ACS Catalysis
Research Article
a
Table 1. Key Reaction Optimization
entry
deviations from the above
yield of 3 (%)
1
2
3
4
5
6
7
8
None
Mn2
Mn3
92 (90)
78
<5
cyclohexane is used as the solvent
THF, dioxane, DMF, and CH3CN are used as solvents
K2CO3 (70 mol %)
K2CO3 (40 mol %)
Na2CO3, Cs2CO3, KHCO3, K2HPO4, and t-BuOK are used as bases
90
up to 57
93 (92)
56
up to 80
<5
at low loading, tolerated a large variety of amines and allylic
alcohol substrates, and can be applied for the diversification of
bioactive molecules and the synthesis of drug molecules. The
beneficial role of the soft sulfur donor in the ligand’s side-arm
has been outlined by equating the activities of Mn1 with its
oxygen analogue and via control experiments. To the best of
our knowledge, phosphine-free base-metal complexes for the
formal anti-Markovnikov hydroamination of allyl alcohols have
not been developed thus far.
secondary allylic alcohols while tolerating several functional
groups. Notably, in all cases, the γ-amino alcohols were
isolated in exclusive selectivities. The N-alkyl anilines
(products 3−8) exhibited higher reactivity over anilines
(products 9−18) due to their higher nucleophilicity from the
alkyl substituent presence on nitrogen. The same is also
evident from the effect of substituents at the aryl ring of the
amine substrates. An electron-donating methoxy group at the
p-position leads to the 98% yield of the γ-amino alcohol 4.
Moderately electronic-biased halogen substituents furnished
the products 5−7 in moderate to good yields. In comparison,
strongly electron-withdrawing trifluoromethyl substituents at
the p-position displayed poor reactivity and yielded 47% of 8.
On the other hand, the reaction was not affected by the sterics
of the aryl substituents as the alkyl substituents present at the
o-, m-, and p-position of the aniline substrates reacted at equal
efficiencies (products 10−13). The halogen-functionalized
anilines also responded equally, furnishing the desired products
15−18 in moderate yields. Notably, the halogen substituents,
including the p-iodo group, were completely retained under
these mild conditions, thus providing a handle for further
derivatizations. Pleasingly, partially reduced heterocyclic aryl-
amines reacted smoothly under these conditions delivering the
products 19 and 20 in high 97 and 98% yields, respectively.
Even double hydroamination could be performed, and the
product 21 was isolated in 90% yield after 24 h.
To further expand the scope of this reaction, a large variety
of aliphatic amines were made to react with allyl alcohol 1.
Aliphatic, acyclic amines furnished the amino alcohols 22 and
23 in 85 and 90% yields, respectively, and cyclic amines such as
pyrrolidine, piperidine, morpholine, and thiomorpholine lead
to complete conversion to γ-amino alcohols 24−27. However,
due to the volatility, the isolated yields for pyrrolidine and
piperidine amino alcohol derivatives (products 24 and 25)
were found to be moderate. Interestingly, the piperazine
derivatives possessing more than one nitrogen atom, which are
important building units in several bioactive molecules, were
Hydroamination of feedstock allyl alcohol (1) with N-
methyl aniline (2) was chosen as the model reaction (Table 1).
Pleasingly, the phosphine-free Mn(I) catalyst Mn1, having a
thiomethoxy side-arm,18g at a 2 mol % loading, efficiently
catalyzed the reaction when the reaction was performed in
toluene (0.25 M) at 100 °C in the presence of a mild base
K2CO3 (entry 1). The desired γ-amino alcohol product 3 was
obtained in 92% yield with exclusive anti-Markovnikov
selectivity. When the reaction was performed with the Mn(I)
complex Mn2, having a thiophene side-arm,18f 78% yield of 3
was noticed (entry 2). On the other hand, more rigid
hydrazone-ligand-derived Mn(I) complex Mn3, which effi-
ciently catalyzed the C-alkylations of nitriles,18b fails to catalyze
the hydroamination reaction (entry 3), indicating the need for
the flexible NNS-ligand framework. Among the solvents tested,
cyclohexane did not alter the reaction outcome (entry 4).
However, polar solvents hampered the reaction (entry 5). The
K2CO3 loading could be reduced to 70 mol % without affecting
the yield (entry 6). Further reduction gave inferior results
(entry 7). Lower yields of the product were also noticed when
other bases were used (entry 8). The control experiments
demonstrated that the product did not form in the absence of
Mn1 or K2CO3 (entry 9). Further details of the reaction
We then set to explore the scope of the anti-Markovnikov
hydroamination reaction (Table 2). We were pleased to find
that a vast range of aromatic and aliphatic amines underwent a
smooth hydroamination reaction with both primary and
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ACS Catal. 2021, 11, 7060−7069