Abstract
Sequential addition of three different Grignard reagents and pivaloyl chloride to 3-oxo-1-cyclohexene-1-carbonitrile installs four new bonds to generate a diverse array of cyclic enamides. Remarkably, formation of the C-magnesiated nitrile intermediate is followed by preferential acylation by pivaloyl chloride rather than consumption by in situ Grignard reagent. Rapid N-acylation of the C-magnesiated nitrile generates an acyl ketenimine that reacts readily with Grignard reagents, or a trialkyl zincate, effectively assembling highly substituted, cyclic enamides.
Cyclic oxonitriles incorporate chemically distinct functionalities ideally suited for multi-component reactions.1 Historically, the synergistic reactivity of oxonitriles was first harnessed in regioselective Robinson annulations2 and elegently employed in several natural product syntheses.3 Subsequently, zipper reactions,4 addition-fragmentations,5 and cycloaddition-cycloreversion6 reactions have exploited oxonitriles in domino reaction sequences for rapidly installing high molecular complexity.
Unsaturated cyclic oxonitriles incorporate three different functionalities capable of selective deployment en route to highly substituted cyclic nitriles (Scheme 1).7 Addition of excess methylmagnesium chloride to 3-oxo-1-cyclohexene-1-carbonitrile (1)8 affords the C-magnesiated nitrile 2 that alkylates a diverse range of electrophiles. Intriguingly, alkylations of the C-magnesiated nitrile 2 are stereoelectronically controlled, with alkyl halide and sulfonate electrophiles alkylating with retention of stereochemistry (2→3), and aldehyde and acyl cyanide electrophiles alkylating with inversion of stereochemistry (2→4).9 Synthetically, the addition-alkylation installs three new stereocenters in which the stereochemistry of the nitrile-bearing carbon can be controlled through judicious choice of electrophile.
Scheme 1.
Grignard Addition-Alkylations of Oxonitrile 1.
Remarkably, alkylating the C-magnesiated nitrile 2 with methyl chloroformate affords neither of the nitriles 3 or 4. Adding excess MeMgCl to oxonitrile 1 and intercepting 2 with excess methyl chloroformate, led to the incorporation of three new carbonyl functionalities and complete loss of the C≡N functionality! Spectral analysis identified the product as the enamide 7 (Scheme 2), presumably resulting from a rare10 N-acylation of the C-magnesiated nitrile 2. Rapid addition of excess MeMgCl to the transient11 acyl ketenimine12 5 followed by sequential N- and O-acylation of the resulting magnesiated enamide 6, leads to the enamide 7. Overall, the Grignard addition-acylation sequence installs six new bonds in one synthetic operation!
Scheme 2.
Grignard Addition-Acylation of Oxonitrile 1.
Experimentally, only two of the three equivalents of MeMgCl are consumed by the oxonitrile 1 prior to the addition of methyl chloroformate. Consequently, at −78 °C methyl chloroformate must react more slowly with MeMgCl than with the metalated nitrile 2! Armed with the speculation that methyl chloroformate might react competitively with MeMgCl and the metalated nitrile 2, the reaction was repeated with excess pivaloyl chloride as a larger, more chemoselective electrophile.13 Indeed, acylating 2 with excess pivaloyl chloride at 0 °C affords enamide 8a considerably more efficiently (Table 1, entry 1).14
Table 1.
Oxonitrile Addition-Acylation Enamides Synthesis
 | ||||
|---|---|---|---|---|
| entry | Grignard reagents | enamide | yield(%) | |
| R1 MgX | R2MgX | |||
| 1 | MeMgCl | MeMgCl |
8a |
57 |
| 2 | PhMgBr | MeMgCl |
8b |
73a |
| 3 | PhMgBr |
|
8c |
40 |
| 4 |
|
MeMgCl |
8d |
69 |
| 5 |
|
MeMgCl |
8e |
69 |
| 6 | MeMgCl | Ph-≡-MgCl |
8f |
50 |
| 7 | PhMgBr | PhMgBr |
8g |
47a,b |
| 8 | MeMgCl |
|
8h |
59 |
| 9 |
|
|
8i |
40b |
The structure was confirmed by x-ray crystallography.16
Incremental portions of Grignard reagent and pivaloyl chloride were added at 0 °C.
Sequential addition of three different Grignard reagents and pivaloyl chloride to oxonitrile 1 generates a diverse array of substituted enamides (Table 1).15 Significant diversity is achieved through the sequential addition of three different Grignard reagents: to the carbonyl group, the alkenenitrile, and the acyl ketenimine. Effectively, the strategy provides excellent control over the substitution pattern simply by varying the addition order (Table 1, compare entry 4 with entry 8). Grignard reagents with sp3 or sp2 hybridization of the carbon-magnesium bond are required for the conjugate addition whereas the nucleophilic attack on the reactive acyl ketenimine tolerates all hybridization types.
Nucleophilic attack on the acyl ketenimine intermediates generate highly congested enamides. X-ray crystallography16 of 8b and 8g secures an enamide geometry consistent with a nucleophilic addition of Grignard reagents to the more accessible face of the acyl ketenimine intermediate 9 (Scheme 3).17 The resulting enamides experience considerable steric compression between the amide nitrogen and the allylic substituent as illustrated in the crystal structure for 8g where the steric interaction is relieved in a chair conformation with the phenyl substituent in an axial orientation (Figure 1).18
Scheme 3.
Organozinc Addition-Acylation
Figure 1.
Crystallographic structure of enamide 8g
Attempts to isolate the putative acyl ketenimine 9 provided key mechanistic insight (Scheme 3). Addition of excess pivaloyl chloride in the absence of a Grignard reagent failed to afford the acyl ketenimine 9 (H = MgCl), which is consistent with the instability of this reactive species.11 Presumably, a slow reaction of pivaloyl chloride with Grignard reagents permits rapid interception of the acyl ketenimine by the nucleophilic organomagnesium reagent immediately upon formation. In some instances, acylation of the C-magnesiated nitrile is slow, resulting in removal of the pivaloyl chloride by the Grignard reagent. In these cases (Table 1, entries 7 and 9) the portion-wise addition of Grignard reagent and pivaloyl chloride permits higher conversions.
The instability, and presumed high reactivity, of the acyl ketenimine 9 suggested intercepting this electrophile with less nucleophilic organometallics. Intercepting 9 with Et2Zn in the presence of pivaloyl chloride affords the expected enamide 8j, although in a disappointing 11% yield (Scheme 3). Assuming Et2Zn to be insufficiently reactive, the portion-wise addition was repeated with a mixed trialkylzincate formed by adding Me3SiCH2Li to Et2Zn.19 Selective transfer of the ethyl group led to formation of the enamide 8j in 63% yield.
Sequential addition of three different Grignard reagents and pivaloyl chloride to 3-oxo-1-cyclohexene-1-carbonitrile (1) generates a diverse array of cyclic enamides. An intrinsic feature of the N-acylation is the preferential reaction of pivaloyl chloride with the C-magnesiated nitrile intermediate rather than with a Grignard reagent! Rapid N-acylation of the C-magnesiated nitrile generates an acyl ketenimine that reacts readily with a Grignard reagent or a trialkyl zincate. Overall, the Grignard addition-acylation with pivaloyl chloride installs four new bonds and provides an effective route to highly substituted, cyclic enamides.
Supplementary Material
1H NMR and 13C NMR spectra for all new compounds and ORTEP’s and CIF files for 8b and 8g. This material is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgments
Financial support from the National Institutes of Health (2R15AI051352), and in part from the National Science Foundation (CHE 0515715, CRIF 024872), is gratefully acknowledged, as is assistance from Dr. Charles Campana, Bruker AXS Inc., in solving the x-ray structure of 8b.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
1H NMR and 13C NMR spectra for all new compounds and ORTEP’s and CIF files for 8b and 8g. This material is available free of charge via the Internet at http://pubs.acs.org.