4
S. Liu et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 2 (continued)
Entry
1
2
Yield of 2b (%)
2:3c
B(pin)
2u
21d
22d
98
>99:1
1u
B(pin)
H3CO
O
99
99
>99:1
>99:1
1v
2v
B(pin)
F
F
23d
2w
1w
B(pin)
24d
25d
99
99
>99:1
54:45
1x
2x
B(pin)
1y
2y
O
(nip)B
O
26d
99
>99:1
NH2
1z
NH2
2z
a
Reaction conditions: 1 (0.3 mmol), B2pin2 (0.36 mmol), NaOt-Bu (0.03 mmol), Cu(OTf)2 (5 mol %), LN5 (10 mol %), MeOH (0.9 mmol), CH3CN (2 mL), 50oC.
Isolated yields.
Determined by GC.
LP7 was used as ligand.
b
c
d
ligands.3a In the alkyne insertion process (or boron migration
available bidentate N-ligands like bipyridine and phenanthroline.
They did give excellent regioselectivity, and among them bipyri-
dine based system had the highest reactivity (Table 1, entries
14–16). Since bipyridine ligand has good regioselectivity and rea-
sonable reactivity, we tried to keep one pyridine ring and change
another pyridine moiety to other less donating nitrogen groups.
Mono-pyridine-mono-pyrazole hybrid ligand LN410 gave good
regioselectivity (Table 1, entry 17). To our delight, tri-dentate
mono-pyridine-di-pyrazole hybrid ligand LN5 gave exclusive
b-selectivity and good reactivity at same time (Table 1, entry 18).
Other nitrogen ligands did not behave well. LN611 based catalyst
has very low reactivity (Table 1, entry 19), this could be explained
by the fact that LN6 could bond with Cu covalently, which blocks
the formation of Cu-B intermediate. LN7 (TMEDA) based catalyst
gave poor regioselectivity (Table 1, entry 20), this could be
explained by the fact that it is less sterically hindered and less
rigid. LN812 based catalyst had good regioselectivity but its reactiv-
ity was not as good as LN5 (Table 1, entry 21).
LN5 can easily prepared from 2,6-dichloropyridine and pyrazole
in one step.13 With the best ligand LN5 in hand, we screened the
effect of solvents, CH3CN gave best regioselectivity and chemical
yields (Table 1, entries 22–28). Also we explored the effect of
bases: weaker bases gave less satisfactory regioselectivity (Table 1,
entries 29–37). Lastly we increased the temperature to 50 °C, we
can obtained almost quantitative yields and exclusive b-selectivity
(Table 1, entry 38). Reducing loading of copper and ligand led to
lower chemical yields, but regioselectivity can be maintained
(Table 1, entry 39). To ensure the effect of LN5, we conducted a con-
trol experiment without ligand under optimized conditions, the
regioselectivity was only 90:10 (Table 1, entry 40).
process), B(pin) acts as a nucleophile, so an electron deficient Cu
complexed alkyne will have high reactivity. Although nitrogen
ligands could be ideal in term of stability and cost, vast majority
of ligands reported are phosphine or NHC ligands. Nitrogen
ligands have only been used in reactive accepter (e.g., ester)
substituted alkynes.8 This could be due to the fact that nitrogen
ligands are usually good
r-donors but not p-accepters. This leads
to copper substituted alkyne/alkenes are not as electron deficient
when nitrogen ligands are employed. So when we select nitrogen
ligands, we have to somehow limit the
r-donor ability (or electron
density) of nitrogen ligands in order to maintain good reactivity
(Scheme 2).
We used borylation of alkyne 1a as our model system to
investigate the effect of metal and especially the ligands on the
regioselectivity (Table 1). First, we explored the ligandless copper
salts catalyzed process (Table 1, entries 1–5) for comparison. All
the copper salts have certain reactivity, and CuII salts especially
CuII(OTf)2 gave both better chemical yields and regioselectivity
(Table 1, entry 5). So we used CuII(OTf)2 complex to study the
ligand effects. So far, most literature reports on Cu catalyzed
borylations are CuI based, relatively few CuII salts have been
used.3h,aa,8,9 Because CuII could be reduced to CuI in situ, we are
not sure about the real catalyst is CuII or CuI yet, but use of
oxygen stable CuII could make our method more robust.
We tested a number of commercially available phosphine
ligands to get some general ideal on how regioselectivity was
affected by steric and electronic factors of ligands. Commonly used
PPh3 and PCy3 increased the chemical yields but not the regioselec-
tivity compared to the ligandless system (Table 1, entries 6–7 vs.
entry 5). Use of bulky mono-dentate Buchwald type ligands did
not improve the regioselectivity (Table 1, entries 8–9). But to our
delight, bidentate phosphine ligands significantly improved the
regioselectivity (Table 1, entries 10–13), especially the skeleton
rigid bidentate ligand LP7 gave exclusive b-adduct (Table 1, entry
12). These data indicate that structurally rigid multi-dentate
ligands may be good for b-selectivity, while the electronic factor
of ligands is not crucial.
With the optimized condition in hand, we explored the scope of
the borylation reaction (Table 2). For aryl substituted terminal
alkynes, excellent yields and exclusive b-regioselectivity can be
obtained (Table 2, entries 1–6). Both electron donating groups
and electron withdrawing groups do not affect the reaction
(Table 2, entries 1–4). Heteroaromatics like pyridine and thiophene
are well tolerated (Table 2, entries 5–6). Simple alkyl group substi-
tuted alkynes also gave good chemical yields (Table 2, entries 7–8).
For sterically hindered cyclohexyl substituted alkyne (Table 2,
entry 7), excellent b-selectivity can be achieved, but for less
Based on effect of phosphine ligands on regioselectivity, we
tried to find suitable nitrogen ligands. First we tested commercially