Table 1. Initial Benchtop Results (eq 1)a
Scheme 2. Hartwig’s Coupling of Malonates and Buchwald’s
Coupling of Nitroalkanes
The higher acidity of nitroacetates (pKa 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 (pKa 9ꢀ13) and nitroalkanes (pKa 10)
(Scheme 2).10ꢀ12 This high acidity would lead to the expec-
tation that only a very mild base would be needed. How-
ever, the resultant anion is a very poor nucleophile and is
poised to form highly favorable O,O0-bound intermediates
such as 4a (Scheme 1). Rearrangement to the C-bound
form 4b, a prerequisite for CꢀC reductive elimination and
formation of 5,11 would require considerable reorganiza-
tion and potentially a second ligand. Initial trials utilizing
conditions reported for the related malonates10a (Scheme 2)
were unsuccesful (Table 1, entry 1). Reasoning that milder
bases could be used, a range of alternate bases were
examined to no avail (entries 2ꢀ5). To determine if the
reductive elimination step was problematic, a more elec-
tron-rich aryl bromide was utilized, but no improvement
was seen (entries 6ꢀ7). Finally, the optimal ligand for
nitroalkanes12a (Scheme 2) was studied with similar poor
results (entry 8).
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 transla-
table to nitroacetates. Since our understanding of how the
reaction variables effect the mechanism was incomplete,
a range of Pd 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 a 0.2 M concentra-
tion (4.4 μL of nitroacetate per vial), it was straightforward
to undertake 96 reactions very quickly in a single plate (3 d
for setup, reaction, and analysis).
a Reaction conditions: Pd2dba3 (2.5 mol %), nitroacetate (2 equiv),
aryl bromide (1 equiv), base (1.2 equiv), and solvent (0.2 M). b Deter-
mined by 1H NMR with respect to ethyl nitroacetate starting material.
(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.
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, block-
ing of palladacycle formation with the isopropyl groups is
necessary.16 Most surprising was the narrow range of steri-
cally 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.
With the t-BuXPhos (L14) ligand and the CsHCO3 base
held constant, further parallel microscale experimentation
was undertaken (Figure 2). On the whole, lower tempera-
tures (75 vs 110 °C) provided better results, presumably
due to product decomposition at the higher temperature.
With every solvent combination, Pd2dba3 CHCl3 and a
3
Based upon the results in Table 1 an unbiased screen
of various phosphines was undertaken at 75 °C with two
Pd sources and four bases spanning a broad pKa range
preformed palladacycle containing the optimal t-BuXPhos
ligand17 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
3
(9) Adolph, H. G.; Kamlet, M. J. J. Am. Chem. Soc. 1966, 88, 4761–
4763.
(10) (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541–555.
(b) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 1360–1370.
(14) Rosen, B. R.; Ruble, J. C.; Beauchcamp, T. J.; Navarro, A. Org.
Lett. 2011, 13, 2564–2567.
(15) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
(11) Hartwig, J. F.; Culkin, D. A. Acc. Chem. Res. 2003, 36, 234–
245.9.
(12) (a) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106–
111. (b) Muratake, H.; Nakai, H. Tetrahedron Lett. 1999, 40, 2355–2358.
(13) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A.
J. Am. Chem. Soc. 2008, 130, 9257–9259.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
(16) (a) Burgos, C. H.; Barder, T. E.; Huang, X.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 4321–4326. (b) Johansson, C. C. C.;
Colacot, T. J. Angew. Chem., Int. Ed. 2010, 49, 676–707.
(17) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686–6687.
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