Pd-Catalyzed Cross-Coupling of Potassium Alkenyltrifluoroborates with 2-Chloroacetates and 2-Chloroacetamides

Abstract

A protocol for the stereocontrolled synthesis of (E)- and (Z)-β,γ-unsaturated esters and amides is reported. 2-Chloroacetates as well as secondary and tertiary 2-chloroacetamides were successfully employed as electrophiles in the Suzuki–Miyaura cross-coupling reaction with potassium (E)- and (Z)-alkenyltrifluoroborates, affording the corresponding products in high yield.

(E)- and (Z)-β,γ-Unsaturated esters and amides are encountered in many natural products that exhibit biological activity,¹ and they are also important precursors for the synthesis of biologically active compounds.²

The stereocontrolled synthesis of this significant class of compounds has been considered quite difficult. The most general method involves the palladium or ruthenium-catalyzed carbonylation of allylic substrates.³ Another common method is the deprotonation/reprotonation of α,β-unsaturated carbonyl compounds. Alternative approaches include the reaction of alkenyl-9-BBN compounds with α-halo carbanions generated from ethyl bromoacetate⁴ or ethyl (dimethylsulfuranylidene) acetate,⁵ cross-metathesis of allyl halides with olefins bearing amides⁶ or by a sequential elimination-reduction process of α-halo-β-hydroxy-γ,δ-unsaturated esters promoted by SmI₂.⁷ Radical addition of alkenylindiums to α-halo carbonyl compounds⁸ and Ni-catalyzed enantioselective addition of alkenylzirconium reagents to α-bromo esters and ketones⁹ have emerged as more recent advances in the synthesis of β,γ-unsaturated carbonyl moieties.

Although numerous pathways toward accessing the β,γ-unsaturated carbonyl motif have been studied, all suffer from specific limitations. Carbonylation reactions require the use of toxic CO gas, which is sometimes required under high pressures.^3a Isomerization reactions afford a mixture of (E)- and (Z)-isomers.¹⁰ Both the cross-metathesis reaction and the SmI₂-catalyzed reactions mentioned above require complex starting materials that are not readily available. Reactions involving other organometallic species, such as alkenylindiums and alkenyl-9-BBN compounds, have proven effective in the formation of β,γ-unsaturated carbonyl esters, but these require preformation of sensitive organometallic species and low temperature reaction conditions. The use of alkenyl-TMS substrates is effective in an asymmetric Hiyama cross-coupling with α-bromoesters,¹¹ but as is the case with alkenylzirconium reagents, a large excess of the organometallic reagent is required (30 mol % and 100 mol %, respectively).

Suzuki–Miyaura cross-coupling reactions have also been applied as a strategy toward accessing this class of compounds. In a recent study, (E)-β,γ-unsaturated amides were obtained in moderate to good yields via the cross-coupling of N,N-dimethyl-2-bromoacetamide with alkenylboranes, which were prepared in situ by hydroboration with dicyclohexylborane in the presence of Pd(dba)₂ and tricyclohexylphosphine.¹²

Additionally, the cross-coupling of α-bromoacetates with alkenylboronic acids has recently been investigated.¹³ Good yields were achieved in this study, but only (E)-alkenylboronic acids were evaluated, none of which provided any evidence of functional group compatibility. Although alkenylboronic acids are efficient substrates and solve many of the prevailing limitations in the synthesis of β,γ-unsaturated carbonyl compounds, they suffer disadvantages related to the instability of alkenylboronic acids. These compounds exhibit a tendency to polymerize readily, which is especially prevalent in low molecular weight examples such as vinyl and propenylboronic acids.¹⁴ Furthermore, the use of a large excess (20 mol %) of the boronic acid partner is usually necessary to obtain good yields of desired product.¹³

Alkenyltrifluoroborates provide advantages over the boronic acid counterparts and are excellent partners in Suzuki–Miyaura reactions wherein the double bond geometry is retained with a high degree of fidelity. Furthermore, alkenyltrifluoroborates can be prepared on large scale and stored indefinitely at room temperature under air.¹⁵ Because of their greater stability compared to alkenylboronic acids, a large excess of the trifluoroborate coupling partner is not generally required.

Herein is reported an efficient and general protocol for the synthesis of β,γ-unsaturated esters and amides through Suzuki–Miyaura cross-coupling of 2-chloroesters or amides with potassium (E)- and (Z)-alkenyltrifluoroborates. Initially, a limited screening of Pd/ligand systems was carried out with benzyl chloroacetate 1a and potassium (E)-styryltrifluoroborate as model substrates. Palladium(II) sources such as Pd(OAc)₂ and (η³-C₃H₅)Pd₂Cl₂ were evaluated with a variety of electron-rich ligands. XPhos (Figure 1) in combination with both Pd sources afforded good conversion to the desired product. However, an increased amount of homocoupling was detected in the presence of Pd(OAc)₂. The combination of K₂CO₃ and THF/H₂O (4:1) proved to be the most effective reaction system, leading to high conversions to the β,γ-unsaturated ester.

Figure 1.

Structures of XPhos ligand and XPhos-Pd-G2 pre-catalyst.

Subsequently, the second generation Buchwald precatalyst, XPhos-Pd-G2 (Figure 1)¹⁶ was evaluated in comparison to the (η³-C₃H₅)Pd₂Cl₂/XPhos system. An increased reaction rate was observed, and the catalyst loading could be reduced to 0.5 mol % on a 0.5 mmol reaction scale. Additionally, 1.05 equiv of potassium trifluoroborate was sufficient to obtain 3a in 96% yield after 8 h (Table 1, entry 1).

Table 1.

Cross-Coupling of 2-Chloroacetates with (E)- and (Z)-Alkenyltrifluoroborates^a

entry	product		time (h)	yield (%)
1		3a	8	96
2		3b	8	94, 86b
3		3c	8	70
4		3d	12	89
5		3e	12	87
6		3f	12	85
7		3g	12	91
8		3h	12	76
9		3i	12	64
10		3j	12	66
11		3k	12	64
12		3l	18	62c
13		3m	18	63c
14		3n	18	74c
15		3o	18	80c
16		3p	8	92d
17		3q	8	72d

^aReaction conditions: chloroacetate (0.5 mmol), potassium alkenyltrifluoroborate (0.525 mmol, 1.05 equiv), K₂CO₃ (1.5 mmol, 3 equiv), XPhos-Pd-G2 (2.5 µmol, 0.5 mol %), solvent (2 mL), 80 °C.

^b5.0 mmol scale, 0.25 mol % XPhos-Pd-G2, 18 h

^c1.0 mol % Pd

^dProduct contains >5% trans isomer.

Once the optimal conditions were determined, various potassium (E)- and (Z)-alkenyltrifluoroborates were evaluated in the cross-coupling reaction with benzyl 2-chloroacetate 1a as shown in Table 1. Unstabilized (E)-and (Z)-alkenyltrifluoroborates were illustrated to be suitable substrates, leading to stereocontrolled β,γ-unsaturated ester products in high yield. The crude ¹H NMR spectra of the reactions reveal that none of the α,β-unsaturated regioisomers of the desired products are formed under the optimized conditions, and the (Z)-1-decenyltrifluoroborate (entry 3) was transformed with complete stereospecificity. However, some E/Z isomerization was observed with cis-propenyl and cis-styrenyl substrates (Table 1, entries 16 and 17, and Table 2, entry 6). Thus, although the commercially obtained starting materials for these two contained ~5% of the corresponding (E) isomers, the cross-coupled products contained about 10–12% of the diastereomer. The levels of the trans isomers that appeared in the final product could not be accounted for soley by preferential reaction of the (E) isomeric starting material, and thus an isomerization event occurred either during the cross-coupling event or upon formation of the final product.¹⁷

Table 2.

Cross-Coupling of N-Benzyl 2-Chloroacetamide with (E)- and (Z)-Alkenyltrifluoroborates^a

entry	product		yield (%)
1		5a	95
2		5b	88
3		5c	93
4		5d	90
5		5e	72
6		5f	89b

^aReaction conditions: N-benzyl 2-chloroacetamide (0.5 mmol), potassium alkenyltrifluoroborate (0.525 mmol, 1.05 equiv), K₂CO₃ (1.5 mmol, 3 equiv), XPhos-Pd-G2 (5 µmol, 1 mol %), solvent (2 mL), 80 °C.

^bProduct contains >5% trans isomer.

The reaction conditions were shown to be compatible with a potassium alkenyltrifluoroborate containing a nitrile group, which afforded the desired product in high yield (Table 1, entry 7). A cyclic substrate was also shown to be a viable nucleophilic partner in the employed reaction conditions (Table 1, entry 6). The scalable nature of the reaction conditions was illustrated by the ability to reduce the Pd loading to 0.25 mol % on a 5.0 mmol scale without a significant decrease in reaction yield (Table 1, entry 2).

Isopropyl and tert-butyl 2-chloroacetates (1c, 1b) were also evaluated as electrophilic coupling partners in the optimized reaction conditions. Both esters showed good selectivity. However, only moderate yields of the desired products were achieved (Table 1, entries 9–11). To illustrate the advantageous nature of these reaction conditions in terms of functional group compatibility, benzyl chloroacetate was cross-coupled with substrates bearing an alkyl chloride (Table 1, entry 12), a tertiary amine (Table 1, entry 13), and benzyl and THP-protected alcohols (Table 1, entries 14–15).

The reactivity of 2-chloroacetamides in the cross-coupling with potassium alkenyltrifluoroborates was subsequently investigated. Longer reaction times were necessary to allow the reaction to proceed to completion, and moderate yields were observed under the initial reaction conditions. Increasing the catalyst loading of XPhos-Pd-G2 to 1 mol % was sufficient for the cross-coupling of N-benzyl-2-chloroacetamide 4a with various alkenyltrifluoroborates as shown in Table 2. An allylic amide that has been demonstrated to be an important substrate in domino hydrocarbonylation reactions¹⁸ and ring-closing metathesis¹⁹ was obtained in good yields (Table 2, entry 5).

In addition to N-benzyl-2-chloroacetamide 3a, several other α-chloroacetamides were successfully employed as the electrophilic coupling partners (Table 3). Primary, secondary, and tertiary amides were successfully cross-coupled under the same reaction conditions. A cyclic, fluorinated alkenyltrifluoroborate was shown to react in good yield under the employed conditions (Table 3, entry 9).

Table 3.

Expanded 2-Chloroacetamide Scope for Cross-Coupling with (E)-Alkenyltrifluoroborates^a

entry	product		yield (%)
1		6a	89
2		6b	91
3		6c	78
4		6d	71
5		6e	87
6		6f	94
7		6g	58
8		6h	68
9		6i	79

^aReaction conditions: 2-chloroacetamide (0.5 mmol), potassium alkenyltrifluoroborate (0.525 mmol, 1.05 equiv), K₂CO₃ (1.5 mmol, 3 equiv), XPhos-Pd-G2 (5 µmol, 1 mol %), solvent (2 mL), 80 °C.

In summary, a simple, scalable, and general protocol to obtain stereoselective, functionalized (E)- and (Z)-β,γ-unsaturated esters as well as primary, secondary, and tertiary amides through mild cross-coupling conditions with low catalyst loading is disclosed. All reaction components are air-stable and are easily prepared or obtained from commercial sources.