Angewandte
Communications
Chemie
[a]
ꢀ
Table 3: Optimization of C4-selective C H borylation of pyridine.
para-selectivity lower than that of N,N-diethylbenzamide
(1a) and the selectivity became even worse when bulkier
Lewis acid was used instead of MAD (see Supporting
Information). In contrast, N,N-diisopropylbenzamide (1c)
and N,N-dihexylbenzamide (1d) showed selectivity higher
than 1b. The same trend was also found for benzamides
ꢀ
derived from cyclic amines (1e–1g). Subsequently, the C H
borylation of ortho-monosubstituted benzamides was exam-
ined. Generally the reaction tolerated a wide range of
functional groups at the ortho-position and afforded good
yields and selectivities. N,N-Diethyl-2-methylbenzamide (1h)
gave good yield and selectivity. Substrate bearing a bulkier
amine moiety 1i afforded improved selectivity. An electron-
donating and Lewis basic methoxy group was tolerated by our
method to give 2j. A substituent on the aryl group of
Entry
LA
Ratio
Yield [%]
6 a
6a
–
64
75
79
7a
–
2
1
2
8a
–
14
4
7 aþ8 a
–
4.0:1.0
12:1.0
12:1.0
1
2
3
4
none
MAD
iBAD
iBABr
5
1
ꢀ
2-arylbenzamide 1k was essential to block the C H boryla-
[a] Yields and selectivities were calculated by crude H NMR spectro-
scopy with 1,3,5-trimethoxybenzene as an internal standard.
tion at its para-position. For 1l, which has a small ortho-
fluorine substituent, a bulky amine moiety was essential to
achieve good selectivity. Our method could also tolerate other
halogen functionalities to give 2m–2p. An ortho-CF3 group
strongly activated the C5-position, which caused the moder-
ate selectivity of 1o. Notably, dicarbonyl substrate 1q was
exclusively borylated at the para-position of the amino-
carbonyl group. On the other hand, substrate-control governs
the regioselectivity with C3-substituted benzamides. While 1r
and 1s bearing a small substituent still showed para-selectiv-
Table 4: Scope of pyridine products.[a]
6a, 76%
(12:1.0)
6b, 65%
(>20:1.0)
6c,[b] 52%
(>20:1.0)
6d, 76%
(>20:1.0)
ꢀ
ity, other substrates directed C H borylation at their meta-
ꢀ
position. Heteroaromatic carboxamide 1w afforded C5 C H
borylation product selectively. 5-Membered heteroarene
ꢀ
substrates 1x and 1y also afforded C5 C H borylation
products. Our method could also be applied to arylphosph-
ꢀ
onate 1z, which afforded a para-C H borylation product with
6e, 81%
(>20:1.0)
6 f, [b] 86%
(>20:1.0)
6g,[b] 81%
(>20:1.0)
6h,[c] 67%
(>20:1.0)
good yield and selectivity. However, other functionalized
arenes, such as arylketones and benzoates, were not tolerated
by our method (see Supporting Information).
[a] Reactions were run with pyridine (1.0 mmol), B2(pin)2 (1.0 mmol),
[Ir(cod)(OMe)]2 (1.0 mol%), dtbpy (2.0 mol%), and iBABr (10 mol%) in
hexane (2.5 mL) at room temperature for 6 h. Selectivities (C4:C5) were
estimated by 1H NMR spectroscopy. [b] MAD (10 mol%) was used.
[c] The reaction was performed with 5h (1.0 mmol), [Ir(cod)(OMe)]2
(0.30 mol%), bpy (0.60 mol%), MAD (20 mol%), and B2(pin)2
(2.0 mmol) in hexane (5.0 mL) at room temperature for 24 h.
ꢀ
The C H borylation of some pyridine derivatives is
reported to be sluggish and lacking in selectivity.[20] Thus, we
wondered whether our method could also accelerate pyridine
functionalization and control C4-selectivity. Initially, we
chose pyridine (5a) as a substrate and examined ligands and
ꢀ
LAs to achieve C4-selective C H borylation (Table 3). The
reaction of 5a with B2(pin)2 in the presence of [Ir(cod)-
(OMe)]2 and dtbpy in hexane at room temperature was
indeed very slow, giving essentially no borylation products
(Table 3, entry 1). However, adding 10 mol% MAD as
a cocatalyst dramatically improved the yield and gave
moderate C4-selectivity (Table 3, entry 2). Increasing the
bulkiness of LA by introducing an isobutyl group instead of
methyl on aluminum improved the C4-selectivity (Table 3,
entry 3). Finally, iBABr[21] slightly improved the yield without
any loss of selectivity (Table 3, entry 4).
ꢀ
but with complete C4-selectivity. 2-Phenylpyridine (5c), C H
functionalization of which often proceeds at the phenyl ring,
afforded moderate yield and excellent C4-selectivity without
ꢀ
any detectable C H borylation on the phenyl group. In this
case, iBABr gave good selectivity but low yield, probably
because of steric repulsion by the C2 phenyl group. Ether and
halogen functionalities were tolerated with excellent
C4-selectivities to give 6d–6g. Bpy could also serve as
a substrate for our method, giving 4,4’-di-borylation product
6h as the sole product, which was the ligand of choice (L1) for
With the optimized conditions in hand, we investigated
ꢀ
ꢀ
the scope of substituted pyridines (Table 4). The C H
the para-selective C H borylation of benzamides (see above).
Our method failed for C3-substituted pyridines, which were
ꢀ
borylation of 5a on a preparative scale gave mono-C H
ꢀ
borylation product 6a in 76% isolated yield. C2-substituted
pyridines were borylated at the C4-position exclusively
because of steric repulsion between C2-substituents and
iBABr, forcing LA to provide more severe steric hindrance
at the C5-position. 2-Picoline (5b) reacted in moderate yield
governed by substrate control to give C5 C H borylation
products mainly.
The origin of the para-selectivity is likely steric repulsion
between the iridium catalysts and MAD-substrate adducts,
which participate in the originally proposed catalytic
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!