N-Heterocyclic Carbene-Catalyzed Conjugate Additions of Alcohols

Abstract

An efficient intermolecular conjugate addition of alcohols to activated alkenes catalyzed by N-heterocyclic carbenes has been developed. With 5 mol % of the free carbene derived from IMes•HCl, unsaturated ketones and esters are competent substrates and a variety of primary and secondary alcohols can be employed as the nucleophile. No oligomerization is observed under these mild conditions for effective hydroalkoxylation. In addition to reactions with activated alkenes, IMes catalyzes the formation of vinyl ethers through the 1,4-addition of alcohols to ynones and promotes tandem conjugate addition/Michael cascade reactions. Preliminary data supports a Brønsted base mechanism with the free carbene.

The carbon-oxygen bond is a key component of biologically active compounds. Classical synthetic approaches to these prevalent linkages include substitution reactions employing a highly nucleophilic alkoxide (e.g., Williamson ether synthesis).¹ The direct formation of these bonds through the intermolecular 1,4-addition of alcohols to conjugate acceptors is a logical approach, but remains challenging due to potential oligomerization of the acceptor and the inherent energetic aspects with this process.² A catalytic approach to this important structural motif is a) desirable due to the reduction of potential waste, and b) opens possibilities to control the overall stereochemistry by means other than traditional approaches. While the addition of metal alkoxides (generated with a full equiv of base) to related nitroalkenes has been successful,³ the catalytic addition of alcohols to α,β-unsaturated ketones in a bimolecular process is much more unusual.⁴

Verkade has shown that proazaphosphatranes promote this transformation and Toste and Bergman have reported a mechanistically intriguing phosphine-catalyzed hydroalkoxylation of simple activated olefins.⁵ A broader scope for this process with possibility of stereocontrol and/or chemoselectivity would allow for direct and catalytic access to a wide variety of useful β-alkoxy carbonyl compounds. Recently, N-heterocyclic carbenes (NHCs) have emerged as powerful Lewis bases and our program in this area continues to explore new possibilities with these highly versatile catalysts.^6,7 While the Lewis basic properties of NHCs are firmly established, their potential as Brønsted base catalysts is only just emerging.⁸ Nolan, as well as Waymouth and Hedrick, independently demonstrated that NHCs catalyze transesterification reactions,⁹ but new processes that capitalize on this Brønsted base characteristic of NHCs remain limited. In this Communication, we report an efficient carbene-catalyzed intermolecular conjugate addition of alcohols to activated alkenes.

We began our investigation with 5 mol % loading of azolium salt A (IMes•HCl) and then surveying different bases in a 1:1 ratio relative to A.¹⁰ Aryl ketone 1 was employed as the conjugate acceptor with benzyl alcohol as the nucleophile in toluene. A weak base such as triethylamine provided no product (entry 1), but KHMDS generated a 70% yield (GC) of β-benzyloxy ketone (2, entry 2). Employing NaH led to a decrease in yield, but n-BuLi in combination with A led to a measurable increase in reaction efficiency (88%). To probe the impact of lithium counter ion further, the addition of 1 equiv of 12-crown-4 was accompanied with an observed decrease in yield (74%). Based on this result, one equiv of LiCl was added (entry 6), which resulted in a 95% yield of the desired β-alkoxy ketone (2).¹¹

With efficient reaction conditions in hand, we surveyed a variety of alcohols in combination with ketone 1. A variety of primary and secondary alcohols are competent nucleophiles in this carbene-catalyzed reaction. The addition of allyl alcohol affords the product in excellent yield. Additionally, p-methoxybenzyl alcohol and 2-(trimethylsilyl)ethanol were also well tolerated. The addition of N-BOC serine tert-butyl ester at the hydroxyl group is successful in the presence of the carbamate (entry 8). Addition of the secondary alcohol 1-(naphthalen-1-yl)ethanol to the parent enone is successful (75% yield) but with no diastereoselectivity observed to date. To date, tertiary alcohols are not competent nucleophiles under the current conditions.

We then set out to determine the substrate scope with respect to conjugate acceptors (Table 3). Replacing the phenyl ring on the ketone with a more electron-deficient aryl rings provided the desired alcohol in good yield (73%, entry 1). Alkyl ketones are also accommodated under the reaction conditions (entry 2), as well are highly reactive conjugate acceptors such as methyl vinyl ketone (entry 3). This particular example underscores the unusual and useful aspects of this reaction given that no polymerization is observed with this highly reactive conjugate acceptor. Additions to esters also proceed in moderate yield, but substrates with aryl substituents in the β-position do not afford desired products (not shown). Based on this profile, a differentially substituted divinyl ketone was subjected to the reaction conditions and provided a regioselective addition in 82% yield (entry 6). Cyclohexenone and cyclopentenone provided ~50% conversion under the reaction conditions (not shown). The differential reactivity exhibited by acyclic and cyclic substrates is currently under investigation.

Table 3.

Survey of Conjugate Acceptors^a

entry	R1	R2	product	yield(%)b
1	Me	4-Cl-C6H4	12	73
2	Me	Et	13	82
3	H	Me	14	50
4	Me	OBn	15	60
5	CH3(CH2)4	Ph	16	70
6	Me		17	82

^aSee Supporting Information for reaction details.

^bIsolated yields.

With the reaction components of this reaction initially charted, we sought to capitalize on the unusual aspects of this NHC-alcohol combination and expand the scope beyond general enones. The addition of alcohols to β-substituted ynones to generate vinyl ethers with selectivity favoring one olefin geometry would be a useful transformation.¹² Gratifyingly, benzyl alcohol underwent 1,4-addition to ynone 18 in good yield and excellent selectivity (eq. 1). Further exploration found that the initial conjugate addition of alcohol 20 can be coupled to an intramolecular Michael reaction to generate tetrahydropyran 21 with excellent diastereoselectivity (eq. 2).

(1)

(2)

Our current understanding of this reaction is illustrated in Scheme 3. While NHCs are known to undergo additions to activated alkenes via a conjugate addition manifold,¹³ we currently favor a Brønsted base-catalyzed process. Consideration of previous work by Movassaghi¹⁴ in combination with our own studies prompted us to invoke a NHC-alcohol complex as a key intermediate (I, Scheme 2).¹⁵ This complex facilitates the 1,4-addition of the alcohol to the conjugate acceptor generating an imidazolium ion and the corresponding enolate (II), presumably stabilized by the addition of a lithium counter ion. Subsequent protonation of the enolate affords the β-alkoxy ketone and regenerates the NHC.^16,17 In contrast to reactions performed under anionic conditions, these mild conditions attenuate unwanted side reactions such as oligomerization of the enone or aldol condensations at ambient temperature.¹⁸

Scheme 2.

Proposed Pathway

An enantioselective version of this reaction would be useful, but is challenging given the control of the stereochemistry and potential reversibility. To date, all studies with intermolecular variants of this process with chiral NHC catalysts have afforded racemic products. However, we then surveyed a variety of azolium precatalysts (A–C) with a substrate capable of intramolecular cyclization (22). While all the yields for this reaction are high (>85%), the reaction with azolium B¹⁹ produces a modest, but reproducible, 10–11% ee at −30 °C for this NHC-catalyzed conjugate addition (eq. 3).²⁰ Reducing the reaction temperature to −78 °C provided much lower levels of conversion and did not improve the enantioselectivity of the process. While this observed selectivity is not synthetically practical as of yet, these results do support a pathway involving the NHC•alcohol complex depicted in Scheme 2. Further exploration and development of this catalytic asymmetric conjugate addition is underway.

(3)

In summary, we have discovered a novel conjugate addition of alcohols that demonstrates carbenes as efficient Brønsted base catalysts. A free carbene with the addition of lithium chloride allows for the addition of alcohols to enones in good to excellent yields at ambient temperature and with no oligomerization of the substrates. This new carbene-alcohol combination does not require stoichiometric amounts of strong base and also extends beyond additions to enones. The formation of vinyl ethers is possible through the 1,4-addition of alcohols to ynones and a tandem conjugate addition/Michael reaction occurs to generate a tetrahydropyran with good selectivity. Studies directed toward enhancing asymmetric induction and exploring further the mechanism are currently ongoing. This particular development of N-heterocyclic carbenes as efficient and unusual Brønsted base catalysts creates new opportunities for future direct bond forming processes.

Scheme 1.

NHC-Catalyzed Conjugate Additions

Table 1.

Conjugate Addition Optimization^a

entry	base	additive	GC yield (%)c
1	Et3N	–	NR
2	KHMDS	–	70
3	NaH	–	60
4	n-BuLib	–	88
5	n-BuLib	12-crown-4	74
6	n-BuLib	LiCl (1 equiv)	95

^aReactions run on 0.4 mmol scale.

^bA and base were combined in THF at −78 °C and warmed to 20 °C. THF was then removed under vacuum.

^cDetermined by gas chromatography with dodecane as an internal standard.

Table 2.

Alcohol Addition Scope

entry	R	product	yield(%)b
1	Bn	2	89
2	Me	3	79
3	allyl	4	78
4	propargyl	5	85
5	4-MeO-C6H4CH2OH	6	81
6		7	80
7		8	75
8c		9	81d
9		10	75d
10		11	89

^aSee Supporting Information for details.

^bIsolated yields.

^cCH₂Cl₂ used as solvent.

^d1.2:1 dr (determined by ¹H NMR spectroscopy).