ACS Catalysis
Research Article
1-heptylamine. After 24 h of refluxing in Et2O under similar
reaction conditions, the formation of the corresponding amide,
N-heptylhexanamide, in 76% yield was observed (Scheme 1),
signifying that complex 2 can also catalyze the synthesis of
amides from esters at low temperatures, presumably via initial
nucleophilic substitution of the ester with the amine to form an
amide and an alcohol, followed by dehydrogenative coupling
between the released alcohol and amine to form amide.12 In
the absence of the ruthenium complex, no conversion of ester
to amide was observed, signifying that the ruthenium complex
catalyzes this reaction, likely acting as a Lewis acid to activate
the ester during the initial amine nucleophilic attack on the
ester.
Based on these observations, the reaction pathway for the
amide formation is shown in Scheme 2. The initial
dehydrogenation of alcohol forms the aldehyde, which further
converts to hemiaminal or hemiacetal via nucleophilic attack of
the amine or alcohol, respectively. Subsequent dehydrogen-
ation of the hemiaminal and hemiacetal intermediates
produces the amide and ester, respectively. The ester is further
converted to amide via nucleophilic substitution by the amine,
assisted by the ruthenium complex under the reaction
conditions.
Mechanistic studies were carried out to further understand
the mechanism of the low-temperature catalytic activities of
the PNNH complexes (Scheme 3). Complex 1, upon addition
of 2 eq of t-BuOK, forms the anionic complex 1a which is
intensely violet in diethyl ether solution (Scheme 3a).11
Addition of 1-hexanol (4 equiv) to this complex results in the
formation of the aromatic alkoxy complex 1b (see Figure S20
for reaction progress). Noteworthily, the alkoxy ligand of 1b
exchanges quickly with the free alcohol in solution, and as the
excess alcohol is removed from the solution, peak broadening
in 31P{1H} and 1H NMR is observed.13 Similar to the
formation of the alkoxy complex, addition of benzylamine(4
equiv) to a solution of 1a resulted in the formation of the
amido complex 1c. Further addition of alcohol to the amido
complex replaced the amido ligand to form the alkoxy complex
along with the generation of amine (Scheme 3a; Figure S21).
On a similar note, addition of a 1/1 alcohol and amine solution
to complex 1a resulted in the selective formation of the alkoxy
complex in solution.
Figure 2. ORTEP diagram of complex 1d.amide. Atoms are drawn
with a probability level of 50%. Selected hydrogen atoms omitted for
clarity. Tert-butyl groups displayed as a wireframe for clarity. Selected
bond lengths (Å) and angles (o): Ru(1)−P(1) 2.2576(5), Ru(1)−
O(2) 2.2380(15), Ru(1)−N(1) 2.0850(19), Ru(1)−N(2)
2.2010(17), Ru(1)−C(26) 1.818(2), O(2)−C(8) 1.394(3), C(7)−
C(8) 1.570(3); P(1)−Ru(1)−H 81.5(11), O(2)−Ru(1)−P(1)
105.13(4), O(2)−Ru(1)−H 168.8(11), N(1)−Ru(1)−P(1)
81.81(5), N(1)−Ru(1)−O(2) 81.74(7), N(2)−Ru(1)−O(2)
72.92(6), C(8)−O(2)−Ru(1) 113.36(13), O(2)−C(8)−C(7)
109.38(18).
tolerated under the reaction conditions (entries 8−9). For the
synthesis of some other amides, such as N-heptyl-2-
methoxyacetamide and N-heptylisovaleramide, a slightly higher
temperature was required for complete conversions (reflux in
MTBE) (entries 10−13).5 Highly reducible groups, such as a
C−C double bond, are also tolerated under the conditions
despite the reaction being associated with the evolution of H2
gas (entry 14). It is to be noted that the nucleophilicity of the
amine plays an important role in the rate of the reactions. For
example, in the case of the synthesis of N-phenylhexanamide,
the low nucleophilicity of aniline necessitates either a higher
reaction temperature (reflux in toluene) or an increased base
concentration (50 mol % KOtBu) for effective amidation
(entries 15−17). Notably, ethylenediamine and ethanol can
also dehydrogenatively couple at low temperatures (reflux in
MTBE) in the presence of complex 2 to provide the diamide in
95% yield (entry 18). We also investigated the possibility of
the synthesis of chiral amides via this method using a β-chiral
alcohol and an α-chiral amine. The chiral centers of the
substrates were largely retained in the product amide
molecules in both cases, as determined from optical rotation
analysis of the products in comparison with literature data,
demonstrating the potential utility of this method in the
synthesis of biologically active amide molecules (entries 19−
When the resulting solution containing complex 1b, amine,
and alcohol was heated at 45 °C in a J. Young NMR tube, the
formation of a new complex was observed after 30 min with
almost quantitative conversion of 1b (Scheme 3a; Figure S21).
This complex exhibits a characteristic peak in the 31P NMR at
119.4 ppm (major isomer) (Figure S14).14 In the proton
NMR, a hydride peak corresponding to this complex was
observed at −15.2 ppm as a doublet (J = 28.5 Hz) (Figure S8).
In the IR spectrum, a strong absorption band at 1900 cm−1 was
observed, corresponding to a CO ligand. Interestingly, the 13
C
NMR spectrum indicated the activation of the N-arm as the
secondary picolylic CH2 unit of the N-arm was converted to a
tertiary CH unit along with another CH unit, presumably from
an alcohol derivative (Figure S11). Based on 1D and 2D NMR
analysis, the structure of 1d was assigned to a new complex
where an in situ generated aldehyde binds to the N-arm of the
ligand through MLC. Single crystals suitable for X-ray
diffraction (XRD) analysis were grown by slow evaporation
from a THF/pentane solution of 1d, and the XRD analysis
confirmed the assigned structure of 1d (Scheme 3a, Figure 2).
Interestingly, in the unit cell of the crystal, a product amide
In some of the reactions of Table 2 (entries 4, 5, 8, and 14),
esters in moderate amounts were detected (∼0−10%). To
understand whether the generated ester is converted to the
amide at this low temperature or is exclusively a competing
reaction pathway, we set up a reaction of hexyl hexanoate with
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ACS Catal. 2021, 11, 7383−7393