Organic Letters
Letter
(Scheme 1b), the acylation remains confined to the use of alkyl
halides. However, the use of amines as an electrophilic
coupling partner in transition metal-mediated acylation is
unknown (Scheme 1c) despite its widespread availability.26−28
Activation of kinetically inert C−N bonds in cross-coupling
reactions is notoriously difficult, and a significant effort has
been made to activate C−N bonds. Transition metal-mediated
cleavage of C(sp2)−N and activated C(sp3)−N (strained,
allylic, and benzylic) bonds is reported.29 Recently, Wat-
son,16,26,30 Glorius,31 Aggarwal,32 and Rueping15 et al. reported
the activation of an unactivated C(sp3)−N bond by converting
various amines into Katritzky pyridinium salts.33
Perceiving the advantage of this approach and in accordance
with our interest in nickel-mediated cross-coupling reactions,34
herein, we demonstrate the feasibility of electrophile−electro-
phile cross-coupling reaction between amines and acid
chlorides as well as carboxylic acids by the synthesis of vital
molecules (Scheme1c) in various facets of chemistry.
whereas NiI2 and Ni(acac)2 yielded moderate results (entries 3
and 4, respectively) with the significant formation of byproduct
6a. In the absence of a bipyridine ligand (entry 5), a substantial
drop in the level of acylation (42% yield) was observed,
suggesting the crucial role of a bipyridine ligand. The in situ-
generated NiBr2·bpy from the trihydrated nickel(II) bromide
offered a slightly lower yield (entry 6), whereas the in situ-
generated NiCl2·bpy from nickel(II) chloride offered a poor
yield with significant formation of byproduct 6a (entry 7).
Control experiments reveal that NiBr2·bpy and Mn are
essential (entries 8 and 10, respectively), and a detrimental
effect was observed when Mn was replaced with Zn (entry 9),
demonstrating the potential role of Mn as a reductant to
generate low-valent nickel and/or an alkyl radical intermediate
from pyridinium salt. Decreasing the amount of either Mn or
acid chloride decreased the yield (entry 11 or 12, respectively),
presumably due to the partial hydrolysis of acid chloride. A
brief screening of solvents showed that the cosolvent system
CH3CN and DMA was the best in terms of chemical yield for
acylation (entries 13 and 14, respectively), and a 95:5 solvent
Information). Remarkably, 5 mol % NiBr2·bpy offered a yield
that was slightly lower than that of 10 mol % NiBr2·bpy (entry
15). A further decrease in catalyst load to 1 mol % reduced the
yield of acylated product 5a (entry 16). Because an anhydride
can also be used as an acylating agent,21,25 we employed the
purified anhydride 3a in place of acid chloride 2a and obtained
5a in 72% yield (entry 17). It is also necessary to purify the
acid chloride 2a prior to the reaction, or the undistilled crude
acid chloride 2a generated by the reaction of either oxalyl
chloride or thionyl chloride offered moderate yields (entry 18
or 19, respectively). The reaction was also carried out with 1
mmol of 4a and produced 5a in 95% isolated yield with 10 mol
% nickel catalyst and 87% isolated yield with 5 mol % nickel
catalyst.
We commenced our study with acid chloride 2a, which was
readily prepared from the corresponding carboxylic acid 1a.
The pyridinium salt 4a was prepared from benzyl amine in two
steps. The optimized condition requires the use of NiBr2·bpy
(10 mol %), 1.8 equiv of Mn, and 2.0 equiv of acid chloride 2a
in a 95:5 CH3CN/DMA mixture at room temperature. Under
this ideal condition, we were delighted to obtain the ketone 5a,
a photochromic dye, in 92% isolated yield (Table 1, entry 1).
36
Nickel complexes NiBr2·bpy35 and NiBr2·bpy2 offered
excellent catalytic activity with similar yields, stressing that
the coordination environment around the nickel center did not
alter the reaction efficiency (entries 1 and 2, respectively),
a
Table 1. Optimization of the Reaction Conditions
Having an optimized condition in hand, we further
expanded the substrate scope, and the results are summarized
in Table 2. A broad range of acid chlorides (10 in total) were
conveniently prepared from the corresponding carboxylic
acids, and the pyridinium salts (12 in total) were made from
the corresponding amines via pyrylium salts (see the
2a offered a yield higher than that of the undistilled acid
chloride (Table 1), some of the acid chlorides in Table 2 were
utilized as a crude because they are prone to undergo
decomposition during distillation. A range of acid chlorides,
including the primary 2a−e and secondary alkyl acid chlorides
2f−i, smoothly underwent cross-coupling reactions with
various pyridinium salts 4 to obtain the cross-coupled product
in good to excellent yields. The sterically hindered tertiary alkyl
acid chloride 2j offered the cross-coupled product 5aa in
moderate yield. Aryl carboxylic acid chloride 2i was also
compatible to offer the coupled product 5ae in 54% yield and
can also be extended to various aryl acid chlorides, which is not
within the scope of this paper. Strikingly, a substrate bearing
alkyl bromide was also well tolerated, although the alkyl halides
are also known to undergo cross-coupling reactions with acid
halides.37 The alkyl acid chloride 2e underwent chemoselective
cross-coupling reaction to afford the acylated products 5b and
5c in 96% and 63% yields, respectively. Various functional
groups, including fluoride 2i, alkene 4e, ether 2b, and carbonyl
4f, were undeterred. The silyl-protected alcohol 2c was also
compatible and underwent smooth cross-coupling to afford
b
b
entry
deviation from standard conditions
6a (%)
5a (%)
g
c
1
2
3
4
5
6
7
8
none
ND
93, 92
NiBr2·bpy2 instead of NiBr2·bpy
NiI2·bpy
Ni(acac)2 + bpy
NiBr2 in the absence of bpy
in situ NiBr2·3H2O + bpy
in situ NiCl2 + bpy
without NiBr2·bpy
Zn instead of Mn
no Mn
1 equiv of 2a
1.2 equiv of Mn
CH3CN alone
DMA alone
5
90
55
d
18
42
5
34
42
d
g
ND
89
20
d
27
ND
g
0
d
9
3
ND
56
g
d
10
11
12
13
14
15
16
17
18
19
0
d
8
74
49
48, 65
d
trace
g
d
d,e
ND
6
2
ND
67
89
60
5 mol % NiBr2·bpy
1 mol % NiBr2·bpy
anhydride instead of acid chloride
in situ 2a from oxalyl chloride
in situ 2a from thionyl chloride
g
f
g
ND
72
60
32
3
ND
g
a
Reaction conditions: 0.295 mmol of 4a, 0.59 mmol of 2a, 0.0295
mmol of NiBr2·bpy, 0.53 mmol of Mn, 0.1 M CH3CN/DMA solution
(95:5). Yields determined by H NMR using 1,3,5-trimethoxyben-
zene as an internal standard. Isolated yield. Leftover 4a was seen in
TLC. After 20 h. Carried out with 2.06 mmol of 4a. Not detected.
b
1
c
d
e
f
g
B
Org. Lett. XXXX, XXX, XXX−XXX