Palladium-Catalyzed Asymmetric Allylic Alkylation of 2-Acylimidazoles as Ester Enolate Equivalents

Abstract

A broad range of highly enantioenriched 2-acylimidazoles are synthesized by palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of 2-imidazolo-substituted enol carbonates. The enantioenriched 2-acylimidazole products can easily be converted to the corresponding carboxylic acid, ester, amide, and ketone derivatives with complete retention of the enantiopurity. The synthetic utility of this new method is demonstrated in the short, efficient synthesis of cetiedil.

The stereocontrolled alkylation of carbonyl compounds is a staple reaction in organic synthesis for the construction of highly enantioenriched materials. In particular, the alkylation of ester enolate equivalents has found widespread use due to the versatility of the resulting ester or amide products.¹ Success in the field of ester enolate alkylations has relied on the use of chiral auxiliaries to direct the stereochemical outcome of the alkylation.² Catalytic asymmetric ester enolate alkylations, although more desirable, are rare.^3,4 Andrus and coworkers have reported the alkylation of a single 2-acylimidazole derivative (1-(1-methyl-1H-imidazol-2-yl)-2-(naphthalen-2-ylmethoxy)ethanone)⁵ with allylic and benzylic bromides that gives products with 75–99% ee under phase transfer catalysis using chiral cinchonidinium catalysts. They later disclosed a similar, albeit less stereoselective, alkylation of specifically phenethyl 2-naphthylacetate.⁶ While promising, these examples have only been demonstrated for a 2-naphthyl substituent and require superstoichiometric amounts of base and alkylating agents. In this report we describe the first catalytic asymmetric allylic alkylation (AAA) of a broad range of 2-acylimidazole-derived enol carbonates, the products of which are easily converted to a variety of ketone and carboxylic acid derivatives.

The transformation of 2-acylimidazoles to carboxylic acid derivatives was first reported by Ohta and coworkers.⁷ They found that while 2-acylimidazoles did not undergo acyl transfer reactions, alkylation of the imidazole nitrogen generated an activated leaving group that allowed substitution to occur (eq. 1). Based on this finding, we envisioned expanding the scope of our AAA reaction of enol carbonates to include 2-acylimidazoles as the first efficient and general example of catalytic asymmetric alkylations of ester enolate equivalents.

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Our initial studies focused on the decarboxylative allylic alkylation reaction of allyl enol carbonates 1 catalyzed by Pd₂(dba)₃·CHCl₃ (2) and L1 (Table 1, entries 1–4). While the reaction proceeded in a number of solvents, conducting it in dioxane generated alkylated product 3a with the highest yield and ee (entry 1). Varying the N-substituent on the imidazole portion of the enol carbonate from methyl (1a) to phenyl (1b) led to higher yields and higher ee of the product 3b (entry 5). Further varying R to 2-methylphenyl (1c) or 1-naphthyl (1d) gave similar yields but led to a small decrease in the ee of the products 3c–d (entries 6–7). In addition, varying the ligand from L1 to L2–L4 gave product 3b in good yields, but with lower enantioselectivity.

Table 1.

Selected optimization studies

entrya	solvent	Nu	R	Ln	3	Yield (%)b	ee (%)c
1	Dioxane	1a	Me	L1	3a	89	87
2	CH2Cl2	1a	Me	L1	3a	10	n.d.
3	Toluene	1a	Me	L1	3a	83	76
4	THF	1a	Me	L1	3a	65	80
5	Dioxane	1b	Ph	L1	3b	96	92
6	Dioxane	1c	2-Tol	L1	3c	95	89
7	Dioxane	1d	1-naph	L1	3d	99	87
8	Dioxane	1b	Ph	L2	3b	99	76
9	Dioxane	1b	Ph	L3	3b	93	76
10	Dioxane	1b	Ph	L4	3b	99	58

^aReactions performed using 0.2 mmol substrate, 2.5 mol % 2, and 6 mol % Ln in 1 mL of solvent at ambient temperature for 16 hr.

^bIsolated yields.

^cDetermined by chiral HPLC analysis. n.d = not determined.

The reaction scope under our optimized conditions (Table 1, entry 5) is summarized in Table 2. A variety of acyclic and cyclic allylic carbonates⁸ (4a–d) participate in the reaction to generate 2-acylimidazole products 5a–d in high yield and high ee (entries 2–5). Aryl and alkyl substitution on the enol carbonate are also tolerated (entries 6–9). The mild reaction conditions also permit the presence of alkynes (entry 6) and heteroaromatic substituents (entry 9). A variety of O-protected α-hydroxyketones can also be generated in good yield and ee using L2. To demonstrate the scalability of this process, reaction of enol carbonate 1b was performed on 2 mmol scale using just 1 mol % 2 and 2.5 mol % L1 to generate product 3b in 97% yield and 94% ee (entry 13).⁹

Table 2.

Reactions of different imidazole enol carbonates

entrya	4	R1	R2	5	Yield (%)b	drc	ee (%)d
1	1b		Me	3b	96		92
2	4a		Me	5a	95		92
3	4b		Me	5b	69	>95:5	>99
4	4c		Me	5c	91	>95:5	97
5e,f	4d		Me	5d	80j		46
6	4e			5e	91		93
7	4f			5f	75		94
8	4g		Ph	5g	99	>95:5	86
9	4h			5h	98	>95:5	97
10g,h	4i		OMOM	5i	85		71
11g	4j		OBn	5j	89		73
12g	4k		OTBDMS	5k	54	10:1	>99
13i	1b		Me	3b	97		94

^aUnless otherwise noted, reactions were performed using 0.2 mmol substrate, 2.5 mol % 2, and 6 mol % L1 in 1 mL of solvent at ambient temperature for 16 hr.

^bIsolated yields.

^cDetermined by ¹H analysis of the crude reaction mixture.

^dDetermined by chiral HPLC analysis.

^eReaction run for 48hrs.

^fL4 was employed.

^gL2 was employed.

^hReaction time was 30 min.

ⁱPerformed on 2 mmol scale with 1 mol % 2 and 2.5 mol % L1 for 18 hr.

^j10:1 mixture trans:cis diene.

Our attention next turned to conversion of the 2-acylimidazole products to the corresponding carboxylic acid or ketone derivatives. While acyl transfer reactions of 2-acylimidazoles are well precedented,¹⁰ we were unsure whether the transformations could be performed without racemizing the α-keto stereocenter. We were delighted to find that hydrolysis of the imidazole under standard conditions (treatment with MeOTf in MeCN followed by addition of H₂O and DBU) gave carboxylic acid 6 in 85% yield with complete retention of stereochemistry (eq 2). In a similar fashion, 2-acylimidazole 5a was converted to the benzyl ester derivative in 96% yield (eq 3). During our derivatization studies we found that direct conversion of the 2-acylimidazoles to amides or thioesters gave racemic products; converting the 2-acylimidazole first to the acid and then to the amide prevents racemization (eq 4). Conversion of imidazole ketone 5d to the corresponding alkyl ketone by treatment of the methylated imidazole with n-hexylmagnesium bromide also proceeded smoothly to give ketone 9 in good yield (eq 5). Synthesizing α-chiral aliphatic ketones using this methodology circumvents the otherwise difficult alkylation of unsymmetrical ketones where regioselective enolization is challenging.

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(5)

The synthetic utility of this new methodology is demonstrated by the concise synthesis of cetiedil (Scheme 1). Cetiedil is currently used clinically in racemic form for the treatment of vascular disease.¹¹ While enantiomerically pure cetiedil is generally obtained by fractional crystallization,¹² one asymmetric synthesis has been reported.¹³ Ours begins with acylation of 1-phenylimidazole with Weinreb amide 10 to give 2-acylimidazole 11. Formation of enol carbonate 4i by O-acylation of the sodium enolate, followed by decarboxylative allylic alkylation of 4i generates 2-acylimidazole 5i in 98% yield and 97% ee. Hydrogenation of the double bond in 5i gives ketone 12 in 90% yield and 90% ee.¹⁴ Treatment of 12 with methyl triflate then amino alcohol 13 produces cetiedil in 89% yield and 90% ee.

Scheme 1.

Synthesis of cetiedil

In summary, we report the synthesis of highly enantioenriched 2-acylimidazoles by palladium-catalyzed decarboxylative asymmetric allylic alkylation of 2-imidazolo-substituted enol carbonates. The absolute configuration of the products of alkylation were established by comparison of carboxylic acid 6¹⁵ and our synthetic cetiedil¹³ to known materials. In contrast to previously reported methods, the catalytic asymmetric alkylation methodology presented herein is quite general in scope for both the allylic electrophile and enolate nucleophile. The enantioenriched 2-acylimidazole products can easily be converted to the corresponding carboxylic acid, ester, amide, and ketone derivatives with complete retention of the enantiopurity.