10.1002/cctc.201900393
ChemCatChem
COMMUNICATION
[a] Optimized geometry of putative anionic Cu(I) phenolate intermediate
[b] Optimized geometry of putative neutral Cu(III) intermediate
S
NH
O
O
N
-1
O
S
H
S
N
1.99
Cu
Å
S
N
O
O
176o
Cu
O
2.63
Å
Figure 3. Computed ground state conformations performed with density functional theory (B3LYP) with the LANL2DZ basis set.
was then added to the solids. The reaction vial was sealed and heated to
ongoing efforts towards the identification of new ligands for other
catalytic transformations will be reported in due course.
80 °C for at least 20 h; reaction progress was monitored by HPLC, LCMS
or TLC. Upon reaction completion, the reaction mixture was quenched with
water (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The
combined organic layers were washed with brine (20 mL), dried over
MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the
crude product, which was then diluted with CH2Cl2 (2 mL). This solution
was wet-loaded onto a silica gel column for flash chromatographic
separation with a gradient between 0 and 50% ethyl acetate in n-hexane.
The fractions containing product were then concentrated to dryness and
analyzed.
Experimental Section
General procedure for phenol coupling: In a nitrogen-filled glovebox,
charged a Schlenk tube equipped with a magnetic stirbar with sodium L-
ascorbate (0.2 equiv), copper (I) chloride (0.05 equiv), N,N’-bis(thiophene-
2-ylmethyl)oxalamide 4i (0.06 equiv), cesium carbonate (2 equiv), phenol
(1.2 equiv) and aryl bromide (1 mmol, 1 equiv). To the vial was added
nitrogen-sparged dioxane (0.2 M relative to aryl bromide). The reaction vial
was capped and the contents were heated to 80 °C for a minimum of 20 h,
unless otherwise noted; reaction progress was monitored by HPLC, LCMS
or TLC. Upon reaction completion, the mixture was cooled and quenched
with water (15 mL), then extracted with MTBE (2 x 15 mL). The combined
organic phase was concentrated in vacuo to afford the crude product which
was diluted with CH2Cl2 (2 mL). This solution was loaded directly onto a
silica gel column for flash chromatographic separation with a gradient
between 5 and 30% ethyl acetate in n-hexane. The fractions containing
product were then concentrated to dryness and analyzed.
Acknowledgements
This work was influenced by on-going efforts of the Non-Precious
Metal Catalysis Alliance between AbbVie, Asymchem,
Boehringer-Ingelheim and Pfizer.
Keywords: copper catalyst • oxalamide • cross-coupling •
Ullmann coupling • hydroxylation
General procedure for hydroxylation with NaOH (condition A): In a
nitrogen-filled glovebox, charged a Schlenk tube with copper (I) bromide
(0.02 equiv), N,N’-bis(thiophene-2-ylmethyl)oxalamide 4i (0.022 equiv),
and sodium hydroxide (2.5 equiv). To the vial was added a 4:1 DMSO/
water solution (0.6 M) of aryl bromide (1 mmol, 1 equiv). The reaction vial
was sealed and the contents were heated to 85 °C for a minimum of 20 h;
reaction progress was monitored by HPLC, LCMS or TLC. Upon reaction
completion, the reaction mixture was quenched with water (5 mL) and then
extracted with ethyl acetate (3 x 10 mL). The combined organic layers were
washed with brine (20 mL), dried over MgSO4, and filtered. The filtrate was
concentrated in vacuo to afford the crude product, which was then diluted
with CH2Cl2 (2 mL). This solution was wet-loaded onto a silica gel column
for flash chromatographic separation with a gradient between 0 and 50%
ethyl acetate in n-hexane. The fractions containing product were then
concentrated to dryness and analyzed.
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General procedure for hydroxylation with (E)-benzaldehyde oxime
(condition B): In a nitrogen-filled glovebox, charged a Schlenk tube with
(E)-benzaldehyde oxime (2.0 equiv), cesium carbonate (2.5 equiv), copper
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