Journal of the American Chemical Society
Communication
a
Amides with an α quaternary carbon are one of the most
important scaffolds in bioactive molecules, pharmaceuticals,
agrochemicals, and functional materials. The importance of
this subclass of amides can be demonstrated by its structural
involvement in the neurokinin-1 receptor antagonist befetu-
piant, neuropeptide Y Y2 receptor antagonist, parathyroid
hormone receptor (PTHR) 1 antagonist, progesterone
receptor modulator WAY-255348, ovarian cancer peritoneal
carcinomatosis inhibitor, agro-herbicide monalide, and foliar
fungicide fenhexamid (Figure 1).20 Despite the development of
Table 1. Optimization of the Reaction Conditions
3aa
3aa′
entry
[Pd]
PdCl2
ligand
PPh3
PPh3
PPh3
P(2-MeOPh)3 HCl
P(4-MeOPh)3 HCl
Xantphos
Dppf
PPh3
PPh3
PPh3
PPh3
PPh3
acid
(%)
(%)
1
2
3
4
5
6
7
p-TsOH
TFA
HCl
7
8
19
12
17
1
3
5
9
10
42
72
85
96
0
0
0
0
2
16
39
10
7
9
0
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdBr2
PdI2
PdCl2
PdCl2
PdCl2
Pd(PPh3)2Cl2
HCl
HCl
HCl
HCl
HCl
HCl
HCl
PhNH2·HCl
PhNH2·HCl
b
8
9
10
c
11
d
12
13
0
0
0
e
PPh3
e
14
a
Conditions: unless otherwise noted, α-methylstyrene 1a (0.24
mmol), aniline (0.2 mmol), [Pd] (3 mol %), ligand (P/[Pd] =
2:1), acid (10 mol %), CO (45 atm), THF (1.2 mL), 110 °C, 24 h.
b
Isolated yields. MeCN was used as the solvent; other solvents are
c
d
much inferior. HCl (aq, 37 wt %, 0.5 equiv). HCl (aq, 37 wt %, 1.0
e
equiv). With aniline hydrochloride (0.2 mmol) as the substrate.
Figure 1. Selective amides with an α quaternary carbon.
Surprisingly, among the catalyst precursors screened, we
found that PdBr2 and PdI2 exhibited important different
reactivities and regioselectivities compared with PdCl2, even in
the presence of excessive HCl ([Pd]/HCl = 3 mol % vs 10 mol
%) (entries 9−10). This finding suggested that the halide ions
played a key role in the reaction, thus inspiring us to further
increase the loading of HCl. Indeed, the reactivity of the
reaction gave rise to a notable improvement, achieving 72%
yield of 3aa when a stoichiometric HCl was used as the
additive (entries 11−12). Therefore, the optimal reaction
conditions were finally obtained by using Pd(PPh3)2Cl2 as the
catalyst and aniline hydrochloride as the substrate (entry 14).
With the optimal reaction conditions in hand, we further
investigated the scope and limitations of the reaction. First, the
scope of anilines was investigated (Table 2A). All of the para-,
meta-, ortho-methyl, and ortho-phenyl substituted aniline
hydrochloride salts afforded the corresponding amides 3ab−
3ae in high yields, thus indicating that the reaction is
insensitive to the steric properties of the anilines. Notably,
the reaction exhibited a broad functional group tolerance in the
anilines. Anilines bearing various functional groups such as
electron-donating MeO, electron-withdrawing F, Cl, or Br,
strongly electron-withdrawing CO2Me, acetyl, CF3, and even
coordinative CN, were compatible with the reaction conditions
to afford the desired Markovnikov hydroaminocarbonylation
products 3af−3as in good to high yields. 2-Naphthylamine
hydrochloride salt underwent the reaction easily to produce
the amide 3at in 78% yield, while 1-naphthylamine hydro-
chloride was less reactive. In addition, secondary anilines were
tolerated in the reaction. N-Methylanilines with different
substituents such as Me, Cl, and Br, as well as benzylaniline
and indoline, were compatible with the above conditions to
give rise to the desired amides 3au−3ay in good to high yields.
We proceeded to investigate the scope of 1,1-disubstituted
alkenes and found the reaction tolerates a wide range of
the tactics and strategies for the formation of fundamentally
important amides,3,21 expeditious catalytic amide-forming
reactions, which could generate previously challenging
architectures as well as reduce or eliminate the need for
stoichiometric reagents, are still in great demand. In this
context, transition metal catalyzed Markovnikov hydroamino-
carbonylation of 1,1-disubstituted or 1,1,2-trisubstituted
alkenes, if developed successfully, would not only address the
problems of the deficiency in this type of reactions but also
offer an ideal method to produce amides with an α all-carbon
quaternary center. Herein, we report the development of a
novel Pd-catalyzed Markovnikov hydroaminocarbonylation of
1,1-disubstituted or 1,1,2-trisubstituted alkenes and anilines
hydrochloride (Scheme 1C).
We started our investigations with Pd-catalyzed Markovni-
kov hydroaminocarbonylation of α-methylstyrene and aniline
at 110 °C under CO atmosphere (45 atm) in THF (Table 1).
Initially, acid additives, which were often used to promote
generation of the required [HPdX] species in Pd-catalyzed
hydrocarbonylations, were screened in the presence of catalytic
PdCl2 and PPh3 (Table 1, entries 1−3). Although the desired
reactions generally resulted in low yields, those with HCl
showed slightly higher reactivity than other acids (entry 3).
Subsequently, reaction parameters such as ligands and solvents
were modified to improve the reaction efficiency. P(4-
MeOPh)3 displayed similar reactivity as PPh3, while Xantphos
and 1,1′-bis(diphenylphosphino)ferrocene (dppf) afforded
anti-Markovnikov 3aa′ as the major product (entries 4−7).
Other solvents including CH3CN, DME, 1,4-dioxane, and
DMF gave rise to results inferior to THF (Table 1, entry 8).
Unfortunately, the extensive investigation of pressure and
temperatures also resulted in less improvement of the
efficiency of the reaction.
7299
J. Am. Chem. Soc. 2021, 143, 7298−7305