Boron-Heck reaction of cyclic enaminones: regioselective direct arylation via oxidative palladium(II) catalysis.

An oxidative boron-Heck reaction of cyclic enaminones with arylboronic acids is reported. This protocol provides a regioselective arylation at the C6 position of cyclic enaminones. When an N-carbamylated cyclic enaminone was employed, a switch to a conjugate addition reaction occurred in the presence of acid.

Six-membered cyclic enaminones (2,3-dihydropyridin-4(1H)-ones) are versatile intermediates for the preparation of piperidine-containing molecules including indolizidines and quinolizidines alkaloids (Scheme 1).[1] These heterocyclic compounds are known to possess a variety of biological activities.[2] In our efforts to diversify cyclic enaminone scaffolds,[3] C5 arylation and olefination reactions have been developed and used to prepare biologically active compounds and natural products.[4] For alkylation/arylation reactions at the C6 position of cyclic enaminones, conjugate addition reactions can be employed to afford 4-piperidones.[5] C6 arylation with retention of the enaminone system has been achieved by cross-coupling of C6-halo derivatives[6] or organocuprate addition followed by oxidation.[7] A few cases of direct arylation involving a Heck-type reaction have been reported, but they are limited to intramolecular reactions.[8] Considering the utility of this scaffold, the development of an efficient Pd-mediated intermolecular C6 arylation would be a beneficial process.

Scheme 1

Utility of Cyclic Enaminones

Cyclic enaminones are considered to be challenging substrates for Heck-type reactions. Cyclic systems often generate a mixture of the Heck product and the conjugate addition product because the syn β-hydride elimination step needed for a Heck reaction is unfavorable.[9] In addition, electron-rich olefins are poor olefin donors for Heck-type reactions, and the scope of the substrates is limited to simple olefins and enamides.[10] Another challenge of a Heck reaction with the cyclic enaminone system is the competing electrophilic palladation (C5 functionalization)[3b−3f] particularly with an electron-donating group at the nitrogen. In our previous research,[3f] a preference for C5 arylation was observed under the typical Jeffery conditions,[11] which was successfully used in intramolecular Heck reactions.[8b,8d]

Recently, boron reagents have emerged as alternative halide surrogates in Heck-type reactions.[12] These oxidative boron–Heck reactions proved to be successful with a few cyclic systems.[12c,13] In parallel with our previous C5 arylation reaction with arylboronic acids,[3e] it was envisioned that an oxidative boron–Heck reaction could be employed to install an aryl group at the C6 position of cyclic enaminones by a slight modification of the C5 arylation conditions (Scheme 2). As shown in our previous studies,[3f] it is necessary to increase the electron density of the palladium catalyst to prevent C5 arylation. An electron-donating N,N′-bidentate ligand[14] was selected with the expectation that this would lead to a switch in the regioselectivity of the reaction. While the palladation is suppressed at the C5 position with an electron-enriched catalytic system, transmetalation will occur with an arylboronic acid to form the arylpalladium(II) complex, and then the insertion with the alkene should take place. Therefore, direct arylation at the C6-position could be accomplished. Herein, the direct C6 arylation using arylboronic acids under Pd(II) catalysis is described.

Scheme 2

Regioselective Arylation of Cyclic Enaminones

We initiated the optimization of the reaction using cyclic enaminone 1 and 4-methoxyphenylboronic acid (2) as model substrates (Table 1).[15] First, the reaction conditions without the ligand were investigated, and a mixture of C6 arylated 3 and C5 arylated 4 was observed (entry 1). The choice of oxidant was essential. It should be noted that C5-arylated derivative 4 was formed preferentially when a copper salt or benzoquinone was used as an oxidant (entries 2 and 3). The conditions with tert-butyl perbenzoate or oxygen provided Heck-type product 3 exclusively, although the yields were moderate (entries 4 and 5). The reaction was affected significantly by the solvent selection. Amide solvents such as DMF and NMP gave the best yields (entries 5–9). As expected, the use of a bidentate ligand is necessary to accomplish the regioselective reaction, and the use of 2,2′-bipyridine provided best results (entries 9–11). Furthermore, the addition of any acid or base additives did not improve the reaction efficiency (entries 12 and 13). Time-monitoring experiments revealed that the reaction decelerated after 6 h, resulting from the depletion of the arylboronic acid by homocoupling. To address this issue, another equivalent of the arylboronic acid was added after 6 h (entry 14).

Table 1

Reaction Optimizationa

	solvent	ligand	oxidant	yield (3/4)g (%)
1b	DMF		Cu(OAc)2	34 (1.8/1)
2	DMF	bpy	Cu(CO2CF3)2	25 (1/12)
3	DMF	bpy	benzoquinone	46 (<1/20)
4	DMF	bpy	PhCO3tBu	21 (>20/1)
5	DMF	bpy	O2f	33 (>20/1)
6	DMSO	bpy	O2f	4 (>20/1)
7	THF	bpy	O2f	7 (>20/1)
8	DMA	bpy	O2f	40 (>20/1)
9	NMP	bpy	O2f	49 (>20/1)
10	NMP	1,10-phen	O2f	39 (>20/1)
11	NMP	dmbpy	O2f	47 (>20/1)
12c	NMP	bpy	O2f	0
13d	NMP	bpy	O2f	27 (>20/1)
14e	NMP	bpy	O2f	68 (>20/1)

Reaction conditions: 1 (0.2 M), 2 (2 equiv), Pd(OAc)2 (10 mol %), ligand (11 mol %), oxidant (2 equiv).

Ag2O (1 equiv).

Cs2CO3 (1 equiv).

AcOH (1 equiv).

Additional 2 (1 equiv) was added after 6 h.

Balloon pressure.

Yields and ratios were determined by 1H NMR. PMP = p-methoxyphenyl, bpy = 2,2′-bipyridine, 1,10-phen = 1,10-phenanthroline, dmbpy = 4,4′-dimethyl-2,2′-bipyridine.

The scope of cyclic enaminones and arylboronic acids (Scheme 3) was investigated using the optimized reaction conditions. Electron-rich as well as electron-deficient arylboronic acids provided moderate to good yields (3a–k). However, 2-methoxyphenyl derivative 3l was not observed, presumably due to steric hindrance. Other cyclic enaminones bearing N-phenyl (3n) or N-methyl (3o and 3p) groups were suitable substrates for this reaction. Bicyclic enaminones with indolizidine and quinolizidine scaffolds also furnished the C6 arylated products 3q and 3r in good yields. While the Heck-type products were obtained exclusively with the substrates containing electron-donating groups at the nitrogen, the N-carbamylated cyclic enaminone produced the Heck product 5a as well as conjugate addition product 5b.

Scheme 3

Scope of the Reaction

Reaction conditions: cyclic enaminone (0.2 M), arylboronic acid (3 equiv), Pd(OAc)2 (10 mol %), ligand (11 mol %), oxygen (balloon pressure).

While investigating the factors for the conjugate addition reactions for a N-carbamylated cyclic enaminone, it was found that the addition of acid can switch the outcome (Table 2). As the acidity of the acid was increased, more conjugate addition product 5b was formed while the yield of the Heck product 5a decreased. A complete shift to the conjugate addition product 5b was observed with 2 equiv of TFA (entry 7), albeit in lower yield than with 1 equiv. It is worth noting that the stereochemistry of 5b was confirmed as trans by X-ray crystallography. Therefore, this protocol provides another route toward the synthesis of trans-2,6-disubstituted piperidones, which have been previously prepared via conjugate addition using Grignard reagents.[5f,5g]

Table 2

Acid-Controlled Conjugate Addition of Cyclic Enaminonesa

	acid (equiv)	yield (5a/5b)c (%)
1b		91 (2.8/1)d
2	AcOH (1.0)	86 (1/1.9)
3	AcOH (5.0)	87 (1/3.8)
4	AcOH (10.0)	82 (1/6.5)
5	TsOH·H2O (1.0)	72 (1/6.2)
6	TFA (1.0)	88 (1/12)
7	TFA (2.0)	60 (<1/20)
8	HCO2H (1.0)	87 (1/2.8)

Reaction conditions: cyclic enaminone (0.2 M), arylboronic acid (2 equiv), Pd(OAc)2 (10 mol %), ligand (11 mol %), oxygen (balloon pressure).

20 h.

Yields and ratios were determined by 1H NMR.

Isolated yield.

A plausible mechanism is depicted in Figure 1. The electron-rich palladium ligand complex favors transmetalation with the arylboronic acid rather than C5 palladation of the cyclic enaminone. Carbopalladation would take place trans to Ar1, followed by a palladotropic shift to generate the palladium enolate.[12c,16] In the presence of acid, this intermediate would undergo protonolysis to furnish the conjugate addition product. The oxidative Heck product would be obtained via elimination reactions.

Figure 1

Proposed reaction mechanisms.

C6-arylated cyclic enaminones can serve as an intermediate in natural product synthesis. For example, lasubine II was obtained from compound 8 following the protocol developed by Rovis.[17] Reaction of 3,4-dimethoxyphenylboronic acid (7) with bicyclic enaminone 6 gave C6-arylated product 8 in 62% yield (Scheme 4). The analytical and spectral data of compound 8 are consistent with the literature report,[17] which establishes the formal synthesis of lasubine II.

Scheme 4

Formal Synthesis of Lasubine II

In summary, we have developed a C6 arylation protocol for 2,3-dihydropyridin-4(1H)-ones using the oxidative boron–Heck reaction that proceeds with excellent selectivity over C5 arylation and conjugate addition reactions.[18] This boron–Heck reaction provides a complementary protocol to previously developed arylations at the C6 position. Furthermore, an acid-controlled reactivity switch to a conjugate addition reaction was observed when the reaction was carried out with a N-carbamylated enaminone in the presence of a strong acid.