共查询到20条相似文献,搜索用时 93 毫秒
1.
Kristin M. Sobie Matthew Albritton Yinuo Yang Mariana M. Alves Adrian Roitberg Alexander J. Grenning 《Chemical science》2022,13(7):1951
Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement. Substrates have been designed which exhibit Cope rearrangement kinetic barriers of ∼23 kcal mol−1 with isoenergetic favorability (ΔG ∼ 0). These fluxional/shape-shifting molecules can be driven forward by chemoselective reduction to useful polyfunctionalized building blocks.Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement.Constructing sterically congested vicinal quaternary–tertiary carbons (4°/3° carbons) via Cope rearrangement is currently quite limited with only a handful of papers on the subject published over the past 40 years. This stands in stark contrast to the plethora of other methods for establishing sterically congested vicinal carbons.1–5 Central to the challenge are kinetic and thermodynamic issues associated with the transformation. In the simplest sense, Cope rearrangements proceed in the direction that results in highest alkene substitution (Fig. 1).6,7 To forge 4°/3° motifs by Cope rearrangement, additional driving forces must be introduced to reverse the [3,3] directionality and compensate for the energetic penalty associated with the steric and torsional strain of the targeted vicinal 4°/3° motif. With limited reports in all cases, oxy-Cope substrates (Scheme 1, eqn (1)),8–14 divinylcyclopropanes (Scheme 1, eqn (2)),15–20 and vinylidenecyclopropane-based 1,5-dienes21 (Scheme 1, eqn (3)) have demonstrated favourability for constructing vicinal 4°/3° carbons. Malachowski et al. put forth a series of studies on the construction of quaternary centers via Cope rearrangement driven forward by a conjugation event (Scheme 1, eqn (4)).22–25 In their work, a single example related to the construction of vicinal 4°/3° centers was disclosed, though kinetic (180 °C) and thermodynamic (equilibrium mixtures) challenges are also observed.23 And of particular relevance to this work, Wigfield et al. demonstrated that 3,3-dicyano-1,5-dienes with the potential to generate vicinal 4°/3° carbons instead react via an ionic mechanism yielding the less congested products (Scheme 1, eqn (5)).26Open in a separate windowFig. 1Cope equilibrium of 1,1,6-trisubstituted 1,5-dienes.Open in a separate windowScheme 1(A) Cope rearrangements for constructing vicinal 4°/3°-centers (B) this report.Our group has been examining strategies to decrease kinetic barriers and increase the thermodynamic favourability of 3,3-dicyano-1,5-diene-based Cope substrates.27–31 Beyond the simplest, unsubstituted variants, this class of 1,5-diene is not particularly reactive in both a kinetic and thermodynamic sense (e.g.Scheme 1, eqn (5)).26,32 Reactivity issues aside, these substrates are attractive building blocks for two main reasons: (1) they have straightforward accessibility from alkylidenemalononitriles and allylic electrophiles by deconjugative allylic alkylation.33 (2) The 1,5-diene termini are substantially different (malononitrile vs. simple alkene) thus allowing for orthogonal functional group interconversion facilitating target and analogue synthesis.34 Herein we report that a combination of 1,5-diene structural engineering28,31 and reductive conditions (the reductive Cope rearrangement29,30) can result in the synthesis of building blocks containing vicinal gem-dimethyl 4°/3° carbons along with orthogonal malononitrile and styrene functional groups for interconversion (Scheme 1B). On this line, malononitrile can be directly converted to amides34 yielding functionally dense β-gem-dimethylamides, important pharmaceutical scaffolds.35This project began during the Covid-19 pandemic lockdown (ca. March–May 2020). As such, we were not permitted to use our laboratory out of an abundance of caution. We took this opportunity to first computationally investigate a Cope rearrangement that could result in vicinal 4°/3° carbons (Scheme 2). Then, when permitted to safely return to the lab, we would experimentally validate our findings (vide infra). From our previous work, it is known that by adding either a 4-aromatic group28 or a 4-methyl group31 to a 3,3-dicyano-1,5-diene, low barrier (rt – 80 °C) diastereoselective Cope rearrangements can occur. Notably, the 4-substituent was found to destabilize the starting material (weaken the C3–C4 bond, conformationally bias the substrate for [3,3]), and stabilize the product side of the equilibrium via resonance (phenyl group) or hyperconjugation (methyl group). In this study, we modelled substrates 1, 3, and 5 that have variable 4-substitution and would result in vicinal gem-dimethyl- and phenyl-containing 4°/3° carbons upon Cope rearrangement to 2, 4, or 6, respectively. We chose to target this motif due to likely synthetic accessibility from simple starting materials but also because of the important and profound impact that gem-dimethyl groups impart on pharmaceuticals.35 Substrate 1 lacking 4-substitution had an extremely unfavourable kinetic and thermodynamic profile (ΔG‡ = 31.6; ΔG = +5.3 kcal mol−1). When a 4-methyl group was added, the kinetic barrier (ΔG‡) dropped appreciably to 28.2 kcal mol; however, the thermodynamics were still quite endergonic (ΔG = +4.4 kcal mol−1). Most excitingly, it was uncovered that the 4-phenyl group dramatically impacted the kinetics and thermodynamics: the [3,3] has a barrier of 22.9 kcal mol−1 (ΔG‡) and is ∼isoenergetic (ΔG = +0.17 kcal mol−1). Thus, the reaction appears to be fluxional/shape-shifting at room temperature.36–40 For this substrate, we also modelled the dissociative pathway (Scheme 2D). It was found that bond breakage to two allylic radical intermediates is a higher energy process than the concerted transition state (Scheme 2Cvs.Scheme 2D). Specifically, the dissociative pathway was found to be kinetically less favourable (ΔG‡ ∼ 27.6 kcal mol; ΔG = 26.2 kcal mol−1) than the concerted process (ΔG‡ = 22.9 kcal mol−1). While the dissociative pathway is less favourable than the concerted transformation, we surmised that the two-step process becomes accessible at elevated temperature (vide infra). Finally, the ionic pathway was calculated to be significantly higher for this substrate (see the ESI†).Open in a separate windowScheme 2Computational analysis of 3,3-dicyano-1,5-diene that in theory could result in vicinal 4°/3° carbons. (A) 4-Unsubstituted 3,3-dicyano-1,5-diene. (B) 4-Methyl 3,3-dicyano-1,5-diene. (C) 4-Phenyl 3,3-dicyano-1,5-diene. (D) The dissociative mechanism for substrate 5 is higher than the closed transition state. (E) visualization of the kinetic- and thermodynamic differences of transformations (A–D).The class of substrate uncovered from our computational investigation could be accessed from γ,γ-dimethyl-alkylidenemalononitrile (7a) and 1,3-diarylallyl electrophiles (such as 8a) by Pd-catalyzed deconjugative allylic alkylation (Scheme 3A).33 As such, model 1,5-diene 5a was prepared to verify the computational results. It was found that upon synthesis of 5a, an inseparable 21 : 79 mixture of 1,5-diene 5a and the 1,5-diene 6a was observed. The predicted ratio of 5a to 6a was 57 : 43 (Scheme 2C). These two results are within the error of the calculations (predicted; slightly endergonic, observed; slightly exergonic). To determine whether the transformation was progressing through the predicted concerted pathway (Scheme 2C) over the dissociative pathway (Scheme 2D), substrate 5b was prepared by an analogous deconjugative allylic alkylation reaction. Similarly, two Cope equilibrium isomers 5b and 6b are observed at room temperature in a 12 : 88 ratio. Upon heating at 100 °C for 3 h, the 1,5-dienes “scramble” (e.g. iso-6b is observed; 0.2 : 1.0 : 1.5 ratio of 5b : 6b : iso-6b) indicating that the dissociative pathway is only accessible at elevated temperature. This is all in good agreement with the calculated kinetics and thermodynamics of this system (Scheme 2).Open in a separate windowScheme 3(A) Observation of fluxional [3,3] and confirmation of calculated predictions. (B) Optimization of a reductive Cope rearrangement protocol for constructing vicinal 4°/3° centers. (C) The Pd-catalyzed deconjugative allylic alkylation must be regioselective.With respect to the synthetic methodology, we aimed to increase the overall efficiency and applicability of the sequence (Scheme 3B). Specifically, we wanted to avoid [3,3] equilibrium mixtures and sensitive/unstable substates and intermediates. It was found that the direct coupling of 7a with diphenylallyl alcohol 9a could take place in the presence of DMAP, Ac2O, and Pd(PPh3)4. When the coupling was complete, methanol and NaBH4 were added to drive the Cope equilibrium forward, yielding the reduced Cope rearrangement product 10a in 76% isolated yield. In terms of practicality and efficiency, this method utilizes diphenylallyl alcohols, which are more stable and synthetically accessible than their respective acetates, and the [3,3] equilibrium mixture can be directly converted dynamically to a single reduced product.With an efficient protocol in hand for constructing malononitrile–styrene-tethered building blocks featuring central vicinal 4°/3° carbons, we next examined the scope of the transformation (Scheme 4). We chose diarylallyl alcohols with the propensity to react regioselectively via an electronic bias (Scheme 3C).41,42 The combination of p-nitrophenyl and phenyl (10b) or p-methoxyphenyl (10c) yielded regioselective outcomes with the electron-deficient arene at the allylic position. This is consistent with the expected regiochemical outcome where the nucleophile reacts preferentially at the α-position and the electrophile reacts at the allylic position bearing the donor-arene (Scheme 3C).41,42 Then, reductive Cope rearrangement occurs to position the electron-deficient arene adjacent to the gem-dimethyl quaternary center. This is an exciting outcome as many pharmaceutically relevant (hetero)arenes are electron deficient. Thus, fluorinated arenes were installed at the allylic position of products 10d–10k. While the phenyl group resulted in poor regioselectivity (1 : 1–3 : 1), the p-methoxyphenyl group enhanced the regiomeric ratios in all cases (3 : 1–15 : 1). The degree of selectivity is correlated with the number and position of fluorine atoms. N-Heterocycles could be incorporated with excellent regioselectivity, generally speaking (10l–10q). For example, 3-chloro-4-pyridyl (10l/10m) groups were installed at the allylic position with >20 : 1 rr. 4-Chloro-3-pyridyl was poorly regioselective (10n), but the combination of 4-trifluomethyl-3-pyridyl/p-methoxyphenyl (10o) gave good regioselectivity of 11 : 1. 2-Pyridyl/p-methoxyphenyl (10q) was also a regioselective combination. We also examined a few other heterocycles including quinoline (10s) and thiazole (10t and 10u) with excellent and modest regioselectivity observed, respectively. As a general trend, when the arenes on the allylic electrophile become less polarized, poor regioselectivity is observed in the Pd-catalyzed allylic alkylation. For example, the combination of p-chlorophenyl and p-methoxyphenyl (10v) or phenyl (10w) yields regioisomeric mixtures of products. This can be circumvented by utilizing symmetric electrophiles (to 10x).Open in a separate windowScheme 4Scope of the 4°/3°-center-generating reductive Cope rearrangement.The phenyl or the p-methoxyphenyl group is necessary to achieve the 4°/3° carbon-generating Cope rearrangement: it functions as an “activator” by lowering the kinetic barrier and increasing thermodynamic favourability. These activating groups can be removed through alkene C C cleavage reactions (e.g. metathesis (Scheme 5) and ozonolysis (Scheme 6B)). In this regard, highly substituted cycloheptenes 11 were prepared by allylation and metathesis (Scheme 4).28,43 The yields were modest to excellent over this two-step sequence. In many cases, where 10 exists as a mixture of regioisomers, the major allylation/RCM products 11 could be chromatographically separated from their minor constituents. As shown in Scheme 6A, the malononitrile can be transformed via oxidative amidation34 to products 12 containing a dense array of pharmaceutically relevant functionalities (amides, gem-dimethyl, fluoroaromatics, and heteroaromatics). Following this transformation, ozonolysis terminated with a NaBH4 quench installs an alcohol moiety on small molecule 13a.Open in a separate windowScheme 5Removal of the “activating group” by ring-closing metathesis.Open in a separate windowScheme 6(A) oxidative amidation of malononitrile. (B) Removal of “activating group” by ozonolysis.These first computational and experimental studies utilizing 3,3-dicyano-1,5-dienes as substrates for constructing vicinal 4°/3° centers sets the stage for much further examination and application. For example, while we focused our efforts on gem-dimethyl-based quaternary carbons, it is likely that other functionality can be installed at this position. For example, while unoptimized, it appears the protocol is reasonably effective at incorporating a piperidine moiety in addition to heteroarenes from the allylic electrophile (7b + 9f → 14a; Scheme 7A). Similar functional group interconversion chemistry as described in Schemes 5 and and66 can thus yield functionally dense building blocks 15 and 16 in good yields.Open in a separate windowScheme 7(A) The construction of 4/3° centres on piperidines. (B) Promoting endergonic [3,3] rearrangements is possible, assuming the [3,3] kinetic barrier is sufficiently low.While the 4,6-diaryl-3,3-dicyano-1,5-dienes offered the most attractive energetic profile (low kinetic barrier, isoenergetic [3,3] equillibrium; Scheme 2C), the 4-methyl analogue is also intriguing to consider as a viable substrate class for reductive Cope rearrangement (Scheme 2B). The challenge here is that the kinetics and thermodynamics are quite unfavourable (not observable by NMR), but potentially not prohibitively so. It is extremely exciting to find that Cope equilibria that are significantly endergonic in the desired, forward direction (e.g.3a to 4a) can be promoted by a related reductive protocol (Scheme 7B). While unoptimized, we were able to isolate product 17 in xx% yield by heating at 90 °C in the presence of Hantzsch ester in DMF. 相似文献
2.
Luca Capaldo Stefano Bonciolini Antonio Pulcinella Manuel Nuo Timothy Noël 《Chemical science》2022,13(24):7325
The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner–Wadsworth–Emmons (HWE) reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and has been applied to structurally complex molecules.We report a flow platform for the modular allylation of strong aliphatic C(sp3)–H bonds based on the merger of photocatalytic HAT and a HWE reaction. This approach enables both early- and late-stage diversification of various hydroalkanes.Modern drug discovery programs capitalize increasingly on the application of late-stage functionalization methodologies to accelerate the lead optimization phase.1,2 Such strategies allow for the rapid and cost-efficient3,4 diversification of the parent molecule by exploiting native functionalities (e.g., C–H bonds), thus effectively avoiding the need to redesign its entire synthetic route to access new leads.5–7 More specifically, the late-stage decoration of organic molecules with multipurpose functional groups would provide new points of entry for subsequent diversification.8 Such a strategy could be particularly convenient when it is realized via a chemo- and regioselective functionalization of C–H bonds in the absence of any proximal directing or activating groups.7 However, while C(sp2)–H activation has been extensively investigated, the direct functionalization of C(sp3)–H bonds remains challenging and is often narrow in scope.9 Recently, photocatalytic Hydrogen Atom Transfer (HAT) has been exploited to enable the late-stage functionalization of C(sp3)–H bonds, showing remarkable levels of regioselectivity even in complex molecules (Scheme 1A).10 In HAT photocatalysis, a catalyst converts light energy into chemical energy for the homolytic cleavage of strong aliphatic C–H bonds.Open in a separate windowScheme 1Allylation of C(sp3)–H bonds. (A) Photocatalytic HAT enables late-stage functionalization of structurally complex molecules. (B) Reported approaches for the photocatalyzed radical allylation of organic molecules. (C) A telescoped approach for the modular allylation of C(sp3)–H bonds (this work).Especially, the decatungstate anion ([W10O32]4−) has shown remarkable selectivity for specific C(sp3)–H bonds, governed by an intricate balance between steric and electronic interactions.9,11,12We envisioned that the regioselective introduction of an allyl moiety onto hydrocarbon frameworks would be particularly useful as it provides a convenient branching point for further late-stage synthetic exploitation.13 To install such moieties, radical allylation has manifested itself as a valuable strategy. One approach relies on the use of transition metal complexes to activate a substrate containing an allylic leaving group to afford a π-allyl complex, which is then suited to trap a C-centered radical (Scheme 1B).14 This strategy can engage a diverse set of allyl coupling partners but typically requires purposely designed radical precursors, which prevents the direct allylation of unactivated C(sp3)–H bonds.Another tactic exploits radicofugal groups X (e.g., X = halide, SO2R, SnR3, etc) in the allylic position to afford the desired product via a radical addition–fragmentation process (Scheme 1B).15–28 However, while synthetically useful, this transformation is not suitable for the synthesis of densely functionalized allylic functionalities.Seeking to address these challenges, we sought to develop a robust and versatile synthetic platform for the allylation of strong aliphatic C(sp3)–H bonds. Hereto, a modular synthetic sequence is preferred in which the allylic moiety is assembled in a stepwise fashion, enabling the rapid generation of structurally diverse analogues. Specifically, our sequence features the merger of two distinct synthetic steps to accomplish this goal (Scheme 1C). First, we planned to activate C(sp3)–H bonds via decatungstate-catalyzed Hydrogen Atom Transfer29,30 and subsequently trap the resulting C-centered radical with a vinyl phosphonate.31,32 The ensuing radical addition product serves as a suitable linchpin for the second step, in which a classical Horner–Wadsworth–Emmons (HWE) olefination33,34 is able to deliver the targeted allylated compounds. In order to streamline these two steps, we reasoned that a telescoped flow protocol where the reactions are performed in tandem without the need for tedious purification of intermediates would be indispensable not only to accelerate access to these valuable building blocks but also to ensure facile scalability.35–37 Herein, we report the successful realization of a flow platform enabling the allylation of a wide range of unactivated hydrocarbons.Our investigations commenced with the decatungstate-enabled hydroalkylation of ethyl 2-(diethoxyphosphoryl)acrylate (2) using cyclohexane as the H-donor (see ESI, Table S1†). Following a careful optimization of different reaction parameters, we found that the photocatalytic radical addition performed optimal in continuous-flow using a commercially available Vapourtec UV-150 photochemical reactor (PFA (perfluoroalkoxy) capillary, ID: 0.75 mm; V = 3.06 mL, flow rate = 0.612 mL min−1, tr = 5 min) equipped with a 60 W UV-A LED light source (λ = 365 nm), which matches the measured absorption spectrum of decatungstate. A 65% NMR yield (64% after isolation) was obtained for the targeted hydroalkylated compound when a CH3CN solution of the acrylate (0.1 M), cyclohexane (20 equivalents) and tetrabutylammonium decatungstate (TBADT, (Bu4N)4[W10O32]) as the photocatalyst (1 mol%)38–46 was irradiated for 5 minutes (see ESI, Table S1, Entry 9†). Other HAT photocatalysts, such as Eosin Y,47 anthraquinone,48 5,7,12,14-pentacenetetrone28 and 9-fluorenone49 were also evaluated, but failed to deliver the targeted product. Interestingly, benzophenone50,51 showed a comparable activity to the decatungstate anion, although only when used at high catalyst loading (20 mol%, 68% NMR yield). Due to the lower extinction coefficient of benzophenone compared to TBADT (<200 vs. 13 500 M−1 cm−1),52,53 and its known tendency to dimerize to form benzopinacol upon UV-A irradiation, we selected TBADT as the best photocatalyst for the targeted hydroalkylation reaction. Notably, this transformation is quite general and a diverse set of alkylphosphonates (3) could be readily isolated and characterized (see ESI, Section 7). A mechanistic study confirmed the radical nature of the process (see ESI, Section 5), where HAT is likely to occur during the rate-determining step (KIE = 1.9).Next, the obtained alkylphosphonates were subjected to the successive HWE olefination (Scheme 2). A telescoped flow approach was developed in which the two individual steps were connected in a single streamlined flow process without intermediate purification. We selected 1,3-benzodioxole (1a), a common moiety in many medicinally-relevant molecules, as the H-donor and exposed it to the photocatalytic reaction conditions. Upon exiting the photochemical reactor, the reaction mixture containing the alkylphosphonate is merged with a stream containing paraformaldehyde (3 equiv.) and lithium tert-butoxide (1.1 equiv.) in tetrahydrofuran. The combined reaction mixture is subsequently introduced into a second capillary microreactor (PFA, ID: 0.75 mm; V = 7.1 mL; tr = 5 min; T = 40 °C) and, after only 5 minutes of residence time, the targeted C(sp3)–H allylated product 4 could be obtained in 80% overall NMR yield (70% after isolation). Interestingly, the reaction performed decently also with 1 equivalent of 1a (65% NMR yield). Notably, the tactical combination of these two steps in flow results in a very efficient and operationally simple protocol, delivering these coveted scaffolds in only 10 minutes overall reaction time. As another benefit, the flow process could be readily scaled to produce 10 mmol of the desired compound 4 (1.52 g, 65% isolated yield, Scheme 2) without the need for tedious reoptimization of the reaction conditions, which is typically associated with batch-type scale up procedures.Open in a separate windowScheme 2Scope of the modular allylation of strong aliphatic C–H bonds with (deuterated) paraformaldehyde. Yields are given over two steps. For further experimental details see the SI. a For (CH2O)n: 0.23 M aldehyde and 0.084 M LiOtBu solution in tetrahydrofuran; flow rate = 0.802 mL min−1; tR = 5 min. For (CD2O)n: 0.11 M aldehyde and 0.084 M LiOtBu solution in tetrahydrofuran; flow rate = 0.802 mL min−1; tR = 8 min. b TBADT was used 5 mol%.This telescoped strategy could be subsequently applied to a wide variety of hydrogen atom donors 1 (Scheme 2). Activated substrates, such as hydrocarbon scaffolds with α-to-O C(sp3)–H bonds (5–7), were regioselectively allylated in yields ranging from 49–66% over two steps. Similarly, substrates containing α-to-S (8 and 9) and α-to-N (10–13) C(sp3)–H bonds were functionalized without difficulty (52–70% overall yield). Allylic functional groups could also be appended to activated benzylic positions (14, 32% overall yield).Finally, even strong, non-activated aliphatic C–H bonds could be readily allylated using our approach (15–19, 44–53% overall yield).To further demonstrate the potential of this operationally facile approach to introduce allylic functional groups, we wondered whether paraformaldehyde-d2 could be used in the HWE step. Such a straightforward, regioselective introduction of deuterium atoms in organic molecules would be of tremendous importance for mechanistic,54,55 spectroscopic and tracer studies.56 Using our two-step flow protocol, the analogous deutero-allylated compound 4-d2 was isolated in 68% yield, perfectly matching the result obtained for the non-deuterated version 4. Similarly, N-Boc piperidinone and N-methyl-2-pyrrolidone were competent substrates for this protocol affording the deuterated products 20 and 21 in 44% and 52% yield, respectively. Finally, in an effort to demonstrate the applicability of this method to the late-stage functionalization of medicinally relevant molecules, we subjected biologically active molecules to our two-step flow protocol: the terpenoid ambroxide (22, 40% yield) and the nootropic drug aniracetam (23, 21% yield) could be decorated with a deuterated allylic moiety.In a similar vein, we turned our attention to introduce aromatic and aliphatic aldehydes in the second step, yielding trisubstituted allylic moieties, which are particularly challenging to synthesize via traditional photocatalyzed radical allylation approaches (Scheme 1B). By exploiting our modular protocol, a virtually limitless array of substituents can be systematically introduced (Scheme 3). In most cases, prolonged reaction times were required to obtain full conversion. In particular, electron-deficient aldehydes were convenient substrates for a fully telescoped manifold, where the flow exiting the photoreactor was directly merged with a stream containing the aldehyde and the base (see e.g., 26–30, 35–40). The HWE step required 30 minutes residence time and the temperature was kept at 40 °C. We found that a range of pyridine-derived nicotinaldehydes and heteroaromatic aldehydes (35–41) were ideal substrates for this approach as well. As for electron-neutral and -rich carbonyl compounds, the HWE step required considerably longer reaction times and thus a fed-batch approach was found to be more practical (e.g., 25, 31). Here, the reaction stream exiting the photoreactor was directly dosed into a stirring solution of aldehyde and base. It is important to stress that a fully telescoped approach was still possible in these cases, however higher reaction temperature (60 °C) and a back-pressure regulator (BPR, 2.8 bar) were needed to obtain full conversion within 1 hour (e.g., 24, 33, 45). Another general observation that could be made is that the presence of ortho-substituents resulted in higher E : Z ratios (e.g., 28–31, 33 and 40).Open in a separate windowScheme 3Scope of the modular allylation of strong aliphatic C–H bonds with aromatic and aliphatic aldehydes. Yields are given over two steps. For the experimental details of the fed-batch procedure see GP4 in the ESI,† while for fully telescoped approach see GP5. a Reactions were carried out on a 0.5 mmol scale and yields refer to isolated products, E : Z ratios were measured by 1H-NMR. b Reaction performed according to GP5, but the HWE step required 60 °C, a BPR (2.8 bar) and 1 hour residence time. c Reaction time: 16 h. d Reaction performed via general procedure GP6 in the ESI.†Next, we turned to investigate different classes of hydrogen donors, such as hydrocarbons (43, 43%), (thio)ethers (44–45, 47–68%), protected amines (46, 51%) and amides (47, 55%): all proved to be competent reaction partners. In all cases, the reaction performed well, delivering densely functionalized alkenes in good yields and stereoselectivity.It is important to note that it would be extremely challenging to access either of these motifs with the current radical allylation methodologies (Scheme 1B). Unfortunately, all attempts to engage ketones in the HWE step did not afford the desired fully-substituted olefins.Interestingly, our protocol was also amenable to aliphatic aldehydes containing enolizable positions (48–52, 57–71% yield). The use of protected piperidine-4-carboxaldehydes allowed to obtain the corresponding allylated products 51 and 52 in excellent yields (60–68%) and with good diastereomeric ratios. In addition, medicinal agents and natural products containing carbonyls, such as acetyl-protected helicin, citronellal and indomethacin aldehyde derivatives, were also reactive delivering the targeted olefins in synthetically useful yields (53–55, 20–63%). This proves the potential of this strategy to rapidly diversify double bonds.Next, the importance of the ester moiety as electron-withdrawing group (EWG) in the substrates to enable the targeted transformations was evaluated (Scheme 4A). Thus, we synthesized different vinyl phosphonates (2′–2′′′) and found that all of them performed well (40–68% 1H-NMR yield) in the photocatalytic radical hydroalkylation. We then tested our streamlined process with benzaldehyde (GP4) to study the effect of the EWG on the diastereomeric ratio in the final allylated compound. The cyano group-bearing substrate furnished the targeted compound 56 with an excellent diasteroselectivity; however, a poor mass balance was observed (22% yield despite full conversion of 3′). In contrast, products 57 and 58 (EWG : COR) were not formed, with a complete recovery of 3′′ and 3′′′. Interestingly, we found that compound 2′′′′ could serve as a suitable radical trap as well (Scheme 4B). Using 1a as coupling partner, the targeted hydroalkylation product was obtained in excellent yield (3′′′′, 90% by 1H-NMR). A solvent switch and a stronger base (nBuLi, n-butyl lithium) were however required to induce the subsequent HWE step yielding styrenes 59–61 in good yields after isolation (see GP7 in the ESI†).57,58Open in a separate windowScheme 4(A) Effect of the EWG on the diasteroselectivity in the final allylated product; (B) synthesis of densely functionalized styrenes by exploiting phenyl-substituted vinyl phosphonate 2′′′′; (C) examples of further diversification of compound 4, including olefin reduction, ester reduction, Giese-type radical addition and Mizoroki–Heck coupling. a Full conversion of 3′ was observed. b Full recovery of the alkyl phosphonates.The regioselective and late-stage installation of allylic groups opens up innumerable possibilities for further diversification.13 As an illustration of this synthetic potential, we explored diverse conditions for the conversion of 4 into functionalized derivatives (Scheme 4C). The olefin and the ester functionalities could be orthogonally reduced by exploiting different reduction conditions, yielding compounds 62 (70%) and 63 (62%), respectively.59,60 Moreover, compound 4 was an ideal substrate for another Giese-type radical addition using decatungstate-photocatalyzed HAT (64, 62%). Finally, product 65 could be obtained via a classical Mizoroki–Heck-type coupling (60%).61 相似文献
3.
Stefan Andrew Harry Michael Richard Xiang Eric Holt Andrea Zhu Fereshte Ghorbani Dhaval Patel Thomas Lectka 《Chemical science》2022,13(23):7007
We report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3′-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with 19F–1H HOESY experiments, calculations, and more. We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.The hydroxy (OH) group is treasured and versatile in chemistry and biology.1 Its ubiquity in nature and broad spectrum of chemical properties make it an attractive source as a potential directing group.2 The exploitation of the mild Lewis basicity exhibited by alcohols has afforded several elegant pathways for selective functionalization (e.g., Sharpless epoxidation,3 homogeneous hydrogenation,4 cross-coupling reactions,5 among others6). Recently, we reported a photochemically promoted carbonyl-directed aliphatic fluorination, and most notably, established the key role that C–H⋯O hydrogen bonds play in the success of the reaction.7 Our detailed mechanistic investigations prompt us to postulate that other Lewis basic functional groups (such as –OH) can direct fluorination in highly complementary ways.8 In this communication, we report a hydroxy-directed aliphatic fluorination method that exhibits unique directing properties and greatly expands the domain of radical fluorination into the less established realm governing high diastereoselectivity.9Our first inclination that functional groups other than carbonyls may influence fluorination regiochemical outcomes was obtained while screening substrates for our published ketone-directed radical-based method (Scheme 1).8a In this example, we surmised that oxidation of the tertiary hydroxy group on substrate 1 cannot occur and would demonstrate functional group tolerance (directing to C11, compound 2). Surprisingly, the two major regioisomers (products 3 and 4) are derivatized by Selectfluor (SF) on C12 and C16 – indicative of the freely rotating hydroxyl directing fluorination. Without an obvious explanation of how these groups could be involved in dictating regiochemistry, we continued the mechanistic study of carbonyl-directed fluorination (Scheme 2A). We established that the regioselective coordinated hydrogen atom abstraction occurs by hydrogen bonding between a strategically placed carbonyl and Selectfluor radical dication (SRD).7 However, we noted that the subsequent radical fluorination is not diastereoselective due to the locally planar nature of carbonyl groups. Thus, we posed the question: are there other directing groups that can provide both regio- and diastereoselectivity? Such a group would optimally be attached to a sp3 hybridized carbon; thus the “three dimensional” hydroxy carbon logically comes to mind as an attractive choice, and Scheme 1 illustrates the first positive hint.Open in a separate windowScheme 1Observed products for the fluorination of compound 1.Open in a separate windowScheme 2(A) Proposed mechanism, (B) β-caryophyllene alcohol hypochlorite derivative synthetic probe, (C) isodesmic relation of transition states showing the general importance of the hydroxy group to reactivity (ωB97xd/6-31+G*), and (D) 1H NMR experiment with Selectfluor and various additives at different concentrations.We began our detailed study with a simple substrate that contains a tertiary hydroxyl group. Alcohol 5 was synthesized stereoselectively by the reaction of 3-methylcyclohexanone, FeCl3, and 4-chlorophenylmagnesium bromide;10 the 4-chlorophenyl substituent allows for an uncomplicated product identification and isolation (aromatic chromophore). We sought to determine optimal reaction conditions by examination of numerous photosensitizers, bases, solvents, and light sources (7 Although we utilize cool blue LEDs (sharp cutoff ca. 400 nm), CFLs (small amount of UVB (280–315 nm) and UVA (315–400 nm)) are useable as well.11 A mild base additive was also found to neutralize adventitious HF and improve yields in the substrates indicated ( Entry Sensitizer 19F yield 1 None 0% 2 Benzil 83% 3 Benzil, no base 63% 4 Benzil, K2CO3 68% 5 Benzil, CFL light source 75% 6 5-Dibenzosuberenone 15% 7 4,4′-Difluorobenzil 63% 8 9,10-Phenantherenequinone 71% 9 Perylene 8% 10 Methyl benzoylformate 42%