Catalytic Enantioselective Synthesis of β-Allenyl Boronic Esters by Conjunctive Cross-Coupling with Propargylic Carbonates

Abstract

Enantioselective conjunctive cross-coupling with propargylic carbonates affords (β-boryl allenes as the reaction product. The reaction is found to proceed through the intermediacy of dimethoxyboronate complexes that are generated in situ by a strain-induced ligand exchange reaction.

Graphical Abstract

Allenes are unique functional groups in organic chemistry.¹ Because they can be stereogenic and possess two independent sites of unsaturation, allenes can engage in a range of distinctive complexity-generating chemical transformations. For these reasons, functionalized allenes can be employed as specialized organic reagents for chemical synthesis,² in addition to being critical components of important natural products.³ While a number of methods allow for construction of simple allene-based compounds,⁴ catalytic methods that allow production of fully-substituted allene groups⁵ are less developed. Collectively, these features inspired us to consider whether catalytic conjunctive cross-coupling reactions that have been under development in our laboratory^6,7 might be employed to construct allene-containing organoboron compounds. Herein, we demonstrate that a novel strain-driven boronic ester exchange reaction can modify the reactivity of organoboron ‘ate’ complexes and facilitate an enantioselective conjunctive cross-coupling to furnish β-boryl allenes. Of note, the compounds that arise from this process have not been accessible from asymmetric catalysis and should have use in chemical synthesis.⁸

To address the problem of allene construction under the manifold of metallate-shift based conjunctive coupling, we considered the use of propargylic electrophiles (Scheme 1).⁹ In this process, oxidative addition of Pd(0) to the propargylic electrophile (2) was expected to furnish a Pd(II) allenyl complex. Since the allenyl/propargyl ligand adopts the η³-propargyl binding mode (i.e. A) in related diphosphine Pd(allenyl) complexes,¹⁰ a critical question in regards to reaction design is whether the coordinatively-saturated Pd center in A can readily convert to the η¹ bonding mode and activate alkenylboronate reactant 1 via structure B. Of relevance, related diphosphine Pd(allyl) complexes do not readily participate in metallate shift-based reactions, likely because the (η³-allyl)Pd(diphosphine) complex lacks a coordination site required for binding to alkene 1.¹¹ Thus, the reactivity of complex A with ate complex 1 was uncertain. Should complex A be able to bind compound 1, it was expected that catalyst-induced metallate shift (B) might provide a route to allenylboronic ester 3.

Scheme 1.

Conjunctive Cross-Coupling with Propargylic Electrophiles

Examination of the reactivity of propargylic electrophiles in conjunctive coupling commenced with the reaction between propargylic acetate 2 and boronate complex 1 in the presence of Pd(OAc)₂ and Mandyphos¹² ligand L (Scheme 1 for structure). This experiment provided coupling product 3 enantioselectively, as well as enyne 4 (Table 1, entry 1). In an effort to increase conversion of 1 to 3 the amount of substrate 2 was increased (entry 2). However, this approach resulted in a decrease in the yield of coupling product 3, along with an increase in elimination product. We considered that enyne 4 may arise from β-hydrogen elimination of a propargyl(Pd) complex, and that subsequent reductive elimination to regenerate the Pd(0) catalyst would release acetic acid which might destroy 1. To counter this effect, a propargylic carbonate was employed such that the elimination side reaction would furnish an alcohol which should be compatible with the “ate” complex. Indeed, employing a propargylic methyl carbonate in the conjunctive coupling furnished an increased yield of 3 relative to the reaction with an acetate leaving group (cf. entries 1 and 3), and increasing the amount of the electrophile led to attendant increases in the yield of 3 (entries 3–6). Of note, in addition to increased reaction yield, the reaction of the methyl carbonate occurred with increased enantioselectivity, suggesting that the presence of methanol may have a beneficial effect on the reaction. To probe this hypothesis, two equivalents of methanol were added to a conjunctive coupling of the methyl carbonate derivative 2b, and this resulted in a significant enhancement in both the yield and selectivity of the coupling reaction (cf. entries 3 and 7). Moreover, addition of increased amounts of methanol led to increased yields and selectivity (entries 8, 9). Notably, the effect of the alcohol additive is dependent upon the alcohol structure as ascertained by the data in entries 10–13.

Table 1.

Effect of Reaction Conditions on the Conjunctive COupling with Propargylic Carbonate 2.^a

entry	X (equiv)	additive	3 (%)	4 (%)	er 3
1	OAc (1.2)	none	40	66	90:10
2	OAc (2)	none	24	140	90:10
3	OCO2Me (1.2)	none	45	30	92:8
4	OCO2Me (2)	none	60	132	93:7
5	OCO2Me (3)	none	83	200	93:7
6	OCO2Me (4)	none	85	300	92:8
7	OCO2Me (1.2)	MeOH (2)	69	80	95:5
8	OCO2Me (1.2)	MeOH (4)	83b	45	96:4
9	OCO2Me (1.2)	MeOH (6)	86	28	97:3
10	OCO2Me (1.2)	EtOH (4)	77	72	95:5
11	OCO2Me (1.2)	2-BuOH (4)	44	93	91:9
12	OCO2Me (1.2)	CF3CH2OH (4)	69	55	98:2
13	OCO2Me (1.2)	PhOH (4)	20	58	96:4

^(a)Yields are by ¹H NMR versus an internal standard, yield in parentheses is after isolation. For entry 7, yield is of the derived alcohol; for the others, yield is of the boronic ester. Enantiomer ratio of derived alcohol was determined by SFC analysis on a chiral stationary phase and in comparison to authentic enantiomer mixture. Diastereomer ratio determined by analysis of the ¹H NMR spectrum.

^(b)Yield for this experiment is after isolation and purification by column chromatography.

To understand the role of alcohol additives on the conjunctive coupling reaction, alkenyl boronate complex 1 was treated with 4 equiv of methanol in THF-d₈ at 60 °C (Scheme 2, eq. 1). Analysis of this reaction by ¹H NMR spectroscopy showed that an equilibrium was rapidly established (within 15 minutes) wherein the pinacol ligand of “ate” complex 1 was replaced with methoxide groups, furnishing complex 5 in 68% conversion (eq. 1). In contrast to the reaction of four-coordinate ate complex 1, treatment of PhB(pin) (6) with methanol did not lead to any detectable ligand exchange (eq. 2); as expected, treatment of PhB(OCH₃)₂ (7) with pinacol led to quantitative formation of PhB(pin) (eq. 3). Collectively, these experiments show that the four-coordinate boronic ester-derived “ate” complexes do not follow the well-known preference for three-coordinate boronic esters to bind pinacol in place mono-ols.¹³ The unexpected ligand exchange that occurs in eq. 1 may arise as a mechanism to relieve steric effects that penalize compound 1 relative to 5. In line with this hypothesis and in opposition to the ligand preferences observed with three-coordinate boronic esters, compound 1 also undergoes ligand exchange with the less hindered neopentyl glycol to furnish the ate complex 8 (69% conversion, eq. 4).¹⁴

Scheme 2.

Exchange Equilibria in Four-Coordinate Versus Three-Coordinate Organoboron Compounds.

Collectively, the data above suggests the conjunctive coupling of propargylic carbonates in the presence of alcohols may occur by the catalytic cycle in Scheme 3 wherein, subsequent to oxidative addition of Pd(0) to the propargylic carbonate, the resulting Pd(allenyl) complex A associates with a dimethoxyboron “ate” complex (C) to give π-complex B. The ensuing metal-induced metallate rearrangement and reductive elimination furnishes the dimethyl boronic ester D, which undergoes transesterification to give the pinacol-derived product. Of note, the ligand exchange process that occurs during catalysis¹⁵ appears to enable an efficient and selective reaction of boron “ate” complex C, a structure that is not readily accessed in a stoichiometric fashion by alternate synthesis routes because of the lability of the methoxy groups.

Scheme 3.

Proposed Mechanism for the Alcohol-Assisted Pd-Catalyzed Conjunctive-Coupling of Propargyl Carbonates.

With an understanding of the features relevant to catalysis, we examined the scope of the conjunctive coupling with propargylic carbonates. As shown in Scheme 4, a broad range of alkyne substituents are accommodated in the reaction, including simple substituted arenes (compounds 9-13) as well as furan and pyridine heterocycles (14-15). In addition to arene migrating groups (compounds 17-20, 22), aliphatic groups such as cyclopropyl (21), n-alkyl (27), and secondary alkyl groups (28) participate, although for more effective reaction, trifluoroethanol was employed in place of methanol when aliphatic migrating groups were employed. Most notably, useful functional groups such as alkenes (23, 25, 32, 36), alkynes (26), alkyl ethers (29), and silyl ethers (30) are also unmodified during the course of the reaction. One current limitation of this process is that propargylic carbonates bearing simple aliphatic chains react in low yield (31); however, inclusion of an electron-withdrawing group (29, 30) or sp²-hybridized carbon (25, 32) provides sufficient substrate activation to allow facile reaction.

Scheme 4.

Catalytic Enantioselective Conjunctive-Coupling Reaction with Propargylic Carbonate Electrophiles.

(a) For these substrates trifluoroethanol was used in place of methanol.

The reactions of allenes are diverse, making them useful tools for chemical synthesis. Considering the importance of pyran and pyrone ring systems in the structures of many bioactive natural products,¹⁶ we were particularly interested to examine cyclization reactions of the hydroxylated allenes prepared as part of this study. It was found that for one substrate spontaneous cyclization occurred during product isolation (i.e. 37, eq. 5); however, this was not observed with

(5)

(6)

other compounds in Scheme 3. For those that did not engage in cyclization directly, efficient conversion of the γ-hydroxy allene to the derived pyran could be accomplished by treatment with an in situ prepared cationic gold catalyst at room temperature for 3 hours (38, 39, eq. 6).¹⁷

In summary, we have established that the catalytic conjunctive coupling of propargylic carbonates can be an efficient enantioselective route to fully substituted allenes bearing an adjacent boron-containing stereocenter. This reaction appears to benefit from alkoxy group exchange of the boron “ate” complex during the course of the catalytic reaction. Further studies in regards to chemical synthesis using these processes is in progress.