol), 1 a (1.4 mmol). [e] Traces of another diastereomer present. [f] Cyclization at ¢40 8C.
with the R2 substituent always being cis oriented with respect to the smaller nitrile group (Acc1). The Michael adduct enolates anti-3 o¢ and anti-3 p¢ provided diastereomers 6 o or 6 p with excellent diastereoselectivity. The syn-enolates furnished two diastereomers 8 o,p and 9 o,p. The diastereomeric ratio seemed to be dependent on the size of the R2 substituent, with the
Scheme 3. Tandem Michael addition/radical cyclization reaction of ester 1 g with 2 A. [a] Yield after Upjohn dihydroxylation.
Figure 3. ORTEP drawing of 6 m (left) and 6 n (right). Displacement ellipsoids are drawn at 30 % probability level. Chem. Eur. J. 2015, 21, 9877 – 9888
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the (E)- or (Z)-enolates of 1 g cannot be selectively generated (see the Supporting Information).[18] The cyclization step proceeded similarly to that of unbranched 1 a; thus, Michael adduct enolate anti-3 q¢ cyclized with high diastereoselectivity, whereas syn-3 q¢ cyclized less selectively. The relative configuration of 6 q was determined by X-ray crystallography (Figure 4). The
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Full Paper relative configuration of 4a-6 r was confirmed by NOE measurements. 4-Alkenoates 1 i and 1 j, with a methyl substituent at the 4position, cleanly underwent the sequence with malonate 2 A but, in contrast to esters 1 a–h, gave selectively the 6-endo cyclization products 19 a–22 a and 19 b, respectively, in reasonable yield, high 2,3-trans diastereoselectivity, and moderate to excellent oxygenation diastereoselectivity (Scheme 5). Only very small amounts of syn-Michael adduct derived 21 a and 22 a were detected, together with trace amounts of the Michael adduct syn-3 (not shown).
Figure 4. ORTEP drawing of 6 q. Displacement ellipsoids are drawn at 30 % probability level.
cyclopentane ring in 6 q adopts an envelope conformation with the more bulky groups in pseudoequatorial positions. The methyl group in the 3-position is pseudoaxially oriented. For the assignment of 7 q–9 q, see the Supporting Information. The tandem reaction of the (Z)-enolate of 3-methylpentenoate 1 h with malonate 2 A provided two diastereomeric cyclopentanes 4a-6 r and 4b-6 r (Scheme 4). Both cyclic products
Scheme 5. Tandem Michael addition/radical 6-endo cyclization reaction of 1 i and 1 j with 2 A. [a] Yield after Upjohn dihydroxylation.
Extension to a ketone and a nitrile 4-Pentenone 1 k and benzylidene malonate 2 A afforded cyclopentane 6 s with very high diastereoselectivity (Table 4, entry 1). Pent-4-enenitrile 1 l similarly reacted with 2 A to provide tetrasubstituted cyclopentane derivative 6 t with orthogonal carbonyl functionalities in good yield and diastereoselectivity (Table 4, entry 2). From both reactions, some Michael adduct 3 was also isolated. Michael acceptors with aliphatic b substituents, such as ethylidene malonate 2 C or cyanoacetate 2 I, afforded the products 6–9 in good yield but with lower diastereoselectivities (Table 4, entries 3–6). For the tandem reaction of 1 k with 2 I, the diastereoselectivity improved in favor of isomer 6 v if the reaction was performed in pure THF (Table 4, entry 6 versus 5). Scheme 4. Tandem Michael addition/radical cyclization reaction of ester 1 h with 2 A.
Reductive cleavage of the alkoxyamine units in compounds 6–9 and 19
display the 2,3-trans configuration and vary only in the relative 3,4-orientation of the substituents. Although the Michael addition proceeded with moderate 3:1 2,3-anti/syn diastereoselectivity, as indicated by an individual experiment (see the Supporting Information), only enolates 2,3-anti-3 r¢ underwent the oxidative cyclization step. However, each diastereomer with the 3,4-syn and 3,4-anti orientation of the methyl substituents reacted with very high cyclization diastereoselectivity to form cyclopentanes 4a-6 r and 4b-6 r, respectively. The relative configurations of 4a-6 r and 4b-6 r were established after reductive alkoxyamine cleavage/lactonization (see below). Moreover the Chem. Eur. J. 2015, 21, 9877 – 9888
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The alkoxyamine unit in compounds 6–9 and 19 represents a protected hydroxy group. Therefore, a chemoselective N¢O bond cleavage must be guaranteed for these compounds to be synthetically useful. Treatment of various diastereomers of compounds 6/7 a,h with zinc in acetic acid at 80 8C gave mixtures of lactones 23/24 a,h in satisfactory yields and with practically unchanged diastereomeric ratios (Table 5, entries 1 and 2). The dinitrile 6/7 l also cyclized after reductive cleavage of the alkoxyamine to give cyano-substituted lactones 23 l and 24 l (Table 5, entry 3). However, the enriched diastereomers of 8 a and 9 a behaved in a strikingly different manner in the de-
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Full Paper amounts of acetate 27 were even detected (Table 5, entry 5). It may be assumed that hydrolysis of the tert-butyl ester and other side reactions compromises the results during the significantly longer reaction times. Lactonization of cyclic cyano diesters 6–9 o,p also proceeded well (Scheme 6). A mixture of 6/8/9 o gave partly separable lac-
Table 4. Tandem Michael addition/radical cyclization/oxygenation reactions of 1 k and 1 l with acceptors 2 A, 2 C, and 2 I.[a]
Entry
1
2
Solvent
6–9
Yield [%]
d.r. 6/7/8/9
3 (yield [%], anti/syn)
1 2 3[c] 4[c] 5[e] 6[e]
k l k k k k
A A C C I I
THF/HMPA THF/HMPA THF/HMPA THF THF/HMPA THF
s t u u v v
66 62 75[d] 68[d] 68[d] 87
17:1:0:0[b] 6:1:0:1 1:0:2:2 3:1:2.5:2.5 2:0:1:1[f] 5:0:1:1[f]
s (5, 1:0) t (19, 1.4:1) – – – –
[a] Standard conditions: LDA (1.6 mmol), solvent, 1 (1.2 mmol), ¢78 8C for 30 min, 2 (1.0 mmol), ¢78 8C for 30 min, warmed to ¢40 8C until complete, addition of 5 and 4 at ¢40 8C. [b] The stereochemistry of the minor diastereomer was not assigned. [c] Reagents: LDA (1.2 mmol), 1 k (1.25 mmol), 2 C (1.0 mmol). [d] Yield after Upjohn dihydroxylation. [e] Reagents: LDA (1.2 mmol), 1 k (1.4 mmol), 2 I (1.0 mmol). [f] Traces of another diastereomer present.
Scheme 6. Chemoselective deprotection of cyano diesters 6–9 o,p and ORTEP drawing of 26 p. Displacement ellipsoids are drawn at 30 % probability level. [a] Traces of 23 p were detected.
tones 23 l, 25 a, and 26 l in a practically unchanged ratio and 79 % yield. The products resulted from completely cis-selective lactonization to either the ester function to give 23 l and 26 l or to the nitrile function to result in ester 25 a, which is identical to the lactone obtained from 8 a. This supports the configuration assignment of the cyclization products. The lactonization of the ethyl derivatives 6/7 p and 6/8/9 p proceeded similarly in good yield. The structure of lactone 26 p was solved by Xray crystallography. The cyclopentane ring adopts a half-chair conformation in the crystal, and all substituents are oriented cis to each other. Cleavage of the alkoxyamine unit in 4a/4b-6 r gave the two lactones a-23 r and b-23 r in an essentially unchanged ratio (Scheme 7). Both lactones gave crystals suitable for X-ray analysis. They have a cis-fused bicyclic core; the cyclopentane ring in a-23 r adopts a half-chair conformation, whereas b-23 r has an envelope conformation. The structures confirm that their relative configurations only differ in the orientation of the methyl substituent. The reductive N¢O bond cleavage of the tertiary alkoxyamine function in cyclohexane derivative 19 a also succeeded in high yield and provided bridged lactone 28 (Scheme 8).
Table 5. Reductive N-O Bond cleavage/lactonization of 6–9.
Entry
6–9
d.r. 6/7/8/9
23–26
Yield [%]
d.r. 23/24/25/26
27 (yield [%])
1 2 3 4 5[b]
a h l a a
30:1:1:1 6:1:0:0[a] 6:1:0:0 1:0:0:2 0:0:4:1
a h l a a
70 54 60 69 27
1:0:0:0 8:1:0:0 8:1:0:0 1:0:0:2 0:0:2.4:1
– – – – 27 (5)
Elimination of tertiary alkoxyamines 6–9 c
[a] Traces of two other diastereomers present. [b] Reaction time of 5 days.
protection. Whereas diastereomer 9 a lactonized cleanly (Table 5, entry 4), the all-cis isomer 8 a reacted sluggishly, the mass recovery was low after the long reaction time, and small Chem. Eur. J. 2015, 21, 9877 – 9888
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Cyclopentane derivatives with tertiary alkoxyamine units in the side chain, such as 6–9 c, slowly eliminated N-hydroxytetramethylpiperidine in solution under ambient daylight to give olefins 10 c, 13 c, and 14 c (Scheme 9). The ease of elimination depends, however, on the relative configuration in 6–9 c. Isomer 6 c underwent this transformation quickly, whereas the elimina-
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Scheme 10. Hydrolysis of 6 a.
fluoroacetic acid in dichloromethane (Scheme 10). The ethyl ester and alkoxyamine functionalities remained unaffected.
Discussion Reactivity patterns
Scheme 7. Alcohol deprotection/lactonization of the alkoxyamine unit of 6 r and ORTEP drawing of a-23 r (left) and b-23 r (right). Displacement ellipsoids are drawn at 30 % probability level.
Scheme 8. Chemoselective deprotection/lactonization of 19 a.
Scheme 9. Deoxygenation of 6/8/9 c and ORTEP drawing of 14 c. Displacement ellipsoids are drawn at 30 % probability level. a) Ambient light, CHCl3, heating to reflux for 72 h; b) microwave, tBuOH, 130 8C, 15 min.
tion from isomers 8 c and 9 c proceeded only slowly and heating at reflux for 72 h was required to form compounds 13 c and 14 c. The elimination of N-hydroxytetramethylpiperidine was much faster with microwave irradiation without loss in the yields. The structure of isopropenylcyclopentane 14 c was proved by X-ray crystallography. These reactions can mechanistically proceed either by intermolecular hydrogen atom transfer after C¢O bond cleavage or by an intramolecular concerted Cope-type elimination, but a distinction cannot be made at present.[19] Hydrolysis of the tert-butyl ester group Acidic hydrolysis of the tert-butyl ester unit of 6 a to form acid 29 was achieved in high yield in the presence of excess triChem. Eur. J. 2015, 21, 9877 – 9888
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The deprotonation of esters 1 a–f,h–j provides (E)- or (Z)-enolates with good diastereoselectivity, whereas ketone 1 k leads always to the corresponding (Z)-enolate, which is consistent with literature precedents (Scheme 11).[20] The Michael addition to b-aryl- or b-alkyl-substituted acceptors 2 leads reliably to Michael adduct enolates 3¢ in high yields and often good diastereoselectivity (see below). However, methyl-substituted acceptors 2 C and 2 D are an exception, because g deprotonation by enolate 1¢ or LDA (leading to dienolates 2¢) competes to a certain extent, especially in the presence of HMPA. All resulting enolates 3¢ (and 2¢) undergo facile SET oxidation by ferrocenium hexafluorophosphate 4, to generate efficiently the corresponding radicals 30. All substrates can now also be envisaged to be oxidized by catalytic amounts of 4, based on very recent results.[21] The major path of stabilization is cyclization, which proceeds under very mild conditions. Only if the rate becomes slower is some Michael adduct 3 often recovered, the formation of which is attributed to hydrogen transfer from the solvent to radical 30 rather than to protonation of unreacted enolate 3¢ . This is based on the fact that, on the one hand, the consumption of 4 was always more than stoichiometric, which indicates complete oxidation of 3¢ to the radical, and, on the other hand, deuterated products were not detected upon quenching the reaction mixtures with D2O. Dimerization competed only in the case of 3 n, which gave 17 as a minor product. Although coupling products similar to 31 were observed before by coupling of malonyl radicals with an excess of 5,[22] coupling products 31 were never detected in the tandem processes. This can be rationalized, on one hand, by the operation of the Thorpe–Ingold effect to accelerate the cyclization and, on the other hand, by the concentration of 5 being kept low through portionwise addition of a mixture of 4 and 5. The cyclization regioselectivity was strongly dependent on the substitution pattern of the double bond in radical 30. The 5-exo cyclization mode furnishing radicals 32 was predominant or exclusive with all unsubstituted or terminally substituted alkene units. Only for radicals derived from malononitrile, Meldrum’s acid, or cyanoacetate precursors anti-3 k–m,o¢ were small amounts of 6-endo cyclization products 16 k–m,o detected. However, radicals 30 with methyl substituents at the internal position of the double bond, such as those derived from
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Scheme 11. Observed reaction pathways for tandem Michael addition/radical cyclization/oxygenation reactions.
1 i,j and 2 A, cyclize exclusively in the 6-endo mode to radicals 33 because of a more hindered 5-exo cyclization trajectory. All cyclized radicals 32 and 33 were oxygenated efficiently by TEMPO (5) to give the products 6–9 a–v, 19 a,b, and 20 a. It must be noted that, in contrast to potential purely radical tandem reactions, b,b-disubstituted Michael acceptors, such as 2 D and 2 G, can be conveniently applied in the anionic/radical sequence in high yields. Diastereoselectivity The diastereoselectivity of the overall tandem sequence is strongly dependent on the diastereoselectivity of the Michael addition step and the substitution pattern of the alkene cyclization acceptor. (Z)-Enolates of esters and ketones give Michael adduct enolates anti-3¢ , often with good diastereoselectivity.[14] The subsequent radical 5-exo cyclization proceeds after oxidation via Beckwith–Houk transition state 34 to radicals 35 with high diastereoselectivity, to give ultimately cyclopentanes 6, if the alkene acceptor is unsubstituted (Scheme 12).[23] However, those anti-3¢ enolates with an internally substituted alkene acceptor (R3 : CH3) cyclize exclusively in the 6-endo mode via chair transition state 36 to provide radicals 37. The radicals derived from 3 k–m,o¢ can also reach the terminus of the alkene and cyclize via the same transition state, 36, which is higher in energy in these cases than that of the 5-exo cyclization. With 1,2-di- and trisubstituted alkene units, the cyclization diastereoselectivity was lower and cyclization via boat transition state 38 becomes competitive, which results in the formation of significant amounts of compounds 7 after oxygenation of radical 39 with 5. Remarkably, the oxygenation of the cyclized radicals 35, 37, and 39 by TEMPO (5) proceeds with good diastereoselectivity if the radical is prochiral. In the case of 35 and 39, the radical conformation is constrained based on Chem. Eur. J. 2015, 21, 9877 – 9888
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Scheme 12. Rationalization of the diastereoselectivity of the oxidative radical cyclizations of enolates anti-3¢ . EWG = electron-withdrawing group.
A-strain and the approach of 5 can only proceed from the front face, because the back face is blocked by the acceptor groups. In the six-membered radical 37, the approach of the bulky TEMPO molecule is more facile from the less hindered a face, which gives access to compounds 19 a,b with a reasonable level of diastereoselectivity. The Michael addition step involving (E)-ester enolates generated predominately Michael adduct enolates syn-3¢ (Scheme 13). SET oxidation and cyclization usually provided two diastereomers. After SET oxidation of syn-3¢ , the cyclization can, in principle, proceed via two energetically similar
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Full Paper and one C¢O bond are formed in the sequence. The methodology is applicable to a wide range of acidic carbonyl compounds and a,b-unsaturated acceptors and, thus, gives the opportunity to construct scaffolds with orthogonal functional groups. The radical cyclization and oxygenation steps proceed with high diastereoselectivity for substrates with an anti arrangement of the substituents in the chain and often result in a single diastereomer. Substrates with a syn configuration usually give two diastereomers. The oxygen functionality can be liberated under reductive conditions. Further advantages compared to traditional cyclization processes are the tin-free, mild conditions and the use of the stable, recyclable, and much less toxic oxidant ferrocenium hexafluorophosphate. Based on the substrate scope, applications of this methodology in the total synthesis of terpenoid natural products are envisaged. Investigations along these lines are in progress.
Experimental Section Tandem Michael addition/radical cyclization/oxygenation of 1 and 2 induced by 4 in the presence of TEMPO (5) and HMPA: General procedure Scheme 13. The diastereoselectivity of the oxidative radical cyclizations of enolates syn-3¢ .
chair transition state arrangements, 40 and 42, in which one of the substituents has to be located pseudoaxially. The cyclization proceeds to form radicals 41 and 43, respectively, which furnish cyclopentanes 8 and 9 in almost equal amounts after coupling with TEMPO (5). However, moderate cyclization diastereoselectivity was observed for enolates syn-3 p,q¢ , which provided predominately 9 p and 9 q, respectively. This suggests a preference for transition state 42, in which the alkoxycarbonyl group is located in the pseudoaxial position. Boat transition states 44 or 45 are less likely to be populated, because they display even more unfavorable interactions. With b,b-disubstituted Michael acceptors 2 D and 2 G, the diastereoselectivity of the radical cyclization remained moderate, which suggests that the difference in the energy of the transition states is similar for an equatorially or axially located alkoxycarbonyl group (not shown).
Conclusion Densely functionalized cyclopentane or cyclohexane derivatives with up to four stereogenic centers can be assembled in a single operation by the sequence of enolate Michael addition/SET oxidation/radical 5-exo (6-endo) cyclization/oxygenation. The sequences proceed with stoichiometric amounts of substrates, in contrast to classical Giese radical addition/cyclization reactions that require a large excess of the radical acceptor. Furthermore, in contrast to Giese additions, b- and even b,b-disubstituted a,b-unsaturated acceptors can be applied with high yields. Moreover, the present strategy allows the efficient incorporation of an oxygen functionality by employing the fast radical coupling agent TEMPO; thus, two C¢C bonds Chem. Eur. J. 2015, 21, 9877 – 9888
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nBuLi (1.0 mL, 1.6 mmol, 1.6 m in hexanes) was added to a solution of iPr2NH (210 mL, 1.6 mmol) in dry THF (10 mL) at ¢78 8C under a nitrogen atmosphere. After the mixture had been stirred for 30 min, dry HMPA (2.5 mL) was added by using a syringe. A solution of 1 (1.2 mmol) in dry THF (0.5 mL) was added by using a syringe. The reaction mixture was stirred at ¢78 8C for 30 min, and 2 (1 mmol) was added, either neat (2 A, 2 C, 2 I) or as a solution in THF (0.5 mL; 2 B, 2 E, 2 F, 2 H). The mixture was slowly warmed from ¢78 8C to a maximum temperature of 0 8C, until the reaction was complete as indicated by TLC (approximately 2 h). TEMPO (5; 20 mg, 0.125 mmol) was added in one portion, followed by small portions of a thoroughly homogenized solid mixture of TEMPO (5; 180 mg, 1.152 mmol) and ferrocenium hexafluorophosphate (4; 400 mg, 1.2 mmol) at ¢40 8C (2 A, 2 B, 2 C, 2 I) or 0 8C (2 E, 2 F, 2 H). Salt 4 was consumed quickly, and the orange solution was subsequently treated with further portions of 4 until the mixture remained blue-green. Stirring at the appropriate temperature was continued for 10 min. The reaction mixture was quenched with four drops of water for 2 A, 2 C, 2 E, 2 H, and 2 I or with HCO2H (130 mL) for 2 B and 2 F, stirred for 5 min, diluted with diethyl ether to double the volume, and filtered through a plug of silica gel. The solvent was evaporated, and the inhomogeneous residue was preadsorbed on silica gel and purified by column chromatography (silica gel, hexanes/EtOAc, 50:1 gradient to 1:1).
Tandem Michael addition/radical cyclization/oxygenation of 1 and 2 induced by 4 in the presence of TEMPO (5): General procedure nBuLi (1.0 mL, 1.6 mmol, 1.6 m in hexanes) was added to a solution of iPr2NH (210 mL, 1.6 mmol) in dry THF (13 mL) at ¢78 8C under a nitrogen atmosphere. After the mixture had been stirred for 30 min, a solution of 1 (1.2 mmol) in dry THF (0.5 mL) was added by using a syringe. The reaction mixture was stirred at ¢78 8C for 30 min, and 2 (1 mmol) was added, either neat (2 A, 2 C, 2 D, 2 G, 2 I) or as a solution in THF (0.5 mL; 2 H). The mixture was slowly warmed from ¢78 8C to a maximum temperature of 0 8C, until the reaction was complete as indicated by TLC (approximately 2 h).
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Full Paper TEMPO (5; 20 mg, 0.125 mmol) was added in one portion, followed by small portions of a thoroughly homogenized solid mixture of TEMPO (5; 180 mg, 1.152 mmol) and ferrocenium hexafluorophosphate (4; 400 mg, 1.2 mmol) at ¢40 8C (2 A, 2 C, 2 D, 2 H, 2 I) or 0 8C (2 F, 2 G). Salt 4 was consumed quickly, and the orange solution was subsequently treated with further portions of 4 until the mixture remained blue-green. Stirring at the appropriate temperature was continued for 10 min. The reaction mixture was quenched with four drops of water for 2 A, 2 C, 2 D, 2 H, and 2 I or with HCO2H (130 mL) for 2 F and 2 G, stirred for 5 min, diluted with diethyl ether to double the volume, and filtered through a plug of silica gel. The solvent was evaporated, and the inhomogeneous residue was preadsorbed on silica gel and purified by column chromatography (silica gel, hexanes/EtOAc, 50:1 gradient to 1:1).
[3]
[4]
Reductive cleavage of the alkoxyamine unit: Typical procedure A mixture of three diastereomers of cyclic cyanoacetates 6 o, 8 o, and 9 o (340 mg, 0.6 mmol, 3:1:1) with AcOH (6 mL), water (2 mL), THF (2 mL), and zinc dust (1.7 g, 26 mmol) was heated to 80 8C for 4 h and subsequently stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and filtered through a plug of silica gel. The solvent was evaporated, and the crude product was dissolved in diethyl ether, washed with brine, and dried with anhydrous Na2SO4. The crude mixture was preadsorbed on silica gel and purified by column chromatography (silica gel, hexanes/EtOAc, 5:1 gradient to 2:1) to give a partly separable mixture (158 mg, 79 %) of three lactonized compounds 23 l, 25 a, and 26 l in a 3:1:1 ratio.
[5]
[6]
Acknowledgements Generous financial support by the Grant Agency of the Czech Republic (13-40188S), the Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (RVO: 61388963), the COST action CM1201 “Biomimetic Radical Chemistry”, and the Gilead Sciences & IOCB Research Center is gratefully acknowledged. I.C. thanks the Ministry of Education, Youth and Sports of the Czech Republic (MSM0021620857) for financial support. Keywords: cyclization · domino reactions · electron transfer · Michael addition · radical reactions [1] Selected books and reviews: a) Domino Reactions: Concepts for Efficient Organic Synthesis (Ed.: L. F. Tietze), Wiley-VCH, Weinheim, 2014; b) Multicomponent Reactions in Organic Synthesis (Eds.: J. Zhu, Q. Wang, M. Wang), Wiley-VCH, Weinheim, 2014; c) H. Pellissier, Asymmetric Domino Reactions, RSC, Cambridge, 2013; d) H. Pellissier, Chem. Rev. 2013, 113, 442 – 524; e) H. Clavier, H. Pellissier, Adv. Synth. Catal. 2012, 354, 3347 – 3403; f) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237 – 294; g) A. Grossmann, D. Enders, Angew. Chem. Int. Ed. 2012, 51, 314 – 325; Angew. Chem. 2012, 124, 320 – 332; h) E. A. Anderson, Org. Biomol. Chem. 2011, 9, 3997 – 4006; i) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. Int. Ed. 2011, 50, 6234 – 6246; Angew. Chem. 2011, 123, 6358 – 6371; j) B. B. Tour¦, D. G. Hall, Chem. Rev. 2009, 109, 4439 – 4486; k) S. K. Bur, A. Padwa, Adv. Heterocycl. Chem. 2007, 94, 1 – 105. [2] For nucleophilicity and electrophilicity scales, see: a) H. Mayr, S. Lakhdar, B. Maji, A. R. Ofial, Beilstein J. Org. Chem. 2012, 8, 1458 – 1478; b) N. Streidl, B. Denegri, O. Kronja, H. Mayr, Acc. Chem. Res. 2010, 43, 1537 – 1549; c) H. Mayr, A. R. Ofial, J. Phys. Org. Chem. 2008, 21, 584 – 595; d) H. Mayr, A. R. Ofial, Nachr. Chem. 2008, 56, 871 – 877; e) H. Mayr, A. R. Ofial Chem. Eur. J. 2015, 21, 9877 – 9888
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Received: February 2, 2015 Published online on May 26, 2015
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