Silver-Catalyzed Vinylogous Fluorination of Vinyldiazoacetates

Abstract

A silver-catalyzed vinylogous fluorination of vinyldiazoacetates to generate γ-fluoro-α,β-unsaturated carbonyls is presented. Application of this method to the fluorination of farnesol and steroid derivatives was achieved.

The development of new methods for achieving selective fluorination is a current research area of intense interest.¹ Organofluorine compounds display broad utility as valuable pharmaceuticals, agrochemicals, materials and tracers for positron emission tomography.² γ-Fluoro-α,β-unsaturated carbonyls represent a versatile class of intermediates in organic synthesis and are prevalent motifs in biologically relevant compounds such as steroids, amino acids and metalloprotease inhibitors.³ Traditional approaches for the synthesis of γ-fluoro-α,β-unsaturated carbonyls mainly rely on electrophilic fluorination of conjugated enol ethers⁴ and Wittig-type reaction of α-fluoro aldehydes or ketones.⁵ Recently, we⁶ and others⁷ have described that metal-stablized vinylcarbenes derived from vinyldiazoacetates can selectively display electrophilic reactivity at the vinylogous position instead of the carbene site. This type of behavior is especially favorable when silver catalysts are used.^6c,6d,7h In this communication, we report a silver-catalyzed vinylogous fluorination to generate highly functionalized γ-fluoro-α,β-unsaturated carbonyls (eq. 1).⁸

(1)

Our fluorination study began with examination of different fluoride sources using the styryldiazoacetate 1 as the model substrate. Among fluoride sources examined, many of the standard nucleophilic sources of fluoride failed to give any fluorinated products (Table 1, entries 1–6), but Deoxo-Fluor and DAST⁹ can provide the desired product 2 in 44% and 55% yield, respectively (Table 1, entries 7 and 8). The use of triethylamine trihydrogen fluoride¹⁰ dramatically improved the yield to 90% (Table 1, entry 9). After determining the effect of different silver salts (Table 1, entries 9–11), we chose silver acetate and triethylamine trihydrogen fluoride in dichloromethane as our standard fluorination conditions. In all of these reactions, the ratio of vinylogous versus carbenoid fluorination is > 20/1.

Table 1.

Vinylogous Fluorination Optimization^a

entry	catalyst	fluoride	yield (%)b
1	AgOAc	TMAF	<5
2	AgOAc	TBAFc	<5
3	AgOAc	TBABF	<5
4	AgOAc	KHF2d	<5
5	AgOAc	Fluolead™	<5
6	AgOAc	TASF	<5
7	AgOAc	Deoxo-Fluor	44
8	AgOAc	DAST	55
9	AgOAc	Et3N-3HF	90
10	AgSbF6	Et3N-3HF	88
11	AgOTf	Et3N-3HF	90

^aVinyldiazoacetate (0.4 mmol, 1.0 equiv), silver catalyst (10 mol %), fluoride source (2.0 mmol, 5.0 equiv), under refluxing in dichloromethane.

^bIsolated yield, <5 refers to no observation of product 2 from ¹H NMR analysis prior to chromatography.

^c1.0 M in THF.

^dDry DMF as solvent at 90 °C.

Having developed the optimized conditions, the scope of the vinylogous fluorination was examined with a variety of vinyldiazo derivatives. The reaction was found to be quite general as illustrated in Scheme 1. The size of ester group (tert-butyl to methyl) did not affect the efficiency of this reaction, affording the desired products 4a–c in high yields (92–94%). A particularly interesting example is the substrate 3d with a substituted allyl ester. The desired product 4d was isolated in 85% yield and no intramolecular cyclopropanation was observed. Moreover, when an amide was used as the acceptor group, the reaction can still afford the desired product 4e in 60% isolated yield. The reaction can tolerate a variety of functionality on the aryl group as illustrated by 4f–o (63–96%). Furthermore, the reaction can also be expanded to alkyl-substituted vinyldiazoacetates as seen from 4p–r (81–86%).

Scheme 1.

Synthesis of Secondary Allylic Fluoridesa

^aVinyldiazoacetate (0.4 mmol, 1.0 equiv), silver catalyst (10 mol %), triethylamine trihydrogen fluoride (322 mg, 5.0 equiv), under refluxing in dichloromethane. ^bNMR yield using dibromomethane as internal standard due to product decomposition upon silica gel chromatography. ^c20 mol% AgOTf and 10 equiv. of Et₃N-3HF.

To further evaluate the fluorination method, we designed and synthesized di-substituted vinyldiazoacetates 5a–g. When these vinyldiazoacetates were subjected to the standard conditions, the fluorinated products 6a–g containing quaternary carbon-centers were readily formed in good to excellent yields (75–91%) with a variety of aryl- and alkyl-substituted vinyldiazoacetates (Scheme 2). A particularly interesting example is the synthesis of the fluorinated farnesol derivative 6g.

Scheme 2.

Synthesis of Tertiary Allylic Fluoridesa

^aVinyldiazoacetate (0.4 mmol, 1.0 equiv), silver catalyst (10 mol %), triethylamine trihydrogen fluoride (322 mg, 5.0 equiv), under refluxing in dichloromethane.

Fluorinated steroids constitute an important class of molecules with significant biological activity.¹¹ Therefore, we sought to apply this method to late-stage fluorination of steroids (Scheme 3). The steroidal diazo derivatives 7 and 9 were readily formed by a diazo transfer reaction on the corresponding steroids. Under slightly modified reaction conditions using silver triflate, diazo 7 and 9 can be converted to the desired fluorinated steroids 8 and 10 in 56% and 60% yield, respectively. An intriguing feature of this fluorination process is the selective formation of the 6-β-fluoro isomer. A similar selectivity has been seen in vinylogous hydroxylation of steroidal diazo via silver catalysis and has been rationalized to be due to stereoelectronic effects from the conformation of the steroid used.^6e

Scheme 3.

Late-Stage Fluorination of Steroids

Considerable interest has been shown in developing fast fluorination methods because they may be useful in developing positron emission tomography (PET tracers with ¹⁸F labeling, ¹⁸F half-life: 110 min).¹² Metal-catalyzed reactions of diazo compounds can be extremely fast¹³ and accordingly we explored the possibility of achieving fast fluorination. Indeed, fluorination of vinyldiazoacetate 3c in 80% isolated yield was achieved in 5 min when 20 mol% of silver triflate was used as catalyst (Scheme 4).

Scheme 4.

Rapid Fluorination Conditions

In summary, we have developed a silver catalyzed vinylogous fluorination of vinyldiazoacetates. This novel methodology is operationally simple and provides a diverse range of γ-fluoro-α,β-unsaturated carbonyl building blocks. The method offers a strategy for rapid late-stage generation of fluorinated compounds that may be used in the synthesis PET radioligands. Future work will be directed towards developing an enantioselective version of this fluorination methodology.