Efficient Stereoselective Carbocyclization to cis-1,4-Disubstituted Heterocycles Enabled by Dual Pd/Electron Transfer Mediator (ETM) Catalysis.

An efficient Pd/ETM (ETM = electron transfer mediator)-cocatalyzed stereoselective oxidative carbocyclization of dienallenes under aerobic oxidation conditions has been developed to afford six-membered heterocycles. The use of a bifunctional cobalt complex [Co(salophen)-HQ] as hybrid ETM gave a faster aerobic oxidation than the use of separated ETMs, indicating that intramolecular electron transfer between the hydroquinone unit and the oxidized metal macrocycle occurs. In this way, a class of important cis-1,4-disubstituted six-membered heterocycles, including dihydropyran and tetrahydropyridine derivatives were obtained in high diastereoselectivity with good functional group compatibility. The experimental and computational (DFT) studies reveal that the pendent olefin does not only act as an indispensable element for the initial allene attack involving allenic C(sp3)-H bond cleavage, but it also induces a face-selective reaction of the olefin of the allylic group, leading to a highly diastereoselective formation of the product. Finally, the deuterium kinetic isotope effects measured suggest that the initial allenic C(sp3)-H bond cleavage is the rate-limiting step, which was supported by DFT calculations.

Introduction

Six-membered heterocycles are ubiquitous core structures in various natural products, as well as in pharmacologically active substances.[1] Glucose, the monosaccharide made during photosynthesis from water and carbon dioxide, is one of the most important compounds in the life sciences.[2] α-d-glucopyranose bears the core structure of tetrahydropyran with substituents stereochemically arranged, including 1,2-, 1,3-, and 1,4-cis configurations of two different hydroxyl groups (Scheme a). The similar stereochemistry can also be found in many other natural products, such as (−)–centrolobine, ophiocerin B, (−)–brevisamide, and pyranicin.[3] For 1,2- and 1,4-disubstituted six-membered rings, a cis configuration will have one substituent in the equatorial position and the other one in the axial position, where the latter suffers from 1,3-diaxial interaction(s) with the axial C–H bond(s) (Scheme b).[4] Moreover, the distance between the two substituents in cis-1,4-disubstituted six-membered rings is much greater than that in the corresponding cis-1,2- or 1,3-disubstituted compounds, which is unfavorable for the control of its stereochemistry when the second substituent is introduced.[5] Therefore, the development of methodologies for efficient synthesis of cis-1,4-disubstituted six-membered rings, including heterocycles, is greatly challenging and highly desirable.[6]

Scheme 1

(a) Selected Natural Products Bearing the Core Structure of Six-Membered Heterocycles with 1,2-, 1,3-, or 1,4-cis Configuration. (b) Comparison of the Difficulties on the Selectivity Control for the Synthesis of cis-1,2-, 1,3-, and 1,4-Disubstituted Six-Membered Rings (X, Y = C, O, N. etc.)

Hetero-Diels–Alder reactions of carbonyl compounds or imines with conjugated dienes constitute a reliable approach toward the synthesis of six-membered heterocycles.[7] However, for the preparation of cis-1,4-disubstituted products, the reaction requires stereoisomerically pure (E,E)- or (Z,Z)-1,3-dienes (Scheme a). Moreover, hetero-Diels–Alder reactions are usually associated with problems in the control of regioselectivity.[8]

Scheme 2

(a) State of the Art and (b) This Work (X = O, NR, etc.; DG = Directing Group; M = Metal)

An alternative elegant solution for obtaining cis-1,4-disubstituted heterocycles is the utilization of transition metal-catalyzed C–H activation reactions (Scheme a). With a suitable directing group (DG) in the R group, the transannular δ-C(sp3)–H functionalization can be realized with the remote selectivity starting from preformed heterocycles.[9,10] The newly introduced functional group will then be installed on the same face of the ring as the R group via a boat-conformation intermediate. However, high-temperature conditions are generally required to overcome the energy barrier for C(sp3)–H activation.[9] Herein, we disclose an alternative efficient approach for the synthesis of cis-1,4-disubstituted heterocycles via a stereoselective carbocyclization. On the basis of our previous work,[11] we envisioned that a selective metalation of the C–H bond would produce Int-A (Scheme b) with a suitable directing/assisting substituent (RDG). Subsequent intramolecular ligand exchange from the directing group in Int-A to the remote olefin leads to intermediates Int-B and/or Int-B′, due to the re- or si-facial coordination of the olefin to the metal. Initial computations indicated that the re-facial coordination in conformation Int-B would be favored over the si-facial coordination in Int-B′ due to interactions between the R and R′ substituents in Int-B′. Surprisingly, the boatlike conformation (Int-B and Int-B′) was more stable than the corresponding chairlike conformations in both cases. Subsequent migratory insertion in the favored intermediate Int-B would generate Int-C, which further could undergo a coupling reaction to afford the corresponding cis-1,4-disubstituted heterocycle as the major product. The corresponding reaction of the less favored intermediate Int-B′ would give the trans-1,4-disubstituted heterocycle Int-C′. In this overall transformation, both the ring-closing reaction and the installation of a new functional group (FG) can be efficiently realized in a one-step manner.

Results and Discussion

A carbon–carbon double bond is a basic yet crucial functional group in organic chemistry.[12] It has been found as a useful directing group in organic transformations, for example, in C–H activation reactions.[13] Moreover, the alkene bond can be diversely transferred to many other functional groups, or easily reduced via hydrogenation.[14] In a previous study, we found that the pendent olefin unit is an indispensable element for the subsequent allene attack via C(sp3)–H bond cleavage (Scheme a).[11] Therefore, an olefin unit was introduced on the enallene moiety and evaluated as a directing group in the carbocyclization reaction (Scheme b). Our initial attempts began with the coupling reaction of dienallene 1a with phenylboronic acid (2aa) under the catalysis of palladium with BQ (p-benzoquinone, 1.1 equiv) as the oxidant. Interestingly, the reaction in THF at room temperature (r.t.) for 5 h afforded the cyclic product 3a in 72% yield, while the direct phenylation product 4a was obtained only in 5% yield. Interestingly, the dihydropyran product 3a was generated in high diastereoselectivity (d.r. = 18:1). From NOE studies of dihydropyran 3a, it was found that the major stereoisomer is the product with cis-1,4-disubstitution.

Scheme 3

(a) Previous Studies and (b) Initial Attempts for this Work

With these initial results in hand, we turned to optimizing the reaction conditions. In the oxidation reactions, the goal was to use environmentally benign oxidants, such as molecular oxygen.[15] However, direct reoxidation of Pd(0) by molecular oxygen is expected to be unfavored due to the high-energy barrier for electron transfer under the reaction conditions of the carbocyclization.[16] Indeed, the attempted palladium-catalyzed oxidative reaction of 1a using molecular oxygen as the only oxidant without any additives did not give any of the product 3a or 4a, and the starting material 1a was recovered in 79% yield (Table , entry 1). A solution to this problem is to add various established electron transfer mediators (ETMs), including metal macrocyclic complexes and BQ to improve the reoxidation efficiency.[16,17] To our delight, in the presence of BQ (10 mol %) and catalytic amount of Fe(Pc) (Pc = phthalocyanine), a 14% yield of dihydropyran 3a was obtained with an 18:1 d.r., while 1a was recovered in 50% yield (Table , entry 2). The employment of Co(Pc) in place of Fe(Pc) led to a decrease of the yield of 3a to 7% (Table , entry 3). Co(salophen) (5 mol %) together with BQ (10 mol %) showed slightly higher efficiency in this oxidative carbocyclization with formation of 3a in 15% yield (d.r. = 18:1) and recovery of dienallene 1a in 60% yield (Table , entry 4). Replacing BQ by HQ (hydroquinone) resulted in a lower yield of 3a (4%) (Table , entry 5). Interestingly, the use of a hybrid catalyst Co(salophen)-HQ,[18] in which metal-macrocycle Co(salophen) (ETM1) and two quinone moieties (ETM2) are merged into one molecule, significantly improved the yield of the desired product 3a to 45% (Table , entry 6). This improvement is probably due to the higher efficiency of the intramolecular electron transfer in the bifunctional cobalt catalyst [Co(salophen)-HQ], compared to that of the two separate ETMs in entry 5. Unfortunately, in this case, side product 4a was also formed in 31% yield, implying a poor chemoselectivity during the reaction. Replacing phenylboronic acid by triphenyl boroxine did not lead to any improvement (entry 7). However, the chemoselectivity toward the formation of 3a was dramatically improved by replacing phenylboronic acid by its neopentylglycol ester (PhBneo) as the arylating reagent (entry 8 vs entry 6). Similarly, PhBpin also showed good reactivity and selectivity albeit in slightly lower yield (46%, entry 9). Notably, stoichiometric amounts of H2O significantly favored the transformation of dienallene 1a to afford 3a and 4a (Table , entries 10–12).[19] When 2 equiv of H2O was added to the reaction mixture, the yield of 3a was further improved up to 75%, along with the phenylated product 4a in 15% yield (Table , entry 12). Finally, by increasing the catalyst loading of Co(salophen)-HQ to 10 mol %, an optimal yield (85%) of 3a was obtained in the presence of 1 equiv of H2O, while side product 4a was kept as low as 8% yield (Table , entry 13).

Table 1

Optimization of the Reaction Conditionsa

Unless otherwise noted, the following reaction conditions were employed: 1a (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv), Pd(OAc)2 (5 mol %), ETM1 (5 mol %), ETM2 (10 mol %), in 0.2 M THF, O2 (balloon, 1 atm) at room temperature (23 °C) for 24 h. Yields and conversions were determined by 1HNMR using anisole as internal standard.

H2O (0.5 equiv) was added to the reaction mixture.

H2O (1.0 equiv) was added to the reaction mixture.

H2O (2.0 equiv) was added to the reaction mixture.

The reaction was run with 10 mol % of Co(salophen)-HQ for 36 h.

Next, the catalytic reaction under aerobic conditions (1 atm of O2) at r.t. with different electron transfer mediators (ETMs) was examined using [5 mol % Co(salophen) + 10 mol % HQ], [5 mol % Co(salophen) + 10 mol % BQ], or [5 mol % Co(salophen)-HQ] in the presence of 5 mol % Pd(OAc)2 (for details of the reaction conditions, see entries 4–6 in Table ). As shown in Figure , the reaction with hybrid catalyst Co(salophen)-HQ resulted in a much higher reaction rate compared to the reaction with separate use of Co(salophen) and HQ (or BQ). These results indicate that an intramolecular electron transfer between the hydroquinone unit and the oxidized metal macrocycle occurs in bifunctional hybrid catalyst Co(salophen)-HQ.

Figure 1

Comparison of catalytic efficiency of different electron transfer mediators (ETMs). Reaction conditions: The reaction was conducted at 25 °C in THF (0.5 mL) with 1a (0.1 mmol), PhBneo (0.13 mmol), and H2O (0.1 mmol) in the presence of Pd(OAc)2 (5 mol %) and ETM(s) under atmosphere of O2.

With the optimal reaction conditions in hand, we turned to investigating the substrate scope of this stereoselective carbocyclization reaction (Scheme ). First, arylboronic acid neopentylglycol esters with a range of substituents in the meta-position of the benzene ring were examined: the meta-analogues with electron-donating substituents, such as Me and MeO, reacted smoothly in high diastereoselectivity (16:1 to 18:1). Substrates bearing electron-withdrawing functional groups in the meta-position, including F and Cl worked equally well, affording the corresponding products 3d and 3e in 74 and 69% yields, respectively. Moreover, substituent effects in the para-position were also studied: functional groups, including Me, Cl, Bu, Br, acetyl, and vinyl groups, in the para-position of the benzene ring of arylboronic acid neopentylglycol esters led to the corresponding products 3f–3k in good yields (54–82%). A higher diastereoselectivity was observed when a 2-naphthylboronic acid neopentylglycol ester was used, which afforded dihydropyran 3l in a d.r. of 20:1. Furthermore, cycloalkylidene allenes could also be employed, yielding products 3m and 3n in 83 and 75% yields, respectively. The substituent on the allene moiety (R1) can not only be an aliphatic group (R1 = Me, Bn, or Cy), but also be an aromatic group (R1 = Ph), and the corresponding dihydropyran derivatives 3o–3r were obtained in 67–84% yields accordingly. Functional groups, such as an ester, an ether, and an imide were nicely tolerated under the catalysis of Pd and Co(salophen)-HQ, yielding products 3s–3u in 41–68% yields. Not only can a terminal olefin act as the directing/assisting group, but also an internal olefin was found to promote the reaction as shown by the formation of products 3v and 3w in 80 and 53% yields, respectively. When a phenyl group was introduced on the distal olefin (R3 = Ph), the corresponding dihydropyran 3x was obtained in 35% yield. Finally, this stereoselective carbocyclization was successfully extended to the synthesis of a tetrahydropyridine derivative 3y.

Scheme 4

Substrate Scope

Enzymatic kinetic resolution (EKR) provides an efficient and scalable method for the preparation of chiral secondary alcohols.[20] EKR of α-allenol 5a catalyzed by CALB (Candida antarctica lipase B) afforded 48% yield of chiral α-allenic acetate (R)-6a with 95% ee on a 1 g scale (Scheme ).[23] Meanwhile, chiral α-allenol (S)-5a was recovered in 46% yield with 99% ee. O-allylation of (S)-5a and subsequent stereoselective carbocyclization under the catalysis of palladium led to the chiral dihydropyran (R,S)-3a in 72% yield (from (S)-5a), with 92% ee and 18:1 d.r. using stoichiometric BQ as oxidant.

Scheme 5

Synthesis of Chiral Product (S)-5a by Using Enzymatic Kinetic Resolution

We believe that the erosion of the ee occurs in the carbo-cyclization step (second step) of the reaction sequence in Scheme .[21] This was supported by the observation that when the conditions of Scheme were used for the carbocyclization, only 81% ee of (R,S)-3a was obtained.[22]

Next, to demonstrate the diversity of this stereoselective carbocyclization reaction, enallenyne 7, bearing the moiety of an internal alkyne, was employed under aerobic oxidative conditions. The corresponding dihydropyran product 8 was isolated in 55% yield, indicating a selective arylating carbocyclization during the reaction (Scheme a). To further confirm the effect of the pendent olefin group in dienallene 1, we carried out comparative experiments using enallene 1a′, in which the vinyl group in 1a had been replaced by an ethyl group (Scheme b). Attempted reaction of 1a′ under standard conditions for 36 h did not give any product, and neither the pyran derivative 3a′ nor the triene product 4a′ could be detected. The starting material 1a′ was recovered in 95% yield. This result indicates that the pendent olefin is an indispensable element for the overall transformations.[11] Under the standard reaction conditions, direct phenylated product 4a″ was obtained in 71% yield by using enallene 1a″, in which the distal vinyl group in 1a had been replaced by a phenyl group (Scheme c). This observation again shows the importance of the pendent olefin for the initial activation of the allene via C(sp3)–H bond cleavage.[11]

Scheme 6

Mechanistic Studies

To gain a deeper insight into the mechanism of this stereoselective carbocyclization reaction, the deuterium kinetic isotope effects (KIE) were studied.[24] An intermolecular competition experiment was carried out using a 1:1 mixture of dienallene 1a and d6-1a at r.t. for 160 min in the presence of stoichiometric amounts of BQ (eq 1, Scheme ). The product ratio 3a/d5-3a (ca. 20% conversion) was measured as 3.5:1. From the product ratio and the reaction conversion, the competitive KIE for this reaction was determined to be kH/kD = 4.7.[25] Moreover, two parallel experiments with 1a and d6-1a gave the same level of KIE (kH/kD from initial rate) value of 4.7 (eqs 2 and 3, Scheme ). These observed kinetic isotope effects indicate that the allenic C–H bond cleavage is the rate-limiting step. The large competitive isotope effect in the allenic C–H bond cleavage (kH/kD = 4.7) requires that this step is the first irreversible step.

Scheme 7

Kinetic Isotope Effects

To gain a better insight into the role of the pendent olefin[11,26] and the origin of the stereoselectivity, we performed density functional theory (DFT) calculations with the dispersion-corrected B3LYP functional (see Supporting Information for computational details) using substrate 1o (R = Me) as a representative case. On the basis of the DFT calculations (Figure ), the catalytic cycle for the reaction shown in Scheme is proposed.[27] The reaction starts with the dissociation of the Pd(II) acetate trimer to monomer, to which 1o coordinates, giving Int-1.[11,28] The lowest-energy binding mode is found to be the coordination of the allene moiety and the pendent olefin of 1o (see the Supporting Information for optimized structures). The energy of Int-1 is calculated to be 12.5 kcal/mol relative to the Pd(II) acetate trimer (Figure a). To proceed, the allenic C(sp3)–H bond cleavage via transition state TS-1 can then take place, generating Int-2. The activation barrier of TS-1 is calculated to be 8.8 kcal/mol relative to Int-1, i.e., 21.3 kcal/mol relative to the Pd(II) acetate trimer, which constitutes the rate-determining barrier of the reaction (Figure a).[29] This is consistent with the above KIE experiments for substrate 1a (Scheme ), showing that this step is the rate-limiting step.[30] This step is also the first irreversible step of the reaction as can be seen from Figure . In addition, the calculated KIE for the C–H cleavage step from DFT calculation is 3.3, which is consistent with the large competitive isotope effect measured (kH/kD = 4.7).

Figure 2

(a) Calculated free energy profile (kcal/mol) and (b) optimized structures of carbocyclization transition states for the Pd-catalyzed stereoselective carbocyclization. Bond distances are in Å.

Scheme 8

Proposed Mechanism

It is interesting to mention that the allenic C(sp3)–H cleavage transition state TS-1′, in which the distal olefin of 1o is coordinated to palladium in place of the pendent olefin, was also located (see the Supporting Information for details). The barrier of TS-1′ was calculated to be 11.1 kcal/mol higher in energy than that of TS-1, i.e., 32.4 kcal/mol relative to Pd(II) acetate trimer. This result is consistent with the fact that C(sp3)–H cleavage does not occur if the pendent olefin is removed.[11]

Direct coupling of Int-2 with arylboronic acid neopentylglycol ester gives side product 4. In the major pathway, the coordination to the palladium ion is changed from the pendent olefin to the distal olefin to form Int-3c, which is calculated to be 9.1 kcal/mol higher in energy than Int-2. Subsequent carbocyclization via transition state TS-2c (Figure b) is shown to take place, giving six-membered ring intermediate Int-4c, which leads to the formation of product 3o through transmetalation and reductive elimination steps.[31,32] The activation energy of TS-2c is calculated to be 15.7 kcal/mol relative to Int-2 (Figure a). Finally, the released Pd0 is reoxidized to PdII by the intramolecular ETM system with molecular oxygen as the terminal oxidant, which closes the catalytic cycle (Scheme ).[33] These reoxidation steps were not explicitly studied by the current calculations.

Importantly, we also considered the formation of the trans-isomer of 3o via the carbocyclization transition state TS-2t, which is calculated to be 2.6 kcal/mol higher in energy than TS-2c. This result is consistent with the experimental finding that the cis-isomer 3o is the main product for this palladium-catalyzed carbocyclization. By scrutiny of the optimized structures of TS-2c and TS-2t, one source of the energy differences could be identified as being the steric repulsion of the pendent olefin with the methyl moiety (Figure b). This interaction appears in TS-2t, but not in TS-2c, resulting in the higher energy of the former.

It is interesting to mention that other carbocyclization transition states, where the forming ring adopts a more chairlike conformation, were also located (see Supporting Information, Figures S8 and S9). However, these transition states were calculated to be more than 4 kcal/mol higher in energy than the TS-2c and can therefore be ruled out as feasible conformations for the cyclization.

Conclusions

In conclusion, we have developed an efficient Pd/ETM-cocatalyzed stereoselective carbocyclization of dienallenes under aerobic oxidation condition that provides access to important cis-1,4-disubstituted six-membered heterocycles. The bifunctional cobalt catalyst [Co(salophen)-HQ] showed high efficiency in this oxidative reaction where molecular oxygen serves as the terminal oxidant. The pendent olefin was shown to be an indispensable element by comparative experiments, and its role is not only to trigger the initial allenic C(sp3)–H bond cleavage but also to control the stereochemical outcome of the carbocyclization as confirmed by the DFT calculations. Dihydropyran and tetrahydropyridine derivatives with cis-1,4-disubstitution were obtained in high diastereoselectivity. The studies on the kinetic isotope effects, both in competition and in parallel experiments show that the initial allenic C(sp3)–H bond cleavage is the first irreversible step and also the rate-limiting step as confirmed by the DFT calculations. The second chiral center in the product was successfully induced by the preformed chiral center in the dienallene, which was obtained via enzymatic kinetic resolution. This methodology provides a novel synthesis of cis-1,4-disubstituted six-membered heterocycles, with potential applications in the synthesis of natural products and pharmacologically active substances.