A Dual CuH- and Pd-Catalyzed Stereoselective Synthesis of Highly Substituted 1,3-Dienes

Abstract

Conjugated dienes are versatile building blocks and prevalent substructures in synthetic chemistry. Herein, we report a method for the stereoselective hydroalkenylation of alkynes, utilizing readily available enol triflates. We leveraged an in situ-generated and geometrically pure vinyl-Cu(I) species to form the Z,Z- or Z,E-1,3-dienes in excellent stereoselectivity and yield. This approach allowed for the synthesis of highly substituted Z-dienes, including pentasubstituted 1,3-dienes, which are difficult to prepare by existing approaches.

Graphical Abstract

Conjugated dienes are prevalent structural elements present in numerous biologically active small molecules^1–3 and constitute a major feedstock for industrial polymer production.^4,5 Because of their unique chemical reactivity, 1,3-dienes are versatile building blocks with the potential to form new C–C and C–heteroatom bonds at all four encompassing carbons.⁶ The utility of conjugated dienes has been demonstrated in a variety of critical synthetic processes, including cycloadditions,^7,8 hydrofunctionalizations,^9–13 and difunctionalizations.^14–17 The stereochemical outcome of these methods is typically influenced by the olefin geometry of the 1,3-diene substrate.^8,14,17 Accordingly, methods to access substituted 1,3-dienes in a stereoselective manner are paramount for their use in fine chemical synthesis.^6,18 While various methods exist for the synthesis of E,E-dienes,^18–20 a general, highly stereoselective process to produce Z-dienes is desirable.

Due to the utility of 1,3-dienes in organic synthesis, a variety of strategies to access these compounds have been developed.^6,18 Olefination of carbonyl compounds with stoichiometric allyl nucleophiles has been widely employed in the synthesis of conjugated dienes;^21–28 however, the products are generally obtained as inseparable E/Z mixtures (Figure 1A).^28,29 Although considerable advances have been made toward stereoselective olefination of carbonyl substrates, most methods to access 1,3-dienes result in the E,E-isomer.^20,26,28,30 To avoid the formation of isomeric product mixtures, transition-metal-catalyzed cross-coupling utilizing preformed organometallic reagents and vinyl (pseudo)halides has emerged as a practical route to stereoselectively synthesize dienes (Figure 1B).^31–36 In these processes, the geometry of the diene product is dictated by the stereochemistry of the coupling partners. Complementary approaches to prepare 1,3-dienes, including C–H activation of olefin starting materials,^37,38 rearrangements of allenes or alkynes,³⁹ and ene-yne metathesis of acyclic precursors,^40,41 have also been developed.^42,43

Figure 1.

(A) Olefination employing stoichiometric allylation reagents. (B) Cross-coupling of vinyl-metal species with stereodefined coupling partners. (C) Proposed dual CuH- and Pd-catalyzed alkyne hydroalkenylation. (D) Potential undesired reactions.

Our group and others have demonstrated the potential of CuH-catalyzed hydrofunctionalization reactions to enable unsaturated substrates to serve as surrogates for preformed organometallic reagents.^44,45 Hydrocupration of an olefinic precursor results in a catalytically generated Cu(I) species [I (Figure 1C)] that can engage in bond-forming reactions with a range of electrophiles, including carbonyls,^46,47 heterocycles,^48,49 and LPd(II) complexes.^50–53 However, the equivalent transformations employing alkyne pronucleophiles have been underexplored.^54–62 Recently, we developed a dual CuH- and Pd-catalyzed hydroalkenylation of olefins (Figure 1C), employing widely available enol sulfonates to synthesize highly substituted α-chiral olefins.⁵³ We reasoned that an analogous approach to generate the otherwise elusive Z,E- and Z,Z-1,3-dienes could be realized by exploiting the syn-selective hydrocupration of alkynes and the rapid transmetalation of a vinyl-Cu(I) species (II) with an LPd(II)-alkenyl complex.⁶³ We anticipated several specific challenges for the dual-catalytic alkyne hydroalkenylation (Figure 1D). It was evident that the 1,3-diene products are competent substrates for hydrofunctionalization reactions. Subsequent reduction,^44,45 isomerization, or oligomerization reactions of the conjugated diene product were also conceivable. Hydrolysis or reduction of the enol triflate to generate the corresponding olefin is also possible. We reasoned that tuning the rates of the catalytic cycles (e.g., hydrocupration, oxidative addition, and transmetalation) would be crucial to suppress off-cycle reactivity and enabling construction of the C–C bond at the resulting diene 2 position.⁵³

We focused on developing a set of dual-catalytic conditions for the stereoselective alkyne hydroalkenylation, using 1-phenyl-1-hexyne (1a) as a model substrate and 1-cyclohexenyl trifluoromethanesulfonate (2a) as the alkenyl coupling partner (Table 1).⁶⁴ Utilizing our previously described reaction conditions for olefin hydroalkenylation,⁵³ we observed the Z-diene (3a) in moderate yield (entry 1, 33% yield, as determined by ¹H NMR). Contrary to our olefin hydroalkenylation process, which was ineffective at room temperature,⁵³ we found that conducting the alkyne hydroalkenylation at room temperature resulted in moderate yield of 3a (entry 3). As hydrocupration of a vinyl arene and 1a readily occurs at room temperature, this dichotomy may arise from the more facile transmetalation of a vinyl-Cu(I) species (II) to a LPd(II) complex, relative to I.⁶³ However, 45 °C was identified as the optimal temperature for the formation of the diene product (entries 1–4). Although similar results were seen with a vinyl bromide (2b), as compared with 2a, the use of the corresponding vinyl iodide (2c) or enol tosylate (2d) was less effective (entries 5–7) and resulted primarily in reduction of the alkenyl coupling partner. Increasing the reaction concentration resulted in an improved yield of 3a (entries 8 and 9). Examination of alternative solvents, ancillary ligands for Cu or Pd, and Cu salts did not improve the yield of 3a (see Tables SI1 and SI2 for details). When the reaction was performed in the absence of a Pd or Cu catalyst, a trace of product or no product was observed, respectively (see Table SI3).

Table 1.

Optimization of the Stereoselective Hydroalkenylation of Alkynes^a

^aReaction conditions: 0.2 mmol of alkyne (1a), alkenyl coupling partner (2) (0.3 mmol, 1.5 equiv). Yields were determined by ¹H NMR spectroscopy of the crude reaction mixtures, using 1,3,5-trimethoxybenzene as an internal standard.

With our optimized protocol for the synthesis of 1,3-dienes, we sought to explore the range of alkynes that could be utilized in this transformation (Scheme 1). When 2a was employed with 1-phenyl-1-hexyne or diphenyl acetylene, the corresponding dienes (3a and 3i) were accessed in good yield with excellent Z selectivity (>20:1 Z:E). A variety of heteroarylcontaining Z-dienes could be prepared with excellent selectivities, including a thiophene (3b), a quinoline (3d), a pyrrole (3h), and an indole (3f). A thiazole containing diene (3g) was the only product for which the E-isomer was detected (2.3:1 Z:E). An ester (3c) was tolerated under the reaction conditions; however, a diethyl acetal was hydrolyzed to the corresponding aldehyde (3e) upon isolation. When unsymmetrical diaryl alkynes were subjected to the reaction conditions, regioisomeric mixtures of diene products were observed (3j and 3k). An electron-deficient 1-aryl alkyne resulted in the expected 1,3-diene (3k) in conjunction with isomer 3l. This isomerized product may arise from a subsequent hydrocupration, to form an allyl-Cu(I) species, followed by β-hydride elimination. A series of 1-silyl-substituted acetylenes, including -TMS and -TIPS, did not result in the diene adduct (3), although a -TES-substituted butadiene (3m) was formed as a minor product, favoring hydride addition β to silicon.⁶⁵ This regiochemical reversal is likely due to stereoelectronic effects exerted by the nearby silicon atom, increasing cationic character at the β position.⁶⁶ When a 1,2-dialkyl alkyne, 4-octyne, was employed as a substrate in the alkyne hydroalkenylation process, only reduction of 2a was observed (see Scheme SI1). This result can possibly be attributed to the more challenging hydrocupration of 1,2-dialkyl alkynes, relative to 1-aryl-2-alkyl alkynes.⁵⁴

Scheme 1. Substrate Scope of Alkyne Coupling Partners^a.

^aAll yields represent the average of at least two isolated yields of reactions conducted with 0.5 mmol of alkyne (1); the corresponding enol triflate was used unless otherwise noted. The yields in parentheses were determined by ¹H NMR spectroscopy of the crude reaction mixtures using 1,1,2,2-tetrachloroethane as an internal standard. The position of the minor regioisomer is denoted by a 1. ^bThe corresponding propargylic diethyl acetal was utilized. ^cIsolated as a 2.3:1 Z:E mixture. ^dIsolated separately from 3k.

The scope with respect to the enol triflate coupling partner was evaluated with a selection of differentially substituted alkynes, as depicted in Scheme 2. A range of alkenyl groups, including benzo-fused (3q), heterocyclic (3p and 3r), and acyclic (3u and 3v) groups, could be appended to the 2 position of the resulting diene. Pentasubstituted 1,3-dienes, such as 3n and 3u, could be prepared with high yield and selectivity (>20:1 Z:E). A variety of functional groups were tolerated in this process, including nitriles (3o and 3q), carbamates (3o and 3x), a tertiary amine (3r), and a ketal (3w). While an alkyne with an unprotected alcohol was a suitable substrate (3s), the corresponding benzyl ether resulted in the 1,3-diene product in improved yield (3t), with 42% and 74% yields, respectively. Despite their increased steric hindrance, acyclic enol triflates enabled access to 3u and 3v in excellent yield and selectivity. Heterocycles such as quinoline (3o), pyridine (3u and 3x), pyrimidine (3v), and indole (3p) were effectively converted to the corresponding Z-dienes. Pharmaceutical derivatives, including a substituted loratadine (3x) and a steroid-derived triene (3y), are readily prepared via this method. A sterically congested α-spirocyclic vinyl bromide resulted in a 4:1 regioisomeric mixture of products (3w), which is in accord with our previous observations.⁵³ Despite olefins and dienes being suitable substrates for hydrofunctionalization reactions, no subsequent dimerization or oligomerization of the products was observed.

Scheme 2. Substrate Scope of Stereoselective Hydroalkenylation of Alkynes with Various Enol Triflate Coupling Partners^a.

^aAll yields represent the average of at least two isolated yields with 0.5 mmol of alkyne (1); the corresponding enol triflate was used unless otherwise noted. The position of the minor regioisomer is denoted by a 1. ^bThe corresponding vinyl bromide was used.

To further demonstrate the utility of this alkyne hydroalkenylation method, we conducted the process on a gram scale (eq 1). Using a commercially available alkyne (1b) and enol triflate (2a), diene 3i could be isolated in 86% yield and high selectivity (>20:1 Z:E).

(1)

In summary, we have developed a highly stereoselective process to prepare substituted Z-1,3-dienes, employing widely available alkynes and enol triflates. Instead of relying on conferring the olefin geometry of the starting material to the product, we leverage an in situ-generated and geometrically pure vinyl-Cu(I) species to access exclusively Z-conjugated dienes. The reaction conditions tolerated numerous important functional groups and enabled the synthesis of highly substituted 1,3-dienes, including pentasubstituted dienes, which are difficult to prepare by complementary strategies.