Nickel-Catalyzed, Carbonyl-Ene-Type Reactions: Selective for Alpha Olefins and More Efficient with Electron-Rich Aldehydes

Abstract

Described are several classes of unusual or unprecedented carbonyl-ene-type reactions, including those between alpha olefins and aromatic aldehydes. Catalyzed by nickel, these processes complement existing Lewis acid-catalyzed methods in several respects. Not only are monosubstituted alkenes, aromatic aldehydes, and tert-alkyl aldehydes effective substrates, but monosubstituted olefins also react faster than those that are more substituted, and large or electron-rich aldehydes are more effective than small or electron-poor ones. Conceptually, in the presence of a nickel-phosphine catalyst, the combination of off-the-shelf alkenes, silyl triflates, and triethylamine functions as a replacement for an allylmetal reagent.

Carbonyl addition reactions are among the most utilized carbon-carbon bond-forming transformations. In many of these the nucleophile is an organometallic reagent, whereas an alkene serves in this capacity in the carbonyl-ene reaction.ⁱ Although alkenes are among the most readily available classes of organic molecules, the full potential of this advantage has yet to be realized in the context of this transformation. Despite decades of research, the chief limitation of this otherwise versatile process is still one of scope. The most efficient reactants are electron-rich olefins (e.g., 1,1-disubstituted alkenes or 2-methoxypropene) and small and/or highly electron-deficient aldehydes (e.g., chloral, formaldehyde, or glyoxylate esters). Few carbonyl-ene reactions of aromatic^{ii, iii} or sterically demanding aldehydes^iv have been reported. Equally rare are those of monosubstituted alkenes, and the vast majority of these are with electron-deficient aldehydes.^v In short, current carbonyl-ene technology is effective for only a small subset of the plethora of possible coupling partners.

(1)

Herein we describe a general means for catalyzing carbonyl-ene-type reactions (eq 1) of several types of compounds that heretofore were of very limited or nonexistent utility, including the most readily available alkenes (alpha olefins^vi) and several important families of aldehydes (aromatic, heteroaromatic, and tertiary aliphatic aldehydes). Catalyzed by a nickel-phosphine complex,^vii these not only are the first intermolecular carbonyl-ene reactions between alpha olefins and aromatic aldehydes,ⁱⁱⁱ but also the first between these alkenes and tert-alkyl aldehydes^iv (t-BuCHO). These are also the first catalytic carbonyl-ene reactions in which a monosubstituted alkene reacts preferentially over a more substituted double bond,^viii and the first in which electron-rich aldehydes are more efficient than those bearing electron-withdrawing substituents.

We recently reported that allylic alcohol derivatives can be prepared directly from alpha olefins, aldehydes, silyl triflates, and an amine base under nickel catalysis, and that homoallylic byproducts are formed in some cases.^{ix, x} We have since found that certain organophosphorus additives (Ph₃P or EtOPPh₂) invert the selectivity, providing an efficient entry into synthetically valuable homoallylic alcohols that previously were unavailable by way of carbonyl-ene processes.

Under these conditions propene (1a) itself undergoes a nickel-catalyzed, carbonyl-ene reaction (Table 1, entry 1), yielding the triethylsilyl ether of allyl phenyl carbinol (2a). The minor product in this case is an allylic alcohol derivative (3a, not shown^xi), but when the alpha olefin 1-octene (1b) is used, the analogous allylic byproducts are formed in only trace amounts (entries 2–8). The E configuration of the double bond is favored over the Z by a factor of 3 to 5 in all cases examined in this series.

Table 1.

Nickel-Catalyzed, Carbonyl-Ene-Type Reactions of Monosubstituted Alkenes.^a

entry	alkene (1)	aldehyde	major product (2)	yield (%)(2:3) b, c	E:Z (2) b
1 d	1a	PhCHO	2a	73 (89:11)	n.a.
2	1b	PhCHO	2b	85 (95:5)	75:25
3 e				72 (>95:5)	75:25
4 e		p-anisaldehyde	2c	85 (>95:5)	75:25
5 e		p-Cl(C6H4)CHO	2d	37 (>95:5)	74:26
6 f		2-naphthaldehyde	2e	88 (>95:5)	70:30
7		1-methyl-2-indole-carboxaldehyde	2f	56 (>95:5)	83:17
8 f		t-BuCHO	2g	64 (>95:5)	78:22
9	1c	PhCHO	2h	86 (92:8)	>95:5
10		p-anisaldehyde	2i	99 (92:8)	>95:5
11 f, g				98 (92:8)	>95:5
12 f		2-naphthaldehyde	2j	88 (95:5)	>95:5
13		1-methyl-2-indole-carboxaldehyde	2k	57 (>95:5)	>95:5
14 f	1dh	p-anisaldehyde	2l	76 (>95:5)	83:17
15	1e	PhCHO	2m	82 (>95:5)	81:19
16	1f		2n	95 (86:14)	n.a.
17	1g		2o	99 (75:25)	n.a.

^aSee Supporting Information and eq 1. Standard conditions (entries 1–7, 15–17): To a solution of Ni(cod)₂ (0.1 mmol) and EtOPPh₂ (0.2 mmol) in toluene (2.5 mL) at 23 °C under Ar were added the alkene (0.5 mL), triethylamine (3.0 mmol), the aldehyde (0.5 mmol), and triethylsilyltriflate (0.875 mmol). The mixture was stirred 48 h at room temperature and purified by chromatography (SiO₂). Entries 8–14: Ph₃P was used in place of EtOPPh₂.

^bDetermined by ¹H NMR.

^cSee Supporting Information for structures of allylic products (3a-3o).

^dPropene (1a, 1 atm) was used in place of Ar.

^eReaction time 18 h.

^fReaction temperature 35 °C.

^gFivefold larger reaction scale (see text).

^h3 equiv of 1d was employed.

The analogous reactions of allylbenzene (1c) are highly selective with respect to both product distribution and olefin geometry (entries 9–13). Identical results (nearly quantitative yield) are obtained when the reaction is performed on a fivefold larger scale and with only 1.5 equiv of allylbenzene relative to p-anisaldehyde (entries 10 and 11). Imide carbonyl groups are tolerated in the reaction (entry 14), as are those bearing β- or α-branching (entries 15 and 16–17, respectively).

Several observations concerning several of the aldehydes deserve further comment. Heteroaromatic aldehydes such as 1-methyl-2-indolecarboxaldehyde are tolerated (entries 7 and 13), despite the fact that the silyl triflate used in the reaction is highly electrophilic. Noteworthy also is the fact that pivaldehyde (t-BuCHO) may be employed in this transformation (entry 8).^xii Silyl ethers of homoallylic alcohols derived from these very sterically demanding aldehydes may thus be accessed directly from the alkene, without preparation of an allylsilane reagent.^xiii Moreover, we are aware of no other examples of intermolecular carbonyl-ene reactions involving a tertiary aliphatic aldehyde.^iv

While reactions of benzaldehyde require 48 h at room temperature to reach completion (compare entries 2 (48 h) and 3 (18 h)), those involving p-anisaldehyde can be complete within 18 h (entry 4) and are generally higher yielding (compare entries 3 and 4 and entries 9 and 10). Furthermore, aromatic aldehydes bearing electron-withdrawing substituents are much less efficient (entry 5).^xiv While we have yet to conduct an exhaustive Hammett analysis, all evidence thus far points to the likelihood that there is a strong dependence of reaction rate upon the electronic nature of the aldehyde. Whatever the cause, we are unaware of other cases of carbonyl-ene reactions in which electron-rich aldehydes are more efficient than electron-poor.

In a similar vein, we have observed that substitution on the alkene has a profound impact on the efficiency of the transformation. Whereas 1,1-disubstituted alkenes are among the most effective olefins in Lewis acid-catalyzed carbonyl-ene reactions, they do not undergo coupling to any noticeable degree with the nickel-catalyzed system. Trans- and cis-disubstituted alkenes are similarly unreactive.^xv

A profound demonstration of this complementary selectivity is illustrated in Scheme 1. When citronellene (1h) and benzaldehyde are treated with Me₂AlCl, only the trisubstituted alkene reacts, and no detectable amount of reaction of the terminal olefin is observed. On the other hand, under nickel-catalyzed conditions, this selectivity is completely reversed. Products corresponding to reaction of the terminal alkene (2p) are the only ones detectable. To the best of our knowledge, this is the first example of a catalytic carbonyl-ene-like reaction that is faster for a monosubstituted alkene than for one more highly substituted.^viii

Scheme 1.

In summary, the nickel-catalyzed carbonyl-ene reactions described here complement Lewis acid-catalyzed methods in several respects (Figure 1). In particular, alpha olefins, aromatic aldehydes, and tert-alkyl aldehydes are excellent starting materials, whereas previously they had not been utilized at all or only to a limited extent. That is, using only off-the-shelf reagents and catalysts, this process effects several classes of unprecedented carbonyl-ene reactions and expands the scope of this venerable transformation significantly. Currently we are investigating the mechanistic basis of the unusual selectivity and reactivity patterns, as well as further demonstration of the general concept of simple, unactivated alkenes functioning as nucleophiles in carbon-carbon bond-forming reactions.^ix

Figure 1.

Complementarity of Catalytic Carbonyl-Ene Reactions