Direct Hiyama Cross-Coupling of Enaminones With Triethoxy(aryl)silanes and Dimethylphenylsilanol

Abstract

2,3-Dihydropyridin-4(1H)-ones undergo direct C–H functionalization at C5 in the palladium(II)-catalyzed Hiyama reaction, using triethoxy(aryl)silanes and dimethylphenylsilanol. The reagent CuF₂ has a dual role in the reactions with triethoxy(aryl)silanes. It is a source of fluoride to activate the silane in the Hiyama reaction and also serves as the reoxidant to convert Pd(0) to Pd(II) in the catalytic cycle.

Cross-coupling reactions that directly convert C–H to C–C bonds are valuable atom efficient chemistry processes when compared with conventional cross coupling reactions.^{1, 2} A transition metal-catalyzed C–H functionalization obviates the need for a preactivation step to set up the substrate for the cross-coupling reaction. As a C–C bond-forming strategy, direct arylation of C–H bonds has attracted considerable attention.³ However, the majority of these reactions have been performed employing aromatic C–H bonds and often involve a directing group. ⁴ We have recently shown that enaminones (2,3-dihydropyridin-4(1H)-ones) can be substrates for direct C–H functionalization in Pd(II)-catalyzed Suzuki-type reactions.⁵ We have proposed that the innate nucleophilicity of C5 of enaminones allows for the direct reaction with electrophilic Pd(II), which is followed by deprotonation of the palladium intermediate, transmetalation, and reductive elimination (Figure 1). ⁶ The catalytic cycle is completed by reoxidation of Pd(0) to Pd(II) with an appropriate oxidant such as Cu(OAc)₂.

Figure 1.

Proposed catalytic cycle for the direct arylation of enaminones 1.

We have recently demonstrated the utility of this chemistry for the concise enantiospecific synthesis of the phenanthropiperidine alkaloids ipalbidine and antofine,⁷ tylocrebrine,⁸ and boehmeriasin A.⁹

Based on our results with the Suzuki-type reactions, we hypothesized that the palladated enaminone intermediate could participate in other cross-coupling reactions, such as the Hiyama coupling. Hiyama reactions typically take place between organohalides (alkyl, aryl, and alkenyl) and organosilanes. ¹⁰ Organosilanes have a number of advantages that make them desirable organic reagents for cross-coupling reactions in comparison to organoboranes or organostannanes. They are stable, relatively non-toxic, and can be easily prepared. Nonetheless, only a few cases of direct C-H arylation with organosilane coupling partners have been reported. Yang et al.¹¹ described the direct Hiyama ortho arylation of acetanilides and Zhou et al.^4k the reaction of cyclic N-acetyl enamides with arylsilanes. In both cases, the palladation is believed to be dependent upon neighboring group assistance. In order to explore whether enaminones could participate directly in the Hiyama reaction, we selected 1-benzyl-2-phenyl-2,3-dihydropyridin-4(1H)-one (1a) as the substrate, Pd(OAc)₂ as the catalyst, Cu(OAc)₂ as the reoxidant, and TBAF to activate the triethoxy(phenyl)silane (2a) (Table 1, entry 1). The initial result was quite discouraging because only a trace amount of the desired reaction product 3a could be identified, accompanied by the biphenyl homocoupled product. Similar results were obtained when potassium fluoride was employed (Table 1, entry 2). Silver(I) fluoride appeared to be a better activator, compared to the more commonly used TBAF and KF, possibly due to the oxidative effect of silver(I) (Table 1, entry 3).

Table 1.

Reaction Optimization for the Hiyama Coupling Reaction of Enaminone 1a

entrya	catalyst	oxidant/activator	solvent	yield (%)b
1	Pd(OAc)2	Cu(OAc)2/TBAF	THF	0c trace
2	Pd(OAc)2	Cu(OAc)2/KF	dioxane	trace
3	Pd(OAc)2	Cu(OAc)2/AgF	dioxane	30%
4	Pd(OAc)2	Cu(OTf)2/AgF	dioxane	0d
5e	Pd(OAc)2	AgF2	dioxane	50 62f
6	White catalystg	AgF2	dioxane	40
7	Pd(TFA)2	AgF2	dioxane	48
8	PdCl2	AgF2	dioxane	trace
9	PdI2	AgF2	dioxane	0
10	NiBr2	AgF2	dioxane	0
11	NiF2	AgF2	dioxane	trace
12	Pd(OAc)2	CuF2	dioxaneh tBuOH/AcOH (4:1)i	0 82
13j	Pd(OAc)2	Cu(OAc)2/TBAF	DMF	80
14j	Pd(OAc)2	Cu(OAc)2/KOTMS	DME	77

^aReaction conditions unless otherwise specified: enaminone 1a (0.1 M), siloxane 2a (2 equiv), catalyst (0.3 equiv), oxidant (2 equiv), activator (2 equiv), 3h.

^bIsolated yield.

^cPhSiMeCl₂ was used.

^dEnaminone 1a decomposed.

^eA typical reaction was completed within 1 h when AgF₂ was used.

^fSiloxane 2a (3.5 equiv).

^g1,2-Bis(phenylsulfinyl)-ethane palladium(II) acetate.

^hEnaminone 1a was recovered.

ⁱPd(OAc)₂ (0.25 equiv), CuF₂ (2.5 equiv), siloxane 2a (2.5 equiv), 65 °C, 3h.

^jPhSiMe₂OH (2b) was used instead of 2a.

Since copper and silver are both in group 11 in the periodic table, we next explored Ag(II) in this reaction because it is expected to possess chemical properties similar to Cu(II). We selected AgF₂, which contains two equivalents of fluoride and is also an oxidant to test the proposition that AgF₂ could not only provide the necessary fluoride atoms for the activation of the silane, but also function as the reoxidant in the palladium catalytic cycle. Gratifyingly, the Hiyama coupling reaction proceeded smoothly and with a satisfactory yield (Table 1, entry 5). When different catalysts were examined in this reaction, Pd(TFA)₂ exhibited comparable activity while other Pd(II) or Ni(II) salts showed inferior catalytic capabilities (Table 1, entries 6–11). The reaction with AgF₂, however, required the use of a large excess of organosilane. Therefore, we decided to replace AgF₂ with CuF₂. An initial attempt with CuF₂, using dioxane as the solvent, did not provide the reaction product (Table 1, entry 12). However, when the solvent was changed to a 4:1 mixture of tert-butyl alcohol and acetic acid, the yield of the Hiyama coupling product increased to 82% (Table 1, entry 12). We also examined dimethylphenylsilanol (2b), an organosilanol introduced by Denmark, as a potential coupling partner. ¹² Both fluoride-containing (Table 1, entry 13) and fluoride-free (Table 1, entry 14) conditions gave excellent results with this reactant. The clean, complete conversion clearly demonstrated the utility of these reagents as alternative coupling partners. To the best of our knowledge, this is the first case where an organosilanol has been used in a direct C–H cross-coupling reaction.

The optimized reaction conditions from Table 1, entry 12 were next used to examine the scope of the reaction with different enaminones and substituted triethoxy(aryl)silanes (Table 2). The Hiyama coupling reactions of enaminone 1a worked well with substituted triethoxy(phenyl)silanes that carry a 4-methyl group (Table 2, entry 1), the electron-withdrawing 4-trifluoromethyl group (Table 2, entry 2), and the electron-donating 4-methoxy group (Table 2, entry 3). The sterically hindered α-naphthyltrimethoxysilane was also a suitable coupling partner (Table 2, entry 6).

Table 2.

Substrate Scope of Hiyama Coupling Reactions

entrya	enaminone	product	yield (%)b
1	1a	3b	85
2	1a	3c	73
3	1a	3d	50
4	1a	3e	65
5	1a	3f	61
6c	1a	3g	43
7	1b	3h	62
8	1c	3i	81
9	1d	3j	75
10	1e	3k	68
11	1f	3l	72
12d	1g	not observed	0
13d	1h	not observed	0

^aReaction conditions: enaminone (0.1 M), Pd(OAc)₂ (0.25 equiv), CuF₂ (2.5 equiv), ArSi(OEt)₃ (2.5 equiv) in ^tBuOH/AcOH (4:1), 65 °C, 3h.

^bIsolated yield.

^cα-Naphthyltrimethoxysilane was used.

^dStarting material recovered.

Both monocyclic and bicyclic enaminones were sufficiently active in the direct coupling reactions (Table 2, entries 7, 8 and 11). TBAF, often used in Hiyama coupling reactions to activate the organosilicon reagent, also deprotects silyl protecting groups and thus presents a limitation of this method. It is of note that the TBS group was stable in the presence of CuF₂ (Table 2, entry 9). We observed that halides on both the enaminone and organosiloxane remained intact, presenting positions for further derivatization (Table 2, entries 4, 5 and 10). Steric (Table 2, entry 12) or electronic factors (Table 2, entry 13) are presumably responsible for the lack of reactivity of enaminones 1g and 1h.

In summary, effective protocols for the Hiyama coupling reaction with enaminones have been developed. In the case of triethoxy(aryl)silanes as the coupling partner, AgF₂ and CuF₂ were employed for the first time as bifunctional activator/re-oxidants. Dimethylpheny-lsilanol was successfully used as well, without fluoride activation. All reactions took place in open air. To the best of our knowledge, this is the first direct Hiyama coupling reaction to take place without neighboring group assistance and with an organosilanol. The reaction conditions are compatible with the TBS protecting groups, and thus, could find utility in multi-step organic syntheses.