Ligand Effects on Negishi Couplings of Alkenyl Halides

Abstract

Negishi couplings at olefinic centers do not always occur with the anticipated maintenance of stereochemistry. The source of erosion has been traced to the ligand, and a modified method has been developed that solves the stereochemical issue and significantly improves yields of Negishi couplings in general.

Virtually every review article and textbook discussing Pd-catalyzed cross-coupling reactions of aryl or alkenyl halides illustrates the same catalytic cycle.¹ Implied in this sequence is the expectation that while the nature of the ligands on Pd(0) may vary, there are no mechanistic consequences due to catalyst variations along these lines. The same assumption applies to the organometallic partner, usually represented in generic form as “R-M,” regardless of the metal (e.g., boron, tin, silicon, zirconium, zinc, etc.). Indeed, the hallmark of Pd-mediated C-C bond constructions is their normally strict maintenance of stereochemistry, where applicable, in going from educt to product.

Several name reactions have their origins tied to couplings involving E- or Z-alkenyl halides.¹ Included among these fundamental processes is the Negishi reaction, traditionally focused on an sp² center undergoing coupling with an sp³-based organozinc halide (R-M = RZnX).

For most, where an aryl or E-vinyl halide is involved, there is either no associated stereochemistry or the starting E-olefinic geometry is pre-disposed toward remaining E- in the product. Only Z-alkenyl halides in unbiased substrates might offer insight regarding the potential role of ligands in affecting Negishi couplings.² We now report that the stereochemical outcome in standard Negishi couplings, contrary to the commonly held view, is highly ligand dependent (Scheme 1),³ and that it can be easily compromised even at ambient temperatures.

Scheme 1.

Negishi Cross-couplings with Z-alkenyl halides.

Educt 1 (Table 1; >99% Z) was examined initially under traditional conditions using catalytic amounts of Pd(PPh₃)₄ or trans-PdCl₂(PPh₃)₂ in THF (entries 1 and 2). Although each reaction led to a mixture of products, including significant amounts of protio-quench product 3 and/or homocoupling products 4,^4,5 almost complete retention of geometry in the resulting Z-olefin 2 was observed. However, in efforts to improve the otherwise poor yields of desired product Z-2, screening commercially available phosphine- or carbene-based ligands of more recent vintage revealed a most unexpected finding: Z-olefin geometry can be easily lost even at room temperature (entries 5–8).

Table 1.

Effects of Catalyst and Additive on Z/E Ratios in 2^a

entry	catalyst	2 / 3 / 4b	2, Z / Ec
1	Pd(PPh3)4	39/31/30	98/2
2	PdCl2(PPh3)2	53/32/15	98/2
3	PdCl2 + 3P(2-Fur)3	80/3/17	98/2
4	PdCl2 + 3P(2-Tol)3	96/2/2	99/1
5	PdCl2(Amphos)2d	88/<1/12	68/32
6	Pd[P(t-Bu)3]2	38/26/36	73/27
7	PdCl2(PCy3)2	95/4/1	33/67
8	PEPPSI	55/33/12	45/55
9	PdCl2(PCy3)2 + 3PPh3	73/9/18	98/2
10	PdCl2(PPh3)2 + TMEDAe	99/<1/<1	>99/1
11	PdCl2(PPh3)2 + Et3Nf	79/5/16	98/2

^aConditions: alkylzinc iodide (1.1 mmol, 1.0 M in THF), vinyl iodide (1 mmol), Pd catalyst (2 mol %). Reactions were run at 0.33 M at rt, 4 h (24 h for entries 10 and 11).

^bby GC.

^cZ/E-ratio determined by NMR or GC on crude material.

^dDefined as dichloro-bis(p-dimethylaminophenyl-di-tert-butylphosphine) palladium(II).

^e1.1 equiv.

^f2.2 equiv.

Maintenance of stereoselectivity and high levels of chemoselectivity⁶ are apparently favored by bulky aromatic phosphine ligands (entry 4). An attempt to combine the benefits in chemoselectivity imparted by tricyclohexylphosphine (entry 7) with the stereo-selectivity maintained in the presence of triphenylphosphine was unsuccessful at preventing significant amounts of side-products 3 and 4 (entry 9).

On the basis of the critical role played by N,N,N’,N’- tetramethylethylenediamine (TMEDA) in Zn-mediated cross-couplings between two halides performed in water at room temperature observed previously,⁷ the impact of TMEDA in these Negishi couplings was investigated. Remarkably, in the presence of TMEDA under otherwise identical (standard) Negishi conditions, virtually complete maintanence of olefin geometry was realized, as was the preference for adduct Z-2 (Table 1, entry 10). The amount of TMEDA (1.1 equiv) is critical for controlling selectivity. Presumably, the presence of an additive in stoichiometric amounts provides a coordinating ligand for both catalytic palladium and stoichiometric zinc. Addition of triethylamine also had a beneficial impact on product ratios, but not to the extent seen with TMEDA (compare entries 2 vs. 11).

The powerful combination of PdCl₂(PPh₃)₂ as catalyst and TMEDA as complexing agent could be applied to a variety of (functionalized) reaction partners (Table 2). Notably, sterically hindered (Z)-1-iodo-3,3-dimethylbut-1-ene afforded stereoisomerically pure cross-coupled products 8 and 9 in good yields, while PdCl₂(PPh₃)₂ as catalyst alone led to low conversions even after 48 hours. It should also be noted that in the coupling of phenethylzinc iodide with (Z)-1-iodooct-1-ene (giving product 5), and coupling of n-decylzinc iodide with (Z)-1-iodo-3,3-dimethylbut-1-ene (giving product 8), in the absence of TMEDA, byproducts were observed in which the double bond had partly migrated.⁸ By contrast, these undesired products were not seen using cat. PdCl₂(PPh₃)₂/TMEDA.

Table 2.

Effect of Ligand and TMEDA on Negishi Cross-couplings of Z-Alkenyl Halides^a

entry	Ratios: Z/E	entry	Ratios: Z/E
1	A: 99/1 (49%)b	3	A: 99/1 (91%)b
2	B: 99/1 (92%)c	4	B: 99/1 (96%)c
5	A: 96/4 (73%)b	7	A: <20% conv
6	B: 98/2 (94%)c	8	B: 99/1 (63%)c
9	A: <20% conv	11	A: 98/2 (64%)b
10	B: 99/1 (84%)c	12	B: 99/1 (96%)c
		13	B: 99/1 (91%)c,d
		14	C: 99/1 (98%)c,d
15	A: 90/10 (37%)b,d
16	B: 98/2 (94%)b,d
17	C: 99/1 (96%)c,d	20	A: 97/3 (78%)b,d
18	D: 2/98 (85%)c,d	21	B: 98/2 (93%)c,d
19	E: 96/4 (90%)b,d	22	D: 1/99 (85%)c,d

^aConditions: organozinc iodide (1.1 mmol, 1.0 M in THF), alkenyl iodide (1 mmol), Pd catalyst (A: PdCl₂(PPh₃)₂ (2 mol %), rt, 4–24 h; B: PdCl₂(PPh₃)₂ (2 mol %) + TMEDA (1.1 equiv), rt, 24–36 h; C: PdCl₂(PPh₃)₂ (1 mol %) + TMEDA (1.1 equiv), 60 °C, 2–3 h; D: PdCl₂(Amphos)₂ (2 mol %), rt, 24–36 h; E: PdCl₂(Amphos)₂ (2 mol %) + TMEDA (1.1 equiv), rt, 24 h). Reactions were run at 0.33 M; Z/E-ratio determined by NMR and GC on crude material.

^bGC yield.

^cIsolated yield.

^dFrom alkenyl bromide.

Alkenyl bromides could also be successfully coupled with alkylzinc reagents. Coupling of n-decylzinc iodide with Z-1-bromooct-1-ene led to the desired isomerically pure product 10 in high yield (entry 13). In general, use of TMEDA tends to slow rates of cross-couplings run at room temperature. When performed at 60 °C, however, they are complete in 2–3 hours, require less catalyst (only 1% of PdCl₂(PPh₃)₂, and lead to stereoisomerically clean products 10 and 11 in close to quantitative yield (entries 14 and 17). Cross-couplings of both (Z)-1-iodo- and (Z)-1-bromooct-1-enes with secondary cyclohexylzinc iodide, however, resulted in less then 50% conversion in each case under a variety of conditions. Interestingly, although PdCl₂(Amphos)₂ catalyzed the alkylation and arylation of Z-β-bromostyrene in high yields, complete isomerization to the E-product took place (entries 18, 22). The presence of TMEDA, however, negates this pathway (compare entries 18 vs. 19). Best results are again obtained using cat. PdCl₂(PPh₃)₂/TMEDA to afford products 11 and 12 (entries 17 and 21).

A controlled Z-to-E isomerization can be used to synthetic advantage, in particular when starting with a mixture of E/Z-isomers of β-bromostyrenes (Scheme 2). Using PdCl₂(Amphos)₂ as catalyst only the E-products are obtained. Likewise, a mixture of E/Z-isomers of (2-bromovinyl)trimethylsilane led to E-14 in good yield Scheme 2). Retention or inversion of configuration could also be achieved for the coupling of PhZnI·LiCl⁹ with an unbiased alkenyl iodide, depending upon the catalyst selected, leading to E- or Z-15. This new method obviates not only losses of the unwanted Z-isomer due to preferential reactivity of E-alkenyl halides,¹⁰ but also averts the need for separation of starting material and/or unwanted side products.

Scheme 2.

Negishi Cross-couplings of Z- and Mixed Z/E-Alkenyl Halides.a

^a Conditions: organozinc iodide (1.1 mmol, 1.0 M in THF), alkenyl halide (1 mmol), PdCl₂(Amphos)₂ (2 mol %). Isolated yields. Reactions were run at 0.33 M at rt for 24 h. Z/E-ratio determined by NMR and GC on crude material. ^b As available commercially. ^c As obtained from 4-MeO-cinnamic acid via Grob fragmentation.

TMEDA, which is present in excess, likely serves several roles, such as (1) a ligand for Pd that may shift equilibria away from bridging dimeric species and toward a more highly (5- and/or 6-) coordinated intermediate. This would minimize ligand exchange that otherwise could lead to species from which homocoupling products arise;⁴ (2) inhibition of elimination of palladium hydride from more highly coordinated intermediates may also add to the enhanced chemoselectivity observed; (3) as a coordinating agent for RZnX¹¹ and/or in situ-derived ZnX₂,¹² thereby negating its Lewis acidity (which could influence the mechanism of isomerization; vide infra); (4) facilitate conversion of any in situ-generated PdH (that could be potentially responsible for Z to E isomerization) to Pd(0).¹³

One explanation for the ligand-related loss of stereointegrity observed during Negishi cross-couplings of Z-vinylic halides calls for isomerization of a Pd(II) intermediate 17 following a likely initial stereospecific¹⁴ Pd-insertion to 16 (Scheme 3). A pathway involving either an anionic¹⁵ (as shown) or cationic^1c,16 zwitterion-metal carbene may follow. Alternatively, isomerization can occur through an η²-vinylphosphonium complex,¹⁷ or possibly via reversible PdH elimination.¹⁸

Scheme 3.

Potential Pathways for Loss of Z-Olefinic Geometry.

These findings potentially offer immediate benefits to all types of Negishi couplings with respect to avoidance of homocoupling and protio-quenching, if not stereoselectivity; e.g., in cross-couplings of aryl halides. For the case of an electron-rich aryl bromide such as 1-bromo-4-methoxybenzene, coupling under standard Negishi conditions with n-decylzinc iodide resulted in very low conversion (Table 3, entry 1).

Table 3.

Effects of Catalyst and Additive on Cross-coupling of Aryl Bromides with n-C₁₀H₂₁ZnI.^a

entry	Ar-Br	catalyst	19 / 20 / 21b
1		PdCl2(PPh3)2	< 5% conv
2	18a	PdCl2(dppf)	7/91/2
3		PdCl2(PPh3)2 + TMEDAc	<1/99/0 (95%)d
4		PdCl2(PPh3)2	4/26/70
5	18b	PdCl2(dppf)	5/91/4
6		PdCl2(PPh3)2 + TMEDAc	<1/98/1 (93%)d

^aConditions: alkylzinc iodide (1.1 mmol, 1.0 M in THF), aryl bromide (1 mmol), Pd catalyst (2 mol %). Reactions were run at 0.33 M at 40 °C, 12 h for entries 1–3, and at rt, 20 h for entries 4–6.

^bby GC on crude material.

^c1.1 equiv.

^dIsolated yield.

While switching to catalyst PdCl₂(dppf)¹⁹ the starting halide was fully consumed, and good selectivity was observed favoring product 20 (entry 2). In reactions of electron-deficient ethyl 4-bromobenzoate, which proceed smoothly even at room temperature, similar levels of chemoselectivity were observed with both catalysts (entries 4, 5). Thus, while use of this bidentate ferrocene-based ligand on Pd dramatically improves the reaction outcome, chemoselectivity issues remain unresolved.⁴ In the presence of TMEDA, however, use of the least expensive of palladium catalysts, PdCl₂(PPh₃)₂,²⁰ leads to full conversion together with virtually complete control of ratios favoring the desired cross-coupling products for both representative electron-rich and electron-poor aryl bromides (entries 3, 6).

In summary, the stereochemical outcome of Negishi couplings on Z-alkenyl halides has been found to vary, contrary to prevailing thinking, as a function of the ligand(s) on the Pd catalyst.²¹ These ligand effects on both stereoselectivity and reaction pathway can be fully negated using a method that relies on catalytic PdCl₂(PPh₃)₂ in the presence of an equivalent of TMEDA.²² This new combination applies to Negishi couplings in general, where enhanced product yields are to be expected. These results suggest that additional new insights regarding mechanistic subtleties associated with Pd-catalyzed C-C bond-forming reactions, perhaps involving other organometallic coupling partners as well, lie ahead. Ongoing studies aimed at further elucidating the interplay between ligands and additives, and their effects on both Stille and Suzuki-Miyaura couplings will be reported in due course.