Mechanistic Insight into Additions of Allylic Grignard Reagents to

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Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds Nicole D. Bartolo, and K. A. Woerpel J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01430 • Publication Date (Web): 06 Aug 2018 Downloaded from http://pubs.acs.org on August 8, 2018

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The Journal of Organic Chemistry

1 Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds Nicole D. Bartolo and K. A. Woerpel* Department of Chemistry, New York University 100 Washington Square East, New York, New York 10003

Abstract: Allylic Grignard reagents exhibit high reactivity and low selectivity in additions to carbonyl compounds. Additions of allylic Grignard reagents to carbonyl compounds were investigated using prenylmagnesium chloride as a mechanistic probe. When the carbonyl group is relatively unhindered, the addition proceeds through a six-membered transition state with allylic transposition. This process generally occurs with no diastereoselectivity because the reaction rates approach the diffusion limit. With hindered ketones, however, this pathway is disfavored and the addition proceeds through a four-membered transition state.

Introduction Commercially available allylic magnesium halides are commonly used to incorporate alkene functional groups into a molecule.1-3 Their high reactivity enables them to react with sterically hindered carbonyl compounds in cases where other allylmetal reagents do not add.4-7 Additions of allylmagnesium halides to carbonyl compounds, however, can occur with lower stereoselectivity than additions of other organomagnesium reagents.1,2 The low selectivity

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2 observed in reactions of allylic magnesium halides arises because reaction rates approach the diffusion limit.8-10 The mechanism responsible for this unique behavior has not been established, however. Several mechanisms can be considered to explain the additions of allylic Grignard reagents to carbonyl compounds.11-16 The additions of Grignard reagents to carbonyl compounds may proceed through monomeric, four-centered transition states resembling 1 or through dimeric, sixcentered transition states such as 2 (Scheme 1).14,16-18 Allylic Grignard reagents, however, have two other pathways available. They may add to carbonyl compounds via a monomeric, sixmembered transition state with allylic transposition (3).11,13 An open SE2’-like transition state (4)14 is also possible, although more recent mechanistic data suggest that this pathway is unlikely.1,19,20 In this Article, we provide experimental evidence that is most consistent with the reactions of allylic Grignard reagents with unhindered carbonyl compounds reacting through a six-membered transition state with allylic transposition (i.e., transition state 3). Furthermore, we describe experiments that suggest this transition state is responsible for the rapid and unselective reactions of allylic Grignard reagents.

Scheme 1. Possible concerted mechanisms for the addition of allylmagnesium halide to a carbonyl compound.


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3 Prenylmagnesium chloride 5 was used as a probe to gain insight into the transition state for addition of allylic Grignard reagents to carbonyl compounds. Spectroscopic data show that prenylmagnesium halides exist as the regioisomer with the magnesium atom bound to the least substituted carbon atom (5, eq 1).21-25 Consequently, the regiochemistry of the addition of prenylmagnesium chloride to a carbonyl compound can be used to infer the pathway through which allylic Grignard reagents likely react (Scheme 2). Addition may occur through transition states 1 or 2, resulting in the α-addition product, alcohol 7. If addition proceeds through the sixmembered transition state 3, however, the γ-addition product, alcohol 8, will be observed due to allylic transposition.13,26 It is also possible that a six-membered transition state resembling 3 could lead to the α-addition product 7, but such a mechanism would require reaction through the highenergy isomer of the reagent (i.e., 6), which is unlikely.25,27 Both γ-addition and α-addition products have been observed in the reactions of allylic Grignard reagents with various carbonyl compounds,3,28,29 but the origin of the variation in regioselectivity has not been determined. Furthermore, no studies have shown the transition from one pathway to the other depending upon the steric hinderance of the electrophile.



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4

Scheme 2. Potential products of the two concerted pathways for the addition of prenylmagnesium chloride 5 to a carbonyl compound. Results and Discussion Initial studies focused on establishing that prenylmagnesium chloride reacts at a comparable rate to allylmagnesium halides (i.e., at the diffusion rate limit) with unhindered ketones.8 Just like allylmagnesium halides, prenylmagnesium chloride was found to be more reactive with propiophenone (9) than other alkylmagnesium reagents were (eq 2). The addition products of the other Grignard reagents were not observed when prenylmagnesium chloride was competed against both methylmagnesium chloride and isopentylmagnesium bromide. When prenylmagnesium chloride was competed against allylmagnesium chloride, however, approximately equal amounts of prenylated and allylated products were formed. These observations indicate that the addition of allylmagnesium chloride and prenylmagnesium chloride occur at comparable rates. Considering that previous studies indicate that allylmagnesium chloride reacts at rates approaching the diffusion limit, it may be concluded that prenylmagnesium chloride also reacts at that rate with relatively unhindered ketones.8


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5

Intermolecular competition experiments demonstrate that prenylmagnesium chloride, like allylmagnesium halides, reacts with low chemoselectivity between an aldehyde and a ketone. This lack of selectivity observed with allylic magnesium reagents is consistent with diffusion-controlled addition. Competition experiments with Grignard reagents and an excess of benzaldehyde (13) and acetophenone (14) showed that both allylmagnesium chloride and prenylmagnesium chloride do not exhibit chemoselectivity in instances where other alkylmagnesium reagents exhibit high chemoselectivity (Table 1).8 These experiments provide further evidence that prenylmagnesium chloride reacts at a similar rate as allylmagnesium chloride does. Table 1. Intermolecular competition experiments to demonstrate chemoselectivity of addition of Grignard reagents to carbonyl compounds.

Entry

R

Product

15:16a

1 Me a 221:18 2 n-Pr b 143:18 3 H2C=CHCH2 c 51:498 4 Me2C=CHCH2 db 60:40 a b Ratios determined by GC analysis. Regioisomers were inseparable by GC. The lack of chemoselectivity for the allylic Grignard reagents can be explained by consideration of the possible transition states for the addition. Complexation of the magnesium



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6 atom to the carbonyl compound (k1) to form a Lewis acid-base complex (17) should occur quickly after the addition of the Grignard reagent to the carbonyl compound (Scheme 3).30 The rate of carbon–carbon bond formation with allylic transposition (18) is faster than dissociation of the complex (k2 >> k–1), resulting in no difference in the rates of addition to different types of carbonyl compounds. In the addition to unhindered carbonyl compounds, the rate of carbon–carbon bond formation through the transition state with allylic transposition (18) is much faster than the rate of carbon–carbon bond formation through the four-membered transition state 19 (k2 >> k3), leading to almost exclusive formation of the γ-addition product.

Scheme 3. Reaction rates of addition of prenylmagnesium chloride to a carbonyl compound A lack of chemoselectivity was also observed in an intermolecular competition experiment between chelating ketone 20 and nonchelating ketone 9. Neither allylmagnesium halide nor prenylmagnesium chloride showed chelation-induced rate acceleration9,31,32 in cases where other alkylmagnesium reagents exhibited high selectivity for chelating ketone 20 (Table 2).9 These experiments reinforce the conclusion that additions of both allylmagnesium halides and prenylmagnesium chloride cannot be expected to exhibit chelation-controlled selectivity because once the reagent complexes to a carbonyl compound, rapid carbon–carbon bond formation through the six-membered transition state must occur (Scheme 3).9


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7 Table 2. Intermolecular competition experiments to demonstrate chelation control in the addition of Grignard reagents to carbonyl compounds.

Entry R Product 21:22a 1 Me a 104:19 2 n-Pr b 338:19 3 H2C=CHCH2 c 49:519 b 4 Me2C=CHCH2 d 49:51 a b Ratios determined by GC analysis. Regioisomers were inseparable by GC. Control experiments established that the regioselectivity of these reactions does not result from reversibility of the addition. In a crossover experiment where prenylmagnesium chloride was added to one ketone (9) followed by addition of a second ketone (23c) no addition to the second ketone was observed, even after stirring at 66 °C for twenty hours (eq 3). This observation is consistent with previous studies of additions of prenylmagnesium halides.33 By contrast, the additions of allyl and crotyl Grignard reagents to hindered carbonyl compounds are reversible at elevated temperatures.34-37

In the additions of prenylmagnesium chloride to α-alkoxy ketones, the γ-addition pathway was the prevailing mode of addition (Table 3). The resulting γ-addition products were formed with



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8 generally low diastereoselectivity, as has been observed for the additions of allylmagnesium halides to α-alkoxy ketones.9 Incrementally increasing the steric hindrance at the carbonyl group only exerted a modest effect on the regioselectivity of addition. For the treatment of more hindered ketones with prenylmagnesium chloride, α-addition products 25c-e were not observed in significant quantities. Table 3. Treatment of propiophenone-derived ketones with prenylmagnesium chloride.

d.r. of d.r. of Yield of 24a 25a 24 (%) 80 ab Me H >99:1 56 b Me OMe 96:4 61:39 >99:1 89 c Ph H 99:1 83 d Ph OMe >99:1 75:25 31 e Ph OH >99:1 >99:1 a 1 Ratios determined by H NMR spectroscopy. b Compound 23a is the same as compound 9; compound 24a is the same as compounds 10 and 21d; compound 25a is the same as compound 11. Entry

R1

R2

24:25a

A significant difference in diastereoselectivity was observed between the two regioisomers of product. Treatment of chelating ketones 23b,d with 5 resulted in low diastereoselectivity for the γ-addition products 24b,d, similar to the addition of allylmagnesium halides to these ketones.9,38 This outcome is consistent with rapid reactions, which is suggested by the results in Tables 1 and 2.8 The α-addition products 25b, however, was formed as a single diastereomer, suggesting that addition through a transition-state controlled pathway was slower.9,39 Slower addition to the


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9 carbonyl group (i.e., k2 in Scheme 3) allows for reaction not with any form of the α-alkoxy ketone, but instead reaction occurred only with the chelated intermediate, leading to stereoselectivity.9,31,32 High regioselectivity and diastereoselectivity, however, were observed in the addition to 23e through the γ-addition pathway. This addition could proceed either through ketone 23e or the corresponding magnesium alkoxide, considering that the rate of addition of allylic Grignard reagents to carbonyl compounds is comparable to the rate of proton transfer.40,41 A control experiment indicated that addition to the magnesium alkoxide is consistent with the selectivity. One equivalent of methylmagnesium chloride was first added to benzoin at –78 °C to deprotonate the hydroxyl group,42 then prenylmagnesium chloride was added to the mixture. In this experiment, the same regioselectivity and diastereoselectivity were observed as above, although conversion was low (33%) after 30 minutes at –78 °C. The high diastereoselectivity observed in this reaction is consistent with chelation-controlled addition because the carbonyl compound with the α-OMgCl group likely chelates magnesium more strongly than other α-alkoxy carbonyl compounds,43 leading to chelation-controlled diastereoselectivity.9 Increasing the steric hinderance at the carbonyl group led to increased quantities of the αaddition product. The addition of prenylmagnesium chloride to camphor (26) at –78 °C resulted in little conversion (99:1 2 20 72:28 >99:1 3 66 51:49 >99:1 a 1 Ratios determined by H NMR spectroscopy Entry Temp. (°C)

27:28a

d.r. of 28a >99:1 >99:1 >99:1

The outcomes of these reactions can be interpreted by considering the possible transition states for addition (Scheme 3). With hindered carbonyl compounds, the rate of carbon–carbon bond formation through the six-membered transition state 18 and the four-membered transition state 19 are slower than the rate of dissociation (k–1 >> k2, k3) because the transition state for addition is sterically destabilized. Furthermore, the rates of the two modes of addition must not be that different. As the temperature was increased, the rates of these slow carbon–carbon bond forming steps (k2 vs. k3) converge, resulting in decreased regioselectivity. By contrast, no such temperature dependence was observed when prenylmagnesium chloride was added to propiophenone (9) over a large temperature range (eq 4), indicating that the inherent difference in rates of addition through the two transition states must be particularly large (k2 >> k3).


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11 In additions to highly sterically hindered ketones, the four-membered transition state 19 (k3, Scheme 3, or its dimeric equivalent 2) appears to be the prevailing mode of addition. Treatment of di-tert-butyl ketone (29) with prenylmagnesium chloride at room temperature resulted in only the α-addition product (30, eq 5); none of the γ-addition product was observed. These reactions are particularly slow, however.8,49 Treatment of 29 with prenylmagnesium chloride at –78 °C resulted in little conversion (

Mechanistic Insight into Additions of Allylic Grignard Reagents to

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