Organic Letters
Letter
a
them in Giese-addition. Lately, TBADT has also been
employed in dual Ni/Pd/photoredox catalysis to cross-couple
the aldehydes and aryl halides.26,27
Table 1. Optimization Table
Despite these initial findings, the scope of the electrophile
remains rather confined to aryl halides (Scheme 1b).26−28 As
such, developing strategies to accommodate more electrophiles
would be beneficial. The use of alkyl amines as an electrophilic
coupling partner in dual TM-photoredox catalysis is under-
developed despite its widespread availability.29,30 On the basis
of recent studies on Katritzky pyridinium salts31 by various
research groups including Watson,32−38 Glorius,39−41 Aggar-
wal,42,43 Martin,44 Rueping,45 and our group,46 we anticipated
that the pyridinium salts could be cross-coupled with alkyl
aldehydes under a suitable TM-photoredox catalytic system.
However, the undesired homocoupling of pyridinium salts and
site selectivity in C−H abstraction must be addressed (Scheme
1d). As a part of our ongoing studies in nickel mediated cross-
coupling reactions,46−48 herein we describe the Ni/TBADT
dual catalysis for the successful realization of coupling between
alkyl aldehydes and benzylic pyridinium salts.
b
b
entry
deviation from above
4
3a
c
1
2
3
4
5
6
7
8
none
3
9
95, 89
88
10 mol % of NiBr2·glyme
10 mol % of NiCl2
20
23
28
21
6
37
20
10 mol % of NiBr2·bpy
10 mol % of Ni(cod)2
10 mol % of Ni(OTf)2
10 mol % of Ni(OAc)2·4H2O
without dtbpy
43
d
13
d
19
8
60
53
38
75
9
10 mol % of bpy
42
27
2
27
21
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
10 mol % of 1,10-phen
20 mol % of DMAP instead of dtbpy
1.8 equiv of K2CO3 instead of K3PO4
1.8 equiv of Li2CO3 instead of K3PO4
1.0 equiv K3PO4
2.5 mol % of TBADT
2.5 mol % of TBADT
5 mol % of Eosin Y
5 mol % of Mes-Acr-ClO4
2 mol % of Ir[dF(CF3)ppy2(dtbpy)]PF6
30 mol % of Benzophenone
410 nm with 2 equiv of 1a
365 nm with 2 equiv of 1a
2 equiv of 1a
e
25
e
37
78
At the outset of our studies, aldehyde 1a was chosen to
identify a suitable reaction condition. An extensive library of
nickel catalysts, ligands, photocatalysts, and solvents was
screened (see SI-4) to suppress the formation of undesired
homocoupled product 4. Of the several nickel catalysts
screened (entries 1−7, Table 1), only NiCl2·glyme and
NiBr2·glyme (entries 1−2) afforded the cross-coupled product
3a in very good yields. NiCl2 and NiBr2·bpy afforded the
ketone 3a only in 37% and 20% yields (entries 3−4), and the
undesired homocoupling of 2a to 4 was seen as a major
byproduct. The other nickel catalysts were also ineffective
(entries 5−7). Having identified NiCl2·glyme as the optimal
catalyst, a small group of ligands were further screened (entries
8−11). Interestingly, the reaction afforded 60% of 3a in the
absence of added ligand dtbpy (entry 8). However, the simple
bpy (entry 9), 1,10-phen (entry 10), and DMAP (entry 11)
ligands led to a significant reduction in the yields affording 3a
only in 53%, 38%, and 75% yields. When K2CO3 or Li2CO3
was employed as a base, the yield of 3a was drastically reduced
(entries 12−13). Lowering the amount of either K3PO4 (entry
14) or catalyst (entry 15−16) also lowered the yield. The high
dielectric constant solvent CH3CN was more efficient than the
other solvents (SI-5). Several photocatalysts were subsequently
investigated. Despite the fact that the absorption spectrum of
TBADT is centered at 324 nm,49 the broad range of its
absorption allows the use of visible light for the excitation. We
obtained excellent yields with both 390 and 365 nm LED lights
(entries 1 and 22), although the use of long-wavelength 410
nm LED light significantly reduced the efficiency of the
reaction (entry 21). Virtually no cross-coupled product was
seen when TBADT was replaced with Eosin Y or Mes-Acr-
ClO4 (entries 17−18). The more efficient Ir[dF(CF3)-
ppy2(dtbpy)]PF6 (E1/2 = 1.21 V vs SCE in CH3CN)50
afforded the ketone 3a only in 58% yield (entry 19), and the
organic photocatalyst benzophenone gave traces of cross-
coupled product (entry 20). The amount of aldehyde 1a
cannot be lowered as it significantly reduces the yield of 3a
(entry 23). In general, the dimerization of 2a accounts for all
the inefficient reactions. Control experiments revealed that
there was no reaction in the absence of K3PO4 or NiCl2·dtbpy
or TBADT or LED (entries 24−27).
f
3
86
g
14
25
5
10
27
12
2
10
ND
ND
28
ND
60
h
ND
h
ND
h
58
e
6
67
c
c
96, 81
87, 80
d
without K3PO4
without NiCl2·dtbpy
without TBADT
without light source
ND
d
ND
d
<5
d
ND
a
0.0075 mmol of TBADT, 0.015 mmol of NiCl2·glyme, 0.015 mmol
of dtbpy, 0.15 mmol of 2a, 0.45 mmol of 1a, 0.27 mmol of K3PO4,
b
c
d
CH3CN (0.1 M), 390 nm. GC yield. Isolated yield. Unreacted 2a
e
was observed in TLC analysis. 365 nm instead of 390 nm LED light
source was used. 7.5 mol % of NiCl2·glyme, 7.5 mol % of dtbpy. 5.0
mol % of NiCl2·glyme, 5.0 mol % of dtbpy. 445 nm instead of 390
nm LED light source was used. DMAP: 4-(Dimethylamino)pyridine.
dtbpy: 4,4′-Di-tert-butyl-2,2′-dipyridyl. bpy: 2,2′-Bipyridine. 1,10-
Phen: 1,10-Phenanthroline. ND: not detected.
f
g
h
in Table 2. The linear alkyl aldehydes 1a−1i, including long
alkyl chain 1fa−1fg and benzylic aldehyde 1d, underwent
cross-coupling reactions with high levels of efficiency to afford
the corresponding ketones 3. The α-branched secondary alkyl
aldehydes 1j−1l including cyclohexanecarbaldehyde 1k and 4-
piperidinecarbaldehyde 1r did not impede the reaction; the
corresponding cross-coupled products were isolated in 85%,
79%, 72%, and 54% yields, respectively. As expected, aryl
aldehydes (1m−1q and 1w−1ae) including 2-naphthaldehyde
1n were also compatible under the optimized reaction
condition. The milder reaction condition granted us to
incorporate various functional groups, including ethers, alkyl
amine 1r, esters 2s and 1ae, medicinally relevant fluorides (1u
and 1z), trifluoromethyl 1ab, chlorides (1v and 1ad), and
propargyl 3y are compatible under the optimized condition.
Similarly, protecting groups such as TBDMS 1w, MOM 1ac,
acetate 1ae, and benzyl 1t groups are also compatible and
afforded the corresponding cross-coupled product in good
yields. This provides us with an opportunity for the further
Having the optimized conditions in hand, we screened a
broad spectrum of aldehydes, and the results are summarized
5390
Org. Lett. 2021, 23, 5389−5393