Synthesis of Alkenyl Boronates from Epoxides with Di-[B(pin)]-methane via Pd-Catalyzed Dehydroboration

Abstract

A practical and broadly applicable catalytic method for the synthesis of (E)-alkenylborons is presented. Reactions are promoted by [Pd(Cl)(η³-C₃H₅)]₂ and proceed by the dehydroboration of cyclic borates. Through the use of epoxides and readily available di-B(pin)-methane (pin = pinacolato), a range of allylic alcohol-containing alkenyl boronates, including those that contain a tertiary alcohol, may be prepared in up to 75% yield and >20:1 E/Z.

Graphical abstract

Alkenylboronic acid pinacol esters are versatile molecules for organic synthesis.¹ As such, a variety of methods have been developed for their preparation; these include alkene cross-metathesis,^2,3 alkyne hydroboration,⁴ alkyne reduction,⁵ cross-coupling,⁶ and alkene C–H borylation.⁷ Of considerable value are protocols that in tandem efficiently form stereodefined alkenylborons as well as establishing allylic functionality.⁸

In addition to the former methods, the boron-Wittig reaction represents an efficient metal-free process for the stereoselective generation of alkenyl boronates by the coupling of aldehydes or ketones with readily available 1,1-diborylalkanes (Scheme 1).⁹ For example, addition of [(pin)B]₂C(H)Li (1) to an aldehyde results in 1,2-positioned alkoxide and B(pin) groups (e.g., A), which undergo elimination via the loss of (pin)BOLi. In connection to research associated with the development of 1,1-diborons as useful reagents for stereoselective synthesis, we became interested in the use of epoxides as electrophilic coupling partners, which represent charge-separated synthons (vs carbonyls). As a result, the addition of [(pin)B]₂C(H)Li to an epoxide leads to 1,3-disposed alkoxide and B(pin) moieties incapable of eliminating (e.g., B) and ready to participate in further reactions.¹⁰ We hypothesized that the loss of H–B(pin) from B would provide a simple strategy for the synthesis of alkenyl boronates bearing an allylic alcohol with stereochemistry arising from the chiral epoxide. Such a process could be accomplished by the use of palladium catalysis to effect a formal dehydroboration, via a transmetalation and β-hydride elimination sequence of events. Newhouse and co-workers reported a related efficient dehydrogenation strategy that employs a Pd salt and an allyl oxidant for the synthesis of α,β-unsaturated amides, esters, and nitriles via zinc enolates (eq 1).¹¹ In this regard, we decided to see if a similar approach could be applied to the dehydroboration of intermediates such as B for the preparation of alkenylborons.

Scheme 1.

Synthesis of Alkenyl Boronates with Diborylmethane

(1)

Herein, we report the stereoselective alkenylation of epoxides by a coupling/dehydroboration method that simultaneously generates a stereodefined allylic alcohol and (E)-alkenyl boronic ester. The overall transformation represents the direct alkenylation of an epoxide, equivalent to a stereoselective aldehyde alkenylation.

We initiated our studies with the coupling of (R)-styrene oxide 2 and 1 (Table 1). Subjecting epoxide 2 to [(pin)B]₂C(H)Li in THF at 22 °C for 1 h, followed by treatment with 2.5 mol % of [Pd(Cl)(η³-C₃H₅)]₂ and allyl chloride as the oxidant, resulted in <5% conversion to desired alkenyl boronate 3 (entry 1). It was found, however, that increasing the temperature to 40 and 60 °C (entries 2 and 3) facilitates the reaction, affording the desired product in 42 and 63% yield, respectively, as the (E)-alkene isomer (>20:1).¹² Other palladium sources such as Pd(PPh₃)₄ (entry 4), PdCl₂(dppb) (entry 5), PdCl₂(dppf) (entry 6), and PdCl₂(binap) were found to be ineffective and only afforded significant amounts of the O-allyl product 4.

Table 1.

Reaction Optimization^a

entry	Pd catalyst	temp °C	conv (%); 3/4b	E/Zb
1	[Pd(allyl)Cl]2	20	<5; –
2	[Pd(allyl)Cl]2	40	42; >98:2	>20:1
3	[Pd(allyl)Cl]2	60	63; >98:2	>20:1
4	Pd(Ph3)4	60	59; <2:98
5	PdCl2(dppb)	60	76; <2:98
6	PdCl2(dppf)	60	46; <2:98
7	Pd(dba)2, binap	60	63; <2:98
8c	[Pd(allyl)Cl]2	60	62; >98:2	>20:1
9d	[Pd(allyl)Cl]2	60	60; >98:2	>20:1

^aReactions performed under N₂ atm.

^bValues determined by analysis of 400 or 600 MHz ¹H NMR spectra of unpurified mixtures with DMF as internal standard.

^cReaction run at [0.16 M].

^dReaction run at [0.05 M].

With optimal conditions in hand, we next set out to explore the reaction scope. As illustrated in Scheme 2, the alkenyl boronate synthesis is general for a wide variety of epoxides. Transformations proceed in the presence of 2.5 mol % of [Pd(Cl)(η³⁻C₃H₅)]₂ and allyl chloride (3 equiv) in THF at 60 °C for 24 h. Various aryl-substituted epoxides can be effectively converted through the alkenylation process into the corresponding alkenyl boronates (3a–e) in good yields (45–67% yield) and stereoselectivity (>20:1 E/Z). Notably, it was found that there is no loss in enantiopurity in the formation of 3a when (R)-styrene oxide (99:1 er) is employed. The transformation is also effective for the preparation of alkyl-substituted alkenyl boronic esters. Under standard conditions, a wide variety of terminal alkyl epoxides, including those that contain methyl, cyclohexyl, phenyl, and TBS-ether functionality, can be converted efficiently and stereoselectively into (E)-alkenyl boronic esters 3f–3j in 61–71% isolated yield. It was found that the epoxide alkenylation reaction is amenable to gram-scale preparation of alkenyl boronic esters, as demonstrated by the preparation of 1.14 g of enantioenriched allylic alcohol 3h under standard conditions. Unsubstituted and volatile ethylene oxide can also be employed in the catalytic dehydroboration process to furnish allylic alcohol 3k as a single alkene isomer, albeit in diminished 23% yield. Alkenyl boronates derived from 1,1-disubstituted epoxides are formed equally effectively. Such examples include isobutylene oxide and α-methylstyrene oxide derived alkenyl boronates 3l and 3m generated in 75 and 67% isolated yield, respectively. Furthermore, the reaction is tolerant of existing stereocenters as tertiary alcohol 3n is formed in a 53% yield and >20:1 E/Z.

Scheme 2. Alkenyl Boron Synthesis Epoxide Scope^a,b.

^aReactions performed under N2 atm.

^bYield represents isolated yield of purified material and is an average of two experiments.

Internal six-membered 1,2-disubstituted epoxides perform equally well for the stereoselective synthesis of trisubstituted alkenylborons. Under standard conditions in Scheme 2, [(pin)B]₂C(H)Li (1) opens the ring of the cyclohexene oxide as well as sterically hindered limonene oxide, and subsequent Pd-catalyzed dehydroboration furnishes 3o and 3p in 50 and 34% yield (>20:1 E/Z). This is in contrast to the reaction with cyclopentene oxide (3r), which does not undergo ring opening with carbanion 1.

The alkenylation process was also found to work well with more complex progesterone- and androsterone-derived 1,1-disubstituted epoxides (Figure 1). For example, following epoxide opening at 45 °C with 1 (1.5 equiv), 4 and 5 are efficiently generated in 47 and 67% yield, respectively. As previously noted in our bis-electrophile couplings with 1,¹⁰ modification of the 1,1-diboron fragment with additional groups (e.g., [(pin)B]₂C(H)Me) is not tolerated in the dehydroboration.

Figure 1.

Alkenylation of steroid-derived epoxides.

The robustness of the alkenylboron protocol was found to extend to variations in both the cyclic ether and nucleophile components, such as oxetane 6 and borylsilyl methane 8 (Scheme 3). First, it was found that parent oxetane (6) can be ring-opened, albeit less efficiently compared to an epoxide, by carbanion 1 to form the corresponding six-membered ring chelate that is reactive enough to undergo C–B(pin) transmetalation to Pd and subsequent β-hydride elimination. In this regard, under standard conditions, 1 equiv of 6 affords homoallylic alcohol 7 in 20% NMR yield (>20:1 E/Z). Notably, the use of excess oxetane (5 equiv), compared to 1, in order to assist ring opening did not lead to an increase in reaction efficiency or yield. Second, we hypothesized that exchanging one of the B(pin) groups in 1 with SiMe₃ to the corresponding mixed B/Si reagent 8¹³ would enable the stereoselective generation of (E)-alkenylsilanes, providing C–B(pin) transmetalation occurs faster than the alternative 1,4-Brook rearrangement. Deprotonation of 8 with LTMP (THF, 0 °C, 30 min) and sequential treatment with 2 followed by catalytic Pd and allyl chloride results in the formation of 9 in 20% yield (>20:1 E/Z) and 23% of product derived from epoxide opening. Notably, while the reaction is low yielding, the vinylsilane is the only observable alkenylation product (>98:2 Si/B), indicating that loss of the B(pin) unit is kinetically faster than the corresponding dehydrosilylation.

Scheme 3. Additional Substrate Variation.

^aNMR yield.

^bDeprotonation of 8 with LTMP (THF, 0 °C, 30 min) proceeds to 65% conversion (see Supporting Information for details).¹⁴

To gain insight into the low conversion to 9, ¹H NMR analysis of the epoxide opening step was investigated (Scheme 3). Treatment of 8 with LTMP followed by 2 results in 59% conversion to cyclic borates C/D in 1.7:1 dr in addition to 32% unreacted 2. Of note, the ratio of A/B did not change with temperature. Attempts to follow the reaction after the addition of 5 mol % of Pd and allyl chloride resulted in a complex mixture, where the amounts of both diastereoisomers C and D decrease, vinylsilane begins to form, but a number unidentifiable resonances are present. While epoxide opening does not seem to be a problem, further studies to understand the details of this process are ongoing.

The (E)-alkenyl boronate allylic alcohols generated through the described protocol can be functionalized in a variety of ways. The examples shown in Scheme 4 are illustrative: (1) The unprotected allylic alcohol 3h undergoes palladium-catalyzed cross-coupling in the presence of 3 mol % of Pd(PPh₃)₄, Cs₂CO₃, and aryl or alkenyl bromides in toluene for 8 h to afford the 1,3-diene 10 and alkenylpyridine 11 in 65 and 59% yields, respectively. (2) The hydroxyl moiety can also be used to direct vinylboron functionalization.¹⁵ For example, subjection of alkenyl boronic ester 3h to Simmons–Smith cyclopropanation conditions reported by Shi [Et₂Zn (5 equiv), CH₂I₂ (5 equiv), CF₃CH₂OH, 22 °C, 18 h]¹⁶ results in an alcohol-directed cyclopropanation to furnish cyclopropyl boronic ester 12 in 65% yield and >20:1 dr.

Scheme 4.

Utility of Alkenyl Boronic Ester Products

In summary, we have developed a practical and robust Pd-catalyzed method for the stereoselective synthesis of (E)-alkenylborons via a coupling/dehydroboration of readily accessible chiral epoxides. Transformations proceed efficiently to furnish di- and trisubstituted alkenyl boronates in good yield and >20:1 E/Z selectivity. Further investigations of stereoselective 1,1-diboron coupling processes are ongoing.