Plamen
Bichovski
,
Thomas M.
Haas
,
Manfred
Keller
and
Jan
Streuff
*
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertsraße 21, 79104 Freiburg, Germany. E-mail: jan.streuff@ocbc.uni-freiburg.de; Fax: +49 761 203 8715; Tel: +49 761 203 97717
First published on 25th January 2016
The titanium(III)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique direct conjugate β-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctionalised building blocks without the requirement of stoichiometric organometallic reagents. In this full paper, the development and scope of the titanium(III)-catalysed cross-selective reductive umpolung of Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experiments a refined mechanistic proposal is presented.
Scheme 1 (a) Traditional β-alkylation of enones using premetallated reagents. (b) Direct titanium(III)-catalysed reductive umpolung enables the use of simple alkene precursors. |
Radical addition reactions to Michael-acceptors are complementary to traditional conjugate additions. They can be used to overcome this drawback and to address in particular conjugate β-alkylation reactions,4 which have remained challenging using conventional catalytic conjugate addition approaches.5 Hence, it has been shown that free radical additions using stoichiometric and catalytic conditions,6 as well as radical additions after titanium-catalysed reductive epoxide opening,7 can lead to the desired β-alkylated products in a very efficient manner. The advantage of the titanium-catalysed process was the superior catalyst control of the reaction selectivity, leading to high regio-, stereo- and even enantioselectivity.4
In 2011, we communicated a direct reductive β-alkylation of enones that enabled the use of readily available activated alkenes such as acrylonitrile as cross-coupling partners (Scheme 1b).8 Thus, the requirement of pre-metallated reagents or free radical conditions was overcome, which should be kept in mind with regard to more recent contributions in the field of reductive conjugate cross-couplings.5a–c,9 The reaction was a titanium(III)-catalysed overall umpolung reaction that led to 1,6-ketonitriles and related products. Related reductive homocoupling reactions were known before and had been applied even on industrial scale,10 but cross-selective tail-to-tail coupling of two Michael-acceptors had no precedence at that time. It should be noted that a redox-neutral NHC-catalysed cross-selective Michael umpolung was published shortly afterwards,11,12 which led to α,β-unsaturated 1,6-difunctionalized motifs.
In this full account, we wish to disclose the initial development of the titanium-catalysed cross-coupling of Michael-acceptors and the further advancement towards substrate classes such as quinolones, chromones and coumarins.13 The results lead to valuable implications for the future development of related transformations and the application of such direct β-alkylation reactions.
Scheme 2 Typical coupling under the previously optimised reactions conditions und key steps of the originally proposed mechanism. Manganese gave inferior results. |
The reaction conditions were the result of a careful optimisation process. For example, tetrahydrofuran, which was often employed in catalyses involving single-electron-transfer reactions, was the most suitable solvent. Interestingly, a number of other solvents with a largely different dielectricity constant or Gutmann-donor number such as hexane, 1,4-dioxane, diethyl ether or dichloromethane gave reasonable yields as well. Other very similar solvents (toluene, chloroform, 1,2-dimethoxyethane) gave essentially no conversion to the product (Table 1). This illustrates that titanium(III)-chemistry is sensitive to a number of effects and reaction outcomes cannot be estimated easily. In fact, THF, which is only a moderate donor, was displaced from the TiIII-centre by acrylonitrile forming a deep-purple complex. Chelating solvents (1,2-DME) and strong donors such as acetonitrile or DMF, on the other hand, inhibited the catalyst through irreversible coordination.19 Thus we concluded, the major role of THF was to ensure a balanced solvation of the reaction partners (Et3N·HCl, is only moderately soluble, for example) and to promote an efficient reduction of TiIV to TiIII by the metallic reductant.
Entry | Solvent | ε ρa | DNb | Yieldc (%) |
---|---|---|---|---|
a Relative permittivity, see ref. 16. b Gutmann donor number, see ref. 17. c Determined by GC-analysis with 1,3-dimethoxybenzene as internal standard. | ||||
1 | n-Hexane | 1.89 (20 °C) | 0 | 60 |
2 | 1,4-Dioxane | 2.22 (20 °C) | 14.8 | 66 |
3 | CCl4 | 2.24 (20 °C) | 0 | 2 |
4 | Toluene | 2.39 (20 °C) | 0.1 | 3 |
5 | Et2O | 4.27 (20 °C) | 19.2 | 79 |
6 | CHCl3 | 4.81 (25 °C) | 4 | 1 |
7 | 1,2-DME | 7.3 (23.5 °C) | 20.0 | 0 |
8 | THF | 7.52 (22 °C) | 20.0 | 90 |
9 | CH2Cl2 | 9.14 (20 °C) | 1 | 61 |
10 | 1,2-DCE | 10.42 (20 °C) | 0 | 61 |
11 | t-BuOH | 12.5 (20 °C) | — | 0 |
12 | MeCN | 36.64 (20 °C) | 14.1 | 16 |
13 | DMF | 38.25 (20 °C) | 26.6 | 5 |
The choice of triethylamine hydrochloride as additive emerged from a screening of various ammonium salts. Without such an ammonium salt additive only poor conversion to the desired product was observed (Table 2, entry 1). Hydrochlorides within a pKa range of pKaH2O = 10–11 gave the most satisfying results. Quinuclidinium and diisopropylethylammonium salts that were within the pKa range of triethylamine gave slightly lower yields (78% and 64%, respectively). The more acidic hydrochlorides of 2,4,6-collidine and pyridine as well as hydrochlorides of secondary amines had a negative impact on the reaction (entries 3, 4, 8, and 9). Interestingly, the addition of unprotonated triethylamine was beneficial too, but also lead to the formation of larger amounts of the trimethylsilylenol ether of cyclohexenone (entry 10). The superiority of triethylamine hydrochloride, however, cannot be explained by its acidity alone and might stem from the tendency of Et3N·HCl to form a TiIII-Et3N·HCl adduct 6 (Scheme 3) with the active titanium(III) monomer 5, which was proposed to stabilize the catalyst.20
Entry | Additive | pKa (H2O)a | Yieldb (%) |
---|---|---|---|
a Literature values, see ref. 18. b Determined by GC-analysis with 1,3-dimethoxybenzene as internal standard. c Significant amounts of the trimethylsilyl enol ether of cyclohexenone were observed. | |||
1 | None | — | 10 |
2 | TFA | 0.23 | 0 |
3 | Pyridine·HCl | 5.25 | 28 |
4 | Collidine·HCl | 7.48 | 55 |
5 | Et 3 N·HCl | 10.75 | 90 |
6 | Quinuclidine·HCl | 11.0 | 78 |
7 | iPr2NEt·TFA | ca. 11 | 64 |
8 | iPr2NH·TFA | 11.05 | 0 |
9 | Piperidine·HCl | 11.22 | 26 |
10 | Et3N | >20 | 48c |
Lowering the catalyst amount to 5 mol% or 3 mol% still gave 70% and 55% yield, respectively (Table 3). However, the above mentioned competing reactions (silyl enol ether formation of 1 and homo-coupling of 1) became more prominent. Without the titanocene catalyst, no product was formed.
Scheme 4 Reductive Coupling of Cyclic Enones with Acrylonitriles. Yield of isolated material. aCombined yield. bSyringe pump addition of the dihydrothiopyranone precursor. cReaction at 0 °C. |
The scope could be further extended towards linear enone substrates that were transformed into the corresponding 1,6-ketonitriles 16–18 in reasonable yields (42–53%). Methyl vinyl ketone, however, led to uncontrolled polymerisation under the reaction conditions and, thus, only 17% of compound 19 were isolated. In addition, α,β-unsaturated amides containing achiral and chiral oxazolidinone units could be employed as well with moderate success. However, no diastereoselectivity was observed, even if precoordination of the substrate by AlEt2Cl was attempted.
The titanium-catalysed reductive umpolung/β-alkylation could be applied to a number of quinones, chromones, and coumarines as described in the following.13 A series of substituted quinolones was treated under the same conditions with acrylonitrile as coupling partner and good yields were obtained for N-methylated and N-benzylated substrates having no further substitution (Table 4). The reaction worked also with substitution at position 7 and 8, although the yields were slightly diminished. For example, 7-methoxy, -methyl, -phenyl, -thiophen-3-yl, and -phenylethynyl groups worked well (entries 3–8). In some cases (e.g. R1 = Ph), however, significant differences in yield were observed for the N-methylated and N-benzylated precursors (entries 5 and 6). Double substitution was tolerated as well (entry 9) and importantly, halogenation of the aromatic backbone was tolerated to some extend (entries 10–12).21 This underlined the mildness of the title reaction.
The coupling worked significantly better with 3-substituted quinolones. Here, yields between 69% and 91% were obtained for 3-methyl and 3-phenyl derivatives (Table 5). Importantly, aqueous workup under protic conditions gave exclusively the syn-diastereomer, which was a result of a pseudo-axial orientation of the cyanoethyl chain due to steric repulsion with the N-alkyl group. Quenching the silyl enol ether under controlled conditions instead produced significant amounts of the anti-diastereomer (in a 2.4:1 syn/anti ratio), which could be separated and structurally confirmed by X-ray analysis (Fig. 1).22,23 The workup had to be carried out with care and removal of the excess in acrylonitrile under reduced pressure was required. Otherwise, overalkylation in form of a subsequent Michael-addition of the enolate to acrylonitrile took place (Scheme 5). For example, if a reaction of 24a (R = Me) or 24b (R = Bn) with acrylonitrile was quenched by addition with TBAF at 0 °C, the desired products 25a and 25b were received in 30% and 42% yield, respectively, together with the corresponding double addition products 27a and 27b (42% and 39%, respectively).
Scheme 5 Workup with TBAF at 0 °C in presence of an excess of acrylonitrile led in part to double cyanoalkylation products. |
Entry | R1 | R2 | Products | Workupa | syn/anti | Yieldb [%] |
---|---|---|---|---|---|---|
a HCl workup: aq. 1 N HCl, 0 °C, 3 h. TBAF workup: TBAF (1 M in THF), −78 °C, 3 h. b Yield of isolated product. | ||||||
1a | Me | Me | 25a, 26a | HCl | >95:5 | 86 |
1b | TBAF | >95:5 | 74 | |||
2a | Me | Bn | 25b, 26b | HCl | >95:5 | 91 |
2b | TBAF | 71:29 | 69 | |||
3a | Ph | Me | 25c, 26c | HCl | >95:5 | 72 |
3b | TBAF | 71:29 | 89 | |||
4a | Ph | Bn | 25d, 26d | HCl | >95:5 | 85 |
4b | TBAF | 70:30 | 69 |
In analogy to the quinolone substrates, C3-unsubstituted chromones were moderately successful substrates for the titanium-catalysed reductive umpolung (Table 6). Manganese powder as reductant gave slightly better reaction yields than zinc dust. Electron-donating substituents were tolerated (37–50%), but no product could be isolated with 6-bromochromone (28d). A 2-methyl substituted chromone gave only 17% product and flavone itself was transformed into the desired chromanone in 31% yield, which corresponded to two catalyst turnovers. As observed before, the yields were significantly improved when C3-substituents were present (Table 7). Interestingly, not only alkyl and aryl groups could be installed at this position, but also halides such as chloride and bromide (entries 4 and 5).
Entry | R1 | R2 | Products | Workup | syn/anti | Yielda [%] |
---|---|---|---|---|---|---|
a Yield of isolated product. b Isolated as diastereomeric mixture. | ||||||
1a | Me | H | 31a, 32a | HCl | 21:79 | 69 |
1b | TBAF | 78:22 | 78 | |||
2a | Ph | H | 31b, 32b | HCl | 21:79 | 73 |
2b | TBAF | 75:25 | 62 | |||
3a | Ph | i-PrO | 31c, 32c | HCl | 37:63 | 82 |
3b | TBAF | 75:25 | 81 | |||
4a | Cl | H | 31d, 32d | HCl | 38:62 | 49b |
4b | TBAF | 64:36 | 54b | |||
5a | Br | H | 31e, 32e | HCl | 22:78 | 42b |
5b | TBAF | 83:17 | 42b |
The relative configuration was opposite to the quinolin-4-one products and the anti-diastereomer was isolated as major component after workup with aqueous HCl.
The workup procedure drastically influenced the product distribution. The diastereoselectivity could be even switched from the favoured anti-products to the syn-products in moderate to good diastereoselectivity when workup was carried out under kinetically controlled conditions (TBAF, −78 °C).
3-Iodochromone 30f, however, was too reactive and suffered from dehalogenation under the reaction conditions and cross-coupling product 29a was isolated (Scheme 6).
Finally, the cross-coupling with acrylonitrile was applied to the reductive β-cyanoalkylation of coumarins. Using precursors with a diverse substitution pattern, moderate yields were achieved for the cross-coupling reaction (Table 8). Attempts to further optimize the reaction outcome were unsuccessful.24 The best yield (65%) was obtained with 6-methylcoumarin (entry 3). A quaternary stereocentre could be installed in 36% yield (entry 8) and α,β-disubstituted 2-chromanones were formed in similar quantities by the reductive cyanoethylation reaction. The diasteroselectivity was again very high and the syn-diastereomers were isolated as sole products. The relative syn-configuration was unambiguously confirmed by X-ray analysis of product 34i (Fig. 2).22
Entry | R1 | R2 | R3 | R4 | R5 | Product | Yielda [%] |
---|---|---|---|---|---|---|---|
a Yield of isolated product. b Calculated yield from an inseparable mixture with the substrate (∼1:1 ratio). c Only the syn-isomer was formed. d A single isomer was formed, which was assigned in analogy to 34i. | |||||||
1 | H | H | H | H | H | 34a | 42 |
2 | Br | H | H | H | H | 34b | 36 |
3 | Me | H | H | H | H | 34c | 65 |
4 | H | Me | H | H | H | 34d | 46 |
5 | H | MeO | H | H | H | 34e | 45 |
6 | H | Me2N | H | H | H | 34f | 26b |
7 | H | H | Me | H | H | 34g | 33 |
8 | H | H | H | Me | H | 34h | 36 |
9 | H | H | H | H | Me | 34i | 44c |
10 | H | Me2N | H | H | Me | 34j | 38b,d |
11 | H | Me2N | H | H | Ph | 34k | 24b,d |
Entry | Product | dr | Yielda [%] | |
---|---|---|---|---|
a Yield of isolated product. b Combined yield. c Cinnamonitrile (20 mol%) was added to the reaction mixture. d Workup with TBAF instead of aq. HCl. | ||||
1 | 35, R = H | — | 71 | |
2 | 36, R = Me | 50:50 | 70b | |
3 | 37 | 50:50 | 27b | |
4 | 38, R = Me | — | 0 | |
5 | 39, R = Ts | — | 73c | |
6 | 40, R = H | 57:43 | 36b | |
7 | 41, R = Me | 58:42 | 90b | |
8 | 42, R = H | 55:45 | 28b | |
9 | 43, R = Me | 62:38 | 29b | |
10 | 44 | 62:38 | 18 | |
11 | 45, R = Me | — | 35d | |
12 | 46, R = Et | — | 47d | |
13 | 47, R = t-Bu | — | 37d | |
14 | 48, R = Ph | — | 52 | |
15 | 49, R = Mes | — | 81 |
In a second series of experiments with N-methyl-4-quinolones 22a and 24a, good results were obtained for the couplings with methacrylonitrile as well. 3-Methylquinolone 24a gave again exclusively the syn-product with respect to the ring substitution in excellent 90% yield. The product was obtained as an inseparable ∼1:1-mixture of diastereomers with respect to the additional stereocentre at the nitrile α-carbon (entry 7). With crotononitrile, the yields were again reduced to ca. 30% (cf. entry 3) but a moderate diastereoselectivity of 1.6:1 dr was observed by NMR for the reaction with 24a (entry 9). Cinnamonitrile, which was employed for entry 5 as a beneficial additive, could be coupled in 18% yield to product 44 (entry 10).
With the 3-methylated quinolone 24a as substrate, acrylates could be employed efficiently in the reductive catalytic umpolung as well (entries 11–15). Here, reasonable results were obtained with methyl, ethyl, and tert-butyl acrylate. The yield was slightly improved with the less electron-rich phenyl acrylate and with the sterically hindered mesityl acrylate,25 the coupling proceeded smoothly in 81% yield. In all cases, no cross-coupling was observed in absence of the titanocene catalyst.
In addition, a number of other electron-deficient alkenes were tested as potential coupling partners with less success (Fig. 3). Other common nitrile-based Michael-acceptors such as 2-chloroacrylonitrile or Knoevenagel products of malononitrile or ethyl cyanoacetate did not undergo the desired reaction. This was also true for 2-nitropropene and β-nitrostyrene as well as vinyl sulfones. A saccharine-derived acrylamide, vinyl diethyl phosphonate or a propargylic ester were not suitable as well. In several cases, the reduction of the activated alkene was observed instead of the desired cross-coupling reaction. With N-acryloylsaccharine, for example, formation of the corresponding propionic amide took place.
As shown in Scheme 7, coordination of the in situ formed titanium(III)-catalyst to the enone substrate could also be interpreted as the formation of an allylic ketyl radical anion that remained coordinated to a titanium(IV)-centre. In fact, the unpaired electron was in part located at the titanium centre, at the β-carbon and at the carbonyl carbon as illustrated by the three resonance structures shown in Scheme 7. This was supported by the calculated spin density distribution at the Cp2TiIIICl–cyclohexenone complex. It was majorly located at the titanium centre and in part located at the carbonyl and β-carbon.24 A similar situation was found for an acrylonitrile–titanium(III) complex. This situation explained our experimental results: reductive coupling at the β-position leading to conjugate addition products (e.g. ketonitrile 3) was the usually preferred pathway. However, substrates with increased sterical bulk at the β-carbon led to a change in the regiochemistry and the corresponding 1,2-addition products were formed.26 For example, the reductive cross-coupling of the Wieland–Miescher ketone gave the corresponding cyanoethylated allylic alcohol 50 in 55% yield and moderate diastereoselectivity. A similar experiment with progesterone afforded the corresponding product 51 in excellent 91:9 dr and 65% yield.
The origin of the hydrogen atom that was transferred to the nitrile α-carbon in course of the standard coupling between cyclohexenone and acrylonitrile was probed as well. A reaction run in THF-d8 did not lead to any deuterium incorporation into the product (Scheme 8). If a carbon-centred radical was present at this position a deuterium radical abstraction from the solvent would have been likely to occur. On the contrary, a reaction with triethylamine deuterochloride resulted in about 70% deuteration of the product at this position, which was evidence for a protonation step under the usual reaction conditions. This protonation at the nitrile α-carbon was unselective due to the absence of stereoelements in its proximity, which explains the formation of 1:1 diastereomeric mixtures in the reactions with methacrylonitrile (see Table 9, entries 2, 6, and 7).
Together with the results from our previous study on the mechanism of the titanium(III)-catalysed cross-acyloin type coupling,27 these observations led to a refined mechanistic proposal for the standard reaction (Scheme 9).
The reaction formally begins with the formation of two equivalents of 5 from [Cp2TiCl2] zinc followed by reaction with enone 1 and nitrile 2 to form coordination complexes. These complexes are in equilibrium through ligand-exchange processes. It is likely that a cationic resting state 52 is formed by solvation of the remaining chloride and coordination of a second acrylonitrile molecule (acrylonitrile was employed in a 50 fold excess with respect to the catalyst). This species could be the reason for the observed colour change to deep purple after addition of acrylonitrile and before addition of TMSCl during the reaction setup. A similar cationic resting state was previously established for the related ketone–nitrile coupling by X-ray analysis.27 The C–C bond formation would then take place in form of a catalyst-controlled radical combination, avoiding the presence of free radicals and leading to bistitanated ketenimine-enolate 53. The metallated ketenimine was quickly protonated by the hydrochloride (which was supported by the deuterium experiment) forming enolate 54. The titanium enolate was then cleaved by chlorotrimethylsilane releasing the crude product in form of silyl enol ether 4 and enabling catalyst turnover. Zinc then regenerated the titanium(III) catalyst 5. If desired, the silyl enol ether 4 could be isolated as one regioisomer in 87% yield (workup with water and filtration over florisil)8 or quenched with HCl or TBAF to afford the corresponding ketonitrile as done for the tables in this work.
For a full list of materials and methods, detailed experimental data, compound characterizations and computational details, see the ESI.†
Footnote |
† Electronic supplementary information (ESI) available: Additional screening tables, experimental and computational details, characterisation data and NMR spectra of new compounds. CCDC 1440298 and 1440299. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob02631h |
This journal is © The Royal Society of Chemistry 2016 |