Efficient Palladium-Catalyzed Cross-Coupling of Highly Acidic Substrates, Nitroacetates

Abstract

Palladium-catalyzed cross coupling conditions were developed that efficiently afford 2-aryl-2-nitroacetates from aryl bromides and the very acidic nitroacetates.

Formation of C–C bonds via metal-catalyzed cross-couplings has become a broadly useful tool for the construction of organic molecules. In the redox neutral variant (i.e. Stille, Negishi, Kumada, Suzuki, etc.) many nucleophiles have been successfully coupled with a range of halide electrophiles.¹ In addition, numerous obstacles, such as metal coordination and cross-reactivity, have also been overcome in the coupling of nucleophiles generated in situ from acidic species. For example, thiolation of aryl halides was one of the first intermolecular cross-couplings involving in situ nucleophile formation.^2,3 Subsequently, Hartwig and Buchwald were the first to cross-couple aryl halides with amines and alcohols without the need to preform the corresponding stannyl nucleophiles.^4,5 Concurrently, reductive elimination utilizing softer carbon nucleophiles was being accomplished. Intermolecular cyanoacetate coupling with phenylbromide was first reported in 1985.^5,6 Since then couplings have been expanded to include α -arylation of ketones, azlactones, glycine imines, 1,3-dicarbonyls, sulfones, imines, sulfoximines, and nitroalkanes.⁷

In this communication, we describe a parallel microscale experimentation (PME) approach to discover suitable conditions for the hitherto unreported coupling of nitroacetates with aryl bromides to generate 2-aryl-2-nitroacetates (Scheme 1). There are few reports⁸ on the synthesis of 2-aryl-2-nitroacetates, highlighting a need for development in this area.

Scheme 1.

Nitroacetate coordination to palladium.

The higher acidity of nitroacetates (pK_a 5.8)⁹ combined with a disposition toward chelation poses a new set of challenges in cross-coupling with aryl halides compared to similar activated methylene compounds such as acyclic 1,3-dicarbonyls (pK_a 9-13) and nitroalkanes (pK_a 10) (Scheme 2).^10–12 This high acidity would lead to the expectation that only a very mild base would be needed. However, the resultant anion is a very poor nucleophile and is poised to form highly favorable O,O′-bound intermediates such as 4a (Scheme 1). Rearrangement to the C-bound form 4b, a prerequisite for C-C reductive elimination and formation of 5,¹¹ would require considerable reorganization and potentially the participation of a second ligand. Initial trials utilizing NaH with tris-tert-butylphosphine and with Pd₂dba₃ as reported for the related malonates^10a (Scheme 2) were unsuccesful (Table 1, entry 1). Reasoning that milder bases could be used, a range of alternate bases was examined to no avail (entries 2-5). To determine if the reductive elimination step was problematic, a more electron-rich aryl bromide was utilized, but no improvement was seen (entries 6-7). Finally, the optimal ligand for nitroalkanes^12a (Scheme 2) was studied with similar poor results (entry 8).

Scheme 2.

Hartwig's coupling of malonates and Buchwald's coupling of nitroalkanes.

Table 1.

Initial benchtop results (eq 1).^a

entry	R	base	solvent	ligand	conversionb (%)
1	H	NaH	THF	P(t-Bu)3	0
2	H	Cs2CO3	THF	P(t-Bu)3	0
3	H	Cs2CO3	DME	P(t-Bu)3	7
4	H	CsHCO3	DME	P(t-Bu)3	2
5	H	NaOAc	DME	P(t-Bu)3	4
6	OMe	CsHCO3	toluene	P(t-Bu)3	3
7	OMe	NaOAc	toluene	P(t-Bu)3	7
8	H	Cs2CO3	toluene	t-BuMePhos	6

^aReaction conditions: Pd₂dba₃ (2.5 mol %), nitroacetate (2 equiv), aryl bromide (1 equiv), base (1.2 equiv), and solvent (0.2 M).

^bDetermined by ¹H NMR with repsect to ethyl nitroacetate starting material.

While the preliminary results secured that conversion of 2 to 5 is achievable, it was clear that the conditions highly effective for malonates and nitroalkanes were not translatable to nitroacetates. Since our understanding of how the reaction variables effect the mechanism was incomplete, a range of palladium sources, ligands, and bases needed to be examined. To effectively complete this study, parallel microscale experimentation was utilized.¹³ By using 1-mL vials with 100 μL reaction volumes at 0.2 M concentration (4.4 μL nitroacetate per vial), it was straightforward to undertake 96 reactions in a single plate. In addition to contributing to efficiency (3 d total time time for set-up, reaction and analysis), only 422 μL (3.84 mmol) of nitroacetate was needed to screen 96 sets of conditions.

Based upon the results in Table 1 an unbiased screen of various phosphines (monodentate, bidentate, hindered, biphenyl, etc.) was undertaken at 75 °C in combination with two palladium sources and four bases spanning a broad pK_a range (Figure 1). The conversion as indicated by the product/internal standard ratio is illustrated in the 3-D plot in Figure 1. Table 2 lists the top screening results along with selected isolated yields when performed on a larger scale.

Figure 1.

Graphical summary of PME screen #1 (eq 1, R = H, T = 75 °C)

Table 2.

Top screening results from PME screen #1 and scale up (eq 1, R = H).

entry	ligand	Pd	base	solvent	product/ISa, yieldb
1	t-BuXPhos	Pd2dba3 • CHCl3	CsHCO3	toluene	6.9, 93%
2	t-BuXPhos	(allylPdCl)2	CsHCO3	DME	5.1, 46%
3	Me4t-Bu XPhos	Pd2dba3 • CHCl3	Cs2CO3	toluene	4.5, N/Ac
4	Me4t-BuXPhos	Pd2dba3 • CHCl3	CsHCO3	toluene	3.7, N/Ac
5	t-BuXPhos	(allylPdCl)2	K3PO4	DME	3.0, N/Ad
6	Me4t-BuXPhos	(allylPdCl)2	Cs2CO3	DME	1.8, N/Ad
7	t-BuXPhos	(allylPdCl)2	Cs2CO3	DME	1.8, 53%
8	Me4t-BuXPhos	(allylPdCl)2	CsHCO3	DME	1.04, N/Ad

^aRelative conversions from screen (IS = internal standard).

^bIsolated yields upon scale up (0.25 mmol scale).

^cNot isolated because conversion by ¹H NMR was low.

^dNot scaled up.

This screen revealed that only three ligands, BrettPhos L10, Me₄ t-BuXPhos L15, and t-BuXPhos L14 (Figure 1) provided any product with the latter two proving superior. Di-tert-butyl substituted biphenylphosphine ligands seem to be superior for cross-couplings of weak nucleophiles as seen here and in other reports.^14,15 In this case, this narrow window suggests that the biphenyl η-1 coordination¹⁵ is critical to forming a reactive species. In addition, blocking of palladacycle formation with the isopropyl groups is necessary.¹⁵ Most surprising was the narrow range of sterically acceptable ligands with the smaller XPhos L9 failing while the two methoxy groups of BrettPhos L10 offset the smaller phosphine cyclohexyl substituents (L9 < L10 ≪ L15 < L14). On the other end, Me₄ t-BuXPhos L15 appears too large.

Holding the t-BuXPhos (L14) ligand and the CsHCO₃ base constant, further parallel microscale experimentation was undertaken to identify the optimal temperature, Pd source, and solvent (Figure 2). On the whole, lower temperatures (75 °C versus 110 °C) provided better results, presumably due to product decomposition at the higher temperature. With every solvent combination, Pd₂dba₃ · CHCl₃ and a preformed palladacycle containing the optimal t-BuXPhos ligand {chloro(2-di-tert-butylphosphino-2′,4′,6′-trisisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl] palladium(II)}¹⁷ gave consistent results, whereas [(allyl)PdCl]₂ and Pd(OAc)₂ were less consistent. Upon scale up, Pd₂dba₃ · CHCl₃ provided high isolated yields (93%) with the preformed catalyst being less effective (88%). In line with the initial screening results, the next most effective palladium source was [(allyl)PdCl]₂ whereas Pd(OAc)₂ was significantly poorer. Reaction was observed in most of the solvents with the nonpolar solvents (toluene and cylopentyl methyl ether) performing better than polar solvents (dioxane, DME, tert-amyl alcohol, THF).

Figure 2.

Graphical summary of PME screen #2 results (eq 1, R = H, base = CsHCO₃, ligand = t-BuXPhos) (CPME = cyclopentyl methyl ether, t-amylOH = tert-amyl alcohol).

Further experiments indicated that a 2:1 ligand:palladium ratio was the most effective, in line with other results with enolates.^10,12 As expected for this reaction where deprotonation of the nitroacetate is a key step, a base was cruical to the success of the process (Table 3, entry 1). An examination of bases (Table 3) found that relative to CsHCO₃ (entry 2) stronger bases (K₃PO₄, Cs₂CO₃, Figure 1; CsOH, NaOt-Bu, entries 3-4) were not as successful. Presumably, stronger bases generate larger amounts of the nitroacetate anion, which is not very soluble.^10a Bases with harder cations (KHCO₃, NaHCO₃, Li₂CO₃, entries 5-7) provided little or no product formation, either due to lower solubility or greater bonding to the nitronate anion, which would impede ligand exchange. On the other end of the spectrum, even softer counterions (Rb₂CO₃, entry 8) performed similarly relative to cesium. CsF (entry 9) with the optimal counterion and a similar pK_a relative to CsHCO₃ was effective, but less so, indicating that the fluoride anion may remain involved. A variety of amine bases were completely ineffective (entries 10–13).

Table 3.

Benchtop screen of bases (eq 1, R = H).^a

entry	base	conversionb(%), yieldc(%)	entry	base	conversionb (%), yieldc(%)
1	none	0, 0	8	Rb2CO3	100, 90
2	CsHCO3	100, 93	9	CsF	60, 60
3	CsOH	41, N/Ad	10	(i-Pr)2NEt	0, 0
4	NaOt-Bu	0, 0	11	DMAP	0, 0
5	KHCO3	19, N/Ad	12	2,6-(t-Bu)2-4-MePy	0, 0
6	NaHCO3	0, 0
7	Li2CO3	0, 0	13	DBU	10, N/Ad

^aReaction conditions: Pd₂dba₃ • CHCl₃ (2.5 mol %), nitroacetate (2 equiv), aryl bromide (1 equiv), base (1.2 equiv), and toluene (0.2 M) at 75 °C.

^bConversion by ¹H NMR with respect to remaining ethyl nitroacetate.

^cIsolated yields.

^dNot isolated.

The best reaction conditions were 2.5 mol % Pd₂dba₃·CHCl₃, 10 mol % t-BuXPhos, 1.2 equiv CsHCO₃ in toluene at 75 °C, which afforded the products from various aryl bromides and ethyl nitroacetate in isolated yields of 52-96% (Table 4). Notably, electron-rich and electron-poor aryl halides reacted well reinforcing the notion that oxidative addition is not the problematic step in the reaction pathway. In addition, heterocyclic compounds (entries 7 and 11) could be employed. Interestingly, ketones did not undergo competing reaction with the nitroacetate anion (entry 4). Reaction selectivity for aryl bromides over aryl chlorides was observed (entry 12) with only a small amount of the dicoupled product isolated (16%).

Table 4.

Reaction of ethyl nitroacetate with aryl bromides (eq 2).^a

entry	aryl bromide	yield (%)	entry	aryl bromide	yield (%)
1		93	7		52
2		79	8		80
3b		69	9		77
4		96	10		76
5		71	11		95
6		81	12		61

^aReaction conditions: 5 mol % Pd, 10 mol % ligand, ethyl nitroacetate (2 equiv), aryl bromide (1 equiv), CsHCO₃ (1.2 equiv), and toluene (0.2 M).

^b20 mol % Pd.

On the other hand, the method was not suitable for aryl iodides, triflates, and chlorides. Since such species undergo oxidative addition under these conditions, we speculate that the nature of the counterion is critical to the transmetallation of 3 to 4 (Scheme 2) in line with related reports on other enolates.¹⁸

While moderately hindered aryl bromides couple (Table 4, entry 3), more hindered compounds such as 1-bromonaphthalene or ortho-bromotoluene were not successful. Hartwig and Culkin notice this downfall in the α-arylation of ketones¹¹ and propose it arises from the inability of the O,O-bound palladium intermediate 4a to rearrange to the carbon-bound intermediate 4b, an already difficult proposition in this system (Scheme 1).

To further probe the reactivity of this system methyl, tert-butyl, and benzyl nitroacetates were synthesized.¹⁹ These nitroacetate couplings afforded product in moderate to good yields (Table 5). The increased tendency of methyl nitroacetate to hydrolyze and decarboxylate lowers the isolated yield (entry 1).

Table 5.

Reaction of various nitroacetates with bromobenzene (eq 3).^a

entry	R	yield (%)
1	Me	53
2	Et	93
3	t-Bu	88
4	Bn	95

^aReaction conditions: 5 mol % Pd, 10 mol % t-BuXPhos, nitroacetate (2 equiv), aryl bromide (1 equiv), CsHCO₃ (1.2 equiv), and toluene (0.2 M).

In summary, we have developed conditions for the catalytic cross coupling of nitroacetates with aryl bromides to generate 2-aryl-2-nitroacetates. A key requirement in the palladium catalyzed coupling is the use of tBuXPhos as ligand, which is likely a result of the high acidity of the nitroacetate substrate as well as O,O′-chelation competing with C-coordination to palladium. An improved understanding of ligand requirements is critical to the more rapid development of these important processes.